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Pegylated Interferon Alfa-2b vs Standard Interferon Alfa-2b, Plus Ribavirin, for Chronic Hepatitis C in HIV-Infected Patients
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JAMA. Dec 15, 2004;292:2839-2848.
SEE EDITORIAL BELOW ON COINFECTION
A Randomized Controlled Trial
Fabrice Carrat, MD, PhD; Firouzé Bani-Sadr, MD; Stanislas Pol, MD, PhD; Eric Rosenthal, MD; Françoise Lunel-Fabiani, MD, PhD; Asmae Benzekri, MD; Patrice Morand, MD, PhD; Cécile Goujard, MD; Gilles Pialoux, MD, PhD; Lionel Piroth, MD, PhD; Dominique Salmon-Céron, MD, PhD; Claude Degott, MD; Patrice Cacoub, MD; Christian Perronne, MD, PhD; for the ANRS HCO2 RIBAVIC Study Team
ABSTRACT
Context: Treatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)--infected patients is a growing concern. Most data on the virologic efficacy and safety of the combination of peginterferon alfa-2b and ribavirin in coinfected patients come from uncontrolled studies.
Objective: To study the safety and efficacy of peginterferon alfa-2b plus ribavirin vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients.
Design and Settings: A multicenter, randomized, parallel-group, open-label trial. Patients were enrolled from February 2000 to February 2002 and followed up for 72 weeks.
Patients: Four hundred twelve HIV-HCV coinfected patients with detectable serum HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 x 106/L, and stable plasma HIV-RNA.
Intervention: Treatment with ribavirin 400 mg twice a day, orally, plus either peginterferon alfa-2b (1.5 µg/kg subcutaneous injection once a week) or standard interferon alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48 weeks.
Main Outcome Measures: Sustained virologic response, defined by undetectable serum HCV-RNA at week 72.
Results: More patients had sustained virologic responses in the peginterferon group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6% for standard interferon, P = .006) but was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon vs 43% for standard interferon, P = .88).
Together, a decline in HCV-RNA of less than 2 log10 from baseline and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures. Histologic activity diminished and fibrosis stabilized in virologic responders. The 2 regimens showed similar tolerability although dose modifications for clinical and biological events were more frequent with peginterferon.
Eleven cases of pancreatitis or symptomatic hyperlactatemia were observed, all in patients receiving didanosine-containing antiretroviral regimens.
Conclusion: In combination with ribavirin, treatment with peginterferon alfa-2b is more effective than standard interferon alfa-2b for HCV infection in HIV-infected patients.
AUTHOR COMMENTS
In this population of HIV-infected patients with chronic HCV, peginterferon alfa-2b plus ribavirin yielded more sustained virologic responses than standard interferon alfa-2b plus ribavirin. Efficacy and tolerability in the peginterferon group were in keeping with the results of 3 uncontrolled trials, in which the sustained virologic response rates to peginterferon alfa-2b plus ribavirin were 28% to 31%. However, the absolute difference between the 2 groups (7%) was smaller than initially expected (15%); and was also smaller than in recent trials comparing peginterferon alfa-2a with standard interferon alfa-2a and in a small single-center trial comparing peginterferon alfa-2b with standard interferon alfa-2b. A high frequency of severe HIV- and/or HCV-related disease (62% of serious adverse events were unrelated to the study treatments, and 40% of our patients had bridging fibrosis or cirrhosis) and a high baseline prevalence of characteristics associated with poorer adherence to treatment (injection drug use, 79%; psychiatric disorders, 21%) may have contributed to the smaller than expected difference between the 2 treatment groups in our study. However, the fact that we did not exclude such patients may make our results relevant to the general population of patients living with HIV and HCV coinfection in the United States and Europe.
The benefit of peginterferon alfa-2b relative to standard interferon alfa-2b was most apparent in patients with genotype 1 or 4 infection. No significant differences were found between the treatment groups in patients with genotype 2 or 3 infection. Similar findings have been reported for HIV-seronegative and HIV-seropositive patients in studies comparing either peginterferon alfa-2b, or peginterferon alfa-2a plus ribavirin with standard interferon plus ribavirin.
The HCV genotype was the predominant predictor of a sustained virologic efficacy, consistent with most previous studies of both HIV-seropositive and HIV-seronegative patients. A young age, a lower HCV-RNA level, or a higher pretreatment alanine amino transferase level are also reported to be predictive of sustained virologic responses. The higher virologic failure rates that we observed among patients treated with protease inhibitors may be related to drug hepatotoxicity, increased HCV replication, restoration of anti--HCV immune responses or cytochrome P450--mediated drug interactions. Liver histology and the CD4 cell count were not independent predictors of the virologic response in our study, contrary to some previous reports but in line with recently published clinical trials.
The effect of treatment on histologic activity was similar to that observed in the HIV-seronegative population. Interestingly, the progression of fibrosis was slowed when a virologic response was achieved.
