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
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.44||Koshy et al.12||Koshy et al.11||Al Faleh et al.22†||Bruno et al.45|
|Study design||RCT||RCT||RCT||Prospective, open-label||Prospective, uncontrolled|
|% cirrhosis||30%|| 0%||100%||NR||16%|
|Treatment||IFN-α-2b + R 1000 mg/day vs IFN mono||IFN-α-2b + R 1000–1200 mg/day vs IFN mono||IFN-α-2b + R 1000–1200 mg/day vs IFN mono||IFN-α-2b + R 1000 mg/day||IFN-α-2b + R 1000–1200 mg/day|
|Duration||24 weeks||24 weeks||24 weeks||24 weeks||48 weeks|
|ETVR||Combo 37%; Mono: 16%||NR||NR||43%||33%|
|SVR||Combo: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.
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.46||Shobokshi et al.47||Esmat et al.48||Diago et al.49||Al Faleh et al.50||Hasan et al.51|
|Type of publication||Letter||Abstract||Abstract||Abstract||Abstract||Abstract|
|Study design||RCT||Randomized, open label||RCT||RCT||RCT||Prospective|
|No. patients||11||180||172 (139 genotype 4)||49||96||44|
|Treatment||PEG-IFN-α-2a mono||PEG-IFN-α-2a + R 800 mg/day vs PEG mono vs IFN-α-2a 4.5 MU TIW + R 800 mg/day||PEG-IFN-α-2b + R 800– 1000 mg/day vsIFN-α-2b + R||Study 1: PEG-IFN-α-2a + R 1000–1200 mg/day Study 2: PEG-IFN-α-2a + variable doses of R||PEG-IFN-α-2b 100 µg/week + R 800 mg.day; IFN-α-2b 3 MU 3/week||PEG-IFN-α-2b 100 µg/week + R 1000–1200 mg/day|
|Duration (weeks)||48||48||48||Study 1: 48 Study 2: 24 or 48||48||48|
|ETVR||73%||PEG combo: 67%, IFN combo: 37%, mono: 59%||At 12 weeks: 71%, at 24 weeks: 66%||NR||70.8%; 52%||77%|
|SVR||45%||Peg combo: 50%, IFN combo: 28%, mono: 30%||NR||79% 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 weeks||43.8%; 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.