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AASLD 2015: Sofosbuvir + Ravidasvir Shows High Response Rates for Genotype 4 Hepatitis C

A regimen of sofosbuvir and the pan-genotypic HCV NS5A inhibitor ravidasvir, with or without ribavirin, demonstrated sustained response rates ranging from 86% to 100% in the largest Phase 3 trial to date of interferon-free treatment for people with hepatitis C virus genotype 4, according to study findings presented at the 2015 AASLD Liver Meeting taking place this week in San Francisco.

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AASLD 2015: New AbbVie Pangenotypic Regimen Cures 97%-100% of Hepatitis C Patients in Early Study

A combination of 2 experimental direct-acting antivirals developed by AbbVie cured 97% to 100% of non-cirrhotic people with genotype 1 hepatitis C in a mid-stage Phase 2 study presented this week at the AASLD Liver Meeting in San Francisco.

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AASLD 2015: Sofosbuvir/ Velpatasvir + GS-9857 for 8 Weeks Cures Most Genotype 1 or 3 Hepatitis C Patients

An 8-week triple combination of Gilead Sciences' sofosbuvir, velpatasvir, and GS-9857 showed a high sustained response rate in a Phase 2 study of difficult-to-treat hepatitis C patients including treatment-experienced people with HCV genotype 3 and liver cirrhosis, according to results presented at the 2015 AASLD Liver Meetingtaking place this week in San Francisco. A 6-week regimen appeared inadequate, however, and more than 8 weeks may be needed for people who previously used direct-acting antivirals.

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AASLD 2015: Sofosbuvir/ Velpatasvir Shows High Cure Rates for All HCV Genotypes in Phase 3

A coformulation of sofosbuvir and the pan-genotypic HCV NS5A inhibitor velpatasvir from Gilead Sciences produced sustained response in 99% of people with hepatitis C virus genotypes 1, 2, 4, 5, and 6, and 95% of those with harder-to-treat genotype 3, according to results from the Phase 3 ASTRAL trials presented at the 2015 AASLD Liver Meeting this week in San Francisco. A related late-breaking poster showed that sofosbuvir/velpatasvir with or without ribavirin cured most people with decompensated liver disease.

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Interferon-free direct-acting antiviral (DAA) therapy has revolutionized treatment for chronic hepatitis C, but researchers continue to try to optimize therapy. An ideal regimen would be of short duration, not require ribavirin, and would be pan-genotypic -- meaning it could be routinely prescribed without the need for genotype testing. HCV genotype 1 is most common in the U.S. and Europe, but genotypes that are more prevalent elsewhere in the world -- including 4, 5, and 6 -- have not been as well studied.

ASTRAL-1

Jordan Feld from Toronto Western Hospital Liver Centre presented results from the ASTRAL-1 trial (NCT02201940), which evaluated sofosbuvir/velpatasvir for patients with all genotypes except 3, which has proven harder to treat with DAAs. Results were published simultaneously in the November 16 online edition of the New England Journal of Medicine. Findings from ASTRAL-2, which looked specifically at people with HCV genotype 2, and ASTRAL-3, which enrolled genotype 3 patients, were also presented at the Liver Meeting.

ASTRAL-1 enrolled 740 chronic hepatitis C patients at 81 sites in the U.S., Canada, Europe, and Hong Kong. Just over half had HCV genotype 1 (including 34% with harder-to-treat subtype 1a), 17% had genotype 2, 19% had genotype 4, 6% had genotype 5, and 7% had genotype 6.

About 60% of participants were men, most were white, and the median age was about 54 years. A third were treatment-experienced (prior failure of interferon/ribavirin or a first-generation HCV protease inhibitor), two-thirds had unfavorable IL28B non-CC gene patterns, and 19% had compensated cirrhosis. People with HIV coinfection were not included.

Participants with genotypes 1, 2, 4, or 6 were randomly assigned (5:1) to receive either a 400 mg/100 mg once-daily fixed-dose coformulation of the HCV NS5B polymerase inhibitor sofosbuvir (marketed separately as Sovaldi) and the pan-genotypic NS5A inhibitor velpatasvir (formerly GS-5816), or else a placebo, for 12 weeks. Because their number was small, all genotype 5 patients received active treatment.

The primary study endpoint was sustained virological response, or continued undetectable viral load, at 12 weeks after completion of treatment (SVR12).

