- Category: Experimental HCV Drugs
- Published on Monday, 11 March 2013 00:00
- Written by Liz Highleyman
Adding the hepatitis C virus (HCV) protease inhibitors simeprevir or faldaprevir to pegylated interferon plus ribavirin produces higher response rates and the potential for shorter treatment for HIV/HCV coinfected people, according to 2 studies presented last week at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
Approximately 20% to 30% of people with HIV are coinfected with HCV, according to Douglas Dieterich from Mt. Sinai School of Medicine, who presented results from both studies. HIV positive people with hepatitis C tend to experience more rapid liver disease progression, and liver-related death due to HCV is a leading cause of death among people with HIV.
Furthermore, coinfected people do not respond as well to interferon-based therapy. The 2004 APRICOT study, for example, showed coinfection response rates of 29% for HCV genotype 1 and 62% for genotypes 2 or 3 using pegylated interferon/ribavirin, compared with just under 50% and about 75%, respectively, for HCV monoinfected people.
Direct-acting antiviral agents that target different steps of the HCV lifecycle have ushered in a new era of treatment for chronic hepatitis C. Studies presented last year showed genotype 1 coinfection response rates of 61% with boceprevir (Victrelis) and 74% with telaprevir (Incivek) added to pegylated interferon/ribavirin, but these first-generation HCV protease inhibitors are difficult to take and come with added side effects.
While interferon-free regimens are on the horizon, many people with advancing liver disease cannot afford to wait. Coinfected people will have to wait even longer, as new agents are typically approved for HCV monoinfected people first.
Dieterich presented findings from the TMC435-C212 study, which evaluated the safety and efficacy of Janssen/Medivir's investigational HCV NS3/4Aprotease inhibitor simeprevir (formerly TMC435) plus pegylated interferon/ribavirin in coinfected individuals with HCV genotype 1.
This open-label, single-arm, Phase 3 study enrolled 106 coinfected people, most of them on antiretroviral therapy (ART), who either had no previous hepatitis C treatment experience or were prior non-responders.
Most (85%) were men, 82% were white, the median age was 48 years, and about one-quarter had the favorable IL28B CC gene pattern. Just over 80% had harder-to-treat HCV subtype 1a, 12% had advanced liver fibrosis (stage F3), and 9% had cirrhosis (stage F4).
Looking at HIV-related characteristics at baseline, they had a median CD4 T-cell count of 629 cells/mm3 (561 cells/mm3 for those on ART, 677 cells/mm3 for those untreated). Almost all patients on ART had HIV viral load <200 copies/mL, as did 23% of those not on HIV therapy. Nearly everyone was using NRTIs, 87% were taking raltegravir (Isentress), 15% were taking rilpivirine (Edurant), and 3% each were using maraviroc (Selzentry) and enfuvirtide (Fuzeon).
All participants received 150 mg once-daily simeprevir in combination with pegylated interferon alfa-2a (Pegasys) plus weigh-adjusted ribavirin. Treatment-naive people and those who relapsed after prior interferon-based therapy received the triple regimen for 12 weeks, then continued on pegylated interferon/ribavirin alone through week 24.
At that point, using a response-guided therapy (RGT) algorithm, early responders (defined as HCV RNA <25 IU/mL at week 4 and undetectable at week 12) stopped all study drugs, while the rest continued on pegylated interferon/ribavirin alone for an additional 24 weeks. Prior partial responders, null responders, and everyone with cirrhosis (regardless of prior response) received the full 48-week regimen.
Dieterich presented data from an interim analysis of 100 patients who completed 24 weeks of treatment or discontinued prior to that point; 71 had reached 28 weeks and 27 had reached 36 weeks of follow-up.
- At week 4, the overall rapid virological response (RVR) rate was 66%.
- Prior treatment-naive patients, relapsers, and partial responders all had good early response (71%, 93%, and 80%, respectively), but the RVR rate for null responders was just 37%.
