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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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