Treatment of Chronic HCV Infection With Telaprevir
This study compared the efficacy and safety of different TVR-based triple therapy regimens in treatment-naïve and -experienced chronic HCV genotype 1 infected patients. Although these different treatment regimens still have not been yet compared in a randomized trial but triple therapy with TVR has been approved for treatment of HCV genotype 1 infections. Utilizing both direct and indirect evidence, various treatment groups and a network of comparisons (Figure 3) were used for a Bayesian MTC-analysis to estimate the effect of TVR-based regimens compared not only to a common comparator, i.e., standard therapy, but also to each other.
The main results of this analysis are that (i) the addition of TVR increases the likelihood of achieving SVR in treatment-naïve and -experienced chronic HCV genotype 1 patients, (ii) the long FLT and RGT regimen (groups B and D) are equally effective, (iii) the short RGT regimen (group E) is only marginally more effective compared to standard therapy and it is inferior compared to the other regimens, (iv) the short FLT regimen (group C) is non-inferior to the long FLT and RGT regimens. Off note is that the results of group D and E for treatment-experienced patients presented in this study was simulated and has not been applied in prospective randomized studies yet.
Several large multi-center trials have been performed to assess the efficacy and safety of TVR in patients with chronic HCV genotype 1 infection. The results show that in most patients and under most circumstances, TVR increases the likelihood of achieving a SVR. Different TVR treatment strategies were employed to document the superiority of TVR but also to explore differing treatment durations. As expected, not all regimens were equally effective. Hofmann et al. conclude that RGT with 12 weeks of TVR, Peg-IFN-α and RBV, followed by 12 weeks of Peg-IFN-α and RBV for all patients and an additional 24 weeks of Peg-IFN-α and RBV for patients who did not achieve RVR appears to be the best treatment regimen, although no direct comparison to other treatment options, e.g., short FLT TVR-therapy exists, and it has not been assessed in treatment experienced patients.
In our analysis, TVR-based treatment regimen demonstrated a boost in achieving SVR in both treatment-naïve and –experienced patients, with the OR value in treatment-naïve patients lower than in treatment-experienced patients. Moreover, the FLT regimen showed better overall SVR rates and OR results in treatment-naïve patients compared to the RGT regimen. Patients with a FLT duration of 12 weeks triple therapy followed by 12 weeks of Peg-IFN-α and RBV in total showed a SVR rate of 72% despite a shorter treatment duration. The length of treatment duration in RGT in TVR protocols is being discussed. In one open-label study designed to investigate the effects of RGT, patients with eRVR to triple therapy were randomized to 24 or 48 weeks of standard treatment to evaluate whether 48-week therapy can gain further benefits. The results showed no further benefit from the 12-week triple therapy over the 48-week standard therapy in patients with eRVR. Collectively, the TVR 12 and Peg-IFN-α/RBV 24 weeks protocol resulted to be more effective and could shorten the therapy duration compared with standard treatment, thus possibly serving as the treatment of choice for chronic HCV genotype 1 infection. Interestingly, the patients of group E did not achieve significantly higher SVR rates compared to a standard treatment for 48 weeks. Although SVR rates may not be statistically different, it should be acknowledged that the 12 weeks triple regimen is much shorter than the 48 weeks standard treatment and may therefore offer reduction of side effects at equal efficacy. Our data suggest that the chance of treatment failure is likely to be similar despite a longer treatment duration, and that FLT regimen would be a good option if the virus is cleared early. It may be possible to prospectively study this hypothesis in prior partial and null responders; however, the study size and enrollment time for such a trial is likely to be impractical given the rapid pace of HCV drug development. This issue is now a point of interest as the FDA approved a RGT scheme for treatment-naïve and –experienced patients. At the time when the FDA approved this regimen, only three phase 3 studies had evaluated the RGT regimen. The RGT regimen was prospectively evaluated only in two registration trials of treatment-naïve subjects. In these studies, the RGT regimen allowed subjects who achieved eRVR, to stop all treatments at week 24. The RGT regimen was not prospectively evaluated in prior relapsers. Therefore, the FDA used data from cross-study comparison which indicated that SVR rates were 62–77% in prior partial responders and 62–71% in prior null responders who achieved eRVR, irrespective of standard treatment duration (24 or 48 weeks), suggesting that the RGT regimen might also be suitable in prior partial and null responders. Our simulated data for treatment-experienced patients shows that a RGT regimen for 12 weeks triple therapy followed by either 12 or 24 weeks of standard treatment could achieve a SVR of 59% with an OR of 8.2 compared to the control group.
