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Comparison of 2 Regimens that Include Interferon--2a plus Ribavirin for Treatment of Chronic Hepatitis C in Human Immunodeficiency Virus Coinfected Patients
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Clinical Infectious Diseases June 15 2003;36:1564-1571
Didier Neau,1,2 Pascale Trimoulet,2 Maria Winnock,3 Anne Rullier,4 Brigitte Le Bail,4 Denis Lacoste,5 Jean-Marie Ragnaud,1 Paulette Bioulac-Sage,4 Marie-Edith Lafon,2 Genevieve Chne,3 and Michel Dupon1 for the ROCO Study Groupa
1Federation des Maladies Infectieuses, Centre Hospitalo-Universitaire Pellegrin, 2Laboratoire de Virologie and 3Unite INSERM U330, Universite Victor Segalen, 4Laboratoire d'Anatomie Pathologique, Centre Hospitalo-Universitaire Pellegrin/Universite Victor Segalen, and 5Federation de Medecine Interne et des Maladies Infectieuses, Hopital Saint-Andre, Bordeaux, France comments from Jules Levin: Although this study is out of date because they treated patients with standard IFN or daily IFN there are some interesting findings worth reviewing. Another study limitation and outdated approach to therapy is they did not initiate RBV until 12 weeks into the study. Data from studies show that response rates are hampered when RBV is not included at the time of starting therapy. In fact data from studies show dose reduction in first 12 weeks for RBV can be more harmful towards sustained response than dose reduction in pegIFN.
"....In our study, posttreatment liver biopsy findings were available mainly for persons without virological response. Fibrosis was unchanged or improved in 76% of the patients but worsened in 24%..... Among the 27 patients who did not clear the virus at week 72 and for whom both biopsy samples were available, liver fibrosis improved in 7 (26%), remained unchanged in 13 (48%), and worsened in 7 (26%); activity improved in 15 (56%) of these patients, was stable in 8 (30%), and worsened in 4 (15%)... In our study, overall tolerance to IFN--2a and ribavirin therapy did not differ from that reported elsewhere for HIV-negative patients.... Because of cumulative toxicity, antiretroviral treatment that includes zidovudine, which also favors the occurrence of neutropenia or anemia, must be avoided or carefully monitored. Similarly, efavirenz may favor neuropsychiatric IFN--2arelated complications... Overall, 16 patients (24%; 7 in the conventional IFN--2a group and 9 in the daily IFN--2a group) did not complete the treatment regimen because of adverse events. For the same reason, doses of IFN--2a or ribavirin were reduced in 21 patients. No deaths were reported during the follow-up period..."
ABSTRACT:
An open-label, randomized trial was conducted to compare the efficacy and safety of 2 regimens of interferon--2a (IFN--2a) plus ribavirin for management of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus
(HIV)coinfected patients. Sixty-eight patients were randomized to receive IFN-
-2a at a dosage of either (1) 6 MU given 3 times per week for 24 weeks,
followed by 3 MU 3 times per week for an additional 24 weeks (group A; 31
patients); or (2) 9 MU per day for 2 weeks, followed by 3 MU per day for 22
weeks, followed by 3 MU 3 times per week for 24 weeks (group B; 37 patients).
Ribavirin was added at week 16 of therapy if HCV RNA remained detectable at
week 12. Sustained virological response was achieved in 10 patients (15%; 6 in
group A and 4 in group B). HCV genotypes 2 or 3 and a decrease in the HCV
load of 3 log10 copies/mL between inclusion and week 4 were associated with
virological response. In conclusion, the combination of conventional IFN--2a
and ribavirin has poor virological efficacy in HCV-HIV coinfected patients.
If HCV RNA was still detectable at week 12 of therapy, oral ribavirin (Produits Roche) was added at a dosage of either 1000 mg twice per day (for patients with a body weight of <75 kg) or 1200 mg twice per day (for those with a body weight of >75 kg) at week 16 and was administered through the end of treatment.
Histological response to anti-HCV therapy was evaluated by comparing the findings of a first liver biopsy (performed before study entry) with the findings of a second one (performed 24 weeks after the end of treatment). Liver lesions, as determined by stage of fibrosis and grade of activity, were evaluated for each biopsy specimen by 2 experienced pathologists using the METAVIR scoring system
INTRODUCTION
Hepatitis C virus (HCV)induced liver disease is now a leading cause of morbidity and mortality among HCV-HIVcoinfected patients. In fact, the natural history of chronic hepatitis C is modified by HIV infection with an accelerated progression to cirrhosis, and HCV-HIVcoinfected patients are at higher risk for developing
hepatotoxicity associated with HAART. On the other hand, HCV coinfection has also been reported to alter immune recovery during HAART. Consequently, stabilized patients receiving HAART should now be considered for treatment
of chronic hepatitis C.
