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Keywords:

  • chronic hepatitis;
  • interferon;
  • pegylated;
  • ribavirin;
  • therapy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Hepatitis C virus (HCV) genotype 4 is predominantly found in the Middle East and North Africa. Because most of the large randomized controlled trials of antiviral therapy for chronic hepatitis C were conducted in North America and Europe, little is known about management of patients with this particular genotype. Based on the available data, sustained virological response rates to interferon-based therapies appear to be intermediate between the relatively resistant HCV genotype 1 and the readily responsive genotypes 2 and 3. Several large prospective studies of pegylated interferon plus ribavirin combination therapy, the current gold-standard treatment, have recently been completed and will be reviewed.

© 2004 Blackwell Publishing Asia Pty Ltd


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Hepatitis C is a major cause of end-stage liver disease in many parts of the world. One hundred and seventy million people are estimated to be infected worldwide.1 Six major genotypes1–6 and more than 50 subtypes of hepatitis C virus (HCV) have been described to date.2 Different isolates of HCV of the same subtype can differ in nucleotide sequence by 5–15%, subtypes by 10–30%, and genotypes by 30–50%. Genotype 1a is the prototype genotype and is common in North America and Europe. Genotype 1b has a worldwide distribution. Genotype 2(a,b) also has a worldwide distribution but is common in Japan and Italy. Genotype 3 is prevalent in the Indian subcontinent. Genotypes 5 and 6 are rare outside of isolated geographic areas, genotype 5 in South Africa and genotype 6 in South-East Asia.2,3 In other parts of Asia, genotypes 1 and 3 are dominant, but genotype 4 is not generally found in any part of the Asia–Pacific region.4

Most attention, at least in clinical trials, has been directed at genotype 1 because it represents the majority of patients in North America and Europe, followed by genotypes 2 and 3, while much less attention has been paid to the other genotypes.

In the present paper we will review the available literature on genotype 4 hepatitis C (HCV4) with emphasis on treatment. All English-language papers have been reviewed given the relatively small numbers of studies involving this genotype.

EPIDEMIOLOGY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Geographical distribution

In general, HCV4 is predominant in Africa and the Middle East.3 In Egypt, where hepatitis C is highly endemic (up to 15% of the population), a study of 190 specimens from 15 geographically diverse regions found that 91% of the patients were infected with HCV4.5 Many studies confirm that HCV4 is the predominant HCV genotype in Saudi Arabia, contributing 50–75% of all detected genotypes.6–8 Subtypes 4c/4d, 4h, and 4e are the most common.9,10 Similarly, genotype 4 is predominant in Kuwait.11,12

Studies from other parts of the Middle East also suggest a high prevalence of HCV4. For example, 37% of HCV-infected Lebanese patients with thalassaemia had genotype 4.13 Several small studies from Africa suggest that HCV4 is the predominant genotype on that continent,14–16 but a recent study from Cameroon in patients coinfected with HCV and HIV showed that HCV4 comprised only 16% of their patients, with genotype 1 being the most predominant genotype.16

In Asia, HCV4 is very rare. In a Japanese study of 899 HCV-positive patients, only four patients (0.4%) were infected with HCV4.17 All four were hemophiliac patients who had received clotting factors from foreign countries.

Although genotype HCV4 accounts for only 1–3% of hepatitis C infection in Western countries, isolated studies report an unexpectedly high prevalence of HCV4 in some European countries. For example, 47% patients in a cross-sectional study in Southern Spain were found to have HCV4.18 Most of these patients used intravenous drugs. In Calabria, Southern Italy, initial studies from 1996 found no evidence of HCV4,19 but subsequently the prevalence of this genotype rose to 4.7% in the most recent studies.20 More typical of the generally low prevalence of HCV4 in Europe is a recent French study that reported that among 1000 patients with HCV infection tested over a period of 3 years, 2.6% were infected with HCV4.21 Most HCV4 patients in this study injected drugs.

