Hepatitis C virus genotype 4 therapy: progress and challenges
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Sanaa M. Kamal1,2
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02385.x
© 2011 John Wiley & Sons A/S
,
Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02385.x
© 2011 John Wiley & Sons A/S
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The hepatitis C virus genotype 4 (HCV-4) is prevalent in Egypt, the Middle East and Africa. Recently, the epidemiology of HCV-4 has changed and this genotype has begun to cross borders and spread to several regions in Europe through immigration and injection drug use. HCV-4 has been considered a difficult-to-treat genotype based on the low sustained virological response (SVR) rates obtained with conventional interferon (IFN)-based regimens. Pegylated interferons (PEG-IFN) plus ribavirin therapy for chronic HCV-4 has been associated with increased SVR rates of more than 60%. Shorter treatment of chronic HCV-4 patients with rapid and early virological responses has been associated with high SVR rates, better compliance, fewer adverse events and lower costs. Despite this progress, the treatment of HCV-4 non-responders, injection drug users, patients coinfected with human immunodeficiency virus, thalassaemic patients, patients on haemodialysis and patients with HCV-4 recurrence after liver transplantation still represents a significant therapeutic challenge. Treatment of HCV-4 has markedly improved, with higher sustained response rates and the possibility of shorter regimens. Despite the recent progress in the treatment of HCV-4, more research is required to optimize current therapy and include genotype 4 patients in clinical trials on emerging therapies such as specifically targeted antiviral therapy for HCV with protease and/or polymerase inhibitors.,
Hepatitis C virus genotype 4 (HCV-4) is the most frequent cause of chronic hepatitis C in the Middle East, North Africa and sub-Saharan Africa (1–3). The global epidemiology of HCV-4 is difficult to establish because most epidemiological studies have focused on the prevalence and distribution of HCV-4 in Egypt, the country with the highest worldwide incidence and prevalence of HCV, with rates of up to 13%, where HCV-4 is the cause of 90% of HCV infections (1–8). The prevalence of HCV-4 is 50% in the Kingdom of Saudi Arabia (9, 10), 30% in Syria (11), 76% in the Gaza Strip (12) and 6% in Jordan (13). A few epidemiological studies have described the prevalence of HCV-4 in African countries such as Gabon, Nigeria, Central Africa, Cameroon and Tanzania (14–18).
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Hepatitis C virus genotype 4: shifting epidemiology
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The HCV-4 has recently spread to Southern Europe through immigration and injection drug use. The prevalence rates of HCV-4 have increased steadily in France (19–21), Italy (22), Greece (23) and Spain (24). In France, the prevalence of HCV-4 increased from 4% in 1990 to more than 11% in a decade (19, 20). In Europe, most HCV-4 cases are clustered among intravenous drug users (19, 21, 23, 24) and patients coinfected with human immunodeficiency virus (HIV) (19–26). A recent study showed that HCV-4 was the second most frequently detected genotype and was found in 23% of a large cohort of HIV-positive homosexual men from England, the Netherlands, France, Germany and Australia (25–27
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Although approximately 20% of the worldwide HCV population is infected with genotype 4, these patients have been underrepresented in large multicentre clinical trials (28, 29) because of the limited prevalence of this genotype in Europe and the United States. As a result, data regarding the responsiveness of genotype 4 have been limited. The treatment of chronic HCV-4 hepatitis has evolved over the past decade. Initially, conventional interferon (IFN)- monotherapy administered at a dose of 3–5 MIU three times a week resulted in disappointing sustained virological response (SVR) rates ranging between 5 and 10%. The addition of ribavirin improved the SVR rates to almost 35% (30–33) which were similar to SVR in HCV genotype 1 patients but lower than HCV genotype 2 and 3 patients (28, 29). As a result of these SVR rates, HCV-4 was considered a ‘difficult-to-treat’ genotype.
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Treatment of chronic hepatitis C virus genotype 4-naïve patients
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A steady improvement in the overall response rates of chronic HCV-4 hepatitis to C therapy was achieved with the introduction of pegylated interferon (PEG-IFN)-2, which resulted in a dramatic improvement in SVR rates compared with conventional IFN- (34–44) (Fig. 1). A meta-analysis of studies conducted until 2003 that included genotype 4 patients showed significantly higher SVR rates among genotype 4 patients receiving PEG-IFN- plus ribavirin than in those receiving conventional IFN- plus ribavirin (55 vs. 30%, P=0.0088) (38). Controlled randomized and non-randomized clinical trials demonstrated high SVR rates ranging between 50 and 79% in chronic HCV-4 hepatitis patients receiving PEG-IFN-2b plus ribavirin (34–46) (Fig. 2).
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Figure 1. Evolution of chronic hepatitis genotype 4 therapy. SVR, sustained virological response.
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Figure 2. Meta-analysis of pegylated interferon and ribavirin therapy clinical trials in chronic hepatitis C. SVR, sustained virological response.
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Thus, the SVR rates in chronic HCV-4 hepatitis are better than those achieved in genotype 1. The next step in optimizing HCV-4 therapy is to adopt an individualized approach to therapy, adapted to host and viral factors, and to determine the duration of therapy and the therapeutic options for special patient populations.,
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Tailoring hepatitis C virus genotype 4 therapy
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The optimal treatment duration must be defined for successful long-term treatment outcomes using the shortest possible treatment duration to maximize therapeutic efficacy, tolerance and cost effectiveness. Therapy could be individualized by tailoring the drug dosage, intended treatment duration and early stopping rules based on HCV genotype, early viral responses to treatment, pretreatment viral load or body mass index (BMI). Tailoring therapy helps to maximize the benefit of HCV therapy by sparing the patient unnecessary adverse events and the cost of therapy associated with unnecessary treatment. Treatment can also be stopped in patients with unfavourable factors.
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Individualization of the duration of therapy based on rapid and early virological response
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A shortened course of treatment may be useful when adverse effects or cost is an issue. In an effort to improve SVR rates, various strategies have been adopted to tailor treatment durations based on on-treatment response. The standard duration of therapy for chronic HCV-4 hepatitis was 48 weeks (34–37) until emerging data from randomized prospective trials (39, 40, 44, 45) clarified the optimal duration to identify the determinants of SVR. In one study (39), patients were randomized to receive PEG-IFN-2b (1.5 μg/kg/week) plus ribavirin (1000–1200 mg/day) for 24, 36 or 48 weeks. Overall, SVR rates were significantly higher in patients receiving treatment for 36 or 48 weeks than in those treated for 24 weeks (66 and 69 vs. 29%, P=0.001 for each comparison). Relapse during follow-up was the highest in patients treated for 24 weeks (20/45, 44%) but relatively rare in the longer treatment arms. There was no significant difference between the 36-week and the 48-week treatment regimens for the overall cohort. Baseline viral load was a predictor of SVR. Patients with pretreatment viral load >2 million copies/ml treated for 24 or 36 weeks had lower SVR rates than those treated for 48 weeks. This suggests that the 48-week treatment regimen may be better suited for patients with high baseline viraemia (Fig. 3).
