Alimentary Pharmacology & Therapeutics
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J. M. Wantuck1, A. Ahmed2, M. H. Nguyen2,*
Article first published online: 19 NOV 2013
© 2013 John Wiley & Sons Ltd
The global burden of hepatitis C (HCV) infection is mostly found in Africa, the Middle East and Asia, where HCV genotypes 4, 5 and 6 are common. The literature on these genotypes is sparse and this synopsis will review characteristics of patients infected with these genotypes.
To review characteristics of patients infected with HCV genotypes 4, 5 and 6.
PubMed search for ‘hepatitis C’ AND ‘genotype 4’, ‘hepatitis C’ AND ‘genotype 5’, and ‘hepatitis C’ AND ‘genotype 6’ was conducted and relevant articles were reviewed.
Intravenous drug use is generally responsible for HCV genotype 4 infection in developed countries, but unsafe medical practices cause most cases of HCV genotypes 4, 5 and 6 in endemic countries. The sustained virological response (SVR) rate for patients with HCV genotype 4 who receive pegylated interferon and ribavirin for 48 weeks ranges from 40% to 70% in various small studies. The SVR rate is in the 60–70% range for HCV genotype 5 and 70–80% range for HCV genotype 6 following 48 weeks with pegylated interferon and ribavirin. Preliminary data suggest that a shorter course of 24 weeks of pegylated interferon and ribavirin may be acceptable for HCV genotype 6, with an SVR rate of approximately 70%.
The current standard-of-care therapy for HCV genotypes 4, 5 and 6 is pegylated interferon and ribavirin for 48 weeks. A shorter course with 24 weeks of therapy may be considered for patients with genotype 6. Newer and much more effective therapies may be forthcoming in the next few years.
The pivotal treatment trials and large epidemiological studies completed for chronic hepatitis C have generally been conducted in North America and Europe, where hepatitis C virus (HCV) genotypes 1, 2 or 3 are prevalent.[1-3] More developed countries in the East, such as Japan and Korea, also have a similar HCV genotype distribution. HCV genotypes 4, 5 and 6 are common in areas of Asia, Africa and the Middle East where HCV infection is endemic; however, data on the epidemiology and therapeutic response of these genotypes are much more limited. This synopsis will review the epidemiology of these lesser known genotypes as well as their response to anti-viral treatment, including the available data on newly approved protease inhibitors and other novel anti-HCV agents for HCV genotype 4, newer treatment studies for HCV genotype 5 and recent randomised controlled trials (RCT) comparing outcomes of 24 vs. 48 weeks of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for HCV genotype 6. Recent advances in the understanding of host IFN sensitivity and interleukin-28B (IL28B) genetic polymorphism, which has varying ethnic distribution, as does the distribution of infection of HCV genotypes 4, 5 and 6 infection, will also be reviewed.
Geographical distribution of hepatitis C virus and hepatitis C virus genotypes
Estimates of HCV prevalence vary according to geographical areas and are largely based on cross-sectional studies of various subpopulations, ranging from blood donors, ambulatory out-patients, to hospital-based and chronic dialysis patients. The World Health Organization in 1999 estimated that between 130 and 170 million people are infected with HCV worldwide.[4, 5] The minority of these people (13 million or 22%) are found in the Americas and Europe.
In the Middle East and Africa, prevalence is highest in Egypt (18%) due to public health campaigns against schistosomiasis in the second half of the last century. Prevalence is approximately 1–2% in Syria and Saudi Arabia. Sub-Saharan Africa is less well studied, but estimates of HCV prevalence are high. Countries in central Africa average 6% prevalence, with the highest prevalence in Cameroon (14%) and the lowest in Equatorial Guinea (2%). In West Africa, the average prevalence is 2.4%, with ranges from 1% to 6%. Similarly, south and east African countries have an average prevalence of 1.6%, with South Africa having the lowest prevalence at 0.1%, while Mozambique is closer to 2.8%.[7, 8]
In the Asia Pacific region, Australia as a developed country populated predominantly by ethnic Europeans has a relatively low prevalence of 1.3%, and IVDU was implicated in 80% of infected subjects. The most common risk factor in most other countries of this region is, however, iatrogenic exposure due to reuse of needles or transfusion of unscreened blood products, including more industrialised countries, such as Japan and Taiwan. HCV prevalence is as high as 6% in Thailand and Vietnam.
