HIV

From testing to treatment, Global Fund HIV services have been hampered by COVID-19. “We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview. 

“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.

Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report. 

But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.

The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:

• Voluntary male circumcision declined by 27%.
• Numbers reached by HIV prevention programs fell by 11%.
• 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
• HIV testing services, including initiation, decreased by 22%.

The numbers tell only a part of the story, according to Dr. Crowley.

“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)

Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.

With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.

Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy. 

“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.” 

Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
 

The imperfect storm globally and in the U.S.

“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.

“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”

Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.

“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.

But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision. 

“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”

Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts. 

“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”

Dr. Crowley and Dr. Beyrer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

From testing to treatment, Global Fund HIV services have been hampered by COVID-19. “We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview. 

“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.

Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report. 

But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.

The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:

• Voluntary male circumcision declined by 27%.
• Numbers reached by HIV prevention programs fell by 11%.
• 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
• HIV testing services, including initiation, decreased by 22%.

The numbers tell only a part of the story, according to Dr. Crowley.

“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)

Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.

With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.

Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy. 

“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.” 

Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
 

The imperfect storm globally and in the U.S.

“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.

“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”

Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.

“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.

But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision. 

“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”

Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts. 

“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”

Dr. Crowley and Dr. Beyrer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

From testing to treatment, Global Fund HIV services have been hampered by COVID-19. “We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview. 

“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.

Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report. 

But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.

The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:

• Voluntary male circumcision declined by 27%.
• Numbers reached by HIV prevention programs fell by 11%.
• 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
• HIV testing services, including initiation, decreased by 22%.

The numbers tell only a part of the story, according to Dr. Crowley.

“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)

Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.

With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.

Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy. 

“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.” 

Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
 

The imperfect storm globally and in the U.S.

“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.

“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”

Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.

“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.

But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision. 

“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”

Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts. 

“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”

Dr. Crowley and Dr. Beyrer report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she’d become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she had never seen anything like it. Even HIV prevention methods she had studied that had worked, such as the dapivirine ring, had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a trial in HIV that used the same platform as Johnson & Johnson’s successful COVID-19 vaccine.

“When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, ‘Well, maybe … maybe this will work for HIV,’ “ she said in an interview.

That turned out to be false hope. The National Institutes of Health (NIH) announced that the trial Dr. Gill was helping to conduct, HVTN 705, was stopping early because it hadn’t generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It’s also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that’s part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants’ immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can’t see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called “prime” shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2,637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months, and 1 year. Then researchers followed the women from month 7 to 2 years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce – and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV – 51 among women who received the vaccine and 63 among those who received a placebo. That’s a 25.2% efficacy rate – but it wasn’t statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the AIDS division at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

“This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months,” he said in an interview. “That’s kind of frustrating. Does it mean there’s a signal or is this just chance? Because that’s what statistics tell us, not to believe your last data point.”

What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, recently finished enrolling participants. Mosaico uses the same adenovirus 26 platform, but it’s loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dr. Dieffenbach said that before NIAID decides what to do with Mosaico they’ve asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on nonneutralizing antibodies like this one have a ceiling of effectiveness that’s just too low to alter the course of the epidemic.

“I think we’ve discovered that there’s not a floor to [these nonneutralizing approaches], but there probably is a ceiling,” he said. “I don’t know if we’re going to get better than” a 25%-29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV – and mostly, it lost.

VCR01 worked only on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Mr. Warren, requires a rethinking of the whole HIV vaccine enterprise while “doubling, tripling, quadrupling down” on the HIV prevention methods we know work, such as preexposure prophylaxis (PrEP).

Dr. Dieffenbach agreed. To clinicians, Dr. Dieffenbach said the message of this HIV vaccine trial is flush with urgency: “Get your HIV-negative, at-risk people on PrEP tomorrow.”

There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Dr. Gill’s site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment’s notice to hometowns on the Eastern Cape, an 11-hour car ride away – longer by bus – for traditional prayers, funerals, and other important events.

Mr. Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they’d turn around and return east.

They did this for 3 years, he said.

“The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV,” he said. “They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations.

“So you can understand the emotion and the sense of sadness, the disappointment – the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.”

For Dr. Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is underway for an HIV vaccine with a platform that was successful in COVID-19 – using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

“I think we need to be careful,” she said, “thinking that the mRNA vaccines are going to crack it.”

Dr. Dieffenbach, Dr. Gill, and Mr. Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape.com.

A 3-month, 12-dose regimen of rifapentine and isoniazid (INH) was less toxic, had better compliance, and showed similar efficacy as 6 months of INH alone in preventing tuberculosis (TB) in people with HIV, according to the results of a clinical trial reported in Annals of Internal Medicine.

The study, a randomized pragmatic trial in South Africa, Ethiopia, and Mozambique, was called WHIP3TB (Weekly High Dose Isoniazid and Rifapentine [P] Periodic Prophylaxis for TB).

Investigators randomized patients to three groups, comparing a 3-month course of weekly rifapentine-INH, given either once or repeated in a year, with daily isoniazid for 6 months. At 1 year, 90% of the rifapentine-INH group (3HP) were still on therapy, compared with only 50.5% in the INH group.

In the study, patients were initially assessed for TB using the World Health Organization four-symptom screen, but the sensitivity in HIV patients on antiretrovirals (ARVs) was only 53%. In addition to symptoms, screening at 12 months included a chest x-ray and sputum culture.

Of the 30 patients at month 12 with confirmed TB, 26 were asymptomatic, suggesting physicians should do further evaluation prior to initiating preventive TB treatment (which was not part of the WHO recommendation when the study was initiated).

Another unexpected finding was that 10.2% of the TB cases detected in the combined 3HP groups in South Africa, along with 18% of the cases in Mozambique, had rifampin resistance.

Investigator Gavin Churchyard, MBBCh, PhD, CEO of the Aurum Institute in Johannesburg, South Africa, said in an interview: “It appeared that taking this potent short course regimen – they’re just taking a single course – provided the same level of protection as taking repeat courses of the antibiotics. So that’s good news.” He noted, too, that TB transmission rates have been declining in sub-Saharan Africa because of ARV, and “so it may just be that a single course is now adequate because the risk of exposure and reinfection” is decreasing.

But Madhu Pai, MD, PhD, associate director, McGill International TB Centre, Montreal, who was not involved in the study, shared a more cautious interpretation. He said in an interview that the 2020 WHO Consolidated Guidelines on Tuberculosis state: “In settings with high TB transmission, adults and adolescents living with HIV ... should receive at least 36 months of daily isoniazid preventive therapy (IPT) ... whether or not the person is on ART.” The problem is that almost no one can tolerate prolonged therapy with INH because of side effects, as has been shown in numerous studies.

For successful TB treatment, Dr. Pai said, “Even 3HP is not going to cut it; they’re going to get reinfected again. So that shortening of that 36 months is what this trial is really all about, in terms of new information ... and they were not successful.” But because this is still the most practical course, Dr. Pai suggests that follow-up monitoring for reinfection will be the most likely path forward.

Dr. Churchyard concluded: “If we wanted to end the global TB epidemic, we need to continue to find ways to further reduce the risk of TB overall at a population level, and then amongst high-risk groups such as people with HIV, including those on ARVs, and who have had a course of preventive therapy. ... We need to look for other strategies to further reduce that risk. Part of those strategies may be doing a more intensive screen. But also, it may be adding another intervention, particularly TB vaccines. ... No single intervention by itself will adequately address the risk of TB in people with HIV in these high TB transmission settings.”

Dr. Pai reported no relevant financial relationships. Dr. Churchyard has reported participation in a Sanofi advisory committee on the prevention of TB. Judy Stone, MD, is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research.”

A version of this article first appeared on Medscape.com.

A 3-month, 12-dose regimen of rifapentine and isoniazid (INH) was less toxic, had better compliance, and showed similar efficacy as 6 months of INH alone in preventing tuberculosis (TB) in people with HIV, according to the results of a clinical trial reported in Annals of Internal Medicine.

The study, a randomized pragmatic trial in South Africa, Ethiopia, and Mozambique, was called WHIP3TB (Weekly High Dose Isoniazid and Rifapentine [P] Periodic Prophylaxis for TB).

Investigators randomized patients to three groups, comparing a 3-month course of weekly rifapentine-INH, given either once or repeated in a year, with daily isoniazid for 6 months. At 1 year, 90% of the rifapentine-INH group (3HP) were still on therapy, compared with only 50.5% in the INH group.

In the study, patients were initially assessed for TB using the World Health Organization four-symptom screen, but the sensitivity in HIV patients on antiretrovirals (ARVs) was only 53%. In addition to symptoms, screening at 12 months included a chest x-ray and sputum culture.

Of the 30 patients at month 12 with confirmed TB, 26 were asymptomatic, suggesting physicians should do further evaluation prior to initiating preventive TB treatment (which was not part of the WHO recommendation when the study was initiated).

Another unexpected finding was that 10.2% of the TB cases detected in the combined 3HP groups in South Africa, along with 18% of the cases in Mozambique, had rifampin resistance.

Investigator Gavin Churchyard, MBBCh, PhD, CEO of the Aurum Institute in Johannesburg, South Africa, said in an interview: “It appeared that taking this potent short course regimen – they’re just taking a single course – provided the same level of protection as taking repeat courses of the antibiotics. So that’s good news.” He noted, too, that TB transmission rates have been declining in sub-Saharan Africa because of ARV, and “so it may just be that a single course is now adequate because the risk of exposure and reinfection” is decreasing.

But Madhu Pai, MD, PhD, associate director, McGill International TB Centre, Montreal, who was not involved in the study, shared a more cautious interpretation. He said in an interview that the 2020 WHO Consolidated Guidelines on Tuberculosis state: “In settings with high TB transmission, adults and adolescents living with HIV ... should receive at least 36 months of daily isoniazid preventive therapy (IPT) ... whether or not the person is on ART.” The problem is that almost no one can tolerate prolonged therapy with INH because of side effects, as has been shown in numerous studies.

For successful TB treatment, Dr. Pai said, “Even 3HP is not going to cut it; they’re going to get reinfected again. So that shortening of that 36 months is what this trial is really all about, in terms of new information ... and they were not successful.” But because this is still the most practical course, Dr. Pai suggests that follow-up monitoring for reinfection will be the most likely path forward.

Dr. Churchyard concluded: “If we wanted to end the global TB epidemic, we need to continue to find ways to further reduce the risk of TB overall at a population level, and then amongst high-risk groups such as people with HIV, including those on ARVs, and who have had a course of preventive therapy. ... We need to look for other strategies to further reduce that risk. Part of those strategies may be doing a more intensive screen. But also, it may be adding another intervention, particularly TB vaccines. ... No single intervention by itself will adequately address the risk of TB in people with HIV in these high TB transmission settings.”

Dr. Pai reported no relevant financial relationships. Dr. Churchyard has reported participation in a Sanofi advisory committee on the prevention of TB. Judy Stone, MD, is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research.”

A version of this article first appeared on Medscape.com.

A 3-month, 12-dose regimen of rifapentine and isoniazid (INH) was less toxic, had better compliance, and showed similar efficacy as 6 months of INH alone in preventing tuberculosis (TB) in people with HIV, according to the results of a clinical trial reported in Annals of Internal Medicine.

