The future for the treatment of genotype 4 chronic hepatitis C
Gamal Esmat, MD,
Endemic Medicine Department, Cairo University
Tel: +(20) 2 338 9959
Fax: +(20) 2 368 2774
Hepatitis C virus genotype 4 (HCV-4) is the most common type of hepatitis C virus (HCV) in the Middle East and Africa, in particular Egypt. Since the development of new protease inhibitors, the response of HCV-4 to the standard regimen of treatment (pegylated interferon/ribavirin) lags behind other genotypes and has become the most resistant type to treat. The development of therapeutic strategies for all patients with HCV-4 whether they are naïve, have experienced a virological breakthrough, are relapsers or non-responders is still a considerable challenge. New types of interferon (Consensus Interferon, Y-shaped, Albinterferon…) and new direct action antiviral drugs (Nitazoxanide, Vit.D, other) may improve the treatment of patients with HCV-4. The IL28B CC polymorphism may be associated with sustained virological response.
end of treatment viral response
early virological response
hepatitis C virus
rapid virological response
sustained virological response
Hepatitis C virus (HCV) is the cause of a significant proportion of cases of chronic liver disease, hepatocellular carcinoma (HCC) and deaths from liver disease, and is the most common indication for liver transplantation (LTx). Projections based on the current prevalence of infection and anticipated rates of progression suggest that morbidity and mortality as well as the costs of medical care for HCV infection will increase alarmingly in the next two decades .
Six major genotypes [1-6] and more than 50 subtypes of HCV have been described . In general, HCV genotype 4 (HCV4) is predominant in Africa and the Middle East . In Egypt, where hepatitis C is highly endemic (up to 15% of the population), 91% of the patients are infected with HCV .
Numerous studies have confirmed that HCV4 is the predominant HCV genotype in Saudi Arabia [5, 6] and Kuwait  and small studies in Africa suggest that HCV4 is the predominant genotype on that continent [8, 9]. Although HCV4 represents 1–3% of the hepatitis C infections in Western countries, some studies report an unexplainably higher prevalence of HCV 4 in certain European countries such as southern Spain , southern Italy  and France . Most HCV4 patients in these studies were intravenous drug abusers.
Treatment of chronic HCV genotype 4 infection
The standard regimen of therapy
Combined treatment with pegylated interferon (PEG-IFN) α-2a or α-2b plus ribavirin (RBV) is now the standard therapy for chronic HCV infection .The addition of the synthetic guanosine analogue RBV to IFN was a major breakthrough in the treatment of HCV infection. Diago et al. reported preliminary results in which 49 HCV4 patients from North America and Europe were treated in one of four groups: PEG-IFNα-2a plus 800 mg of RBV or 1000–1200 mg of RBV for 24 weeks or 48 weeks. Seventy nine per cent of patients who were treated with PEG-IFN plus 1000–1200 mg of RBV achieved a sustained virological response (SVR), while the SR was lower in other groups .
Shobokshi et al. treated 180 HCV4 patients in a randomized open label multicenter trial. The first group received PEG-IFNα-2a 180 μg weekly plus RBV 800 mg/day for 48 weeks, the second group received PEG-IFN monotherapy and the third group was treated with standard IFN-α-2a 4.5 MU TIW plus RBV 800 mg/day. The end of treatment viral response (ETVR) was 67%, 59% and 37% respectively. The SVR was obtained in 50%, 28% and 30% respectively .
Al Faleh et al. randomized 96 patients for treatment with either 100 μg of PEG-IFN-α-2b plus 800 mg/day of RBV or standard IFN plus RBV combination therapy. The ETVR was 70% in the PEG-IFN arm and 52% in the standard IFN arm. A SVR was achieved in 43.8% of patients in the PEG-IFN arm and in 29.2% of patients in the standard IFN arm. These results were probably not statistically significant because of the relatively small sample size .
We reported results from a randomized trial involving 200 patients, 90% of whom had HCV4. One hundred patients were randomized to receive PEG-IFN-α-2b 100 μg/week plus 800–1000 mg of RBV based on body weight or standard IFN plus RBV for 48 weeks. A SVR was achieved in 45% of those receiving PEG-IFN compared with 38% in the IFN group .
In a prospective open label study from Kuwait using PEG-IFN-α-2b, Hasan et al. enrolled 66 patients to receive a higher (currently standard) dose of RBV (1000–1200 mg/day) resulting in a higher ETVR and SVR (77% and 68%, respectively) than in other studies .
An early virological response (EVR) helps predicts patients who will probably not respond to combination therapy. Patients who are HCV-RNA negative after 4 weeks of treatment are defined as having a rapid virological response (RVR). In contrast to EVR, RVR is predictive of patients who will probably respond to combination therapy . Treatment of HCV-4 non-responders, injection drug users, patients coinfected with the HIV, thalassaemic patients, patients on haemodialysis and patients with HCV-4 recurrence after LTx is still a significant therapeutic challenge . Identifying new IFN molecules and other combination therapies, especially direct acting antiviral drugs is an important mission for all clinical researchers whose goal is to improve the current treatment response.
