Objective: To evaluate the influence of hepatitis C virus (HCV) coinfection on clinical, immunological, and virological responses and on adverse reactions to nevirapine-containing highly active antiretroviral therapy (HAART) in Chinese adult antiretroviral-naive HIV-positive patients.
Methods: This prospective, multicentric study enrolled 175 HIV-1-positive subjects who initiated HAART and attended follow-up visits over 100 weeks from 2005 to 2007. They were grouped based on HCV antibody and HCV RNA test results. Virological and immunological responses and adverse events were monitored at baseline and at the end of weeks 4, 12, 24, 36, 52, 68, 84, and 100. For data analyses, we used repeated measures of variance.
Results: There were 117 patients who were HCV antibody negative (anti-HCV−), 24 who were anti-HCV+ but HCV RNA−, and 34 who were anti-HCV+ and HCV RNA+. Compared with both anti-HCV− group and anti-HCV+ HCV RNA− group, the anti-HCV+ HCV RNA+ group had a higher incidence of rash (P = 0.044) and hepatotoxicity (P = 0.001) from adverse drug reactions. We observed no statistically significant differences in viral load responses among the 3 groups during follow-up. CD4+ and CD8+ T-cell responses were similar among the 3 groups.
Conclusions: HCV/HIV coinfection does not affect immunological and virological responses to HAART. However, the positive anti-HCV and HCV RNA in serum worsened adverse drug reactions to HAART such as rash and hepatoxicity in HIV patients.
From the Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Received for publication September 2, 2009; November 23, 2009.
This study was supported by National Key Technologies R&D Program for the 11th Five-year Plan (2008ZX10001-006), Ministry of Health Clinical HIV/AIDS Research Grant (2007-2009) and Beijing Science and Technology Program Fund (D0906003040491).
Correspondence to: Li Taisheng, MD, PhD, Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan, Wangfujing Street, Beijing, China 100730 (e-mail: email@example.com).
Coinfection with hepatitis C virus (HCV) is common in HIV-1-infected individuals because of the shared routes of transmission.1 Currently, there are no nation-wide studies, which demonstrate the prevalence of HIV/HCV coinfection in China. Only reported in studies with small samples, the prevalence of coinfection with HIV and HCV is 17.6% among drug users in Southern China, and HCV was present in 95.1% of HIV-positive heroin users. Unlike Northern China where HCV genotype 1 (especially 1b) and 3 predominate, Southern China is characterized by a high prevalence of genotype 6.2,3 Studies have demonstrated higher rates of cirrhosis and more advanced fibrosis stages in the livers of HIV-1/HCV-coinfected patients than that of HCV-monoinfected patients after comparable periods of infection.4 Nevirapine (NVP) is used widely in resource-limited areas because of its convenience and tolerability. The impact of HCV coinfection on the response to NVP-containing highly active antiretroviral therapy (HAART) in HIV disease is less clear. There are a number of discordant findings. Some studies have demonstrated that HCV coinfection was associated with impaired CD4+ T cells recovery5,6 and lower viral suppression after HAART.6 However, other cohort studies have not found such an association.7,8 Patients were grouped according to HCV serological status rather than by HCV polymerase chain reaction in the majority of these studies. To our knowledge, there have been no studies showing the influence of HCV coinfection on the adverse event profile of NVP-containing HAART, and we are confident that there are no such published studies regarding Chinese HIV-positive patients. To address these questions, we assessed the influence of HCV coinfection on antiretroviral (ARV) potency, immunological reconstitution, and adverse events in Chinese HIV-positive patients on NVP-containing HAART, stratified by HCV antibody and HCV RNA status.