The study, a randomized pragmatic trial in South Africa, Ethiopia, and Mozambique, was called WHIP3TB (Weekly High Dose Isoniazid and Rifapentine [P] Periodic Prophylaxis for TB).

Investigators randomized patients to three groups, comparing a 3-month course of weekly rifapentine-INH, given either once or repeated in a year, with daily isoniazid for 6 months. At 1 year, 90% of the rifapentine-INH group (3HP) were still on therapy, compared with only 50.5% in the INH group.

In the study, patients were initially assessed for TB using the World Health Organization four-symptom screen, but the sensitivity in HIV patients on antiretrovirals (ARVs) was only 53%. In addition to symptoms, screening at 12 months included a chest x-ray and sputum culture.

Of the 30 patients at month 12 with confirmed TB, 26 were asymptomatic, suggesting physicians should do further evaluation prior to initiating preventive TB treatment (which was not part of the WHO recommendation when the study was initiated).

Another unexpected finding was that 10.2% of the TB cases detected in the combined 3HP groups in South Africa, along with 18% of the cases in Mozambique, had rifampin resistance.

Investigator Gavin Churchyard, MBBCh, PhD, CEO of the Aurum Institute in Johannesburg, South Africa, said in an interview: “It appeared that taking this potent short course regimen – they’re just taking a single course – provided the same level of protection as taking repeat courses of the antibiotics. So that’s good news.” He noted, too, that TB transmission rates have been declining in sub-Saharan Africa because of ARV, and “so it may just be that a single course is now adequate because the risk of exposure and reinfection” is decreasing.

But Madhu Pai, MD, PhD, associate director, McGill International TB Centre, Montreal, who was not involved in the study, shared a more cautious interpretation. He said in an interview that the 2020 WHO Consolidated Guidelines on Tuberculosis state: “In settings with high TB transmission, adults and adolescents living with HIV ... should receive at least 36 months of daily isoniazid preventive therapy (IPT) ... whether or not the person is on ART.” The problem is that almost no one can tolerate prolonged therapy with INH because of side effects, as has been shown in numerous studies.

For successful TB treatment, Dr. Pai said, “Even 3HP is not going to cut it; they’re going to get reinfected again. So that shortening of that 36 months is what this trial is really all about, in terms of new information ... and they were not successful.” But because this is still the most practical course, Dr. Pai suggests that follow-up monitoring for reinfection will be the most likely path forward.

Dr. Churchyard concluded: “If we wanted to end the global TB epidemic, we need to continue to find ways to further reduce the risk of TB overall at a population level, and then amongst high-risk groups such as people with HIV, including those on ARVs, and who have had a course of preventive therapy. ... We need to look for other strategies to further reduce that risk. Part of those strategies may be doing a more intensive screen. But also, it may be adding another intervention, particularly TB vaccines. ... No single intervention by itself will adequately address the risk of TB in people with HIV in these high TB transmission settings.”

Dr. Pai reported no relevant financial relationships. Dr. Churchyard has reported participation in a Sanofi advisory committee on the prevention of TB. Judy Stone, MD, is an infectious disease specialist and author of “Resilience: One Family’s Story of Hope and Triumph Over Evil” and of “Conducting Clinical Research.”

A version of this article first appeared on Medscape.com.

More than half of individuals who started HIV preexposure prophylaxis (PrEP) in a large Northern California care management organization discontinued PrEP in a 6.5-year study period, researchers report. African American and Latinx individuals, women, and participants with substance use disorder were more likely to experience gaps in the PrEP care continuum, from initial contact with a provider to adherence over time.

While PrEP is highly effective at preventing HIV when taken as prescribed, research suggests that access to and usage of the medication is lower in the communities that need it most. Even if someone in these groups gets access to PrEP, he or she is less likely to start taking the medication and more likely to discontinue treatment, Carlo Hojilla, PhD, RN, lead author of the study and research fellow with the Kaiser Permanente Northern California Division of Research in Oakland, Calif., said in an interview.

By identifying and tracking these at-risk individuals and subgroups, “we can better characterize at what points in the PrEP continuum people are falling off so we can then better develop interventions to address those gaps,” he said. The results of the analysis were published Aug. 26.

The investigators looked at the electronic health records (EHR) from 13,906 adults (18 years or older) linked to PrEP services at Kaiser Permanente Northern California (KPNC) from July 16, 2012 – when PrEP received regulatory approval in the United States – through March 31, 2019. The total follow-up in the study was 26,210 person-years.

Individuals were included if they had a PrEP referral or a PrEP-coded clinical encounter in the EHR and were KPNC health members for at least 6 months during the study period. The analysis also included age, sex, self-reported race and ethnicity, and socioeconomic status, approximated by participants’ zip codes. Individuals were followed from the initiation of PrEP services to the end of the study period or until HIV diagnosis, discontinuation of KPNC health plan membership, or death.

Nearly all of the study cohort (95.1%) were male, and the median age of participants was 33. Nearly half (48.7%) of the cohort was White, 21.6% were Latinx, 14.8% were Asian, and 7% were African American.

Of all individuals linked to PrEP care in the study, 88.1% received a PrEP prescription. Of those, 98.2% filled their prescription and were assumed to have initiated the medication. More than half (52.2%) of participants discontinued PrEP at least once during the study period, and 60.2% of those participants eventually restarted their regimen.

Participants were most likely to discontinue PrEP within the first 2 years of treatment, the authors found. “With earlier data that we’ve gotten from PrEP trials and studies, we’ve been under the impression that the first few months were the most critical to keeping people engaged in care and maintaining a high degree of adherence,” Dr. Hojilla said. “But I think our findings suggest that it may be more than just a few months.”

Compared with White participants, both African American and Latinx participants had lower rates of PrEP prescriptions, were less likely to initiate PrEP, and more frequently discontinued PrEP. Compared with men, women had lower rates of PrEP prescription and initiation, and were nearly twice as likely (hazard ratio, 1.99) to discontinue their regimen during the study period. Young adults (18-25 years of age), individuals with lower socioeconomic status, and people with substance use disorder also experienced disparities throughout the PrEP continuum of care.

Over the study period, 136 individuals were diagnosed with HIV, with one-third (33.1%) diagnosed during their initial PrEP assessment. Excluding this group, the overall HIV incidence was 0.35 new infections per 100 person-years, with the highest incidence among those who had discontinued and did not reinitiate PrEP (1.28 new infections per 100 person-years.) No individuals who consistently took PrEP were diagnosed with HIV during the study period.

Although the findings are not surprising, the study “corroborates what a lot of us have looked at on the clinic level, which is basically that a lot of people discontinue PrEP who probably need it,” said Amy Nunn, ScD, a professor of behavioral and social sciences at the Brown University School of Public Health in Providence, R.I. She was not involved with the study. As “one of the largest studies to date” to look at HIV PrEP adherence, the study also gives a better picture of what is going on at a population level, she said.

Because the authors retrospectively looked at EHR data, a limitation they acknowledged, it was not clear what was driving these patients to discontinue care or neglect adherence, Dr. Nunn noted.

Dr. Nunn’s previous research found that unexpected out-of-pocket costs can be one reason people discontinue PrEP, and there are many structural barriers such as medical mistrust and community stigma that can contribute to disrupted care, added Jessica Jaiswal, PhD, MPH, a public health scientist at the University of Alabama in Tuscaloosa. And since all the study’s participants had health insurance, the findings do not reflect additional struggles of accessing care while uninsured. “If this is what they found among folks who are insured, then it’s very likely that the barriers are more intense or formidable for folks without insurance,” said Dr. Jaiswal, who was not associated with the study.

Dr. Hojilla reported receiving grants from the National Institute on Drug Abuse and Kaiser Permanente Northern California during the conduct of the study and salary for clinical work from the San Francisco Department of Public Health outside the submitted work. Dr. Jaiswal and Dr. Nunn have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than half of individuals who started HIV preexposure prophylaxis (PrEP) in a large Northern California care management organization discontinued PrEP in a 6.5-year study period, researchers report. African American and Latinx individuals, women, and participants with substance use disorder were more likely to experience gaps in the PrEP care continuum, from initial contact with a provider to adherence over time.

While PrEP is highly effective at preventing HIV when taken as prescribed, research suggests that access to and usage of the medication is lower in the communities that need it most. Even if someone in these groups gets access to PrEP, he or she is less likely to start taking the medication and more likely to discontinue treatment, Carlo Hojilla, PhD, RN, lead author of the study and research fellow with the Kaiser Permanente Northern California Division of Research in Oakland, Calif., said in an interview.

By identifying and tracking these at-risk individuals and subgroups, “we can better characterize at what points in the PrEP continuum people are falling off so we can then better develop interventions to address those gaps,” he said. The results of the analysis were published Aug. 26.

The investigators looked at the electronic health records (EHR) from 13,906 adults (18 years or older) linked to PrEP services at Kaiser Permanente Northern California (KPNC) from July 16, 2012 – when PrEP received regulatory approval in the United States – through March 31, 2019. The total follow-up in the study was 26,210 person-years.

Individuals were included if they had a PrEP referral or a PrEP-coded clinical encounter in the EHR and were KPNC health members for at least 6 months during the study period. The analysis also included age, sex, self-reported race and ethnicity, and socioeconomic status, approximated by participants’ zip codes. Individuals were followed from the initiation of PrEP services to the end of the study period or until HIV diagnosis, discontinuation of KPNC health plan membership, or death.

Nearly all of the study cohort (95.1%) were male, and the median age of participants was 33. Nearly half (48.7%) of the cohort was White, 21.6% were Latinx, 14.8% were Asian, and 7% were African American.

Of all individuals linked to PrEP care in the study, 88.1% received a PrEP prescription. Of those, 98.2% filled their prescription and were assumed to have initiated the medication. More than half (52.2%) of participants discontinued PrEP at least once during the study period, and 60.2% of those participants eventually restarted their regimen.

Participants were most likely to discontinue PrEP within the first 2 years of treatment, the authors found. “With earlier data that we’ve gotten from PrEP trials and studies, we’ve been under the impression that the first few months were the most critical to keeping people engaged in care and maintaining a high degree of adherence,” Dr. Hojilla said. “But I think our findings suggest that it may be more than just a few months.”

Compared with White participants, both African American and Latinx participants had lower rates of PrEP prescriptions, were less likely to initiate PrEP, and more frequently discontinued PrEP. Compared with men, women had lower rates of PrEP prescription and initiation, and were nearly twice as likely (hazard ratio, 1.99) to discontinue their regimen during the study period. Young adults (18-25 years of age), individuals with lower socioeconomic status, and people with substance use disorder also experienced disparities throughout the PrEP continuum of care.

Over the study period, 136 individuals were diagnosed with HIV, with one-third (33.1%) diagnosed during their initial PrEP assessment. Excluding this group, the overall HIV incidence was 0.35 new infections per 100 person-years, with the highest incidence among those who had discontinued and did not reinitiate PrEP (1.28 new infections per 100 person-years.) No individuals who consistently took PrEP were diagnosed with HIV during the study period.

