JAIDS Journal of Acquired Immune Deficiency Syndromes:
Daily Versus Thrice-Weekly Interferon Alfa-2b Plus Ribavirin for the Treatment of Chronic Hepatitis C in HIV-Infected Persons: A Multicenter Randomized Controlled Trial
Sulkowski, Mark S. MD*; Felizarta, Franco MD†; Smith, Cheryl MD‡; Slim, Jidah MD§; Berggren, Ruth MD¶; Goodman, Russell BA**; Ball, Lisa RN; Khalili, Mandana MD††; Dieterich, Douglas T. MD‡‡; for the Hepatitis Resource Network Clinical Trials Group
From *Johns Hopkins University School of Medicine, Baltimore, MD; †Clinica Sierra Vista, Bakersfield, CA; ‡North General Hospital, New York, NY; §St. Michael’s Medical Center, Newark, NJ; ¶Tulane University School of Medicine, New Orleans, LA; **Hepatitis Resource Network, Puyallup, WA; ††University of California, San Francisco; ‡‡Mt. Sinai School of Medicine, New York, NY.
Received for publication July 25, 2003; accepted January 12, 2004.
This study was supported by an unrestricted grant from Schering-Plough Corporation, which had no role in the collection, analysis, or interpretation of the data for this study.
Dr. Sulkowski has research grants or funding/lecture sponsorships/honoraria for continuing medical education (CME) programs from, or advisor or consultant for Boehringer Ingelheim, Hepatitis Resource Network, Human Genome Sciences, Ortho-Biotech, Roche, and Schering, and government grants or research funding (R01 DA13806).
Dr. Felizarta has received research grants from Schering-Plough Corporation.
Reprints: Mark S. Sulkowski, Johns Hopkins Medical Institutions, 18030 East Monument Street, Room 448, Baltimore, MD 21205 (e-mail: email@example.com).
Abstract: Among HIV-infected persons, chronic hepatitis C virus (HCV) infection causes substantial morbidity and mortality. However, few studies have evaluated the safety and efficacy of interferon alfa (IFN) and ribavirin (RBV) therapy in co-infected persons. Accordingly, a randomized, controlled, open-label, multicenter trial was conducted to establish the safety, tolerability, and efficacy of IFN alfa-2b 3 mIU daily plus RBV 800 mg/d compared with IFN alfa-2b 3 mIU thrice weekly (TIW) plus RBV 800 mg/d in HCV treatment–naive, HIV-infected subjects with compensated liver disease and stable HIV disease. The primary endpoint was sustained virologic response (SVR), defined as an undetectable HCV RNA level 24 weeks after discontinuation of HCV therapy. At study entry, subjects in both groups were similar with respect to age, gender, HCV genotype, and HIV disease status. Of 180 randomized subjects, 162 received at least 1 dose of study medication, constituting the modified intention-to-treat population. After 12 weeks of therapy, 122 (75%) had serum HCV RNA levels assessed; of these subjects, early virologic response (undetectable HCV RNA or >2 log10 decrease from baseline) was observed in 33 (42%) and 13 (16%) of subjects taking daily and TIW IFN, respectively (P < 0.001). SVR was observed in 15 (19.0%) and 7 (8.4%) of subjects taking daily and TIW IFN, respectively (P = 0.05). Adverse events were similar in both groups. However, while no deaths or opportunistic infections were observed, nearly 30% of subjects stopped treatment due to adverse events and 7 subjects experienced a serious adverse event. In conclusion, SVR was achieved in 19% of HIV/HCV coinfected subjects treated with daily IFN plus RBV, but the effectiveness of therapy was substantially diminished by relatively high rates of treatment-related toxicity.
In the United States, 150,000–300,000 persons are coinfected with HIV and hepatitis C virus (HCV), representing 15–30% of all HIV-infected and 5–10% of all HCV-infected persons. 1–3 Whereas HCV-related liver disease was once a relatively minor medical problem in HIV-infected persons, since the advent of highly active antiretroviral therapy (HAART), there has been a marked decline in most opportunistic illnesses, and HCV infection has emerged as an important cause of morbidity and mortality. 4–8 Medical management of HCV infection has improved in recent years with the advent of interferon (IFN) alfa and ribavirin (RBV) combination therapy and recently published guidelines state that HIV/HCV co-infected patients are candidates for such therapies. 9–14 However, there are currently no antiviral agents licensed for the treatment of HCV in HIV-infected patients, and there are few published data addressing the safety and efficacy of IFN alfa and RBV therapy in this population. 15–21 Accordingly, the objectives of this randomized, controlled clinical trial were to evaluate the safety, tolerability, and efficacy of anti-HCV therapy with IFN alfa-2b plus RBV for the treatment of chronic HCV in HIV-infected adults and to test the hypothesis that continuous exposure to IFN via daily injections is more effective than intermittent exposure via thrice-weekly (TIW) injections.