Results

  • All but 2 participants receiving sofosbuvir/velpatasvir completed treatment.
  • The overall SVR12 rate was 99%.
  • Broken down by genotype, sustained response rates were 98%, 99%, 100%, 100%, 97%, and 100%, respectively, for genotypes 1a, 1b, 2, 4, 5, and 6.
  • SVR12 rates were the same (99%) for previously untreated and treatment-experienced patients, and for people with and without cirrhosis.
  • Sequencing showed that 257 participants (42%) had NS5A resistance-associated variants (RAVs) at baseline, and this group also had a 99% cure rate.
  • Of the participants who did not achieve sustained response, 2 relapsed (1 each in the genotype 1a and 1b groups), 2 were lost to follow-up, 1 withdrew consent, and 1 died from an unrelated cause.
  • Sofosbuvir/velpatasvir was generally safe and well-tolerated.
  • 15 people (2%) taking the coformulation experienced serious adverse events and 1 discontinued treatment due to an adverse event.
  • Grade 3-4 laboratory abnormalities were uncommon (7%).
  • While more than three-quarters of patients treated with sofosbuvir/velpatasvir- reported some adverse events, this was also the case in the placebo group.
  • The most common side effects were headache, fatigue, nasopharyngitis, and nausea, again reported with similar frequency in the active treatment and placebo arms.

Based on these findings, the researchers concluded, "[Sofosbuvir/velpatasvir] for 12 weeks provides a simple, safe and highly effective treatment for patients with HCV genotype 1, 2, 4, 5 or 6 infection."

ASTRAL-2

Mark Sulkowski from Johns Hopkins presented findings from the ASTRAL-2 trial (NCT02220998), which looked at a larger number of people with HCV genotype 2. While ASTRAL-1 included just 35 genotype 2 patients, ASTRAL-2 enrolled 240 patients at 51 sites in the U.S. About 60% were men, about 90% were white, and the median age was 57 years; 15% were treatment-experienced and 14% had cirrhosis.

Participants in this open-label study were randomly assigned (1:1) to receive sofosbuvir/velpatasvir or sofosbuvir plus ribavirin -- standard therapy for this genotype -- for 12 weeks. The once-daily fixed-dose combination would be more convenient than ribavirin (usually taken twice-daily) and eliminating ribavirin would reduce the risk of anemia.

All but 2 patients (1 in each arm) completed treatment. SVR12 rates were 99% in the sofosbuvir/velpatasvir arm and 94% in the sofosbuvir plus ribavirin arm. Here too, SVR12 rates with sofosbuvir/velpatasvir were similar for treatment-naive and treatment-experienced patients, and for those with and without cirrhosis, while response rates were more variable in the sofosbuvir plus ribavirin arm. Of those without SVR, 6 people relapsed -- all taking sofosbuvir plus ribavirin -- and 3 were lost to follow-up.

Again, treatment was generally well-tolerated. In each arm 2 patients experienced serious adverse events and 1 person taking sofosbuvir/velpatasvir discontinued due to an adverse event. While most other side effects were similar in the 2 treatment arms, 6 people taking ribavirin -- but none using the ribavirin-free regimen -- developed anemia (hemoglobin <10 g/dL).

Sofosbuvir/velpatasvir for 12 weeks "provides a single-tablet, once-daily, highly effective, ribavirin-free treatment for patients with HCV genotype 2 infection," the researchers concluded.

ASTRAL-3

Alessandra Mangia of Casa Sollievo della Sofferenza Hospital in Italyreported findings from ASTRAL-3 (NCT02201953), which focused on people with HCV genotype 3 -- currently considered the hardest genotype to treat.

ASTRAL-3 enrolled 552 genotype 3 patients at 76 sites in the U.S., Canada, Europe, Australia, and New Zealand. Just over 60% were men, most were white, and the median age was 50 years. About a quarter were treatment-experienced, 60% had unfavourable IL28B variants, and 30% had cirrhosis.

Participants in this open-label trial were randomly assigned (1:1) to receive either sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus ribavirin for 24 weeks.

Sofosbuvir plus ribavirin is not highly effective against genotype 3, but before the approval of daclatasvir (Daklinza) it was the recommended regimen. Unlike velpatasvir, the NS5A inhibitor ledipasvir in the Harvoni coformulation has little activity against genotype 3.

