The present study involved the largest cohort of patients infected with HCV-4 to be reported in the literature after treatment with the combination of PEG-INF alfa-2a and RBV for 48 weeks, and shows that this group of patients can no longer be considered “difficult to treat”. Indeed, with the use of this regimen, SVR was achieved in 44.6% of the whole cohort, in 50.8% of those who completed treatment and in 68.8% of those who achieved ETVR. These results are similar to the responses achieved in previous studies that involved cohorts with predominantly genotype 1 and are less than the responses in patients infected with genotype 2 or 3.36,39,40
Only 18 (12.2%) did not complete their course due to either side effects (n=5) or loss to follow up (n=13) and a total of 34 (26.2%) patients were classified as non-responders. This rate of non-response can be accepted if we put into consideration the tertiary nature of our hospital and the inclusion of many complicated cases such as those who failed previous interferon therapy, cases with organ transplantation, and cases copinfected with HIV and/or HBV. The impression that patients infected with HCV-4 respond poorly to interferon-based therapy and are generally “difficult to treat” came from many earlier studies where conventional interferon-alfa was used alone or in combination with RBV ().24,28,30–34
However, the use of PEG-INF alfa-2 and RBV for 48 weeks lead to a substantial improvement in the rate of SVR as evidenced by other studies who used PEG-INF alfa-2b,23,25,29
and PEG-INF alfa-2a,35
as was the case in our study.
Neither the fibrosis stage nor the inflammation grade in the pre-treatment liver biopsy was found to be statistically different between sustained responders and those who developed virological relapse after ETVR. This is contrary to what was previously reported by other studies in patients infected with genotype 14–6
and genotype 4.29
It should be noted that only 72 of the 96 patients who achieved ETVR in the present study underwent a pre-treatment liver biopsy. Also, only 23 patients in our cohort had fibrosis stage ≥3, and only 3 patients had fibrosis stage 4 (cirrhosis). In addition, liver biopsies had not been performed immediately before the onset of therapy. Moreover, in the study by Hassan et al, SVR was less in patients with an advanced fibrosis score, but this was only in a univariate analysis, and no multivariate analysis was performed.29
The study of Kamal et al, however, showed that only age of >40 years and pre-treatment viral load of >2 million copies/mL, can independently predict SVR, and not the pre-treatment liver pathology.25
We believe that the effect of pre-treatment fibrosis on the SVR to therapy becomes more obvious if comparisons between cohorts with predominantly stage 3-4 are compared with those with predominantly stage 1-2 are made.
Contrary to other reports,25
pre-treatment HCV viral load was not found to be a predictor of SVR in our study. It is well-known that viral load fluctuates and a single reading of HCV quantification may not reflect the actual viral load at the time of treatment, especially if we know that viral load was assessed at varying intervals from the onset of treatment. It has also been reported that the differences in interferon response could be secondary to either a difference in the viral virulence and/or replication rate among different HCV genotypes and not the absolute viral load.40
The safety profile of the combination therapy of PEG-INF alfa-2a and RBV used in the present study is comparable to what was previously described in the literature.25,29,41
Indeed, only 18 (12.2%) patients did not complete their course of treatment in our study due to the development of side effects, loss to follow-up and/or transfer to liver transplantation or development of decompensated cirrhosis or hepatocellular carcinoma.
The significantly lower SVR in our patients who previously received interferon therapy (28.8%) compared to those who were treatment-naïve (55.1%) is consistent with the results of many studies in both genotype 1 and genotype 4.27,29,41–43
Our results were better than those of Shiffman et al42
and Mathew et al,43
who reported SVR of 12% to 16% in previously treated patients and 24% to 28% in treatment naïve patients. The mechanism(s) underlying this lower response is not known. However, it may be related to the development of an intrinsic or immunological resistance to the direct anti-viral effect of interferon. Interestingly, interferon-inducible protein 10 kDa (IP-10), which is a chemokine produced by hepatocytes that targets T-lymphocytes, natural killer cells and monocytes was recently identified.44,45
Elevated serum levels of IP-10 before initiation of therapeutic intervention for HCV infection were reported in patients not achieving SVR.46,47
A recent study confirmed that pre-treatment IP-10 levels predict SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load.48
Thus, assessment of pre-treatment IP-10 may help in identifying patients for whom current therapy is beneficial. This needs to be tested in patients infected with HCV-4.