PATIENTS AND METHODS
This investigator-initiated study was performed at 65 academic and community-based gastroenterology and HIV treatment centers in the United States. HIV-infected patients 18 years or older were eligible for participation if they had chronic HCV infection, evidenced by a reactive HCV serology and HCV RNA detectable in the serum by polymerase chain reaction (PCR), and had not previously been treated with IFN alfa with or without RBV. Participants were eligible to participate with normal or elevated serum alanine aminotransferase levels. Liver biopsy was recommended but not required for study inclusion; other causes of chronic liver disease were excluded by appropriate serologic studies including chronic hepatitis B virus infection. HCV genotype testing was not required for study entry. If available, genotype data were collected based upon historical information in the patient’s medical record or local testing during screening.
Patients were excluded if they had decompensated liver disease (history of ascites, encephalopathy, or variceal bleeding), anemia (hemoglobin <11 g/dL), thrombocytopenia (platelet count <70,000/mL), neutropenia (absolute neutrophil count <1250/mm3), poorly controlled psychiatric disease, renal disease, uncontrolled cardiopulmonary illness, or active illicit drug or alcohol use. Study participants were excluded if their CD4+ T-cell count was <100/mm3 while those with CD4+ T-cell counts between 100 and 199/mm3 were eligible only if their serum HIV RNA level was suppressed below the limit of detection by PCR within 4 weeks of study entry. Subjects with active HIV-related opportunistic infections were excluded. Concurrent antiretroviral therapy was not required for study inclusion; however, no alterations in anti-HIV therapy were permitted for a period of at least 4 weeks prior to enrollment. This study was approved by central or institutional (at participating centers) ethical review boards; all participants provided informed, written consent.
Eligible subjects were randomized to receive open-label therapy with RBV (Rebetol, Schering Corp., Kenilworth, NJ 800 mg/d plus IFN alfa-2b (Intron A Schering Corp., Kenil-worth, NJ) at a dose of 3 million units self-administered either daily or TIW by subcutaneous injection for a period of 48 weeks. Subjects were followed for a period of 24 weeks after stopping therapy. Subjects were monitored for safety at treatment weeks 1, 2, and 4 and then every 4 weeks until week 48 and at follow-up weeks 4, 8, 12, and 24. HIV RNA levels and CD4+ T-cell counts were repeated every 12 weeks and changes in antiretroviral therapy were carefully recorded. Per protocol, HCV RNA testing (by PCR-based assay) was performed at local laboratories after 12, 24, and 48 weeks of HCV therapy and at 24 weeks following treatment discontinuation. Subjects with HCV RNA level <1000 copies/mL were considered to be undetectable; participants with detectable HCV RNA after 24 weeks of HCV therapy were permitted but not required to discontinue treatment.
The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA in the serum by reverse transcription PCR-based assay measured at 24 weeks after treatment. Secondary endpoints included the early virologic response (EVR) (defined as an undetectable or >2 log reduction in HCV RNA level from the baseline level at treatment week 12) and end-of-treatment (EOT) virologic response (defined as undetectable HCV RNA in the serum at treatment week 48); changes in HIV disease parameters (measured by changes in HIV RNA levels in the serum, and CD4+ T-cell counts); and safety and tolerability (defined as laboratory and clinical adverse events and premature treatment discontinuation). All data were analyzed as modified intention-to-treat according to the original treatment assignment and included all subjects who received at least 1 dose of study medication.
Descriptive statistics were calculated for key variables. Frequencies and percentages were calculated for categorical variables; means (SD) or medians (intraquartile range [IQR]) were calculated for continuous variables. Baseline and key characteristics were compared according to treatment group serostatus using χ2 tests for categorical variables and Mann-Whitney U tests for continuous variables. Similarly, as appropriate, these tests were used to assess association between key variables and viral response, safety, and tolerability in each treatment group. Stepwise multivariate logistic regression was used to analyze factors associated with EVR and SVR at treatment week 12 and posttreatment week 24, respectively. Statistical analyses were performed using STATA (version 6.0, College Station, TX) and SAS (version 8.02, Cary, NC).