This was a prospective study conducted at 13 research centers in China. Enrollment began in January 2005. The research centers were from several different regions of China, including Beijing, Shanghai, Shenzhen, Guangzhou, Xian, Henan province, Hunan province, Zhejiang province, and Yunnan province. Thus, the patients represent a broad cross section of Chinese HIV-1-positive patients. HIV antibody was determined by standard serum enzyme-linked immunosorbent assay tests and also by Western blot analyses. Patients were only considered for enrollment in this study if they were ARV naive. Eligibility criteria for participants included a CD4+ T-cell count between 100 and 350 cells per cubic millimeter and a plasma viral load (VL) of greater then 500 copies per milliliter. The main exclusion criteria were pregnancy or breastfeeding, anticipated nonadherence, an AIDS-defining illness within 2 weeks of entry, white blood cell count less than 2.0 × 109/L, absolute neutrophil count less than 1.0 × 109/L, hemoglobin level less than 90 g/L, platelet count less than 0.75 × 1012/L, transaminase and alkaline phosphatase level more than 3 times the upper limit of the normal range, bilirubin level more than 2.5 times the upper limit of the normal range, and serum creatinine level more than 1.5 times the upper limit of the normal range. HAART for this group of patients was defined as NVP-containing regimens with the combination of 2 nucleoside reverse transcriptase inhibitors-either zidovudine + lamivudine, stavudine + lamivudine or zidovudine + didanosine. None of the patients was an injection drug user. Patients were tested for HCV antibody before the initiation of HAART. If HCV antibody was positive, HCV RNA was tested. Patients were divided into 3 groups: an anti-HCV− group, an anti-HCV+ HCV RNA− group, and an anti-HCV+ HCV RNA+ group. None of the patients was treated with pegylated interferon and ribavirin as none could afford these treatments.
(a) The patients were followed as per protocol for 2 years, at weeks 4, 12, 24, 36, 52, 68, 84, and 100. At each visit, clinical assessment was recorded on the case report forms, and samples were taken for laboratory assessment, including T-cell subsets and plasma HIV VL. Adverse events were classified and graded according to the Division of AIDS table for determining the grading of the severity of adult and pediatric adverse events.9 Pill counts were conducted at every visit by trained HIV-positive community health workers to determine the level of adherence.
(b) For VL measurements and HCV serology results, plasma was separated from whole blood by centrifugation within 4 hours of collection and was stored at −80°C until tested. The QUANTIPLEX HIV-1 RNA assay, version 3.0 (bDNA 3.0 assay), was performed according to the manufacturer's instructions. The limits of detection of the assay, indicated by the manufacturer, were 50-500,000 HIV-1 RNA copies per milliliter. HCV serology results were determined by contemporary HCV commercial enzyme immunoassays. HCV RNA was only measured in patients whose HCV antibody was positive. HCV RNA was measured using COBAS Amplicor HCV Monitor 2.0 (Roche Diagnostics) with a linear range of 600-700,000 IU/mL.
(c) For immunofluorescent surface staining and flow cytometric analysis, peripheral blood mononuclear cells were obtained by centrifugation. Subpopulations of CD3+, CD4+, and CD8+ cells were determined by 3-color flow cytometry (Beckman-Coulter, Brea, CA) at week 0 (baseline) and at the end of weeks 4, 12, 24, 36, 52, 68, 84, and 100. The following groups of monoclonal antibodies were used: PEcy5-CD4/PE-CD8/FITC-CD3 (CD4+/CD8+ T-cell counts). All monoclonal antibodies were purchased from Beckman-Coulter and Immunotech.
(d) Blood panels including liver function and serum lipids were administered by the clinical laboratory departments of each research center.