- Preliminary sustained virological response rates, calculated for RGT-eligible patients, were 86% at 4 weeks after completion of treatment (SVR4), with 77% still having undetectable HCV RNA at 12 weeks post-treatment (SVR12).
- Corresponding rates were 84% and 75%, respectively, for treatment-naive patients, and 90% and 80% for prior relapsers.
- A large majority of eligible participants (88%) met the RGT criteria and finished therapy at week 24; for this group, the SVR4 rate was 85% and the SVR12 rate was 75%.
- Overall, 15% of patients experienced on-treatment failure and ended therapy based on non-response stopping rules; rates ranged from 0% for prior relapsers, to 9% for treatment-naive, to 36% for prior null responders.
- 13% overall experienced relapse during post-treatment follow-up (10% of treatment-naive and 18% of prior relapsers); all relapses occurred in people with HCV subtype 1a.
- Prior null responders were still being followed, but 64% had not experienced treatment failure at the interim analysis.
- None of the participants on antiretroviral therapy saw an increase in HIV RNA indicating loss of viral suppression.
- Absolute CD4 cell counts fell during interferon treatment -- a typical finding --but CD4 percentages rose or remained stable.
- Triple therapy with simeprevir was generally safe and well-tolerated.
- 5% of participants reported serious adverse events and 4% discontinued treatment for this reason.
- The most common side effects were fatigue (41%), headache (27%), and nausea (26%), typical for pegylated interferon/ribavirin.
- 27% developed neutropenia, 21% had anemia, 20% reported itching, and 17% developed skin rash.
- Bilirubin elevation was common, mostly mild-to-moderate, and not associated with increased liver enzymes.
Simeprevir plus pegylated interferon/ribavirin "led to high virologic response in co-infected patients, regardless of prior response," the investigators concluded. "Simeprevir was well tolerated, with a safety profile similar to HCV mono-infected patients."
Dieterich also reported earlier findings from the STARTVerso 4 trial, looking at the safety and efficacy of Boehringer Ingelheim's HCV NS3/4Aprotease inhibitor faldaprevir (formerly BI 201335) plus pegylated interferon/ribavirin in genotype 1 coinfected individuals. Sustained response data were not yet available for this study.
This open-label Phase 3 trial enrolled 308 coinfected people who were either never before treated for hepatitis C (78%) or relapsed after prior interferon-based therapy (22%).
Patient characteristics were similar to those in the simeprevir study. About 80% were men, a similar proportion were white, and the average age was 47 years. Nearly 80% had HCV subtype 1a, 17% had compensated liver cirrhosis, and about 80% had high baseline HCV viral load.
They also had well-controlled HIV at study entry, with a mean CD4 count of approximately 540 cells/mm3. Nearly 25% were taking ART regimens containing efavirenz (Sustiva), about 20% were taking ritonavir-boosted atazanavir (Reyataz) or darunavir (Prezista), 47% were taking raltegravir or other anti-HIV drugs, and 4% were not on any ART.
Participants were treated with once-daily faldaprevir with once-weekly pegylated interferon alfa-2a and weigh-adjusted ribavirin. Faldaprevir doses were adjusted according to which antiretrovirals were used, based on data from drug-drug interaction studies.
Three separate Phase 1 trials -- described at the same session by Jens Kort from Boehringer Ingelheim --tested pharmacokinetic interactions between faldaprevir and darunavir/ritonavir, efavirenz, and tenofovir (Viread, also in several coformulations) in healthy HIV negative volunteers; a study of atazanavir is underway.
The studies showed no clinically relevant effect of faldaprevir on these medications. This is important because interactions that lower antiretroviral drug levels in the body could lead to loss of HIV control. Conversely, faldaprevir levels increased by approximately 130% when taken with boosted darunavir, but fell by approximately 35% when taken with efavirenz
Therefore, STARTVerso 4 participants taking efavirenz received 240 mg faldaprevir, people taking boosted atazanavir or darunavir got 120 mg, and those on raltegravir or maraviroc were randomized to 1 of the 2 doses.