Overall, tolerability was similar in the peginterferon and standard interferon groups. However, serious adverse events were far more frequent (35%) than what has been reported among HIV-seronegative patients (10%-15%). The incidence of opportunistic infections did not appear to be affected by anti-HCV therapy. Mitochondrial toxicity was particularly frequent in patients receiving didanosine, as previously reported, possibly owing to increased intracellular concentrations of active triphosphorylated didanosine metabolites. As a result, a warning was added to the didanosine product information in September 2002, stating that ribavirin should be used cautiously in patients also receiving didanosine. It is noteworthy that the patient who died from liver failure that was possibly related to the treatment had cirrhosis at the time of death and received didanosine; both these factors were recently reported as independent risk factors for hepatic decompensation.
In combination with ribavirin, peginterferon alfa-2b is more effective than standard interferon alfa-2b for initial treatment of HCV infection with genotypes 1 and 4 in HIV-infected patients. Treatment can be discontinued after 3 months if a satisfactory virologic response is not obtained at this time. Coadministration of ribavirin with didanosine should be avoided. However, the poor outcome of HIV-coinfected patients and particularly that of patients with HCV genotype 1 infections calls for new therapeutic approaches in this setting.
INTRODUCTION
About one third of human immunodeficiency virus (HIV)--infected patients in Europe and the United States are also infected by hepatitis C virus (HCV) while 5% to 10% of HCV-infected patients are also infected by HIV.1-2 Human immunodeficiency virus coinfection accelerates the progression of HCV infection, which is now a leading cause of morbidity and mortality among HIV-infected individuals.
The treatment of chronic HCV infection was transformed in the 1990s by the advent of the interferon-ribavirin combination and was further improved with the use of pegylated interferon (peginterferon), in which a polyethylene glycol molecule is added to standard interferon, yielding a longer half-life and more favorable pharmacokinetics. Two forms of peginterferon (alfa-2a and alfa-2b) have been approved for use with or without ribavirin. In combination with ribavirin, both peginterferons provide sustained virologic responses in 54% to 63% of HIV-seronegative HCV-infected patients (7% to 12% higher than with standard interferon-ribavirin).
In vitro antagonism between ribavirin and some antiretrovirals (especially zidovudine and stavudine) delayed the use of ribavirin in HIV-coinfected patients, but a recent randomized trial of the stavudine-ribavirin combination showed no negative impact on antiretroviral efficacy.
Recently, 2 randomized controlled studies showed the efficacy and safety of peginterferon alfa-2a plus ribavirin in HIV-HCV coinfected patients. The few available data on the virologic efficacy and tolerability of peginterferon alfa-2b plus ribavirin in HIV-HCV coinfected patients come mainly from small uncontrolled or single-center trials. The aim of our prospective randomized study of initial treatment of chronic HCV in HIV-infected patients was to compare the efficacy of a 48-week course of ribavirin combined with either standard interferon alfa-2b or peginterferon alfa-2b.
Patient Selection
Adults who had never received interferon and who had the following characteristics were eligible for the study: second-generation enzyme-linked immunosorbent assay positivity for anti-HCV antibodies and polymerase chain reaction--based assay positivity for HCV-RNA in serum; interpretable results of liver biopsy performed within the previous 18 months, showing at least mild activity or fibrosis; anti-HIV antibody positivity and a stable plasma HIV-1 RNA level (variation of less than 1 log10 copies x 106/L during the 3 months before randomization); stable antiretroviral treatment during the preceding 3 months (or no antiretroviral treatment); and a CD4 cell count higher than 200 x 106/L. Patients were not eligible if they had neutropenia (<1.5 x 109/L neutrophils); thrombocytopenia (<100 x 103/µL platelets); anemia (<11.0 g/dL hemoglobin); a serum creatinine level higher than 1.70 mg/dL (150 µmol/L); circulating hepatitis B surface antigen positivity; decompensated cirrhosis (defined as biopsy-proved cirrhosis with serum albumin below the lower limit of normal: a prothrombin level <60%; a total bilirubin level higher than the upper limit of normal; or a history of ascites, hepatic encephalopathy or esophageal varices); biliary, tumoral, or vascular liver disease; psychiatric disorders (history of major depression, suicide attempts, suicidal ideation, or other severe psychiatric disorders; psychosis); a history of seizures; cardiovascular disease; poorly controlled diabetes mellitus; or autoimmune disorders; or if they had actively injected illicit drugs 3 months before enrollment or reported daily alcohol intake greater than 40 g (women) or 50 g (men). Women were not eligible if they were unwilling to use effective contraception.
