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New Treatments for Hepatitis C

, by Liz Highleyman

Hepatitis C was a major theme at the 21st Conference on Retroviruses and Opportunistic Infections this week in Boston. While development of new HIV drugs has slowed in recent years, hepatitis C treatment is undergoing a revolution comparable to the advent of combination antiretroviral therapy in the mid-1990s.

The standard of care for chronic hepatitis C has evolved from interferon-based therapy—which had to be injected weekly for six months to a year, caused difficult and sometimes dangerous side effects, and only cured about half of treated patients—to very well tolerated, interferon-free, all-oral regimens that can cure most people in as little as six to 12 weeks.

Douglas Dieterich at CROI 2014 (photo: Liz Highleyman)

Douglas Dieterich at CROI 2014 (photo: Liz Highleyman)

The first of a new wave of direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus lifecycle—Gilead Sciences’ HCV polymerase inhibitor sofosbuvir (Sovaldi) and Janssen’s next-generation HCV protease inhibitor simeprevir (Olysio)—were approved late last year. According to Douglas Dieterich from Mt. Sinai, sofosbuvir has been “flying off the shelves” at a rate of about 2,000 prescriptions per week.

Interferon-Free Combos

One of the most exciting presentations at the conference was a report from the SYNERGY study showing that a three-drug oral regimen taken for just six weeks can cure most people with genotype 1 hepatitis C being treated for the first time.

Anita Kohli from the National Institutes of Health and colleagues (abstract 27LB) aimed to find simple, brief, and well-tolerated therapy for patients traditionally considered difficult-to-treat. This study enrolled 60 mostly low-income people with hepatitis C in Washington, DC. Around 90% were African-American, 70% had hard-to-treat HCV subtype 1a, and about one-quarter had advanced liver fibrosis or cirrhosis.

“We believe this population is really reflective of the hepatitis C population in the U.S., which historically has been a difficult-to-treat population,” Kohli said.

Anita Kohli at CROI 2014

Anita Kohli at CROI 2014 (photo: Liz Highleyman)

Participants were treated with a coformulation of sofosbuvir and the NS5A inhibitor ledipasvir, either alone for 12 weeks or in in combination with a third drug—the HCV polymerase inhibitor GS-9669 or the HCV protease inhibitor GS-9451—for six weeks.

Sustained virological response rates at 12 weeks post-treatment (SVR12) were very high: 100% for the sofosbuvir/ledipasvir coformulation alone and for the GS-9451 combo, and 95% for the GS-9669 combo. All regimens were safe and well tolerated, with no drug-related serious adverse events or treatment discontinuations.

“This short duration simple therapy for HCV may prove relevant for the global elimination of hepatitis C, where uncomplicated, well-tolerated therapy is required to ensure adherence and minimize health care expenditures,” the researchers concluded.

Another interferon-free study tested a 12-week regimen of three DAAs being developed by AbbVie: the HCV protease inhibitor ABT-450, the NS5A inhibitor ABT-267, and the polymerase inhibitor ABT-333, with or without ribavirin. AbbVie hopes to gain FDA approval for this “3D” regimen by the end of 2014.

As described by Rajendar Reddy from the University of Pennsylvania (abstract 29LB), the PEARL-III study looked at a somewhat easier-to-treat population of 419 previously untreated patients with HCV genotype 1b and no liver cirrhosis. Here, the cure rate was 99% with or without ribavirin. Again, treatment was generally well tolerated, although people who included ribavirin often developed anemia.

High cure rates were also seen with a three-drug oral regimen containing Bristol-Myers Squibb’s NS5A inhibitor daclatasvir, HCV protease inhibitor asunaprevir, and polymerase inhibitor BMS-791325 taken for 12 weeks.

Trevor Hawkins from the Southwest CARE Center (abstract 25) reported data from a study of 166 previously untreated hepatitis C patients. More than 80% had HCV subtype 1a and about 10% had cirrhosis. The SVR12 rate was 92% and this regimen was also well tolerated.

Finally, Christophe Hezode (abstract 28LB) presented findings from a trial testing daclatasvir plus simeprevir, with or without ribavirin, for 12 or 24 weeks. The main study enrolled people with HCV 1b, both treatment-naive and prior non-responders. About one-third had advanced fibrosis or cirrhosis.

Sustained response rates were 85% for the two-drug regimen and 75% for the three-drug combo. For prior null responders, rates were 65% and 95%, respectively.

A common theme of these and other recent studies is that many of the factors that traditionally predicted poor response to interferon-based therapy are no longer so important with interferon-free treatment. These include black race, favorable IL28B gene variants, high pre-treatment viral load, and extent of liver damage.

“All the old predictors of response are gone when you have a potent 2-3 drug combination,” Dietrich said at a hepatitis C press briefing on the conference’s opening day.

HIV/HCV Coinfection

HIV coinfection is another factor associated with poorer response to interferon that appears to play little or no role when using new direct-acting antivirals. However, some of these new drugs can interact with antiretroviral medications.

Dieterich reported findings from two studies of DAAs—simeprevir and Boehringer Ingelheim’s faldaprevir—added to interferon and ribavirin for HIV/HCV coinfected patients (abstracts 24 and 23).

