Response-guided Therapy for Patients With Hepatitis C Virus Genotype 6 Infection
A Pilot Study
P. Tangkijvanich; P. Komolmit; V. Mahachai; K. Poovorawan; S. Akkarathamrongsin and Y. Poovorawan
Posted: 06/07/2012; J Viral Hepat. 2012;19(6):423-430. © 2012 Blackwell Publishing
Abstract
The optimal duration of treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) in patients with hepatitis C virus (HCV) genotype 6 is unknown. This study was aimed at determining treatment response on the basis of rapid virological response (RVR) of HCV genotype 6 in comparison with genotypes 1 and 3. Sixty-six treatment naïve patients were treated with PEG-IFN-α2a (180 μg/week) plus weight-based RBV (1000–1200 mg/day). Patients with genotype 1 n = 16) and genotype 3 (n = 16) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients with genotype 6 (n = 34) who achieved RVR were treated for 24 weeks (response-guided therapy) and the remaining patients were treated for 48 weeks (standard therapy). The mean baseline HCV RNA levels were not statistically different between groups (6.4 ± 0.8, 6.0 ± 1.0 and 6.5 ± 0.8 Log10 IU/mL for genotypes 1, 3 and 6, respectively). Patients with genotypes 1, 3 and 6 achieved RVR in 43.8%, 87.5% and 73.5% of cases, respectively. One patient with genotype 1 and 3 with genotype 6 were considered nonresponders and discontinued therapy. Sustained virological response (SVR) was achieved in 62.5%, 81.3% and 76.5% of patients with genotypes 1, 3 and 6, respectively. The SVR rate in patients with genotype 6 who underwent response-guided therapy was 88%. This pilot study suggested that the SVR rate of HCV genotype 6 was at an intermediate level between those of genotypes 3 and 1. Treatment with PEG-IFN plus RBV for 24 weeks may be sufficient for patients with genotype 6 who achieve RVR. Prospective randomized trials are required to evaluate this response-guided strategy in a larger number of patients with genotype 6.
Discussion Only
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Currently, the treatment outcome of patients with genotype 6 has not been adequately studied because of the limited number of cases in western countries. However, the optimal treatment duration of HCV genotype 6 is a particularly important consideration in south China and many south-east Asian countries in which this genotype is prevalent.[18,19] Most prior studies of HCV genotype 6 included patients treated for 48–52 weeks.[12,20,21] Recently, a small study of Asian American patients comparing a 48-week to a shortened 24-week regimen showed that a significantly higher SVR rate was achieved in those treated by the 48-week course (75% vs 49%).[22] However, the limitation of the study was its retrospective design and the results were not analysed with regard to an intention-to-treat method. A retrospective study conducted in China showed that the rate of SVR in 22 patients with genotype 6 treated for 24 weeks was comparable with that of genotypes 2/3 (82% and 83%, respectively).[10] In that study, the positive predictive values of RVR and EVR for HCV genotype 6 were comparable with those for genotypes 2/3 (87%vs 91% and 86%vs 87%, respectively). More recently, a randomized controlled trial of 60 patients with genotype 6 demonstrated that there was no significant difference in SVR rates in patients treated with 48-week and 24-week regimens (79% and 70%, respectively).[13] In that study, RVR was a significant predictor of SVR in the 48-week group and tending towards significance in the 24-week group, although a sizeable number of patients did not have RVR measurement performed. These data indicate that 24 weeks of PEG-IFN plus RBV could effectively treat a subset of patients with genotype 6. However, the feasibility of a response-guided therapy by individualizing the duration of treatment according to viral kinetics in patients with genotype 6 has never been investigated.
To our knowledge, the present report is the first study directly examining the optimal duration of therapy based on RVR in patients with genotype 6. In this study, more than 70% of patients with genotype 6 achieved RVR and received an abbreviated 24-week regimen. Among these patients, the rate of relapse was approximately 10%, and nearly 90% of them eradicated the virus. These data are consistent with observations regarding treatment of HCV genotypes 1, 2, 3 and 4,[23] which suggest that monitoring RVR might be useful to guide treatment duration for patients with genotype 6. In particular, therapy might be shortened to 24 weeks in patients with genotype 6 achieving RVR, whereas a 48-week course was appropriate for those who cleared the virus after week 4. Thus, the integration of RVR into treatment decisions might identify patients with genotype 6 for whom an abbreviated course of therapy has proven to be satisfactory. The abbreviated regimen could offer advantages by reducing unnecessary medication exposure, which may make the treatment of HCV genotype 6 more affordable and maximize the cost effectiveness of therapy.