Mode of transmission

The available evidence suggests that there is a difference in the mode of transmission of this genotype of HCV based on geographic location. Most studies from Saudi Arabia and Kuwait show that less than 20% of infected patients have clear historical risk factors identified.11,12,22 Although not proven, it is strongly suspected that the majority of the remaining patients were infected through iatrogenic routes. In two Kuwaiti studies, the majority of patients with HCV were Egyptians living in Kuwait. Multiple large community-based studies from Egypt have shown a strong association between a history of receiving parenteral antischistosomal therapy (in the 1960s and 1970s) and the prevalence of anti-HCV antibody.23–25 Rao et al. reported that among Egyptians residing in the Nile delta region, the prevalence of HCV was 38% in patients who reported no history of schistosomiasis and 68% in individuals with a history of parenteral antischistosomiasis treatment (P < 0.0001).24 The high prevalence even in those without parenteral therapy risk factors suggests that other modes of transmission are also contributing. Other risk factors have been demonstrated, including blood transfusion, invasive medical procedures, injections from ‘informal’ health-care providers, and caesarean section or abortion.26,27 Some Egyptian studies suggest that the risk of vertical transmission is also important, up to 36% in HCV-RNA-positive mothers.28 Why this rate is so much higher than the worldwide average of approximately 6% reported by other studies29 remains unclear.

In contrast, most studies from Europe suggest that the predominant route of HCV4 transmission there is intravenous drug use.18,21 Zylberberg et al. found that HCV4 infection through intravenous drug use was much more common in French patients compared to patients who were born in highly endemic countries.30

Natural history

In general, HCV genotypes differ little in clinical expression and are not associated with different clinical outcomes.31,32 Some studies suggest that there are two epidemiologic types of HCV4 infection in Europe. The first type is the infection acquired by intravenous drug use or blood transfusion; this is more common in patients who are originally from Europe. The second type is seen in immigrants who were born in endemic countries, and presumably reflects iatrogenic transmission. Although the response to interferon (IFN) therapy seems similar in both groups, some studies suggest that the risk of fibrosis and cirrhosis is higher in the second group.30 This is likely to be related to the longer duration of infection, considering that the majority of patients in endemic countries were infected through contaminated parenteral treatments in the 1960s and 1970s.

Recently, two studies, one from an Australian transplant center, and the other in abstract form, reported that HCV4 patients have a worse prognosis compared to other HCV genotypes after liver transplantation.33,34 Both studies suggested that recurrent HCV infection after transplantation induced more severe and rapid hepatic fibrosis progression in the HCV4 patients. The conclusions of these studies are based on relatively small numbers of HCV4 patients, and it will be interesting to see if these trends are confirmed when the small transplant centers in Africa and the Middle East start increasing their patient numbers in the next few years.

TREATMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

In general, patients with HCV4 were underrepresented in all the major multicenter trials of treatment in hepatitis C. This is due to the small percentage of patients with this genotype in North America and Europe, where most of the studies were conducted. For example, in the studies of non-pegylated IFN plus ribavirin combination therapy, only approximately 1–3% of the patients had genotypes other than 1, 2 or 3.35,36 Similarly, in the pegylated interferon (PEG-IFN) trials, there were minimal numbers of patients with genotype 4. In the study by Zeuzem et al. using PEG-IFN-α-2a monotherapy, HCV4 patients represented 2% of the total;37 and in the study in cirrhotic patients by Heathcote et al. they represented approximately 1%.38 Similarly, in the PEG-IFN plus ribavirin combination studies only 3% of patients did not have genotypes 1, 2 or 3.39,40

Interferon monotherapy

In a randomized controlled trial, Al Faleh et al. reported the results of treating 80 consecutive Saudi Arabian patients with 5 million units (MU) of IFN-α-2b, three times weekly (TIW) for 24 weeks versus no active treatment.41 Genotyping was performed on only 34 patients, and 14 proved to have genotype 4. Eleven patients had early cirrhosis. In this study, only biochemical response (alanine aminotransferase (ALT) normalization) was reported after 24 weeks of follow up. Using this definition, no response was seen in the control group, while in the treatment arm, 28% had a complete end-of-treatment response and 16% had sustained biochemical response. The presence of cirrhosis was the only negative predictor of response.

El Zayadi et al. from Egypt treated 100 HCV4 patients with IFN-α-2a at a dose of 3 MU TIW for a total of 6 months.42 Forty-five per cent of the patients had cirrhosis. At end of treatment, 31% had ALT normalization and 22% had undetectable HCV-RNA. However, sustained virological response (SVR) was observed only in 4% of the patients.