Safety is the biggest concern when TVR-based therapy regimens are used. Despite theencouraging efficacy in terms of enhanced SVR and decreased relapse rates, TVR combination treatment is coupled with an increased incidence of adverse events, including but not limited to rash, anemia, pruritus, anemia, fatigue, flu-like syndrome, headache, nausea, insomnia, diarrhea, and pyrexia, among which rash and anemia are the most common adverse events. These adverse events can lead to discontinuation of treatment in severe cases. The incidences of both SAE and discontinuation of treatment are increased with TVR-based regimen, as shown in this Bayesian MTC. Therefore, the use of TVR is limited in interferon-intolerant patients, and caution should be taken when TVR is used over a long period of time. Since the currently used standard therapy already has numerous adverse effects, we tried to discover whether the potentially shortened treatment duration by adding TVR can reduce the drug toxicity of a longer treatment period with Peg-IFN-α and RBV. Interestingly, this Bayesian MTC demonstrated that the group of patients that initially received 12 weeks triple therapy followed by a fixed-length 24-weeks-treatment with Peg-IFN-α and RBV had the lowest rate of adverse events and discontinuation rate.
In this analysis the results from treatment-naïve or –experienced patients were pooled and analyzed. Five of the included trials investigated the efficacy and safety of TVR in treatment-naïve patients, where only two studies examined treatment-experienced patients. This is a major limitation of this Bayesian MTC. Recently, empirical cross-trial data on triple therapy presented and analyzed by the FDA implied that in prior relapsers, interferon responsiveness does not change in Peg-IFN-α/RBV-experienced subjects. The rationale to pool different patient populations was based on this report. Because the difference in previous treatment status may increase heterogeneity and become a potential liability, in this Bayesian MTC a stratified analysis was performed. The stratified MTC analysis allows, for the first time, an estimate of the effect of RGT in treatment-experienced patients to be determined. Nevertheless, it must be noted that the results of treatment-experienced patients with RGT regimen are only simulated.
Another considerable difference in the patient population was the definition of in- or exclusion criteria for patients with cirrhosis, as it is known to be associated with a reduced SVR. In two trials patients with cirrhosis were excluded, whereas in the others, only patients with decompensated cirrhosis were excluded. A stratified analysis was not possible due to the small number of trials that excluded patients with cirrhosis. Differences in efficacy of TVR in cirrhosis were therefore not analyzed.
There are seven randomized trials included in this Bayesian MTC. Six studies were supported by pharmaceutical industry, which may weaken the strength of evidence demonstrated in this article, although the number of patients included in these 7 randomized trails was fairly large. The heterogeneity of the study collective for this analysis is relatively high, due to the small number of included randomized trails and the different study populations and treatment durations. Inter-study variation may compromise the reliability of these results. However, sensitivity analysis showed that the results of our analysis were stable and reliable. Finally, most of the populations studied here are caucasians, thus the conclusion may not be true for other races or areas. All these limitations point out the direction for future studies.
The therapy options for individuals with chronic HCV genotype 1 infection are widening. To offer these patients the best possible therapy, various predictive factors need to be be assessed before initiating therapy. These factors include demographics, virology, host allelic variation of interleukin-28B and interferon-λ4, laboratory values and histological features. A treatment-naïve patient with favorable predictive factors probably does not need a triple therapy but can be effectively treated with a standard antiviral therapy consisting of Peg-IFN-α and RBV.