Although the findings are not surprising, the study “corroborates what a lot of us have looked at on the clinic level, which is basically that a lot of people discontinue PrEP who probably need it,” said Amy Nunn, ScD, a professor of behavioral and social sciences at the Brown University School of Public Health in Providence, R.I. She was not involved with the study. As “one of the largest studies to date” to look at HIV PrEP adherence, the study also gives a better picture of what is going on at a population level, she said.

Because the authors retrospectively looked at EHR data, a limitation they acknowledged, it was not clear what was driving these patients to discontinue care or neglect adherence, Dr. Nunn noted.

Dr. Nunn’s previous research found that unexpected out-of-pocket costs can be one reason people discontinue PrEP, and there are many structural barriers such as medical mistrust and community stigma that can contribute to disrupted care, added Jessica Jaiswal, PhD, MPH, a public health scientist at the University of Alabama in Tuscaloosa. And since all the study’s participants had health insurance, the findings do not reflect additional struggles of accessing care while uninsured. “If this is what they found among folks who are insured, then it’s very likely that the barriers are more intense or formidable for folks without insurance,” said Dr. Jaiswal, who was not associated with the study.

Dr. Hojilla reported receiving grants from the National Institute on Drug Abuse and Kaiser Permanente Northern California during the conduct of the study and salary for clinical work from the San Francisco Department of Public Health outside the submitted work. Dr. Jaiswal and Dr. Nunn have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than half of individuals who started HIV preexposure prophylaxis (PrEP) in a large Northern California care management organization discontinued PrEP in a 6.5-year study period, researchers report. African American and Latinx individuals, women, and participants with substance use disorder were more likely to experience gaps in the PrEP care continuum, from initial contact with a provider to adherence over time.

While PrEP is highly effective at preventing HIV when taken as prescribed, research suggests that access to and usage of the medication is lower in the communities that need it most. Even if someone in these groups gets access to PrEP, he or she is less likely to start taking the medication and more likely to discontinue treatment, Carlo Hojilla, PhD, RN, lead author of the study and research fellow with the Kaiser Permanente Northern California Division of Research in Oakland, Calif., said in an interview.

By identifying and tracking these at-risk individuals and subgroups, “we can better characterize at what points in the PrEP continuum people are falling off so we can then better develop interventions to address those gaps,” he said. The results of the analysis were published Aug. 26.

The investigators looked at the electronic health records (EHR) from 13,906 adults (18 years or older) linked to PrEP services at Kaiser Permanente Northern California (KPNC) from July 16, 2012 – when PrEP received regulatory approval in the United States – through March 31, 2019. The total follow-up in the study was 26,210 person-years.

Individuals were included if they had a PrEP referral or a PrEP-coded clinical encounter in the EHR and were KPNC health members for at least 6 months during the study period. The analysis also included age, sex, self-reported race and ethnicity, and socioeconomic status, approximated by participants’ zip codes. Individuals were followed from the initiation of PrEP services to the end of the study period or until HIV diagnosis, discontinuation of KPNC health plan membership, or death.

Nearly all of the study cohort (95.1%) were male, and the median age of participants was 33. Nearly half (48.7%) of the cohort was White, 21.6% were Latinx, 14.8% were Asian, and 7% were African American.

Of all individuals linked to PrEP care in the study, 88.1% received a PrEP prescription. Of those, 98.2% filled their prescription and were assumed to have initiated the medication. More than half (52.2%) of participants discontinued PrEP at least once during the study period, and 60.2% of those participants eventually restarted their regimen.

Participants were most likely to discontinue PrEP within the first 2 years of treatment, the authors found. “With earlier data that we’ve gotten from PrEP trials and studies, we’ve been under the impression that the first few months were the most critical to keeping people engaged in care and maintaining a high degree of adherence,” Dr. Hojilla said. “But I think our findings suggest that it may be more than just a few months.”

Compared with White participants, both African American and Latinx participants had lower rates of PrEP prescriptions, were less likely to initiate PrEP, and more frequently discontinued PrEP. Compared with men, women had lower rates of PrEP prescription and initiation, and were nearly twice as likely (hazard ratio, 1.99) to discontinue their regimen during the study period. Young adults (18-25 years of age), individuals with lower socioeconomic status, and people with substance use disorder also experienced disparities throughout the PrEP continuum of care.

Over the study period, 136 individuals were diagnosed with HIV, with one-third (33.1%) diagnosed during their initial PrEP assessment. Excluding this group, the overall HIV incidence was 0.35 new infections per 100 person-years, with the highest incidence among those who had discontinued and did not reinitiate PrEP (1.28 new infections per 100 person-years.) No individuals who consistently took PrEP were diagnosed with HIV during the study period.

Although the findings are not surprising, the study “corroborates what a lot of us have looked at on the clinic level, which is basically that a lot of people discontinue PrEP who probably need it,” said Amy Nunn, ScD, a professor of behavioral and social sciences at the Brown University School of Public Health in Providence, R.I. She was not involved with the study. As “one of the largest studies to date” to look at HIV PrEP adherence, the study also gives a better picture of what is going on at a population level, she said.

Because the authors retrospectively looked at EHR data, a limitation they acknowledged, it was not clear what was driving these patients to discontinue care or neglect adherence, Dr. Nunn noted.

Dr. Nunn’s previous research found that unexpected out-of-pocket costs can be one reason people discontinue PrEP, and there are many structural barriers such as medical mistrust and community stigma that can contribute to disrupted care, added Jessica Jaiswal, PhD, MPH, a public health scientist at the University of Alabama in Tuscaloosa. And since all the study’s participants had health insurance, the findings do not reflect additional struggles of accessing care while uninsured. “If this is what they found among folks who are insured, then it’s very likely that the barriers are more intense or formidable for folks without insurance,” said Dr. Jaiswal, who was not associated with the study.

Dr. Hojilla reported receiving grants from the National Institute on Drug Abuse and Kaiser Permanente Northern California during the conduct of the study and salary for clinical work from the San Francisco Department of Public Health outside the submitted work. Dr. Jaiswal and Dr. Nunn have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

A version of this article first appeared on Medscape.com.

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

A version of this article first appeared on Medscape.com.

The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).

In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4,566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published Aug. 11 in the New England Journal of Medicine.

“The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed,” Raphael J. Landovitz, MD, lead author and codirector of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, said in an interview.

“The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren’t able to take PrEP the way it was prescribed,” he said.

Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
 

• An oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5.
• An injection at week 9 and every 8 weeks thereafter through week 153.
• An open-label “tail” phase consisting of oral TDF/FTC to provide ongoing for participants discontinuing injections.

The median age of study participants was 26 years (interquartile range [IQR], 22-32 years); 12.5% (570) identified as transgender women; 49.8% (845/1,698) of U.S. participants were Black patients.

During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 in the CAB group, incidence 0.41 per 100 person-years, vs. 39 in the TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% confidence interval, 0.18-0.62) CAB vs. TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.

Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in one of four of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.

Although injection site reactions were reported in 81.4% (1,724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0-2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2-6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.

Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs. 13.5% with TDF-FTC) and a decrease in creatine clearance (7.0% with CAB vs. 8.3% with TDF-FTC).

In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05-1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18-0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
 

New modality, new challenges

“We’re constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP,” Lina Rosengren-Hovee, MD, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, N.C., said in an interview. “Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence,” she added.

Dr. Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. “It’s still a conversation that you’ll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it’s fairly uncommon,” she said.

When asked, Dr. Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.

“CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [e.g., a viral load or RNA-based test] rather than a conventional HIV test,” Dr. Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and health care communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.

“By default, PrEP is much more decentralized and demedicalized, especially in primary care,” said Dr. Rosengren-Hovee. “We need more studies looking at real-world scenarios.”

Dr. Rosengren-Hovee reports no relevant financial relationships. Dr. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.

A version of this article first appeared on Medscape.com.

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

A version of this article first appeared on Medscape.com.

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

A version of this article first appeared on Medscape.com.

“One of the most important considerations before switching HIV patients to injectable long-acting cabotegravir/rilpivirine [CAB/RPV LA; Cabenuva, ViiV Healthcare] is for the patient and the clinician to arrive at this decision together,” Elliot DeHaan, MD, told this news organization. “This therapy is not necessarily for everyone.”

Dr. DeHaan is lead author of the newly released clinical guideline from the New York State Department of Health AIDS Institute for use of CAB/RPV LA as replacement antiretroviral therapy (ART) in virally suppressed adults with HIV. He explained that the guidance expands upon Health & Human Services’ Feb. 24 CAB/RPV LA recommendations, highlighting some of the most important clinical and patient considerations necessary to implement injectable ART. “There are a lot of things that need to be laid out beforehand,” he said.
 

Gaining consensus

Approved by the FDA in late January 2021, CAB/RPV LA is considered an optimization strategy for individuals with HIV whose virus is suppressed by oral ART and who might prefer monthly injections to daily oral therapy. While there are various reasons why patients might wish to switch to a long-acting injectable, one of the primary concerns is adherence. Of note, the guidance points to phase 3 clinical study findings that suggest high levels (86%-91%) of patient satisfaction with CAB/RPV LA, which portends a promising future for this therapeutic approach.

With regard to patient preference, recommendations focus on the need to thoroughly discuss several critical requisites with potential candidates, including a 4-week lead-in daily oral ART course (CAB [Vocabria] 30 mg, RPV [Edurant] 25 mg) before initiating a loading dose. Patients should be advised of the potential for development of resistance should dosing be interrupted for any reason (CAB and RPV have extended half-lives ranging from mean 5.6 to 11.5 weeks for CAB and 13 to 28 weeks for RPV), as well as the need to return to oral bridging therapy if subsequent injections are not administered within the 7-day window period. If the maintenance dose is delayed beyond 2 months, a loading dose and restart is necessary.

CAB/RPV LA therapy is administered into opposing gluteal muscles (CAB into one gluteus medius and RPV into the contralateral gluteus medius), and injection-site pain beginning 1 day post-injection and lasting 3-4 days is common. In phase 3 clinical trials, as many as 83% of patients experienced adverse effects (AEs), which also include nodules, induration, and swelling at the injection sites. Fortunately, 99% of AEs were of mild to moderate severity. While pain tends to decline over several injections, Dr. DeHaan said that it’s an important part of the initial discussion about switching therapies.
 

Other considerations

Prior resistance testing, ART treatment history, and/or baseline genotypic resistance testing that includes both reverse transcriptase and integrase genes should be reviewed or conducted before initiating treatment. K103 mutations alone are not considered exclusionary. Virologic failures (defined as two consecutive plasma HIV-1 RNA measurements greater than 200 copies/mL), while rare, were reported in 13 clinical trial participants. Recent data suggest that patients who developed resistance despite adherence had at least two of three factors: a body mass index greater than 30 kg/m², the HIV-1 subtype A6/A1, and the presence of proviral RPV RAMS.

CAB/RPV LA does not treat hepatitis B (HBV) coinfections, reinforcing the need for concurrent oral HBV therapy.

And there’s a paucity of data on the safety and efficacy of CAB/RPV in children and adolescents, or during pregnancy/lactation, precluding its use in those patient populations.
 