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Figure 3. A proposed algorithm for the treatment of chronic hepatitis C genotype 4. EVR, early virologic response; HCV, hepatitis C virus; RVR, rapid virological response.
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A non-randomized study (40) compared PEG-IFN-2b (100 μg/week) plus ribavirin (1000–1200 mg/day) for 24 or 48 weeks. Virological outcomes were similar in patients receiving PEG-IFN- plus ribavirin for 24 or 48 weeks (SVR, 48.6 vs. 55.0%, P=0.517). However, patients were not randomized but were allocated to the different arms according to the affordability of treatment.
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Rapid virological response (RVR), defined as undetectable serum HCV RNA at week 4 of therapy, is becoming an important predictor of the duration of PEG-IFN- and ribavirin therapy and is a key opportunity to individualize therapy according to treatment-related viral kinetics (42, 43). Several studies have shown that 24 weeks of therapy is sufficient to induce SVR in patients with chronic HCV-4 patients achieving RVR (44, 45). One study (44) assessed the predictability of response in patients with chronic HCV-4 infection and determined the efficacy of a variable shorter-duration PEG-IFN-2b plus ribavirin treatment regimen based on viral load at weeks 4 and 12.
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Participants were randomly assigned to receive treatment either for the standard fixed duration of 48 weeks (control group, n=50) or a shorter treatment based on interim viral load. In patients with chronic HCV-4 and undetectable HCV RNA at weeks 4 and 12, treatment with PEG-IFN-2b and ribavirin for 24 weeks and 36 weeks, respectively, yielded high SVR rates with significantly fewer adverse events and better compliance. After controlling for predictors, low baseline histological grade and stage were associated with SVR (P less then 0.029) in all groups. In addition, in patients treated for 48 weeks, older age (P=0.04), higher baseline BMI (P=0.013) and low baseline HCV RNA (P less then 0.001) were also associated with SVR.
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Overall, these data suggest that in patients with chronic HCV-4 and undetectable HCV RNA at weeks 4 and 12, treatment with PEG-IFN-2 and ribavirin for 24 weeks and 36 weeks, respectively, is sufficient. Another study (45) reported an SVR rate of 86.7% [95% confidence interval (CI): 69.3–96.2%] in patients infected with HCV-4 who were assigned to 24 weeks of treatment with PEG-IFN-2a 180 mug/week plus ribavirin 1000/1200 mg/day after achieving a RVR.
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This prospective study also confirms that a 24-week regimen of PEG-IFN-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy. Recently, the combination of nitazoxanide, PEG-IFN-2a and ribavirin increased the percentage of patients with RVR and SVR, compared with patients given PEG-IFN plus ribavirin, without an increase in adverse events (47). The addition of nitozoxanide to standard of care helped increase SVR rates and shorten the treatment duration to 24 or 36 weeks. Given the adequate safety profile of nitazoxanide and the reasonable cost of this oral therapy, the short duration of triple therapy with pegulated interferon (PEG-IFN), ribavirin and nitazoxanide could be a cost-effective regimen for chronic HCV-4 hepatitis
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Pharmacogenetics, race, ethnicity and personalized medicine for hepatitis C virus therapy
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Race and ethnicity play a critical role in pharmacogenetics and population-level differences in drug response. Certain studies have demonstrated that in non-responders, some IFN-stimulated genes were upregulated before treatment (48–51). These findings associated with clinical, biochemical and histological data may help detect potential non-responders before starting treatment. This is an important issue since the standard treatment is physically demanding and costly. The aim of pharmacogenetics is to identify the individual genetic determinants of drug activity so that therapy can be tailored to the individual patient.
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It has been shown that certain ethnicities such as African Americans, Hispanics and Asians might respond differently to HCV therapy. Currently, it is not clear whether patients with chronic HCV-4 respond differently to PEG-IFN- and ribavirin therapy. A retrospective analysis of SVR rates in French, Egyptian and African patients with chronic HCV-4 showed an overall better response in Egyptian patients infected with the 4a subtype (52).
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In multivariate analysis, two factors were independently associated with SVR: an Egyptian origin of transmission and the absence of severe fibrosis. It is not clear from this study whether the difference in SVR was related to ethnicity, HCV-4 subtype or the mode of transmission. Egyptian patients acquired the infection through antischistosomal therapy, while most of the French and African patients acquired the infection through illicit drug use. Another study (53) showed that treatment of patients with chronic HCV-4 infection by PEG-IFN-2b and ribavirin results in a more rapid decrease in HCV RNA level and a better SVR rate (62 vs. 13%) in Egyptians than in non-Egyptians.
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In contrast, a Spanish study (54) evaluating the response of chronic HCV-4 treatment-naïve Spanish patients to combination therapy revealed a SVR of 55%. Patients infected with HCV-4 had a lower stage of fibrosis, lower viraemia and a higher SVR rate compared with those with genotype 1. Despite these interesting observations, it is not known why Egyptians infected with HCV-4 respond better to therapy than chronic HCV patients in the West or sub-Saharan Africa. The difference could be due to the mode of infection because genotype 4 infection is prevalent in special populations in Europe and sub-Saharian Africa namely injecting drug users, HIV-coinfected and homosexual men, all of whom have been identified in several studies as difficult-to-treat groups.
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The variations in response to HCV therapy could be because of different pharmacogenetics because individual genetic make-up could influence the individual response, resistance to therapy or the development of potential side effects. Identifying individuals with a high probability of response or upfront resistance to therapy, determining the probability of adverse events and understanding how certain individuals metabolize drugs are the basis of personalized medicine. Some studies have identified genetic variations in the IL28B gene (coding for IFN-λ3) that determines the outcome of IFN--based therapy for patients with genotype 1 chronic HCV infection (49, 50). This polymorphism is located within the promoter of IL28B and several independent genome-wide association studies reported SNPs in the IL28B region, associated with response to treatment (48–50).
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The exact mechanisms underlying this association are unknown (52). It has been shown that in non-responders, some IFN-stimulated genes were highly expressed; thus, preactivation of the IFN system in patients appears to limit the effect of IFN antiviral therapy (51, 52) However, the link between genetic polymorphisms and IFN response is not clearly established. This finding could help develop personal treatment options in patients with chronic HCV infection and explain some of the apparent genetic differences in response to treatment, for instance in African Americans, Asians or Hispanics.
Testing the patient's genotype to determine how likely they are to respond to anti-HCV therapy would be a major step in personalized medicine
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Tailoring hepatitis C virus therapy and financial constraints
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Many genotype 4 patients reside in the developing countries of Africa and the Middle East, where delivery of quality health care is often limited by lack of resources, and economic constraints frequently prevent adequate treatment intervention.
