User login
Injectable HIV prevention better than pills in two trials
MONTREAL – , according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.
Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.
“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”
The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.
In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).
Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.
CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”
“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).
Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”
She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”
The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – , according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.
Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.
“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”
The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.
In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).
Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.
CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”
“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).
Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”
She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”
The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – , according to new data from two HIV Prevention Trials Network (HPTN) studies reported at the International AIDS Society Conference.
Follow-up data from the HPTN 084 trial, which compared the two regimens in 3,224 sub-Saharan persons who were assigned female sex at birth, show that three new HIV infections occurred in the CAB LA group in the 12 months since the study was unblinded, versus 20 new infections among the TDF-FTC group. That translates to an 89% lower risk of infection in the CAB LA arm across both the blinded and unblinded phases of the trial, said lead investigator Sinead Delany-Moretlwe, MD, PhD, director of research, Wits Reproductive Health and HIV Institute, the University of the Witwatersrand, Johannesburg, South Africa, during a press conference.
“The trial was designed with the assumption that both drugs were highly effective in preventing HIV infection but that, given the challenges with taking a pill a day, that injectable cabotegravir may offer an adherence advantage,” she said in an interview. “Our data appear to confirm this, as most of the participants in the TDF-FTC arm who became infected with HIV had evidence of poor or inconsistent use of PrEP.”
The study also found that pregnancy incidence increased “two- to threefold” between the blinded and the unblinded period, “and this emphasizes to us the desire of women to conceive safely, without the threat of HIV, and the importance of us continuing to evaluate the safety and pharmacology of cabotegravir in pregnant and breastfeeding women during open-label extension phase of HPTN 084, so that [they] are not excluded from access to this highly effective PrEP agent,” she said. To date, no congenital anomalies have been reported in babies born during the study.
In an update report from HPTN 083, which also showed superiority of CAB LA over TDF-FTC in cisgender men and transgender women (TGW), researchers reported the safety and efficacy of CAB LA use in TGW using gender-affirming hormone therapy (GAHT).
Among the 4,566 participants in HPTN 083, 570 were TGW, and of those, 58% used GAHT at baseline, reported Beatriz Grinsztejn, MD, PhD, head of the STD/AIDS Clinical Research Laboratory at the Instituto Nacional de Infectologicia/Fundação Oswaldo Cruz.
CAB LA drug concentrations measured in a subset of 53 TGW who received on-time CAB injections were comparable between those taking (n = 30) and those not taking GAHT (n = 23), “suggesting the lack of a gender-affirming hormone effect on CAB pharmacokinetics,” she said. “These are very promising results, as we all know that the use of gender-affirming hormone therapy is a major priority for our transgender women community, ... so the lack of drug-drug interaction is really a very important result.”
“Cabotegravir long-acting PrEP is now approved for all at-risk populations, including men who have sex with men, transgender women, and cisgender women, after the results of HPTN 083 and 084,” commented Monica Gandhi, MD, MPH, an infectious disease physician, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco (UCSF).
Dr. Gandhi, who was not involved in either study, is also director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “The incredible efficacy of long-acting PrEP for cisgender women shown by HPTN 084 is game-changing for our practice, and we have already instituted CAB LA across a range of populations at Ward 86,” she said in an interview. “The durability of the 89% additional efficacy of CAB LA over oral TDF/FTC is thrilling and will lead to a greater use of long-acting options.”
She acknowledged that information on potential interactions of GAHT was needed from the HPTN 083 trial. “That cabotegravir levels did not change with the use of estradiol or spironolactone for gender-affirming therapy is important news for our practice and to reassure our TGW that they can safely and effectively use CAB LA for HIV prevention.”
The HPTN 084 and 083 trials were funded by the National Institutes for Allergy and Infectious Diseases. Dr. Delany-Moretlwe, Dr. Grinsztejn, and Dr. Gandhi have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AIDS 2022
Landmark ALLIANCE results offer tenofovir guidance in HIV/HBV coinfection
MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.
, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.
The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.
For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).
No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.
“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”
“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question.
“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.
The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.
A version of this article first appeared on Medscape.com.
MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.
, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.