New types of interferon
Interferon alfacon-1 or consensus interferon (CIFN), a completely synthetic interferon administered with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. Bacon et al. included 487 patients; 245 received CIFN 9 μg/day and RBV, and 242 received CIFN 15 μg/day and RBV. Advanced fibrosis was present in 59.3% of these patients at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 μg group and 10.7% (26/242) in the 15 μg group. In the intent-to-treat analysis, SVR rates were higher in patients with a > 2-log10 decrease in HCV RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 μg group and 23% (7/31) in the 15 μg group. The SVR rates in patients with lower baseline fibrosis scores (F0–F3) were 7.8% (15/192) in the 9 μg group and 13.1% (23/175) in the 15 μg group. If a > 2-log10 decrease in HCV RNA with previous PEG-IFN/RBV treatment had been achieved in this same group (F0–F3), SVR rates improved to 10.7% and 31.6% in the 9 and 15 μg groups, respectively. The CIFN/RBV combination retreatment was safe and well tolerated .
In another recent study in 597 patients, 15 mcg of CIFN was administered per day subcutaneously combined with standard doses of RBV. Treatment lasted a mean 21 weeks; CIFN was discontinued within 4 weeks in 24%. Haematological growth factors were used in 49%. Post-treatment viral loads were available in 385 patients. An SVR to CIFN/RBV was achieved in 11%, and was significantly higher in prior PEG-IFN/RBV relapsers than in non-responders (31% vs. 6%, respectively; P < 0.0001). A decrease of 2-log10 or more in HCV RNA after 24 weeks of PEG-IFN/RBV was predictive of later SVR to CIFN/RBV. This study showed that the overall SVR was low, although the response was significantly better in prior PEG-IFN/RBV relapsers and in those who had a decrease in HCV RNA of 2-log10 or more than in non-responders .
Albinterferon α-2b, a fusion protein including interferon α-2b and human albumin, is being studied in combination with RBV in a series of ongoing phase II and III trials. In January 2008, all patients receiving albinterferon α-2b at a dose of 1200 every other week in phase III trials were switched to a lower dose of 900 μg every other week because of a higher incidence of serious pulmonary adverse events in those receiving the higher dosage. The combination of albinterferon alfa-2b plus RBV was evaluated in prior non-responders to IFN-based therapy according to the current standard of care. The overall SVR rate was 17.4% (20 of 115 patients) with doses up to 1800 μg every other week. After 48 weeks of treatment the SVR rate in genotype 1 patients who were non-responders to PEG-IFN plus RBV therapy, was 10.7% (8 of 75 patients) .
Y shaped Interferon
This novel interferon molecule was recently evaluated in Egypt in 84 treatment naïve chronic HCV infected Egyptian patients. Patients were randomized into three groups according to interferon dosage intervals. They received Y shaped IFN 180 mcg either weekly (26 patients: group A), every 10 days (30 patients: group B) or every 14 days (28 patients: group C) plus a fixed dose of RBV (15 mg/kg/day). The EVR was 96%, 87% and 79% in groups A, B and C respectively (P = 0.16).
The most common adverse effects were a decrease in haemoglobin to below 10 g/100 ml in 6 (23%), 7 (23%), and 3 (11%) patients respectively (P = 0.39), a low neutrophilic count (<750/mm3) in 3 (11.1%) in group A, 5 (16.7%) in group B and 1 (3.6%) patients in group C (P = 0.27). Thrombocytopenia (<75,000/mm3) was observed in 2 (7.7%) in group A, 1 (3.3%) in group B and 3 (10.7%) patients in group C (P = 0.55). Thyroid dysfunction was detected in 3 (11.5%), 2 (6.7%), and 2 (7.1%) (P = 0.78) patients in groups A, B and C respectively. This ongoing study showed that pegylated Y shaped IFN-α 2a is a safe and effective option for the treatment of chronic HCV patients. No statistically significant difference in response was found among the studied dose intervals. The 2 week interval seems to be as effective as the 1 week and 10 day intervals with fewer side effects .
New direct acting antiviral drugs
The approval of new direct inhibitors of HCV replication should significantly improve the management of HCV. Many compounds are currently in phase II and III trials, mainly inhibitors of the HCV NS3/4A protease and NS5B polymerase [25, 26]. The first two HCV protease inhibitors (telaprevir and boceprevir) were recently approved for genotype-1 HCV, in some countries. Most of these new antiviral drugs have only been developed and investigated for genotype-1 HCV. The SVR rates with telaprevir in naïve patients and previously unresponsive patients have improved by 70% and up to 40% respectively [27, 28]. The results of the concept study show that telaprevir is active against HCV-4 after 15 days of monotherapy or in combination with PEG-IFN and RBV compared with PEG-IFN, RBV and placebo . Boceprevir the other drug with direct action, is also effective in HCV-1 patients , however, preliminary data suggest that boceprevir might not be effective in HCV-4 with the present regimen .