For example, in Egypt, despite the government's nationwide campaign for treating patients with chronic HCV infection, certain patients may not have adequate health insurance coverage or access to treatment. Thus, the person's financial status often plays a major role in poor compliance and many patients cannot afford to complete a full course of therapy with PEG-IFN plus ribavirin (41). Recent studies have suggested that the PEG-IFN and ribavirin regimen will probably be replaced by the addition of specifically targeted antiviral therapy for HCV (STAT-C).
However, these antivirals will probably not be available in the near future in regions with a high prevalence of HCV genotype 4 for several reasons. Firstly, none of the clinical trials on new HCV drugs have enrolled enough patients with HCV-4 infection to test the efficacy and duration of a new regimen for chronic HCV-4 hepatitis although the HCV genotype significantly influences therapy. Secondly, resistance to new antivirals such as HCV protease inhibitors and the potentially resistant strains of HCV are likely to develop.
Thirdly, the new antivirals are used in combination with the standard of care, leading to a significant increase in the cost of therapy. Therefore, it is important to test the efficacy of direct antiviral combinations in areas in which the HCV genotype 4 predominates. Thus, determining the safe therapeutic regimen that induces high SVR rates is paramount to restrict the transmission of HCV, halt the progression of chronic hepatitis and provide cost-effective treatment, because this regimen will reduce the cost of care in patients with end-stage liver disease and hepatocellular carcinoma. In Egypt and the Middle East, no adequate economic evaluation of the available therapeutic regimen for hepatitis C has been conducted thus far.
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However, as new therapeutic approaches become available, economic evaluation studies are critical to maximize the cost benefit of available combinations. This is particularly important in developing countries and countries with a high prevalence of HCV such as Egypt, where HCV infection is a major public health problem and a heavy economic burden. An economic evaluation is important to identify, measure and evaluate a wide range of therapeutic alternatives. This can provide decision makers with necessary information about the cost effectiveness of therapeutic options.
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Treatment of non-responders Treatment of non-responders is a challenge in all genotypes.
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Management of chronic HCV-4 hepatitis patients who do not respond to IFN therapies has only been studied in one small trial (54) on the efficacy and safety of PEG-IFN plus ribavirin with or without amantidine in 63 non-responders to conventional IFN therapy.
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Patients were randomized to receive either weekly PEG-IFN-2b, 1.5 μg/kg and ribavirin 1000–1200 mg or PEG-IFN and ribavirin as in group A, plus amantadine. Only one patient (5%) treated with dual therapy and three patients (7%) treated with triple therapy achieved SVR. Further clinical trials are necessary to investigate the management options for this population.
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Treatment of chronic hepatitis C virus and human immunodeficiency virus coinfections
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Although in Europe, HCV-4 is frequent among HCV- and HIV-coinfected patients, few clinical trials have evaluated the efficacy of PEG-IFN and ribavirin therapy in patients with HIV and HCV-4 coinfection (55–57). In a case series study, SVR rates of 16.7% were obtained in genotype 4 patients receiving various IFN-based antiviral therapies (55). Overall, SVR was attained in 11.1% of patients receiving IFN- monotherapy, 9.1% of patients receiving IFN- plus ribavirin combination therapy and 22.7% of patients receiving PEG-IFN-2b (1.5 μg/week) plus ribavirin (800 mg/day).
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In this study, the overall SVR rates in genotype 4 patients (16.7%) were similar to those achieved by genotype 1 patients (11.2%) and lower than those in genotype 2/3 patients (40.4%). In another study, end of treatment response and SVR rates were lower in HIV/HCV-coinfected patients than in HCV-monoinfected patients (30 vs. 66%, P=0.06; 15 vs. 50%, P=0.06 respectively) receiving PEG-IFN- plus ribavirin (1000–1200 mg/day) for 48 weeks; the difference between the cohorts was not significant in either case.
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The SVR rates of less the 20% reported in coinfected patients are clearly lower than those reported in HCV-monoinfected genotype 4 patients receiving combination therapy with PEG-IFN- plus ribavirin (50–79%) (56). A recent Italian Spanish study (57) assessed the efficacy of PEG-IFN and ribavirin therapy in 75 HCV-G4 patients coinfected with HIV. The overall SVR was 28% in Spanish and 34% in Italian HCV-4 patients respectively. .
These studies suggest that coinfected HCV-4 patients can be considered to be a difficult-to-treat population.
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Treatment of acute hepatitis C virus genotype 4
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A few clinical trials have addressed the optimal treatment regimen in acute HCV-4 infection and have shown high SVR with IFN-based therapies compared with no treatment (58–60). These studies have shown that patients with acute HCV-4 infection have higher rates of SVR than genotype 1 patients. The SVR rates in acute HCV genotype 4 patients reached 93 and 100% compared with 60 and 88% in genotype 1 patients after 12 and 24 weeks of treatment respectively (59).
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Treatment of thalassaemia major patients with chronic hepatitis C virus infection genotype 4
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Although many thalassaemia patients are infected with HCV, the treatment of these patients has not been established. A randomized study (61) evaluated the efficacy of PEG-IFN- with or without ribavirin in 20 patients with thalassaemia and HCV-4. SVR occurred in four of 12 and five of eight patients in the monotherapy and combination groups (30 and 62.5%, P=0.19) respectively.
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Transfusion requirements increased by 34% in the combination arm (P=0.08). In another study (62), overall SVR rates were 46% with PEG-IFN-2b and 64% with PEG-IFN-2b+RBV combination therapy. However, adverse events and withdrawals were more frequent with PEG-IFN-2b+RBV combination therapy than with PEG-IFN-2b alone. Combination therapy was associated with a temporary increase in transfusion requirements.
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Predictors of sustained virological response in chronic hepatitis C virus genotype 4
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Some studies have evaluated the predictors of SVR in HCV-4. Rapid virological response has been established as an excellent predictive factor of SVR (44–47). Recent studies (63, 64) showed that RVR proved to be the most sensitive on treatment parameter for predicting SVR identifying 96% of subjects likely to develop SVR. RVR was also shown to have excellent specificity (98%), discriminating between subjects who will probably go on to achieve SVR from those who will not. RVR misses only a fraction of the subjects who do not achieve SVR because of the very high negative predictive value and positive predictive value of RVR (96 and 97% respectively). Jessner et al. (65) studied very early viral kinetics on IFN treatment in chronic HCV-4 infection by measuring viral load before and 24 h after 10 MU IFN-2b. The study showed that a 24-h log 10 change after 10 MU IFN-2b could be a good predictor of SVR on PEG-IFN-2a/RBV combination therapy.