The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.
For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).
No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.
“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”
“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question.
“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.
The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.
A version of this article first appeared on Medscape.com.
MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.
, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.
The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.
For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).
No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.
“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”
“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question.
“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.
The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.
A version of this article first appeared on Medscape.com.
AT AIDS 2022
Doxycycline cuts STI risk in men and trans women having sex with men
MONTREAL – (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.
“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).
The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.
The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).
“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”
Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”
Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.
For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.
“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.
Calling the doxyPEP regimen a “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”
“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.
“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”
The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.
Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.
“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).
The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.
The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).
“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”
Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”
Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.
For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.
“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.
Calling the doxyPEP regimen a “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”
“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.
“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”
The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.
Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – (PrEP). The results of the open-label DoxyPEP trial were reported at a press conference at a meeting of the International AIDS Society.
“It is time to take action on the data that we have and really think about incorporating it into guidelines and rolling this out in a safe and thoughtful way,” said co-principal investigator Annie Luetkemeyer, MD, of Zuckerberg San Francisco General Hospital, and professor of medicine at the University of California, San Francisco (UCSF).
The open-label trial, conducted in Seattle and San Francisco, randomized MSM/TGW living with HIV or on PrEP, and with a history of N. gonorrhoeae (GC), C. trachomatis (CT), or early syphilis in the past year, to either doxycycline or none within 72 hours of having condomless sex. It was stopped early in May when a planned interim analysis showed those randomized to take doxycycline had substantially fewer STIs than participants assigned to the control group.
The intent-to-treat analysis included 501 patients with at least one quarter of follow-up: 327 taking PrEP and 174 living with HIV. Among those taking PrEP, new STIs (GC, CT or syphilis) occurred in 31.9% of control participants vs. 10.7% of those taking doxycycline – a reduction of 66% per quarter (P < .001). Among participants living with HIV, new STIs occurred in 30.5% of controls vs. 11.8% taking doxycycline, for a 62% reduction in STIs per quarter (P < .0001).
“Participants reported taking doxycycline 87% of the time after having condomless sex, about half of participants took fewer than 10 doses per month, 30% took 10-20 doses per month, and 16% took more than 20 doses of doxycycline per month,” said Dr. Luetkemeyer, adding that there were no serious – grade 2 or greater – adverse events, and “the majority of participants reported that taking doxy was acceptable or very acceptable.”
Asked how broadly doxycycline prophylaxis could be used in other populations, Dr. Luetkemeyer was cautious. “Our study participants had a very high rate of new STIs – a 30% incidence per quarter and using doxyPEP was well tolerated and very effective to reduce new STIs. However, this is a fairly limited population,” she said. “Whether doxyPEP should be considered for other groups, such as women on PrEP or with an elevated risk for STIs, will need more data which will be forthcoming from ongoing studies.”
Dr. Luetkemeyer said her group is looking at three possible risks of antibiotic resistance with the doxyPEP regimen: the risk to bystander bacteria such as Staphylococcus aureus or commensal neisseria; the impact on the gut; and the risk of resistance to antibiotic treatments for STI.
For the latter, “we don’t really think this is going to be an issue in chlamydia and syphilis, and we’re looking carefully at gonorrhea,” she said, adding that it will be challenging to get definitive data from this particular study because of its short follow-up.
“Available culture data from those who had gonorrhea infections during the study demonstrated a relatively low rate of tetracycline resistance, which is a proxy for doxycycline resistance, at 20%. ... However, larger studies and population-based surveillance of those taking doxycycline as PEP are needed to understand if doxycycline use could drive the element of tetracycline resistance in gonorrhea,” she said, emphasizing that doxycycline is not used to treat active gonorrhea infections.
Calling the doxyPEP regimen a “game-changing strategy,” Sharon Lewin, AO, PhD, president-elect of the International AIDS Society, said many physicians are already prescribing it off label based on the IPERGAY study (N Engl J Med. 2015; 373:2237-46) “but there’s a clear need for more evidence to guide the use of this intervention.”
