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Hepatitis C Now a Theme at International AIDS Conference

, by Liz Highleyman

Jean-Michel Molina and Mark Sulkowski (photo: Liz Highleyman)

Jean-Michel Molina and Mark Sulkowski (photo: Liz Highleyman)

Given the advent of effective new treatments, hepatitis C was a major topic at the 20th International AIDS Conference held last week in Melbourne, Australia.

An estimated 150 to 200 million people worldwide are living with hepatitis C virus (HCV) and roughly 7 million are HIV/HCV coinfected, researcher Mark Sulkowski from Johns Hopkins said at a media briefing. “It’s a huge global problem that we haven’t really even touched.”

HIV/HCV coinfected people experience more rapid liver disease progression than people with hepatitis C alone and do not respond as well to interferon-based therapy. But new direct-acting antiviral drugs (DAAs) that target different steps of the HCV lifecycle offer the prospect of shorter treatment, fewer side effects, and higher cure rates.

An oral abstract session focused on studies of new therapies for coinfected people (described below), but the subject of hepatitis C arose often throughout the conference as participants discussed access to treatment as part of the overall theme of “Stepping Up the Pace.”

Treatment Cost and Access

At the opening session on July 20, and again at the closing, conference co-chair and outgoing International AIDS Society president Francoise Barré-Sinoussi emphasized that the hepatitis C treatment revolution “has the potential to completely change the global landscape in this area.”

But to make that happen, clinicians, patients, and advocates need to exert the same kind of pressure that led to expanded global access to HIV treatment. “Let’s use the experience gained in HIV to reduce HCV treatment cost and make universal access a dream come true for the 150 million people with hepatitis C,” she said.

Indeed, hepatitis C treatment cost and access was a thread woven throughout the conference. At the opening session, former Australian high court justice the Honorable Michael Kirby spoke of the “human right to health” and the barriers imposed by unaffordable drug prices.

Kirby also gave a talk on the same theme at a pre-conference satellite meeting on HIV/viral hepatitis coinfection. This was followed by a panel discussion featuring representatives from the World Health Organization, funders, community organizations, and Gilead Sciences and Janssen, the companies that market the two currently approved next-generation DAAs, sofosbuvir (Sovaldi) and simeprevir (Olysio).

“The key issue addressed at the coinfection meeting was how the highly successful global response to HIV could facilitate responses to hepatitis B and C, in particular strategies to enable access to highly effective antiviral therapies,” satellite organizer Gregory Dore from the University of New South Wales told BETA.

Gilead executive Gregg Alton was the target of a protest at a special session on “The Future of HIV and HCV Treatment,” where activists held a die-in and presented him a liver on a silver platter.

Gilead argues that the price of sofosbuvir is less than the cost of treating advanced liver disease that can result from uncontrolled HCV infection. Activists counter that most people living with hepatitis C around the world will never have the hope of a liver transplant.

Another satellite meeting on “The Hepatitis C Treatment Revolution” featured speakers discussing WHO’s new global hepatitis C guidelines, intellectual property laws, patent protection, and generic drugs.

Beyond bringing down drug costs, some new DAAs are “pangenotypic,” meaning they are active against all HCV genotypes. This could eliminate the need for genotypic testing prior to treatment. And shorter and better-tolerated treatment may allow general practitioners to manage hepatitis C care rather than costly specialists.

“HIV is one of the great medical success stories—no one thought it was possible to treat 13 million people,” said Andrew Hill from the University of Liverpool, who calculated that a course of generic DAAs could be produced for less than $200. “This success story should not stand alone. We have the ability to do it again, and this time it should be done more quickly.”

Also on the advocacy front, several speakers addressed the need for drug policy reform as part of the effort to stem the epidemics of HIV and viral hepatitis among people who use drugs.

“When you define public policy as a war, you are going to produce war casualties,” E. Ross Albers from the U.K. said in his closing address representing drug users. “Without overhauling international drug laws, we will not end HIV and hepatitis C.”

HCV Treatment Studies

Jean-Michel Molina from University of Paris Diderot presented data from the Phase 3 PHOTON-2 trial, which evaluated an interferon-free regimen of sofosbuvir plus ribavirin for HIV/HCV coinfected people (abstract MOAB0105LB).

This study included 274 coinfected participants in Europe and Australia. Almost all were on stable suppressive antiretroviral therapy, the mean CD4 T-cell count was nearly 600 cells/mm3, and 20% had liver cirrhosis.

A small number of previously untreated patients with easier-to-treat HCV genotype 2 took sofosbuvir plus ribavirin for 12 weeks. Everyone with HCV genotypes 1, 3, or 4, and all who had previously received interferon-based therapy, took the same regimen for 24 weeks.

Sustained virological response rates at 12 weeks after completing treatment (known as SVR12) were 85% for people with HCV genotype 1, 88% for those with genotype 2, 89% for genotype 3, and 84% for genotype 4. Cure rates did not differ significantly between HCV subtypes 1a and 1b, but the number of people with the latter type was small. Among people with genotype 1, those with cirrhosis had a lower cure rate than non-cirrhotic patients (65% vs 88%, respectively).

