There has been considerable progress in antiviral therapy for hepatitis C since 1989 when six months of interferon monotherapy was shown first to be effective in normalizing serum alanine aminotransferase (ALT) levels in a proportion of patients with chronic non-A, non-B hepatitis.1 However, once the hepatitis C virus was identified, it became apparent that only a small proportion of these patients cleared virus after treatment.2 Extending the course of treatment to a year doubled the rate of viral clearance.3 More impressively, the addition of the oral nucleoside ribavirin to the interferon regimen dramatically increased the durable viral clearance rate compared to interferon alone.4, 5 Up until this point, the dose and duration of therapy were fixed and did not consider differences in the host or virus. One size fits all. However, the initial studies of the combination of interferon and ribavirin found that viral genotype had a significant impact on interferon sensitivity and treatment response.4, 5 Indeed, in patients infected with genotype 2 or 3 the sustained viral response (SVR) was the same whether they received 6 or 12 months of treatment.4, 5 Thereafter, the duration of therapy was modified according to the genotype of the infecting virus. This “tailoring” of therapy continued as pegylation of the parent interferon drug extended its half life allowing greater exposure to the drug despite less frequent dosing. When combined with ribavirin, pegylated interferons increased the SVR to more than 50%.6, 7 Hadziyannis demonstrated that a 6-month course of this new antiviral combination regimen was just as effective as a full year patients with genotype 2 and 3 and also found that a lower dose of ribavirin could be used.8
Treatment was further customized with the concept of “stopping rules” that modified treatment based the viral response, or rather the lack of response, during the initial weeks of treatment. For example, patients who still had detectable virus in the blood after the first 24 weeks of treatment with standard interferon and ribavirin almost never reached a sustained viral response, even if they continued treatment for an entire year.4, 5 Discontinuation of therapy was justified in these early non-responders. A similar observation led to the concept of the “12 week rule” for genotype 1 infected patients who received therapy with pegylated interferon and ribavirin. Failure to reduce the HCV RNA level by at least 2 logs after the first 3 months of treatment (early viral response; EVR) predicted treatment failure and justified discontinuation of therapy.9
Clinical investigators have long sought to determine whether higher doses or a longer duration of therapy might improve the SVR rate in genotype 1 patients; in other words, tailoring treatment to those patients who are more resistant to conventional therapy. High-dose interferon induction failed to accomplish this. More recently, prolonging pegylated interferon and ribavirin treatment to 18 months also proved to be of little benefit.10, 11 However, the latter studies used a low dose of ribavirin, so it is difficult to completely dismiss the potential benefit of long-term therapy in some genotype 1 patients. Indeed, higher doses of either pegylated interferon or ribavirin throughout the entire course of treatment have shown some promise in typically insensitive patient groups such as African-Americans and patients with advanced hepatic fibrosis.12, 13
While most studies in the past focused on trying to improve the SVR rate by increasing the intensity of therapy, several recent studies, including the paper by Jensen and colleagues in this issue of HEPATOLOGY, have shown that patients who are quite sensitive to the antiviral effects of interferon-based treatment might achieve excellent outcomes with shorter courses of therapy.14–18 Not surprisingly, three studies have shown that just 12 to 16 weeks, rather than 24 weeks, of treatment may be adequate in patients with hepatitis C who are infected with genotype 2 or 3 and able to eliminate detectable HCV RNA after the first 4 weeks of therapy (rapid viral response; RVR).14–16 However, a higher than usual dose of ribavirin was required to achieve response with the shorter course of treatment. Shorter courses with the usual dose of 800 mg per day are currently being studied in the international ACCELERATE trial. In addition, responses to the shorter courses were not as robust if patients had a high pretreatment virus level, particularly in patients with genotype 3, or hepatic fibrosis. In contrast to the HCV patients infected with genotype 2 or 3, those with genotype 1 have always been less sensitive to interferon-based therapy. So, the recent reports suggesting that shorter courses of therapy might also be possible in some of these cases are surprising. It is important to note, however, that those who appear to benefit from the shorter course are a relatively small and select subset. Indeed, Zeuzem concluded that 24 weeks of treatment was insufficient for the overwhelming majority of genotype 1 patients.17 He found that the benefit was confined to those with a pre-treatment virus level less than 250,000 IU/mL who lost detectable HCV RNA after just 4 weeks of treatment. The conclusions of Jensen and colleagues18 were similar when they reanalyzed data from a previously published randomized phase III study that had compared different doses and durations of pegylated interferon and ribavirin.8 They noted that about a quarter of patients infected with genotype 1 had RVR (HCV RNA undetectable after 4 weeks) and durable clearance of virus (SVR) eventuated in 89% of those randomized to 24 weeks of treatment. The likelihood of SVR among patients with RVR was not increased by extending treatment to the usual 48 weeks. As with the previously mentioned study, the potential of a shorter course of treatment was mostly confined to those with low pretreatment levels of HCV RNA.
Although these findings are exciting, the implications for our patients are not so clear. The obvious advantage of testing for RVR at week 4 is that it may shorten therapy in about 10% to 20% of genotype 1 patients. It might also be reassuring to know that a patient had achieved RVR if they subsequently need to decrease the dose of one of the drugs or discontinue therapy. However, it is important to recognize the limitations of RVR. We still do not know whether RVR portends a similarly high chance of SVR in patients with low viral loads who are typically difficult to treat, such as African-Americans or those with fibrosis, hepatic steatosis, insulin resistance, or alcohol use. These patients were uncommon in the cited studies and, until further data are available, they should continue to receive standard therapy.
Perhaps the biggest downside of RVR is the potential impact of increasing the complexity of the treatment algorithm for chronic hepatitis C. Utilization of RVR will entail stratifying patients to different regimens of treatment based on baseline genotype and levels of virus before initiation of therapy. In the case of genotype 1 patients with low viral loads, treatment might need to be further modified based on either the week 4 qualitative HCV RNA (RVR) or the week 12 quantitative HCV RNA (EVR). Adding RVR to the already complicated hepatitis C algorithm will increase its complexity and risk doing one of two things. It may either make physicians even more reluctant to treat patients with hepatitis C or increase the risk that the treatment is not correctly managed. With respect to the latter, it important that we recognize RVR for what it is and is not. RVR identifies the small subset of patients who are most likely to achieve SVR with only 24 weeks of treatment. It is not, however, a surrogate for SVR. Indeed, only about 30% to 35% of genotype 1 patients who ultimately achieve SVR will be HCV RNA negative by the 4th week of treatment.6, 18 Thus, failure to achieve RVR does not imply that the patient is a non-responder and certainly does not justify discontinuation of therapy. In other words, RVR does not replace EVR.
So, is this progress? I believe so. RVR does complement EVR and helps us further tailor therapy to the virus and our patient. Are we ready to use RVR in our clinical practices and modify the standard of care? Probably not quite yet. Some physicians who are comfortable with the nuances of treatment may wish to integrate RVR into their treatment armamentarium, but the applicability to other patient groups must be shown before this becomes common practice. I believe that shorter treatment for those with RVR will be increasingly accepted over time. We can be certain of one thing… one size no longer fits all.