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This test may be useful to identify probable non-responders to PEG-IFN-/RBV therapy in genotype 4 patients. Among the baseline criteria, one study showed that a low baseline histological grade and stage (P less then 0.029), BMI (P=0.013) and HCV RNA (P<0.001)>F2) [odds ratio (OR)=0.4, 95% CI: 0.2–0.8] as well as the presence of steatosis (OR=0.5, 95% CI: 0.3–0.97) (43).
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Moderate to severe steatosis with or without sinusoidal fibrosis is present in about 70% of patients with genotype 4 chronic hepatitis C (43).
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Moderate to severe steatosis with or without sinusoidal fibrosis is present in about 70% of patients with genotype 4 chronic hepatitis C (43).
Advanced fibrosis and steatosis have been associated with lower SVR rates (43). Two studies (66, 67) reported that the treatment outcomes were improved in genotype 4 patients with mild liver disease compared with those with more advanced liver disease. In patients receiving PEG-IFN-2b plus ribavirin (1000–1200 mg/day) for 48 weeks, the SVR rates were significantly higher in those without or with mild fibrosis (84 vs. 29%, P less then 0.0002). Another study showed that SVR was independently associated with HOMA-IR less then 2 (P=0.001, OR=5.314, 95% CI: 1.953–14.459) and non-severe fibrosis (P less then 0.001, OR=8.059, 95% CI: 2.512–25.855) (64).
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Emerging new regimen for the treatment of chronic hepatitis C virus genotype 4
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A phase II, randomized, double-blind, placebo-controlled study of nitazoxanide treatment for 24 weeks in 50 patients with chronic HCV-4 hepatitis was performed to evaluate the safety of prolonged administration and to determine the antiviral efficacy of nitazoxanide monotherapy (46). This study sequentially allocated 97 Egyptian patients with chronic HCV-4 hepatitis into three treatment arms: PEG-IFN-2a and ribavirin for 48 weeks (n=40), nitazoxanide monotherapy for 12 weeks, followed by nitazoxanide plus PEG-IFN -2a for 36 weeks (n=28), or nitazoxanide monotherapy for 12 weeks, followed by nitazoxanide plus PEG-IFN-2a and ribavirin for 36 weeks (n=28).
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The percentages of patients with RVR and SVR were significantly higher in patients receiving triple therapy than in those receiving the standard of care (64 vs. 38%, P=0.048 and 79 vs. 50%, P=0.023 respectively). Patients given nitazoxanide plus PEG-IFN-2a had intermediate rates of RVR (54%) and SVR (61%). Adverse events were similar across treatment groups, except for a higher rate of anaemia in the groups receiving ribavirin. In the nitazoxanide group, virological responses were maintained through the end of treatment with no virological breakthroughs. Of note, the use of nitazoxanide was associated with reduced relapse rates (3/20 patients in the PEG-IFN plus nitazoxanide arm and 1/23 patients in the triple arm with PEG-IFN, ribavirin and nitazoxanide) vs. 10/30 patients in the standard-of-care arm.
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Conclusions and future prospects
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Hepatitis C virus genotype 4 is responsible for about 20% of hepatitis C infections worldwide. HCV-4 is rapidly spreading to the West through immigration and injection drug use. Recent clinical data have provided new insights on HCV-4 infection and helped to refine treatment strategies. These data can now be used as a platform for optimizing treatment regimens for patients infected with HCV-4. Further research is needed to investigate the response of HCV-4 infections to emerging therapies such as STAT-C in particular protease and/or polymerase inhibitors.
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World Health Organization. Hepatitis C. WHO Fact Sheet 164. Geneva, Switzerland: World Health Organization, 2000 Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html (accessed 12 October 2008).
Web of Science® Times Cited: 65
2
Nguyen MH, Keeffe EB. Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6. Clin Gastroenterol Hepatol 2005; 3 (Suppl. 2): S97–101.
CrossRef,
PubMed,
ChemPort
3
Simmonds P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 2004; 85 (Part 11): 3173–88.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 224
4
Egyptian Ministry of Health Annual report, 2007. Available at http://www.mohp.gov.eg/Main.asp (accessed 12 October 2008).
5
Abdel-Aziz F, Habib M, Mohamed MK, et al. Hepatitis C virus (HCV) infection in a community in the nile delta: population description and HCV prevalence. Hepatology 2000; 32: 111–5.
PubMed,
ChemPort,
Web of Science® Times Cited: 70
6
Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL. Genetic epidemiology of hepatitis C virus throughout Egypt. J Infect Dis 2000; 182: 698–707.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 121
7
Angelico M, Renganathan E, Gandin C, et al. Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections. J Hepatol 1997; 26: 236–43.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 65
8
Kamal S, Madwar M, Bianchi L, et al. Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni. Liver 2000; 20: 281–9.
PubMed,
ChemPort,
Web of Science® Times Cited: 47
9
Shobokshi OA, Serebour FE, Skakni L, Al-Saffy YH, Ahdal MN. Hepatitis C genotypes and subtypes in Saudi Arabia. J Med Virol 1999; 58: 44–8.
Direct Link:
Abstract
PDF(72K)
References
10
Al-Knawy B, Okamoto H, El-Mekki A, et al. Distribution of hepatitis C genotype andco-infection rate with hepatitis G in Saudi Arabia. Hepatol Res 2002; 24: 95–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 7
11
Abdulkarim AS, Zein NN, Germer JJ, et al. Hepatitis C virus genotypes and hepatitis G virus in hemodialysis patients from Syria: identification of two novel hepatitis C virus subtypes. Am J Trop Med Hyg 1998; 59: 571–6.
PubMed,
ChemPort,
Web of Science® Times Cited: 25
12
Shemer-Avni Y, el Astal Z, Kemper O, et al. Hepatitis C virus infection and genotypes in Southern Israel and the Gaza Strip. J Med Virol 1998; 56: 230–3.
Direct Link:
Abstract
PDF(115K)
References
13
Bdour S. Hepatitis C virus infection in Jordanian haemodialysis units: serological diagnosis and genotyping. J Med Microbiol 2002; 51: 700–4.
PubMed,
Web of Science® Times Cited: 24
14
Xu L-Z, Larzul D, Delaporte E, Bréchot C, Kremsdorf D. Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon). J Gen Virol 1994; 75: 2393–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 63
15
Ndjomou J, Pybus OG, Matz B. Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon. J Gen Virol 2003; 84: 2333–41.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 37
16
Njouom R, Frost E, Deslandes S, et al. Pépin predominance of hepatitis C virus genotype 4 infection and rapid transmission between 1935 and 1965 in the Central African Republic. J Gen Virol 2009; 90 (Part 10): 2452–6.
CrossRef,
ChemPort,
Web of Science® Times Cited: 5
17
Wansbrough-Jones MH, Frimpong E, Cant B, et al. Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana. Trans R Soc Trop Med Hyg 1998; 92: 496–9.