“This study has huge implications for clinical care,” said Monica Gandhi, MD, MPH, an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at UCSF. “Although the data on drug resistance is very important to evaluate, we should certainly consider at this point using doxycycline PEP within 72 hours of condomless sex for our patients for STI prevention,” she said in an interview.
“In our practice, we are very excited about the possibility of a simple one-pill postexposure prophylactic agent (doxycycline 200 mg) to reduce the risk of a number of STIs. We have used PEP for HIV infection for a number of years and are very familiar with the concept of preventing infections after an exposure,” said Dr. Gandhi, director of the UCSF Center for AIDS Research and medical director of the HIV Clinic (“Ward 86”) at San Francisco General Hospital. “We are planning to institute doxycycline as PEP at my clinic after the release of these findings and will follow the remainder of the study findings closely.”
The trial was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, through grant R01AI143439. It was conducted at the HIV clinic at Zuckerberg San Francisco General Hospital and the San Francisco City Clinic, both part of the San Francisco Department of Public Health, and the Madison Clinic and the Sexual Health Clinic at Harborview Medical Center, both at the University of Washington. Medications were provided by Mayne Pharmaceuticals, and lab support by Hologic & Cepheid.
Dr. Lewin has the following disclosures: investigator-initiated, industry-funded research for Gilead, Viiv, Merck; scientific advisory board (honoraria paid to her personally) for Gilead, Merck, Viiv, Esfam, Immunocore, Vaxxinity; collaborative research (nonfunded) for AbbVie, Genentech, BMS. Dr. Luetkemeyer and Dr. Gandhi reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AIDS 2022
Prolonged remission in patient with HIV may open new avenues to functional cure
MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.
Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) –
“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”
The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”
In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.
“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”
Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”
Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).
A version of this article first appeared on Medscape.com.
MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.
Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) –
“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”
The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”
In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.
“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”
Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”
Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).
A version of this article first appeared on Medscape.com.
MONTREAL – The case of a patient in an HIV study whose viral load dropped to undetectable levels and whose immune cells soared has captured the attention of organizers at a meeting of the International AIDS Society.
Although the 59-year-old woman is one of many who are known as posttreatment controllers (PTCs) – having been in remission for more than 15 years after stopping antiretroviral therapy (ART) –
“This case opens new avenues in the HIV functional-cure field,” lead investigator Núria Climent, PhD, of the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
“As far as we know, this is the first time that the gamma-delta T cells have been identified in a PTC, and concerning the memory-like NK cells, there are very few published data and only sparse information presented in several congresses,” she said, explaining that these cells “have a high capacity to inhibit the replication of the virus in vitro. For that reason, we think that this PTC has cells able to dramatically reduce the virus amount. We think that the potential capacity to increase these cells in this PTC woman could be not only mediated by especial genetic factors ... but also mediated by early ART treatment and might be by the immunomediated treatment.”
The findings suggest the potential for “increasing the amount of those memory-like NK cells and gamma-delta T cells in order to translate this potent antiviral activity in new therapies to achieve an HIV functional cure,” she said, adding: “As far as we know, aiming to increase these specific cells has never been done before in people living with HIV.”
In a press conference during the meeting, Dr. Climent explained that the patient was enrolled in a study in which she received a combination of ART and immunomodulatory therapy. This involved a combination of cyclosporine A, low-dose interleukin 2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa-2b.
“None of the other 19 patients included in the trial controlled viral replication,” senior investigator Jose Miro, MD, PhD, also from the HIV unit at Hospital Clinic-IDIBAPS/University of Barcelona, told this news organization.
Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the conference, said in an interview that although the significance of the case is unclear, the IAS selected it as a highlight for the meeting. “It is important for clinicians to understand the complexities in interpreting these case reports. Their patients are probably likely to ask them about the report, and it’s important [that] they can explain it to them.”
Dr. Lewin, who is professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity in Melbourne, added that it is impossible to determine the mechanism of action from a single case report. “We don’t know if the intervention played a role or if this person is a ‘posttreatment controller,’ which has been previously described many times,” she said in an interview. “In this patient, the virus is at very low, but controlled, levels, and virus could be grown out. While it’s still exciting and important, this is really what we would consider a remission. The intense study of a single case such as this is certainly worthwhile and important but can only provide new ideas for research. So, I don’t think we can draw any conclusion on the role of NK cells, et cetera. We need much larger case series or controlled trials to reach any conclusion on the reasons for her remission.”