In Europe, HCV prevalence is approximately 1–2% in most countries, but ranges from the lowest prevalence of ≤0.5% in northern countries to the highest (≥3%) in Romania and rural areas of Greece, Italy and Russia.
Similarly, the distribution of HCV genotypes also varies according to geographical area and is noteworthy because it is one of the most important predictors of response to anti-viral therapy. HCV genotypes 1, 2 and 3 are widely distributed among the world's population, but the lesser known genotypes tend to have a more focused geography and are associated with certain methods of transmission according to regional medical practices and public health standards. HCV genotype 4 is common in Africa and the Middle East (Figure 1 and Table 1).[1, 8, 11-23] HCV genotype 5 is found almost exclusively in South Africa and expatriates from that area, while HCV genotype 6 is found mostly in Southeast Asia, Southern China and immigrants from those regions.
|Country or region||HCV genotype 4 prevalence|
Figure 1. Map of geographical areas in which hepatitis C virus (HCV) genotypes 4, 5 and 6 are prevalent.
Another important factor influencing treatment outcome in chronic hepatitis C is the recently discovered IL28B gene polymorphism that is also distributed according to ethnic and geographical areas. The CC allele polymorphism occurs in 33% of Americans of European ancestry, 14% of African Americans and 29% of Hispanic Americans. The frequency of the CC genotype is much higher in studies of Asian populations, up to 84% in a recent study of 282 healthy Japanese volunteers.[25, 26] Individuals carrying IL28B polymorphism with CC alleles have the best prognosis, with two to three times the rate of sustained virological response (SVR) with IFN-based anti-HCV therapy, while those with TT alleles have the worst SVR rates. Most of the initial studies of this polymorphism were completed on genotype 1 patients; however, a recent study has shown that, in patients with HCV genotype 4, patients with CC, CT and TT genotypes have 82%, 47% and 29% SVR rates respectively.
The remainder of this synopsis will discuss the epidemiology and treatment outcomes of HCV genotypes 4, 5 and 6.
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).[8, 11-23] More recently, HCV-4 has been reported in the Caribbean region and in India.[23, 29, 30] In South Indian patients, HCV-4 prevalence is 6.2% among HCV-infected patients.[23, 30] 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.[32, 33] Newer studies also reported poorer post-transplant outcomes from graft-related vascular complications and recurrent hepatitis C for patients with HCV-4.[34, 35] 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.[38, 39] 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%).[40, 41] 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.[42, 43] 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).[44-47] 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.[48-50]
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).
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.[54-56] 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.[59-64] 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.[60, 62, 63]
Hepatitis C virus genotype 5
Epidemiology of hepatitis C genotype 5
HCV genotype 5 (HCV-5) is found almost exclusively in South Africa. Smuts et al. studied a population of 130 HCV-infected subjects from different areas of South Africa. HCV-5 was the most common genotype (39.2%), followed by HCV-1 (33%), HCV-2/3(21.5%) and HCV-4 (2.3%). Most often found in South Africa, HCV-5 can also be found in European regions hosting a mixture of ethnicities, such as Belgium, the Netherlands and Luxembourg. HCV-5 has also been reported at a surprisingly high prevalence of 14.2% among a population of settled, rural inhabitants of central France who had little contact with people from other countries. However, studies on data collected between 1989 and 1997 from HCV-infected patients at 14 tertiary care centres in France and between 2000 and 2003 from HCV-infected patients in the Midi-Pyrenees showed a much lower prevalence of HCV-5 (1.2% and 1.4% respectively).[68, 69] In a follow-up study carried out to determine the mode of transmission, the authors enrolled 131 HCV-5 patients in France who were not of South African origin and determined that transmission was probably associated with exposure to the care of one local physician, and that those persons then donated blood and caused additional infections in transfused patients. Another focus of infection was recently found in Syria, where 10% of HCV-infected patients had HCV-5. Thirty-three per cent of these patients lived in the same town, which suggests an aetiology similar to that in central France. Similar localised outbreaks of HCV-5 have also occurred in southeast Spain and the Greek isles.[73, 74]
Treatment of hepatitis C genotype 5
Treatment response to HCV-5 is less studied, although HCV-5 appears to be an easier to treat genotype, with outcomes more similar to those seen with hepatitis C genotypes 2 and 3 (HCV-2/3). The largest study to date was a multicentre retrospective study from 12 centres in France by Bonny et al. and included 87 HCV-5 patients treated with either standard dose PEG-IFN plus RBV (n = 59) or IFN plus RBV (n = 28) for 48 weeks and demonstrated similar SVR rates in the two study groups (58% vs. 64%, P = 0.75). The SVR rate for the total cohort of 87 HCV-5 patients was 60% overall and 75% for adherent patients. Of note, the limit of detection of HCV RNA PCR assay used in this study was 600–615 IU/mL, a much higher limit of detection than currently available. In this study, SVR rate was 37% for HCV-1 and 63% for HCV-2/3 overall. Figure 4 summarises results of treatment outcomes of HCV-5 patients.[75-78] SVR rates for HCV-5 in the study by D'Heygere was more similar to those of HCV-1 rather than HCV2/3, but this may be due to a much higher proportion of patients with cirrhosis in the HCV-5 group.