Everyone assigned to 120 mg faldaprevir stayed on triple therapy for 24 weeks, while those taking 240 mg were randomly assigned to do so for 12 or 24 weeks. Using a response-guided therapy algorithm, people with "early treatment success" (defined as unquantifiable HCV RNA at week 4 and undetectable at week 8) were re-randomized at week 24 to either stop treatment or continue pegylated interferon/ribavirin alone through week 48, while everyone without early response got the longer course.
Dieterich presented interim data from 12 weeks on treatment; faldaprevir dose assignments for the randomized group remained blinded.
- At week 4, 60% of previously untreated participants and 74% of prior relapsers had HCV RNA below the level of detection, rising to 82% and 91% at week 12.
- Early response rates for relapsers were similar to those previously seen in the SILEN-C1 HCV monoinfection study, at 76% and 93%, respectively.
- Most participants -- 77% of treatment-naive and 88% of relapsers -- had early viral clearance and were eligible for randomization to shorter treatment.
- Again, none of the participants on antiretroviral therapy experienced an increase in HIV viral load.
- Triple therapy was generally safe and well-tolerated. The most common side effects were nausea (37%), fatigue (33%), diarrhea (27%), headache (23%), and weakness (22%) -- rates similar to those seen with pegylated interferon/ribavirin alone.
- 10% experienced serious adverse events and there were 3 deaths (none considered related to study medications).
- Looking at side effects that have proven problematic with other HCV drugs, 18% developed anemia, 16% had neutropenia, and 18% reported skin rash.
- At the time of the interim analysis, 18 participants had withdrawn early due to adverse events.
"Interim data compare well with early response rates in monoinfected patients," the researchers concluded. "Adverse events were comparable to those with faldaprevir and [pegylated interferon/ribavirin] in HCV monoinfected patients."
A Significant Advance
At a press conference discussing hepatitis C research, Dieterich said the combined findings were "very encouraging," showing that HIV/HCV coinfected people have outcomes "about equal" to those of HCV monoinfected individuals.
These next-generation HCV protease inhibitors "represent a significant advance" over boceprevir and telaprevir, he said, as they are once-daily, easier to take, and have dramatically reduced side effects and higher success rates. When a cure is achieved, he noted, not only does the risk of liver disease fall dramatically, but HIV-related complications are reduced as well.
"We don’t know when interferon-free regimens will be on the market, and in the meantime were still stuck seeing patients every day, and some are really sick and need to be treated now," he continued. These new compounds are "easier and far superior" and can be used until interferon-free treatment is available.
Moderator David Thomas of Johns Hopkins University predicted that while the approval of interferon-free combinations is not expected this year, the first components likely will be. Comparing the hepatitis C drug development process to HIV, he stated, "It's as if we're going from Crixivan to Atripla in a year and a half."
D Dieterich, V Soriano, M Nelson, et al. STARTVerso 4: High Rates of Early Virologic Response in Hepatitis C Virus Genotype 1/HIV Co-infected Patients Treated with Faldaprevir + Pegylated Interferon and Ribavirin. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 40LB.
J Sabo, Jens Kort, M Haschke, et al. Pharmacokinetic Interactions of Darunavir/ritonavir, Efavirenz, and Tenofovir with the Hepatitis C Virus Protease Inhibitor Faldaprevir in Healthy Volunteers. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 35.
D Dieterich, JK Rockstroh, C Orkin, et al. Simeprevir with Pegylated Interferon/Ribavirin in Patients Co-infected with Chronic Hepatitis C Virus and HIV-1: Week-24 Interim Analysis of the TMC435-C212 Study. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 154LB.
Boehringer Ingelheim. Boehringer Ingelheim Announces Interim Results Evaluating Virologic Response Rates in HCV/HIV Co-Infected Patients Treated with Faldaprevir. Press release. March 4, 2013.