Study Design and Treatment Regimens
This randomized, phase 3, open-label, parallel-group study was conducted in 71 French centers. The study was approved by the ethics committee of Saint-Germain en Laye hospital and by the sponsor's institutional review board (Agence Nationale de Recherches sur le SIDA [ANRS]). All the patients gave their written informed consent. The study was designed by the Groupe d'Etude et de Recherche en Médecine Interne et Maladies Infectieuses sur le Virus de l'Hépatite C (GERMIVIC) joint study group, which comprised experts in internal medicine, infectious diseases, and hepatology. Data analysis was performed by the sponsor and the authors, both of whom were independent of the drug manufacturers. The study followed the Helsinki Declaration and Good Clinical Practices.
Patients were randomly assigned to receive subcutaneous injections of 1.5 µg/kg peginterferon alfa-2b (Peg Intron, Schering-Plough, Kenilworth, NJ) once a week or subcutaneous injections of 3 million units of interferon alfa-2b (Intron A, Schering-Plough) 3 times a week for 48 weeks. All patients also received 400 mg of ribavirin twice a day (Rebetol, Schering-Plough), orally. Randomization was managed by the central data center (INSERM U444, Paris, France). Randomization was balanced within centers, with blocking within strata. The randomization code was developed using a computerized random number generator to select random permuted block sizes of 2, 4, 6, and 8. The randomization list was concealed from the medical monitor (located in the data center), who assigned participants to the treatment groups after reviewing the eligibility criteria. Allocated treatments were communicated to the investigator during the week preceding the visit at which the first treatment prescription was planned.
The patients were evaluated after 2 and 4 weeks of treatment, every 4 weeks thereafter during treatment, and 4, 12, and 24 weeks after treatment was completed. Patients were followed up until week 72 to assess sustained responses.
Biochemical and hematologic tests were performed in local laboratories. Hepatitis C virus--RNA tests, viral genotyping, and histological evaluation of biopsy specimens were performed in central laboratories. Liver biopsy was performed at the end of follow-up.
Assessment and End Points. Hepatitis C virus--RNA was detected with a polymerase chain reaction assay (Amplicor 2.0 HCV Monitor, Roche Diagnostics Systems, Basel, Switzerland) with a detection limit of 50 IU (100 copies) x 103/L. Hepatitis C virus--RNA levels were measured with a branched-chain DNA assay (bDNA3.0, Bayer Diagnostics, Tarrytown, NY) with a detection limit of 615 IU (3200 copies) x 103/L. Hepatitis C virus genotyping was performed by sequence analysis of the 5' untranslated region. The primary end point for efficacy was a sustained virologic response, defined as undetectable serum HCV-RNA at week 72. The secondary end point was histological improvement. Virologic and histologic end points were evaluated by individuals blinded to the treatment assignments. Pretreatment biopsy specimens were examined locally before randomization and were then coded and evaluated in parallel with those obtained at week 72, by 2 experienced pathologists (A.B. and C.D.). Hepatic inflammation and fibrosis were graded with the Metavir scoring system20 (scores ranging from 0 [none] to 3 for severe necroinflammatory activity, and 0 [none] to 4 for cirrhosis) and Ishak's classification21 (scores ranging from 0 [none] to 12 for severe inflammation, and 0 [none] to 6 for cirrhosis). Histological improvement in disease activity or fibrosis was defined as a decrease of 1 point or more between the relevant pretreatment and posttreatment Metavir and Ishak subscores.22 Histological aggravation was defined as a score increase of 1 point or more.
Special attention was paid to the possible effect of treatment on HIV infection (CD4 cell count, HIV viral load). Adverse events were graded 1 (mild) to 4 (life-threatening), using the ANRS grading system.23 Stepwise reductions in the peginterferon alfa-2b dose to 1 and 0.5 µg/kg per week, and reductions in the interferon alfa-2b dose to 1.5 million units 3 times a week or the ribavirin dose to 600 mg/d, were allowed to manage adverse events or laboratory abnormalities that had reached predefined thresholds. Patients who discontinued therapy prematurely because of adverse effects were encouraged to remain in the study.
Statistical Analysis
The study was designed to have a power of 80% to detect a 15% difference (chosen for its clinical relevance) between the rates of sustained virologic response (from 20% vs 35% to 40% vs 55%) at a 5% level of significance (2-tailed test). Intention-to-treat analysis was used as the primary analysis for all measures of efficacy. Patients violating major eligibility criteria were excluded from the analyses. Patients who missed the final examination (week 72) were included as nonresponders. Histological responses were only analyzed in patients who underwent both a pretreatment and a posttreatment biopsy. Patients who received at least 1 dose of study medication were included in the safety analysis.
The Cochran-Mantel-Haenszel test (or Fisher exact test) was used to compare categorical variables, with stratification by center for comparisons between treatment groups and stratification by center and treatment group for other categorical variables. The Wilcoxon rank-sum test was used to compare quantitative variables between the groups. Logistic regression analyses were used to explore the influence of treatment and pretreatment characteristics on the response. Characteristics with P values below 0.20 in univariate analysis were included in multivariate models based on a backward elimination procedure. Adjusted odds ratios were transformed into approximated risk ratios (RRs) to correct for overestimation due to common events. The Mac-Nemar {chi}2 test or the Wilcoxon signed-rank test was used to compare pretreatment and posttreatment characteristics. All statistical tests were 2-tailed; P<.05 was considered statistically significant. We used SAS, version 8.2 (SAS Institute Inc, Cary, NC).
