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Hepatitis C Therapy in Non-genotype 1 Patients
Current Standard-of-care Treatment Treatment Results in Non-GT-1 HCV Infection
The recommended first-line treatment for non-GT-1 chronic hepatitis C is based on the use of any of the two pegylated IFN-α available administered weekly subcutaneously and daily oral ribavirin. PEG-IFN-α2a should be used at a dose of 180 μg once per week, whereas PEG-IFN-α2b should be used at a weight-based dose of 1.5 μg/kg per week. The ribavirin dose depends on the HCV genotype. Patients infected with GT-4, GT-5 or GT-6 should receive a weight-based dose of ribavirin of 15 mg/kg body weight per day. Patients infected with GT-2 or GT-3 can be treated with a flat dose of 800 mg of ribavirin daily; however, those with baseline factors predictive of a low responsiveness should receive a weight-based dose of ribavirin similar to GT-4, GT-5 and GT-6. Although initially the duration of treatment was fixed, 24 weeks for GT-2 and GT-3 and 48 weeks for GT-4, GT-5 and GT-6, the treatment duration should now be tailored to the on-treatment virological response in most non-GT-1 HCV patients.
Patients infected with GT-2 or GT-3 are not a homogenous population. There is now mounting evidence that these two genotypes should be distinguished from one another and not be anymore labelled together as the 'easy-to–treat' group. Indeed, SVR rates with a SOC 24-week treatment range from 75% to 97% and 62% to 92% in GT-2 and GT-3 patients, respectively. Shortening the duration of treatment without compromising the chances of cure has been investigated in GT-2/GT-3 patients with conflicting results. A meta-analysis concluded that in rapid virological responders (RVR, defined as undetectable HCV RNA at 4 weeks), shortening of treatment duration to 16 weeks is possible in GT-2 patients or in GT-3 patients with an optimal weight-based ribavirin dose. Whatever the genotype, shortening of treatment duration is not recommended in cirrhotic patients. Extension of the treatment to 48 weeks is suggested in the absence of an RVR and/or in the presence of predictive factors of lower SVR such as advanced liver fibrosis or high BMI. The impact of the IL28B polymorphism is unclear in GT-2/GT-3 patients. While some studies have failed to demonstrate any clear association between IL28B polymorphism and SVR, others have reported a positive association between the favourable rs12979860 CC or rs8099917 TT genotype, respectively, with RVR, but not SVR, suggesting an increased rate of relapse in this population along with higher pretreatment viral loads and ALT levels. Finally, two European studies showed that CC genotype is associated with SVR. In an Italian study, IL28B CC genotype is highly predictive of SVR among non-RVR patients.
In patients infected with GT-4, despite the lack of data validating the response-guided therapy concept, it has been suggested by an international panel that a response-guided approach similar to the one used in GT-1 patients may be considered. Thus, RVR are highly likely to achieve SVR and are candidate to 24-week regimens in the absence of poor baseline predictive factor of response. Patients with RVR and pejorative predictive factors and complete early virological responders (EVR defined as undetectable HCV RNA at week 12) should be treated for 48 weeks. Patients with partial EVR (detectable HCV RNA but >2 log10 drop at week 12 and undetectable HCV RNA at week 24) may be considered for treatment prolongation to 72 weeks. IL28B polymorphism is an important baseline predictive factor of response in GT-4 patients. Genotype CC in the SNP rs12979860 is associated with SVR but not with liver severity in these patients. However, its predictive weight is lower than in GT-1 patients, and RVR remains the strongest predictive factor of response.
In patient infected with GT-6, two studies evaluated response-guided therapy in a pilot trial and a randomized trial. They demonstrated that patients with RVR could be treated for 24 weeks. However, those without RVR had very low SVR. In GT-5-infected patients, there are no data on response-guided therapy, and 48-week regimens should therefore be recommended.
Apart from clinical trials, observation cohorts provide us with real-life results. In the PROPHESYS cohort, 37% of the 7163 patients included were infected with a non-GT-1 HCV. The observed SVR rates after SOC treatment were of 41%, 61%, 68% and 71% in GT-4, GT-3, GT-5/GT-6 and GT-2 patients, respectively. In the German cohort, which included 23 893 patients, 39 patients were infected with GT-5 and 39 patients with GT-6. SVR after 48 weeks of treatment was 58% and 59% for GT-5 and GT-6, respectively.
Current results of SOC treatment in non-GT-1 patients are not optimal especially in GT-4 and GT-3 patients.
Standard-of-care treatment will not be successful in 30–60% of patients. A second course of PEG-INF and ribavirin for a longer duration with an optimal dose of ribavirin is currently the only available option. This leads to unsatisfactory results with poor SVR rates ranging from 19% to 34% in previous nonresponders to 46% in relapsers. Therefore, new treatments are urgently needed in this population.