Key points

Hepatitis C virus genotype 4 epidemiology and virus diversity

Hepatitis C virus (HCV) genotype 4 (GT4) accounts for approximately 20% among the 170 millions of HCV-infected subjects worldwide (approximately 34 million). This population accounts for most new infections that have limited access to therapy. Although HCV GT4 is responsible for 1% to 2% of HCV infections in the United States, it is the main cause of HCV infection in the Middle East and sub-Saharan Africa regions, and has recently been increasing in southern Europe. However, only limited country-specific estimates of HCV prevalence are available. In Egypt, where the prevalence of HCV is the highest in the world, the reuse of glass syringes during the parenteral therapy campaigns to control endemic schistosomiasis is widely held to be responsible for a very large number of iatrogenic transmissions. GT4 has a large diversity with numerous subtypes. In Egypt, GT4a is predominant, and in sub-Saharan Africa subtypes non-4a and non-4d account for most infections. In France and southern Europe, all the subtypes are represented, depending on country where patients immigrated and also the source of contamination.

Hepatitis C virus genotype 4 epidemiology and virus diversity

Hepatitis C virus (HCV) genotype 4 (GT4) accounts for approximately 20% among the 170 millions of HCV-infected subjects worldwide (approximately 34 million). This population accounts for most new infections that have limited access to therapy. Although HCV GT4 is responsible for 1% to 2% of HCV infections in the United States, it is the main cause of HCV infection in the Middle East and sub-Saharan Africa regions, and has recently been increasing in southern Europe. However, only limited country-specific estimates of HCV prevalence are available. In Egypt, where the prevalence of HCV is the highest in the world, the reuse of glass syringes during the parenteral therapy campaigns to control endemic schistosomiasis is widely held to be responsible for a very large number of iatrogenic transmissions. GT4 has a large diversity with numerous subtypes. In Egypt, GT4a is predominant, and in sub-Saharan Africa subtypes non-4a and non-4d account for most infections. In France and southern Europe, all the subtypes are represented, depending on country where patients immigrated and also the source of contamination.

Pegylated interferon plus ribavirin: historical perspectives

HCV GT4 has been considered “difficult to treat” with pegylated interferon (PEG) and ribavirin (RBV), with sustained virological response (SVR) rates of approximately 50%. Large real-life cohort data have been published and provide interesting information, regarding proportion of patients with HCV GT4, and SVR. In the real-life cohort Prophesys, HCV GT4 has been underrepresented with approximately 7% of the total number of patients treated (317/4520 = 7%). The SVR rate was 41% (130/317) ( Fig. 1 A). In a German real-life cohort, HCV GT4 prevalence was low (474/7835) = 6%, with an SVR rate of 44% (207/474) (see Fig. 1 B).

( A ) SVR with PEG-IFN plus RBV in the real-life cohort Prophesys. HCV GT4 has been underrepresented with approximately 7% of the total number of patients treated (317/4520 = 7%). SVR rate was 41% (130/317). ( B ) SVR with PEG-IFN plus RBV in a German real-life cohort, HCV-GT4 prevalence was low (474/7835) = 6%, with an SVR rate of 44% (207/474).

( Data from [ A ] Marcellin P, Cheinquer H, Curescu M, et al. High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials. Hepatology 2012;56(6):2039–50; and Mauss S, Berger F, Vogel M, et al. Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany. Z Gastroenterol 2012;50(5):441–4; [ B ] Mauss S, Berger F, Vogel M, et al. Treatment results of chronic hepatitis C genotype 5 and 6 infections in Germany. Z Gastroenterol 2012;50(5):441–4.)

A major predictor of response to PEG-RBV therapy in patients with HCV GT4 was the interleukin (IL)-28B genotype. SVR rates for patients with IL-28B rs12979860 CC ranged from more than 80% to approximately 30% for patients with genotype TT. Egyptian patients infected with HCV GT4 treated with PEG-RBV in Europe responded better than French/European or African patients infected with the same genotype ( Fig. 2 ). An overall better response was observed in patients infected with the HCV GT4 subtype 4a, which was the predominant subtype among patients infected in Egypt compared with patients from sub-Saharan Africa. IL-28B polymorphism distribution among different ethnicities may be the explanation for this difference in terms of SVR: rs12979860 CC is more frequent among Egyptian than among Caucasian, and even more than among black Africans.

( A ) IL-28B genotype distribution according to ethnicity. The genotype distributions for single nucleotide polymorphism rs12979860 were significantly different among the 3 ethnic groups: Egyptian, Caucasian, and sub-Saharan African. ( B ) IL-28B 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.

( Data from [ B ] Asselah T, De Muynck S, Broët P, et al. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol 2012;56(3):527–32.)