Dr. Climent disclosed no relevant financial conflicts of interest. Dr. Lewin has disclosed investigator-initiated industry-funded research (Gilead, ViiV, Merck), scientific advisory board honoraria paid to her personally (Gilead, Merck, ViiV, Esfam, Immunocore, Vaxxinity), and nonfunded collaborative research (AbbVie, Genentech, Bristol-Myers Squibb).
A version of this article first appeared on Medscape.com.
AT AIDS 2022
Fourth patient cleared of HIV after stem cell transplant for blood cancer
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
MONTREAL – from a naturally HIV-resistant donor, U.S. researchers announced at a meeting of the International AIDS Society.
The man received the transplant nearly 3.5 years ago. Since discontinuation of antiretroviral therapy (ART) more than 17 months ago, he has shown no evidence of HIV-1 RNA rebound and no detectable HIV-1 DNA, reported lead investigator Jana K. Dickter, MD, associate clinical professor in the division of infectious diseases at City of Hope, a Duarte, Calif.–based stem cell transplantation center for patients with blood cancers and patients with HIV/blood cancer.
Known as the City of Hope (COH) patient, he is different from the three previously reported patients in that “he was the oldest person to successfully undergo a stem cell transplant with HIV and leukemia and then achieve remission from both conditions,” Dr. Dickter said during a press briefing for the meeting. “He has been living with HIV the longest of any of the patients to date – more than 31 years prior to transplant – and he had also received the least immunosuppressive preparative regimen prior to transplant,” she added.
She said that, like the three previous patients, known as the Berlin, London, and New York patients, the COH patient received a transplant from a donor with natural resistance to HIV because of a rare CCR5-delta 32 mutation.
Dr. Dickter and her coinvestigators used the term “remission” but went further, suggesting that an “HIV cure is feasible” after transplant, given this and the previous cases.
“It’s a bit early to say the patient is cured, but they are clearly in remission,” said Sharon Lewin, MD, president-elect of the International AIDS Society, which runs the meeting. Nevertheless, Dr. Lewin, professor of medicine at the University of Melbourne and director of the Peter Doherty Institute for Infection and Immunity, in Melbourne, acknowledged that cure is “very likely.”
“Two of the previously reported patients have been off ART for long periods of time – Berlin, 12 years (until Timothy’s death in 2020); London, 4 years – and both had far more extensive investigations to try and find intact virus, including very large blood draws, tissue biopsies, etc. For the New York and now this COH patient, the duration off ART has been much shorter. ... But given the prior cases, it is very likely that the New York and COH patients are indeed cured. But I think it’s too early to make that call, hence my preference to use the word, ‘remission,’ “ she told this news organization.
“Although a transplant is not an option for most people with HIV, these cases are still interesting, still inspiring, and help illuminate the search for a cure,” she added.
Dr. Dickter acknowledged that the complexity of stem cell transplant procedures and their potential for significant side effects make them unsuitable as treatment options for most people with HIV, although she said the COH case is evidence that some HIV patients with blood cancers may not need such intensive pretransplant conditioning regimens.
The COH patient received a reduced-intensity fludarabine and melphalan regimen that had been designed at Dr. Dickter’s center “for older and less fit patients to make transplantation more tolerable,” she said. In addition, the graft-vs.-host disease prophylaxis that the COH patient received included only tacrolimus and sirolimus, whereas the previous patients received additional immunosuppressive therapies, and some also had undergone total body irradiation.
Dr. Dickter has disclosed no relevant financial relationships. Dr. Lewin has relationships with AbbVie, BMS, Esfam, Genentech, Gilead, Immunocore, Merck, Vaxxinity, and Viiv.
A version of this article first appeared on Medscape.com.
AT AIDS 2022
CAR T-cell therapy turns 10 and finally earns the word ‘cure’
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Tofersen linked to slow, positive effects in ALS
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
caused by superoxide dismutase 1 (SOD1) gene mutations.