CrossRef,
ChemPort,
Web of Science® Times Cited: 29
18
Simmonds P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 2004; 85: 3173–88.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 224
19
Kamal S, Nasser I. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology 2008; 47: 1371–83.
Direct Link:
Abstract
Full Article (HTML)
PDF(398K)
References
20
Payan C, Roudot-Thoraval F, Marcellin P, et al. Changing of hepatitis C virus genotype patterns in France at the beginning of the third millennium: the GEMHEP GenoCII Study. J Viral Hepat 2005; 12: 405–13.
PubMed,
ChemPort,
Web of Science® Times Cited: 60
21
Nicot F, Legrand-Abravanel F, Sandres-Saune K, et al. Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France. J Gen Virol 2005; 86: 107–14.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 34
22
Ansaldi F, Bruzzone B, Salamaso S, et al. Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy. J Med Virol 2005; 76: 327–32.
Direct Link:
Abstract
PDF(145K)
References
23
Katsoulidou A, Sypsa V, Tassopoulos NC, et al. Molecular epidemiology of hepatitis C virus (HCV) in Greece: temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates. J Viral Hepat 2006; 13: 19–27.
PubMed,
ChemPort,
Web of Science® Times Cited: 23
24
Fernandez-Arcas N, Lopez-Siles J, Trapero S, et al. High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): phylogenetic and epidemiological analyses. J Med Virol 2006; 78: 1429–35.
ChemPort
25
Franco S, Tural C, Clotet B, Martínez MA. Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1. Virus Res 2007; 123: 161–9.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 15
26
de Bruijne J, Schinkel J, Prins M Emergence of hepatitis C virus genotype 4 phylogenetic analysis reveals three distinct epidemiological profiles. J Clin Microbiol 2009; 47: 3832–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 2
27
van de Laar T, Pybus O, Bruisten S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009; 136: 1609–17.
CrossRef,
PubMed,
Web of Science® Times Cited: 20
28
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 2548
29
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.
PubMed,
ChemPort,
Web of Science® Times Cited: 2830
30
Zylberberg H, Chaix ML, Brechot C. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha. Ann Intern Med 2000; 132: 845–6.
PubMed,
ChemPort,
Web of Science® Times Cited: 40
31
Kamal SM, Madwar MA, Peters T, Fawzy R, Rasenack J. Interferon therapy in patients with chronic hepatitis C and schistosomiasis. J Hepatol 2000; 32: 172–4.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 23
32
Koshy A, Madda JP, Marcellin P, et al. Treatment of hepatitis C virus genotype 4-related cirrhosis: ribavirin and interferon combination compared with interferon alone. J Clin Gastroenterol 2002; 35: 82–5.
PubMed,
ChemPort,
Web of Science® Times Cited: 23
33
Koshy A, Marcellin P, Martinot M, Madda JP. Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis. Liver 2000; 20: 335–9.
Direct Link:
Abstract
PDF(84K)
34
Esmat GH, Abouzied A, Abdel-Hamid M, et al. Results of a randomized clinical trial of genotype-4 infected subjects when treated with standard or pegylated interferon alfa-2b in combination with ribavirin. Hepatology 2003; 38 (Suppl.): 314A–5A (abstract).
CrossRef
35
Shobokshi A, Serebour PE, Skakni L, et al. Combination therapy of peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) significantly enhance sustained virological and biochemical response rate in chronic hepatitis C genotype 4 patients in Saudi Arabia. Hepatology 2003; 38 (Suppl.): 636A (abstract).
CrossRef
36
Alfaleh FZ, Hadad Q, Khuroo MS, et al. Peginterferon a-2b plus ribavirin compared with interferon a-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004; 24: 568–74.
Direct Link:
Abstract
Full Article (HTML)
PDF(118K)
References
37
Hasan F, Asker H, Al-Khaldi J, et al. Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4. Am J Gastroenterol 2004; 99: 1733–7.
Direct Link:
38
Diago M, Hassanein T, Rodes J, Ackrill AM, Sedarati F. Optimized virologic response in hepatitis C virus genotype 4 with peginterferon-alpha2a and ribavirin. Ann Intern Med 2004; 140: 72–3.
PubMed,
Web of Science® Times Cited: 25
39
Khuroo MS, Khuroo MS, Dahab ST. Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4. Aliment Pharmacol Ther 2004; 20: 931–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 34
40
Kamal SM, El Tawil AA, Nakano T, et al. Peginterferon alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4 impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54: 858–66.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 65
41
Zayadi A-R, Attia M, Barakat EMF, et al. Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-a2b/ribavirin or induction-dose interferon-a2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005; 100: 2447–52.
42
Derbala MF, Al Kaabi SR, El Dweik NZ, et al. Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage. World J Gastroenterol 2006; 12: 5692–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 10
43
Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008; 46: 78–84.
PubMed,
Web of Science® Times Cited: 28
44
Martinot-Peignoux M, Maylin S, Moucari R, et al. Virological Response at 4 weeks predict outcome of Hepatitis C treatment with pegylated interferon and ribavirin. Antivir Ther 2009; 14: 501–11.
PubMed,
ChemPort,
Web of Science® Times Cited: 7
45
Kamal S, Kamary S, Shardell M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2000; 46: 1732–40.
46
Ferenci P, Laferl H, Austrian Hepatitis Study Group et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008; 135: 45–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 53
47
Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009; 136: 856–62.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 27
48
Ge D, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.
CrossRef,
ChemPort,
Web of Science® Times Cited: 160
49
Tanaka Y., et al. Genome-wide association of IL28B with response to pegylated interferon- and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105–10.
CrossRef,
ChemPort,
Web of Science® Times Cited: 95
50
Suppiah V, et al. IL28B is associated with response to chronic hepatitis C interferon- and ribavirin therapy. Nat Genet 2009; 41: 1100–4.
CrossRef,
ChemPort,
Web of Science® Times Cited: 85
51
Asselah T, Essioux L, Marcellin P, et al. A chromosome 19 SNP (RS12979860) predicts outcome (EVR/SVR) in HCV patients treated with interferon, independent of pegylation or ribavirin. J Hepatol 2010; 62: A1180.
52
Roulot D, Bourcier V, Grando V., et al. Observational VHC4 study group Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepat 2007; 14: 460–7.
Direct Link:
Abstract
Full Article (HTML)
PDF(473K)
References
53
Elefsiniotis IS, Vezali E, Mihas C, Saroglou G. Predictive value of complete and partial early virological response on sustained virological response rates of genotype-4 chronic hepatitis C patients treated with PEG-interferon plus ribavirin. Intervirology 2009; 52: 247–51.