The R7128 is another nucleoside analogue polymerase inhibitor shown to be a potent antiviral. The interim analysis at week 12 with the combination of R7128 plus PEG-IFN α-2a and RBV in treatment-naïve patients with HCV-1 and 4 has shown that the rates of EVR are high with R7128 with good safety profiles and low rates of resistance or breakthrough .
Another compound with a different mode of action, nitazoxanide (NTZ), a synthetic antiprotozoal agent, was licensed in the United States for the treatment Cryptosporidium parvum and Giardia lamblia infections. The antiviral properties of this compound were discovered accidentally in HIV–HCV co-infected patients treated for cryptosporidiosis. The NTZ activates the protein kinase activated by double-stranded RNA (PKR), a key kinase that regulates the cell's innate antiviral response . Two clinical trials have been published on NTZ. The first, investigating NTZ monotherapy in Egyptian patients infected with HCV-4, showed that HCV-RNA became undetectable in 7 of 23 patients . The second study by Mederacke and Wedemeyer classified 96 HCV-4 Egyptian patients into two groups. The first was treated with the combination of NTZ/PEG-IFN/RBV and the second was treated with PEG-IFN/RBV . Seventy nine per cent of the patients receiving triple therapy with NTZ and PEG-IFN/RBV achieved a SVR compared with 50% in the control group who received PEG-IFN/RBV alone. Although these results are statistically significant and promising, the number of patients was small and the percentage of patients with cirrhosis was low (5 of 96) . Thus further studies are needed to investigate NTZ in genotype 4 patients.
The cyclophilin inhibitior Debio 025 suppresses HCV replication by inhibiting endogenous cyclophilin and interacting with the NS5B polymerase. HCV-RNA was shown to decrease by up to 4.75 log after 29 days of combination therapy with Debio 025, PEG-IFN alfa-2a, and RBV in treatment naive HCV-1 patients. Two HCV-4 patients were treated in that study with a viral load decrease of > 2 log10.
Seven days intravenous treatment (20 mg/kg/day) with the new drug silibinin, whose mechanism of action is not yet completely understood, resulted in a mean 3 log10 IU/ml decrease in HCV-RNA. This molecule has mainly been investigated in genotype 1 patients and single patients with genotypes 2, 3, or 4 infections. No data are available on the specific antiviral activities for the different HCV genotypes . In a recent case study by Beinhardt et al. the use of silibinin IV was associated with prevention of graft re-infection in a patient with mixed genotype 1a/4 .
Abu-Mouch et al. have recently suggested that vitamin D could increase the response to PEG-IFN/RBV treatment in HCV genotype 1 patients. In a study with 58 patients randomized to standard treatment or treatment combined with vitamin D, a RVR was obtained at week 4 in 44% of the vitamin D group and 18% of the control group. At week 12 there was a significant difference between the groups (P < 0.001): 96% of the vitamin D groups were HCV RNA-negative, compared with 48% of the control group. Although the group receiving vitamin D had a higher initial viral load and fibrosis, twice as many patients in this group were HCV RNA-negative at the end of the 12th week of treatment than in the group without vitamin D .
The HCV nonstructural protein 5A (NS5A) is a multifunctional protein that is expressed in basally phosphorylated (p56) and hyperphosphorylated (p58) forms. NS5A phosphorylation has been shown to play a role in regulating numerous aspects of HCV replication. Classes of compounds that potently inhibit HCV RNA replication by targeting NS5A were recently discovered . Multicenter randomized blind controlled phase 2b clinical trials are ongoing worldwide with a new NS5A replication complex inhibitor in patients with HCV genotype 1 (n = 365) & 4 (n = 30) sub classified into PEG-IFNα/RBV/NS5AI group and PEG-IFNα/RBV/placebo group. Initial results have shown that NS5AI combined with PEG-IFNα/RBV provided higher rates of EVR compared with placebo + PEG-IFNα/RBV. This regimen was well tolerated with similar adverse events to those of the placebo group, thus supporting the initiation of phase 3 studies .
IL28B polymorphism and HCV genotype 4 infection
Polymorphisms in the region of the interleukin IL28B gene have been associated with PEG-IFN and RBV treatment response mainly in genotype 1 HCV infections. A recent article evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity . This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. These data showed that IL28B rs12979860 CC genotype was associated with a better treatment response rate. The response rates were 81.8%, 46.5% and 29.4% for genotype CC, CT and TT respectively. No significant relationship was found between rs12979860 and the severity of the disease. Analysis of IL28B genotype might be used to guide treatment for these patients.
The development of new drugs and off-label use of other drugs is still of interest to improve the treatment of chronic HCV, especially in patients with genotype 4. Many promising molecules must still be evaluated to determine their potency, efficacy and safety.
Conflicts of interest
GE and MEG have received funds from BioGenesic Phasma and BMS: the remaining authors declare no conflicts of interests.