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Rapid virological response as a predictor of a sustained virological response in Egyptian patients with chronic hepatitis C genotype 4

Gheit, Samir A.H.; Keddeas, Marcel W.; Safwat, Eslam

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doi: 10.1097/01.ELX.0000424248.63976.02
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The hepatitis C virus (HCV) is a public health problem worldwide and a leading cause of chronic liver disease 1. Chronic hepatitis C is an important cause of end-stage liver disease. In Egypt, HCV is the single most important cause of liver disease 2, where high HCV rates have been reported among several population groups, reaching up to 20% 3.

The primary goal of treatment of chronic hepatitis C is the achievement of a sustained virological response (SVR), defined as the absence of HCV RNA in the serum 24 weeks after the cessation of treatment using a sensitive test. Host factors including age, body weight, race, and advanced fibrosis influence the outcome of treatment but are poor predictors of response. In contrast, viral factors such as the genotype and the on-treatment pattern of viral response can be used to determine the likelihood of treatment success and guide the treatment duration individually. They have been found to be very useful in clinical practice 4,5.

Rapid virological response (RVR), defined as HCV RNA negative at treatment week 4 by a sensitive PCR-based quantitative assay, was proposed to be highly predictive of achieving an SVR 6. Genotype is generally considered one of the most important predictors of SVR 7. The role of RVR in predicting SVR has not been adequately studied in chronic HCV genotype 4 patients.

Accordingly, in this study, we aimed to determine the relative importance of RVR compared with other baseline host and virological factors in predicting an SVR in Egyptian patients with chronic HCV genotype 4 patients treated with pegylated interferon (peg-IFN) and ribavirin.

Patients and methods

Between February 2009 and July 2010, 66 patients with chronic HCV genotype 4, who started treatment with peg-IFNα-2a and ribavirin at our institution, were enrolled in this prospective study.

Patients with other liver disease, other etiologies of chronic hepatitis (e.g. HBV, alcoholic), or those with liver cirrhosis were excluded from the study. Also, patients with neutropenia (<1500/mm3) or thrombocytopenia (<90 000/mm3) and those with renal impairment (serum creatinine>1.5 upper limit of normal), or with evidence of severe cardiac, pulmonary, retinal, thyroid, or psychiatric disorders were excluded. HIV coinfection, pregnancy, breast feeding, and autoimmune diseases were also considered as exclusion criteria.

Baseline assessment included a thorough medical history and full clinical examination before and during therapy. The following biochemical variables were determined: complete blood count, liver function tests, and kidney function tests. BMI was calculated for all participants.

Manual PCR using Cobas Amplicor HCV 2.0 (Roche molecular system, Pleasanton, California, USA) was used for quantifying HCV RNA before the onset of therapy (the lower limit of detection is 10–50 IU/ml), where a level below 600 000 IU/ml was considered a low viral load whereas a level of at least 600 000 IU/ml was considered a high viral load. Genotyping of HCV was also carried out using the Inno-Lipa HCV2 Line Probe Assay (Innogenetics, Ghent, Belgium).

Pretreatment liver biopsy for pathological grading and staging was carried out in all patients. The hepatic inflammation (grade) and fibrosis (stage) in the biopsy specimens were evaluated according to the METAVIR scoring system.

Patients were then treated with peg-IFNα-2a (40 kDa, 180 µg weekly; Pegasys, F. Hoffmann-La Roche, Basel, Switzerland) plus ribavirin (1000–1200 mg daily) for 48 weeks. Adherence to treatment was defined as taking at least 80% of each drug for at least 80% of the duration of therapy.

During therapy, the following virological responses were assessed: RVR at 4 weeks of treatment, early virological response at 12 weeks, and end of treatment response at 48 weeks. SVR was assessed 24 weeks after the end of treatment.

IBM SPSS (V.19, 2010; IBM Corp., New York, New York, USA) was used for data analysis. Data were expressed as mean±SD, number, and percentages. Student’s t-test for comparison between two independent mean groups for parametric data, Wilcoxon rank-sum test (Z) for comparison between two independent groups for nonparametric data, and χ2-test for comparison between two independent groups for the categorized data were used. P value less than 0.05 was considered statistically significant and a P value less than 0.01 as highly significant.