(e) Sample size and statistical analysis: All statistical analyses were performed using the SPSS 10.0 statistical package. To compare VL and lymphocyte T cells during follow-up among the 3 groups, analyses were performed using repeated measures of variance. The VL curve was denoted by mean and standard deviation. The CD4+ T-cell curve was expressed by median, 25th and 75th percentile. Using a χ2 test, we compared the rates of response among the treatment groups in terms of the percentage of patients with suppression of plasma HIV-1 RNA levels to less than 400 copies per milliliter and the percentage of patients less than 50 copies per milliliter. For all tests, P < 0.05 was considered to be statistically significant. Percentage of adherence for each ARV drugs was calculated using the following formula: percent adherence = (number of pills patient should have taken − number of pills missed) ÷ (number of pills patient should have taken) × 100%.10
Of the 362 subjects screened, 175 HIV+ ARV-naive patients were recruited into the study. Baseline characteristics of the groups are summarized in Table 1. The adherence rate was 95%. Fifty-eight patients (33.1%) were anti-HCV+. Of these, 34 (19.4%) were positive for HCV RNA. After 100 weeks of HAART, 15 patients (8.6%) were lost to follow-up. Forty-six patients (26.3%) were discontinued due to adverse reactions-8 (4.6%) due to severe rash, 5 (2.9%) because of severe gastrointestinal symptoms, and 27 (15.4%) for hepatoxicity. Six patients (3.4%) were discontinued for other reasons. Blood transmission was the main route of infection in anti-HCV+ patients. The percentage of males was higher in the anti-HCV− group and anti-HCV+ HCV RNA+ group than the anti-HCV+ HCV RNA− group. The anti-HCV+ HCV RNA− group also had a longer period of prior AIDS diagnosis than the other 2 groups. There were no significant differences, however, in the CD4+ T-cell counts and HIV RNA levels at baseline among the 3 groups.
Plasma VL Response
The changes in plasma VL during the 100 weeks of HAART among the 3 groups are shown in Figure 1. With intent-to-treat (ITT) analyses and per-protocol (PP) analyses, there were no significant differences among the 3 groups in the plasma VLs (PP analyses are not shown in Fig. 1). The magnitude of decline in HIV-1 VL among the 3 groups after HAART was similar. Also, there were no differences in the viral response rate between the 3 groups with plasma VL of less than 400 copies per milliliter, and patients with plasma VL of less than 50 copies per milliliter (ITT analyses shown in Fig. 2). The results of VL response rates by PP analysis (not shown) were similar to that in the ITT analysis. At the endpoint of the study, the percentage of patients who achieved plasma VL of <50 copies per milliliter was 34.2% in the anti-HCV− group, 29.2% in the anti-HCV+ HCV RNA− group, and 38.2% in the anti-HCV+ HCV RNA+ group (P = 0.646). The percentage of patients who achieved a plasma VL of <400 copies per milliliter was 81.6% in the anti-HCV− group, 87.5% in the anti-HCV+ HCV RNA− group, and 86.4% in the anti-HCV+ HCV RNA+ group (P = 0.477).
There were no statistical differences in the CD4+ T-cell counts, CD8+ T-cell counts, and CD4/CD8 ratios between the 3 groups during follow-up in the ITT analyses or PP analyses (CD4+ T-cell counts are shown in Fig. 3 by ITT analyses; the results of CD8+ T-cell count and CD4/CD8 ratio are not shown).
Clinical Outcomes and Adverse Events
Adverse events are shown in Table 2.
The incidence rate of rash was 12 of 117 (10.3%), 5 of 24 (20.8%), and 9 of 34 (26.5%), respectively, in the 3 groups. The incidence of rash in the HCV RNA+ group was significantly higher than the anti-HCV− group (P = 0.034).
Hepatotoxicity was assessed by an increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin (Tbil). The incidence rate of hepatotoxicity was 43 of 117 (36.8%), 5 of 24 (20.8%), and 24 of 34 (70.6%), respectively, in the 3 groups. The anti-HCV+ HCV RNA+ group had a higher incidence of hepatoxicity than the anti-HCV+ HCVRNA− and anti-HCV− groups (P = 0.001). The incidence rate of severe hepatotoxicity, as defined by grade 3 or 4 levels of ALT, AST, or Tbil, was 21 of 117 (17.9%), 3 of 24 (12.5%), and 9 of 34 (26.5%), respectively. However, there were no significant differences in the values of ALT, AST, and Tbil between the 3 groups.
There were also no significant differences in other adverse reactions such as hair loss, neutropenia, thrombocytopenia, hyperlipidemia, nausea, or anorexia.
Because HIV and HCV share transmission routes, dual infection is common.1 NVP-based ARV treatments are the most accessible regimens in developing countries, so understanding the ability of HCV+ patients to tolerate NVP is important. This was a prospective multicentric study to evaluate the influence of HCV coinfection on the efficacy and safety of NVP-containing HAART in Chinese HIV-1-infected patients over a 2-year follow-up period.