RESULTS
Characteristics of the Patients
Patients were enrolled from February 2000 to February 2002. The trial ended in October 2003. A total of 442 patients were screened for eligibility, of whom 416 met the entry criteria and were randomly assigned to a treatment group. Four patients were excluded after randomization: 3 patients tested HCV-RNA--negative in the central laboratory, and one patient had previously received interferon alfa. Twenty-nine patients withdrew before receiving the study treatment because they refused or did not come for treatment or because a serious medical event occurred between randomization and the first treatment visit. During the follow-up period 4 patients in the peginterferon group and 1 patient in the standard interferon group withdrew. The pretreatment characteristics of the patients were similar in the 2 groups.
Body weight: 65-67 kg
75% from France
CDC Disease Stage A: 53%
HIV RNA <400: 65%
Median VL: 3.6 log
ART: 17% not on ART; 40% on PI; 32% on NNRTI.
Estimated duration of HCV-infection: 17 yrs
IDUs: 80%
ALT mean: 2.2 x ULN
HCV RNA: 937 IU x 106/L vs 842 IU x 1-6/l
48% genotype 1
38% genotype 2/3
13% genotype 4
LIVER HISTOLOGY:
Metavir activity: 1.7
Metavir fibrosis: 2.3
Bridging fibrosis: 39%
Virologic Responses
A sustained virologic response (main end point) was obtained in 56 patients (27%) in the peginterferon group and 41 patients (20%) in the standard interferon group (P = .047). End-of-treatment virologic responses (at 48 weeks) were obtained in 72 (35%) and 44 (21%) of patients, respectively (P = .001). Undetectable serum HCV-RNA was obtained in 30 patients (15%) in the peginterferon group and 15 patients (7%) in the standard interferon group (P = .04) at week 4, 67 (33%) and 51 (25%) at week 12 (P = .09), and 83 (40%) and 57 (28%) at week 24 (P = .004).
A total of the 67 (99%) of the 68 patients in the peginterferon group and all 91 (100%) of patients in the standard interferon group who had detectable serum HCV-RNA and a viral load decline of less than 2 log10 IU x 103/L from baseline at week 12 failed to achieve a sustained virologic response at week 72 (P = .43, Fisher exact test).
Twenty-one patients (17%) with HCV genotype 1 or 4 infection who received peginterferon alfa-2b plus ribavirin had a sustained virologic response compared with 8 patients (6%) who received interferon-alfa2b plus ribavirin (P = .006). Among patients with HCV genotype 2, 3, or 5 infection, the rates of sustained virologic response were not different between the 2 treatment groups (35 [44%] vs 33 [43%], respectively, P = .88). Among patients who took at least 80% of the planned total dose, sustained virologic responses were achieved in 44 (40%) of 111 patients in the peginterferon group and 33 (29%) of 115 patients in the standard interferon group (P = .30).
Independent Factors Associated With Sustained Virologic Response
Preliminary analysis showed that the sustained virologic response rates were influenced by the HCV genotype. A first multiple logistic regression model confirmed this result and showed that HCV genotypes 2, 3, or 5 were the main predictors of response (adjusted risk ratio [RR], 3.77; 95% confidence interval [CI], 2.69-4.93; P<.001). Other predictors were no protease inhibitor treatment, age 40 years or younger, and baseline alanine aminotransferase greater than 3 upper limits of normal. Because preliminary findings also indicated that the treatment effect differed according to the HCV genotype, further exploratory analyses were stratified according to the genotype. In patients with HCV genotype 1 or 4 infection, peginterferon treatment (RR, 2.43; 95% CI, 1.12 to 3.79; P = .03) and HCV viral load <=5.7 log10 IU x 103/L (RR, 2.07; 95% CI, 1.04 to 3.74; P = .04) were independently associated with a sustained virologic response. In patients with HCV genotypes 2, 3, or 5, the absence of protease inhibitor treatment (RR, 1.80; 95% CI, 1.17-2.42; P = .01), age 40 years or younger (RR, 1.60; 95% CI, 1.08-2.10; P = .02), and baseline alanine aminotransferase more than 3 times the upper limits of normal (RR, 1.57; 95% CI, 1.07-2.02; P = .03) were independently associated with a sustained virologic response. Liver histology, the per kilogram body weight ribavirin dose, and the CD4 cell count were not independently associated with a sustained virologic response.