An informed consent was obtained from each candidate in the study and the study protocol was approved by the hospital’s ethical committee.


Sixty-six chronic HCV genotype 4 candidates for peg-IFNα-2a and ribavirin combination therapy were enrolled in the study. There were 64 men and two women. Their ages ranged from 25 to 64 years, mean age 49.7±9.7 years. Their BMI ranged between 22.5 and 33.9 kg/m2, mean 26.6±2.6 kg/m2.

Overall, of the 66 patients, 41 (62.12%) could achieve an RVR and 54 (81.8%) could achieve an SVR.

The ages of the patients and their BMI were found to have no impact on either RVR or SVR (P>0.05) (Table 1). Also, baseline alanine transaminase (ALT) and aspartate transaminase, measured before the onset of therapy, were found to have no influence on the achievement of either an RVR or an SVR (P>0.05) (Table 2).

Table 1
Table 1:
Demographic data and achievement of rapid virological response and sustained virological response
Table 2
Table 2:
Liver enzymes and achievement of rapid virological response and sustained virological response

A significantly higher number of patients with a low pretreatment viral load (<600 000 IU/ml) could achieve an RVR and SVR than patients with a high viral load (P<0.05) (Tables 3 and 4).

Table 3
Table 3:
Pretreatment viral load and stage of liver fibrosis in patients with rapid virological response
Table 4
Table 4:
Rapid virological response, pretreatment viral load, and stage of liver fibrosis in patients with sustained virological response

In terms of the stage of liver fibrosis, of those who achieved an RVR, nine (22%) were in fibrosis stages 0, 1; 27 (65.9%) were in stages 2, 3; and only five patients (12.2%) were in stage 4 (P<0.05) (Table 3). Of those who achieved an SVR, 10 (18.5%) were in stages 0, 1, 37 (68.5%) were in stages 2, 3, and only seven patients (13%) were in stage 4 (P<0.01) (Table 4).

Of the 54 patients with an SVR, 41 (75.9%) had achieved an RVR (P<0.01). The positive predictive value of RVR for predicting SVR is 100%, whereas the negative predictive value is only 48%, with 100% specificity and 75% sensitivity.

Stepwise logistic multiregression analysis shows that a pretreatment HCV RNA below 1282 821 with positivity of RVR are sensitive markers for the prediction of a patient who will achieve an SVR (F-ratio=20.361, P<0.001).


Combination therapy with peg-IFN and ribavirin is the standard of care for the treatment of chronic HCV infection. The goal of treating a patient with chronic HCV is to eradicate the virus or, in purely clinical terms, to attain an SVR. Pretreatment predictors of response are useful for advising patients on their likelihood of an SVR 7,8.

In the current study, the ages of patients were found to have no impact on either RVR or SVR (P>0.05). This finding agrees that of with Lindh et al. 9 who found that SVR was not influenced by age in genotype 1 patients with RVR. In contrast to our results, other authors found that the age of patients is a factor that might determine the treatment response, where younger patients (<40 years) had higher SVR rates with peg-IFN and ribavirin 8,10. It was proposed that immunological suppression, chronic diseases, and other medication used in the elderly age group could impair the drug response significantly 8. Huang et al. 11 have reported that older patients with HCV infection had a higher frequency of adverse events and poorer adherence to the standard-of-care regimen, which may be the major reason for treatment inferiority.

In terms of BMI, there was no statistical difference in the mean BMI between patients who achieved and those who did not achieve RVR or SVR. However, it is important to note that the patients studied were not obese (BMI<30). These findings are in agreement with those of other researchers who found no difference in the mean BMI between patients who achieved and those who did not achieve an SVR 12,13. They reported that early viral kinetics is not influenced by body weight or BMI when weight-based ribavirin is prescribed 13.

