- Category: HCV Treatment
- Published on Tuesday, 29 January 2013 00:00
- Written by Liz Highleyman
Triple therapy with a direct-acting antiviral drug was more effective than pegylated interferon and ribavirin alone for people with chronic hepatitis C, but there is not yet enough data to determine many differences between boceprevir (Victrelis) and telaprevir (Incivek), or to see effects on long-term clinical outcomes, according to 2 recent medical literature reviews.
The advent of the first direct-acting agents that target hepatitis C virus (HCV) has ushered in a new era of treatment. Pivotal clinical trials are required for regulatory approval of novel drugs, but a larger body of information is needed to inform evidence-based medicine. This critical mass of data is now becoming available for the new hepatitis C therapies.
Dual vs Triple Therapy
As described in the January 15, 2013, Annals of Internal Medicine, Roger Chou from Oregon Health and Science University and colleagues performed a systematic review of the comparative effectiveness of antiviral treatments for chronic hepatitis C.
The analysis was funded by the Agency for Healthcare Research and Quality (AHRQ), a federal agency within the Department of Health and Human Services that is charged with "improve[ing] the quality, safety, efficiency, and effectiveness of health care for all Americans."
The study authors conducted a search of English language medical literature using MEDLINE (from 1947 through August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries, looking for randomized clinical trials of antiviral treatment, as well as studies evaluating associations between sustained virological response (SVR) -- or continued undetectable HCV viral load after completing treatment -- and clinical outcomes.
- The authors found no trials that evaluated the effectiveness of hepatitis C treatment in terms of long-term clinical outcomes -- largely because modern therapies have not been available very long.
- Looking at dual therapy, pegylated interferon alfa-2a (Pegasys) plus ribavirin was associated with a higher likelihood of SVR than pegylated interferon alfa-2b (PegIntron) plus ribavirin for previously untreated patients, with an absolute difference of 8%, based on 7 trials of poor to fair quality.
- Pegylated interferon alfa-2b was associated with a lower frequency of serious adverse events, but the absolute difference was small (about 1%), side effects were usually temporary, and there was no difference in likelihood of treatment discontinuation for this reason.
- For people with easier-to-treat HCV genotypes 2 or 3, pegylated interferon/ribavirin for 24 weeks led to higher SVR rates than treatment for 12-16 weeks, and lower doses of pegylated interferon were less effective than standard doses, based on 2-4 fair quality trials.
- For people with difficult-to-treat HCV genotype 1, triple therapy with pegylated interferon, ribavirin, and either boceprevir (based on 2 fair quality trials) or telaprevir (based on 4 fair quality trials) yielded a higher likelihood of SVR than pegylated interferon/ribavirin alone, with an absolute difference of 22% to 31%.
- Compared with dual therapy, adding boceprevir increased the risk for hematologic adverse events such as anemia, while adding telaprevir increased the risk for anemia and skin rash.
- Across all antiviral regimens, treatment response rates were lower for older patients, black patients, people with higher baseline viral load, or more advanced liver fibrosis.
- 1 large, well-designed Veterans Affairs cohort study and 18 smaller cohort studies found that achieving SVR was associated with lower risk for all-cause mortality compared with lack of sustained response.
"SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy," the researchers concluded. "An SVR after antiviral therapy appears associated with improved clinical outcomes."
As a limitation of their analysis, they noted that several trials included "highly selected populations" -- so they might not be good predictors of real-world outcomes -- and observational studies "did not always adequately control for confounders."
These findings confirm that adding a direct-acting antiviral to pegylated interferon/ribavirin increases side effects, but shortens treatment duration for many patients and significantly improves the likelihood of achieving a cure.
Boceprevir vs Telaprevir
The second combined analysis, published in the January 15, 2013, issue of Clinical Infectious Diseases, focused on differences in safety and efficacy between the HCV protease inhibitors boceprevir and telaprevir.
Jennifer Kieran from Trinity Centre for Health Sciences in Dublin and colleagues performed a systematic literature review and meta-analysis of studies evaluating these 2 drugs for treatment-naive people and patients who did not achieve SVR with a prior course of interferon-based therapy. The latter group includes null responders who experience little or no drop in viral load after starting treatment, partial responders whose viral load falls but does not reach undetectable, and relapsers whose viral load is undetectable at the end of therapy but rebounds after treatment is completed.
The study authors identified 499 relevant studies, but only 10 met the inclusion criteria. Study arms that evaluated boceprevir or telaprevir for durations other than the licensed schedule or without standard doses of both pegylated interferon and ribavirin were excluded.
- Studies showed that telaprevir had significantly greater efficacy for prior relapsers, with an odds ratio (OR) of 2.61 -- or nearly 3-fold greater likelihood of SVR -- and a confidence interval (CI) of 1.24-5.52.
- However, differences in relative efficacy did not reach statistical significance for other types of patients, although odds of responding were similar or greater.
o Treatment-naive patients:
* Boceprevir vs standard of care (1417 total patients): OR 3.06, CI 2.43-3.87;
* Telaprevir vs standard of care (1309 patients): OR 3.24, CI 2.56-4.10;
* Telaprevir vs boceprevir: OR 1.06, CI 0.75-1.47.
o Treatment-experienced patients:
* Boceprevir vs standard of care (604 total patients): OR 6.53, CI 4.20-10.32;
* Telaprevir vs standard of care (891 patients): OR 8.32, CI 5.69-12.36;
* Telaprevir vs boceprevir: OR 1.27, CI 0.71-2.30.
"Telaprevir had greater relative efficacy than boceprevir in patients who had previously relapsed," the researchers concluded. "There was insufficient evidence to detect a difference in treatment outcomes between the 2 agents in the overall population."
"It was not possible to determine relative efficacy for subgroups such as patients with cirrhosis owing to small numbers," they added.
Meta-analyses such as these typically run behind the current state of the science, especially in a field as fast-moving as hepatitis C treatment. People with HCV and their clinicians are now awaiting all-oral regimens -- several of which are currently under study -- that promise to shorten treatment duration and raise cure rates even further (as high as 100% for some patient groups) without the difficult side effect of interferon.
R Chou, D Hartung, B Rahman, et al. Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review. Annals of Internal Medicine 158(2):114-123. January 15, 2013.
J Kieran, S Schmitz, A O'Leary, et al. The Relative Efficacy of Boceprevir and Telaprevir in the Treatment of Hepatitis C Virus Genotype 1. Clinical Infectious Diseases 56(2):228-235. January 15, 2013.