Histological Responses
Paired pretreatment and posttreatment histological results were available for 205 patients (50%). The reasons for missing posttreatment results were refusal of biopsy in 153 cases (74%), failure to return in 46 cases (22%), and clotting disorders in 8 cases (4%). The only significant difference in baseline characteristics between patients with and without posttreatment biopsy was a higher mean (SD) Metavir fibrosis score in patients with available posttreatment results (2.4 [1.0] vs 2.2 [1.0]), P = .03).
For disease activity, the Metavir score change was --0.19 in the peginterferon group and 0.01 in the standard interferon group (P = .02); and the mean changes in the Ishak grade were --0.57 and --0.26 (P = .24), respectively. The decline in both subscores was significant among sustained virologic responders while the subscores were stable among nonresponders. Changes in fibrosis did not differ between the 2 groups, but fibrosis worsened in patients who did not have a sustained virologic response. Steatosis improved significantly in patients infected by HCV genotype 3 who had a sustained virologic response (--13%, P<.001).
Safety
Similar proportions of patients in the 2 groups withdrew from the study because of clinical adverse events or laboratory abnormalities (Table 4). The doses of the study treatments were modified in 31 (16%) of patients in the peginterferon group and 13 (7%) of patients in the standard interferon group because of clinical adverse events (P = .004), and in 38 (20%) and 13 (7%) of patients respectively because of laboratory abnormalities (P = .004).
INCIDENCE OF TREATMENT DISXCONTINUATION, DOSE MODIFICATIONS, and ADVERSE EVENTS
DOSE MODIFICATIONS
All reasons: 33% Peg, 21% IFN; clinical AE: 13% Peg vs 6% IFN
Lab abnormality: 14% Peg vs 4% IFN
Neutropenia: 7% Peg, 2% IFN
Thrombocytopenia: 5% Peg, 1% IFN
AE-
Mild: 80%
Moderate: 90%
Severe: 64% Peg, 57% IFN
Life-threatening: 33%
FLU-like symptoms: 89% Peg, 80% IFN
Depression: 24% Peg, 29% IFN
Weight loss: 24% Peg, 16% IFN
Inj site react: 21% Peg, 3% IFN
Reduced appetite: 18%
Ittitability: 16% Peg, 21% IFN
Cough or bronchitis: 13% Peg, 18% IFN
Insomnia: 10% Peg, 17% IFN
HIV RELATED CLINICAL AEs
Increased lipodystrophy: 19% Peg, 21%IFN
Oral candidiasis: 15%
>= SAE: 35%
>= treatment-related SAE: 15%, 12%
Psych disorder: 4%, 4%
Liver faiure: 2%, 2%
Pneumonia, sepsis: 3%, 7%
Liver enzyme activity > 10xULN: 8%
Neutropenia <5 x 106/L: 5% Peg, 2% IFN
The incidence of most clinical adverse events was similar between the 2 treatment groups. The following parameters were not significantly different by week 12 in the peginterferon vs standard interferon groups: hemoglobinemia (--18 and --14 g/L, respectively, P = .01, at week 12), platelets (--34.3 vs --21.3 x 103/µL, P = .004), neutrophils (--1.10 vs --0.70 x 109/L, P = .009), lymphocytes (--0.66 vs --0.54 x 109/L, P = .06), and CD4 cells (--121 vs --110 x 106/L, P = .21). These parameters generally remained stable after week 12, then returned to near baseline values shortly after treatment cessation. When viral loads less than 400 copies/mL were attributed a value of 2.6 log10, mean (SD) HIV viral load (log10 copies/mL) was 2.96 (0.66) at baseline and 3.12 (0.86) at the end of treatment in the peginterferon group (P<.001), 3.04 (0.73) and 3.09 (0.78) respectively, in the standard interferon group (P = .12).
Seven deaths occurred among randomized patients: there were 5 deaths in the peginterferon group (2 from liver failure, 1 from metastatic neuroendocrine carcinoma, 1 from metastatic vulvar cancer—the patient who tested negative for HCV infection in the central laboratory—and 1 from accidental nitrate propyl overdose before the first dose of study treatment), and 2 deaths in the standard interferon group (1 from liver failure and 1 from liver cancer). One of the deaths from liver failure was considered possibly related to peginterferon-ribavirin therapy. This patient had fibrosis (F2) on a biopsy performed 9 months before the first dose of study treatment, was at Centers of Disease Control and Prevention stage A, and received didanosine, stavudine, and abacavir. He discontinued the study treatment after 8 weeks because of severe thrombocytopenia. He was hospitalized at week 12 with symptoms of decompensated cirrhosis and ascites infection. Liver biopsy showed significant cirrhosis (F4). Death occurred at week 32 from sepsis and liver failure. The proportion of patients reporting serious adverse events was generally similar among the groups. Symptomatic mitochondrial toxicity (symptomatic hyperlactatemia, lactic acidosis, or acute pancreatitis) occurred in 11 patients, 9 patients receiving peginterferon and 2 patients receiving standard interferon. All these patients were receiving didanosine.
