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Shortened Therapy for Hepatitis C Virus Genotype 2 or 3 - Is Less More? EDITORIAL
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NEJM, July 12, 2007
T. Jake Liang, M.D., NIH
"....The data clearly indicate that 24 weeks of therapy was superior to 16 weeks of therapy (more for genotype 2 than for genotype 3)... In patients with chronic hepatitis C virus genotype 2 or 3 participating in this randomized trial, the sustained virologic response rate was higher with 24 weeks of peginterferon and ribavirin than with 16 weeks of treatment (70% vs. 62%, P<0.001). In the subgroup of patients with a rapid virologic response, sustained response rates were 85% in the 24-week group and 79% in the 16-week group (P=0.02)...."
....BUT, many factors are involved in predicting response rather than a 'one-size fits all' approach by saying 14 or 16 weeks for everyone: The answer appears to be more complicated than the findings of the current study suggest...A variety of host and viral factors that affect treatment response are often used clinically to estimate the potential response rate of a patient infected with HCV... genetic diversity among human populations.... As more markers associated with responses to treatment for HCV infection are identified, a mathematical model based on all such markers could be developed to predict the ultimate treatment response in a given patient. Instead of shortened therapy for patients with HCV genotype 2 or 3, a customized management and therapeutic regimen would be designed for each patient. In the context of the study by Schiffman et al., patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration."
Infection with hepatitis C virus (HCV) is a major worldwide cause of chronic liver disease, cirrhosis, and liver cancer, which together represent a chief global public health burden. Therapy has improved substantially since the introduction of interferon-alfa monotherapy in the late 1980s, when the response rate was less than 10%; now, combination therapy with peginterferon and ribavirin has a success rate of about 50%.1,2 Much like the diverse outcomes of HCV infection, the response to treatment varies. Important factors associated with treatment response include the race, age, sex, weight, and biochemical and histologic characteristics of patients. However, viral genotype and, to a lesser extent, viral level remain the primary factors in determining treatment response.
HCV is classified into six genotypes that differ in nucleotide sequence by 30 to 40%.3 On the basis of phylogenetic analyses and population-genetics studies, the virus has been estimated to have first entered a human host several hundred years ago.4 HCV genotype 1 has a worldwide distribution, whereas genotypes 2 and 3 probably originated more recently and have a more restricted geographic distribution, with genotype 2 most common in Western Africa and genotype 3 on the northern Indian subcontinent.3,4 The selection process underlying this divergent genotypic evolution is unclear but probably involves unique aspects of viral transmission and host adaptation in various human populations over hundreds of years. The most revealing insight into the functional divergence of HCV genotypes actually came from studies of the treatment of HCV infection. Patients infected with HCV genotypes 2 and 3 consistently had a much better response to interferon-alfa-based therapy than did those infected with genotype 1.
Studies involving therapy with peginterferon and ribavirin5,6 showed rates of sustained virologic response (defined as an undetectable serum HCV RNA level [<50 IU per milliliter] at 24 weeks after the end of treatment) of 75 to 80% among people infected with HCV genotype 2 or 3, whereas those with genotype 1 had response rates of only 40 to 45%. This difference in response rates according to genotype has prompted the development of different treatment regimens. The current recommendation calls for 24 weeks of therapy with 800 mg of ribavirin daily for patients infected with HCV genotype 2 or 3, as compared with 48 weeks with 1000 to 1200 mg of ribavirin daily for those infected with genotype 1. Because of the substantial side effects and costs associated with treatment, more recent studies have attempted to determine whether the duration of treatment can be further reduced for patients infected with genotype 2 or 3.
Two randomized, controlled studies designed to address this issue7,8 showed that treatment for either 12 or 16 weeks appeared equivalent to treatment for 24 weeks among patients infected with HCV genotype 2 or 3 who have a rapid virologic response (defined as an undetectable serum HCV RNA level by week 4 of therapy). These two studies, although involving modest numbers of study subjects, did provide support for a shortened course of therapy. However, they did not provide information as to whether shortened therapy is as effective as the standard 24-week therapy in people infected with genotype 2 or 3 who do not undergo early virologic monitoring.