In a French study, 20 patients with HCV4 infection (out of 74 patients, which represents 27% of the HCV population who had genotyping) were treated with IFN monotherapy.30 Three of the 20 patients had cirrhosis. The definition of a sustained response was unclear but it was reported to be 5% in the genotype 4 patients compared to 35% in genotype 3a patients (P < 0.05). Another French study reported an 11% SVR in 17 patients with HCV4 treated with IFN monotherapy for a mean of 8 months.21

In contrast, Huraib et al. treated 17 Saudi patients with end-stage renal disease on hemodialysis with IFN monotherapy for 1 year and found a surprising 71% SVR.43 Ten of the 17 had genotype 4. One possible explanation for this high response rate is the relatively low viral load in these patients (mean: 0.85 ± 0.23 mEq/mL) and the mild disease on liver biopsy that may have been due to a short duration of infection in dialysis patients.

Interferon plus ribavirin combination therapy

A summary of these studies is given in (Table 1). An Egyptian study randomized 52 HCV4 patients to receive either IFN-α-2b 3 MU TIW or IFN plus 1000 mg/day of ribavirin for 24 weeks.44 Approximately 30% in each arm had cirrhosis. The SVR rates were 20% in the combination arm and 8% in the IFN monotherapy arm.

Table 1.  Summary of studies using standard interferon plus ribavirin in the treatment of genotype 4 hepatitis C
 El Zayadi et al.44Koshy et al.12Koshy et al.11Al Faleh et al.22Bruno et al.45
  • These data represent subgroup analyses of 97 patients, 40 of which were genotype 4. Combo, combination of IFN + R regimen; ETVR, end-of-treatment virological response; IFN, interferon; mono, IFN monotherapy; NR, not reported; PEG-IFN, pegylated interferon; R, ribavirin; RCT, randomized controlled trial; SVR, sustained virological response.

Study designRCTRCTRCTProspective, open-labelProspective, uncontrolled
No. patients52112474018
% cirrhosis30%  0%100%NR16%
TreatmentIFN-α-2b + R 1000 mg/day vs IFN monoIFN-α-2b + R 1000–1200 mg/day vs IFN monoIFN-α-2b + R 1000–1200 mg/day vs IFN monoIFN-α-2b + R 1000 mg/dayIFN-α-2b + R 1000–1200 mg/day
Duration24 weeks24 weeks24 weeks24 weeks48 weeks
ETVRCombo 37%; Mono: 16%NRNR43%33%
SVRCombo:20%; Mono: 8%Combo: 42%; Mono: 8%Combo: 14%; Mono: 0%16%11%

Koshy et al. treated 112 non-cirrhotic HCV4 patients with either 5 MU of IFN-α-2b TIW (52 patients), or IFN plus ribavirin 1000 mg/day for bodyweight <75 kg or 1200 mg/day for bodyweight >75 kg (60 patients).12 Sustained viral response was observed only in 8% of patients in the monotherapy group versus 42% in the combination group (P = 0.0001). The same group also reported on 26 HCV4 cirrhotic patients treated with either IFN or IFN plus ribavirin combination therapy in similar doses.11 No SVR was observed in the IFN monotherapy group compared to 14% in the combination therapy group.

Al Faleh et al. conducted a prospective open-label trial in 97 patients from Saudi Arabia.22 Genotyping was available on 76 patients; 55% had genotype 4. Sixty-eight patients were non-responders to previous IFN monotherapy while 29 patients were treatment-naïve. Patients were treated with IFN-α-2b 3 MU TIW plus ribavirin 1000 mg daily for 6 months. End-of-treatment virological response (ETVR) was 28% in the previously treated group and 58% in the naïve patients, while SVR was 12% and 5%, respectively (P = NS). When only the 40 patients with genotype 4 were analyzed, the ETVR was 43% and the SVR was 16%. One possible explanation for the surprisingly low SVR in the naïve patients compared to the previously treated patients is that >70% of the naïve patients had a high or medium viral load. In addition, the treatment duration was only 6 months, which may explain the relatively high ETVR compared to the low SVR.