Clinical, institutional considerations

Adaptation of CAB/RPV LA as ART requires specific clinical institutional planning, especially in light of current pandemic-related resource and staffing limitations. Monthly dosing must be done within a 7-day window and requires preparations akin to initial loading doses. In addition to pharmacy resources and onsite storage requirements, the guidance points to patient scheduling and reminder systems, access (patient transportation, work constraints, parking), and most importantly, contingency plans for care (including oral bridging therapy) should a clinic be forced to shut down for any reason. Additional factors include billing protocols, insurance or third party authorizations, and provision of counseling and education training.

“Given that this is a completely new way of thinking among providers, we’re all learning together,” said David Koren, PharmD, MPH, a clinical pharmacy specialist in infectious diseases at Temple University, Philadelphia. “The guidelines provide a nice framework for taking the next step to operationalize these processes into practice, taking into account that barriers to implementation are still unknown.” Dr. Koren was not involved in the development of the guidelines.

Dr. DeHaan has disclosed no relevant financial relationships. Dr. Koren disclosed serving on a prior Advisory Panel for ViiV Healthcare US.

A version of this article first appeared on Medscape.com.

Over the past 25 years, antiretroviral therapy (ART) has led to a dramatic decrease in HIV-associated morbidity and mortality. Patients who initiate ART today can now expect a nearly normal life expectancy.¹ Despite the overwhelming benefits of ART, some patients experience immune reconstitution inflammatory syndrome (IRIS), a disease- or pathogen-specific immune response that can mimic the presentation of an active opportunistic infection (OI). IRIS can occur at any CD4 count. However, it is most often associated with the rapid increase in CD4 count and decrease in viral load that typically follows ART initiation in patients who are severely immunocompromised and have high viral loads.^2-6

IRIS manifests in two primary ways. Paradoxical IRIS refers to the worsening of a previously diagnosed disease after ART initiation, whereas unmasking IRIS refers to the appearance of a previously undiagnosed disease following ART initiation.

The Medical Care Criteria Committee of the New York State Department of Health AIDS Institute Clinical Guidelines Program recently published an update to its guideline, Management of IRIS . This update incorporates recent data and summarizes how to identify and manage IRIS associated with several OIs. Important goals of this update were to raise awareness among healthcare providers about IRIS, including its clinical presentation, and provide treatment recommendations.
 

For most patients, ART should be started quickly

Over the past few years, rapid initiation of ART has become the new standard of care, with same-day initiation on the day of HIV diagnosis recommended whenever possible. For many years, however, the presence of an active OI was felt to justify delaying ART initiation until the OI was completely treated. This approach changed in 2009 when a randomized trial by the AIDS Clinical Trials Group demonstrated that patients who initiated ART within 2 weeks of OI diagnosis did not experience more adverse events than those who waited.⁷ Moreover, although the finding did not reach statistical significance, participants in the early ART arm appeared to experience lower mortality and progression of AIDS than those in the delayed ART arm. Therefore, patients diagnosed with most OIs can start ART as soon as they are tolerating the treatment for the OI.

Some OIs do require a delay in ART

Symptoms associated with IRIS are typically mild or moderate; life-threatening complications are rare. Most patients newly diagnosed with HIV who have an active OI can therefore initiate ART quickly. However, IRIS involving the central nervous system or eye carries a much greater risk of morbidity and mortality. OIs that do warrant a delay in ART initiation, therefore, include tuberculosis (TB) meningitis, cryptococcal meningitis, and cytomegalovirus (CMV) retinitis.

Several randomized clinical trials have found that in patients with HIV and pulmonary TB coinfection, ART should be started as soon as the patient is tolerating anti-TB therapy.^8-10 What’s more, in patients with CD4 counts less than 50 cells/microL, there is a mortality benefit when ART is initiated within 2 weeks of starting TB treatment, compared with waiting 8 weeks.

For TB meningitis, however, a clinical trial conducted in Vietnam did not show any mortality benefit when ART was started within 7 days (vs. 2 months); however, severe adverse events were more common in the immediate ART group, raising the concern that patients in that group had experienced complications of IRIS of the central nervous system.¹¹ Limited data are available to guide specific timing of ART in patients with TB meningitis, but based on the results of this trial, most clinicians wait approximately 2 months before initiating ART, and consultation with an expert is recommended.

Optimal timing of ART in patients with cryptococcal meningitis is also uncertain, and there have been contradictory results from several small studies. However, in 2014, the larger COAT trial, conducted in Uganda and South Africa, found 15% higher mortality in patients who initiated ART within 2 weeks, compared with more than 5 weeks.¹² Although exactly how long to wait is still unknown, ART should be delayed by at least 2 weeks after a patient starts antifungal therapy.

CMV-IRIS can have devastating effects, including vision loss or blindness. Therefore, ART initiation should be delayed in patients with diagnosed or strongly suspected CMV.¹³ Importantly, however, patients with advanced HIV may have asymptomatic or subclinical CMV retinitis. As a result, all patients with HIV who have CD4 counts less than 100 cells/mm³ who do not have known or strongly suspected CMV should be screened for signs of CMV by dilated ophthalmological examination as soon as possible after initiation of ART. If signs of CMV are seen on dilated exam, clinicians should consult with an experienced HIV care provider to determine if ART must be temporarily paused.
 

Diagnosing IRIS

Broadly, IRIS presents as a clinical deterioration after ART initiation, with localized tissue inflammation, with or without a systemic inflammatory response, but the presentation of IRIS varies depending on the underlying OI or illness. In most cases, IRIS occurs within 4-8 weeks of ART initiation or regimen change. A rise in CD4 count often but does not always precede IRIS and is not a diagnostic criterion. There is no diagnostic test for IRIS, and when assessing a patient for possible IRIS, clinicians should exclude HIV disease progression, new infections, OI drug resistance, OI treatment nonadherence, and drug reactions as possible causes for inflammatory signs or symptoms.

Treatment of IRIS

Most cases of IRIS are mild, and patients can be reassured that the symptoms will resolve with time. Clinicians should interrupt ART only if a patient has a severe, life-threatening case of IRIS. Unnecessary ART interruption may increase a patient’s risk of new opportunistic infections, recurring IRIS upon resumption of ART, and development of HIV-drug resistance. Any newly unmasked OIs should be treated promptly while ART is continued. For patients with severe IRIS, clinicians can use prednisone to treat inflammatory symptoms – generally for 1-2 weeks, followed by a taper as needed. Prednisone, however, should not be used in patients with cryptococcal meningitis or Kaposi sarcoma as it is associated with worse outcomes.^14-17

In patients newly diagnosed with HIV, prompt initiation of ART is, with the exceptions outlined above, the highest priority. IRIS is an unfortunate complication of ART, and patients may be discouraged when they find themselves feeling worse shortly after starting treatment. While providing supportive and symptomatic care, clinicians can reassure patients by explaining that immune reconstitution is, in fact, the goal of ART and that their symptoms do not represent the progression of HIV disease. It is hoped that with more frequent HIV testing, earlier diagnosis, and earlier ART initiation at higher CD4 counts, IRIS will become a less frequent nuisance to patients and providers. 

Dr. Brust is in the department of medicine at Albert Einstein College of Medicine/Montefiore Medical Center, New York. He reported having no relevant financial relationships. A version of this article first appeared on Medscape.com.

References

1. Marcus JL et al. JAMA Netw Open. 2020;3:e207954.

2. Breton G et al. Clin Infect Dis. 2004;39:1709-12.

3. Shelburne SA et al. Clin Infect Dis. 2005;40:1049-52.

4. Shelburne SA et al. AIDS. 2005;19:399-406.

5. Muller M et al. Lancet Infect Dis. 2010;10:251-61.

6. Novak RM et al. AIDS. 2012;26:721-30.

7. Zolopa A et al. PLoS One. 2009;4:e5575.

8. Havlir DV et al. N Engl J Med. 2011;365:1482-91.

9. Abdool Karim SS et al. N Engl J Med. 2011;365:1492-501.

10. Blanc FX et al. N Engl J Med. 2011;365:1471-81.

11. Torok ME et al. Clin Infect Dis. 2011;52:1374-83.

12. Boulware DR et al. N Engl J Med. 2014;370:2487-98.

13. Ortega-Larrocea G et al. AIDS. 2005;19:735-8.

14. Beardsley J et al. N Engl J Med. 2016;374:542-54.

15. Gill PS, Loureiro C et al.  Ann Intern Med. 1989;110:937-40.

16. Elliott AM et al. J Infect Dis. 2004;190:869-78.

17. Volkow PF et al. AIDS. 2008;22:663-5.

Over the past 25 years, antiretroviral therapy (ART) has led to a dramatic decrease in HIV-associated morbidity and mortality. Patients who initiate ART today can now expect a nearly normal life expectancy.¹ Despite the overwhelming benefits of ART, some patients experience immune reconstitution inflammatory syndrome (IRIS), a disease- or pathogen-specific immune response that can mimic the presentation of an active opportunistic infection (OI). IRIS can occur at any CD4 count. However, it is most often associated with the rapid increase in CD4 count and decrease in viral load that typically follows ART initiation in patients who are severely immunocompromised and have high viral loads.^2-6

IRIS manifests in two primary ways. Paradoxical IRIS refers to the worsening of a previously diagnosed disease after ART initiation, whereas unmasking IRIS refers to the appearance of a previously undiagnosed disease following ART initiation.

The Medical Care Criteria Committee of the New York State Department of Health AIDS Institute Clinical Guidelines Program recently published an update to its guideline, Management of IRIS . This update incorporates recent data and summarizes how to identify and manage IRIS associated with several OIs. Important goals of this update were to raise awareness among healthcare providers about IRIS, including its clinical presentation, and provide treatment recommendations.
 

For most patients, ART should be started quickly

Over the past few years, rapid initiation of ART has become the new standard of care, with same-day initiation on the day of HIV diagnosis recommended whenever possible. For many years, however, the presence of an active OI was felt to justify delaying ART initiation until the OI was completely treated. This approach changed in 2009 when a randomized trial by the AIDS Clinical Trials Group demonstrated that patients who initiated ART within 2 weeks of OI diagnosis did not experience more adverse events than those who waited.⁷ Moreover, although the finding did not reach statistical significance, participants in the early ART arm appeared to experience lower mortality and progression of AIDS than those in the delayed ART arm. Therefore, patients diagnosed with most OIs can start ART as soon as they are tolerating the treatment for the OI.

Some OIs do require a delay in ART

Symptoms associated with IRIS are typically mild or moderate; life-threatening complications are rare. Most patients newly diagnosed with HIV who have an active OI can therefore initiate ART quickly. However, IRIS involving the central nervous system or eye carries a much greater risk of morbidity and mortality. OIs that do warrant a delay in ART initiation, therefore, include tuberculosis (TB) meningitis, cryptococcal meningitis, and cytomegalovirus (CMV) retinitis.

Several randomized clinical trials have found that in patients with HIV and pulmonary TB coinfection, ART should be started as soon as the patient is tolerating anti-TB therapy.^8-10 What’s more, in patients with CD4 counts less than 50 cells/microL, there is a mortality benefit when ART is initiated within 2 weeks of starting TB treatment, compared with waiting 8 weeks.