Better identification of the pre-treatment host or viral factors that can identify which patients respond better to therapy is currently attracting more attention. For instance, HCV-4 subtyping has been proposed to affect the response to PEG-INF alfa-2a plus RBV combination therapy.49–50
Other predictors under investigation include increased baseline insulin resistance and AFP levels.51,52
We have shown that diabetes mellitus and AFP levels were less in sustained responders by univariate analysis. However, neither were found to be independent predictors by multivariate regression analysis. These factors need to be assessed in HCV-4 patients in well-designed prospective studies.
This study demonstrates for the first time that lower baseline serum AST and not ALT is an independent predictor of SVR to PEG-INF alfa-2a and RBV in patients with chronic HCV-4. We believe that these lower AST levels reflect less severe histological parameters in the sustained responders. A study by Zechini et al showed a statistically significant positive correlation of baseline aminotransferase values with the hepatitis activity index and fibrosis score.53
In support of our results, a study by Assy et al reported a significant positive correlation between AST values and the extent of hepatic fibrosis.54
We compared our patients who had fibrosis stage 0-2 (n=86) and those who scored 3-4 (n=24) for all baseline parameters and found that only younger age and lower AST levels are independent predictors of fibrosis stage 0-2.
Unlike the situation in most randomized controlled trials, the patients included in this study were heterogeneous: 10.1% had previous organ transplantation, 8.1% were positive for liver autoantibodies (classified as overlap syndrome), 19.6% were positive for HBV or HIV serology, 39.9% were non-responders to previous interferon-based therapy and 6.1% had renal impairment. These factors are known to affect the natural history of chronic HCV infection. However, this sample of patients represents what we usually face in real life. If we exclude cases with all the above co-morbidities, our results will only be applicable to patients with isolated HCV infection. As shown in , sustained responders and relapsers after ETVR were similar regarding transplantation status, BMI, autoantibody status, renal function and HBV or HIV status.
The potential limitations of the current study include the fact that post-treatment biopsy was not done as our main objective was to assess pre-treatment predictors of SVR. There is a solid evidence that SVR is associated with improved outcomes,55
stabilization, and/or regression in hepatic fibrosis stage in response to treatment, especially if it associated with viral clearance.56–58
In addition, assessing the impact of therapy on liver histopathology was beyond the scope of this study. Due to the retrospective nature of the present study, baseline liver biopsy was performed in the majority, but not all cases. Obviously, a better assessment of the predictive role of these two parameters can be done if they were performed in all patients. However, the similarity of the SVR achieved in the present study to what has already been reported by others makes it less likely to substantially affect the results. Another limitation is that patients were followed up for 24 weeks after completion of therapy and thus longer term clinical outcomes could not be determined. Indeed, it has been reported that late relapse may occur after 4 years of completion of interferon therapy.59
However, by definition SVR is the persistence of the ETVR for 24 weeks, which was assessed in this study. In addition, early viral kinetics at week 4, which is called rapid virological response (RVR) was not assessed in this study. Indeed, a recently published work from Egypt showed that the duration of combination therapy with PEG-INF alfa-2b and RBV can be shorter treatment for patients who have attained RVR or EVR.60
However, the concept of RVR was not entertained at the beginning of our study. This needs to be confirmed in another prospective trial. We have recently published a study involving 335 patients with HCV infection of all genotypes.61
It showed that the response of genotype 4 patients to combination therapy is more or less similar to genotype 1. Both showed a worse response compared to those infected with genotypes 2 or 3.
In conclusion, combination therapy with PEG-INF alfa-2a and RBV, if tolerated and completed, is effective in treating chronic HCV-4 patients especially if they are younger than 40 years of age, have no previous interferon therapy and have lower pre-treatment AST levels. Attempts to improve adherence to therapy and the early detection together with treatment of complications are needed to achieve better response to therapy. Further studies addressing other potential predictors of SVR in chronic HCV-4 patients such as the IP10, insulin resistance, HCV-4 subtype heterogeneity are warranted.