A small Italian study reported on 18 HCV4 patients treated with IFN-α-2b 5–6 MU TIW plus ribavirin 1000–1200 mg/day for 48 weeks.45 Three patients had cirrhosis and seven had been treated previously with IFN monotherapy. Only 33% had an ETVR and 11% had an SVR.

Pegylated interferons

A summary of PEG-IFN treatment is given in (Table 2). In addition to the very limited number of patients with genotype 4 infection in the large multicenter HCV treatment trials, we found one letter and five abstracts discussing the results of treatment with PEG-IFN in this population.

Table 2.  Summary of studies using pegylated interferon regimens in treatment of genotype 4 hepatitis C
 Sherman et al.46Shobokshi et al.47Esmat et al.48Diago et al.49Al Faleh et al.50Hasan et al.51
  1. Combo, combination of IFN + R regimen; ETVR, end-of-treatment virological response; IFN, interferon; mono, IFN monotherapy; NR, not reported; PEG-IFN, pegylated interferon; R, ribavirin; RCT, randomized controlled trial; SVR, sustained virological response.

Type of publicationLetterAbstractAbstractAbstractAbstractAbstract
Study designRCTRandomized, open labelRCTRCTRCTProspective
No. patients11180172 (139 genotype 4)499644
% cirrhosis25NRNRNR629
TreatmentPEG-IFN-α-2a monoPEG-IFN-α-2a + R 800 mg/day vs PEG mono vs IFN-α-2a 4.5 MU TIW + R 800 mg/dayPEG-IFN-α-2b + R 800– 1000 mg/day vsIFN-α-2b + RStudy 1: PEG-IFN-α-2a + R 1000–1200 mg/day Study 2: PEG-IFN-α-2a + variable doses of RPEG-IFN-α-2b 100 µg/week + R 800 mg.day; IFN-α-2b 3 MU 3/weekPEG-IFN-α-2b 100 µg/week + R 1000–1200 mg/day
Duration (weeks)484848Study 1: 48 Study 2: 24 or 484848
ETVR73%PEG combo: 67%, IFN combo: 37%, mono: 59%At 12 weeks: 71%, at 24 weeks: 66%NR70.8%; 52%77%
SVR45%Peg combo: 50%, IFN combo: 28%, mono: 30%NR79% PEG-IFN + R 1000–1200 mg/day × 48 weeks 63% PEG-IFN + R 800 mg/day × 48 weeks 67% PEG-IFN + R 1000–1200 mg/day × 24 weeks 0% PEG-IFN + R 800 mg/dayNR  × 24 weeks43.8%; 29.2%68%

As a subgroup of the large phase 2 and 3 trials including 1205 hepatitis C patients, Sherman et al. reported the results of 16 patients with HCV4. Five patients received treatment with IFN-α-2a and 11 patients were treated with PEG-IFN-α-2a weekly for 48 weeks.46 Four patients had cirrhosis. No patient treated with standard IFN achieved ETVR or SVR, whereas of the patients treated with PEG-IFN 73% showed ETVR and 45% had an SVR.

In an abstract from Saudi Arabia, Shobokshi et al. treated 180 HCV4 patients in a randomized open-label multicenter trial.47 The first group received PEG-IFN-α-2a 180 µg weekly plus ribavirin 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 ribavirin 800 mg/day. Sixty-seven percent of the patients were HCV-RNA negative at the end of treatment in the PEG-IFN combination arm compared to 59% in the monotherapy arm and 37% in the standard IFN combination arm. At the end of follow up, SVR was seen in 50% of the patients in the PEG-IFN combination therapy group compared with 28% in the PEG-IFN monotherapy group and 30% in the standard IFN combination arm. Importantly, none of the patients who did not have a significant response at 12 weeks of therapy achieved an SVR.

Esmat et al. reported preliminary results from an ongoing randomized trial involving 172 patients, 138 of which had HCV4.48 Patients were randomized to receive PEG-IFN-α-2b 100µg/week plus 800–1000 mg of ribavirin based on bodyweight or standard IFN plus ribavirin for 48 weeks. At 12 weeks, HCV-RNA was undetectable in 71% of the patients in the PEG-IFN arm and in 65% of patients in the regular IFN arm. At 24 weeks, HCV-RNA was undetectable in 66% of the patients in the PEG-IFN arm and 59% of the patients in the regular IFN arm. No results are yet available for ETVR or SVR.