In contrast with interferon-based therapy, sofosbuvir plus ribavirin was generally safe and well-tolerated. The most common side effects were fatigue, insomnia, headache, nausea and diarrhea. While 10% developed low hemoglobin levels—a known side effect of ribavirin—only one person had severe anemia.

Results from the PHOTON-1 trial were published the same week in the Journal of the American Medical Association. This study tested the same regimen but it was conducted in the U.S. and had a different HCV genotype distribution. Here, the overall SVR12 rate for genotype 1 was 76%. Among people with genotype 2, cure rates were similar for treatment-naive patients treated for 12 weeks and treatment-experienced patients treated for 24 weeks (88% and 92%, respectively). Among those with genotype 3, however, previously untreated people taking the shorter duration had a lower response rate (67% vs 94%).

These response rates in the PHOTON trials are not particularly impressive compared with the 90% to 100% cure rates seen in other recent interferon-free trials. Studies have shown that sofosbuvir works better when combined with other DAAs such as the NS5A inhibitors ledipasvir or daclatasvir (Daklinza), which are expected to be approved soon. A disadvantage of ledipasvir, however, is that it does not work against HCV genotypes 2 or 3.

Molina suggested that sofosbuvir plus ribavirin may be a good option for genotype 2 or 3 coinfected patients without cirrhosis. “Ribavirin is generic,” he noted, and this combination “might be attractive in places where you don’t have access to all the new drugs.”

Sulkowski and fellow investigators with the Phase 3 TURQUOISE-I trial evaluated the safety and efficacy of AbbVie’s “3D” regimen for HIV/HCV coinfected patients (abstract MOAB0104LB).

This regimen—which is under FDA review, with a decision expected by the end of the year—contains the HCV protease inhibitor ABT-450, a boosting dose of ritonavir, and the NS5A inhibitor ombitasvir in a once-daily coformulation, taken with the HCV polymerase inhibitor dasabuvir and ribavirin.

This analysis included 63 coinfected participants with HCV genotype 1. Two-thirds were previously untreated for hepatitis C, with the rest being prior relapsers or non-responders. About 90% had harder-to-treat HCV subtype 1a and 19% had cirrhosis. Participants had well-controlled HIV and were taking antiretrovirals found not to interact with the AbbVie drugs. They were randomly assigned to treatment for either 12 or 24 weeks.

The SVR12 rate in this study was 94% for people in the 12-week arm. In the 24-week arm, 97% had undetectable HCV viral load at 4 weeks post-treatment (SVR4), though this is too soon to be considered a cure.

Here too, the 3D regimen plus ribavirin was generally safe and well-tolerated, with no serious adverse events or early dropouts for this reason. The most common side effects were fatigue, insomnia, nausea, and headache. Again, several people developed low hemoglobin, but no one progressed to severe anemia.

In response to a question, Sulkowski agreed that people with easier-to-treat HCV subtype 1b probably do not need to include ribavirin with the 3D regimen, and most patients probably need only 12 weeks of treatment. The biggest concern, he said, is hard-to-treat prior null responders with subtype 1a and cirrhosis. Both participants who experienced treatment failure in TURQUOISE-I were in this group.

Given that participants in both studies had cure rates and side effects similar to those previously seen in people with hepatitis C alone, conference rapporteur Cristina Mussini concluded that HIV/HCV coinfected people should no longer be considered a “special population.”

Daniel Cohen (photo: Liz Highleyman)

Daniel Cohen (photo: Liz Highleyman)

Finally, Daniel Cohen from AbbVie presented findings from a Phase 2 study evaluating the safety and efficacy of the 3D combination for people with HCV genotype 1 who were on stable opioid substitution therapy using either methadone or buprenorphine, with or without naloxone (abstract MOAB0103).

Because HCV is readily transmitted through shared needles, people who inject drugs have high rates of hepatitis C worldwide. However, only a small proportion of this population have received treatment due to concerns about tolerability, adherence, and poor efficacy.

This study included 38 participants at eight sites in North America. Most had never been treated for hepatitis C, two-thirds had HCV subtype 1a, and 21% had moderate or advanced liver fibrosis (although people with cirrhosis were excluded). Unlike the other two studies, this one looked at people with HCV alone, not HIV/HCV coinfection.

After 12 weeks of therapy plus 12 weeks of post-treatment follow-up, the SVR12 rate was 97%. One participant dropped out of the study at week 2, but there were no viral breakthroughs or relapses. Again, treatment was well-tolerated and no one required adjustment of their methadone or buprenorphine doses due to withdrawal symptoms during hepatitis C treatment.

Cohen noted that the study participants demonstrated “very good adherence” according to pill counts, indicating that concern about people who use drugs being unable to stay on therapy is not a reason to withhold treatment with effective new interferon-free regimens.

Liz Highleyman (liz (at) hivandhepatitis.com) is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.

 

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