In HCV-monoinfected patients, the current reference treatment for chronic hepatitis C is pegylated interferon (PEG-IFN--2a) plus ribavirin [7, 8]. In HCV-HIVcoinfected patients, data concerning the virological efficacy of anti-HCV
treatment are scarce. In 1999, when the present study was designed, PEG-IFN--2a was not available. However, the pharmacokinetic characteristics of a daily administration of interferon were expected to resemble closely those provided by PEG-IFN--2a. Also, ribavirin, a guanosine nucleoside analogue, was reported to inhibit the intracellular phosphorylation of zidovudine, stavudine, and zalcitabine in vitro, but no data were available concerning in vivo interactions and their potential consequences in patients receiving HAART.
Because conventional IFN-ribavirin therapy was shown to yield an undetectable HCV load 24 weeks after completion of the treatment regimen in only 38% of HCV-monoinfected patients, we aimed to evaluate the efficacy and safety of an
optimized IFN regimen, consisting of an initial loading dose followed by daily administration, in HIV-infected patients with chronic hepatitis C. To avoid a failure of antiretroviral therapy related to interactions between ribavirin and HAART, we decided to add ribavirin to IFN at week 16 of treatment only for patients who had not cleared HCV after 12 weeks of IFN treatment. By that time, these patients were considered not to have had a virological response and, from an ethical viewpoint, could receive combined IFN-ribavirin therapy.
Study Population
Patients aged 1865 years who had chronic hepatitis C and HIV-1 infection and who had not been previously treated with IFN or ribavirin were eligible for the study. Patients had detectable plasma HCV RNA levels and elevated serum alanine aminotransferase (ALT) levels (i.e., levels that were greater than the upper limit of the normal range) at least twice during the year before randomization. A liver biopsy finding confirming chronic hepatitis, regardless of
whether cirrhosis was present, had to be available within a year before study entry. Patients had a CD4 cell count of >250 cells/L and a plasma HIV RNA level of <10,000 copies/mL (determined using Quantiplex HIV RNA 2.0; Bayer).
Patients were not required to be receiving antiretroviral therapy, and all treatment regimens were allowed.
Patients were not included in the study if circulating hepatitis B surface antigen was present, if they actively abused alcohol (i.e., self-reported consumption of >40 g per day), if they had a hemoglobin level of <11 g/dL, if they had platelet and neutrophil levels of <70 g/L and <1.5 g/L, respectively, or if they had experienced an opportunistic infection 6 months before study entry. Patients who presented with evidence of decompensated liver disease (i.e., ascites, bleeding varices, hepatic encephalopathy, a serum albumin level of <35 g/L, and a prothrombin time of <70%), hepatocellular carcinoma, or other relevant disorders or risk factors, such as previous organ transplantation, a preexisting psychiatric condition, cardiovascular disease, poorly controlled diabetes or seizure disorders, hemoglobinopathy, or autoimmune disease, were not included in the study.
RESULTS
From April 1999 through June 2000, 31 patients were randomized to the conventional IFN--2a group, and 37 were randomized to the daily IFN--2a group. At baseline, the 2 groups were similar, except for CD4 cell count, which was slightly higher in the daily IFN--2a group: before ART 384 vs 269 CD4, and at beginning of HCV treatment 578 vs 491 CD4. 75% had IDU transmission route; age 37 yrs. About 50% had undetectable HIV-RNA. Estimated duration of HCV-infection was 14 yrs. 42% were genotype 1, 13/31 in standard IFN group and 15/35 in daily IFN group. About 7 million HCV RNA at baseline. METAVIR SCORE: activity- grade 1 22%, grade 2 50%, grade 3 25-30%; fibrosis- grade 1 23%, grade 2 48%, grade 3 20%, grade 4 3-10%. So, in total 19/68 (27%) patients had grade 3/4 fibrosis.
Virological Response
Overall, at week 12 of treatment, early virological response was achieved in 14 patients (21%), with no statistical difference between the 2 groups. All 49 patients who did not clear the virus at week 12 of treatment started
receiving ribavirin. By week 48, 15 patients (22%) had end-of-treatment virological response. By week 72, sustained virological response was achieved in 10 patients (15%; 6 patients in the conventional IFN--2a group and 4 in the daily IFN--2a group) who were infected with genotype 3 (7 patients) or 1 (3 patients); 3 of these patients received combined IFN--2a plus ribavirin therapy. Differences between groups with regard to early, end-of-treatment, and
sustained virological response did not reach statistical significance.
Biochemical Response
At week 72 of the study, 20 patients (29%) had normalized their ALT concentrations (table 2). Among them, 11 were infected with HCV genotype 1 or 4, and 9 were infected with HCV genotype 2 or 3. ALT levels had already
normalized by week 48 (end of treatment) in 26 patients (38%). All 10 patients with sustained virological response also had normalization of their ALT levels. Among the 49 patients who did not have a virological response at week 72, the
ALT concentration had normalized in 10 patients (3 of 21 in the conventional IFN--2a group and 7 of 28 in the daily IFN--2a group). There was no statistically significant difference between treatment groups.