Diago et al. reported preliminary results of 49 HCV4 patients from North American and European sites in two large phase III trials.49 In the first trial, 13 patients were treated with PEG-IFN-α-2a plus ribavirin 1000–1200 mg/day for 48 weeks, while in the second trial 36 patients were treated in one of four groups: PEG-IFN-α-2a plus 800 mg of ribavirin or 1000–1200 mg of ribavirin for 24 weeks or 48 weeks. Among patients who were treated with PEG-IFN plus 1000–1200 mg of ribavirin, 79% achieved an SVR. Patients treated with ribavirin at a dose of 800 mg for 48 weeks or ribavirin 1000–1200 mg for 24 weeks achieved slightly lower SVR of 63% and 67%, respectively. No SVR was seen in patients treated with ribavirin 800 mg/day for 24 weeks.

Two studies were recently presented in which PEG-IFN alfa-2b was used, one study from Saudi Arabia and another from Kuwait. In the first abstract, Al Faleh et al. randomized 96 patients to be treated with either 100 µg of PEG-IFN-α-2b plus 800 mg/day of ribavirin or standard IFN plus ribavirin combination therapy. At the end of treatment, the virological response was 70% in the PEG-IFN arm compared with 52% in the standard IFN arm.50 SVR was achieved in 43.8% of patient in the PEG-IFN arm and in 29.2% of patients in the standard IFN arm. These results did not achieve statistical significance probably because of the relatively small sample size. In the other study in which PEG-IFN-α-2b was used, Hasan et al. enrolled 66 patients in a prospective open-label study. In this study, a higher (currently standard) dose of ribavirin, that is 1000–1200 mg/day, was used. This resulted in much higher end-of-treatment and sustained virological responses of 77% and 68% respectively.51

Given the two studies by Diago and Hasan, both showing high SVR results, in the 70% range, it seems clear that high-dose ribavirin, that is 1000–1200 mg/day, should be used in HCV4 patients, as for HCV1 patients, irrespective of the type of PEG-IFN used.

Predictors of response to therapy

Given the small number of patients with HCV4 enrolled in the large HCV treatment trials and the relatively small number of studies specifically investigating HCV4 patients, definitive conclusions cannot be reached about predictive factors for treatment response. From studies using regular IFN, Al Faleh et al. found that a high pretreatment viral load was the most important negative predictive factor for response to therapy followed by an advanced histological stage.22 Similar results were found in some of the studies from Egypt.42,44 In contrast, Koshy et al. did not find any significant pretreatment variables that would predict treatment response.12 Unfortunately, because all the large studies of PEG-IFN in treatment of HCV4 are currently only in abstract form with no SVR data yet, at present any predictors of treatment response remain completely unknown.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Genotype 4 HCV is most prominent in the Middle East and North Africa, but with worldwide immigration and travel, can be found in small numbers elsewhere. The major mode of transmission in the endemic countries of the Middle East and Africa appears to be iatrogenic. The natural history seems to be generally similar to other HCV genotypes, but the suggestion that HCV4 is associated with a worse prognosis after liver transplantation needs to be confirmed by larger studies.

Treatment results with regular IFN monotherapy are very disappointing, in the range of 10–15%. It is clear that this treatment cannot be recommended for HCV4 patients. For non-pegylated IFN plus ribavirin combination therapy the results are variable, but approximately 20% of patients achieve SVR after 24 weeks of treatment. Higher SVR percentages can be expected with longer duration of treatment and optimal doses of ribavirin. The use of PEG-IFN combination therapies should result in improved response rates, based on the preliminary data, with SVR expected to range from 40% to 70%. The best preliminary results to date have used PEG-IFN, higher doses of ribavirin, and a 48 week duration of therapy, resulting in 79% SVR, results similar to HCV genotypes 2 and 3.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Dr Lee is supported by an Alberta Heritage Foundation for Medical Research Senior Scholarship award. He has consulted for Hoffman-Laroche, received research grant funds from Schering Plough and Hoffman-Laroche, and is on the speakers’ bureau of both companies.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. EPIDEMIOLOGY
  5. TREATMENT
  6. CONCLUSIONS
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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