Coinfection

IAS 2015: Daclatasvir + Sofosbuvir Cures Most Coinfected People in French Compassionate Use Study

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 Interferon-free treatment using daclatasvir (Daklinza) and sofosbuvir (Sovaldi), with or without ribavirin, was well-tolerated and produced sustained virological response rates of 95%-100% for HIV/HCV coinfected people with advanced liver disease, according to a presentation at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) last month in Vancouver. These results, from a French program that provides new drugs to patients in need of treatment prior to regulatory approval, demonstrate that outcomes in the "real world" can be as good as those seen in clinical trials of the new drugs.

It is estimated that about one-third of people with HIV worldwide are coinfected with hepatitis C virus (HCV). Over years or decades chronic hepatitis C can progress to serious liver disease including cirrhosis and liver cancer. HIV/HCV coinfected people typically experience faster disease progression than those with HCV alone, and liver disease is a leading cause of illness and death among people living with HIV. People with HIV do not respond as well as HIV-negative people to interferon-based hepatitis C treatment and they may have worse side effects, so they especially stand to benefit from new direct-acting antiviral agents (DAAs) that can be used in interferon-sparing regimens.

Dominique Salmon of Hôpital Cochin in Paris presented findings from an analysisof HIV/HCV coinfected people receiving Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir plus Gilead Sciences' NS5B polymerase inhibitor sofosbuvir in a compassionate use program at more than 200 centers in France (AI444-258).

Compassionate use programs provide experimental drugs prior to approval for patients with an urgent medical need who cannot use or do not benefit from existing therapeutic options. This analysis looked at people seeking hepatitis C treatment in a real-world clinical care setting, rather than as part of a clinical trial. Sometimes outcomes among people treated in the real world are not as good as clinical trial results because trials may select participants who are most likely to benefit and often provide intensive monitoring and patient support.

The researchers looked at 564 coinfected people who accessed daclatasvir and sofosbuvir through the compassionate use program between March and October 2014. (The drugs received European Union marketing approval in January 2014 and August 2014, respectively.)

Within this group, the primary efficacy analysis included 147 people who had HCV viral load measurements available at 12 weeks post-treatment, allowing determination of sustained virological response (SVR12).

Nearly three-quarters of the patients were men and the median age was 52 years. The most common HCV genotype was 1a (51%), followed by 4 (20%), 1b (16%), and 3 (10%). About 85% had previously been treated for hepatitis C, usually with interferon.

To be eligible for compassionate use patients had to have either advanced liver fibrosis (Metavir stage F3 or higher) or less extensive fibrosis with extrahepatic manifestations. People awaiting a liver transplant or who had HCV recurrence after transplantation were also eligible. A majority (76%) had liver cirrhosis, generally with well-compensated disease. Most were categorized as Child-Pugh class A, meaning modest loss of liver function and high short-term survival probability.

The patients were on antiretroviral therapy (ART) with undetectable HIV viral load. More than 60% were taking ART regimens that included an integrase inhibitor, while 36% used HIV protease inhibitors and 24% used NNRTIs. The median CD4 T-cell count at baseline was 592 cells/mm3.

The recommended hepatitis C treatment regimen was 60 mg daclatasvir plus 400 mg sofosbuvir, both taken once daily; however, the daclatasvir dose was adjusted up or down depending on which antiretrovirals the patients were taking. While 68% were treated for the recommended duration of 24 weeks, 31% finished therapy at 12 weeks. Ribavirin could be added at the discretion of the treating physician, and was used by 10% of the patients.

Results

  • The overall sustained virological response rate at 12 weeks post-treatment was 97%.
  • Cure rates were similar for people treated with daclatasvir plus sofosbuvir alone for 12 or 24 weeks (98% vs 97%, respectively).
  • All of the 14 people who added ribavirin were cured with either treatment duration.
  • All patients with HCV genotype 3 and all but 1 with genotype 4 were cured.
  • Non-responders included 9 relapsers and 2 people with viral breakthrough while on therapy.
  • In a safety analysis that included 564 treated patients, there were just 2 treatment-related serious adverse events and 2 people discontinued treatment due to adverse events.
  • HIV remained under control during hepatitis C treatment.

These results, Salmon said, show that there was no extra benefit from adding ribavirin or extending treatment duration from 12 to 24 weeks. Cirrhosis status and HCV genotype also did not affect the likelihood of sustained response. This is important because while other effective treatment options are available for HCV genotype 1 -- namely Gilead's sofosbuvir/ledipasvir coformulation (Harvoni), Janssen's simeprevir (Olysio), and AbbVie's Viekira Pak regimen -- genotype 3 does not respond well to these other drugs.

These compassionate use response rates matched the 96%-98% SVR12 rates for mostly non-cirrhotic HIV/HCV coinfected patients treated for 12 weeks in the Phase 3 ALLY-2 trial. In that study, the response rate fell to just 76% for people treated for only 8 weeks. (ALLY-2 results are published in the July 21 online edition of the New England Journal of Medicine).

Based on these findings, the researchers concluded that daclatasvir plus sofosbuvir "provided high SVR12 rates in this real-world, interim analysis in HIV/HCV coinfected patients," and that daclatasvir plus sofosbuvir with or without ribavirin "was generally well tolerated and compatible with a wide range of antiretrovirals."

8/5/15

Reference

K Lacombe, H Fontaine, C Dhiver, D Salmon, et al. Daclatasvir plus sofosbuvir with or without ribavirin in patients with HIV-HCV co-infection: interim analysis of a French multicenter compassionate use program. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. AbstractTUAB0207LB.