Telaprevir for Chronic Hepatitis C with Genotype 1: A Meta-Analysis

Telaprevir for Chronic Hepatitis C with Genotype 1: A Meta-Analysis

Dang SS, Wang WJ, Wang XF, Li YP, Li M, Jia XL, Wang Y, Liu E, Zhao S; Hepato-Gastroenterology 59 (114)
S-S Dang, et al.
http://www.hepato-gastroenterology.org/
DOI 10.5754/hge11312
2012; 59(114): Ahead of print.

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Background/Aims:
The examination of HCV virological clearance through several randomized clinical trials of telaprevir in genotype 1 chronic hepatitis C.

Methodology:
We analyzed the effect of telaprevir on the end of treatment virological response and the sustained response, and investigated its harmful effect using meta-analysis of 5 randomized controlled trials.

Results:
Overall analysis revealed a significant effect of telaprevir in both naive patients (RR, 1.32; 95% CI, 1.08-1.60) and previously failed treated patients (p<0.0001). Monotherapy and double therapy seemed to show no effect in naive patients.
Triple therapy followed with PegIFN-2a plus ribavirin seemed to be effective in both naive patients and previously failed treated patients. Telaprevir was associated with a significantly higher incidence of serious adverse events (RR, 1.45; 95% CI, 1.00-2.10) and with discontinuation (RR, 2.23; 95% CI, 1.40-3.55) because of adverse events. In naive patients, relapsers and non-responders, the regimen of telaprevir/ PegIFN-2a/ribavirin for 12 weeks followed by PegIFN-2a/ribavirin for 12 weeks (T12PR24) was the optimal regimen regarding to efficiency and duration.

Conclusions:
Telaprevir combined with PegIFN-2a plus ribavirin may improve sustained response in genotype 1 chronic hepatitis C. Regimen T12PR24 may be the best regimen in this respect. New randomized controlled trials are required to confirm this meta-analysis.

ABBREVIATIONS: Sustained Response (SR); End Of Treatment Response (ETR); Interferon (IFN); Nonstructural3/4A (NS3/4A); Randomized Controlled Trial (RCT); Relative Risk (RR); Confidence Interval(CI); Telaprevir/Pegifn-2a/Ribavirin for 12 weeks, followed by Placebo/Pegifn-2a/Ribavirin for 12 weeks(T12PR24); Telaprevir/Pegifn-2a/Ribavirin for 24 weeks, followed by Pegifn-2a/Ribavirin for 24 weeks(T24PR48); Telaprevir/Pegifn-2a for 24 weeks (TP24); Placebo/Pegifn-2a/Ribavirin for 24 weeks, followedby Pegifn-2a/Ribavirin for 24 weeks (PR48); Telaprevir/Pegifn-2a/Ribavirin for 12 weeks, followed by Placebo/Pegifn-2a/Ribavirin for 36 weeks (T12PR48); Telaprevir/Pegifn-2a/Ribavirin for 12 weeks (T12PR12);Telaprevir/Pegifn-2a for 12 weeks (T12P12).

INTRODUCTION
Hepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV)(1). HCV is a major public health problem and a leading cause of chronic liver disease.Currently, an estimated 180 million people are infected worldwide (2). About 50-80%of patients with primary HCV infection develop chronic infection; about 25% ofpatients with chronic infection develop cirrhosis within 10 to 30 years; and 5-10% of patients with cirrhosis develop hepatocellular carcinoma (HCC) (3).More than ten years ago, interferon (IFN) therapy provide a sustained virologicalresponse (SR) in 15-20% of patients with chronic hepatitis C. Combining ribavirinwith IFN improved the SR to 40% (4) and until recently has been the most effectivetherapy. Several factors influence the rate of SR. In naive HCV patients with genotype1, which is the predominant genotype in Europe and North America, the SR is about40-50%, whereas an SR is observed in 80% of patients with genotype 2 or 3. Patientswho do not have an SR to the combination therapy have a low likelihood of successwith retreatment, only 12-22% (5-8).