CrossRef,
ChemPort,
Web of Science® Times Cited: 1
54
Trapero-Marugan M, Moreno-Monteagudo JA, Garcia-Buey L, et al. Clinical and pathological characteristics and response to combination therapy of genotype 4 chronic hepatitis C patients: experience from a Spanish center. J Chemother 2007; 19: 423–7.
PubMed,
ChemPort,
Web of Science® Times Cited: 7
55
Hasan F, Al-Khaldi J, Asker H, et al. Peginterferon alpha-2b plus ribavirin with or without amantadine [] for the treatment of non-responders to standard interferon and ribavirin. Antivir Ther 2004; 9: 499–503.
PubMed,
ChemPort,
Web of Science® Times Cited: 9
56
Soriano V, Nunez M, Sanchez-Conde M, et al. Response to interferon-based therapies in HIV-infected patients with chronic hepatitis C due to genotype 4. Antiviral Ther 2005; 10: 167–70.
PubMed,
ChemPort,
Web of Science® Times Cited: 11
57
Legrand-Abravanel F, Nicot F, Boulestin A, et al. Pegylated interferon and ribavirin therapy for chronic hepatitis C virus genotype 4 infection. J Med Virol 2005; 77: 66–9.
Direct Link:
Abstract
PDF(91K)
References
58
Martín-Carbonero L, Puoti M, García-Samaniego J, et al. Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4. J Viral Hepat 2008; 15: 710–5.
Direct Link:
Abstract
Full Article (HTML)
PDF(132K)
References
59
Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006; 130: 632–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 72
60
Kamal SM, Moustafa KN, Chen J, et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006; 43: 923–31.
PubMed,
ChemPort,
Web of Science® Times Cited: 54
61
Kamal SM, Ismail A, Graham CS, et al. Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 2004; 39: 1721–31.
PubMed,
ChemPort,
Web of Science® Times Cited: 90
62
Inati A, Taher A, Ghorra S, et al. Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection. Br J Haematol 2005; 130: 644–6.
Direct Link:
Abstract
Full Article (HTML)
PDF(60K)
References
63
Kamal S, Fouly A, Mohamed S, et al. Peginterferon alfa-2b therapy with and without ribavirin in patients with thalassemia: a randomized study. Abstract 585 presented at the 41st Annual Meeting of the European Association for the Study of the Liver, 26–30 April 2006, Austria Center, Vienna, Austria.
64
Kamal S, Ahmed A, Mahmoud S, et al. Pegylated Interferon alfa-2a Plus Ribavirin over Pegylated Interferon alfa-2b plus Ribavirin in Chronic Hepatitis C Genotype 4: a randomized trial and quality of life analysis. Liver Int 2010 (in press).
Web of Science® Times Cited: 1
65
Jessner W, Gschwantler M, Formann E, et al. Very early viral kinetics on interferon treatment in chronic hepatitis C virus genotype 4 infection. Antivir Ther 2008; 13: 581–9.
PubMed,
ChemPort,
Web of Science® Times Cited: 2
66
Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008; 57: 516–24.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 41
67
Moucari R, Ripault MP, Martinot-Peignoux M, et al. Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut 2009; 58: 1662–9.
ChemPort
.
Emerging new regimen for the treatment of chronic hepatitis C virus genotype 4
.
A phase II, randomized, double-blind, placebo-controlled study of nitazoxanide treatment for 24 weeks in 50 patients with chronic HCV-4 hepatitis was performed to evaluate the safety of prolonged administration and to determine the antiviral efficacy of nitazoxanide monotherapy (46). This study sequentially allocated 97 Egyptian patients with chronic HCV-4 hepatitis into three treatment arms: PEG-IFN-2a and ribavirin for 48 weeks (n=40), nitazoxanide monotherapy for 12 weeks, followed by nitazoxanide plus PEG-IFN -2a for 36 weeks (n=28), or nitazoxanide monotherapy for 12 weeks, followed by nitazoxanide plus PEG-IFN-2a and ribavirin for 36 weeks (n=28).
,
The percentages of patients with RVR and SVR were significantly higher in patients receiving triple therapy than in those receiving the standard of care (64 vs. 38%, P=0.048 and 79 vs. 50%, P=0.023 respectively). Patients given nitazoxanide plus PEG-IFN-2a had intermediate rates of RVR (54%) and SVR (61%). Adverse events were similar across treatment groups, except for a higher rate of anaemia in the groups receiving ribavirin. In the nitazoxanide group, virological responses were maintained through the end of treatment with no virological breakthroughs. Of note, the use of nitazoxanide was associated with reduced relapse rates (3/20 patients in the PEG-IFN plus nitazoxanide arm and 1/23 patients in the triple arm with PEG-IFN, ribavirin and nitazoxanide) vs. 10/30 patients in the standard-of-care arm.
,
Conclusions and future prospects
,
Hepatitis C virus genotype 4 is responsible for about 20% of hepatitis C infections worldwide. HCV-4 is rapidly spreading to the West through immigration and injection drug use. Recent clinical data have provided new insights on HCV-4 infection and helped to refine treatment strategies. These data can now be used as a platform for optimizing treatment regimens for patients infected with HCV-4. Further research is needed to investigate the response of HCV-4 infections to emerging therapies such as STAT-C in particular protease and/or polymerase inhibitors.
,
World Health Organization. Hepatitis C. WHO Fact Sheet 164. Geneva, Switzerland: World Health Organization, 2000 Available at http://www.who.int/mediacentre/factsheets/fs164/en/print.html (accessed 12 October 2008).
Web of Science® Times Cited: 65
2
Nguyen MH, Keeffe EB. Prevalence and treatment of hepatitis C virus genotypes 4, 5, and 6. Clin Gastroenterol Hepatol 2005; 3 (Suppl. 2): S97–101.
CrossRef,
PubMed,
ChemPort
3
Simmonds P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 2004; 85 (Part 11): 3173–88.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 224
4
Egyptian Ministry of Health Annual report, 2007. Available at http://www.mohp.gov.eg/Main.asp (accessed 12 October 2008).
5
Abdel-Aziz F, Habib M, Mohamed MK, et al. Hepatitis C virus (HCV) infection in a community in the nile delta: population description and HCV prevalence. Hepatology 2000; 32: 111–5.
PubMed,
ChemPort,
Web of Science® Times Cited: 70
6
Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL. Genetic epidemiology of hepatitis C virus throughout Egypt. J Infect Dis 2000; 182: 698–707.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 121
7
Angelico M, Renganathan E, Gandin C, et al. Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections. J Hepatol 1997; 26: 236–43.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 65
8
Kamal S, Madwar M, Bianchi L, et al. Clinical, virological and histopathological features: long-term follow-up in patients with chronic hepatitis C co-infected with S. mansoni. Liver 2000; 20: 281–9.
