All-oral regimens found highly active against chronic HCV genotype

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.

SAN DIEGO – Patients with chronic hepatitis C of genotype 1 may soon be able to treat their disease by taking a safe and well-tolerated regimen consisting solely of oral antiviral agents, a study has shown.

Investigators conducted a randomized, open-label phase 2 trial among 571 patients with chronic hepatitis C genotype 1 infection who were either treatment naive or had not had a response to prior interferon and ribavirin therapy.

They tested three oral investigational agents having direct antiviral activity, giving two to three of them together, with ritonavir, and with or without ribavirin, for varying treatment durations.

The results of the trial – known as Aviator – showed that across regimens, more than 80% of patients had a sustained virologic response at 24 weeks after the end of treatment (SVR24), Dr. Kris Kowdley reported at the annual meeting of the American College of Gastroenterology.

High SVR rates were seen consistently whether patients were treatment naive or prior null responders. In addition, a treatment duration of 12 weeks worked essentially as well as one of 24 weeks.

Adverse events were generally mild and led to treatment discontinuation in only about 2% of patients.

"What the Aviator trial has shown us is that for genotype 1 patients, a paradigm of all-oral treatment with direct-acting antivirals, with or without ribavirin, is highly effective, and this regimen was safe," Dr. Kowdley commented in a related press briefing. "This paradigm ... is promising and, particularly because we have been able to show this in patients who were prior interferon nonresponders, holds hope for many of our hepatitis C patients going forward."

Dr. Zobair N. Younossi, who comoderated the session in which the results were presented and moderated the press briefing, noted that the regimens were complex.

"We know that when it goes to the community, effectiveness falls because of the complex regimen. Do you think there is an attempt to combine these in the same pill so that there is not this complexity associated with this regimen?" he asked.

"Absolutely. We are focused on pill burden, and we are focused on simplicity," replied Dr. Kowdley, a gastroenterologist at the digestive disease institute, Virginia Mason Medical Center, Seattle. Thus, efforts are underway to combine the direct-acting antivirals given once daily into a single pill and to determine if once-daily dosing is effective for the antiviral that is currently given twice daily.

"The observation that we have certainly in our clinical trials [is that] the relapse rate appears to be largely driven by the efficacy of the regimen rather than the complexity of the regimen," he added. Still, "even though it’s a short amount of time [on treatment], continued efforts to simplify the regimens and formulate multiple combinations into one should certainly be our goal going forward."

Dr. Younossi, vice president for research for the Inova Health System and executive director of the center for liver diseases at Inova Fairfax Hospital, Falls Church, Va., further noted that rates of SVR12 and SVR24 in the study were very similar, whereas the latter has typically been viewed as the key predictor of mortality reduction. "Do you think that SVR12 now is the same ... [in predicting] long-term outcome?" he asked.

"Certainly if you look at the FDA’s guidance and their modification of achievement of treatment success as you know for the current [protease inhibitors], telaprevir and boceprevir, SVR12 is considered a perfectly adequate time point," Dr. Kowdley replied. "Whether in fact SVR12 and SVR24 with interferon-based regimens will ultimately have the same significance with all-oral regimens is hard to know."

"But certainly, I would not be surprised if we started seeing significant changes and more dramatic changes in terms of short-term outcomes as we start to treat patients with hepatitis C who have more advanced disease," he added. "And I would not be surprised if we saw something similar to what we saw in hepatitis B, where we started treating patients on the transplant list, with advanced MELD [Model for End-Stage Liver Disease] scores, with all-oral agents, and all of a sudden, they didn’t need a transplant. So I think that if anything, with all-oral regimens on the horizon or in the clinic, we’ll see even more dramatic responses with SVR12."

The Aviator trial enrolled adults with chronic hepatitis C of genotype 1 who did not have cirrhosis and were not coinfected with HIV or hepatitis B.

All patients received ritonavir (Norvir). In addition, they received two or three novel direct-acting antivirals (manufactured by AbbVie and Enanta): ABT-450, an NS3/4A protease inhibitor dosed once daily with ritonavir; ABT-267, an NS5A inhibitor dosed once daily; and ABT-333, a nonnucleoside polymerase inhibitor dosed twice daily. Most also received ribavirin.

The trial’s nine arms varied with respect to the specific combination of agents, treatment duration, and patient treatment history.

The patients had a mean age of about 50 years, and approximately 80% were white. Roughly two-thirds had viral subgenotype 1a.

Across trial arms, patients had high rates of SVR12 (85%-99%) and SVR24 (83%-96%), Dr. Kowdley reported.

The optimal regimen appeared to be the combination of three direct-acting antivirals plus ribavirin given for 12 or 24 weeks; the longer treatment duration provided little to no gain.

Among the 247 patients treated with that optimal regimen, relapse and breakthrough were uncommon, each seen in no more than 3% of patients.

Whether treatment naive or null responders, these patients had no clinically meaningful differences in the achievement of SVR by pretreatment predictors.

"In fact, by multivariable analysis, sex, age, race, baseline viral load, subtype, BMI [body mass index], or presence or absence of the need for ribavirin, dose reduction did not influence SVR independently," Dr. Kowdley noted.

Among the patients given the optimal regimen, the rate of discontinuation resulting from adverse events was 2.4%, and the rate of serious adverse events was 1.6%.

"The majority of the adverse events were mild and of the type we often see in clinical trials – headache, fatigue, nausea, insomnia, and diarrhea, and not different between the treatment-naive patients and null responders," Dr. Kowdley commented.

The most common adverse events overall were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), and diarrhea (15%).

The rate of grade 3 laboratory abnormalities was low; the most common, seen in six patients, was total bilirubin level at least three times the upper limit of normal. A single patient had an elevated alanine aminotransferase (ALT) level.

"All of these [cases of hyperbilirubinemia] resolved, typically within 1 week and spontaneously with continued therapy, consistent with the inhibition of OAPT1B1 as a bilirubin transporter that was often observed. None of the bilirubin elevations was associated with an increased ALT level," he noted.

Dr. Kowdley disclosed that he receives grant/research support from AbbVie, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Gilead/Pharmasset, Ikaria, Intercept, Merck, Mochida, and Vertex, and that he is a consultant to Novartis and an adviser to AbbVie, Gilead, Merck, and Vertex. The trial was sponsored by AbbVie (previously sponsored by Abbott). Dr. Younossi disclosed that he is an advisory committee/board member for Coneatus, Enterome, Gilead, Janssen, Salix, and Vertex.