Excerpt from an excellent article in Medscape. I copied only the chapter on treatment. This excerpt discusses the current treatment guidelines, weight based Ribavine, and 48 weeks of treatment for those without an RVR, as well as the SVR rates for Genotype 3. To read the entire article, go to Medscape, register (free), and search for the article title:
Is 3 the New 1: Perspectives on Virology, Natural History and Treatment for Hepatitis C Genotype 3
E. B. Tapper, N. H. Afdhal
Treatment: Pegylated Interferon and Ribavirin (PEG-IFN/RBV)
Genotype has long been known to influence response to PEG-IFN and RBV therapy, with the potential for shorter durations of therapy and higher SVR rates for HCV-2 and HCV-3 compared with HCV-1 infection.[37,38] Historically, HCV-2 and HCV-3 have been lumped together as, relative to HCV-1, patients infected with these genotypes have responded best to interferon-based therapies. On closer inspection of treatment trials, however, HCV-3-infected patients clearly respond more poorly to interferon-based therapy than do patients with HCV-2. For much of the past decade, the focus on therapy has been the determination of therapy duration. There have been several landmark trials experimenting with duration of PEG-IFN and RBV for patients with chronic HCV-2 and HCV-3 infection examining 12, 14, 16 and 24 week treatment durations[39–48] (Table 1). These trials show consistent evidence of poorer therapeutic response in patients with HCV-3 compared with HCV-2, which might be explained by the concomitant steatohepatitis and more advanced fibrosis in HCV-3. .....
Two important early trials established shortened duration (24 weeks) therapy as a viable option. Mangia et al.[41] examined 12- and 24-week courses and found equal rates of SVR overall, 77% and 76%, respectively. There were, however, somewhat striking intergenotype differences. The rate of SVR was 80% for patients with HCV-2 and 66% for patients with HCV-3. Zeuzem et al.[46] treated 42 HCV-2-infected patients and 182 HCV-3-infected patients with PEG-RBV for 24 weeks. SVR was achieved in 93% of HCV-2 patients and 79% of HCV-3 patients.
In 2008, two trials were published comparing 24 weeks to 14 and 12 weeks of therapy. The North-C group found an overall SVR rate of 81.1% and 90.7% in 14- and 24-week courses following an RVR in the intention-to-treat analysis, respectively. Again, genotype-specific response was seen with SVR achieved in 97% of the 31 HCV-2 patients receiving 24 weeks of therapy compared with 92% of the 110 patients with HCV-3 experiencing RVR. Meanwhile, in the population who did not experience RVR, 75.0% (15 of 20) with HCV-2 and 56.3% (54 of 96) with HCV-3 experienced SVR.[39] The NORDynamic Study group saw a similar pattern of results after 24 weeks with HCV-3 patients achieving SVR 58% of the time after 12 weeks and 78% after 24 weeks.[45] More recently, in the PEG-RBV control arm of the FISSION trial, there was a significant difference in the attainment of SVR between genotype 2 and 3 patients, 77.6% vs 62.5%.[3]
ACCELERATE randomly assigned 1469 patients equally divided amongst HCV-2 or HCV-3 to receive 180 μg of peginterferon-alpha-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks.[43] 16 weeks of therapy was inferior to 24 with respect to SVR (62% vs 70%). SVR was achieved in 82% of HCV-2 patients receiving 24 weeks of therapy compared with 71% of HCV-3 patients in the per protocol analysis (67.0% in the intention-to-treat analysis). Amongst patients with a rapid virological response (RVR), SVR rates were 79% and 85% in the 16- and 24-week groups. Interestingly, there was no difference in the rate of SVR between genotypes for the patients that experienced RVR (85% vs 85%), confirming the findings of a prior, smaller trial.[42] ACCELERATE also showed that patients with advanced fibrosis fared poorly by comparison, achieving SVR 43% of the time after 16 weeks and 49% after 24 weeks. The major limitation of this trial is that it used fixed dose RBV 800 mg for all patients rather than weight based. The current consensus is that weight-based ribavirin is necessary for shortened treatment duration, particularly for HCV-3.[43]
For IFN-based treatment, RVR and IL-28b are important predictors of response. While patients with RVR experience SVR at a rate that ranges from 69% to 100%, those without RVR achieve SVR from 30% to 60% of the time.[48] In a follow-up analysis from ACCELERATE, it was shown using multiple logistic regression that patients with low baseline viral load who achieve RVR were the best candidates for abbreviated (16 week) therapy.[49] Confirmatory results were obtained by Mangia et al.[50] in their randomized trial of 24 weeks of PEG-RBV compared with 12 or 36 variable duration ('personalized') course depending on the viral response at week 4. Their results demonstrated that RVR resulted in comparable rates of SVR for patients with HCV-3 (86.4% vs 83.7%) in those treated for 24 weeks or the 12 weeks in the variable duration arm. This study also showed that for HCV-3 patients who did not achieve RVR, 36 weeks of therapy resulted in a higher rate of SVR than 24 weeks (72.5% vs 63.0%). Similarly, in their analysis of data from 3 large studies,[38, 43, 51] Fried et al. showed that RVR on PEG-RBV therapy (achieved by 60% of those with HCV-3) was the most important on-treatment predictor of SVR. The proportion of patients with RVR subsequently achieving SVR was similar across genotypes (88–100%).[52] Meanwhile, the odds of achieving RVR were significantly associated with genotype. Compared to HCV-1, the odds ratio for RVR was 36.017 and 11.943 for HCV-2 and HCV-3, respectively.[52] Accordingly, it is accepted that for HCV-3-infected patients, a 24-week duration is standard with only potential shortening of treatment for patients with RVR for a total duration of 12–16 weeks.[53] The N-CORE study compared treatment duration in 188 HCV-3 patients without RVR on PEG-RBV. Preliminary results from this study suggest that amongst patients completing the study, SVR is achieved in 73% after 48 weeks compared with 54% after 24 weeks.[54] The results of this literature are summarized in the EASL guidelines[55] (Fig. 1).
Guideline based therapy for patients with chronic Genotype 3 Hepatitis C infection. Treatment decisions are based on the patient's viral load response to therapy with measurements at the beginning of therapy as well as 4 and 12 weeks into treatment. Abbreviations: HCV (hepatitis C), RNA (ribonucleic acid), RVR (rapid virological response), and EVR (extended virological response).
The IL-28B gene codes for interferon (IFN)-k3 and has been shown to predict PEG-RBV treatment response in HCV-1.[56] Moghaddam et al. retrospectively reviewed 281 chronic HCV-3-infected patients who were treated with PEG-RBV to determine the role of IL-28b in post hoc prediction of response. They found that while IL-28b polymorphisms do not predict SVR, they do predict RVR; the odds ratio for RVR C/C versus T/T was 1.3 (95% CI: 1.0–1.6).[57] These findings were confirmed in a similar retrospective analysis..[58] On the other hand, in a retrospective evaluation of Mangia et al.'s 2005 trial, IL-28b polymorphisms were also predictive of SVR in the 55 patients with HCV-3 for whom RVR was not achieved.[59]
In summary, genotype 3 is an intermediate IFN responsive strain of HCV and should always be evaluated separately from genotype 2. Evaluating the data, overall genotype 3 has never been truly 'easy to treat' but has a larger subset compared with genotype 1 that attains RVR as a measure of viral response and can subsequently have shortened duration of therapy. Host factors such as Asian ethnicity, IL-28b status and presence of cirrhosis remain important factors in the response to IFN-based therapy.