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Peginterferon Alfa-2b Plus Ribavirin for the Treatment of Chronic Hepatitis C Genotype 4
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American Journal of Gastroenterology
Volume 99 Issue 9 Page 1733 - September 2004
Fuad Hasan, M.D. , Haifa Asker, M.D. , Jameela Al-Khaldi, M.D. , Iqbal Siddique, M.D. , Misfer Al-Ajmi, M.D. , Salim Owaid, M.D. , Rosh Varghese, M.D. , and Basil Al-Nakib, M.D.
Department of Medicine, Faculty of Medicine, Kuwait University; Thunayan Al-Ghanim Gastroenterology Center, Al-Amiri Hospital, Kuwait; and Division of Gastroenterology, Department of Medicine, Mubarak Al-Kabeer Hospital, Kuwait
BACKGROUND: The hepatitis C virus (HCV) genotype is an important predictive parameter for the success of pegylated interferon plus ribavirin therapy. To date, most published therapeutic trials have enrolled patients infected mainly with HCV genotypes 1, 2, and 3. Data regarding the responsiveness of genotype 4, the predominant type of HCV in the Middle East, are very limited.
OBJECTIVE: To assess the efficacy of peginterferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis caused by HCV genotype 4.
METHODS: Sixty-six treatment-naive patients infected with HCV genotype 4 were enrolled in this open label, prospective study. Cohort characteristics included the following: 48 M/18 F, mean age 45 ± 9 years, and mean weight 74 ± 8 kg. All patients had raised alanine aminotransferase (ALT) and were compensated. The mean pretreatment HCV-RNA level was 4.2 × 106 copies/ml (8.4 × 105 iu/ml) and median was 2.15 × 106 copies/ml. Twenty patients (29%) exhibited cirrhosis or severe fibrosis on pretreatment liver biopsy specimens. Participants were to receive peginterferon alfa-2b, 1.5 mcg/kg/wk plus ribavirin 1,000--1,200 mg/day for 48 wk. Patients were followed up for 24 wk after completing therapy. End of treatment viral response and sustained viral response (SVR) were defined as the absence of HCV-RNA from serum (<100 copies/ml) at 48 wk of treatment and at the end of follow-up, respectively. Data were analyzed on an intention-to-treat basis.
RESULTS: End of treatment and sustained virologic response were 77% and 68%, respectively. Among patients with pretreatment HCV-RNA >=2 × 106 (2 million) SVR was 55% compared with SVR of 86% among patients with HCV-RNA < 2 × 106 (p= 0.05).
Patients with cirrhosis or severe fibrosis had significantly lower SVR rate compared to those with mild or no fibrosis (29 vs 84%; p < 0.0002). Three patients (4%) discontinued therapy because of severe flu-like symptoms. Four patients developed hypothyroidism. Dose reduction of ribavirin and peginterferon alfa-2b was necessary in 15% and 6% of the patients, respectively.
CONCLUSION: Peginterferon alfa-2b in combination with ribavirin is effective in the treatment of HCV genotype 4. The treatment was well tolerated by most of the patients.
INTRODUCTION
Until recently, the combination of interferon plus ribavirin was the standard treatment for chronic hepatitis C. However, this combination was associated with a sustained viral response (SVR) in only 38-43% of the patients. The limited efficacy of interferon was attributed to its short half-life. Lately, pegylated interferon preparations have replaced unmodified interferon as the treatment of choice for hepatitis C. Peginterferons have longer half-lives than standard interferon, and can be administered once weekly. Importantly, recent clinical trials have shown that peginterferon plus ribavirin therapy was superior to unmodified interferon plus ribavirin in inducing SVR. In a pivotal, large multicenter study conducted in Europe, North America, and Australia, weekly administration of peginterferon alfa-2b (1.5 mcg/kg) plus ribavirin (800 mg/day) resulted in an overall SVR rate of 54%. A major determinant of response was viral genotype. Patients with genotypes 2 or 3 were more likely to respond than those infected with genotype 1 (SVR rate 82 vs 42%). The number of patients with genotype 4, who were enrolled in the study, was too small to include in statistical analysis. This is not surprising because most Western and Asian patients are infected with genotypes 1, 2, and 3.
Although rare in the West, genotype 4 is the most common hepatitis C virus (HCV) variant in the Middle East and North Africa, where the prevalence to HCV infection is one of the highest in the world. The aim of this study was to assess the efficacy and safety profile of peginterferon alfa-2b in combination with ribavirin in Middle Eastern patients infected mainly with HCV genotype 4.