Study C212 enrolled 106 coinfected people, both treatment-naive and prior relapsers or non-responders. Most had HCV 1a and about 20% had cirrhosis. Participants took once-daily simeprevir plus pegylated interferon and ribavirin for 12 weeks, then continued on pegylated interferon/ribavirin alone for 12 or 36 more weeks.

Overall, 74% achieved SVR12 (79% of previously untreated, 87% of relapsers, 70% of prior partial responders, and 57% of prior null responders). People without advanced liver damage responded somewhat better.

The STARTVerso4 trial enrolled 308 treatment-naive and previous relapsers or partial responders. Most had HCV 1a and 15% had cirrhosis. They either did not yet need HIV treatment or were on antiretrovirals that had manageable interactions with faldaprevir. They took triple therapy with once-daily faldaprevir plus pegylated interferon and ribavirin for 12 or 24 weeks, then continued on pegylated interferon/ribavirin alone.

Here, the overall SVR12 rate was 72%. Prior relapsers responded better than treatment-naive patients (83% and 69%, respectively). As seen in other faldaprevir studies, however, people with liver cirrhosis responded as well as non-cirrhotics.

Both simeprevir and faldaprevir were well tolerated, though many patients had side effects related to interferon or ribavirin.

Turning to interferon-free treatment for coinfection, Susanna Naggie from Duke Clinical Research Institute (abstract 26) reported findings from the PHOTON-1 trial, which tested sofosbuvir plus ribavirin. Unlike some HCV protease inhibitors, sofosbuvir has no significant interactions with widely used antiretrovirals.

This trial included 114 genotype 1 treatment-naive patients (treated for 24 weeks), 68 genotype 2 or 3 treatment-naive people (treated for 12 weeks), and 41 genotype 2 or 3 treatment-experienced people (also treated for 24 weeks). Most genotype 1 patients had subtype 1a and rates of liver cirrhosis ranged from 4% to 24%.

For genotype 1 patients, the SVR24 was 75%. Among treatment-experienced people treated for 24 weeks, SVR24 rates were 92% for genotype 2 and 94% for genotype 3. While treatment-naive people with genotype 2 responded well to only 12 weeks of treatment (88%), genotype 3 patients did not do so well with the shorter duration (67%).

Taken together, the good news from these studies is that response rates and adverse events were the same in HIV/HCV coinfected patients and people with HCV alone, according to Dieterich.

Challenges Remain

Despite these promising findings, it is still unclear how the new hepatitis drugs will be used in the real world, given barriers such as inadequate HCV screening, high drug costs, and a shortage of experienced health care providers. After years of “warehousing” to await more effective interferon-free therapy, doctors are now starting to manage the backlog, often starting with the sickest patients first.

Traditionally, hepatitis C treatment has been recommended only for people with progressive liver disease. But this could change with better-tolerated and more effective new therapies. As with HIV, effective hepatitis C treatment not only benefits the health of infected individuals, but also prevents transmission to others.

“At the moment we’re a bit busy treating the sicker patients first,” said Dieterich. “We’re waiting for test-and-treat for asymptomatic and healthier patients later on when things get easier and cheaper.”

Given their serious side effects, some experts, including Hawkins, believe “we have to move away from interferon-based treatment and eventually away from ribavirin.” Cost considerations could lead to continued use of interferon, but after adding in the cost of managing side effects—for example, erythropoietin or blood transfusions for anemia—Dieterich argued that interferon-based therapy “is really not cheaper in the real world.”

While hepatitis C has the benefit of a cure, it lacks the political will, global collaborations, research networks, infrastructure, funding, and community identity that have turned around the HIV epidemic, explained Tracy Swan of the Treatment Action Group at the annual Martin Delaney memorial lecture. “HCV treatment is a dribble, not a cascade,” she said. “One thing HIV has taught us that the community response is absolutely essential to transforming an epidemic.”

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

Selected Sources

Dieterich, D. and others. Faldaprevir plus pegylated interferon alfa-2a/ribavirin in HIV/HCV coinfection: STARTVerso4. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). March 3–6, 2014. Boston. Abstract 23.

Dieterich, D. Simeprevir (TMC435) plus pegIFN/ribavirin in HCV genotype-1/HIV-1 coinfection (Study C212). CROI 2014. Abstract 24.

Everson, G. and others. All-oral combination of daclatasvir, asunaprevir, and BMS-791325 for HCV genotype 1 infection. CROI 2014. Abstract 25.

Ferenci, P. and others. PEARL III: SVR 99% After 12 wks of ABT-450/r/267 + ABT-333 ± RBV in treatment naïve HCV GT1b infection. CROI 2014. Abstract 29LB.

Kohli, A. and others. Combination oral, hepatitis C antiviral therapy for 6 or 12
weeks: final results of the SYNERGY trial. CROI 2014. Abstract 27LB.

Naggie, S. Sofosbuvir plus ribavirin for HCV genotype 1-3 infection in HIV coinfected patients (PHOTON-1). CROI 2014. Abstract 26.

Zeuzem, S. and others. Daclatasvir in combination with simeprevir ± ribavirin for hepatitis C virus genotype 1 infection. CROI 2014. Abstract 28LB.

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