New hope with data available with direct-acting antivirals for hepatitis C virus genotype 4

The introduction of all-oral, interferon (IFN)-free regimens that combine direct-acting antiviral (DAA) agents has significantly advanced the treatment of HCV, especially for patients with HCV GT1 infection. High efficacy rates (greater than 95%), short treatment duration (12 weeks), and favorable adverse event (AE) profiles have been demonstrated with multiple regimens, both with and without RBV. Several original articles reporting efficacy of DAAs for the treatment of chronic GT4 HCV infection have been published recently. However, we have to recognize that the total number of trials with DAAs in patients with HCV GT4 infection is limited and with a small number of patients.

Direct-acting antivirals plus pegylated interferon plus ribavirin

Data from several studies with PEG-IFN have recently become available, and the data are summarized in Fig. 3 .

Results (SVR12) in studies involving DAAs with PEG-IFN.

( Data from Refs. )

Sofosbuvir plus pegylated interferon plus ribavirin (Neutrino study)

Sofosbuvir is the first-in-class, potent nucleotide analogue polymerase inhibitor that acts as a chain terminator within the catalytic site of the NS5B polymerase.

The Neutrino trial was a single-group, open-label phase III study of sofosbuvir (SOF) plus PEG-IFN/RBV in 327 naïve patients infected with HCV GT 1, 4, 5, or 6. Most of the patients who were included in the study had HCV GT1 (89%), 9% had GT4, and 2% had GT5 or 6. All patients received SOF, PEG-IFN/RBV for 12 weeks. Sofosbuvir was given orally at a dose of 400 mg, once a day, along with RBV, also given orally in a dose based on body weight. A total of 295 (90%) of the 327 patients had an SVR12. According to the HCV genotype: 89% for patients with HCV GT1 and 96% (27/28) of those with GT4 had SVR.

Almost all the patients with HCV GT4 had HCV GT4a subtypes (Egyptian ancestry). The single patient with G5 and all 6 patients with G6 in this trial had an SVR. Treatment discontinuation because of AEs was uncommon among patients receiving SOF regimens, with rates of 2%. The most common AEs in all patient groups were fatigue, headache, nausea, and insomnia.

Simeprevir plus pegylated interferon plus ribavirin (Restore study)

Simeprevir is a second-wave first-generation NS3/4A protease inhibitor with potent antiviral activity in HCV GT1, GT2, and GT4.

The Restore study was an open-label, single-arm study to assess the efficacy and safety of simeprevir (SMV) with PEG-IFN-α-2a/RBV in patients with chronic HCV GT4 infection ( NCT01567735 ). A total of 107 patients that included, treatment-naïve (n = 35) and prior relapsers (n = 22) received SMV 150 mg every day + PEG-IFN/RBV (12 weeks), followed by PEG-IFN/RBV alone (12 or 36 weeks, response-guided [HCV RNA <25 IU/mL detectable/undetectable at week 4 and <25 IU/mL undetectable at week 12]). Previous nonresponders (partial, n = 10; null, n = 40) received SMV/PEG-IFN/RBV (12 weeks), followed by PEG-IFN/RBV for 36 weeks. Overall, 65.4% (70/107) of patients achieved SVR12 (82.9% [29/35] treatment-naïve, 86.4% [19/22] prior relapsers, 60.0% [6/10] prior partial responders, 40.0% [16/40] prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% [31/35] and 90.9% [20/22]), SVR12 rates were high: 93.5% (29/31) and 95.0% (19/20), respectively. Overall on-treatment failure and relapse rates were 23.4% (25/107) and 14.6% (12/82), respectively. AEs were mainly grade 1/2; serious AEs were infrequent (4.7%) and considered unrelated to SMV. The SVR12 rate in patients with METAVIR score F4 was 46.7% (14/30); of note, most of these patients (63%; 19/30) were prior partial and null responders. The SVR12 rate in patients with METAVIR score F0 to F2 was 76.3% (45/59) compared with 66.7% (10/15) in patients with F3; 37% (22/59) of patients with METAVIR F0 to F2 and 13% (2/15) of those with F3 were prior partial or null responders. The effectiveness of protease inhibitor–based regimens in combination with PEG-IFN/RBV may be limited in patients who are nonresponders to previous PEG-IFN/RBV therapy. The investigators concluded that efficacy and safety of SMV 150 mg every day for 12 weeks with PEG-IFN/RBV in treatment-naïve or experienced patients with chronic HCV GT4 infection were in line with previous reports for HCV GT1 infection. These results support the use of an response guided therapy-based approach to individualize the duration of treatment in HCV GT4–infected patients. Shortening of treatment duration in these patients may be beneficial, as it would reduce overall drug exposure and minimize therapy costs. A 12-week trial with SMV and PEG-IFN/RBV is ongoing ( NCT01846832 ).