PubMed,
ChemPort,
Web of Science® Times Cited: 47
9
Shobokshi OA, Serebour FE, Skakni L, Al-Saffy YH, Ahdal MN. Hepatitis C genotypes and subtypes in Saudi Arabia. J Med Virol 1999; 58: 44–8.
Direct Link:
Abstract
PDF(72K)
References
10
Al-Knawy B, Okamoto H, El-Mekki A, et al. Distribution of hepatitis C genotype andco-infection rate with hepatitis G in Saudi Arabia. Hepatol Res 2002; 24: 95–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 7
11
Abdulkarim AS, Zein NN, Germer JJ, et al. Hepatitis C virus genotypes and hepatitis G virus in hemodialysis patients from Syria: identification of two novel hepatitis C virus subtypes. Am J Trop Med Hyg 1998; 59: 571–6.
PubMed,
ChemPort,
Web of Science® Times Cited: 25
12
Shemer-Avni Y, el Astal Z, Kemper O, et al. Hepatitis C virus infection and genotypes in Southern Israel and the Gaza Strip. J Med Virol 1998; 56: 230–3.
Direct Link:
Abstract
PDF(115K)
References
13
Bdour S. Hepatitis C virus infection in Jordanian haemodialysis units: serological diagnosis and genotyping. J Med Microbiol 2002; 51: 700–4.
PubMed,
Web of Science® Times Cited: 24
14
Xu L-Z, Larzul D, Delaporte E, Bréchot C, Kremsdorf D. Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon). J Gen Virol 1994; 75: 2393–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 63
15
Ndjomou J, Pybus OG, Matz B. Phylogenetic analysis of hepatitis C virus isolates indicates a unique pattern of endemic infection in Cameroon. J Gen Virol 2003; 84: 2333–41.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 37
16
Njouom R, Frost E, Deslandes S, et al. Pépin predominance of hepatitis C virus genotype 4 infection and rapid transmission between 1935 and 1965 in the Central African Republic. J Gen Virol 2009; 90 (Part 10): 2452–6.
CrossRef,
ChemPort,
Web of Science® Times Cited: 5
17
Wansbrough-Jones MH, Frimpong E, Cant B, et al. Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana. Trans R Soc Trop Med Hyg 1998; 92: 496–9.
CrossRef,
ChemPort,
Web of Science® Times Cited: 29
18
Simmonds P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J Gen Virol 2004; 85: 3173–88.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 224
19
Kamal S, Nasser I. Hepatitis C genotype 4: what we know and what we don't yet know. Hepatology 2008; 47: 1371–83.
Direct Link:
Abstract
Full Article (HTML)
PDF(398K)
References
20
Payan C, Roudot-Thoraval F, Marcellin P, et al. Changing of hepatitis C virus genotype patterns in France at the beginning of the third millennium: the GEMHEP GenoCII Study. J Viral Hepat 2005; 12: 405–13.
PubMed,
ChemPort,
Web of Science® Times Cited: 60
21
Nicot F, Legrand-Abravanel F, Sandres-Saune K, et al. Heterogeneity of hepatitis C virus genotype 4 strains circulating in south-western France. J Gen Virol 2005; 86: 107–14.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 34
22
Ansaldi F, Bruzzone B, Salamaso S, et al. Different seroprelavence and molecular epidemiology pattern of hepatitis C virus infection in Italy. J Med Virol 2005; 76: 327–32.
Direct Link:
Abstract
PDF(145K)
References
23
Katsoulidou A, Sypsa V, Tassopoulos NC, et al. Molecular epidemiology of hepatitis C virus (HCV) in Greece: temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates. J Viral Hepat 2006; 13: 19–27.
PubMed,
ChemPort,
Web of Science® Times Cited: 23
24
Fernandez-Arcas N, Lopez-Siles J, Trapero S, et al. High prevalence of hepatitis C virus subtypes 4c and 4d in Malaga (Spain): phylogenetic and epidemiological analyses. J Med Virol 2006; 78: 1429–35.
ChemPort
25
Franco S, Tural C, Clotet B, Martínez MA. Complete nucleotide sequence of genotype 4 hepatitis C viruses isolated from patients co-infected with human immunodeficiency virus type 1. Virus Res 2007; 123: 161–9.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 15
26
de Bruijne J, Schinkel J, Prins M Emergence of hepatitis C virus genotype 4 phylogenetic analysis reveals three distinct epidemiological profiles. J Clin Microbiol 2009; 47: 3832–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 2
27
van de Laar T, Pybus O, Bruisten S, et al. Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 2009; 136: 1609–17.
CrossRef,
PubMed,
Web of Science® Times Cited: 20
28
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 2548
29
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958–65.
PubMed,
ChemPort,
Web of Science® Times Cited: 2830
30
Zylberberg H, Chaix ML, Brechot C. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha. Ann Intern Med 2000; 132: 845–6.
PubMed,
ChemPort,
Web of Science® Times Cited: 40
31
Kamal SM, Madwar MA, Peters T, Fawzy R, Rasenack J. Interferon therapy in patients with chronic hepatitis C and schistosomiasis. J Hepatol 2000; 32: 172–4.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 23
32
Koshy A, Madda JP, Marcellin P, et al. Treatment of hepatitis C virus genotype 4-related cirrhosis: ribavirin and interferon combination compared with interferon alone. J Clin Gastroenterol 2002; 35: 82–5.
PubMed,
ChemPort,
Web of Science® Times Cited: 23
33
Koshy A, Marcellin P, Martinot M, Madda JP. Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis. Liver 2000; 20: 335–9.
Direct Link:
Abstract
PDF(84K)
34
Esmat GH, Abouzied A, Abdel-Hamid M, et al. Results of a randomized clinical trial of genotype-4 infected subjects when treated with standard or pegylated interferon alfa-2b in combination with ribavirin. Hepatology 2003; 38 (Suppl.): 314A–5A (abstract).
CrossRef
35
Shobokshi A, Serebour PE, Skakni L, et al. Combination therapy of peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin (COPEGUS®) significantly enhance sustained virological and biochemical response rate in chronic hepatitis C genotype 4 patients in Saudi Arabia. Hepatology 2003; 38 (Suppl.): 636A (abstract).
CrossRef
36
Alfaleh FZ, Hadad Q, Khuroo MS, et al. Peginterferon a-2b plus ribavirin compared with interferon a-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4. Liver Int 2004; 24: 568–74.
Direct Link:
Abstract
Full Article (HTML)
PDF(118K)
References
37
Hasan F, Asker H, Al-Khaldi J, et al. Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4. Am J Gastroenterol 2004; 99: 1733–7.
Direct Link:
38
Diago M, Hassanein T, Rodes J, Ackrill AM, Sedarati F. Optimized virologic response in hepatitis C virus genotype 4 with peginterferon-alpha2a and ribavirin. Ann Intern Med 2004; 140: 72–3.