Between February 2000 and October 2001, 180 HIV-infected adults were enrolled and randomized to receive daily (90 subjects) or TIW (90 subjects) IFN plus RBV. At baseline, the 2 treatment groups were similar with respect to age, gender, weight, race, history of injection drug use, presence of stable psychiatric disease, and hematologic parameters (Table 1). More than 80% of subjects in each group received antiretroviral therapy and >70% had undetectable HIV RNA levels. The mean CD4+ T-cell count was 551 and 534 cells/mm3 in the daily and TIW IFN groups, respectively (P = 0.92). The HCV RNA level and genotype distribution (available in 85% of subjects) were similar between the 2 study groups; however, African American subjects were more likely to be infected with HCV genotype 1 compared with white and Hispanic patients (91% and 74%, respectively, P = 0.01). Liver biopsy was available in 86 subjects (48%), of whom 7 (8.1%) had histologic evidence of cirrhosis (Table 1).
Eighteen subjects (daily, 11 and TIW, 7) did not receive any study medication due to: withdrawal of consent (10 subjects); lost to follow-up (7 subjects); and refused treatment randomization (1 subject). Subjects who failed to initiate HCV therapy were similar to those in the modified intention-to-treat study population (162 subjects; 79 daily and 83 TIW IFN) with respect to baseline demographic and clinical parameters, including gender, race, HIV and HCV disease status, and history of injection drug use or psychiatric disease (data not shown).
Early Virologic Response
After 12 weeks of anti-HCV therapy, 122 subjects (59 subjects daily and 63 subjects TIW IFN) had a quantitative HCV RNA level performed, whereas 37 subjects (18 daily and 19 TIW IFN) discontinued therapy and 3 (2 daily and 1 TIW IFN) did not have HCV RNA testing performed. Among those who stopped therapy prior to week 12 (n = 37), 7 subjects (2 daily, 5 TIW IFN) were lost to follow-up; 22 subjects (12 daily, 10 TIW IFN) discontinued due to an adverse event(s); 4 subjects (2 daily, 2 TIW IFN) withdrew consent; 3 subjects (2 daily, 1 TIW IFN) were nonadherent to the protocol; and 1 subject (TIW) was discontinued due to site closure.
At week 12, EVR, defined as an undetectable HCV RNA level or >2 log10 decrease compared with the baseline HCV RNA level, was observed among 33 of 79 (42%) of subjects treated with daily IFN and 13 of 83 subjects (16%) treated with TIW IFN, based on the modified intention-to-treat population (relative risk [RR] 2.67; 95% CI, 1.52–4.68; P = 0.0002) (Fig. 1).
In multivariate logistic regression analysis, EVR was independently associated with daily IFN therapy (odds ratio [OR], 6.42; 95% CI, 2.48–16.61), no history of opportunistic infection (OR, 10.67; 95% CI, 1.78–63.64), nonblack race (OR, 4.36; 95% CI, 1.42–13.4), baseline HCV RNA level <6.0 log10 copies per mL (OR, 3.04; 95% CI, 1.18–7.82), and leukocyte count >6300/mm3 (OR, 1.67; 95% CI, 1.09–2.55). Conversely, stable psychiatric illness and a history of injection drug use were not associated with failure to achieve an EVR (Tables 2 and 3). Notably, due to incomplete data, the effect of HCV genotype could not be assessed in the model.
Sustained Virologic Response
An EOT virologic response was observed in 28 subjects (19 daily and 9 TIW IFN) (OR, 2.31; 95% CI, 1.12–4.78). Among those with an EOT virologic response, 22 subjects had an SVR, 3 subjects experienced a virologic relapse, and 3 subjects failed to complete any scheduled follow-up visit after discontinuation of therapy. Overall, SVR was observed in 15 of 79 subjects (19.0%) receiving daily IFN and 7 of 83 subjects (8.4%) receiving TIW IFN, based on the modified intention-to-treat populations (RR, 2.25; 95% CI, 0.98–5.22, P = 0.05) (Fig. 1). Among those with an SVR, 15 subjects (10 daily, 5 TIW) were infected with HCV genotype 1; 6 subjects (4 daily, 2 TIW) were infected with HCV genotype 2 or 3; and 1 subject did not have genotype testing available. Virologic relapse was documented in 3 of 25 (12%) of subjects with an undetectable HCV RNA level at the EOT who had at least 1 posttreatment HCV RNA test. After inclusion of the 3 subjects without any documented posttreatment HCV testing as failures, the virologic relapse rate was 21% (6 of 28 subjects).
