In addition to HCV genotype, viral load and liver fibrosis stage, recent studies have demonstrated an association between certain host genetic factors and successful treatment outcome [23
]. Among the on-treatment predictors, viral load decline of more than 2log10
at week 4 and week 12 has been shown to have a high predictive value for achieving an SVR [17
Because of the high cost of treatment and relatively low effectiveness of current treatment regimens among genotype 1 patients, it is important to identify markers that can reliably predict the likelihood of treatment success. Early prediction of treatment outcome is essential for encouraging the continuation of therapy among patients with a high likelihood of cure and deferring treatment when the chances of achieving an SVR are minimal.
Because of the high cost of antiviral treatment, neither the health system nor the insurance schemes in Georgia will cover the costs of hepatitis C treatment services. Therefore, less than 10% of the patients diagnosed with HCV infection who are in urgent need of antiviral treatment undergo antiviral therapy. Moreover, nearly all of those patients have to pay for their treatment out of pocket, an option that is not possible for most patients. Thus, the early identification of reliable markers of treatment success is of critical importance.
We have performed a detailed evaluation of the first and second phase viral declines in conjunction with identifying IL28B genotypes among patients with chronic HCV infections in Georgia who were receiving treatment with pegylated interferon and ribavirin. The main findings of our study were that among patients infected with HCV genotype 1 with homozygous C/C alleles, the viral load decline (>2log 10) at week one and two was highly predictive of SVR (PPV-100%) and was as useful as RVR in predicting a successful outcome of therapy. Therefore, the probability of reaching an SVR can be assessed as accurately at week one and two as at week 4 or 12. Additionally, the chance of achieving SVR among genotype 1 C/C patients without URVR at week one and two or RVR, is greater than that among the non C/C group. Therefore, according to our data, it is useful both to measure the presence of virological response to therapy at weeks one and two and also to determine the IL28B genotype of HCV genotype 1 patients in order to predict the eventual probability of an SVR.
Our finding was consistent with the finding of Thompson et al
] in which they reported that patients with C/C genotype had the strongest viral reduction levels at week two compared to other IL28B genotypes and therefore were associated with an SVR. In addition, our study showed the effect of URVR at week one to be the earliest effective prediction time point for an SVR. This observation differed from the finding of Bochud et al
] and Arends et al
]. They reported the effect of viral load decline at 24 and 48 hours as the earliest markers for the prediction of an SVR among C/C carriers. As the first phase viral load decline is largely dependent on the fibrosis stage, as well as insulinemia and gamma-glutamyl transpeptidase levels, the differences observed in our cohort may be due to demographic differences between study populations. Despite the effect of C/C genotype for achieving higher URVR and SVR rates among genotype 2 and 3 patients, there was not a significant association between C/C genotypes and viral reduction rates at week 4, although the RVR was numerically higher among C/C carriers than those with C/T and T/T genotypes.
Our results were slightly different from Mangia et al
] and Rallon et al
]. Similarly to the Mangia results, the rate of an SVR was high among patients who attained URVR and RVR regardless of the IL28B genotype. However, unlike their reports, the C/C genotype was not predictive of SVR among patients not achieving URVR and RVR. An unexplained observation was found among this group as C/C genotype was a predictor for achieving URVR and SVR but not attaining RVR, EVR and ETR. The numbers in IL28B genotype groups not achieving URVR and RVR were small; therefore we cannot draw firm conclusions. However, we can speculate that a favorable IL28B genotype influences early viral kinetics and does not have a substantial effect in the later treatment course among genotype 2 and 3 patients. Thus, RVR and not IL28B genotype can be regarded as the better predictor for SVR among genotype 2 and 3 patients unlike genotype1 patients. Altogether these observations suggest that different mechanisms of viral eradication may be operative during the early and late treatment course among patients infected with different HCV genotypes.
Our study has several important implications. First, it is the first study of HCV viral kinetics and IL28B genotypes among the Georgian population, who represent a highly homogeneous ethnic group. Second, we have identified URVR at week one and two to be the earliest effective treatment predictor for SVR among C/C genotype carriers. Third, we found the influence of C/C genotype for SVR among patients in Georgia who were infected with different HCV genotypes. The effect of the C/C genotype among HCV genotype 1 patients is not only mediated by its effect on URVR and RVR, but still is predictive of a favorable outcome of therapy among patients who do not achieve a URVR or RVR. Finally, our data suggest that, a favorable IL28B genotype might only influence the viral eradication early in the treatment course among genotype 2 and 3 patients and does not have a beneficial effect later during therapy among patients without URVR and RVR.
There were several important limitations to our study that should be considered. First, we did not have a large number of female participants in the study, which might allow us to evaluate the gender related responses to interferon therapy among women with different IL28B genotypes. Second, due to the limited number of patients, we did not evaluate HCV treatment responses among genotype 1 patients with different subtypes. Third, the liver fibroses score was evaluated by transient elastography and not liver biopsy, which some consider to be the gold standard for liver fibrosis evaluation. Nevertheless, transient elastography has been shown to accurately diagnose patients with advanced fibrosis and, i.e. METAVIR scores of F2 or 3. Fourth, we do not have information on the liver enzymes or hepatic steatosis and insulinemia levels; these factors have been reported to be related to SVR responses to interferon treatment. Finally, we did not study the effect of other SNPs on interferon responses.
Our study demonstrates importance of defining IL28B genotypes and URVR as the earliest prediction marker for SVR among HCV genotype 1 mono-infected Georgian patients undergoing antiviral therapy. In addition, genotype 1 patients who had an unfavorable IL28B genotype and did not achieve URVR or RVR had a minimal chance of eventually achieving an SVR; however, treatment discontinuation cannot be considered at this point. The predictive power of the IL28B genotype for an SVR continues to be significant beyond the early therapeutic course; however, an RVR is the most important predictor of an SVR among genotype 2 and 3 patients regardless of the IL28B genotype. More research is needed to fully understand the predictive role of URVR and IL28B genotypes among larger patients groups consisting of females and subjects who are co-infected with HIV or HBV.