- Category: Experimental HCV Drugs
- Published on Sunday, 18 May 2014 00:00
- Written by Liz Highleyman
Some factors traditionally associated with poorer response to interferon-based therapy for hepatitis C played little role in clinical trials of the HCV protease inhibitor faldaprevir, according to several studies presented at Digestive Disease Week this month in Chicago. HCV subtype 1a and prior treatment did not significantly worsen response, while HIV/HCV coinfection may be associated with better response.
The advent of direct-acting antiviral agents has brought about a revolution in HIV treatment. The previous standard of care -- pegylated interferon plus ribavirin -- was poorly tolerated and only cured about half of people with hepatitis C virus (HCV) genotype 1. Several groups had poorer response on average, including people of African descent, prior non-responders, and people with HIV/HCV coinfection. Adding direct-acting agents to interferon-based therapy may help overcome these negative predictors.
Prior Response and Coinfection
Douglas Dieterich from Mount Sinai School of Medicine presented findings from a pooled analysis of the Phase 3 STARTVerso trials, which evaluated Boehringer Ingelheim's HCV protease inhibitor faldaprevir plus pegylated interferon and ribavirin.
This analysis compared sustained virological response rates at 12 weeks post-treatment (SVR12) in HIV/HCV coinfected patients and those with hepatitis C alone. Prior studies have shown that people with HIV both respond more slowly to interferon -- potentially necessitating longer treatment -- and have lower cure rates (i.e., 29% SVR in the APRICOT trial compared with 40%-50% for HCV monoinfected patients).
The analysis included pooled data from 1520 treatment-naive patients and prior relapsers, of whom 308 were HIV/HCV coinfected (null responders were not included). STARTVerso 1 and 2 enrolled previously untreated patients with HCV alone, STARTVerso 3 enrolled treatment-experienced HCV monoinfected people, and STARTVerso 4 enrolled HIV/HCV coinfected people, both treatment-naive and prior relapsers. Participants received faldaprevir at doses of 120 or 240 mg once-daily for either 12 or 24 weeks plus pegylated interferon/ribavirin for either 24 or 48 weeks.
Across all studies, a majority of participants (53%-84%) were men, most (71%-86%) were white, and the mean age was approximately 50 years. Just under half of HCV monoinfected participants had harder-to-treat HCV subtype 1a, but this rose to about 80% in the coinfected group. About 30%-40% had the favorable IL28B CC genetic variant associated with interferon responsiveness. 9%-20% had liver cirrhosis, with higher rates seen in treatment-experienced and coinfected patients.
SVR12 rates were very similar in all 3 trials: 72%-73% in STARTVerso 1 and 2, 70% in STARTVerso 3, and 71%-72% in STARTVerso 4. The researchers found no significant differences according to faldaprevir dose or prior treatment history (naive vs relapser).
Factors significantly associated with poorer response in a regression analysis included IL28B non-CC variants, higher baseline HCV viral load, HCV subtype 1a (vs 1b), older age, advanced fibrosis or cirrhosis (stage F3-F4 vs stage F0-F2), GGT and platelet levels, and black race.
After adjusting for other factors, people with HIV/HCV coinfection actually had higher SVR12 rates than those with hepatitis C alone (adjusted odds ratio 1.68). Since almost all coinfected patients were on antiretroviral therapy with undetectable HIV viral load, the researchers suggested that ability to achieve good treatment adherence might explain this finding.
In a related study of coinfected patients in STARTVerso 4, Cristina Tural and colleagues found that liver cirrhosis and HCV subtype were not significantly associated with SVR in a multivariate analysis. Age, IL28B status, and baseline HCV viral load, however, remained significantly associated with treatment response in this group.
Josep Mallolas from Hospital Clinic Barcelona and colleagues looked at treatment duration for HIV/HCV coinfected patients in STARTVerso 4. Because people with HIV respond more slowly to interferon-based therapy, some experts have recommended pegylated interferon/ribavirin durations of up to 72 weeks. However, the researchers found that among patients treated with faldaprevir plus pegylated interferon/ribavirin, those who achieved "early treatment success" with HCV RNA <25 IU/mL -- but still detectable -- at week 4 and undetectable at week 8 had similar sustained response rates with either 24 or 48 weeks of treatment.
Kristi Berger from Boehringer Ingelheimand colleagues analyzed response rates according to HCV clade, a narrower subdivision than genotype and subtype. Having determined that HCV subtype 1a is associated with lower response to faldaprevir plus pegylated interferon/ribavirin compared with 1b, they looked more closely at the 1a group.
They found that HCV 1a clade 1 -- predominant in North America -- was more likely to have the Q80K polymorphism, which is associated with reduced susceptibility to some DAAs, including the HCV protease inhibitor simeprevir (Olysio). However, neither clade 1 nor the Q80K variant were associated with lower rates of sustained response to treatment with faldaprevir.
Tarik Asselah from INSERM and colleagues looked at development of anemia -- a known side effect of ribavirin -- and whether ribavirin dose reduction affected response rates of treatment-naive patients in STARTVerso 1 and 2.
About one-quarter of participants developed anemia with hemoglobin <10 g/dL. Anemia incidence did not differ between people taking the 120 vs 240 mg faldaprevir doses, and adding faldaprevir did not increase the risk of anemia compared with pegylated interferon/ribavirin alone.
Overall, 60% of patients with anemia reduced their ribavirin dose, 13% stopped ribavirin, and 27% did not change therapy; about 4% used erythropoietin to stimulate red blood cell production and 1% received blood transfusions. Participants who reduced their ribavirin dose had SVR12 rates similar to those of patients who did not change treatment.
DT Dieterich, P Ferenci, IM Jacobson, et al. Similar Adjusted SVR12 Rates for HIV Co-Infected and HCV Mono-Infected Patients and No Dose or Population (Treatment-Naive/Relapser) Effect: Pooled Analysis of Faldaprevir Phase III Trials. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract 240.
C Tural, J Rockstroh, M Nelson, et al. Impact of Baseline Variables on Response to Faldaprevir Plus Pegylated Interferon α-2A and Ribavirin in Patients With HIV/HCV Genotype-1 Coinfection in a Phase III Trial. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1055.
J Mallolas, M Battegay, J Guardiola, et al. Comparison of 24 and 48 Weeks of Treatment With Faldaprevir and Pegylated Interferon/Ribavirin in Patients With Detectable but Not Quantifiable HCV RNA At Week 4. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1052.
K Berger, C Sarrazin, IM Jacobson, et al. Faldaprevir Efficacy in HCV Genotype-1-Infected Patients in Four Phase III Trials: Analysis by NS3 Baseline Polymorphisms, Genotype-1 Subtype and Genotype-1a Clades. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1020.
T Asselah, DM Jensen, G Foster, et al. Virological Response in Treatment-Naive Patients With Chronic HCV Genotype-1 Infection Receiving Faldaprevir Plus Pegylated Interferon alfa-2A and Ribavirin Is Unaffected by Ribavirin Dose Reduction. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1053.
T Asselah, DM Jensen, G Foster, et al. Faldaprevir Plus Pegylated Interferon/Ribavirin Did Not Increase Anaemia Compared With Pegylated Interferon/Ribavirin in HCV Genotype-1, Treatment-Naive Patients: Pooled Analysis of Phase III Studies. Digestive Disease Week (DDW 2014). Chicago, May 3-6, 2014. Abstract Su1060.