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Treatment Duration for Genotypes 2 and 3: Still Confusing After All These Years - editorial review
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Journal of Clinical Gastroenterology:
September 2010 - Volume 44 - Issue 8 - pp 527-528
Jensen, Donald M. MD
Department of Medicine, Center for Liver Diseases, University of Chicago Medical Center, Maryland, Chicago, IL
Funding: None.
Reprints: Donald M. Jensen, MD, Center for Liver Diseases, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637 (e-mail: djensen@medicine.bsd.uchicago.edu).
Conflict of Interest: Advisory Board member and clinical research investigator for Roche/ Genentech Pharmaceuticals.
Ever since the landmark study by Hadziyannis in 20041 which demonstrated that hepatitis C virus (HCV) genotypes 2 and 3 could be effectively treated with 24 weeks of therapy with pegylated interferon and 800mg/d of ribavirin, there has been a search for the shortest, effective treatment. Early viral kinetics provided the tools with which to study this problem, and several trials were conducted incorporating different treatment durations. Several of these trials demonstrated that treatment could indeed be shortened to 12 to 16 weeks without significant reduction in sustained viral response (SVR) provided that HCV RNA was undetectable after week 4, that is a rapid viral response (RVR).2-4 Not all trials, however, were able to confirm these results, and the largest, prospective randomized trial actually demonstrated that the response to shorter duration (16wk), even in the presence of an RVR, was inferior to 24 weeks.5-7 In 2010, the field remains confused.
Several clinical reviews and other meta-analyses have attempted to address this issue with somewhat conflicting conclusions. As one might anticipate, the clinical trials undertaken to address the issue of response-guided treatment duration have varied considerably in both patient population and design. These variables have included: treatment duration (12, 14, 16wk vs. 24wk), ribavirin dose (800mg/d, 800 to 1400mg/d weight based, and 1000 to 1200mg/d weight based), type of peginterferon (α-2a or α-2b), randomization at baseline or week 4, definition of high viral load, discontinuation rates, and genotype population (both genotypes 2 and 3, all genotype 2). Presumably, because of this confusion, the American Association for the Study of Liver Diseases guideline on HCV recommends 24 weeks treatment duration for all genotypes 2 and 3 individuals.8 Perhaps it would be worthwhile assessing the prior meta-analyses for perceived differences.
Andriulli and colleagues9 analyzed 4 clinical trials comparing genotype 2 versus genotype 3 response. They concluded that genotypes 2 and 3 patients with an RVR, irrespective of basal viral load, responded similarly to short (12 to 16wk) or standard therapy. In an unpublished abstract, Arif et al10 performed a meta-analysis of 6 studies involving 1970 genotypes 2 and 3 patients and concluded that shortened therapy in those subjects with an RVR was inferior to standard therapy both in SVR and relapse rates (RR). A more recent meta-analysis by Slavenburg et al,11 reviewing 8 randomized clinical trials (3 of which were in abstract form and 1 of which used standard rather than pegylated interferon) concluded that "a shorter course (12 to 16wk) of combination therapy does not impair efficacy compared with a 24 week course in HCV genotypes 2 and 3 patients who achieve an RVR." However, when analyzed according to whether patients were randomized to short or standard treatment duration at baseline rather than after week 4, there was an advantage to standard 24 week duration. Further, an analysis of only full-text manuscripts which randomized at RVR, demonstrated no statistical difference between short and standard durations.
In this issue, Drs Singal and Anand performed a meta-analysis to compare 6 clinical trials of treatment duration in genotypes 2 and 3.12 These trials comprised 2434 participants in full-text, published, randomized clinical investigations incorporating peginterferon and ribavirin therapy and which compared short duration (12 to 16wk) to standard treatment duration (24wk) in those with an RVR. The studies were considered homogeneous with similar end of treatment responses in both short and standard treatment duration groups. However, the SVR rate was 79% in the standard group compared with 70% in the short treatment group, which was significant (P=0.008). This difference was largely explained by a greater difference in RR in the short treatment duration subjects (23%) than in the standard treatment group (9%) (P<0.00001). Subgroup analysis failed to demonstrate a significant effect of baseline viral load or genotype on either SVR, RR, or end of treatment responses. Discontinuation rates, however, were higher for those treated for 24 weeks (12%) compared with those treated for shorter durations (5%) (P<0.0001). They conclude that despite of the overall 9% difference in SVR rates, reduced treatment duration could be offered to some genotypes 2 and 3 where the better rate of compliance and lower cost might offset the higher RR. Thus, they raise the possibility that those who relapse after a short course of therapy could be retreated for 24 weeks with an overall cost savings.
