Therapy with peg-IFN alpha 2a and ribavirin 800 mg/day achieves SVR rates in over 70% when those with genotype 2 and 3 infections are treated as a homogenous group [10
]. The remainder either does not respond to antiviral therapy or relapses after cessation of therapy. This study demonstrates that there was a significant interaction between cirrhosis and genotype 3 infections. The SVR rate among genotype 2 infections with cirrhosis was 78% compared with 17% among those patients with genotype 3 and cirrhosis. Our findings show the negative effect on treatment response of advanced fibrosis, especially cirrhosis, is limited to genotype 3 infections with no demonstrable effect on genotype 2.
The influence of hepatic fibrosis on responsiveness to antiviral therapy has been previously demonstrated in one other clinical trial involving patients with genotype 2 and 3 infections [9
]. Other investigators, however, have not found the same association between hepatic fibrosis and SVR among genotypes 2 and 3 [8
There are several possible explanations for the discrepancy between our results and those of other trials of peg-IFN for the treatment of genotype 2 and 3. Similar to the study by Dalgard et al.
], more than a quarter of our patients had advanced fibrosis (17% F3 and 11% F4); this compares well with the 18% F3 plus only 6% F4, and 18% of patients with METAVIR fibrosis score of ≥3 in the studies of Zeuzem et al.
] and Mangia et al.
], respectively. In these two studies, demonstrating an association between baseline viral load and SVR among genotype 3, the focus was on courses of therapy of ≤24 weeks. In the study by Von Wagner et al.
], the group treated for 16 weeks with genotype 3 and a high baseline viral load, had a poorer response.
Most importantly, during the development of our MLR analysis we did not dichotomize variables such as fibrosis score and baseline viral load as was done in previously mentioned studies of patients with genotype 2 and 3. This analytical approach allowed for improved statistical power and data-driven exploratory analysis rather than arbitrarily choosing non-data-driven cut-off points to dichotomize variables.
Our finding of an interaction between genotype and cirrhosis is limited by the sample size of 21 patients with cirrhosis in our study. Of course there are problems with inter-observer variability for the histological scoring of liver biopsies. This is less of a problem in staging of fibrosis compared with grading of activity especially with expert pathologists [26
]. However, one would expect that any variability in identifying cirrhosis would occur equally in patients with genotype 2 or 3. As the power was robust, it is unlikely that this represents a type 1 statistical error. Although our sample size is small, it is larger than the number of patients with advanced fibrosis in the trials listed above specifically addressing the treatment of genotype 2 and 3 infections. Because of the published recommendations suggesting that a pretreatment liver biopsy does not need to be performed in those patients with genotype 2 and 3 there is a paucity of data available from other clinical studies to address the interaction between genotype 3 and fibrosis [27
]. Regardless of this, our findings will need to be confirmed in subsequent studies with a larger population.
The precise pathophysiological mechanism explaining the difference in SVR among patients with cirrhosis and genotype 2 vs
genotype 3 is uncertain. Yet this may be explained in part by the different early viral dynamics between the two genotypes in response to antiviral therapy, especially among those with advanced fibrosis. Early decreases in HCV viral load have been shown by several investigators to be an independent predictor of subsequent SVR to antiviral agents [9
]. Hepatic fibrosis has been demonstrated to be associated with a slowing in the decline in HCV-RNA within the first 24 h of interferon therapy [31
], and lack of fibrosis is an independent predictor of rapid virological response [9
]. Genotype 2 infections are associated with a more rapid, free virion clearance rate, better inhibition of viral replication and enhanced killing of HCV-infected cells in response to IFN therapy [14
]. Even though a genotype 2-infected patient may have advanced hepatic fibrosis, the high IFN sensitivity of genotype 2 may be able to overcome the negative impact of fibrosis. In comparison, among genotype 3 infections the viral killing in association with antiviral therapy may not be able to overcome the influence of hepatic fibrosis.
Current recommendations for the treatment of genotype 2 and 3 infections do not include pretreatment liver biopsy. The most recent NIH recommendations state that as the favourable response to current antiviral therapy that occurs in more than 70% of patients infected with genotype 2 or 3, it may not always be necessary to perform a liver biopsy [27
]. Our data would support this recommendation for those with genotype 2 infections, yet in genotype 3 infections a pretreatment liver biopsy would yield important information on the patient’s subsequent response to antiviral therapy and perhaps question their appropriateness for shorter courses of therapy. Although rapid virologic response is also a valuable tool predicting ultimate SVR among genotype 3 patients, it may not alleviate the need for pretreatment liver biopsy. In order to provide patients with subsequent information about the likelihood of achieving a clinical cure, they need to endure a minimum of 4 weeks of therapy [9
In conclusion this study demonstrates an interaction between genotype and cirrhosis, where patients with genotype 3 and cirrhosis respond less well to therapy than those with genotype 2 and cirrhosis. If these findings are confirmed in a larger population, patients with genotype 3 infections may benefit from pretreatment liver biopsies in order to determine their degree of hepatic fibrosis and likelihood of subsequent response to antiviral therapy. Whether patients with genotype 3 and advanced fibrosis may benefit from more prolonged courses of peg-IFN and ribavirin also needs further examination.