To our knowledge, this is the first study of the influence of HCV-HIV coinfection on adverse drug reactions to NVP-based HAART, and we provide a direct comparison between patients with viremia and those with self-limited HCV infection.
We found that HCV coinfection anti-HCV+ alone or anti-HCV+ HCV RNA+ did not influence the antiviral efficacy of HAART in VL suppression or improvement of CD4+ T-cell counts.
HCV coinfection did not seem to alter the extent of CD4+ T-cell decline because CD4+ T-cell counts were similar at baseline among the 3 groups and increased at the same rate after the initiation of HAART. This finding is in contrast to the result of a Swiss cohort,11 and other studies,5,6 which pointed to an impairment in CD4+ T-cell recovery in HCV-coinfected patients. Our study is in agreement with other results.7,8,12 A recent study within the EuroSIDA cohort indicated that neither HCV serostatus, nor HCV viremia, nor distinct HCV genotypes influenced the CD4 recovery in patients with HIV with maximum virological suppression after starting combination ARV therapy.13 These conflicting results could be explained by variations in demographic characteristics of patients. For example, our population were all Asian and did not inject drugs.
Subanalyses examining virological responses indicated no differences in the percentage of patients achieving HIV-1 VL of less than 50 copies per millimeter or in subsequent VL control among the 3 groups during follow-up. The overall virological responses to HAART were not affected by HCV serostatus in accordance with other studies.5,8,11
In our study, HCV viremia worsened adverse drug reactions in terms of rash and hepatoxicity with a higher incidence of rash in the HCV RNA+ group. A former study14 from our group indicated that hepatoxicity was associated with positive HCV antibody and a higher CD4+ T-cell baseline. However, it now seems that it is not simply a positive HCV antibody status that is associated with hepatotoxicity but HCV replication itself. Underlying chronic hepatitis C significantly increases the risks of hepatotoxicity during ARV therapy.15 This complication could lead to changes in ARV drug regimens or even treatment discontinuation.16 Labarga et al17 found that sustained HCV clearance after Interferon-based therapy reduced the risk of liver toxicity during ARV therapy, which supports the treatment of chronic hepatitis C in HIV-coinfected patients before commencement of ARV therapy.
Mild rash was also common in the HCV viremic patients in our study. We are the first to find that HCV viremia may increase the incidence of rash in HIV-infected patients treated with NVP-based ARV treatments. However, the mechanism is unclear.
There are some limitations to our study. HCV viremia in the absence of detectable HCV antibodies has been reported in HIV-infected individuals.18,19 We would have missed these patients as we measured HCV RNA only when HCV antibody was positive. We also did not analyze the HCV genotype.
In the baseline characteristics, the prior HIV/AIDS period of the anti HCV+ HCV RNA− group was longer than the other 2 groups. It is unclear if this might have any bearing on the results.
In conclusion, HCV/HIV coinfection does not seem to affect immunological or virological responses to HAART. HCV viremia, however, seems to exacerbate adverse reactions, such as rash and hepatoxicity, to NVP-based HAART. We suggest NVP not be used as part of a HAART regimen when HCV RNA replication exists. In addition, successful treatment of hepatitis C should perhaps be completed before commencing HAART. Increased attention is required to improve the prognosis in the HIV/HCV-coinfected patient.
We thank Charles Frank Farthing, MD, former US Director of Scientific Virology, US Director of Scientific Affairs, Virology, Merck & Co, Inc, North Wales, PA, for his assistance with the article. We thank Chen Ray, International Research Branch DAIDS/NIAID/NIH/DHHS, and Hanmo Li, University of Queensland, Australia, for their contributing to the article revise. We thank the study participants for their cooperation. The following clinical Institutions or Hospitals participated in this study: Beijing Youan Hospital; Beijing Ditan Hospital; The First Affiliated Hospital, Henan Medical University; Xian Tangdu Hospital; The second Affiliated Hospital, Xiangya Medical University; Shanghai Public Health center; Shenzhen CDC; and The 8th Hospital of Guangzhou; HIV/AIDS Care Center of Yunnan; Zhejiang Medical University.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
HCV; coinfection; HAART; HIV; AIDS