In multivariate logistic regression analysis, SVR was independently associated with nonblack race (OR, 4.78; 95% CI, 1.04–21.81), baseline HCV RNA level <6.0 log10 copies/mL (OR, 3.14; 95% CI, 1.17–8.47), and daily IFN (OR, 2.51; 95% CI, 1.01–6.80) (Table 2). Conversely, SVR was not associated with baseline CD4+ T-cell count or log HIV RNA level, stable psychiatric disease, history of injection drug use, gender, or age (data not shown). Notably, due to incomplete data, the effect of HCV genotype could not be accurately assessed in the model.
Predictive Value of Early Virologic Response
Only 34 of the 122 subjects (28%) who underwent HCV RNA testing at treatment week 12 completed 48 weeks of antiviral therapy. However, most treatment discontinuations were observed among subjects who failed to achieve an EVR; 70 of 76 (92%) week 12 virologic failures did not complete the 48-week course. Conversely, 28 of 46 (60%) of subjects who achieved an EVR completed the 48-week course and SVR was observed in 22 of 46 subjects (48%) with evidence of a week 12 EVR. Of the 24 subjects with an EVR who failed to achieve an SVR, 3 subjects experienced a documented virologic relapse after discontinuation of therapy at 48 weeks, 3 subjects were lost to follow-up after discontinuation of therapy at 48 weeks, 11 discontinued therapy due to an adverse event, 4 experienced virologic failure (at treatment week 24), and 3 were nonadherent to the protocol. Importantly, both subjects and investigators received HCV response information in real time during the study, suggesting that the knowledge of treatment futility or success influenced the decision to discontinue or continue treatment. The high rate of treatment discontinuation precludes the calculation of the negative predictive value of week 12 response since the impact of additional therapy cannot be assessed.
Clinical and Laboratory Adverse Events
Serious adverse events were observed in 7 subjects (5, daily and 2, TIW IFN) including neuropsychiatric events (e.g., depression), 3 subjects; bacterial pneumonia, 3 subjects; and symptomatic hyperlactemia syndrome/pancreatitis, 1 subject. No subjects died during the study period. In addition, 35 subjects (17, daily and 18, TIW IFN) discontinued therapy due to a nonserious adverse event (Table 4). In multivariate logistic regression analysis, discontinuation of treatment due to an adverse event (n = 42) was independently associated with a hemoglobin level < 12 g/dL at study entry (OR, 4.64; 95% CI, 1.35–16.0) but not HCV treatment group, age, ethnicity, gender, body weight, baseline CD4+ T-cell count or HIV RNA level, history of psychiatric disease or injection drug use, or the use of zidovudine or didanosine.
In addition, no adverse effect on control of HIV replication was detected, including among those subjects receiving zidovudine and stavudine. The absolute CD4 cell count decreased in both treatment groups; however, no significant change was observed in the CD4 cell percentage and no subjects experienced an opportunistic infection (Table 5). Overall, 14 subjects received didanosine in conjunction with RBV, of whom 1 subject experienced symptomatic hyperlactemia, characterized by lactic acidosis, pancreatitis, and hepatitis. This serious adverse event resulted in hospitalization followed by complete recovery after discontinuation of study medication and antiretroviral therapy.
Due to an increased risk of liver disease in the setting of HIV infection, current guidelines recommend that HIV coinfected patients be considered for HCV treatment with IFN- and RBV-based therapies. 9–11 However, published data on the safety and efficacy of these therapies in persons with HIV/HCV coinfection are limited. In this community-based, randomized controlled trial, we found that the SVR rate was significantly higher in persons randomized to receive daily IFN injections plus RBV (19.0%) compared with those receiving TIW IFN injections plus RBV (8.4%).
