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Long-term efficacy of combination therapy with interferon-2b and ribavirin for severe chronic hepatitis C in HIV-infected patients
 
 
This patient group was a difficuly to treat group in France, as you can see below. But I think this group is representative of a portion of HCV/HIV coinfected patients. In addition, 18% of the patients had previously received interferon monotherapy; 55% had cirrhosis. 39% had genotype 1. CD4 count was 411. 39/51 men. age 39. HIV-RNA 15,000 copies/ml. HCV-RNA 20 million. ART 47%. Past alcohol use 32%. 94% IVDUs, average use 15 years. 16 patients on methadone or buprenorphine. 35% experienced decline in hemoglobin to <12 in this study. IFN dose reduced in 17% of patients from 3 MU 3 times per week to 1.5 MU 3 times per week. There was a high discontinuation rate: in total, 15 of the 51 patients in the study (29%) stopped the treatment because of adverse events (four patients) or inefficacy, and thus did not complete the total duration of therapy. Week 12 response was predictive of sustained viral response.
 
Alain Landau; Dominique Batissea; Christophe Pikettya; Jean Paul Duong Van Huyenb; Francis Bloch; Laurent Belecc; Patrick Brunevalb; Laurence Weissa; Raymond Jian; Michel D. Kazatchkinea
 
From the Department of Hepatology and Gastroenterology, the aDepartment of Clinical Immunology, the bDepartment of Pathology, and the cDepartment of Virology, Hopital Européen Georges Pompidou and Université Pierre et Marie Curie, Paris, France.
 
AIDS 2001;15:2149-2155
 
Background: We have assessed the long-term efficacy and safety of a combination therapy of interferon alpha-2b (IFN) and ribavirin (RBV) for the treatment of severe chronic hepatitis C in co-infected HIV-seropositive patients in an open prospective study.
 
Methods: Fifty-one patients were treated for 12 months. Mean baseline CD4 cell count, alanine aminotransferase and aspartate aminotransferase were 412 ± 232 ? 106/l, 113 ± 75 IU/l and 111 ± 84 IU/l respectively. The mean Knodell score was 11.5 ± 2.1 with 28 patients (55%) exhibiting histological evidence of active cirrhosis.
 
Results: Fifteen (29%) patients discontinued the treatment prematurely because of adverse events. An end of treatment response (ETR) as defined by the lack of detectable hepatitis C virus (HCV) RNA in plasma at the end of treatment was achieved in 15 patients (29%). A sustained virological response (SVR), defined by the lack of detectable HCV RNA in plasma 6 months after completion of combination therapy, was achieved in 11 patients (21%). The HCV genotype 3a was associated with ETR and SVR (P = 0.002 and P = 0.003, respectively). HCV viraemia at baseline was lower in patients who achieved SVR and ETR than in those who did not (6.7 ± 7.8 versus 24 ± 26.7 ? 106 genome equivalents/ml, P = 0.03 and 14.3 ± 28.7 versus 22.5 ± 23, P = 0.05, respectively).
 
Conclusion: Our results indicate that combination therapy with IFN and RBV is effective in approximately 20% of co-infected patients with severe liver disease. These rates of response are comparable to those reported in immunocompetent monoinfected patients with severe chronic hepatitis C [19]. We further observed an incidence of relapse and virological breakthrough similar to that reported in immunocompetent patients treated with IFN and RBV combination therapy (36% versus 34% and 18% versus 10%, respectively) [18,24]. The patients in our cohort had poor predictive factors of a sustained response, including a high serum HCV viral load, a high prevalence of active cirrhosis, and a high prevalence of non-3a HCV genotype.
 
The prevalence of genotypes 1a (39%) and 3a (33%) was similar to that found previously in immunocompetent injecting drug users [26]. As reported previously in HIV-seronegative individuals, the presence of HCV of genotype 3a was associated with ETR and SVR, whereas the presence of HCV of genotype 1a was associated with a lack of SVR. A late clearance of HCV RNA was observed in 27% of the individuals who exhibited a sustained response to combination therapy, which differs from reports of a predictive value of HCV RNA PCR at week 12 in immunocompetent patients treated with IFN alone [29]. With combination therapy, however, the lack of association between early viral clearance and the occurrence of SVR has also been reported in immunocompetent monoinfected patients.
 
Most of the adverse events encountered in this study were similar to those reported in HIV-seronegative immunocompetent patients, including irritability, depression, persistent flu-like syndrome despite paracetamol, pruritus and cough [16­18]. Discontinuation of treatment due to adverse events occurred, however, at a lower rate in our cohort (8%) than reported during combination therapy in immunocompetent patients (21%).
 
Our results, together with preliminary reports from others, suggest that hepatitis C should be treated before the occurrence of severe immunodepression in HIV disease.
 

Discussion
 
The seroprevalence of hepatitis C virus (HCV) infection in HIV-seropositive individuals is 10­20% among homosexual/bisexual men and up to 80% in intravenous drug users in the USA and in Europe [1­3]. chronic hepatitis C was shown to exhibit an accelerated progression to liver fibrosis in HIV-infected patients as compared with HIV-seronegative immunocompetent individuals. Increased survival with highly active antiretroviral therapy (HAART) is associated with an increased liver-related morbidity in co-infected individuals. Here, we have investigated the safety, efficacy and predictors of a virological response of a combined treatment with IFN and RBV in an open cohort of 51 HCV/HIV co-infected patients with severe chronic hepatitis C. We report on the occurrence of ETR and of a SVR in 29% and 21% of the patients in the cohort, respectively, in the absence of significant adverse events. Given the potential of progression of hepatitis C in co-infected individuals, our observations strongly support the use of IFN and RBV in HIV-infected individuals with severe chronic hepatitis C.
 
