Epidemiology and Therapy of Chronic HCV Genotypes 4, 5, and 6
Epidemiology and Therapy of Chronic HCV Genotypes 4, 5, and 6
HCV genotype 4 (HCV-4) is encountered throughout Africa, eastern Mediterranean countries, and usually among immigrants from endemic areas or indigenous injection drug users or individuals infected with human immunodeficiency virus (HIV) in North America and Europe (Table 1). More recently, HCV-4 has been reported in the Caribbean region and in India. In South Indian patients, HCV-4 prevalence is 6.2% among HCV-infected patients. With regard to the relatively high rates of HCV genotype 4 in southern European countries, the ancient historic link between regions in southern Italy and Spain and North Africa or the Middle East, injections with multiple-use needles and glass syringes, and the use of non-HCV-tested blood products may have contributed to the spread of HCV genotype 4 to this region. For instance, in a French study, phylogenetic analysis of HCV-4 patients showed two distinct patterns of subtypes: 4a or 4d among injection drug users of French origin and 4f, 4k or 4r among immigrants from Central Africa and the Middle East, thus showing that the subtypes have spread differently. HCV genotype 4d was also a common subtype among homosexual men with acute hepatitis C and HIV co-infection in France.
Regarding clinical characteristics, HCV-4 patients have been reported to have higher rates of liver-related complications leading to liver transplantation or liver-related death. Newer studies also reported poorer post-transplant outcomes from graft-related vascular complications and recurrent hepatitis C for patients with HCV-4. However, HCV-4 was not an independent predictor of clinical outcomes on multivariate analysis in such studies. Potential explanations for such inconsistencies may be lack of control for duration of infection and other ethnicity-related factors, as these studies were conducted outside the regions endemic for HCV-4 and usually included either IVDUs or immigrants with early acquisition of HCV infection related to medical procedures. A large study of HCV-4 patients in Europe comparing patients who were infected in France, Sub-Saharan Africa and Egypt showed that those infected in France were usually infected from IVDU (56.9%), while those from Egypt were infected primarily from other reasons (97.1%). In addition, those infected in Egypt had higher rates of advanced fibrosis (44.6% vs. 24.2%) in concert with their longer duration of infection (22 vs. 28 years). These data could account for the lack of evidence identifying HCV-4 as an independent predictor of poorer outcomes in both the natural history of the disease and in post-transplant outcomes. There was also report of significant association of HCV subtypes 4a and 4o with hepatocellular carcinoma in Egypt, with subtype 4a accounting for 63% of those with genotype 4. Similarly, studies to date have not confirmed that HCV-4 patients develop extrahepatic complications, such as cryoglobulinaemia, more often than patients with other genotypes. The literature, however, consistently demonstrates poor response of patients with HCV-4 to older regimens of anti-viral therapy.
Combination Therapy With Interferon and Ribavirin. Combination therapy with IFN and RBV produced SVRs ranging from 5% to 42%, whereas IFN-alone arms ranged from 6% to 8%, which was comparable to earlier studies of IFN monotherapy (10–11%). Thus, results for HCV-4 were similar to, or worse than, results for HCV-1.
Combination Therapy With Pegylated Interferon and Ribavirin. Pivotal trials of PEG-IFN and RBV included few patients with HCV-4, comprising only 2–4% of all subjects, which is far too small a sample from which to draw conclusions. The duration of treatment in most studies is 48 weeks, with few studies also comparing responses between 24- and 48-week treatment duration. Figure 2 summarises results of studies for HCV-4 with 48 weeks of therapy using standard-dose PEG-IFN and RBV (PEG-IFNα-2a 180 μg or PEG-IFNα-2b 1.5 mg/kg and RBV 1–1.2 g/day). SVR generally ranged from 50% to 70%, except in one small study with SVR only 32%. Figure 3 summarises results of treatment responses with different duration of standard-dose PEG-IFN and RBV showing much more inferior SVR rates with 24 weeks of therapy and thus making the longer 48-week duration the standard of care.
(Enlarge Image)
Figure 2.
Sustained virological response to 48 weeks of combination therapy in patients with hepatitis C virus genotype 4. All studies were randomised control trials with intention-to-treat analysis: (P < 0.001); (P < 0.01); (P = NS); (P = 0.43).
(Enlarge Image)
Figure 3.
Hepatitis C genotype 4 treatment with PEG-IFN and RBV: 24 vs. 48 weeks. (P = not reported); (P = 0.001); (P = 0.006).
Nitazoxanide Therapy. Nitazoxanide is an agent capable of inhibition of HCV replication. Several studies have evaluated its use in HCV treatment. In one study of HCV-4 patients, IFN monotherapy with nitazoxanide was compared with placebo, showing that 17% achieved an SVR vs. 0% in the placebo group (P = 0.05). Another study comparing a regimen of standard PEG-IFN and RBV vs. pre-treatment for 12 weeks with nitazoxanide followed by 36 weeks of standard treatment in an ITT analysis found a 50% SVR in the first group (n = 40) and 79% SVR in the second (n = 28). With newer agents becoming available, research into nitazoxanide therapy for HCV has been fading, although it remains a possibility for therapy in regions where novel and expensive therapies are not available.
