- Category: Experimental HCV Drugs
- Published on Tuesday, 04 March 2014 00:00
- Written by Liz Highleyman
The hepatitis C virus (HCV) protease inhibitor faldaprevir added to pegylated interferon and ribavirin cured nearly three-quarters of genotype 1 HIV/HCV coinfected patients in the STARTVerso4 trial, equaling response rates for people with HCV alone, according to a report this week at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) in Boston.
Direct-acting antiviral agents have revolutionized treatment for chronic hepatitis C. These drugs were initially tested as add-ons to the previous standard of care, pegylated interferon plus ribavirin. Although interferon-free combinations are now becoming available, regimens containing single direct-acting drugs plus interferon may remain an option for some patients.
Douglas Dieterich from Mt. Sinai Ichan School of Medicine presented data from the open-label Phase 3 STARTVerso4 trial, which evaluated Boehringer Ingelheim's faldaprevir (formerly BI 201335) plus pegylated interferon and ribavirin for HIV/HCV coinfected patients who were previously untreated for hepatitis C or relapsed after a prior course of interferon-based therapy. Coinfected people experience more rapid liver disease progression, on average, and do not respond as well to interferon as those with HCV alone.
STARTVerso4 enrolled 308 coinfected patients with HCV genotype 1, mostly in Europe and North America. Most were men, 83% were white, 14% were black, and the average age was 47 years. About 80% had harder-to-treat HCV subtype 1a, one-third had the favorable IL28B CC gene variant, and 15% had compensated liver cirrhosis. More than three-quarters were hepatitis C treatment-naive and 22% were prior relapsers; this study did not include the most difficult-to-treat group, prior null responders.
Participants were either on stable antiretroviral therapy (ART) or had a high enough CD4 T-cell count that they did not yet need HIV treatment. At baseline, 95% were on ART, most had undetectable HIV viral load, and the mean CD4 count was approximately 540 cells/mm3. They used antiretrovirals that either did not have clinically relevant interactions with faldaprevir or interactions that could be managed with dose adjustments. Nearly half took raltegravir (Isentress), about 27% took efavirenz (Sustiva), and about 22% took either ritonavir-boosted atazanavir (Reyataz) or darunavir (Prezista).
All participants were treated with once-daily faldaprevir plus pegylated interferon alfa-2a (Pegasys) and weight-based ribavirin. Patients using HIV protease inhibitors received 120 mg faldaprevir for 24 weeks, those using efavirenz took 240 mg faldaprevir for either 12 or 24 weeks, and those using raltegravir or not on ART were randomized to one of these doses.
Duration of pegylated interferon/ribavirin was determined using response-guided therapy. People with "early treatment success" (HCV RNA <25 IU/mL at week 4 and undetectable at week 8) were re-randomized to either stop all drugs at 24 weeks or to continue pegylated interferon/ribavirin alone through week 48. All patients without early treatment success received the longer course.
The primary study end-point was sustained virological response, or continued undetectable HCV RNA at 12 weeks after the end of treatment (SVR12).
- Overall SVR12 rates were 71% for people treated with 120 mg faldaprevir for 24 weeks and 72% for all those treated with 240 mg faldaprevir.
- 87% and 85%, respectively, of patients who had early treatment success went on to achieve SVR12.
- Prior relapsers responded significantly better than treatment-naive patients, with SVR12 rates of 83% and 69%, respectively.
- IL28B status also had a significant effect, with SVR12 rates or 88% and 64%, respectively, for CC and non-CC variants.
- People with liver cirrhosis responded as well as non-cirrhotics, with SVR12 rates of 73% and 72%, respectively.
- HCV subtype also had little effect, with SVR12 rates of 76% for those with 1b and 71% for those with 1a.
- Presence of the Q80K resistance mutation also did not seem to affect outcomes in this coinfected population, with SVR12 rates of 75% for those with and 71% for those without the mutation at baseline.
- Response rates did not differ significantly between people with early treatment success who continued pegylated interferon/ribavirin for 24 weeks or 48 weeks.
- Faldaprevir combination therapy was generally safe and well-tolerated, with most side effects being typical of interferon-based therapy.
- 10% experienced serious adverse events and 7% had adverse events leading to hepatitis C treatment discontinuation.
- The most common side effects were nausea (37%), fatigue (34%), diarrhea (27%), headache (25%), and weakness (23%).
- The most common laboratory abnormality was elevated bilirubin (19%).
- Photosensitivity, or increased sensitivity to sunburn, was uncommon.
"Faldaprevir was highly efficacious and well-tolerated in difficult-to-treat patients coinfected with HIV and HCV genotype 1," the researchers concluded. "Among patients with [early treatment success], 24 weeks total duration of therapy was possible without compromising SVR12 rates.
They added that the safety profile of faldaprevir in coinfected patients "was similar to that observed in HCV genotype 1 monoinfected patients."
Although faldaprevir improved treatment response rates compared with pegylated interferon/ribavirin alone, other researchers at CROI reported that various interferon-free regimens yielded higher SVR rates in the 90% to 100% range with fewer side effects. Faldaprevir has demonstrated good efficacy and tolerability in all-oral regimensfor HCV monoinfected people.
"It is hard to consider using any drug now with interferon, but I know in many parts of the world that will still be the case for many years to come," Dieterich acknowledged.
Reviewing results from this and other hepatitis C trials at a CROI opening press conference, Dieterich noted that direct-acting agents can overcome many of the factors traditionally associated with poor treatment response, including HIV coinfection, race/ethnicity, and liver cirrhosis. "All the old predictors of response are gone when you have a potent 2-3 drug combination," he said.
Faldaprevir was submitted for U.S. Food and Drug Administration approval this past October and it is also undergoing expedited review by the European Medicines Agency, with approval expected in May.
D Dieterich, C Tural, M Nelson, et al. Faldaprevir Plus Pegylated Interferon Alfa-2a/ Ribavirin in HIV/HCV Coinfection: STARTVerso4. Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 23.