However, other studies have found BMI to be an important predictor (P<0.05) of SVR 14. They concluded that chronic HCV patients with BMI more than 30 kg/m2 are more likely to be insulin resistant, to have more advanced hepatic steatosis or steatohepatitis and fibrosis, and to experience a reduced response to combination therapy 15,16. It was postulated that the poor response observed in obese patients may be because of impaired IFN absorption and altered metabolism because of the production of cytokines from adipocytes 17. Furthermore, it was suggested that induction of hepatic suppressor of cytokine signaling-3 expression may be one mechanism by which obesity reduces the biological response to IFNα 18.

In the present study, baseline liver enzymes were not associated with achievement of either an RVR or an SVR (P>0.05). This was not in agreement with researches who suggested that an elevated ALT level (three-fold higher than the upper limit of normal) is associated with a favorable treatment response and lower ALT was significantly associated with treatment failure 19,20. However, baseline ALT levels were not associated with treatment response in the multilogistic regression analysis 7.

Among patients with an RVR, 27 patients (65.9%) had a low viral load (<600 000 IU/ml) (P<0.05). Thirty-four patients (63%) of those with an SVR had a low viral load, (P<0.05). These findings highlight the importance of pretreatment viral load as a predictor of an SVR. A low baseline viral load (<600 000–800 000 IU/ml) was shown to be an independent predictor of SVR irrespective of genotype in numerous studies 7,8. Interestingly, the effect of viral load as a predictor was found to be nonlinear. Although for HCV RNA concentrations up to ∼400 000 IU/ml a linear correlation with an SVR was shown, for higher HCV RNA levels, relatively stable SVR rates without a significant further decrease have been observed in peg-IFNα-2a/ribavirin-treated patients 21. However, because of the significant differences in the HCV RNA concentrations obtained using the different commercially available assays despite standardization to IU absolute cut-off values for low or high HCV RNA baseline concentrations are difficult to define 7.

In contrast to others, Hu et al. 22 reported that pretreatment HCV viral load was not found to be a predictor of an SVR, explaining this finding by the well-known fact that the viral load fluctuates and a single reading of HCV quantification may not reflect the actual viral load at the time of treatment. They also reported that differences in IFN response could be secondary to either a difference in the viral virulence and/or the replication rate among different HCV genotypes and not the absolute viral load.

In this work, pretreatment histopathological assessment was performed using the METAVIR scoring system. Nine (22%), 27 (65.9%), and five (12.2%) patients achieving an RVR were in fibrosis stages 0, 1, 2, 3, and 4, respectively (P<0.05). With respect to an SVR, 10 (18.5%), 37 (68.5%), and seven (13%) patients were in fibrosis stages 0, 1, 2, 3, and 4, respectively (P<0.05). Our results are in agreement with those of Moraes Coelho and Villela-Nogueira 23, who concluded that strategies to predict an SVR included fibrosis stage. Moreover, Derbala et al. 24 found that severe fibrosis is a strong and independent predictor of failure of response to treatment. However, Prati et al. 25 had an opposite opinion as they mentioned that the SVR rates were not significantly influenced by the fibrosis stage in patients treated with peg-IFNα-2a.

Assessment of RVR is increasingly being recognized as one of the most important determinants of treatment response. In the current study, of the 54 patients who had an SVR, 41 (75.9%) patients had achieved an RVR (P<0.01). Thus, the initial response to treatment is being considered an important predictor of SVR (positive predictive value 100%) in Egyptian genotype 4 patients. Many previous studies in different genotypes have reported that rapid virologic clearance rates are commonly observed to be closely associated with an SVR with variable relations to other pretreatment parameters 26–28. In contrast to early virological response, which is used to predict which patients are unlikely to have a successful outcome with combination therapy, RVR predicts which patients are most likely to have a successful outcome with combination therapy 4,6.


In HCV genotype 4, the most important determinant of SVR is the low pretreatment viral load and RVR. However, further studies on a larger scale of patients are required to identify patients for whom a shortened treatment course is appropriate. Also, the role of other host factors (e.g. sex, IL-28B polymorphism) and viral factors (e.g. quasispecies) should be studied.


Conflicts of interest

There are no conflicts of interest.


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hepatitis C virus genotype 4; rapid virological response; sustained virological response

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