The 1-year results, presented at the European Network for the Cure of Amyotrophic Lateral Sclerosis (ENCALS) 2022 meeting, show a deceleration in functional decline that is similar, but “more pronounced” than the previously reported 6-month results, which were not statistically significant, said lead investigator Timothy Miller, MD, PhD, professor of neurology and director of the ALS Center, Washington University, St. Louis.
“What I thought we saw in the first data cut is confirmed by what we saw in the longer data,” he said in an interview. “There were trends [showing] those treated with tofersen did a bit better, but it was hard to be sure. It was hard to be confident in what we were seeing at that early time point.”
Now, with 6 more months of data, Dr. Miller says he is confident that tofersen is slowing down the neurodegenerative disease process. “I see results that I’m encouraged by,” he said. “As a clinician who treats people with ALS with this mutation I would want this drug to be available to people that I see in my clinic.”
One-year VALOR study results
The primary efficacy objective of the VALOR study was to show the 28-week impact of 100 mg tofersen (three doses given about 2 weeks apart, then five doses given every 4 weeks), versus placebo, on function, measured on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R). The open-label extension switched placebo-treated patients to tofersen (delayed-start group) and continued to compare them with the early-start group up to 1 year. This open-label extension phase included 49 patients who had been on early-start tofersen and 18 patients in the delayed-start group.
For the primary endpoint, change from baseline in 48-point ALSFRS-R score, there was a statistically significant benefit for the early-start patients with these patients scoring 3.5 points higher than the delayed-start group (P = .0272, 95% confidence interval [CI], 0.4-6.7). This means that both groups declined in function, which is expected in ALS, but the early-start group declined more slowly.
There was also a benefit associated with early-start tofersen for a number of secondary endpoints, including change from baseline in total SOD1 cerebrospinal fluid concentration (CSF SOD1), plasma neurofilament light chain (NfL) levels, and respiratory function.
“This drug targets the MRNA of SOD1, so it lowers the MRNA and then the SOD1 protein falls,” explained Dr. Miller, adding that these levels dropped 21% in the delayed start group, and 33% in the early-start group. “I think the data pretty clearly show that [tofersen] does what it is supposed to do, and that is the first step.”
Neurofilament light chain, a marker of neurodegeneration, also dropped by 41% in the delayed-start group, and 51% in the early-start group.
Respiratory function, as measured by percent predicted slow vital capacity (SVC), also declined 9.2% more slowly in the early- versus delayed-start group (P = .0159).
Finally, muscle strength, as measured by handheld dynamometry (HHD) score, declined more slowly in the early-start group compared with the late-start group, with an adjusted mean difference in score of 2.8 (P = 0.0186).
Dr. Miller said that the data show that it takes time for tofersen to impact clinical function, but there are signs of benefit before that. “I think what you see is that just starting on the drug, the first thing that happens is SOD1 goes down, the next thing is that neurofilament decreases, but clinical function is not yet changing. It takes time. What I see in these data is that it takes time for us to see that effect on clinical function.”
The bigger picture
While acknowledging that tofersen acts on a genetic mutation found in only about 2% of ALS, Dr. Miller said the study findings carry significance for the wider ALS patient population.
“Assuming we agree there is a clinical effect here, assuming we agree that there is real stabilization of clinical function, I think if we agree on that point then we know that ALS is now a treatable disorder. And that’s a really important point. I’m not sure that we knew that before,” he said. “Yes, there are FDA-approved medications that slow down ALS a bit, but they don’t stabilize it, and if we get the target correct – and we have the correct genetic target here – there can be a substantial influence on slowing down the disease, so that’s one thing to learn for the whole ALS community.”
What lies ahead?
Asked to comment on the study, Richard Bedlack, MD, PhD, who was not involved in the research, said the findings are important and show “clinically meaningful” results. “Based on the new benefit-to-burden ratio, I believe most of my patients with SOD1 mutations will want to try this drug. I would like to be able to offer it to them. But I am curious to see what the FDA will do with these data,” said Dr. Bedlack, professor of neurology at Duke University in Durham, N.C., and director of the Duke ALS Clinic.