While our study did not directly compare HIV-infected with HIV-uninfected patients, the SVR rate observed in our population receiving TIW IFN plus RBV is substantially lower than historical SVR rates (~ 42–46%) observed with a similar regimen in HIV-negative patient populations. 13,14 This observation is consistent with other published studies of standard IFN plus RBV in HIV-infected persons. However, the majority of these studies have been uncontrolled, nonrandomized trials of IFN, which enrolled relatively heterogeneous patient populations (e.g., IFN-experienced and -naive persons). For example, Sauleda et al. 17 reported that 8 of 20 HCV/HIV coinfected hemophiliacs achieved an SVR with IFN alfa-2b TIW and RBV. Similarly, Landau et al. 16 observed an SVR rate of 21% among 51 HIV/HCV coinfected subjects treated with a similar regimen for 12 months. Interestingly, Kostman et al. 21 treated 110 coinfected persons with IFN alfa-2b TIW plus RBV or placebo; and similar to our findings, SVR was observed in 8% of subjects who received TIW IFN and RBV. Taken together with our findings, the available data indicate that standard TIW IFN plus RBV is ineffective in HIV-infected persons, and, while daily IFN plus RBV was associated with greater efficacy, the SVR rate observed in our study (19%) was significantly lower than rates observed historically in HIV-negative patients with TIW IFN combination therapy.
The reasons for limited efficacy of standard IFN plus RBV in coinfected patients have not been fully elucidated. Interestingly, in our study, the rate of virologic relapse among EOT virologic responders (21%) was not substantially different than that observed in HIV-uninfected historical controls, suggesting that factors related to early HCV response may be more important than those related to viral eradication among those with complete suppression of HCV replication. 13,14 In our study, multivariate analysis suggested lower viral response rates among patients of African American ethnicity and higher baseline HCV RNA levels. In our analysis, one measure of immune function, the baseline CD4 cell count, was not associated with SVR; however, the baseline HCV RNA level may better reflect the status of the host interaction with the HCV, serving as an indirect measure of HCV-specific immunity. Unfortunately, the evaluation of other factors associated with SVR was limited due to the relatively small number of SVR outcomes and the lack of complete data on HCV genotype; larger studies are needed to better understand host and disease factors associated with virologic response in HIV-infected persons.
In addition, the limited efficacy of treatment in our population may be explained, in part, by the HCV treatment regimen studied. Similar to other ongoing studies involving HIV coinfected patients, the RBV dose of 800 mg daily was selected based on the predicted tolerability and efficacy of this dose. However, among HIV-negative patients infected with HCV genotype 1, recent data indicate that higher doses of RBV (1000–1200 mg daily) are associated with greater antiviral efficacy compared with the lower dose (800 mg daily). 22 Furthermore, we used daily IFN to deliver continuous antiviral therapy and, while our data indicate that daily IFN was more effective, the current HCV therapies involve the use of once-weekly peginterferon alfa (PEG-IFA) alfa plus RBV. 9,12,22,23 Among HIV-uninfected patients, 2 randomized, controlled trials demonstrated that PEG-IFN alfa-2a or alfa-2b plus RBV is superior to standard IFN alfa-2b and RBV, with a similar frequency of adverse events. 12,23 To date, only one published study has reported SVR data among HIV/HCV coinfected patients treated with PEG-IFN/RBV. Perez-Olmeda et al. 19 reported that 28% of 68 coinfected patients treated with PEG-IFN alfa-2b plus RBV achieved an SVR. Additionally, preliminary data from an ongoing AIDS Clinical Trials Group Study, which randomized 134 persons to receive IFN alfa-2a or standard IFN plus RBV, demonstrated higher rates of on-treatment viral suppression among patients receiving PEG-IFN (44%) compared with those receiving standard IFN (15%). 20 Thus, while more robust efficacy and safety data are anticipated from ongoing large, randomized controlled trials, the preliminary reports indicate that the virologic response rates among HIV-infected persons treated with PEG-IFN/RBV may be significantly lower than those historically observed among HIV-negative persons treated with similar regimens. Even so, in light of its greater efficacy and the convenience of once-weekly dosing, PEG-IFN plus RBV represents the current standard of care for treatment of HCV in HIV-infected persons. 9
While our study did not evaluate PEG-IFN/RBV, the other principal finding of the study, the relatively poor tolerability of anti-HCV therapy, is directly applicable to current regimens since the safety and adverse effects of PEG-IFN are similar to those of standard IFN. Although the nature of the adverse events was similar to those reported in HIV-uninfected patients, we found that approximately 25% of subjects failed to complete at least 12 weeks of therapy. Since these subjects stopped therapy before the first assessment of HCV response, these treatment discontinuations were driven by adverse effects and poor tolerability rather than knowledge of virologic efficacy. 24,25 Conversely, our data also indicate that >90% of subjects without an EVR at treatment week 12 stopped anti-HCV therapy, suggesting that investigators (and subjects) were influenced by the observation among HIV-negative subjects that the lack of an EVR was strongly associated with subsequent failure to achieve an SVR (negative predictive value, 97–99%). 26 Additional large studies will be needed to validate the negative predicative value of week 12 viral response patterns among HIV-infected patients.