Newly Approved Protease Inhibitors (Boceprevir and Telaprevir) and Investigational Compounds. Current standard-of-care therapy for patients with chronic hepatitis C genotype 1 is a combination of PEG-IFN and RBV plus either boceprevir or telaprevir. Both of these new agents are protease inhibitors with direct-acting activity against HCV and were recently approved by the Food and Drug Administration in the US for the treatment of patients with chronic hepatitis C genotype 1. With the new standard-of-care therapy, treatment-naive HCV-1 patients can expect an SVR of 75% overall with telaprevir and 68% with boceprevir (but lower rates of 53% for Black patients) compared to 40–44% with PEG-IFN and RBV only (23% for Black patients).
Very little has been published on the success of the novel targeted anti-virals specifically aimed at genotypes 4, 5 and 6. Patients with HCV genotypes 4, 5 and 6 were not included in the pivotal studies with boceprevir or telaprevir. In a phase IIa study of 24 HCV-4 patients randomised to three arms, including telaprevir alone, PEG-IFN and RBV only, and telaprevir plus PEG-IFN and RBV three-drug regimen induced a 4.32 log10 decline in HCV RNA levels by day 15 of the study. However, telaprevir monotherapy in HCV-4 patients was not nearly as effective as it was in HCV-1, inducing only a 0.77 log10 decline in viral load vs. the 4.77 log10 decline seen with HCV-1 patients. SVR rates were approximately 50% in each group of this small study.
Currently, there are numerous anti-HCV investigational agents of various classes ('second- generation' protease inhibitors, nucleoside/nucleotide analogue polymerase inhibitors, nonnucleoside/nucleotide polymerase inhibitors, HCV NS5A inhibitors and cyclophilin inhibitors). Major effort is targeted at chronic hepatitis C genotype 1, but some of these newer agents have been shown to be pan-genotypic with activities against HCV genotypes 1 to 4 and 6. Sofosbuvir (formerly PSI-7977 or GS-7977) in combination with PEG-IFN and RBV induced viral suppression in 11 HCV-4 subjects included in this preliminary study. In a more recent phase III trial of 327 patients treated with a 12-week regimen of sofosbuvir plus peginterferon alpha-2a and ribavirin (NEUTRINO), 28 patients had HCV genotype 4 and SVR was achieved in 27 of these 28 patients (96%). Other compounds with promising efficacy against HCV-4 are daclatasvir (BMS-790052, a NS5A inhibitor), PEG- IFN-γ and the cyclophilin inhibitor Debio 025.
Hepatitis C Virus Genotype 4
Epidemiology of Hepatitis C Genotype 4
HCV genotype 4 (HCV-4) is encountered throughout Africa, eastern Mediterranean countries, and usually among immigrants from endemic areas or indigenous injection drug users or individuals infected with human immunodeficiency virus (HIV) in North America and Europe (Table 1). More recently, HCV-4 has been reported in the Caribbean region and in India. In South Indian patients, HCV-4 prevalence is 6.2% among HCV-infected patients. With regard to the relatively high rates of HCV genotype 4 in southern European countries, the ancient historic link between regions in southern Italy and Spain and North Africa or the Middle East, injections with multiple-use needles and glass syringes, and the use of non-HCV-tested blood products may have contributed to the spread of HCV genotype 4 to this region. For instance, in a French study, phylogenetic analysis of HCV-4 patients showed two distinct patterns of subtypes: 4a or 4d among injection drug users of French origin and 4f, 4k or 4r among immigrants from Central Africa and the Middle East, thus showing that the subtypes have spread differently. HCV genotype 4d was also a common subtype among homosexual men with acute hepatitis C and HIV co-infection in France.
Regarding clinical characteristics, HCV-4 patients have been reported to have higher rates of liver-related complications leading to liver transplantation or liver-related death. Newer studies also reported poorer post-transplant outcomes from graft-related vascular complications and recurrent hepatitis C for patients with HCV-4. However, HCV-4 was not an independent predictor of clinical outcomes on multivariate analysis in such studies. Potential explanations for such inconsistencies may be lack of control for duration of infection and other ethnicity-related factors, as these studies were conducted outside the regions endemic for HCV-4 and usually included either IVDUs or immigrants with early acquisition of HCV infection related to medical procedures. A large study of HCV-4 patients in Europe comparing patients who were infected in France, Sub-Saharan Africa and Egypt showed that those infected in France were usually infected from IVDU (56.9%), while those from Egypt were infected primarily from other reasons (97.1%). In addition, those infected in Egypt had higher rates of advanced fibrosis (44.6% vs. 24.2%) in concert with their longer duration of infection (22 vs. 28 years). These data could account for the lack of evidence identifying HCV-4 as an independent predictor of poorer outcomes in both the natural history of the disease and in post-transplant outcomes. There was also report of significant association of HCV subtypes 4a and 4o with hepatocellular carcinoma in Egypt, with subtype 4a accounting for 63% of those with genotype 4. Similarly, studies to date have not confirmed that HCV-4 patients develop extrahepatic complications, such as cryoglobulinaemia, more often than patients with other genotypes. The literature, however, consistently demonstrates poor response of patients with HCV-4 to older regimens of anti-viral therapy.