All but 2 sofosbuvir/velpatasvir recipients completed treatment while 21 in the sofosbuvir plus ribavirin arm dropped out early. SVR12 rates were 95% in the sofosbuvir/velpatasvir arm and 80% in the sofosbuvir plus ribavirin arm -- a significant difference. A total of 22 people (4%) relapsed in the sofosbuvir/velpatasvir arm compared with 38 (14%) in the sofosbuvir plus ribavirin arm. Among the 16% of participants with NS5a RAVs at baseline, the sofosbuvir/velpatasvir SVR12 rate was 88%.

Here too, response rates with sofosbuvir/velpatasvir were statistically similar for treatment-naive and treatment-experienced patients (97% and 90%, respectively), and for people with and without cirrhosis (91% and 97%). In the sofosbuvir plus ribavirin group, however, SVR12 rates were quite low for both treatment experienced people and cirrhotic patients (63% and 66%, respectively). Combining treatment history and cirrhosis status, response was lowest for treatment-experienced people with cirrhosis -- but this was substantially higher with sofosbuvir/velpatasvir than with sofosbuvir plus ribavirin (89% vs 58%, respectively).

Again, treatment was generally well-tolerated. 6 people in the sofosbuvir/velpatasvir arm and 15 in the sofosbuvir plus ribavirin arm experienced serious adverse events, and 3 people -- all in the ribavirin-containing arm -- discontinued treatment due to adverse events. Sofosbuvir/velpatasvir side effects were similar to those seen in the other ASTRAL trials; 4 people taking ribavirin developed anemia.

In summary, sofosbuvir/velpatasvir for 12 weeks resulted in a 95% overall SVR12 rate in people with HCV genotype 3 infection -- showing it was statistically superior to sofosbuvir plus ribavirin for 24 weeks -- and 91% for patients with cirrhosis.

"[Sofosbuvir/velpatasvir] for 12 weeks provides a simple, safe, highly effective, ribavirin-free treatment for patients with HCV genotype 3 infection," the researchers concluded.

ASTRAL-4

Finally, Michael Charlton from Intermountain Medical Center in Salt Lake City and colleagues presented a late-breaking poster describing results from ASTRAL-4 (NCT02201901), which looked at patients of all genotypes with decompensated liver disease, which remains a challenging population. These findings were also published in the November 16 New England Journal of Medicine.

ASTRAL-4 included 267 patients with Child-Pugh-Turcotte (CPT) class B, indicating about a 20% risk of death in the next year. CPT scores are based on total bilirubin, serum albumin, prothrombin time, and presence of ascites (abdominal swelling) and hepatic encephalopathy.

About 70% were men, most were white, and the mean age was 58 years. About 60% had genotype 1a, 18% had 1b, 15% had genotype 3, less than 5% had genotypes 2 or 4, and none had genotype 5. Just over half were treatment-experienced. The median CPT score was 8; about a third had a MELD score <10, about 60% had a score of 10-15, and 5% had >16, indicating severely impaired liver function. People with hepatocellular carcinoma and liver transplant recipients were excluded.

Participants were randomized to receive sofosbuvir/velpatasvir alone for 12 or 24 weeks, or sofosbuvir/velpatasvirplus weight-based ribavirin for 12 weeks.

Overall SVR12 rates were 83% and 86% for patients treated with sofosbuvir/velpatasvir for 12 or 24 weeks, respectively, rising to 94% for those who added ribavirin. Looking at just genotype 1, the corresponding SVR12 rates were 88%, 92%, and 96%. Response rates were lower for genotype 3 -- only 50% using sofosbuvir/velpatasvir alone for 12 or 24 weeks, and 85% with ribavirin. Everyone with genotype 2, 4, or 6 was cured except for 1 genotype 2 patient who died of liver failure. Of those with virological failure, 2 people (both with genotype 3) experienced viral breakthrough while on therapy and 20 relapsed after finishing treatment.

Treatment was generally safe and well-tolerated considering how sick the patients were. About 18% experienced serious adverse events, occurring with similar frequency across arms. The most common side effects were fatigue (29%), nausea (23%), and headache (22%). Nearly a third of people taking ribavirin developed anemia.

Looking at liver function, at 12 weeks post-treatment 47% of participants saw their CPT score improve from baseline, 42% remained stable, and 11% worsened. Among patients with lower baseline MELD scores (<15), 51% had an improved score, 22% saw no change, and 27% worsened. However, among those with the most severe liver disease, 81% had an improved MELD score, 11% had no change, and 7% worsened.