In this issue of the Journal, Shiffman et al. report the results of a large, randomized, multinational noninferiority study designed to compare 16-week therapy and 24-week therapy for patients infected with HCV genotype 2 or 3.9 The data clearly indicate that 24 weeks of therapy was superior to 16 weeks of therapy. The difference appears to be more dramatic for patients infected with genotype 2 than for those infected with genotype 3. Indeed, subgroup analysis of patients with genotype 3 showed no significant difference in sustained virologic response rates between the 16-week group and the 24-week group, although there was a trend toward a significant difference that might have been obscured because the study was underpowered.
Other important observations by Shiffman et al. are that people with HCV genotype 2 appear to have a better response than those with genotype 3 and that 16-week therapy is associated with a higher relapse rate but a lower dropout rate than is 24-week therapy. The frequencies of adverse events were similar in the two groups, although more episodes of dose reduction occurred in the 24-week group. Additional data suggest that patients with a rapid virologic response indeed had a high sustained virologic response rate (nearly 80% or more), but the 24-week group still had a better response rate than the 16-week group (85% vs. 79%, P=0.02), in contrast with the findings of the previous two studies. However, since the study by Shiffman et al. was not designed to evaluate the responses of patients with and those without a rapid virologic response (patients were not randomly assigned to treatment groups on that basis), such a post hoc analysis may be flawed.
So does the study by Shiffman et al. tell us whether all patients infected with HCV genotype 2 or 3 should be treated for the currently recommended 24 weeks? The answer appears to be more complicated than the findings of the current study suggest. The fundamental issue raised by this and other studies is whether one can apply any predetermined parameters to guide the treatment regimen for HCV infection.
As a result of thousands of years of evolution, humans are genetically diverse and thus are known to be divergent in their genetic susceptibilities to various diseases and to have variable responses to infections and therapeutic interventions. The marked heterogeneity of HCV infection further underscores the complexity of the clinical spectrum and therapeutic response in humans infected with HCV. A variety of host and viral factors that affect treatment response are often used clinically to estimate the potential response rate of a patient infected with HCV. Recently, virus-kinetic analyses have been applied to data on HCV therapy.10 As a result, among other factors, a rapid virologic response has been promulgated as a useful predictor of the ultimate treatment response. A "stop" rule based on a decrease in the viral RNA level of less than 2 log units after 3 months of therapy is already part of the treatment guidelines.2
In this post-genomic era, much effort has been directed toward understanding genetic diversity among human populations.11 Creation of a comprehensive compendium of these genetic differences is believed to be the necessary step to unravel the genetic and molecular codes of health and disease. Gene-expression profiling and large-scale genomic-marker analysis have already delivered tantalizing insights into the variable nature of disease progression and treatment response in people with HCV infection.12,13,14,15 In addition, they provide important tools to guide therapeutic options.
How can we harness these advances for the clinical management of infection with HCV? Such management, like that for other complex chronic diseases, may be morphing into a personalized approach that could gradually supplant "one-size-fits-all" medicine. This paradigm shift signifies an emerging trend in the future of medicine, as we translate basic science into clinical medicine. This translation has already occurred in cancer chemotherapy and other therapeutics, with the use of the genetic blueprints of individual patients.16,17 As more markers associated with responses to treatment for HCV infection are identified, a mathematical model based on all such markers could be developed to predict the ultimate treatment response in a given patient. Instead of shortened therapy for patients with HCV genotype 2 or 3, a customized management and therapeutic regimen would be designed for each patient. In the context of the study by Schiffman et al., patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
References
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17. Kemming D, Vogt U, Tidow N, et al. Whole genome expression analysis for biologic rational pathway modeling: application in cancer prognosis and therapy prediction. Mol Diagn Ther 2006;10:271-80.
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