EDITORIAL
Treatment of Hepatitis C in HIV-Infected Patients
Significant Progress But Not the Final Step
Michael P. Manns, MD; Heiner Wedemeyer, MD
JAMA. 2004;292:2909-2913.
In the modern era of highly active antiretroviral therapy (HAART), hepatitis C virus (HCV) has emerged as a major cause of morbidity and death in human immunodeficiency virus (HIV) infection. An estimated 15% to 30% of HIV-infected individuals are coinfected with HCV, representing 150,000 to 300,000 patients in the United States alone. The prevalence of anti-HCV antibodies in HIV-infected persons differs significantly according to the HIV-exposure risk category, ranging from less than 10% in homosexual men to more than 85% in injecting drug users. In the vast majority of immunocompetent non--HIV-infected persons, chronic hepatitis C usually takes a relatively mild course, leading to liver cirrhosis in 2% to 25% after 20 to 25 years depending on the individual risk factor profile. Liver-related death is only slightly more frequent in HCV-infected individuals. In contrast, hepatitis C may take a much more severe course in HIV-infected patients. In men with hemophilia, the prevalence of cirrhosis as well as liver-related deaths is significantly higher in HCV-HIV--coinfected individuals than in patients infected with HIV alone.6 However, these findings may not necessarily reflect the situation in other cohorts in which HCV infection has not been shown to increase the risk of death.
Since antiretroviral therapy can be associated with significant hepatotoxicity, there has been some concern that HAART,
specifically protease inhibitors, may promote progression of fibrosis in HCV-RNA--positive patients. Fortunately, this has not been the case, and antiretroviral therapy has even been shown to reduce long-term liver-related mortality in HIV-HCV--coinfected patients. In contrast, HCV infection appears to influence the natural history of HIV disease. In the Swiss HIV cohort, among more than 3000 HIV-infected individuals, those also infected with HCV had a modestly increased risk for developing AIDS and a less robust increase in CD4 cell counts after initiation of antiretroviral therapy compared with patients infected with HIV alone. On the other hand, a study from Baltimore found that HCV coinfection had no influence on developing AIDS or response to HAART. These differences highlight the problem that different cohorts may be difficult to compare because both HIV and HCV disease may have different trajectories depending on the route of infection (eg, blood transfusions vs community acquired) and other factors.
Interactions between HCV and HIV are difficult to investigate. Although the primary site of replication differs (for HCV, the liver; for HIV, T cells, monocytes, and dendritic cells), HCV may also replicate in dendritic cells and monocytes, while HIV can cause hepatitis. Thus, both viruses may directly interact with the other's replication and influence the host's immune response to the other virus. Hepatitis C virus replication is much more rapid in HIV-infected patients than in patients infected with HCV alone, indicating decreased immune function. On the other hand, HCV proteins may directly inhibit the function of dendritic cells and natural killer cells and thus alter the anti-HIV--specific immune response. Thus, coinfection with HIV and HCV may influence viral load and immune responses and thereby affect efficacy of antiviral treatment against both HIV and HCV.
Treatment options for patients infected with hepatitis C have significantly improved only in recent years. Acute hepatitis C as well as chronic HCV genotype 2 or 3 infection is now considered a curable disease in immunocompetent patients. Even patients infected with the more difficult-to-treat HCV genotypes 1 and 4 can achieve sustained clearance rates of HCV-RNA in about 50%. Three major steps led to this significant improvement. First, the introduction of therapy with interferon alfa plus ribavirin increased response rates from less than 20% to more than 40%. Second, the development of pegylated interferons, permitting therapy to be administered weekly instead of 3 times per week, further increased responses above 50%. Third, treatment adherence increased due to better understanding of and response to adverse events by patients and their treating physicians.
Currently, 2 pegylated interferons are available: peginterferon alfa-2a, with a branched 40-kDa methoxypolyethylene glycol moeity attached covalently to interferon alfa-2a, and peginterferon alfa-2b, with a single 12-kDa polyethylene glycol molecule attached to interferon alfa-2b. Peginterferon alfa-2a is predominantly metabolized in the liver, whereas peginterferon alfa-2b is predominantly cleared by the kidney. The pegylation process also restricts the volume of distribution, such that the 40-kDa peginterferon alfa-2a is limited to the blood and interstitial fluid, whereas the 12-kDa peginterferon alfa-2b has a wider distribution. As a result, peginterferon alfa-2a does not need to be adjusted for body weight. Although no large studies have compared the 2 drugs directly, when they are administered in combination with ribavirin to patients infected with HCV alone, the differences in sustained virologic response rates are small and both peginterferons can be recommended equally.