“Sometimes that open-label extension gives us time to see differences between patients who initially got drug and those who initially got placebo. That seems to be the case with tofersen here, and it was also the case with AMX0035 [Amylyx Pharmaceuticals Inc.], which did not show a survival benefit in the first 6 months but did in the open-label extension.” A recent FDA advisory board panel concluded there was insufficient evidence of benefit for AMX0035, he noted. “I wonder if the same concern will be raised here, necessitating confirmation in another trial. I hope not, but only time will tell.”
Dr. Miller added that these results “highlight how difficult ALS drug development still is. Among the many uncertainties in setting up a trial (targets, doses, inclusion criteria, outcomes), we still do not know how long we need to treat patients in order to see statistically significant changes in the clinical measures we use (ALSFRS-R, respiratory function, strength, survival, etc.). Most American studies are 6 months long and most European studies are 12 months long. Longer studies may be more likely to show benefits on certain measures (e.g., survival), but they cost more, they are challenged by dropouts as the disease progresses, and the idea of randomizing someone to a placebo for a whole year is psychologically difficult for patients, families, and many clinicians (myself included). So, we are seeing more studies like this one where the first 6 months are randomized, blinded, and placebo controlled, and then there is an open-label extension that lasts many months more.”
The study was sponsored by Biogen. Writing and editorial support was provided by Excel Scientific Solutions. Tofersen was discovered by Ionis Pharmaceuticals Inc. Dr. Miller disclosed ties with Biogen, Ionis Pharmaceuticals Inc., Cytokinetics, C2N, Disarm Therapeutics, and UCB Pharma. Dr. Bedlack disclosed ties with Biogen.
FROM THE ENCALS MEETING 2022
My choice? Unvaccinated pose outsize risk to vaccinated
according to a mathematical modeling study.
The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.
“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.
As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.
The study was published online in the Canadian Medical Association Journal.
Relative contributions to risk
The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.
The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”
When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
Self-regarding risk?
The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”
The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
Mandates and passports
“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”
The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
Illuminating the discussion
Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.
During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.
It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”
The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a mathematical modeling study.
The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.
“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.
As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.
The study was published online in the Canadian Medical Association Journal.
Relative contributions to risk
The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.
The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”
When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
Self-regarding risk?
The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”
The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
Mandates and passports
“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”
The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
Illuminating the discussion
Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.
During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.
It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”
The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
according to a mathematical modeling study.
The study, which simulated patterns of infection among vaccinated and unvaccinated populations, showed that, as the populations mixed less, attack rates decreased among vaccinated people (from 15% to 10%) and increased among unvaccinated people (from 62% to 79%). The unvaccinated increasingly became the source of infection, however.
“When the vaccinated and unvaccinated mix, indirect protection is conferred upon the unvaccinated by the buffering effect of vaccinated individuals, and by contrast, risk in the vaccinated goes up,” lead author David Fisman, MD, professor of epidemiology at the University of Toronto, told this news organization.
As the groups mix less and less, the size of the epidemic increases among the unvaccinated and decreases among the vaccinated. “But the impact of the unvaccinated on risk in the vaccinated is disproportionate to the numbers of contacts between the two groups,” said Dr. Fisman.
The study was published online in the Canadian Medical Association Journal.
Relative contributions to risk
The researchers used a model of a respiratory viral disease “similar to SARS-CoV-2 infection with Delta variant.” They included reproduction values to capture the dynamics of the Omicron variant, which was emerging at the time. In the study, vaccines ranged in effectiveness from 40% to 80%. The study incorporated various levels of mixing between a partially vaccinated and an unvaccinated population. The mixing ranged from random mixing to like-with-like mixing (“assortativity”). There were three possible “compartments” of people in the model: those considered susceptible to infection, those considered infected and infectious, and those considered immune because of recovery.
The model showed that, as mixing between the vaccinated and the unvaccinated populations increased, case numbers rose, “with cases in the unvaccinated subpopulation accounting for a substantial proportion of infections.” However, as mixing between the populations decreased, the final attack rate decreased among vaccinated people, but the relative “contribution of risk to vaccinated people caused by infection acquired from contact with unvaccinated people ... increased.”
