HCV/HIV Coinfection: new French study of 20 patients reported in Journal of AIDS (May 2000 issue)

This is a report published in the May AIDS Journal of a study of 20 caucasians coinfected with HCV/HIV. The patients had an average of about 14 million genome equivalents/ml of HCV RNA at baseline. Eleven of the antiretroviral-treated patients (65%) were receiving a combination of two nucleoside reverse transcriptase inhibitors (NRTI) whereas six patients were taking a triple drug combination therapy. The patients had an average of several thousand HIV RNA viral load at baseline. Their average CD4 at baseline was 350. Absolute CD4 count declined during therapy to average of 280. But CD4 percentages did not change. HIV Viral loads were measured at 0, 3, and 6 months and no change was detected. D4T was being used by patients in study. Six of the 20 were on methadone maintenance or its European equivalence. Fourtenn of 20 had genotype 1. Nine of 20 (45%) had cirrhosis. At the end of treatment (6 months) 50% had undetectable HCV RNA. HCV and HIV viral load was evaluated thusly--

Serum HCV RNA was measured by a qualitative PCR assay (Amplicor HCV Monitor; Roche Diagnostic System, Neuilly sur Seine, France; threshold 1000 copies/ml) and quantitative HCV RNA was evaluated by a branched DNA signal amplification assay test (Quantiplex HCV RNA 2.0, Chiron, Emeryville, California, USA; range of detection, 200±250 000 copies/ml). Serum levels of HIV RNA were determined by the branched DNA test (Quantiplex HIV RNA 2.0; Chiron; threshold: 500 copies/ml).

Efficacy and safety of combination therapy with interferon-·2b and ribavirin for chronic hepatitis C in HIV-infected patients
AIDS 2000, 14:839-844

Alain Landau, Dominique Batisse a , Jean Paul Duong Van Huyen b ,Christophe Piketty a , Francis Bloch, Gilles Pialoux c , Laurent Belec d ,Jean Pierre Petite, Laurence Weiss a and Michel D Kazatchkine a
>From the Department of Hepatology and Gastroenterology, a Department of Clinical Immunology, b Department of Pathology, Hoˆ pital Broussais, c Department of Infectious Diseases, Hoˆ pital Rothschild and d Department of Virology Hoˆ pital Broussais, Paris, France.

Received: 10 August 1999; accepted: 19 January 2000.

ABSTRACT: Objectives: To evaluate the efficacy and safety of a combination therapy of interferon- ·2b (IFN) and ribavirin for the treatment of chronic hepatitis C in HIV-seropositive patients.

Design: Open prospective trial.

Methods: Twenty patients co-infected with hepatitis C virus (HCV) and HIV, with a mean CD4 cell count of 350 ±153 3 10 6 /l were treated with IFN (3 MU three times per week) in combination with ribavirin (500 mg or 600 mg twice a day) for 6 months. Tolerance and efficacy were monitored at weeks 12 (month 3) and 24 (month 6). The primary endpoint was a complete virological response, as deÆned by the lack of detectable HCV RNA in serum.

Results: Baseline values of alanine aminotransferase (ALT) and aspartate aminotrans- ferase (AST) were 121 ±72 IU/l and 75 ±67 IU/l, respectively. The total Knodell score was 10.4 _ 2.4, with nine patients showing histological evidence of active cirrhosis (45%). All patients exhibited circulating HCV RNA. The treatment was well tolerated, with no impact on the course of HIV infection. After 6 months of combination therapy with IFN and ribavirin, 10 patients (50%) exhibited no further detectable HCV RNA viraemia, seven of whom achieved undetectable viraemia at month 3. Levels of ALT and AST decreased after 6 months of treatment from a mean of 121 ±72 to 51 ±40 IU/l and from a mean of 129 ±58 IU/l to 68 ±61 IU/l, respectively (P , 0.0002 and P , 0.0001).

Conclusion: Our results indicate that combination therapy with IFN and ribavirin is effective in 50% of cases in clearing serum HCV RNA and may thus provide effective means of therapy in HIV±HCV-coinfected patients as initial treatment or in patients who have previously failed IFN monotherapy.

EXCERPTED FROM PUBLISHED REPORT:

There is an increasing need for active therapeutic regimens to treat hepatitis C virus (HCV) infection in HIV-positive patients. There is evidence that the deleterious impact of HIV on chronic hepatitis C is mainly related to three factors: (i) an accelerated course of liver disease in HIV-infected patients as compared with that in HIV-seronegative patients [1,2]; (ii) a higher rate of liver-related deaths in co-infected patients who are receiving combinations of antiretroviral drugs. This could be a result of immune restoration following highly active antiretroviral therapy (HAART) [3±5]; and (iii) a higher rate risk of hepatotoxicity of antiretroviral drugs in those suffering from chronic hepatitis C [6]. Given the poor efficacy of monotherapy with interferon-·2b (IFN) in patients co-infected with HCV and HIV [7,8], and the promising results of combination therapy with IFN and ribavirin in immunocompetent patients [9], we investigated the safety, tolerability and efficacy of 6-months treatment with IFN and ribavirin in an open trial involving 20 HIV-seropositive patients with chronic hepatitis C.

Upon inclusion into the study, all patients were given 3 MU of IFN (Viraferon; Schering-Plough, Kenilworth, New Jersey, USA) three times a week in combination with ribavirin (Rebetol; Schering-Plough). Ribavirin was given orally twice a day to a total dose of 1000 mg (body weight , 75 kg) or 1200 mg (body weight > 75 kg) per day.

Nine out of the 20 patients showed histological evidence of cirrhosis (45%). At baseline, HCV viraemia was 14.8 million genome equivalents ± 11.8.