How might we reconcile the different conclusions? First, RVR may not be the only factor associated with response to shortened therapy, albeit the most important factor. Mangia and colleagues13 evaluated the effect of ribavirin dose in the rates of RVR in genotypes 2 and 3 patients from 2 large multicenter clinical trials. A ribavirin dose of 15.2mg/kg/d was best for discriminating RVR from non-RVR subjects. Furthermore, low baseline viremia, genotype 2, and high ribavirin dose were independent RVR predictive factors by linear regression analysis. Slavenburg et al11 also found that patients treated with weight-based ribavirin achieved higher SVR rates than those using fixed dose (800mg/kg/d). The 2 largest clinical trials used a fixed 800mg/d dose of ribavirin and both demonstrated that shortened treatment duration was inferior to standard 24 weeks.5,7 Finally, more virologic relapses generally occur in those assigned shortened treatment duration. In analyzing the determinants of relapse after a short course (12wk) of therapy, only body mass index greater than 30 and a platelet count <140,000 were independently associated with relapse.14
In summary, finding convincing evidence to support RVR-guided duration shortening in all genotypes 2 and 3 subjects is still not available, as the meta-analysis by Singal and Anand attest. The difference in SVR rates, however, remains small (<10%) and narrower still for those patients with low baseline viral load. As the authors point out, it may not be unreasonable in selected cases-perhaps those with an RVR yet poorly tolerant of side effects-to strongly consider shortening therapy and if relapse occurs, retreat for a longer duration.
REFERENCES
1. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355.
2. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 versus 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005;352:2609-2617.
3. Von Wagner M, Huber M, Berg T, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129:522-
4. Yu ML, Dai CY, Huang JF, et al. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut. 2007;56:553-559.
5. Shiffman ML, Suter F, Bacon BR, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124-
6. Dalgard O, Bjoro K, Ring-Larsen H, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology. 2008;47:35-42.
7. Lagging M, Langeland N, Pedersen C, et al. Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection. Hepatology. 2008;47:1837-
8. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.
9. Andriulli A, Mangia A, Iacobellis A, et al. Meta-analysis: the outcome of anti-viral therapy in HCV genotype 2 and 3 infected patients with chronic hepatitis. Aliment Pharmacol Ther. 2008;28:397-404.
10. Arif M, Thapar M, Matteson M, et al. Pegylated interferon and ribavirin therapy for 24 weeks versus shorter duration for patients with hepatitis C virus genotype 2 and 3 infection and rapid virologic response: a meta-analysis. Gastroenterology. 2009;136:A791.
11. Slavenburg S, Weggelaar I, van Oijen MG, et al. Optimal length of antiviral therapy in patients with hepatitis C virus genotypes 2 and 3: a meta-analysis. Antivir Ther. 2009;14:1139-1148.
12. Singal A, Anand B. Tailoring treatment duration to 12 to 16 weeks in hepatitis C genotype 2 or 3 with rapid virologic response: systematic review and metaanalysis of randomized controlled trials. J Clin Gastroenterol. 2010;44:583-587.
13. Mangia A, Dalgard O, Minerva A, et al. Ribavirin dosage in HCV genotypes 2 and 3 patients completing short therapy with peginterferon alfa-2b and ribavirin. Aliment Pharmacol Ther. 2010. [Epub ahead of print].
14. Mangia A, Minerva N, Bacca D, et al. Determinants of relapse after a short (12 week) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotypes 2 or 3 infection. Hepatology. 2009;49:358-363.
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