For TB meningitis, however, a clinical trial conducted in Vietnam did not show any mortality benefit when ART was started within 7 days (vs. 2 months); however, severe adverse events were more common in the immediate ART group, raising the concern that patients in that group had experienced complications of IRIS of the central nervous system.¹¹ Limited data are available to guide specific timing of ART in patients with TB meningitis, but based on the results of this trial, most clinicians wait approximately 2 months before initiating ART, and consultation with an expert is recommended.

Optimal timing of ART in patients with cryptococcal meningitis is also uncertain, and there have been contradictory results from several small studies. However, in 2014, the larger COAT trial, conducted in Uganda and South Africa, found 15% higher mortality in patients who initiated ART within 2 weeks, compared with more than 5 weeks.¹² Although exactly how long to wait is still unknown, ART should be delayed by at least 2 weeks after a patient starts antifungal therapy.

CMV-IRIS can have devastating effects, including vision loss or blindness. Therefore, ART initiation should be delayed in patients with diagnosed or strongly suspected CMV.¹³ Importantly, however, patients with advanced HIV may have asymptomatic or subclinical CMV retinitis. As a result, all patients with HIV who have CD4 counts less than 100 cells/mm³ who do not have known or strongly suspected CMV should be screened for signs of CMV by dilated ophthalmological examination as soon as possible after initiation of ART. If signs of CMV are seen on dilated exam, clinicians should consult with an experienced HIV care provider to determine if ART must be temporarily paused.
 

Diagnosing IRIS

Broadly, IRIS presents as a clinical deterioration after ART initiation, with localized tissue inflammation, with or without a systemic inflammatory response, but the presentation of IRIS varies depending on the underlying OI or illness. In most cases, IRIS occurs within 4-8 weeks of ART initiation or regimen change. A rise in CD4 count often but does not always precede IRIS and is not a diagnostic criterion. There is no diagnostic test for IRIS, and when assessing a patient for possible IRIS, clinicians should exclude HIV disease progression, new infections, OI drug resistance, OI treatment nonadherence, and drug reactions as possible causes for inflammatory signs or symptoms.

Treatment of IRIS

Most cases of IRIS are mild, and patients can be reassured that the symptoms will resolve with time. Clinicians should interrupt ART only if a patient has a severe, life-threatening case of IRIS. Unnecessary ART interruption may increase a patient’s risk of new opportunistic infections, recurring IRIS upon resumption of ART, and development of HIV-drug resistance. Any newly unmasked OIs should be treated promptly while ART is continued. For patients with severe IRIS, clinicians can use prednisone to treat inflammatory symptoms – generally for 1-2 weeks, followed by a taper as needed. Prednisone, however, should not be used in patients with cryptococcal meningitis or Kaposi sarcoma as it is associated with worse outcomes.^14-17

In patients newly diagnosed with HIV, prompt initiation of ART is, with the exceptions outlined above, the highest priority. IRIS is an unfortunate complication of ART, and patients may be discouraged when they find themselves feeling worse shortly after starting treatment. While providing supportive and symptomatic care, clinicians can reassure patients by explaining that immune reconstitution is, in fact, the goal of ART and that their symptoms do not represent the progression of HIV disease. It is hoped that with more frequent HIV testing, earlier diagnosis, and earlier ART initiation at higher CD4 counts, IRIS will become a less frequent nuisance to patients and providers. 

Dr. Brust is in the department of medicine at Albert Einstein College of Medicine/Montefiore Medical Center, New York. He reported having no relevant financial relationships. A version of this article first appeared on Medscape.com.

References

1. Marcus JL et al. JAMA Netw Open. 2020;3:e207954.

2. Breton G et al. Clin Infect Dis. 2004;39:1709-12.

3. Shelburne SA et al. Clin Infect Dis. 2005;40:1049-52.

4. Shelburne SA et al. AIDS. 2005;19:399-406.

5. Muller M et al. Lancet Infect Dis. 2010;10:251-61.

6. Novak RM et al. AIDS. 2012;26:721-30.

7. Zolopa A et al. PLoS One. 2009;4:e5575.

8. Havlir DV et al. N Engl J Med. 2011;365:1482-91.

9. Abdool Karim SS et al. N Engl J Med. 2011;365:1492-501.

10. Blanc FX et al. N Engl J Med. 2011;365:1471-81.

11. Torok ME et al. Clin Infect Dis. 2011;52:1374-83.

12. Boulware DR et al. N Engl J Med. 2014;370:2487-98.

13. Ortega-Larrocea G et al. AIDS. 2005;19:735-8.

14. Beardsley J et al. N Engl J Med. 2016;374:542-54.

15. Gill PS, Loureiro C et al.  Ann Intern Med. 1989;110:937-40.

16. Elliott AM et al. J Infect Dis. 2004;190:869-78.

17. Volkow PF et al. AIDS. 2008;22:663-5.

Over the past 25 years, antiretroviral therapy (ART) has led to a dramatic decrease in HIV-associated morbidity and mortality. Patients who initiate ART today can now expect a nearly normal life expectancy.¹ Despite the overwhelming benefits of ART, some patients experience immune reconstitution inflammatory syndrome (IRIS), a disease- or pathogen-specific immune response that can mimic the presentation of an active opportunistic infection (OI). IRIS can occur at any CD4 count. However, it is most often associated with the rapid increase in CD4 count and decrease in viral load that typically follows ART initiation in patients who are severely immunocompromised and have high viral loads.^2-6

IRIS manifests in two primary ways. Paradoxical IRIS refers to the worsening of a previously diagnosed disease after ART initiation, whereas unmasking IRIS refers to the appearance of a previously undiagnosed disease following ART initiation.

The Medical Care Criteria Committee of the New York State Department of Health AIDS Institute Clinical Guidelines Program recently published an update to its guideline, Management of IRIS . This update incorporates recent data and summarizes how to identify and manage IRIS associated with several OIs. Important goals of this update were to raise awareness among healthcare providers about IRIS, including its clinical presentation, and provide treatment recommendations.
 

For most patients, ART should be started quickly

Over the past few years, rapid initiation of ART has become the new standard of care, with same-day initiation on the day of HIV diagnosis recommended whenever possible. For many years, however, the presence of an active OI was felt to justify delaying ART initiation until the OI was completely treated. This approach changed in 2009 when a randomized trial by the AIDS Clinical Trials Group demonstrated that patients who initiated ART within 2 weeks of OI diagnosis did not experience more adverse events than those who waited.⁷ Moreover, although the finding did not reach statistical significance, participants in the early ART arm appeared to experience lower mortality and progression of AIDS than those in the delayed ART arm. Therefore, patients diagnosed with most OIs can start ART as soon as they are tolerating the treatment for the OI.

Some OIs do require a delay in ART

Symptoms associated with IRIS are typically mild or moderate; life-threatening complications are rare. Most patients newly diagnosed with HIV who have an active OI can therefore initiate ART quickly. However, IRIS involving the central nervous system or eye carries a much greater risk of morbidity and mortality. OIs that do warrant a delay in ART initiation, therefore, include tuberculosis (TB) meningitis, cryptococcal meningitis, and cytomegalovirus (CMV) retinitis.

Several randomized clinical trials have found that in patients with HIV and pulmonary TB coinfection, ART should be started as soon as the patient is tolerating anti-TB therapy.^8-10 What’s more, in patients with CD4 counts less than 50 cells/microL, there is a mortality benefit when ART is initiated within 2 weeks of starting TB treatment, compared with waiting 8 weeks.

For TB meningitis, however, a clinical trial conducted in Vietnam did not show any mortality benefit when ART was started within 7 days (vs. 2 months); however, severe adverse events were more common in the immediate ART group, raising the concern that patients in that group had experienced complications of IRIS of the central nervous system.¹¹ Limited data are available to guide specific timing of ART in patients with TB meningitis, but based on the results of this trial, most clinicians wait approximately 2 months before initiating ART, and consultation with an expert is recommended.

Optimal timing of ART in patients with cryptococcal meningitis is also uncertain, and there have been contradictory results from several small studies. However, in 2014, the larger COAT trial, conducted in Uganda and South Africa, found 15% higher mortality in patients who initiated ART within 2 weeks, compared with more than 5 weeks.¹² Although exactly how long to wait is still unknown, ART should be delayed by at least 2 weeks after a patient starts antifungal therapy.

CMV-IRIS can have devastating effects, including vision loss or blindness. Therefore, ART initiation should be delayed in patients with diagnosed or strongly suspected CMV.¹³ Importantly, however, patients with advanced HIV may have asymptomatic or subclinical CMV retinitis. As a result, all patients with HIV who have CD4 counts less than 100 cells/mm³ who do not have known or strongly suspected CMV should be screened for signs of CMV by dilated ophthalmological examination as soon as possible after initiation of ART. If signs of CMV are seen on dilated exam, clinicians should consult with an experienced HIV care provider to determine if ART must be temporarily paused.
 

Diagnosing IRIS

Broadly, IRIS presents as a clinical deterioration after ART initiation, with localized tissue inflammation, with or without a systemic inflammatory response, but the presentation of IRIS varies depending on the underlying OI or illness. In most cases, IRIS occurs within 4-8 weeks of ART initiation or regimen change. A rise in CD4 count often but does not always precede IRIS and is not a diagnostic criterion. There is no diagnostic test for IRIS, and when assessing a patient for possible IRIS, clinicians should exclude HIV disease progression, new infections, OI drug resistance, OI treatment nonadherence, and drug reactions as possible causes for inflammatory signs or symptoms.

Treatment of IRIS

Most cases of IRIS are mild, and patients can be reassured that the symptoms will resolve with time. Clinicians should interrupt ART only if a patient has a severe, life-threatening case of IRIS. Unnecessary ART interruption may increase a patient’s risk of new opportunistic infections, recurring IRIS upon resumption of ART, and development of HIV-drug resistance. Any newly unmasked OIs should be treated promptly while ART is continued. For patients with severe IRIS, clinicians can use prednisone to treat inflammatory symptoms – generally for 1-2 weeks, followed by a taper as needed. Prednisone, however, should not be used in patients with cryptococcal meningitis or Kaposi sarcoma as it is associated with worse outcomes.^14-17

In patients newly diagnosed with HIV, prompt initiation of ART is, with the exceptions outlined above, the highest priority. IRIS is an unfortunate complication of ART, and patients may be discouraged when they find themselves feeling worse shortly after starting treatment. While providing supportive and symptomatic care, clinicians can reassure patients by explaining that immune reconstitution is, in fact, the goal of ART and that their symptoms do not represent the progression of HIV disease. It is hoped that with more frequent HIV testing, earlier diagnosis, and earlier ART initiation at higher CD4 counts, IRIS will become a less frequent nuisance to patients and providers. 

Dr. Brust is in the department of medicine at Albert Einstein College of Medicine/Montefiore Medical Center, New York. He reported having no relevant financial relationships. A version of this article first appeared on Medscape.com.

