The treatment of chronic hepatitis C (CHC) infections took a great step forward in 2011 when the first direct-acting antivirals (DAAs) were approved for therapy by the US Food and Drug Administration for patients infected with genotype 1 CHC. This milestone increased sustained virological response (SVR) rates overall and particularly for interleukin-28 (IL-28) C/T patients, patients with genotype 1b infections, and previous relapsers. The phase 3 trials leading up to the approval of boceprevir and telaprevir showed significant increases in SVR rates in comparison with those achieved with pegylated interferon (PEG-IFN)/ribavirin dual therapy (67%-68% versus 40% and 69%-75% versus 44%, respectively).
Undoubtedly, the addition of these protease inhibitors has improved our ability to cure genotype 1 CHC infections; however, the addition of these agents to the treatment regimen has come at a substantial cost: the health care monitoring that is required and adverse events resulting in significant morbidity and even mortality among patients with cirrhosis. In addition to potentiating the anemia seen with PEG-IFN and ribavirin, boceprevir and telaprevir have their own unique side effects. There are also numerous drug-drug interactions that must be addressed with these new agents because of their cytochrome P450 system metabolism. Furthermore, these agents are not approved for non–genotype 1 CHC infections.
Mericitabine (R7128) is a selective nucleoside analogue inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B RNA–dependent RNA polymerase. A nucleoside analogue inhibitor has several advantages, including low rates of resistance and broad genotypic coverage. Initial studies showed no evidence of resistance in patients treated for 14 days with mericitabine monotherapy, and follow-up studies demonstrated antiviral activity across all HCV genotypes.
This issue of Hepatology presents two large, multicenter, phase 2b clinical trials investigating the efficacy of mericitabine plus PEG-IFNα2a and ribavirin versus PEG-IFNα2a and ribavirin alone. Wedemeyer et al. in the PROPEL trial used 4 experimental arms with 500 or 1000 mg of mericitabine twice daily for 8 or 12 weeks and a fifth control arm with PEG-IFN and ribavirin alone in a treatment-naive genotype 1 or 4 CHC population. A response-guided therapy approach was used in all treatment arms; patients for whom HCV RNA was undetectable in serum (virus negativity) at weeks 4 to 22 [extended rapid virological response (eRVR)] discontinued therapy at week 24, whereas all other patients continued PEG-IFN and ribavirin for a total treatment duration of 48 weeks. Patients who received mericitabine showed a high rate of early responses to therapy, with 80% in treatment arms A to D achieving virus undetectability at week 12; however, the SVR rates were not statistically different across the various mericitabine-treated groups or in comparison with PEG-IFN and ribavirin. Although these results did not demonstrate appreciably superior responses in comparison with the standard of care, it is notable that mericitabine demonstrated a high barrier to resistance, and the drug was well tolerated without additional side effects beyond those expected with PEG-IFN and ribavirin alone.
Pockros et al. subsequently carried out a second study to investigate treatment regimens with a longer course of mericitabine combined with PEG-IFN and ribavirin. This similarly large, multicenter, double-blind, parallel-group study in treatment-naive genotype 1 and 4 patients randomly assigned patients to receive either 24 weeks of mericitabine (1000 mg twice daily) or a placebo in addition to PEG-IFN and ribavirin. Mericitabine-treated patients who achieved an eRVR discontinued all treatment at week 24; all others completed 48 weeks of treatment with PEG-IFN and ribavirin. The SVR rate was higher for the mericitabine-treated patients (56.8%) versus the patients receiving PEG-IFN and ribavirin alone (36.5%). Fewer patients in the placebo group achieved eRVR; however, the overall relapse rates were comparable (27.7% and 32% for the mericitabine and placebo groups, respectively). The safety profile of mericitabine was acceptable, with no differences in side effects in comparison with the placebo; a resistance analysis of the 31 patients who met the criteria for resistance monitoring demonstrated no evidence of genotypic or phenotypic resistance to mericitabine. The high dropout rate in this study was notable: 59 patients (35.5%) were prematurely withdrawn, with the majority of the withdrawals (67.8%) due to nonsafety reasons, and it should be noted that fewer patients in the mericitabine group discontinued treatment for safety reasons (6 versus 13).