Nonetheless, we found that nearly one-third of subjects stopped treatment due to an adverse event, including 11 subjects (24%) who achieved an EVR. Specifically, psychiatric and hematologic (e.g., neutropenia, anemia) toxicity accounted for approximately 40 and 15% of these early discontinuations, respectively. These observations suggest that strategies to manage psychiatric complications, such as close supervision or the use of psychotropic medications, may reduce early treatment dropout. Moreover, the use of growth factors, such as filgrastim and epoetin alfa, may prevent treatment interruptions due to hematologic toxicity. 27 In addition to these documented toxicities, nearly 20% of our subjects were lost to follow-up or were nonadherent to therapy. While it is likely that treatment-related toxicity contributed to the failure in such subjects, strategies to improve adherence such as directly administered, weekly PEG-IFN injections or moderated support groups may lead to the more effective delivery of HCV care. Such comprehensive approaches will also serve to better address the physical and psychiatric morbidity associated with PEG-IFN/RBV.
Importantly, although drug-related toxicity substantially limited the effectiveness of anti-HCV therapy, we did not detect evidence of a significant adverse impact of IFN/RBV on markers of HIV disease or on the effectiveness of its treatment with antiretroviral drugs. 10,28,29 As previously reported, the absolute CD4+ T-cell count decreased as a result of IFN-related lymphopenia, but the proportion of these lymphocytes that were CD4+ cells increased. 20,30 In addition, while 3 cases of bacterial pneumonia were observed, no subject developed an acute opportunistic infection. Furthermore, among subjects taking antiretroviral therapy, we did not detect an adverse impact on suppression of HIV replication, including in those subjects taking drugs that, in vitro are antagonized by RBV, such as zidovudine or stavudine. 28,29 Conversely, 1 subject receiving didanosine developed symptomatic hyperlactemia, highlighting recent data indicating that didanosine and RBV should not be coadministered. 31,32 While we did not observe substantial adverse effects on the management of HIV disease, additional studies are needed to define the appropriate sequencing of antiretroviral and HCV therapy as well as to formally evaluate the significance of potential drug-drug interactions.
Our findings are subject to several other potential limitations. First, subjects in our study discontinued therapy at a relatively high rate; however, this is an important observation as a marker of tolerability and all analyses were conducted as modified intention to treat. Second, the majorities of subjects were effectively treated with HAART and had relatively intact immune function (<7% had a CD4 cell count <200 cells/mm3). Consequently, our findings cannot be applied to HIV-infected patients with compromised immune function (e.g., CD4 cell count <100 cells/mm3). Lastly, enrolled subjects met strict criteria regarding their health status and comorbidities, which may limit the applicability of these results to some patient groups such as those with active drug and alcohol use or renal disease. However, one-third had stable psychiatric disease and nearly two-thirds had a history of injection drug use, suggesting our data are generalizable to many patients with HIV/HCV coinfection. 2,33,34
In conclusion, our data indicate that chronic HCV can be safely and effectively treated in HIV-infected persons. However, the observed EVR and SVR rates were substantially lower than historical rates seen in HIV-negative persons receiving similar ant-HCV regimens. Similarly, while no adverse impact was detected on HIV disease or its treatment with HAART, the overall effectiveness of therapy was diminished by relatively high rates of discontinuation due to medication-related toxicity. Clearly, more research is needed to understand the host, virus, and treatment factors that limit the effectiveness of anti-HCV therapy among persons with HIV/HCV coinfection. Finally, although we anticipate that many of our findings will be directly applicable to the current standard therapy—PEG-IFN plus RBV—large, well-designed clinical trials are needed to assess the safety, tolerability, and efficacy of these regimens in this population.
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Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin
Seminars in Liver Disease, 25(1):
GutTreating viral hepatitis C: Efficacy, side effects, and complicationsGut
Journal of Antimicrobial ChemotherapyChronic hepatitis C in patients with HIV/AIDS: a new challenge in antiviral therapyJournal of Antimicrobial Chemotherapy
Journal of Clinical Gastroenterology
Role of growth factors in the treatment of patients with HIV/HCV coinfection and patients with recurrent hepatitis C following liver transplantation
Journal of Clinical Gastroenterology, 39(1):
HCV; HIV; interferon; ribaviron
© 2004 Lippincott Williams & Wilkins, Inc.
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