PubMed,
Web of Science® Times Cited: 25
39
Khuroo MS, Khuroo MS, Dahab ST. Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4. Aliment Pharmacol Ther 2004; 20: 931–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 34
40
Kamal SM, El Tawil AA, Nakano T, et al. Peginterferon alpha-2b and ribavirin therapy in chronic hepatitis C genotype 4 impact of treatment duration and viral kinetics on sustained virological response. Gut 2005; 54: 858–66.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 65
41
Zayadi A-R, Attia M, Barakat EMF, et al. Response of hepatitis C genotype-4 naive patients to 24 weeks of peg-interferon-a2b/ribavirin or induction-dose interferon-a2b/ribavirin/amantadine: a non-randomized controlled study. Am J Gastroenterol 2005; 100: 2447–52.
42
Derbala MF, Al Kaabi SR, El Dweik NZ, et al. Treatment of hepatitis C virus genotype 4 with peginterferon alfa-2a: impact of bilharziasis and fibrosis stage. World J Gastroenterol 2006; 12: 5692–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 10
43
Poordad F, Reddy KR, Martin P. Rapid virologic response: a new milestone in the management of chronic hepatitis C. Clin Infect Dis 2008; 46: 78–84.
PubMed,
Web of Science® Times Cited: 28
44
Martinot-Peignoux M, Maylin S, Moucari R, et al. Virological Response at 4 weeks predict outcome of Hepatitis C treatment with pegylated interferon and ribavirin. Antivir Ther 2009; 14: 501–11.
PubMed,
ChemPort,
Web of Science® Times Cited: 7
45
Kamal S, Kamary S, Shardell M, et al. Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis C: the role of rapid and early virologic response. Hepatology 2000; 46: 1732–40.
46
Ferenci P, Laferl H, Austrian Hepatitis Study Group et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008; 135: 45–8.
CrossRef,
ChemPort,
Web of Science® Times Cited: 53
47
Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009; 136: 856–62.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 27
48
Ge D, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.
CrossRef,
ChemPort,
Web of Science® Times Cited: 160
49
Tanaka Y., et al. Genome-wide association of IL28B with response to pegylated interferon- and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105–10.
CrossRef,
ChemPort,
Web of Science® Times Cited: 95
50
Suppiah V, et al. IL28B is associated with response to chronic hepatitis C interferon- and ribavirin therapy. Nat Genet 2009; 41: 1100–4.
CrossRef,
ChemPort,
Web of Science® Times Cited: 85
51
Asselah T, Essioux L, Marcellin P, et al. A chromosome 19 SNP (RS12979860) predicts outcome (EVR/SVR) in HCV patients treated with interferon, independent of pegylation or ribavirin. J Hepatol 2010; 62: A1180.
52
Roulot D, Bourcier V, Grando V., et al. Observational VHC4 study group Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection. J Viral Hepat 2007; 14: 460–7.
Direct Link:
Abstract
Full Article (HTML)
PDF(473K)
References
53
Elefsiniotis IS, Vezali E, Mihas C, Saroglou G. Predictive value of complete and partial early virological response on sustained virological response rates of genotype-4 chronic hepatitis C patients treated with PEG-interferon plus ribavirin. Intervirology 2009; 52: 247–51.
CrossRef,
ChemPort,
Web of Science® Times Cited: 1
54
Trapero-Marugan M, Moreno-Monteagudo JA, Garcia-Buey L, et al. Clinical and pathological characteristics and response to combination therapy of genotype 4 chronic hepatitis C patients: experience from a Spanish center. J Chemother 2007; 19: 423–7.
PubMed,
ChemPort,
Web of Science® Times Cited: 7
55
Hasan F, Al-Khaldi J, Asker H, et al. Peginterferon alpha-2b plus ribavirin with or without amantadine [] for the treatment of non-responders to standard interferon and ribavirin. Antivir Ther 2004; 9: 499–503.
PubMed,
ChemPort,
Web of Science® Times Cited: 9
56
Soriano V, Nunez M, Sanchez-Conde M, et al. Response to interferon-based therapies in HIV-infected patients with chronic hepatitis C due to genotype 4. Antiviral Ther 2005; 10: 167–70.
PubMed,
ChemPort,
Web of Science® Times Cited: 11
57
Legrand-Abravanel F, Nicot F, Boulestin A, et al. Pegylated interferon and ribavirin therapy for chronic hepatitis C virus genotype 4 infection. J Med Virol 2005; 77: 66–9.
Direct Link:
Abstract
PDF(91K)
References
58
Martín-Carbonero L, Puoti M, García-Samaniego J, et al. Response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C due to genotype 4. J Viral Hepat 2008; 15: 710–5.
Direct Link:
Abstract
Full Article (HTML)
PDF(132K)
References
59
Kamal SM, Fouly AE, Kamel RR, et al. Peginterferon alfa-2b therapy in acute hepatitis C: impact of onset of therapy on sustained virologic response. Gastroenterology 2006; 130: 632–8.
PubMed,
ChemPort,
Web of Science® Times Cited: 72
60
Kamal SM, Moustafa KN, Chen J, et al. Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006; 43: 923–31.
PubMed,
ChemPort,
Web of Science® Times Cited: 54
61
Kamal SM, Ismail A, Graham CS, et al. Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 2004; 39: 1721–31.
PubMed,
ChemPort,
Web of Science® Times Cited: 90
62
Inati A, Taher A, Ghorra S, et al. Efficacy and tolerability of peginterferon alpha-2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection. Br J Haematol 2005; 130: 644–6.
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References
63
Kamal S, Fouly A, Mohamed S, et al. Peginterferon alfa-2b therapy with and without ribavirin in patients with thalassemia: a randomized study. Abstract 585 presented at the 41st Annual Meeting of the European Association for the Study of the Liver, 26–30 April 2006, Austria Center, Vienna, Austria.
64
Kamal S, Ahmed A, Mahmoud S, et al. Pegylated Interferon alfa-2a Plus Ribavirin over Pegylated Interferon alfa-2b plus Ribavirin in Chronic Hepatitis C Genotype 4: a randomized trial and quality of life analysis. Liver Int 2010 (in press).
Web of Science® Times Cited: 1
65
Jessner W, Gschwantler M, Formann E, et al. Very early viral kinetics on interferon treatment in chronic hepatitis C virus genotype 4 infection. Antivir Ther 2008; 13: 581–9.
PubMed,
ChemPort,
Web of Science® Times Cited: 2
66
Asselah T, Bieche I, Narguet S, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008; 57: 516–24.
CrossRef,
PubMed,
ChemPort,
Web of Science® Times Cited: 41
67
Moucari R, Ripault MP, Martinot-Peignoux M, et al. Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4. Gut 2009; 58: 1662–9.
ChemPort
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