When the vaccination rate was increased in the model, case numbers among the vaccinated declined “as expected, owing to indirect protective effects,” the researchers noted. But this also “further increased the relative contribution to risk in vaccinated people by those who were unvaccinated.”
Self-regarding risk?
The findings show that “choices made by people who forgo vaccination contribute disproportionately to risk among those who do get vaccinated,” the researchers wrote. “Although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population.”
The fact that like-with-like mixing cannot mitigate the risk to vaccinated people “undermines the assertion that vaccine choice is best left to the individual and supports strong public actions aimed at enhancing vaccine uptake and limiting access to public spaces for unvaccinated people,” they wrote.
Mandates and passports
“Our model provides support for vaccine mandates and passports during epidemics, such that vaccination is required for people to take part in nonessential activities,” said Dr. Fisman. The choice to not be vaccinated against COVID-19 should not be considered “self-regarding,” he added. “Risk is self-regarding when it only impacts the person engaging in the activity. Something like smoking cigarettes (alone, without others around) creates a lot of risk over time, but if nobody is breathing your secondhand smoke, you’re only creating risk for yourself. By contrast, we regulate, in Ontario, your right to smoke in public indoor spaces such as restaurants, because once other people are around, the risk isn’t self-regarding anymore. You’re creating risk for others.”
The authors also noted that the risks created by the unvaccinated extend beyond those of infection by “creating a risk that those around them may not be able to obtain the care they need.” They recommended that considerations of equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be included in formulating vaccination policy.
Illuminating the discussion
Asked to comment on the study, Matthew Oughton, MD, assistant professor of medicine at McGill University, Montreal, said: “It is easy to dismiss a mathematical model as a series of assumptions that leads to an implausible conclusion. ... However, they can serve to illustrate and, to an extent, quantify the results of complex interactions, and this study does just that.” Dr. Oughton was not involved in the research.
During the past 2 years, the scientific press and the general press have often discussed the individual and collective effects of disease-prevention methods, including nonpharmaceutical interventions. “Models like this can help illuminate those discussions by highlighting important consequences of preventive measures,” said Dr. Oughton, who also works in the division of infectious diseases at the Jewish General Hospital, Montreal.
It’s worth noting that the authors modeled vaccine effectiveness against all infection, “rather than the generally greater and more durable effects we have seen for vaccines in prevention of severe infection,” said Dr. Oughton. He added that the authors did not include the effect of vaccination in reducing forward transmission. “Inclusion of this effect would presumably have reduced overall infectious burden in mixed populations and increased the difference between groups at lower levels of mixing between populations.”
The research was supported by a grant from the Canadian Institutes of Health Research. Dr. Fisman has served on advisory boards related to influenza and SARS-CoV-2 vaccines for Seqirus, Pfizer, AstraZeneca, and Sanofi-Pasteur Vaccines and has served as a legal expert on issues related to COVID-19 epidemiology for the Elementary Teachers Federation of Ontario and the Registered Nurses Association of Ontario. Dr. Oughton disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE CANADIAN MEDICAL ASSOCIATION JOURNAL
Drug combo holds promise as on-demand contraceptive: Study
A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.
The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.
“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.
Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”
The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m2. All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.
Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.
The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.
Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.
“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”
When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.
“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”
The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”
Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”
The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.
A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.
The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.
“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.
Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”
The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m2. All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.
Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.
The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.
Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.
“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”
When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.
“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”
The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”
Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”
The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.
A combination of ulipristal acetate (UA) and a cyclo-oxygenase-2 (COX-2) inhibitor holds promise as a pericoital, “on- demand” female oral contraceptive, taken only when needed, according to an exploratory study published in BMJ Sexual & Reproductive Health.
The prospective, open-label, pilot study showed that UA and meloxicam successfully disrupted ovulation at “the peak of luteal surge, when conception risk is highest,” reported lead author Erica P Cahill, MD, of Stanford (Calif.) University, and colleagues.