Histological Response
Paired pre- and posttreatment biopsy samples were available for only 31 patients (18 in the conventional IFN--2a group and 13 in the daily IFN--2a group); the other patients refused to undergo a second biopsy. Among 4 patients with sustained virological response for whom both biopsy samples were available, liver fibrosis improved in 2, was stable in 1, and worsened in 1; activity improved in 3 of these patients and was stable in 1. Among the 27 patients who did not clear the virus at week 72 and for whom both biopsy samples were available, liver fibrosis improved in 7 (26%), remained unchanged in 13 (48%), and worsened in 7 (26%); activity improved in 15 (56%) of these patients, was stable in 8 (30%), and worsened in 4 (15%).
Clinical and Laboratory Toxicity Associated with Anti-HCV Therapy
Overall, 16 patients (24%; 7 in the conventional IFN--2a group and 9 in the daily IFN--2a group) did not complete the treatment regimen because of adverse events. For the same reason, doses of IFN--2a or ribavirin were reduced in 21 patients. No deaths were reported during the follow-up period.
CAUSE of dose reduction and treatment disct: most commonly anemia, neutropenia, depression, fatigue.
The frequency of clinical events was not different between treatment groups. The most frequent side effects were flulike and neurological symptoms.
None of the 6 patients who experienced neurological adverse events received efavirenz concomitantly. Twelve severe hematological adverse events were reported. Six of 9 patients with neutropenia received zidovudine simultaneously. Severe anemia occurred in 3 patients in the conventional IFN--2a group at weeks 16, 30, and 46 of the study. These 3 patients were receiving zidovudine, and none of them had received ribavirin. Finally, for 5 patients, a severe elevation in the ALT level (>5 times the upper limit of normal) obligated modification of the anti-HCV treatment.
Evolution of Markers of HIV Disease
CD4 CELL COUNT
In the conventional IFN--2a group, the median CD4 count decreased from the time of study entry (491 cells/L; range, 300-961 cells/L) to its lowest value at week 48 (402 cells/L; range, 216-616 cells/L), and it returned to the baseline level at week 72 (478 cells/L; range, 127960 cells/L). In the daily IFN--2a group, the median CD4 count was 578 cells/L (range, 269-1644 cells/L) at baseline and decreased to its lowest value at week 2, after receipt of the loading dose (448 cells/L; range, 138-947 cells/L). It was at a plateau
through week 48 (453 cells/L; range, 128-1013 cells/L) and was higher than baseline at week 72 (562 cells/L; range, 1822500 cells/L). At week 24, the CD4 percentage increased from 28.2% and 26.0% at baseline to 28.8%
(range, 12%-44.6%) and 34.0% (range, 17.5%-48.1%) in the conventional IFN--2a and daily IFN--2a groups, respectively. Thereafter, the percentages returned to baseline values.
Plasma HIV RNA level
Overall, the proportion of patients with undetectable plasma HIV RNA levels did not differ significantly at the initiation of anti-HCV therapy (49%) from that observed at the end of the follow-up period (37%). Seven patients had an increase in the plasma HIV RNA level of 0.5 log10 copies/mL between study entry and week 72. Two patients discontinued antiretroviral treatment because of side effects, and 3 received 2 antiretroviral drugs each. For the other 2 patients, compliance with antiretroviral treatment was uncertain.
DISCUSSION
The virological response rate obtained in our study was disappointing when we consider that the patients had a satisfactory immune status and that IFN--2a was administered daily. The loading dose was expected to induce a rapid
decrease in the HCV load. Indeed, a 3-log10 decrease after 4 weeks of therapy has been shown to be predictive of a sustained response in immunocompetent patients. In our study, the delayed addition of ribavirin, which was also
proposed by Sauleda et al. 1 month after the beginning of IFN--2a therapy, may have had a negative effect on the response.
In our study, overall tolerance to IFN--2a and ribavirin therapy did not differ from that reported elsewhere for HIV-negative patients. Hematological tolerance was poor in our study, especially in patients who received daily doses
of IFN--2a. Because of cumulative toxicity, antiretroviral treatment that includes zidovudine, which also favors the occurrence of neutropenia or anemia, must be avoided or carefully monitored. Similarly, efavirenz may favor
neuropsychiatric IFN--2arelated complications. A potential risk of lactic acidosis associated with the use of ribavirin and purine nucleoside analogue reverse-transcriptase inhibitors has been reported. Such a complication was not observed in our study. Reports from before the HAART era described persistent IFN--2ainduced lymphopenia in HIV-infected patients with chronic hepatitis C. Our results confirm that anti-HCV treatment has no detrimental effect on long-term CD4 cell count. Finally, results of HIV plasma load monitoring do not argue for the existence of in vivo interactions between ribavirin and antiretroviral drugs.
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