Figure 4. Sustained virological response to 48 weeks of pegylated interferon and ribavirin in hepatitis C genotype 5 patients, with comparison to other genotypes (Bonnyet al. and D'Heygere et al.).[75-78]
Another more recent, but also retrospective, study from Syria included 17 patients treated with IFN plus RBV and 9 patients with PEG-IFN and consisted of arms having both 24-week and 48-week treatment durations. In this study, SVR rate was 75% in the 4 patients treated with PEG-IFN plus RBV for 48 weeks compared to 60% for the 24-week group. The corresponding SVR rates for the IFN plus RBV group were 48% and 44% respectively. However, the small sample size of this study limits its conclusion and the standard duration of 48 weeks with PEG-IFN plus RBV should be recommended.
To date, no studies have been performed to test activities by the two newly approved protease inhibitors boceprevir and telaprevir against HCV-5.
Hepatitis C virus genotype
Diagnosis of HCV genotype 6
The diagnosis of HCV-6 has not always been straightforward. Prior to approximately 2004, the primary assay used to genotype HCV-6 patients was a line probe assay (INNO-LiPA HCV I; Innogenetics, Zwijnaarde, Belgium) that characterised genotypes by the hybridisation of denatured 5'-UTR products. This assay was invalidated in a 2003 study of various genotyping methods and was found to mislabel HCV genotype 6a as 1b.[78, 79] A second version of the test was introduced (INNO-LiPA HCV II; Innogenetics) and has been shown, in multiple studies, to be highly accurate for distinguishing HCV-6 and HCV-1 and to correctly classify the genotype 99.4% of the time.[80, 81] The implications of this information are that earlier studies using the old INNO-LiPA HCV I assay could have significantly under-reported the prevalence of HCV-6 in the populations studied. Similarly, SVR rates in HCV-1 patients could also have been inflated if there were HCV-6 patients mislabelled as HCV-1 cases, as HCV-6 patients generally have better treatment response than HCV-1 patients as discussed below.
Epidemiology of hepatitis C genotype 6
Similar to HCV-4 and HCV-5, HCV genotype 6 (HCV-6) is more geographically restricted compared with HCV genotypes 1 to 3 and has been found in parts of East Asia (South China, Hong Kong, Taiwan, Macao) and Southeast Asia (Singapore, Malaysia, Vietnam, Thailand, Indonesia and Burma).[1, 84-91] Previously reported genotypes 7, 8, 9 and 11 (Southeast Asia) have recently been reclassified as variants of HCV-6, while genotype 10 (Indonesia) was reclassified as a variant of HCV-3.[92, 93] There are now six genotypes with various subtypes. For example, HCV-6 is divided into 21 subtypes, the most recently sequenced being 6r and 6s.
The Philippines represents a unique genotypic distribution from its Southeast Asian neighbours. A survey in Metro Manila reported an HCV prevalence of 7% (n = 41) with the following HCV genotype distribution: 68% for 1a, 11% for 1b and 10% for 2a/b. This genotypic distribution seems to be more similar to that found in the West, perhaps representing migration patterns or differences in the mode of transmission.
The prevalence of HCV genotype 6 in Hong Kong was 33% among 66 blood donors and 26% among 27 out-patients with HCV infection.[87, 88] In mainland China, HCV genotype 6a seems to be rare except in South China, where it is the second most common genotype after genotype 1b. The unusual subtype 6v was also found in South China. In a study conducted in the San Francisco Bay Area, HCV-1 and HCV-6 were the two most common genotypic groups among 308 HCV-infected Vietnamese out-patients seen at a community gastroenterology practice (42% and 41% respectively).