Patients
Middle Eastern patients, 18 years or older, were included in this study if they satisfied the following criteria: (a) anti-HCV positive; (b) HCV-RNA detectable by transcription mediated amplification or the branched DNA assay; (c) raised ALT levels; (d) biopsy proven chronic hepatitis with or without cirrhosis. Criteria for exclusion were: (a) clinical or biochemical evidence of hepatic decompensation; (b) serum creatinine >140 μmol/L; (c) hemoglobin level <120 g/L, WBC <3 x 109/L, platelets <50 x109/L; (d) concomitant liver disease other than hepatitis C; (e) alcohol or drug abuse; (f) serious comorbid conditions; (g) suspected hepatocellular carcinoma; (h) severe psychiatric disease; (i) treatment with antiviral or immunosuppressive agents prior to enrollment. The study was conducted in accordance with the ethical standards of our institution.
Study Design
This prospective open-label trial was carried out in the two hepatology referral centers in Kuwait. Treatment consisted of 48 wk of subcutaneous peginterferon alfa-2b (Schering-Plough, Kenilworth, NJ) at a dose of 1.5 mcg/kg once a week and oral ribavirin 1,000 mg/day and 1,200 mg/day for patients weighing <75 kg and >=75 kg, respectively. Peginteferon injections were administered in the outpatient department. Patients were followed up for 24 wk after cessation of therapy. The dose of peginterferon was reduced to 1 mcg/kg if WBC count was <1.5 x 109/L or the granulocyte count dropped below 0.5 x109/L or platelets were <50 x 109/L. The dose of ribavirin was reduced to 600 mg/day if hemoglobin level was <100 g/L and was discontinued if hemoglobin was <85g/L.
Participants were evaluated as outpatients at baseline and at weeks 2, 4, 8, and every 6 wk during the treatment. During posttreatment follow-up, patients were assessed at weeks 12 and 24. Besides clinical evaluation, baseline investigations included serum liver chemistry tests, a complete blood count, alfa-fetoprotein, serum iron, total iron-binding capacity, thyroid stimulating hormone (TSH) levels, and a liver sonogram. During treatment and follow-up, evaluations included a complete blood count, and liver and renal chemistry profiles. HCV-RNA concentration and TSH levels were determined at weeks 12, 24, 36, and 48 of treatment and weeks 12 and 24 of follow-up. Patients from areas endemic for schistosomiasis were screened for bilharzia antibodies by indirect hemagglutination test. Those whose antibody titers exceeded 1:16 were treated with a single standard dose of praziquantil.
Virologic Tests
HCV-RNA was measured by a branched-DNA assay (Quantiplex, Bayer Diagnostics), with a lower limit of detection of 3,200 copies/ml (320 iu/ml). If HCV-RNA was undetected by the branched-DNA assay, serum was tested by transcription-mediated amplification (Ultraquant assay, Specialty Laboratories, MI). This assay can qualitatively detect virus between 100 and -5,500 copies/ml (10 to 550 iu/ml). HCV genotyping was performed using a line probe assay (1NNO-LiPA HCV, Innogenetics, Zwinjndrecht, Belgium).
Liver Biopsy
Pretreatment liver biopsy specimens were classified following the Metavir standardized criteria.
Assessment of Efficacy
The primary endpoint was SVR defined as the absence of detectable HCV-RNA at the end of followup according to the transcription-mediated amplification assay. End of treatment virology response was defined as undetectable HCV-RNA at the end of treatment.
RESULTS
Characteristics of Patients
Between February 2000 and February 2002, 66 patients infected with HCV genotype 4 were enrolled. Egyptians constituted 52% of the study population. The rest were Kuwaiti or Syrian nationals. During the same period, 20 consecutive patients infected with genotype 1 were also treated with the same regimen of peginterferon plus ribavirin. These patients were comparable to genotype 4 patients in terms of mean age (48 ± 10, p= 0.11), mean viral load (3.4 x 106 copies/ml, p= 0.87), and degree of fibrosis (mean 1.75 vs 1.66; p= 0.77). However, all genotype 1 patients were Kuwaiti nationals and 65% were females.
Virologic Response
The overall SVR rate among genotype 4 patients was 68%. At 12 wk, 52 patients had >=2 log10 drop in serum HCV-RNA or complete clearance of viremia. Forty-eight (92%) of these patients had an end of treatment virologic response. However, five of them relapsed. Thus 82.7% of patients with a virologic response at 12 wk achieved an SVR. In contrast, 2 of the 14 patients (14%) who failed to achieve a virologic response at 12 wk had SVR.
The SVR among genotype 1 patients was lower than that observed in genotype 4 patients but the difference did not reach a statistical significance level (45 vs 68%; p= 0.11). Using univariate analysis, baseline viral load and the degree of fibrosis were the strongest predictors of virologic response. Patients with pretreatment HCV-RNA <2 x 106 copies/ml had a significantly higher rate of SVR compared to patients with serum HCV-RNA >=2 x 106 copies/ml (86 vs 55%, p= 0.05). Similarly, SVR among patients with mild or no fibrosis was more likely than in patients with severe fibrosis or cirrhosis (84 vs 29%; p< 0.0002). Variables that were not associated with SVR included age (p= 0.11), nationality (p= 0.04), and body weight (p= 0.89).