References

1. Marcus JL et al. JAMA Netw Open. 2020;3:e207954.

2. Breton G et al. Clin Infect Dis. 2004;39:1709-12.

3. Shelburne SA et al. Clin Infect Dis. 2005;40:1049-52.

4. Shelburne SA et al. AIDS. 2005;19:399-406.

5. Muller M et al. Lancet Infect Dis. 2010;10:251-61.

6. Novak RM et al. AIDS. 2012;26:721-30.

7. Zolopa A et al. PLoS One. 2009;4:e5575.

8. Havlir DV et al. N Engl J Med. 2011;365:1482-91.

9. Abdool Karim SS et al. N Engl J Med. 2011;365:1492-501.

10. Blanc FX et al. N Engl J Med. 2011;365:1471-81.

11. Torok ME et al. Clin Infect Dis. 2011;52:1374-83.

12. Boulware DR et al. N Engl J Med. 2014;370:2487-98.

13. Ortega-Larrocea G et al. AIDS. 2005;19:735-8.

14. Beardsley J et al. N Engl J Med. 2016;374:542-54.

15. Gill PS, Loureiro C et al.  Ann Intern Med. 1989;110:937-40.

16. Elliott AM et al. J Infect Dis. 2004;190:869-78.

17. Volkow PF et al. AIDS. 2008;22:663-5.

A body mass index (BMI) of at least 30 kg/m², rilpivirine resistance–associated mutations, and the HIV-1 subtype A6/A1 can raise a person’s risk for confirmed virologic failure (CVF) of long-acting cabotegravir (CAB) and rilpivirine (RPV) therapy, new research suggests. A combination of at least two of these factors was necessary to increase risk.

Long-acting CAB/RPV (Cabenuva) is a Food and Drug Administration–approved antiretroviral therapy that is administered intramuscularly on a monthly basis. Although CVF was rare in all three clinical trials of the drug regimen, understanding the factors that may predispose patients to this outcome is necessary, the authors wrote. “This information will help inform clinicians and patients, allowing them to assess the potential benefits and risks of this novel long-acting therapy.” The results were published July 15, 2021, in AIDS.

In the study, researchers pooled the clinical data from the FLAIR, ATLAS, and ATLAS-2M trials for long-acting CAB/RPV. Using these data, they examined whether participant factors such as sex, body weight, resistance mutations, and dosing regimen influenced risk for CVF using a multivariable analysis.

Of the 1,039 participants included in the analysis, 13 (1.3%) experienced CVF; 272 participants (26%) in the study population had at least one of the three risk factors, but no single variable raised risk on its own.

“When we looked at the presence of only one baseline factor, it was no different than having no baseline factors,” Bill Spreen, PharmD, an author of the study, said in an interview. Dr. Spreen is the medicine development leader for cabotegravir at ViiV Healthcare, in Research Triangle Park, N.C. CVF rates for participants with no risk factors and those with only one risk factor were 0.4%.

In comparison, CVF occurred in 9 of the 35 participants (25.7%) who had at least two risk factors, and the 1 participant who had all three risk factors also experienced CVF. The HIV subtype A1/A6, a subtype largely limited to Russia, together with a BMI greater than 30 was the most common combination, occurring in 21 individuals. Ten participants had both RPV resistance mutations and a BMI greater than 30, and only three had HIV subtype A1/A6 and RPV resistance mutations.

“The higher the BMI, typically, the lower the absorption rate of the drug, so it was not surprising to see that come out,” Dr. Spreen said. Previous research has associated subtype A1/A6 with L74I polymorphism, which may lower the barrier to resistance to integrase strand transfer inhibitors such as CAB. In the current study, researchers found that the L74I polymorphism mutation was not associated with CVF, in particular among those individuals with non-A1/A6 subtypes.

Although A1/A6 was the most common risk factor in the study, testing patients for the subtype prior to initiating CAB/RPV is likely unnecessary in the United States, where the subtype is very rare, Susan Swindells, MBBS, an expert in HIV/AIDS therapeutics from the University of Nebraska Medical Center, Omaha, said in an interview. Dr. Swindells was not an author of this study but was involved in all three CAB/RPV clinical trials. The most common risk factors health care professionals will likely encounter are high BMI and resistance mutations.

In cases in which a patient may have both a high BMI and resistance mutations, Dr. Swindells would not recommend starting a CAB/RPV regimen “unless there was a very pressing reason to do it,” as, for example, in rare cases in which a patient can’t take medications orally. “It’s all a question of balancing the risk and benefit.”

A version of this article first appeared on Medscape.com.

A body mass index (BMI) of at least 30 kg/m², rilpivirine resistance–associated mutations, and the HIV-1 subtype A6/A1 can raise a person’s risk for confirmed virologic failure (CVF) of long-acting cabotegravir (CAB) and rilpivirine (RPV) therapy, new research suggests. A combination of at least two of these factors was necessary to increase risk.

Long-acting CAB/RPV (Cabenuva) is a Food and Drug Administration–approved antiretroviral therapy that is administered intramuscularly on a monthly basis. Although CVF was rare in all three clinical trials of the drug regimen, understanding the factors that may predispose patients to this outcome is necessary, the authors wrote. “This information will help inform clinicians and patients, allowing them to assess the potential benefits and risks of this novel long-acting therapy.” The results were published July 15, 2021, in AIDS.

In the study, researchers pooled the clinical data from the FLAIR, ATLAS, and ATLAS-2M trials for long-acting CAB/RPV. Using these data, they examined whether participant factors such as sex, body weight, resistance mutations, and dosing regimen influenced risk for CVF using a multivariable analysis.

Of the 1,039 participants included in the analysis, 13 (1.3%) experienced CVF; 272 participants (26%) in the study population had at least one of the three risk factors, but no single variable raised risk on its own.

“When we looked at the presence of only one baseline factor, it was no different than having no baseline factors,” Bill Spreen, PharmD, an author of the study, said in an interview. Dr. Spreen is the medicine development leader for cabotegravir at ViiV Healthcare, in Research Triangle Park, N.C. CVF rates for participants with no risk factors and those with only one risk factor were 0.4%.

In comparison, CVF occurred in 9 of the 35 participants (25.7%) who had at least two risk factors, and the 1 participant who had all three risk factors also experienced CVF. The HIV subtype A1/A6, a subtype largely limited to Russia, together with a BMI greater than 30 was the most common combination, occurring in 21 individuals. Ten participants had both RPV resistance mutations and a BMI greater than 30, and only three had HIV subtype A1/A6 and RPV resistance mutations.

“The higher the BMI, typically, the lower the absorption rate of the drug, so it was not surprising to see that come out,” Dr. Spreen said. Previous research has associated subtype A1/A6 with L74I polymorphism, which may lower the barrier to resistance to integrase strand transfer inhibitors such as CAB. In the current study, researchers found that the L74I polymorphism mutation was not associated with CVF, in particular among those individuals with non-A1/A6 subtypes.

Although A1/A6 was the most common risk factor in the study, testing patients for the subtype prior to initiating CAB/RPV is likely unnecessary in the United States, where the subtype is very rare, Susan Swindells, MBBS, an expert in HIV/AIDS therapeutics from the University of Nebraska Medical Center, Omaha, said in an interview. Dr. Swindells was not an author of this study but was involved in all three CAB/RPV clinical trials. The most common risk factors health care professionals will likely encounter are high BMI and resistance mutations.

In cases in which a patient may have both a high BMI and resistance mutations, Dr. Swindells would not recommend starting a CAB/RPV regimen “unless there was a very pressing reason to do it,” as, for example, in rare cases in which a patient can’t take medications orally. “It’s all a question of balancing the risk and benefit.”

A version of this article first appeared on Medscape.com.

A body mass index (BMI) of at least 30 kg/m², rilpivirine resistance–associated mutations, and the HIV-1 subtype A6/A1 can raise a person’s risk for confirmed virologic failure (CVF) of long-acting cabotegravir (CAB) and rilpivirine (RPV) therapy, new research suggests. A combination of at least two of these factors was necessary to increase risk.

Long-acting CAB/RPV (Cabenuva) is a Food and Drug Administration–approved antiretroviral therapy that is administered intramuscularly on a monthly basis. Although CVF was rare in all three clinical trials of the drug regimen, understanding the factors that may predispose patients to this outcome is necessary, the authors wrote. “This information will help inform clinicians and patients, allowing them to assess the potential benefits and risks of this novel long-acting therapy.” The results were published July 15, 2021, in AIDS.

In the study, researchers pooled the clinical data from the FLAIR, ATLAS, and ATLAS-2M trials for long-acting CAB/RPV. Using these data, they examined whether participant factors such as sex, body weight, resistance mutations, and dosing regimen influenced risk for CVF using a multivariable analysis.

Of the 1,039 participants included in the analysis, 13 (1.3%) experienced CVF; 272 participants (26%) in the study population had at least one of the three risk factors, but no single variable raised risk on its own.

“When we looked at the presence of only one baseline factor, it was no different than having no baseline factors,” Bill Spreen, PharmD, an author of the study, said in an interview. Dr. Spreen is the medicine development leader for cabotegravir at ViiV Healthcare, in Research Triangle Park, N.C. CVF rates for participants with no risk factors and those with only one risk factor were 0.4%.

In comparison, CVF occurred in 9 of the 35 participants (25.7%) who had at least two risk factors, and the 1 participant who had all three risk factors also experienced CVF. The HIV subtype A1/A6, a subtype largely limited to Russia, together with a BMI greater than 30 was the most common combination, occurring in 21 individuals. Ten participants had both RPV resistance mutations and a BMI greater than 30, and only three had HIV subtype A1/A6 and RPV resistance mutations.

“The higher the BMI, typically, the lower the absorption rate of the drug, so it was not surprising to see that come out,” Dr. Spreen said. Previous research has associated subtype A1/A6 with L74I polymorphism, which may lower the barrier to resistance to integrase strand transfer inhibitors such as CAB. In the current study, researchers found that the L74I polymorphism mutation was not associated with CVF, in particular among those individuals with non-A1/A6 subtypes.

Although A1/A6 was the most common risk factor in the study, testing patients for the subtype prior to initiating CAB/RPV is likely unnecessary in the United States, where the subtype is very rare, Susan Swindells, MBBS, an expert in HIV/AIDS therapeutics from the University of Nebraska Medical Center, Omaha, said in an interview. Dr. Swindells was not an author of this study but was involved in all three CAB/RPV clinical trials. The most common risk factors health care professionals will likely encounter are high BMI and resistance mutations.

In cases in which a patient may have both a high BMI and resistance mutations, Dr. Swindells would not recommend starting a CAB/RPV regimen “unless there was a very pressing reason to do it,” as, for example, in rare cases in which a patient can’t take medications orally. “It’s all a question of balancing the risk and benefit.”

A version of this article first appeared on Medscape.com.

For the first time, an HIV prevention trial that was limited to adolescent girls and young women found that, given sufficient support, girls will use either daily oral pre-exposure prophylaxis (PrEP) or the vaginal dapivirine ring to protect themselves from HIV.

The secret, said Gonasagrie Nair, MBChB, faculty of medicine and health sciences at Stellenbosch University, Zimbabwe, is offering intensive wraparound services to support teenagers – a lesson that may be useful as adolescent and family medicine professionals in the United States begin to roll out HIV prevention in their clinics.

This is important in the United States because cisgender Black women make up 60% of all new HIV cases in the United States while accounting for just 14% of the overall U.S. population. The Centers for Disease Control and Prevention has found that only about 1% of Black Americans who could benefit from PrEP have access to it.