Data on clinical characteristics of patients with chronic hepatitis C genotype 6 are very limited, but in one US study of Vietnamese and Chinese Vietnamese immigrant patients, no significant differences were found between patients with HCV-6 and those with HCV-1 and HCV-2/3 in regard to age, gender distribution, HCV RNA levels, cirrhosis, ALT levels and other hepatic synthetic markers. Additional data on chronic hepatitis C in Asians have been discussed and summarised elsewhere.
Treatment of hepatitis C virus genotype 6
In recent years, additional data on treatment outcomes of HCV-6 patients have been forthcoming, especially in regard to the effect of treatment duration, i.e. 24 vs. 48 weeks.[98, 99]
In general, several small studies have examined treatment outcomes in this patient population.[78, 81, 98, 100-106] Generally, SVR was 60–90% in patients treated for 48 weeks with standard doses of PEG-IFN and RBV (Figure 5).[101-105] The first multicentre RCT using PEG-IFN α-2a and weight-based RBV (1000/1200 mg) conducted in the US with ITT analysis showed no statistically significant differences in SVRs between the 24- and 48-week groups (n = 27, 33) (Figure 6).[98, 99] In this study, early virological response (EVR) did not correlate with SVR. Another RCT has also been conducted in Vietnam to compare SVRs of patients treated with 24 (n = 35) vs. 48 weeks (n = 70) of PEG-IFN α-2b and weight-based RBV (15 mg/kg/day). As with the previous RCT on this topic, this study found no statistically significant differences in SVRs in the 24- and 48-week treatment groups. In addition, this latter study suggests that rapid virological response (RVR) may be predictive of SVR, as in the case of HCV-1; however, those without RVR did not seem to benefit from the longer treatment duration. Thus, while there were no statistically significant differences between SVRs with 24 vs. 48 weeks of therapy in these two RCTs, the small sample size in both of these studies did not allow for detection of smaller differences.
Figure 5. Sustained virological response to 48 weeks of pegylated interferon and ribavirin in hepatitis C genotype 6 patients.[101-105]
As in the case of HCV-5 above, no studies including in vitro experiments have been performed to test activities by the two newly approved protease inhibitors boceprevir and telaprevir against HCV-6. In a preliminary study, the investigational compound GS-7977 (formerly PSI-7977) induced rapid viral suppression in five HCV-6 patients as well as in other patients with HCV-1 to HCV-4. In a recent phase III trial of sofosbuvir plus peginterferon alpha-2a and ribavirin in a 12-week regimen (NEUTRINO), six of the patients had genotype 6 and had a 100% SVR. Additional data with larger study sample with sofosbuvir and other newer generations of anti-HCV therapies with pan-genotypic activities are probably forthcoming in the next few years.
Infection with HCV-4 through HCV-6 is relatively uncommon in most developed countries. However, these genotypes are widely distributed in many parts of Asia, Africa and the Middle East, where the disease burden of chronic hepatitis C is among the highest in the world. Injections with multiple-use needles and glass syringes and the use of non-HCV tested blood products in many parts of the developing world will continue to contribute to the spread of HCV infection in these areas. Further studies to examine epidemiological characteristics, natural history and clinical outcomes of patients infected with these lesser known HCV genotypes are needed. From the limited data available, it seems that HCV-4 and HCV-6 patients will respond well to some of the novel agents, but limited data do not allow for a general recommendation at this time. As novel therapies debut in the next several years, studies should be conducted to assess efficacy and safety in all of the HCV genotypes prior to widespread use. For the time being, HCV-4 and HCV-5 patients should be offered 48 weeks of standard PEG-IFN and RBV. For HCV- 6 patients, treatment with PEG-IFN and RBV should probably be offered for 48 weeks as well, although a 24-week course of treatment may be reasonable in those with RVR or poor tolerance to treatment.
Guarantor of the article: Mindie Nguyen.
Author contribution: James Wantuck and Mindie Nguyen: concept development, data collection, drafting of the paper. Aijaz Ahmed: review of the paper. All authors approved the final version of the manuscript.
Declaration of personal interests: Aijaz Ahmed, MD: Grants/Research Support: Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche Genentech, Romark Laboratories; Consultant/Advisor: Bristol-Myers Squibb, Gilead Sciences, Kadman, Merck, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Roche Genentech, Romark Laboratories, Vertex Pharmaceuticals. Mindie H. Nguyen: Research support: Roche Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Novartis Pharmaceuticals, Idenix Pharmaceuticals. Consulting: Bristol-Myers Squibb, Novartis Pharmaceuticals, Gilead Sciences.
Declaration of funding interests: None.