Recent viral pharmacokinetic studies with mericitabine may help to explain the relatively modest increases in SVR rates observed in the JUMP-C and PROPEL trials. Guedj et al. analyzed the rates of viral decline in 32 treatment-experienced genotype 1 patients given mericitabine (750 or 1500 mg once or twice daily for 14 days) and found that 12 of the 32 patients exhibited a monophasic viral decline slower than that seen with PEG-IFN or other DAAs with their typical biphasic pattern. Twice daily treated patients showed antiviral effectiveness of 0.98 (750 mg twice daily) and 0.997 (1500 mg twice daily), whereas the once daily groups showed effectiveness of 0.80 and 0.90, respectively. Discontinuation of the drug led to a rapid rebound of the viral load to pretreatment levels. In all, the slower rates of viral decline and the rapid rebound after drug discontinuation suggest that although there is less resistance with mericitabine in comparison with the currently approved protease inhibitors, this agent is less potent than other DAAs and is likely to not be useful as a backbone therapy with PEG-IFN and ribavirin as seen in the PROPEL trial, particularly when it is used with response-guided therapeutic regimens. Furthermore, this low potency would explain the similar relapse rates seen in the mericitabine groups from both trials in comparison with their respective placebo arms (27.7% versus 32.0% in the JUMP-C trial and 29.3% versus 31.1% in the PROPEL trial).
The holy grail of CHC treatment is an all-oral, interferon-free regimen, and certain characteristics of mericitabine suggest that it may be more effective in conjunction with other DAAs rather than as part of a traditional PEG-IFN–based regimen. The resistance profile of mericitabine is notable only for the S282T serine-to-threonine substitution, which leads to a 15% reduction in replication capacity in comparison with the wild type. A pooled analysis of more than 600 patients who were given mericitabine in phase 1/2 trials demonstrated no evidence of genotypic resistance when it was administered as monotherapy, in combination with PEG-IFN and ribavirin, or in conjunction with other DAAs.
The INFORM-1 study investigated mericitabine in combination with the nonstructural protein 3/4 protease inhibitor danoprevir and showed a steady, rapid decline in HCV RNA through 13 days of treatment in 72 of 73 patients without evidence of viral breakthrough due to resistance.[11, 12] An in-depth analysis of the HCV quasispecies from the 14 patients who still had detectable HCV RNA at the end of 13 days showed no evidence of the known mericitabine resistance mutation S282T and, more importantly, no enrichment of the preexisting protease inhibitor resistance variants that were present at the baseline. Therefore, mericitabine may prevent the selection of danoprevir-resistant mutants, and phase 2 and 3 trials combining these agents in an interferon-free regimen are needed. Interestingly, an IL-28 polymorphism may also be important outside PEG-IFN regimens: IL-28 CC patients had a greater mean reduction in HCV RNA than non-CC patients (5.01 log versus 4.59 log) in the INFORM-1 study. This was also seen in the JUMP-C trial, in which mericitabine-treated patients with the IL-28B CC genotype were found to have a 100% end-of-treatment response rate, but this was tempered by a relapse rate of more than 20%. The authors attributed the high relapse rate to the response-guided therapy (i.e., 24 weeks) that these patients received. However, further study is required to better understand which genotypic and phenotypic variants predict a response and a risk for relapse.
In summary, JUMP-C and PROPEL were not the great leaps forward that their monikers would have predicted them to be, but instead they may represent smaller steps toward the goal of an all-inclusive, effective treatment for CHC. Interferon-free trials with mericitabine in conjunction with other DAAs are ongoing and offer hope for those in need of treatment.
Dawn M. Torres, M.D.1
Stephen A. Harrison, M.D.2
1Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Bethesda, MD
2Division of Gastroenterology and Hepatology, Department of MedicineSan Antonio Military Medical Center, Fort Sam Houston, San Antonio, TX