“There are many people who report being interested in preventing pregnancy who are not using contraception,” Dr. Cahill said in an interview. The ideal is to be able to take a medication to prevent ovulation and know that you wouldn’t ovulate or be able to become pregnant for the next 3-5 days. These would be pericoital contraceptive pills that one could take prior to or immediately after intercourse that would expand the contraceptive options available and meet some of this need, she said.
Dr. Cahill said currently approved emergency contraceptives containing ulipristal acetate or levonorgestrel “work by inhibiting ovulation at the level of the luteal surge, the pituitary signal that starts the ovulation cascade. Because of this mechanism, they are only effective when taken prior to that signal. If they are taken near or after ovulation has occurred, they are not effective.” She said combining meloxicam with UA could address this because meloxicam “has been shown to prevent some of the later steps of ovulation just prior to the egg being released.”
The study included nine healthy women, with a mean age of 31.4 years, and a mean body mass index of 24.5 ± 3.9 kg/m2. All subjects had no exposure to hormonal medication, pregnancy, or lactation in the prior 3 months.
Each participant was followed for two cycles: The first without treatment, to establish normal ovulatory function; and the second during treatment with a one-time dose of UA 30 mg and meloxicam 30 mg during the “fertile window.” This window was defined as when the lead ovarian follicle had a mean diameter of 18 mm, and was determined via thrice-weekly ultrasounds, as well as luteinizing hormone (LH) measurements.
The primary outcome of the study was ovulation disruption, defined as unruptured dominant follicle for 5 days, a blunted LH peak, defined as <15 IU/L, and a nonovulatory luteal phase progesterone level, defined as <3 ng/mL.
Ovulation disruption was achieved in six subjects (67.7%), with eight subjects (88.9%) meeting some criteria.
“When we compare ovulation disruption rates in our study with the previous studies on which our protocol is based, the combination of UA and meloxicam disrupted ovulation at each phase of the fertile window more than any other medication previously studied,” the researchers wrote. “This medication combination is an important candidate to evaluate as oral pericoital contraception.”
When comparing subjects’ baseline cycles with their treatment cycles, the latter were approximately 3 days longer, although there was no difference in endometrial stripe thickness or irregular bleeding.
“Cycle length changes are an important parameter as people interested in oral, on-demand contraception may also be using fertility awareness methods which can be affected by cycle length changes.”
The authors noted that measures of full efficacy and side effects were beyond the scope of the study and would require repeat dosing. Similarly, liver enzymes were not measured, because there was only one dose of study medication, but “given the potential impact of repeat UA on liver enzymes, this measurement is critical for future studies.”
Asked to comment on the study, Eve Espey, MD, said that although it was limited in size and the use of an “intermediate outcome” of ovulation disruption, “the combination does show some promise as a focus of future research.” However, Dr. Espey, distinguished professor and chair in the department of obstetrics and gynecology at the University of New Mexico, Albuquerque, said it is too early to determine the significance of the findings. “But it does point the way to further research,” she noted. “Compared with existing emergency contraception, this study shows that the UA-meloxicam combination disrupts ovulation over a broader mid-cycle time period – [an] extended duration of action [that] could theoretically translate into increased effectiveness as a contraceptive.”
The study was supported by the Society for Family Planning Research Fund. None of the authors, or Dr. Espey, declared competing interests.
FROM BMJ SEXUAL & REPRODUCTIVE HEALTH
Three symptoms suggest higher risk for self-injury in cancer
, according to a Canadian study.
In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.
“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.
Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”
The study was published online in JAMA Oncology.
Nine common symptoms
The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).
The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
Toward tailored intervention
A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).
“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”
In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.
“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
Self-injury vs. suicidality
Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.
“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”
The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.
“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.
The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to a Canadian study.
In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.
“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.
Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”
The study was published online in JAMA Oncology.
Nine common symptoms
The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).
The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
Toward tailored intervention
A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).
“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”
In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.
“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
Self-injury vs. suicidality
Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.
“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”
The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.
“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.
The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to a Canadian study.
In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.
“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.
Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”
The study was published online in JAMA Oncology.
Nine common symptoms
The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).
The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
Toward tailored intervention
A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).
“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”
In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.
“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
Self-injury vs. suicidality
Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.
“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”
The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.
“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.
The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY