New direct-acting antiviral agents for the treatment of Hepatitis C virus infection and perspectives
The treatment of Hepatitis C was revolutionized in 2011 when 2 recently developed direct-acting antiviral agents (DAA) were FDA approved and made available for clinicians to treat Hepatitis C. These DAA's were developed through the intense study of the viral life cycle and in contrast to the non-specific antiviral activity of interferon and ribavirin, these agents specifically are designed to inhibit viral proteins involved in the Hepatitis C virus life cycle. The 2 agents approved in 2011 are specifically NS3/4A serine protease inhibitors. The first 2 agents approved in the new class of DAA were telaprevir (Incivek; Vertex Pharmaceuticals, Cambridge, Massachusetts, USA) and boceprevir (Victrelis; Merck and Company, White House Station, New Jersey, USA). These 2 agents were FDA approved for the indication of treatment of genotype 1 Hepatitis C in patients with compensated liver disease. They are not approved for use in HIV/Hepatitis C co-infected individuals, individuals with decompensated liver disease, and in those individuals following liver transplant. The FDA approval of these 2 agents has changed the SOC to a triple drug regimen for those individuals infected with genotype 1 Hepatitis C. Genotype 1 is the most prevalent genotype of HCV in the United States.
Telaprevir is a selective peptidomimetic NS3/4A protease inhibitor that forms a covalent reversible enzyme-inhibitor complex. It is used in combination with pegylated interferon and ribavirin in both treatment- naive and treatment- experienced individuals with genotype 1 Hepatitis C. The studies cited to prove their efficacy include both Phase 2b (PROVE 1, PROVE 2 and PROVE 3) and Phase 3 (ADVANCE) trials. The Phase 3 ADVANCE study confirmed the superiority of triple drug therapy with telaprevir pegylated interferon and ribavirin to the old SOC (pegylated interferon and ribavirin) for those individuals infected with genotype 1 chronic Hepatitis C. There were significantly higher (SVR) rates in both telaprevir arms compared with controls with 75% and 69% in the 12 and 8 week arms of telaprevir achieving SVR, respectively, compared with 44% in the SOC group (P<0.0001). In Incivek's package insert, SVR rates are sited at 79%, 72%, and 46% respectively due to re-analysis of the data by the FDA. Relapse rates were observed in 9% in each telaprevir arms versus 28% in the SOC control arm. In the now approved 12 week telaprevir regimen, 58% of patients achieved an eRVR (Hepatitis C RNA undetectable at weeks 4 and 12), of whom 89% went on to achieve a SVR. An impressive SVR rate of 62% was observed in those patients with bridging fibrosis or cirrhosis treated with telaprevir, pegylated interferon and ribavirin versus 33% in the SOC control arm. Among African Americans telaprevir increased the SVR rates to 62% in the 12-week arm and 58% in the 8-week arm of telaprevir plus pegylated interferon and ribavirin as compared to only 25% in the SOC arm. Grade 3 rash occurred in 6% of the 12 week telaprevir group. Telaprevir was associated with incremental declining hemoglobin levels of 1 to 1.15 g/dl. In addition, anorectal complaints were noted in the telaprevir treated patients in 29% versus 7% in controls. Critical to the use of telaprevir is that it must be combined with both pegylated interferon and ribavirin.
In the ILLUMINATE Study, the foundation for Response Guided Therapy (RGT) in treatment-naïve patients was established for telaprevir based regimens. In the trial all patients were treated with 12 weeks telaprevir plus pegylated interferon and ribavirin. Those that achieved an eRVR (no detectable Hepatitis C RNA at weeks 4 and 12) were then randomized to either 12 or 36 additional weeks of pegylated interferon and ribavirin. In the ILLUMINATE study 65% of the study patients achieved an eRVR. The study found that in individuals who achieved an eRVR a total treatment duration of 24 weeks was not inferior to the of 48 weeks regimen with SVR rates of 92% versus 88%, respectively. These high SVR rates were achieved irregardless of race, ethnicity, or the absence or presence of advanced fibrosis. However, it is cautioned that insufficient numbers were included to recommend the use of RGT in those individuals with cirrhosis.
In the Phase3 REALIZE trial telaprevir-based therapy was investigated in treatment-experienced patients including prior responder/relapsers, partial responders (>2 log decline in HCV RNA at week 12 but detectable at week 24) and null responders (<2 log decline in HCV RNA at week 12 of previous interferon and ribavirin based therapy). The findings of the REALIZE trial indicated that among prior relapsers (end of treatment Hepatitis C RNA negative with prior interferon and ribavirin based treatment but then subsequently relapsed) the SVR rate was ultimately 88% in the telaprevir delayed start arm and 83% in the simultaneous start arm compared with only 24% in the control group that received SOC (PEG+RBV) treatment. For previous partial responders, the SVR rate was 54% and 59% in the delayed and simultaneous start arms, respectively, versus 15% in controls. Of those prior null responders (<2 log decrease in HCV RNA at week 12 of interferon and ribavirin based therapy) only 33% and 29% achieved SVR with telaprevir plus pegylated interferon and ribavirin versus 5% in controls. Of note, those individuals with cirrhosis who had had a prior null response to interferon and ribavirin therapy the SVR rate was only 14%. Prior partial responders with bridging fibrosis with cirrhosis had an acceptable SVR rate of 44% but the numbers are low. Prior relapsers to interferon and ribavirin therapy are allowed for RGT as an independent study 107 and the Prove 3 trial demonstrate 94% SVR in relapsers with eRVR on 24 week total treatment duration.
Telaprevir is now approved for the treatment of genotype 1 CHC. Tablets are dosed at 750 mg to be taken every eight hours (plus or minus one hour) in combination with pegylated interferon and ribavirin. One practical consideration is that the telaprevir must be taken with a fat-containing meal. The major additional toxicities include worsened anemia, the possibility of severe even life threatening skin reactions, and anorectal complaints. The stopping rules for discontinuation of telaprevir plus pegylated interferon and ribavirin include a HCV RNA level greater than 1000 IU/ml at weeks 4 or 12 or detectable HCV RNA at week 24.
As telaprevir is a potent inhibitor of CYP3A, there are considerable drug-drug interactions that must be taken into consideration. There are published lists of contraindicated drugs and the more extensive list of drugs with potential interactions. These are available in the package insert for telaprevir or available on various websites.
Boceprevir is a selective peptidomimetic NS3/4A PI that forms a covalent but reversible enzyme-inhibitor complex. The Phase 2b SPRINT-1 trial demonstrated the improved viral eradication rates with the addition of Boceprevir to SOC pegylated interferon and ribavirin. A suggestion for a potential role for a 4 week lead in of pegylated interferon and ribavirin before the initiation of Boceprevir interferon and ribavirin was also suggested. The Phase 3 SPRINT -2 trial studied Boceprevir in combination with pegylated interferon and ribavirin in treatment-naïve genotype 1 HCV patients. All patients received a 4 week lead in of pegylated interferon and ribavirin and then were randomly assigned to receive placebo plus pegylated interferon ribavirin for an additional 44 weeks, boceprevir 800 mg TID plus pegylated interferon and ribavirin for an additional 44 weeks, or RGT with boceprevir 800 mg TID plus pegylated interferon and ribavirin dependent on response (RGT). The non-black cohort boceprevir groups had significantly improved SVR rates of 68% in the boceprevir/pegylated interferon/ribavirin 48 week treatment group and 67% in the RGT group versus 40% in the control arm of pegylated interferon ribavirin alone. Among African Americans, the SVR rate in the control group was predictably lower at 23%. However this was improved with the addition of boceprevir to 53% in the 48 week treatment group of boceprevir plus pegylated interferon and ribavirin and 42% in the RGT group. Adverse affects included anemia, which was much more common in the boceprevir treated patients and dysgeusia was also common with boceprevir but rarely was drug limiting.
In the Phase 3 RESPOND-2 trail boceprevir was studied in treatment- experienced patients. This trial included previous non-responders that were partial-responders (>2 log decrease in HCV RNA at week 12 but had persistent viraemia at week 24) and those that had responded but relapsed (end of treatment HCV RNA non-detectable with subsequent relapse documented). A somewhat complicated RGT algorithm was utilized. SVR rates were significantly higher in both the boceprevir plus pegylated interferon and ribavirin group (66%) and the RGT group (59%) compared with SOC pegylated interferon and ribavirin controls (21%). Previous relapsers had superior SVR rates in comparison with non-responders in all 3 arms which is as expected. Among the interferon sensitive group that achieved a 1 log or greater decline in HCV RNA at the end of the 4 week lead in phase of pegylated interferon and ribavirin 79% achieved SVR when followed by boceprevir plus pegylated interferon ribavirin in the 44 week group and 73% in the RGT group. In those individuals with less than 1 log declined HCV RNA during the lead-in phase, the SVR rates were superior in both the boceprevir groups (34% and 33% respectively) as compared to the control group of 0%.
Boceprevir is now approved for the treatment of genotype 1 CHC. The tablets are dosed at 800 mg every 8 hours (plus or minus one hour) in combination with pegylated interferon ribavirin. All patients receive a 4 week lead-in of pegylated interferon and ribavirin and then boceprevir is added. RGT dictates the ultimate total duration of therapy. The readers are referred to specific algorithms which are available in the package insert or the Merck website. Treatment futilities are determined by a HCV RNA level 100 IU or greater at treatment week 12 or HCV RNA detectability at treatment week 24. These futility points dictate that all three drugs should be discontinued. Patients with cirrhosis are not eligible for RGT. In addition, individuals who did not achieve at least a 2 log decline HCV RNA during previous interferon ribavirin treatment are not eligible for RGT and should be treated for a 4 week lead-In of pegylated interferon and ribavirin followed by 44 weeks of triple therapy with boceprevir plus pegylated interferon and ribavirin.
Boceprevir is also a potent inhibitor of CYP3A. It is contraindicated with the concurrent use of medications that strongly induce CYP3A to avoid loss of efficacy. It is also contraindicated for use with medications that are highly dependent on CYP3A clearance due to potential toxic concentrations of these drugs resulting from simultaneous usage. As with telaprevir, boceprevir is not dose reduced and monotherapy is strictly prohibited. The reader is encouraged to access the Victrelis website for drug-drug interaction consideration.
Additional discussion in this review paper involves the use of IL-28B CC genotype. The IL-28B genotype does not predict SVR in the setting of triple therapy with protease inhibitors added to pegylated interferon and ribavirin but does predict those individuals that are likely to require only 24 to 28 weeks of therapy with these protease inhibitors. The clinical utility of this testing is uncertain. The strength of the protease inhibitors is that is does overcome the strong predictive nature of the IL-28B CC genotype that is seen in SOC pegylated interferon and ribavirin treated patients.