"Treatment with sofosbuvir/velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir/velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis," the researchers concluded.

Taken together, the ASTRAL studies demonstrate that sofosbuvir/velpatasvir is highly effective against all HCV genotypes, including for patients with predictors of poorer response.

Availability of a "one-size-fits-all" pangenotypic regimen may help solve the issue of treatment access, Mangia suggested.

11/17/15

References

JJ Feld, K Agarwal. C Hézode, et al. A Phase 3 Double-Blind Placebo-Controlled Evaluation of Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Naïve and Experienced Genotype 1, 2, 4, 5, 6 HCV Infected Patients with and without Cirrhosis: Results of the ASTRAL-1 Study. AASLD Liver Meeting. San Francisco, November 13-17, 2015. Abstract LB-2.

JJ Feld, IM Jacobson, C Hézode, et al. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. New England Journal of Medicine. November 16, 2015 (online ahead of print).

MS Sulkowski, N Brau, E Lawitz, et al. A Randomized Controlled Trial of Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks Compared to Sofosbuvir with Ribavirin for 12 Weeks in Genotype 2 HCV Infected Patients: The Phase 3 ASTRAL-2 Study. AASLD Liver Meeting. San Francisco, November 13-17, 2015. Abstract 205.

A Mangia, SK Roberts, S Pianko, et al. Sofosbuvir/GS-5816 Fixed Dose Combination for 12 Weeks Compared to Sofosbuvir with Ribavirin for 24 Weeks in Genotype 3 HCV Infected Patients: The Randomized Controlled Phase 3 ASTRAL-3 Study. Abstract 249.

MR Charlton, JG O'Leary, NH Bzowej, et al. Sofosbuvir/Velpatasvir Fixed Dose Combination For The Treatment Of HCV In Patients With Decompensated liver Disease: The Phase 3 ASTRAL-4 Study. AASLD Liver Meeting. San Francisco, November 13-17, 2015. Abstract LB-13.

MP Curry, JG O'Leary, N Bzowej, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. New England Journal of Medicine. November 16, 2015 (online ahead of print).

AASLD 2015: HCV Infection During Anal Sex May Happen without Blood, Study Finds

Hepatitis C virus is present in large enough quantities in the rectal fluid of men with HIV and hepatitis C coinfection to permit HCV transmission without the presence of blood, researchers from the Icahn School of Medicine at Mount Sinai Hospital in New York City reported Sunday at the AASLD Liver Meeting in San Francisco.

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AASLD 2015: People with Cirrhosis Cured of Hepatitis C Still Have Elevated Liver Cancer Risk

The burden of liver cancer and cirrhosis caused by hepatitis C virus (HCV) is likely to continue to grow in the U.S. despite curative treatment, and people who have cirrhosis at the time they are cured of hepatitis C will require long-term monitoring for liver cancer, studies presented this week at the AASLD Liver Meeting in San Francisco show.

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AASLD 2015: Grazoprevir/ Elbasvir Shows High Cure Rate for People Who Inject Drugs

Merck's grazoprevir/elbasvir coformulation demonstrated an overall sustained response rate of 92% for injection drug users receiving opioid substitution therapy in the C-EDGE CO-STAR study, according to a presentation at the 2015 AASLD Liver Meeting taking place this week in San Francisco. Participants maintained good adherence and had a high cure rate even though many continued to use illicit drugs.

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AASLD 2015: Liver Doctors and Advocates Call for Wider Treatment of People with Hepatitis C

The need for more people living with hepatitis C to received treatment before they develop advanced liver disease was a recurring theme at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting this week in San Francisco. Many providers expressed frustration about not be able to treat all their patients who need it, while hepatitis C advocates held 2 protests outside the conference venue calling for lower drug prices and wider access to treatment.

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IDWeek 2015: HIV/HCV Coinfected People Achieve High Cure Rates with Grazoprevir/Elbasvir

A dual combination of Merck's grazoprevir and elbasvir taken for 12 or 16 weeks cured most HIV-positive people coinfected with hepatitis C virus (HCV) genotypes 1, 4, or 6, and was generally safe and well-tolerated, according to an integrated analysis of three trials presented at the recent IDWeek 2015 conference in San Diego.

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