All 20 patients were caucasians. At baseline, there were: 17/20 males; mean age 41; 90% IVDU mode of transmission, 10 sex; 17.7 years estimated duration of HCV & HIV infection; 50% had 10 year past alcohol use; 6/20 were on methadone maintenance or buprenorphine; mean CD4 count was 350±153; mean HIV RNA was 3.8 log±4.1 (3.8 log is above the limit of detection, 3.0 log equals 1000 copies/ml); mean HCV RNA was 14.8 geq  copies/ml; 20/20 had detectable HCV RNA; 14/20 had genotype 1, 6 had genotype 3 or 4.

Seventeen of the patients (85%) had been receiving antiretroviral drugs for 3.8±2.0 years at the time of inclusion into the study. Eleven of the antiretroviral-treated patients (65%) were receiving a combination of two nucleoside reverse transcriptase inhibitors (NRTI) whereas six patients were taking a triple drug combination therapy including two NRTI and a protease inhibitor, indinavir (n=5) and ritonavir (n=1). Eleven patients were receiving stavudine and lamivudine as part of their antiretroviral regimen. There was a past history of alcohol abuse in 50% of the patients. All patients exhibited a positive PCR for HCV RNA in serum. One patient had presented with a relapse 7 months after a successful initial 6- month course of IFN monotherapy. Three patients had failed on IFN alone given for 6 months.

At baseline, the total Knodell score was mean of 10.4; necro-inflammatory score was mean of 7.5; fibrosis score was mean of 3.1; 9/20 or (45%) had cirrhosis; 6/20 had bridging fibrosis.

* Necrotico-inflammatory activity was calculated by combining the scores of the three components of the Knodell assessment of liver damage (portal necrosis, lobular necrosis and portal inØammation).

RESULTS

During 6 month course of treatment the mean ALT and AST values in the study population were 121 and 129 at baseline, respectively. The mean Knodell score was 10.4. The necrotico-inflammatory and fibrosis scores were 7.5 and 3.1, respectively. Nine out of the 20 patients showed histological evidence of cirrhosis (45%). All individuals completed 24 weeks of treatment without any serious or potentially life-threatening adverse. After 24 weeks of combination therapy with IFN and ribavirin, the mean levels of ALT and AST decreased to 51 and 68 respectively. Among the non-responders the mean levels of ALT decreased from 139 at baseline to 80 at month 6 ( P , 0.0004). An improvement in the gamma glutamyl transferase activity was also observed after 6 months of treatment (103 as compared with 159 at baseline; P , 0.0002). At baseline HCV viraemia was 14.8 million genome equivalents/ml. No difference was found between complete responders and non-responders for baseline HCV viraemia: 12.1±11.3 versus 17.0±12.2 x 10 6 geq/ml, respectively.

*  Compared with baseline. NS, Not significant.

All individuals completed 24 weeks of treatment without any serious or potentially life-threatening adverse events; there were no drug-related deaths. The mean haemoglobin concentration and neutrophil count decreased significantly after 6 months of treatment with IFN and ribavirin (13.5± 2.1 versus 12.2±1.7 g/dl and 3.0±1.5 versus 2.4±1.8 3 P , 0.001 and P , 0.01, respectively). The dose of ribavirin was reduced to 600 mg per day from month 3 in two patients in whom the haemoglobin concentration had decreased to , 9.5 g/dl. Neither of these two patients were receiving zidovudine. Strong fu-like complaints that occurred despite the administration of paracetamol (n=5), a diminished ability to concentrate and irritability (n=3), nausea (n=3), cough (n=2) and pruritus (n=2) were observed during therapy. There was no change in the requirements for methadone and buprenorphine during the study period in patients who were on maintenance therapy with these drugs.

Ten patients (50%) exhibited a complete virological response, achieving undetectable levels of HCV RNA in serum at 24 weeks of treatment; all of these patients exhibited normal values of ALT at 6 months of therapy. Of these 10 patients, seven exhibited no detectable serum HCV RNA after 3 months of treatment, whereas the virological response was delayed to 6 months in the three remaining patients; there was no difference in HCV viral loads and liver histology at baseline between those with rapid and late HCV RNA clearance (data not shown). Two of the 10 responders were previous non-responders to IFN monotherapy and one patient had exhibited a relapse after a first course of IFN alone.

No significant difference was found between responders and non-responders in terms of antiretroviral regimen, age, sex, body weight, previous duration of injecting drug use, liver histology and CD4 cell counts at baseline Bridging fibrosis [n (%)] 6 (30).

There was no change in the mean level of serum HIV RNA during the follow-up period. A significant decrease in the absolute number of CD4 cells was observed at 24 weeks (284±141 versus 350±153 at baseline; P , 0.01), although the relative percentage of CD4 cells among total lymphocytes remained unchanged. Among the nine patients exhibiting undetectable HIV viraemia at baseline, one patient had detectable HIV RNA (3.1 log10 ) in serum at 6 months. No AIDS-defining event occurred during the study period.

HIV viral loads were measured at months 0, 3, and 6. As stated above, no changes were observed but that does not exclude transient blips in between the tests. In addition these were averaged HIV RNAs for all participants. It's possible that some had elevations.

In two patients, the daily intake of ribavirin had to be decreased to 600 mg per given blood products contaminated with hepatitis C.

No significant change in the percentage of CD4 cells among the total lymphocyte count nor in serum levels of HIV RNA was observed throughout the study. The absolute number of CD4 cells, however, decreased during treatment suggesting that cells became trapped in extravascular sites.

How do these results compare to treatment experience with HIV negatives?

In the large IFN+RBV study published by McHutchison which he reported in the New England Journal of Medicine, he reported 53% had a virologic response (<100 copies/ml) at the end of 24 weeks of treatment. For those who received 48 weeks of treatment, 50% had <100 copies/ml.