Several studies have explored the efficacy of interferon alfa plus ribavirin combination therapy in HCV-HIV--coinfected patients, but they showed disappointing results. Thus, the question arose whether pegylated interferons, established as more effective in non--HIV-infected patients, could enhance virologic responses in coinfected patients. Two trials of peginterferon alfa-2a plus ribavirin in HCV-HIV--positive individuals were published recently. Torriani et al conducted the larger trial in countries, with most patients recruited in Europe.25 Chung et al conducted a smaller study in the United States. In this issue of JAMA, Carrat and colleagues report the third trial investigating pegylated interferon and the first investigating peginterferon alfa-2b in combination with ribavirin for the treatment of HCV in HIV-positive patients. The study was performed in France in 71 centers and included more than 400 individuals. Study design, baseline characteristics, and virologic response rates of all 3 trials are summarized in the Table.
| Torriani | Chung | Carrat | | RBV Dose | 800mg/d | 1000mg/d | 800mg/d | | White: | 79% | 48% | 93%(france/Medit) | | Blacks: | 11% | 33% | NS | | Cirrhosis: | 14% | 10% | 39%(bridging fib or cirr) | | HCV RNA | | | | | Mean IU/mL x 105: | 5.8 | 6.2 | 889.5 | | CD4 mean: | 530 | 474 | 482 | | % undet HIV: | 60% <50 | 60% <50 | 67% <400 | | ART: | 84% | 86% | 83% | | Therapy comnpleted: | 61% | 88%* | 57% | | SVR | | | | | Peg+RBV: | 40% | 27% | 27% | | IFN: | 12% | 12% | 20% | | Peg+RBV G1: | 29% | 14% | 17% | | Peg+RBV G2/3: | 62% | 73% | 44% |
*42% of pts in the peg group stopped therapy at week 24 according to protocol.
Comparing the 3 trials yields several important and some hard-to-explain differences. First, the trial by Torriani et al showed the highest response rates in the peginterferon-plus-ribavirin group. However, the conventional interferon-plus-ribavirin group had surprisingly low responses, with a sustained virologic response rate of only 12%.25 The unblinded injection schedule may explain in part the higher discontinuation rates in the conventional interferon group, assuming patients believed they were receiving the less effective treatment. On the other hand, in the study by Carrat et al, responses in the standard interferon alfa-2b-plus-ribavirin group were rather high at 20%.27 Neither report convincingly explains these differences. Even the 2 trials that used peginterferon alfa-2a showed significant differences in viral responses. For peginterferon alfa-2a monotherapy, differences in treatment responses between US patients28 and patients from Europe, Canada, and Australia29 have already been reported and may be explained by a higher proportion of black patients and higher baseline body mass index values in US trials, both of which are associated with lower response rates.
Carrat et al achieved sustained viral response rates of 17% for patients with an HCV genotype of 1 or 4. This rate, as well as the sustained virologic response rates of patients infected with genotype 1 in the other 2 studies, is especially low compared with immunocompetent patients infected with genotype 1. Whether prolonging therapy beyond 48 weeks could improve the poor outcome in genotype 1 patients remains to be investigated; in immunocompetent patients, individuals with a high body mass index and high viral load may benefit from prolonged treatment.30 Importantly, Carrat et al reported that all but 1 patient who did not respond by 12 weeks also had not responded at the 72-week end point, confirming the usefulness of the 12-week stopping rule for HIV-HCV--coinfected patients.
The study by Carrat et al also had significantly lower response rates in patients with HCV genotype 2 or 3 compared with the 2 other trials. Recently, genotype 2 was shown to respond better to peginterferon-based therapies than was genotype 3.31 The study by Carrat et al and the previous 2 studies do not report the distribution of genotype 2 and 3. Regardless, the low response rate for the "good" genotypes 2 and 3 in the study by Carrat et al highlights the need for 48 weeks of therapy in HIV-positive patients vs only 24 weeks for genotypes 2 and 3 in patients who are not infected with HIV. Carrat et al found that for patients infected with HCV genotypes 2 and 3, peginterferon alfa-2b was not superior to conventional interferon alfa-2b, a finding that replicates the results for HIV-negative patients infected with the same virus genotypes.
Ribavirin causes hemolysis in a dose dependent manner, a significant problem particularly for HIV-infected patients receiving HAART. Thus, compared with doses used for patients infected with HCV alone, ribavirin was underdosed in all 3 trials on HIV-infected patients. The importance of a sufficient ribavirin dose has been shown now by several investigators. Future studies have to address this important issue. Whether drugs such as viramidine, currently under investigation, can induce less hemolysis and still retain the immunomodulatory function of ribavirin remains to be seen. Epoetin alfa may be an alternative to maintain ribavirin dose in some patients.
Another interesting point of the article by Carrat et al is that successful antiviral therapy was associated with decreased hepatic steatosis in patients infected with genotype 3. Similar findings have been reported for patients not infected with HIV. However, the importance of reduced fat in the liver may be much more significant for HIV-positive persons. Steatosis indicates mitochondrial toxicity and thus can limit the administration of appropriate antiretroviral therapies.