Biochemical Response
End of treatment and sustained normalization of ALT occurred in 45 (68%) and 43 (65%) patients, respectively (Table 2). Undetectable HCV-RNA at 24 wk of follow-up (SVR) had a high predictive value for normal ALT at the end of follow-up because 43 of 45 patients (95%) with SVR had sustained biochemical response. Only two patients with SVR continued to have slightly raised ALT (<1.5 times normal).
Safety and Tolerability
The most common side effects were flu-like symptoms, weight loss, and anemia. Three patients, who dropped out due to severe flu-like symptoms, were considered nonresponders.
Five patients missed 1-3 doses of peginterferon. The dose of peginterferon was reduced to 1 mcg/kg/wk in four patients (6%). Ribavirin dose adjustments were necessary in 10 patients, seven of whom were females. All patients took >=80% of the prescribed dose of ribavirin. The mean dose of ribavirin taken by the patient was 13.1 mg/kg/day.
Among genotype 1 patients, two dropped out and three missed 2-3 doses of the entire prescribed dose of peginterferon. The dose of ribavirin was reduced per protocol in four female and one male patient. The average dose of ribavirin was 14 mg/kg/day.
AUTHOR DISCUSSION
Hepatitis C is a major public health problem in Middle Eastern populations. In some Arabian countries, anti-HCV seropositivity among volunteer blood donors ranges between 6 and 20%. Although peginterferon plus ribavirin combination therapy has been an impressive progress in the management of chronic hepatitis C, the response to therapy is variable and depends mainly on virologic factors. In previous clinical trials, the most important predictor of response was HCV genotype. Peginterferon in combination with ribavirin induced the highest SVR rates in patients infected with genotypes 2 and 3, whereas genotype 1 patients were relatively less responsive. Moreover, peginterferon plus ribavirin has also been shown to be cost effective in Western populations infected mainly with genotypes 1, 2, and 3.
HCV genotype 4-infected individuals constitute around 20% of the world's HCV-infected population. Nonetheless, these patients were underrepresented in clinical trials conducted mostly in the West where genotype 4 is rare. Establishing responsiveness of this genotype 4 to peginterferons and ribavirin has obvious economic and public health implications in the developing countries of the Middle East and Africa.
The results of this study indicate that peginterferon alfa-2b and weight-based ribavirin therapy was associated with a higher SVR rate among genotype 4 compared to genotype 1 patients (68 vs 45%). However, the difference did not reach statistical significance (p= 0.11) possibly due to the small number of genotype 1 patients (type 2 error). Moreover, we could not directly compare the responsiveness of genotype 4 with that of genotype 2/3 because none of our patients was infected with the latter variants. Nonetheless, registration trials carried out in Western countries reported SVR rates of around 88-94% among genotype 2/3 patients. Our findings suggest that the responsiveness of genotype 4 is intermediate between genotype 1 on one hand and genotypes 2/3 on the other.
As in previous trials, patients with low viremia were more likely to respond than patients with a high viral load. Moreover, severe fibrosis and cirrhosis were associated with lower rates of SVR. Also, the lack of an early virologic response, defined as either a >=2 log10 drop in viral load or disappearance of HCV-RNA, predicted failure to achieve SVR in 86% of nonresponders and relapsers. This observation allows for early termination of treatment in those who are unlikely to respond to the full course of treatment.
In this trial we did not compare the efficacy of peginterferon-ribavirin combination therapy directly with that of the unmodified interferon plus ribavirin. However, previous trials have shown that unmodified interferon plus ribavirin therapy produced a sustained viral response in 21-30% of patients infected with genotype 4. Thus, peginterferon-based combination therapy appears to be more effective than unmodified interferon-ribavirin regimen in this patient population.
Most patients reported some side effects, particularly flu-like symptoms. The latter were the most common cause of treatment withdrawal. Interferon-induced leukopenia and thrombocytopenia were also common but were tolerated well. None of our patients experienced septic or hemorrhagic complications. Interferon-related thyroid dysfunction occurred in 10% of the patient but did not warrant the discontinuation of treatment. In contrast, ribavirin-induced hemolytic anemia was a frequent reason for dose modification or temporary withdrawal of treatment particularly in female patients possibly because of the relatively low baseline hemoglobin level.
Finally, this study did not address the optimal dose regimens and duration of therapy for genotype 4. The most recent NIH consensus statement regarding the management of hepatitis C concluded that patients infected with genotype 1 achieve the highest response rate with 48 wk regimens, whereas type 2/3 patients can be treated with shorter courses (24 wk). Moreover, the recommended dose of ribavirin for genotype 2/3 was 800 mg/day whereas genotype 1 patients required 1,000-1,200 mg/day. The statement did not make reference to genotype 4 probably because of lack of data on this issue.
In conclusion, the combination of peginterferon alfa-2b plus ribavirin is an effective and safe treatment for HCV genotype 4. The optimal duration and dose regimen await further studies.
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