Upon inclusion in the study, all patients were given 3 MU of IFN (Viraferon, Schering-Plough, Kenilworth, New Jersey, USA) three times a week in combination with RBV (Rebetol, Schering-Plough). RBV was given orally twice a day to a total dose of 1000 mg (body weight < 75kg) or 1200 mg (body weight 75kg) per day. We evaluated patients with a fibrosis score >2. Patients were treated for 12 months.
 
Results
 
The baseline demographics of the patient population are given in Table 1. Of the patients, 94% (n = 48) were injecting drug users, with a mean duration of drug use of 15.8 ± 2.7 years. Of these, 16 were receiving substitutive therapy with methadone or buprenorphine. Twenty-two patients (33%) had presented an AIDS-defining event prior to inclusion in the study. Forty-seven of the patients (92%) were receiving antiretroviral treatment during the study and four (8%) remained naive to antiretroviral drugs. Treated patients had been receiving antiretroviral drugs for a mean duration of 4.5 ± 1.9 years at the time of inclusion in the study. Twenty-four of the patients (47%) were receiving a combination of two nucleoside reverse transcriptase inhibitors (NRTI), including stavudine or zidovudine in association with lamivudine; 11 patients (22%) were taking a triple drug combination including two NRTI and a PI. Twelve patients (23%) were receiving a triple combination of NRTI and non-nucleoside reverse transcriptase inhibitors. There was a past history of alcohol abuse in 32 patients (63%). All patients were naive to RBV. Nineteen patients (18%) had received IFN monotherapy prior to inclusion in the study.
 
The mean haemoglobin concentration fell from 13.8 ± 1.7 to 12.8 ± 1.8 g/dl (P = 0.002) at the end of treatment. The haemoglobin values fell below 12.0 g/dl in 18 patients (35%) requiring a decrease in the dose of RBV to 600 mg daily. Due to biochemical or clinical side-effects, the dosge of IFN was reduced by the treating physicians in nine (17%) patients from 3 MU three times per week to 1.5 MU three times per week. In total, 15 of the 51 patients in the study (29%) stopped the treatment because of adverse events (four patients) or inefficacy, and thus did not complete the total duration of therapy.
 
Among the patients in whom serum HCV RNA was undetectable at the end of treatment, the PCR for HCV RNA became negative during the first 12 weeks of treatment in nine (64%). Eight (73%) of the 11 patients who achieved a SVR exhibited an early virological response to treatment with HCV RNA PCR becoming negative at week 12. HCV RNA breakthroughs were observed in nine out of the 51 patients (18%) on at least one occasion during the study period.
 
Serum ALT levels were normal by the end of treatment in 11 of 15 patients who exhibited a complete virological response at the end of treatment (73%). Of the 11 patients who exhibited a SVR, three remained with elevated serum ALT levels.
 
Surrogate markers of HIV disease
 
A significant decrease in the mean CD4 cell count was observed between baseline and the end of treatment 411 versus 340 in the absence of change in the mean plasma levels of HIV RNA. Six months after the end of treatment, the median CD4 cell count returned to baseline values. CD4 cells as a percentage of total lymphocytes also exhibited significant changes between baseline and the end of treatment (22.9 ± 10.2% versus 24.9 ± 10.1%; P = 0.04), returning to baseline values 6 months after cessation of IFN and RB V (22.2 ± 9.8; not significant compared to baseline values). Seventeen patients exhibited undetectable levels of plasma HIV RNA at the end of treatment as compared with 20 at baseline.
 
Predictive factors for ETR and SVR
 
ETR was correlated with the presence of HCV genotype 3a (10/15 versus 7/36; P = 0.002) and a lower mean HCV viraemia at baseline (14.3 million versus 22 million; P = 0.05) (Table 4). SVR was also found to be correlated with a lower mean HCV viraemia at baseline (6.7 million versus 24 million genome equivalents/ml in those who did not achieve SVR;P = 0.03) and HCV genotype 3a (8/11 versus 9/40;P = 0.003). The presence of genotype 1a HCV was significantly related to a lack of SVR (1/11 versus 19/40; P = 0.03). A relationship was also observed between ETR and a baseline CD4 cell count > 200 (15/15 versus 27/36; P = 0.04). The mean CD4 cell count was higher in the group of patients who achieved an ETR than in those who did not (454 versus 393; not significant). The mean CD4 cell count was higher in the group of patients who achieved a SVR than in those who did not (479 versus 393; not significant). The frequency of SVR and ETR was not related to the presence of fibrosis or cirrhosis at baseline, nor to age, sex, past history of alcohol abuse, ongoing substitutive therapy for drug abuse, plasma HIV RNA levels at baseline, ALT and AST values at baseline and the total dose of RBV received. Pretreatment ALT values were not predictive of either ETR or SVR. The number of patients in the study did not allow for multivariate analysis of the data.
 
 
 
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