Therapy with interferon-based therapies can cause significant adverse effects including flulike symptoms, autoimmune disorders such as thyroiditis, and psychiatric diseases.34 Carrat et al reported only slightly higher frequencies of the major adverse effects compared with previous studies of patients infected with HCV alone.27 Treatment was completed according to protocol in about three-fifths of the patients. Psychiatric adverse effects including depression were reported with low frequency, suggesting that the presence of psychiatric diseases may not necessarily require exclusion from interferon alfa-based therapies. Patients with more severe psychiatric disease might benefit from consultation with a psychiatrist before and during treatment to ensure optimal adherence with therapy. Antidepressant medication can significantly reduce the frequency of depression during interferon therapy. Importantly and again consistent with findings in patients infected with hepatitis C alone, adherence to therapy was a major factor determining treatment response in the study by Carrat et al. Therefore, treating patients in an optimal setting of experts in different fields may help to achieve this goal.
Pancreatitis is an important consideration if peginterferon-plus-ribavirin therapy is started in HIV-infected patients receiving HAART. Some HIV patients receiving HAART treated with ribavirin for hepatitis C experience hyperlactatemia.38 Ribavirin, a guanosine nucleoside analogue, may interact with nucleoside reverse transcriptase inhibitors and antagonizes anti-HIV drugs such as zidovudine and stavudine in vitro. In addition, through inhibition of inosine-5'-monophosphate dehydrogenase, ribavirin facilitates conversion of didanosine to its active metabolite and thus potentially causes mitochondrial toxicity. Three cases of pancreatitis were reported in the ribavirin groups in the trial by Torriani et al while 1 case of pancreatitis was reported in the trial by Chung et al. Carrat et al reported 11 cases of pancreatitis, all in patients treated with didanosine-containing antiretroviral regimens. Thus, careful evaluation of antiretroviral therapy is mandatory before ribavirin therapy is started in patients infected with HIV. If possible, the HAART regimen should be changed if didanosine is included.
Patients with cirrhosis may experience hepatic decompensation during interferon therapy. In the trial by Torriani et al, 10% of patients with cirrhosis experienced decompensation while receiving treatment40 and 6 of these 14 patients died, highlighting that close monitoring of patients with cirrhosis and HCV infection is warranted, whether or not they also have HIV infection. In the study by Carrat et al, 2 of the 80 patients with significant fibrosis or cirrhosis taking peginterferon alfa-2b plus ribavirin experienced liver failure.
Although CD4 cell counts of patients in the study by Carrat et al decreased during antiviral therapy, CD4 cell counts normalized after the end of therapy or even increased compared with baseline levels. However, patients selected for all 3 trials had relatively high baseline CD4 cell counts with a mean of about 500 x 106/L. Patients with CD4 counts below 200 x 106/L should not be considered for interferon-based therapies. Human immunodeficiency virus--viral load was not affected by treatment in the studies by Chung et al and Carrat et al. In the trial by Torriani et al, patients receiving peginterferon alfa-2a experienced a 0.7 log decline of HIV-RNA from week 0 to week 48. Overall, all 3 studies showed the safety of peginterferon-plus-ribavirin therapy in for patients infected with HIV if patients are selected carefully based on their individual risk profile.
A final issue that has not been considered by any of the 3 studies is the presence or absence of GBV-C (hepatitis G) coinfection. In 1998, Heringlake et al41 reported an improved course of HIV infection if patients were also coinfected with the GBV-C virus, a phenomenon that has been confirmed by several groups in different parts of the world. This also held true for patients receiving HAART. However, interferon alfa not only induces clearance of the flavivirus HCV but also clearance of the flavivirus GBV-C. A recent study by Williams et al showed that the patients with the worst outcomes were those who lost GBV-C during follow-up. None of the 3 studies in coinfected patients reported prevalence of GBV-C infection in their cohorts or eradication rates of GBV-C due to peginterferon plus ribavirin anti-HCV treatment. Careful follow-up studies are needed to address whether clearance of GBV-C by interferon-based therapies may worsen the outcome of HIV infection in these patients.
In summary, the study by Carrat et al adds significantly to current knowledge of treatment of hepatitis C in HIV-infected patients. Drugs are now available that can lead to a reasonable proportion of patients being able to clear HCV. However, responses are still low and most patients infected with HCV genotype 1 do not show long-term benefits from treatment. In addition, many patients have contraindications to treatment. If treatment is initiated, patients should be selected carefully and must be monitored closely. Thus, alternative treatment options are still urgently needed for this difficult-to-treat cohort. The introduction of peginterferon alfa plus ribavirin for hepatitis C in HIV-infected patients represents a major step—but it is not the final goal by far. Additional therapies for HCV in HIV-infected patients will be needed, but likely will remain interferon-based. Approaches to improve adherence to the full dose of treatment will be essential to improve outcomes in coinfected patients.
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