“Younger women and adolescent girls in particular face a number of cultural and social challenges that impact their ability to make decisions related to their own health,” said Dr. Nair, who presented the data at the International AIDS Society (IAS) Conference 2021. “The adherence support provided by this study empowered them to make choices and stick to these choices,” she said.

In total, 247 women and girls aged 16 to 21 who were without HIV were enrolled in the Reversing the Epidemic in Africa with Choices in HIV Prevention (REACH) trial in two sites in South Africa and one each in Uganda and Zimbabwe beginning in February 2019. One-third of the participants were minors; the average age was 18.2 years.

The women were good candidates for PrEP. More than 1 in 3 of the women started the study with a sexually transmitted infection (STI), the most prevalent of which was chlamydia. This is often a good marker for condomless sex. Of the participants, 89% had a primary sex partner; a quarter of those thought their partner was having sex with other people. Only 7% of participants reported being very worried about acquiring HIV. More than 1 in 3 (39%) weren’t worried about HIV at all. This conforms to previous data suggesting that those who could most benefit from PrEP often don’t perceive their own vulnerability.

In the study, the women were randomly assigned two groups. In one group, the participants used the dapivirine ring for 6 months; in the other, participants used oral PrEP for 6 months. The participants then swapped prevention methods and used the alternative method for 6 more months. After a year of trying both methods, the women will be asked to choose one of the two prevention method or to stop PrEP altogether. At the IAS conference, the researchers reported interim data from the first year of the study, before the girls had the opportunity to choose for themselves.

During that first year, girls received intensive adherence support, including daily or weekly text check-ins, phone check-ins, peer buddy support, additional onsite counseling visits, access to adherence support groups, participation in online support groups via apps such as WhatsApp, and in-person social events designed to empower young women and to teach them skills. Support included discussion of adherence, contraceptives, and STIs. In addition, when girls came in for study visits, staff provided feedback on how adherent the girls had been, as determined on the basis of residual levels of dapivirine in the rings or, with regard to oral pills, drug levels as determined with blood spots.

Girls were considered to have had high adherence if they were found to have oral PrEP concentrations equivalent to four or more doses per week or if residual levels of dapivirine in their rings were 0.1071 mg/d. Moderate adherence was the equivalent of one to three doses of oral PrEP a week or dapivirine levels between 0.0321 mg/d and 0.1071 mg/d.

In total, 95.6% of ring users showed some adherence to the ring. Of those, adherence was high for 50.2%; 49.8% used the ring perfectly. For oral PrEP, 98.5% showed some level of PrEP use; for 58.6%, lab results suggested adherence high enough to provide protection from HIV, and 22% took their pills at least six times a week. Between the two arms, 54.3% of all participants used the medication sufficiently to be protected from HIV.

One person acquired HIV during the study. Dr. Nair did not say which study arm that participant was in or how adherent that person has been to their prevention method.

That level of adherence is on par with studies in the United States, which have found 56% adherence to PrEP among adolescent and young men who have sex with men. But the level of adherence is far higher than has been found in other studies that tested oral PrEP among women who did not have a partner with HIV. In particular, the VOICE and FEM-PrEP trials were both stopped early for lack of adherence. In those placebo-controlled oral-PrEP trials, fewer than 25% of participants used the oral prevention pills. Although adherence to the vaginal ring was estimated to be 61% for women older than 25 in the ASPIRE trial, it was effectively zero among women aged 18 to 21 years. Adherence has been the “bugaboo of efficacy for PrEP in young women,” said Judith Auerbach, PhD, independent science and policy consultant and professor of medicine at the University of California, San Francisco. But health care professionals have a long way to go to support young people in general in using PrEP.

“Yes, this shows improvement compared to previous studies,” Dr. Auerbach told this news organization. “But is it sufficient to have an epidemiological impact at the population level?”

Medical Advocacy and Outreach (MAO) is an HIV clinic and services program in Montgomery, Alabama, that offers a clinic specifically for some of their 144 clients to receive oral PrEP. In addition to in-person testing, MAO offers home HIV testing and lab work and televisits to support the college students they serve in taking PrEP whether they’re at school or at home on break. Currently, MAO provides a series of support groups and other social support programs for their clients living with HIV, but there are none for those receiving PrEP. The organization is in the process of hiring a social worker for the PrEP side of the clinic.

Until that person is on board, “I’m their support system in an unofficial capacity,” Shericka Williams, MPH, told this news organization. She runs education programs at MAO and handles all the phone calls from PrEP clients. “My title changes a lot, but the one I like to go with most often is the PrEP navigator,” she said.

She said she was intrigued by the dapivirine ring and oral PrEP data but said that currently, the women they serve are still learning that PrEP is for them, too. The women report that all the ads and all the information they receive is aimed at gay or bisexual men or transgender women. It takes a while for them to recognize that they could benefit, so a lot of the work that Ms. Williams does is focused on explaining the benefit of PrEP.

In MAO, the number of women receiving PrEP fluctuates more than for men. Mostly, women start PrEP because of they are in a relationship with someone who receives HIV care from MAO’s other wing – women who potentially would experience less vulnerability to HIV if their partners had undetectable viral loads. The other reason women take it is because they suspect that their partner is cheating or because they are in abusive relationships in which they want their partner to use a condom but the partner won’t. As in the PrEP trials, they often see women discontinue PrEP when they leave those relationships. In part, her job is to educate women regarding all the ways PrEP could serve them.

“Most of the time, they’re just no longer in that relationship, and they’re just taking some time for themselves,” she said in an interview. “We definitely try to bring up other reasons to stay on PrEP, but we don’t want to seem like we’re bullying someone to stay on it.”

Dr. Nair, Dr. Auerbach, and Ms. Williams report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the first time, an HIV prevention trial that was limited to adolescent girls and young women found that, given sufficient support, girls will use either daily oral pre-exposure prophylaxis (PrEP) or the vaginal dapivirine ring to protect themselves from HIV.

The secret, said Gonasagrie Nair, MBChB, faculty of medicine and health sciences at Stellenbosch University, Zimbabwe, is offering intensive wraparound services to support teenagers – a lesson that may be useful as adolescent and family medicine professionals in the United States begin to roll out HIV prevention in their clinics.

This is important in the United States because cisgender Black women make up 60% of all new HIV cases in the United States while accounting for just 14% of the overall U.S. population. The Centers for Disease Control and Prevention has found that only about 1% of Black Americans who could benefit from PrEP have access to it.

“Younger women and adolescent girls in particular face a number of cultural and social challenges that impact their ability to make decisions related to their own health,” said Dr. Nair, who presented the data at the International AIDS Society (IAS) Conference 2021. “The adherence support provided by this study empowered them to make choices and stick to these choices,” she said.

In total, 247 women and girls aged 16 to 21 who were without HIV were enrolled in the Reversing the Epidemic in Africa with Choices in HIV Prevention (REACH) trial in two sites in South Africa and one each in Uganda and Zimbabwe beginning in February 2019. One-third of the participants were minors; the average age was 18.2 years.

The women were good candidates for PrEP. More than 1 in 3 of the women started the study with a sexually transmitted infection (STI), the most prevalent of which was chlamydia. This is often a good marker for condomless sex. Of the participants, 89% had a primary sex partner; a quarter of those thought their partner was having sex with other people. Only 7% of participants reported being very worried about acquiring HIV. More than 1 in 3 (39%) weren’t worried about HIV at all. This conforms to previous data suggesting that those who could most benefit from PrEP often don’t perceive their own vulnerability.

In the study, the women were randomly assigned two groups. In one group, the participants used the dapivirine ring for 6 months; in the other, participants used oral PrEP for 6 months. The participants then swapped prevention methods and used the alternative method for 6 more months. After a year of trying both methods, the women will be asked to choose one of the two prevention method or to stop PrEP altogether. At the IAS conference, the researchers reported interim data from the first year of the study, before the girls had the opportunity to choose for themselves.

During that first year, girls received intensive adherence support, including daily or weekly text check-ins, phone check-ins, peer buddy support, additional onsite counseling visits, access to adherence support groups, participation in online support groups via apps such as WhatsApp, and in-person social events designed to empower young women and to teach them skills. Support included discussion of adherence, contraceptives, and STIs. In addition, when girls came in for study visits, staff provided feedback on how adherent the girls had been, as determined on the basis of residual levels of dapivirine in the rings or, with regard to oral pills, drug levels as determined with blood spots.

Girls were considered to have had high adherence if they were found to have oral PrEP concentrations equivalent to four or more doses per week or if residual levels of dapivirine in their rings were 0.1071 mg/d. Moderate adherence was the equivalent of one to three doses of oral PrEP a week or dapivirine levels between 0.0321 mg/d and 0.1071 mg/d.

In total, 95.6% of ring users showed some adherence to the ring. Of those, adherence was high for 50.2%; 49.8% used the ring perfectly. For oral PrEP, 98.5% showed some level of PrEP use; for 58.6%, lab results suggested adherence high enough to provide protection from HIV, and 22% took their pills at least six times a week. Between the two arms, 54.3% of all participants used the medication sufficiently to be protected from HIV.

One person acquired HIV during the study. Dr. Nair did not say which study arm that participant was in or how adherent that person has been to their prevention method.

That level of adherence is on par with studies in the United States, which have found 56% adherence to PrEP among adolescent and young men who have sex with men. But the level of adherence is far higher than has been found in other studies that tested oral PrEP among women who did not have a partner with HIV. In particular, the VOICE and FEM-PrEP trials were both stopped early for lack of adherence. In those placebo-controlled oral-PrEP trials, fewer than 25% of participants used the oral prevention pills. Although adherence to the vaginal ring was estimated to be 61% for women older than 25 in the ASPIRE trial, it was effectively zero among women aged 18 to 21 years. Adherence has been the “bugaboo of efficacy for PrEP in young women,” said Judith Auerbach, PhD, independent science and policy consultant and professor of medicine at the University of California, San Francisco. But health care professionals have a long way to go to support young people in general in using PrEP.

“Yes, this shows improvement compared to previous studies,” Dr. Auerbach told this news organization. “But is it sufficient to have an epidemiological impact at the population level?”

Medical Advocacy and Outreach (MAO) is an HIV clinic and services program in Montgomery, Alabama, that offers a clinic specifically for some of their 144 clients to receive oral PrEP. In addition to in-person testing, MAO offers home HIV testing and lab work and televisits to support the college students they serve in taking PrEP whether they’re at school or at home on break. Currently, MAO provides a series of support groups and other social support programs for their clients living with HIV, but there are none for those receiving PrEP. The organization is in the process of hiring a social worker for the PrEP side of the clinic.

Until that person is on board, “I’m their support system in an unofficial capacity,” Shericka Williams, MPH, told this news organization. She runs education programs at MAO and handles all the phone calls from PrEP clients. “My title changes a lot, but the one I like to go with most often is the PrEP navigator,” she said.

She said she was intrigued by the dapivirine ring and oral PrEP data but said that currently, the women they serve are still learning that PrEP is for them, too. The women report that all the ads and all the information they receive is aimed at gay or bisexual men or transgender women. It takes a while for them to recognize that they could benefit, so a lot of the work that Ms. Williams does is focused on explaining the benefit of PrEP.