Discussion
This study compared the efficacy and safety of different TVR-based triple therapy regimens in treatment-naïve and -experienced chronic HCV genotype 1 infected patients. Although these different treatment regimens still have not been yet compared in a randomized trial but triple therapy with TVR has been approved for treatment of HCV genotype 1 infections. Utilizing both direct and indirect evidence, various treatment groups and a network of comparisons (Figure 3) were used for a Bayesian MTC-analysis to estimate the effect of TVR-based regimens compared not only to a common comparator, i.e., standard therapy, but also to each other.
The main results of this analysis are that (i) the addition of TVR increases the likelihood of achieving SVR in treatment-naïve and -experienced chronic HCV genotype 1 patients, (ii) the long FLT and RGT regimen (groups B and D) are equally effective, (iii) the short RGT regimen (group E) is only marginally more effective compared to standard therapy and it is inferior compared to the other regimens, (iv) the short FLT regimen (group C) is non-inferior to the long FLT and RGT regimens. Off note is that the results of group D and E for treatment-experienced patients presented in this study was simulated and has not been applied in prospective randomized studies yet.
Several large multi-center trials have been performed to assess the efficacy and safety of TVR in patients with chronic HCV genotype 1 infection. The results show that in most patients and under most circumstances, TVR increases the likelihood of achieving a SVR. Different TVR treatment strategies were employed to document the superiority of TVR but also to explore differing treatment durations. As expected, not all regimens were equally effective. Hofmann et al. conclude that RGT with 12 weeks of TVR, Peg-IFN-α and RBV, followed by 12 weeks of Peg-IFN-α and RBV for all patients and an additional 24 weeks of Peg-IFN-α and RBV for patients who did not achieve RVR appears to be the best treatment regimen, although no direct comparison to other treatment options, e.g., short FLT TVR-therapy exists, and it has not been assessed in treatment experienced patients.
In our analysis, TVR-based treatment regimen demonstrated a boost in achieving SVR in both treatment-naïve and –experienced patients, with the OR value in treatment-naïve patients lower than in treatment-experienced patients. Moreover, the FLT regimen showed better overall SVR rates and OR results in treatment-naïve patients compared to the RGT regimen. Patients with a FLT duration of 12 weeks triple therapy followed by 12 weeks of Peg-IFN-α and RBV in total showed a SVR rate of 72% despite a shorter treatment duration. The length of treatment duration in RGT in TVR protocols is being discussed. In one open-label study designed to investigate the effects of RGT, patients with eRVR to triple therapy were randomized to 24 or 48 weeks of standard treatment to evaluate whether 48-week therapy can gain further benefits. The results showed no further benefit from the 12-week triple therapy over the 48-week standard therapy in patients with eRVR. Collectively, the TVR 12 and Peg-IFN-α/RBV 24 weeks protocol resulted to be more effective and could shorten the therapy duration compared with standard treatment, thus possibly serving as the treatment of choice for chronic HCV genotype 1 infection. Interestingly, the patients of group E did not achieve significantly higher SVR rates compared to a standard treatment for 48 weeks. Although SVR rates may not be statistically different, it should be acknowledged that the 12 weeks triple regimen is much shorter than the 48 weeks standard treatment and may therefore offer reduction of side effects at equal efficacy. Our data suggest that the chance of treatment failure is likely to be similar despite a longer treatment duration, and that FLT regimen would be a good option if the virus is cleared early. It may be possible to prospectively study this hypothesis in prior partial and null responders; however, the study size and enrollment time for such a trial is likely to be impractical given the rapid pace of HCV drug development. This issue is now a point of interest as the FDA approved a RGT scheme for treatment-naïve and –experienced patients. At the time when the FDA approved this regimen, only three phase 3 studies had evaluated the RGT regimen. The RGT regimen was prospectively evaluated only in two registration trials of treatment-naïve subjects. In these studies, the RGT regimen allowed subjects who achieved eRVR, to stop all treatments at week 24. The RGT regimen was not prospectively evaluated in prior relapsers. Therefore, the FDA used data from cross-study comparison which indicated that SVR rates were 62–77% in prior partial responders and 62–71% in prior null responders who achieved eRVR, irrespective of standard treatment duration (24 or 48 weeks), suggesting that the RGT regimen might also be suitable in prior partial and null responders. Our simulated data for treatment-experienced patients shows that a RGT regimen for 12 weeks triple therapy followed by either 12 or 24 weeks of standard treatment could achieve a SVR of 59% with an OR of 8.2 compared to the control group.