Several prospective trials of PEG-IFN and RBV have examined the use of RVR to select patients with HCV genotype 1 and non-1 genotypes for abbreviated therapy.[15,24–26] These studies have shown that a subset of patients with genotypes 2/3 and genotypes 1/4 who achieve RVR may be able to shorten therapy to 12–16 weeks, and 24 weeks, respectively, if certain pretreatment conditions are fulfilled. In recent meta-analyses of randomized controlled trials, it has been demonstrated that abbreviated therapies do not significantly compromise the likelihood of SVR among rapid responders with most favourable characteristics for SVR, including genotype 1 or 2 with low viral load and genotype 3 with a weight-adjusted RBV regimen.[27] On multivariate analysis, the independent factors associated with SVR among patients with genotype 6 in this study were RVR and low pretreatment viral load. In fact, all rapid responders with low pretreatment viral load eventually eradicated HCV infection after completing 24 weeks of therapy, whereas the relapse rate was relatively high (20%) in rapid responders with high pretreatment viral load. These data suggested that abbreviated therapy for HCV genotype 6 might be particularly effective for rapid responders who had low pretreatment viral load. However, owing to the small sample sizes analysed, the ability to draw conclusions was rather limited, and further studies would be required before an abbreviated course could be generally recommended.
In this study, we found that the rate of RVR in patients with genotype 6 was slightly lower than that of genotype 3 (74% and 88%, respectively), but was significantly higher than that of genotype 1 (44%). These results might reflect a predictive indicator of the subsequent SVR rate of patients with genotype 6, which was at an intermediate level between those of genotypes 3 and 1, as demonstrated in previous reports.[8–11] It should be mentioned that patients with genotype 2 have higher SVR rates than patients with genotype 3.[28] Thus, it is speculated that patients with genotype 2 should have a higher probability of achieving SVR than patients with genotype 6. Also of interest was the observation that, although the proportion of patients achieving RVR varied by genotype, the probability of achieving SVR was consistently high (88–93%) across all genotypes among patients who achieved RVR. This result is consistent with previous data that patients who achieve RVR have the highest rates of SVR (80–90%), regardless of HCV genotype.[23]
Although PEG-IFN represents the backbone of treatment, combination with RBV has been shown to directly influence the outcome of therapy in that it prevents relapse. Current guidelines recommend a weight-adjusted dose of RBV in combination with PEG-IFN for treating patients with genotype 1, while a flat, low dose of RBV (800 mg/day) is recommended for treating patients with genotype 3.[7] However, a weight-adjusted dose of RBV might be useful to enhance the response rate in patients with genotype 3 who do not achieve RVR and in those with RVR undergoing abbreviated therapy.[29,30] Currently, the optimal dose of RBV for the treatment of patients with genotype 6 is unknown. In previous studies, daily weight-based or fixed doses of RBV had been used, rendering comparisons rather complicated. Nonetheless, a recent prospective trial has adopted a weight-based dosage of RBV for abbreviated treatment (24 weeks), which might result in achieving SVR equivalent to that obtained with longer treatment duration (48 weeks).[13] In our study, all patients, regardless of HCV genotypes, received a weight-adjusted dose of RBV (1000–1200 mg/day). Taken together, these data might reflect the need of a weight-based dosage of RBV in patients with genotype 6 undergoing abbreviated therapy.
Regarding risk factors for HCV acquisition, our data showed that patients with genotype 6 had a significantly higher proportion of previous history of intravenous drug users compared with patients infected with other genotypes. This discrepancy might be due to the small sample size of the study because barely statistical significance was observed. In this respect, a recent larger study of Southeast Asian Americans did not find significant differences in terms of risk factors among patients with HCV genotypes 1, 2/3 and 6.[31] In contrast, another study conducted in Hong Kong showed that patients with genotype 1 were mainly infected through blood transfusion, while a statistically larger proportion of patients with genotype 6 were infected through intravenous drug injection.[11]
In conclusion, the results of this pilot study suggest that the overall response rate of HCV genotype 6 is slightly lower than that of genotype 3 but higher than that of genotype 1. Although the small sample size that might limit conclusions on utility of both RVR and EVR, our data suggest that a response-guided therapy based on viral kinetics may be useful to optimize treatment in patients with HCV genotype 6. In particular, shortened treatment duration of 24 weeks could be sufficient in patients with low pretreatment viral load who achieve RVR. Further prospective randomized trials are required to evaluate this response-guided strategy in a larger number of patients with genotype 6.
http://www.medscape.com/viewarticle/764199
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