In MAO, the number of women receiving PrEP fluctuates more than for men. Mostly, women start PrEP because of they are in a relationship with someone who receives HIV care from MAO’s other wing – women who potentially would experience less vulnerability to HIV if their partners had undetectable viral loads. The other reason women take it is because they suspect that their partner is cheating or because they are in abusive relationships in which they want their partner to use a condom but the partner won’t. As in the PrEP trials, they often see women discontinue PrEP when they leave those relationships. In part, her job is to educate women regarding all the ways PrEP could serve them.

“Most of the time, they’re just no longer in that relationship, and they’re just taking some time for themselves,” she said in an interview. “We definitely try to bring up other reasons to stay on PrEP, but we don’t want to seem like we’re bullying someone to stay on it.”

Dr. Nair, Dr. Auerbach, and Ms. Williams report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For the first time, an HIV prevention trial that was limited to adolescent girls and young women found that, given sufficient support, girls will use either daily oral pre-exposure prophylaxis (PrEP) or the vaginal dapivirine ring to protect themselves from HIV.

The secret, said Gonasagrie Nair, MBChB, faculty of medicine and health sciences at Stellenbosch University, Zimbabwe, is offering intensive wraparound services to support teenagers – a lesson that may be useful as adolescent and family medicine professionals in the United States begin to roll out HIV prevention in their clinics.

This is important in the United States because cisgender Black women make up 60% of all new HIV cases in the United States while accounting for just 14% of the overall U.S. population. The Centers for Disease Control and Prevention has found that only about 1% of Black Americans who could benefit from PrEP have access to it.

“Younger women and adolescent girls in particular face a number of cultural and social challenges that impact their ability to make decisions related to their own health,” said Dr. Nair, who presented the data at the International AIDS Society (IAS) Conference 2021. “The adherence support provided by this study empowered them to make choices and stick to these choices,” she said.

In total, 247 women and girls aged 16 to 21 who were without HIV were enrolled in the Reversing the Epidemic in Africa with Choices in HIV Prevention (REACH) trial in two sites in South Africa and one each in Uganda and Zimbabwe beginning in February 2019. One-third of the participants were minors; the average age was 18.2 years.

The women were good candidates for PrEP. More than 1 in 3 of the women started the study with a sexually transmitted infection (STI), the most prevalent of which was chlamydia. This is often a good marker for condomless sex. Of the participants, 89% had a primary sex partner; a quarter of those thought their partner was having sex with other people. Only 7% of participants reported being very worried about acquiring HIV. More than 1 in 3 (39%) weren’t worried about HIV at all. This conforms to previous data suggesting that those who could most benefit from PrEP often don’t perceive their own vulnerability.

In the study, the women were randomly assigned two groups. In one group, the participants used the dapivirine ring for 6 months; in the other, participants used oral PrEP for 6 months. The participants then swapped prevention methods and used the alternative method for 6 more months. After a year of trying both methods, the women will be asked to choose one of the two prevention method or to stop PrEP altogether. At the IAS conference, the researchers reported interim data from the first year of the study, before the girls had the opportunity to choose for themselves.

During that first year, girls received intensive adherence support, including daily or weekly text check-ins, phone check-ins, peer buddy support, additional onsite counseling visits, access to adherence support groups, participation in online support groups via apps such as WhatsApp, and in-person social events designed to empower young women and to teach them skills. Support included discussion of adherence, contraceptives, and STIs. In addition, when girls came in for study visits, staff provided feedback on how adherent the girls had been, as determined on the basis of residual levels of dapivirine in the rings or, with regard to oral pills, drug levels as determined with blood spots.

Girls were considered to have had high adherence if they were found to have oral PrEP concentrations equivalent to four or more doses per week or if residual levels of dapivirine in their rings were 0.1071 mg/d. Moderate adherence was the equivalent of one to three doses of oral PrEP a week or dapivirine levels between 0.0321 mg/d and 0.1071 mg/d.

In total, 95.6% of ring users showed some adherence to the ring. Of those, adherence was high for 50.2%; 49.8% used the ring perfectly. For oral PrEP, 98.5% showed some level of PrEP use; for 58.6%, lab results suggested adherence high enough to provide protection from HIV, and 22% took their pills at least six times a week. Between the two arms, 54.3% of all participants used the medication sufficiently to be protected from HIV.

One person acquired HIV during the study. Dr. Nair did not say which study arm that participant was in or how adherent that person has been to their prevention method.

That level of adherence is on par with studies in the United States, which have found 56% adherence to PrEP among adolescent and young men who have sex with men. But the level of adherence is far higher than has been found in other studies that tested oral PrEP among women who did not have a partner with HIV. In particular, the VOICE and FEM-PrEP trials were both stopped early for lack of adherence. In those placebo-controlled oral-PrEP trials, fewer than 25% of participants used the oral prevention pills. Although adherence to the vaginal ring was estimated to be 61% for women older than 25 in the ASPIRE trial, it was effectively zero among women aged 18 to 21 years. Adherence has been the “bugaboo of efficacy for PrEP in young women,” said Judith Auerbach, PhD, independent science and policy consultant and professor of medicine at the University of California, San Francisco. But health care professionals have a long way to go to support young people in general in using PrEP.

“Yes, this shows improvement compared to previous studies,” Dr. Auerbach told this news organization. “But is it sufficient to have an epidemiological impact at the population level?”

Medical Advocacy and Outreach (MAO) is an HIV clinic and services program in Montgomery, Alabama, that offers a clinic specifically for some of their 144 clients to receive oral PrEP. In addition to in-person testing, MAO offers home HIV testing and lab work and televisits to support the college students they serve in taking PrEP whether they’re at school or at home on break. Currently, MAO provides a series of support groups and other social support programs for their clients living with HIV, but there are none for those receiving PrEP. The organization is in the process of hiring a social worker for the PrEP side of the clinic.

Until that person is on board, “I’m their support system in an unofficial capacity,” Shericka Williams, MPH, told this news organization. She runs education programs at MAO and handles all the phone calls from PrEP clients. “My title changes a lot, but the one I like to go with most often is the PrEP navigator,” she said.

She said she was intrigued by the dapivirine ring and oral PrEP data but said that currently, the women they serve are still learning that PrEP is for them, too. The women report that all the ads and all the information they receive is aimed at gay or bisexual men or transgender women. It takes a while for them to recognize that they could benefit, so a lot of the work that Ms. Williams does is focused on explaining the benefit of PrEP.

In MAO, the number of women receiving PrEP fluctuates more than for men. Mostly, women start PrEP because of they are in a relationship with someone who receives HIV care from MAO’s other wing – women who potentially would experience less vulnerability to HIV if their partners had undetectable viral loads. The other reason women take it is because they suspect that their partner is cheating or because they are in abusive relationships in which they want their partner to use a condom but the partner won’t. As in the PrEP trials, they often see women discontinue PrEP when they leave those relationships. In part, her job is to educate women regarding all the ways PrEP could serve them.

“Most of the time, they’re just no longer in that relationship, and they’re just taking some time for themselves,” she said in an interview. “We definitely try to bring up other reasons to stay on PrEP, but we don’t want to seem like we’re bullying someone to stay on it.”

Dr. Nair, Dr. Auerbach, and Ms. Williams report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.

A two-drug fixed-dose tablet therapy of dolutegravir/lamivudine (Dovato, ViiV Healthcare; DTG/3TC) shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral (ART) regimens. But, DTG/3TC also shows feasibility as a first-line regimen in a test-and-treat setting, according to two studies presented at the virtual meeting of the International AIDS Society.

The results on the switch to DTG/3TC are from the phase 3 SALSA trial, which compared patients with HIV-1 who either remained on any current three- or four-drug ART regimen or who switched to the two-drug dolutegravir option.

For the primary endpoint, rates of virologic failure at 48 weeks were noninferior in the DTG/3TC group versus the three- or four-drug regimen (.4% vs. 1.2; adjusted difference: –.8% [95% confidence interval, –2.4%, .8%]).

In addition, rates of virologic suppression at week 48 were noninferior, with 94.3% of patients achieving HIV-1 RNA < 50 c/mL in the DTG/3TC group versus 92.7% in the three- or four-drug regimen (adjusted difference: 1.6% [95% CI, –2.8%, 5.9%).

“These data build upon the previous TANGO study and support DTG/3TC as a robust switch option with high levels of efficacy, good safety and tolerability, and a high barrier of resistance,” first author Josep M. Llibre, MD, PhD, consultant, infectious diseases department, Germans Trias i Pujol University Hospital, Barcelona, said in presenting the findings.

The two-drug dolutegravir-based regimen had previously been shown in the phase 3 GEMINI-1 and GEMINI-2 trials to have virologic noninferiority and safety compared with three- or four-drug DTG plus tenofovir/emtricitabine (TDF/FTC) ART regimens in treatment-naive individuals, and, in the subsequent TANGO trial, the regimen was also noninferior versus tenofovir alafenamide–based regimens among treatment-experienced patients, at 144 weeks in both studies.


 

Trial details

The new SALSA trial, designed to broaden the comparison to treatment with any current three- or four-drug ART regimen, involved 493 patients at 120 study sites in 17 countries.

All patients were initially on a three- or four-drug regimen, with HIV-1 RNA of less than 50 c/mL for more than 6 months, and without prior virologic failure or nucleoside reverse transcriptase inhibitors or dolutegravir resistance-associated mutations.

The participants were randomized 1:1 to remain on their current regimen (n = 247) or to switch to the once-daily, fixed-dose tablet two-drug combination of dolutegravir 50 mg/lamivudine 300 mg (n = 246) for 52 weeks.

In addition to the noninferior virologic outcomes, there were no serious drug-related adverse events, no confirmed virologic withdrawals, and no resistance mutations in either group.

Of note, weight increase was higher in the DTG/3TC group (8%; n = 20) versus the current ART arm (2%; n = 5), as has been observed in previous studies. The adjusted mean change in weight from baseline to week 48 in the DTG arm was 2.1 kg versus 0.6 kg in the current ART arm.

Dr. Llibre pointed out that many of the participants who switched were discontinuing regimens such as TDF and efavirenz that are associated with weight loss, “so discontinuation could be more related to weight gain than the introduction of dolutegravir, but this deserves further study,” he noted.

There were no significant differences in changes in eGFR and fasting lipids, or in changes in inflammatory biomarkers between the groups.

Bone and renal biomarkers were more favorable in the dolutegravir two-drug arm, suggesting that bone and renal function was either maintained or even improved with the drug switch, Dr. Llibre noted.

STAT trial: Feasibility of two-drug DTG/3TC as first-line treatment

In further findings presented at the meeting on the STAT trial, researchers evaluated the feasibility not of switching to, but of initiating patients on, the two-drug DTG treatment as a first-line therapy, within 14 days of HIV-1 diagnosis.

The “test-and-treat” approach counters common belief that the regimen should be started only after the traditional three-drug regimens, because of the potential of transmitted resistance and baseline hepatitis B virus coinfection.

In the study of 131 patients, at week 48, 82% (107/131) of all participants and 97% (107/110) of those with available data achieved HIV-1 RNA levels of < 50 c/mL.

While two participants had confirmed virologic failure in the study, there were no treatment-emergent resistance-associated mutations, and neither patient discontinued the two-drug DTG treatment. There were low rates of drug-related adverse events (8%) and they were not serious.