Safety is the biggest concern when TVR-based therapy regimens are used. Despite theencouraging efficacy in terms of enhanced SVR and decreased relapse rates, TVR combination treatment is coupled with an increased incidence of adverse events, including but not limited to rash, anemia, pruritus, anemia, fatigue, flu-like syndrome, headache, nausea, insomnia, diarrhea, and pyrexia, among which rash and anemia are the most common adverse events. These adverse events can lead to discontinuation of treatment in severe cases. The incidences of both SAE and discontinuation of treatment are increased with TVR-based regimen, as shown in this Bayesian MTC. Therefore, the use of TVR is limited in interferon-intolerant patients, and caution should be taken when TVR is used over a long period of time. Since the currently used standard therapy already has numerous adverse effects, we tried to discover whether the potentially shortened treatment duration by adding TVR can reduce the drug toxicity of a longer treatment period with Peg-IFN-α and RBV. Interestingly, this Bayesian MTC demonstrated that the group of patients that initially received 12 weeks triple therapy followed by a fixed-length 24-weeks-treatment with Peg-IFN-α and RBV had the lowest rate of adverse events and discontinuation rate.
Strength and Weaknesses
In this analysis the results from treatment-naïve or –experienced patients were pooled and analyzed. Five of the included trials investigated the efficacy and safety of TVR in treatment-naïve patients, where only two studies examined treatment-experienced patients. This is a major limitation of this Bayesian MTC. Recently, empirical cross-trial data on triple therapy presented and analyzed by the FDA implied that in prior relapsers, interferon responsiveness does not change in Peg-IFN-α/RBV-experienced subjects. The rationale to pool different patient populations was based on this report. Because the difference in previous treatment status may increase heterogeneity and become a potential liability, in this Bayesian MTC a stratified analysis was performed. The stratified MTC analysis allows, for the first time, an estimate of the effect of RGT in treatment-experienced patients to be determined. Nevertheless, it must be noted that the results of treatment-experienced patients with RGT regimen are only simulated.
Another considerable difference in the patient population was the definition of in- or exclusion criteria for patients with cirrhosis, as it is known to be associated with a reduced SVR. In two trials patients with cirrhosis were excluded, whereas in the others, only patients with decompensated cirrhosis were excluded. A stratified analysis was not possible due to the small number of trials that excluded patients with cirrhosis. Differences in efficacy of TVR in cirrhosis were therefore not analyzed.
There are seven randomized trials included in this Bayesian MTC. Six studies were supported by pharmaceutical industry, which may weaken the strength of evidence demonstrated in this article, although the number of patients included in these 7 randomized trails was fairly large. The heterogeneity of the study collective for this analysis is relatively high, due to the small number of included randomized trails and the different study populations and treatment durations. Inter-study variation may compromise the reliability of these results. However, sensitivity analysis showed that the results of our analysis were stable and reliable. Finally, most of the populations studied here are caucasians, thus the conclusion may not be true for other races or areas. All these limitations point out the direction for future studies.
The therapy options for individuals with chronic HCV genotype 1 infection are widening. To offer these patients the best possible therapy, various predictive factors need to be be assessed before initiating therapy. These factors include demographics, virology, host allelic variation of interleukin-28B and interferon-λ4, laboratory values and histological features. A treatment-naïve patient with favorable predictive factors probably does not need a triple therapy but can be effectively treated with a standard antiviral therapy consisting of Peg-IFN-α and RBV.
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