Treatment of Hepatitis C Genotype 4
Combination Therapy With Interferon and Ribavirin. Combination therapy with IFN and RBV produced SVRs ranging from 5% to 42%, whereas IFN-alone arms ranged from 6% to 8%, which was comparable to earlier studies of IFN monotherapy (10–11%). Thus, results for HCV-4 were similar to, or worse than, results for HCV-1.
Combination Therapy With Pegylated Interferon and Ribavirin. Pivotal trials of PEG-IFN and RBV included few patients with HCV-4, comprising only 2–4% of all subjects, which is far too small a sample from which to draw conclusions. The duration of treatment in most studies is 48 weeks, with few studies also comparing responses between 24- and 48-week treatment duration. Figure 2 summarises results of studies for HCV-4 with 48 weeks of therapy using standard-dose PEG-IFN and RBV (PEG-IFNα-2a 180 μg or PEG-IFNα-2b 1.5 mg/kg and RBV 1–1.2 g/day). SVR generally ranged from 50% to 70%, except in one small study with SVR only 32%. Figure 3 summarises results of treatment responses with different duration of standard-dose PEG-IFN and RBV showing much more inferior SVR rates with 24 weeks of therapy and thus making the longer 48-week duration the standard of care.
(Enlarge Image)
Figure 2.
Sustained virological response to 48 weeks of combination therapy in patients with hepatitis C virus genotype 4. All studies were randomised control trials with intention-to-treat analysis: (P < 0.001); (P < 0.01); (P = NS); (P = 0.43).
(Enlarge Image)
Figure 3.
Hepatitis C genotype 4 treatment with PEG-IFN and RBV: 24 vs. 48 weeks. (P = not reported); (P = 0.001); (P = 0.006).
Nitazoxanide Therapy. Nitazoxanide is an agent capable of inhibition of HCV replication. Several studies have evaluated its use in HCV treatment. In one study of HCV-4 patients, IFN monotherapy with nitazoxanide was compared with placebo, showing that 17% achieved an SVR vs. 0% in the placebo group (P = 0.05). Another study comparing a regimen of standard PEG-IFN and RBV vs. pre-treatment for 12 weeks with nitazoxanide followed by 36 weeks of standard treatment in an ITT analysis found a 50% SVR in the first group (n = 40) and 79% SVR in the second (n = 28). With newer agents becoming available, research into nitazoxanide therapy for HCV has been fading, although it remains a possibility for therapy in regions where novel and expensive therapies are not available.
Newly Approved Protease Inhibitors (Boceprevir and Telaprevir) and Investigational Compounds. Current standard-of-care therapy for patients with chronic hepatitis C genotype 1 is a combination of PEG-IFN and RBV plus either boceprevir or telaprevir. Both of these new agents are protease inhibitors with direct-acting activity against HCV and were recently approved by the Food and Drug Administration in the US for the treatment of patients with chronic hepatitis C genotype 1. With the new standard-of-care therapy, treatment-naive HCV-1 patients can expect an SVR of 75% overall with telaprevir and 68% with boceprevir (but lower rates of 53% for Black patients) compared to 40–44% with PEG-IFN and RBV only (23% for Black patients).
Very little has been published on the success of the novel targeted anti-virals specifically aimed at genotypes 4, 5 and 6. Patients with HCV genotypes 4, 5 and 6 were not included in the pivotal studies with boceprevir or telaprevir. In a phase IIa study of 24 HCV-4 patients randomised to three arms, including telaprevir alone, PEG-IFN and RBV only, and telaprevir plus PEG-IFN and RBV three-drug regimen induced a 4.32 log10 decline in HCV RNA levels by day 15 of the study. However, telaprevir monotherapy in HCV-4 patients was not nearly as effective as it was in HCV-1, inducing only a 0.77 log10 decline in viral load vs. the 4.77 log10 decline seen with HCV-1 patients. SVR rates were approximately 50% in each group of this small study.
Currently, there are numerous anti-HCV investigational agents of various classes ('second- generation' protease inhibitors, nucleoside/nucleotide analogue polymerase inhibitors, nonnucleoside/nucleotide polymerase inhibitors, HCV NS5A inhibitors and cyclophilin inhibitors). Major effort is targeted at chronic hepatitis C genotype 1, but some of these newer agents have been shown to be pan-genotypic with activities against HCV genotypes 1 to 4 and 6. Sofosbuvir (formerly PSI-7977 or GS-7977) in combination with PEG-IFN and RBV induced viral suppression in 11 HCV-4 subjects included in this preliminary study. In a more recent phase III trial of 327 patients treated with a 12-week regimen of sofosbuvir plus peginterferon alpha-2a and ribavirin (NEUTRINO), 28 patients had HCV genotype 4 and SVR was achieved in 27 of these 28 patients (96%). Other compounds with promising efficacy against HCV-4 are daclatasvir (BMS-790052, a NS5A inhibitor), PEG- IFN-γ and the cyclophilin inhibitor Debio 025.