Therefore, the development of effective regimens is required, especially in patients who did not have an SR to previous therapy.Telaprevir, also known as VX-950, has been developed to treat hepatitis C. It is anorally bio available inhibitor of the non-structural 3/4A (NS3/4A) HCV serine protease,an enzyme required for viral replication (9,10). Recently, some controlled clinical trials have shown that telaprevir treatment appears to be promising. However, its effect varied depending on how it was combined with IFN, with or without ribavirin,and treatment duration. We were unable to identify any systematic reviews or meta-analysis addressing the effects of telaprevir for patients with chronic hepatitis C. In this systematic review, we sought to assess both the beneficial and harmful effect of telaprevir. For this purpose,we used an evidence-based approach consisting of meta-analysis of randomized controlled trials (RCT). We assessed its antiviral efficiency in untreated patients and in patients who did not have an SR to previous therapy in order to identify an optimal regimen for each type of patient.

DISCUSSION
After combining all sorts of telaprevir regimens, our meta-analysis found that telaprevir was associated with a higher rate of SR than in control, both in naive patients and previously failed treated patients. However, in naive patients, we did not find that telaprevir monotherapy or double therapy produced an improved rate of SR versus control. This may be due to small-sized samples in the monotherapy or double therapy groups. In fact, not all telaprevir/IFN/ribavirin regimens induced a higher rate of SR than the recommended IFN + ribavirin regimen. The regimen telaprevir/PegIFN-2a/ribavirin for 12 weeks without followed PegIFN-2a/ribavirin did not improve SR, although it improved ETR. However, longer duration of followed PR may not induce higher rates of SR, as 48 weeks and 24 weeks of followed PR did not show a significant difference in the rate of SR.

Regarding efficiency and duration, the T12PR24 regimen may be the best regimen for chronic hepatitis C in genotype 1 naive patients according to the recent RCTs. In previously failed treated patients, of which the majority were relapsers and non-responders, double therapy with telaprevir did not seem to improve SR.

Two regimens of triple therapy with telaprevir (T12PR24 and T24PR48) improved SR versus the recommended PR regimen. However, the T24PR48 regimen, which had alonger duration of telaprevir and IFN plus ribavirin treatment than the T12PR24 regimen, did not further improve SR, regardless of relapsers or non-responders.

Regarding efficiency and duration, the T12PR24 regimen may be the best regimen for chronic hepatitis C in genotype 1 relapsers or non-responders according to the recent RCTs. We found that telaprevir intervention was associated with a significant increase in serious adverse events and with discontinuation because of adverse events. Increased adverse events such as rash, pruritus, hemorrhoids and nausea were also likely due to telaprevir. From the available data in only one trial (14) it was difficult to estimate the effects of duration of intervention therapy on the incidence of adverse events.

In the analysis of these data, we found that adverse events and the discontinuation because10 of adverse events were more common in long-duration therapy, although they were not statistically significant. Therefore, the T12PR24 regimen appeared to provide a better risk-benefit profile than the T24PR48 regimen. However, there were several factors which limited the context of our results. Firstly,only 5 RCTs could be included in the review. Secondly, our compiled data lacked the long-term outcomes of intervention, such as liver histology, the incidence of endstage liver disease or requirement for liver transplantation and liver-related mortality.

However, no clinical trials assessing these outcomes have been carried out. Finally, 2RCTs (55,56) did not supply SR, one of the most important outcomes. However,because of their low numbers of patients, they were less weighted and results were less influenced. Although the total number of patients included in this review seems sufficient in underlining the effects telaprevir, more trials are required: to confirm its treatment effect; to identify any adverse events associated with it; and to assess the effect of telaprevir on subgroups of patients regarding factors influencing treatment effect (such as other genotype, ALT level, cirrhosis, etc.).
In summary, this meta-analysis of five RCTs indicates that telaprevir is an effective therapy in naive patients, relapsers, and non-responders with genotype 1 chronic hepatitis C with respect to virological sustained response, albeit with higher rates of discontinuation because of adverse events. The T12PR24 regimen may have been the optimal treatment regimen for HCV. It is advisable to carry out more randomized trials in order to draw a firmer analysis of the long-term effects of telaprevir.

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