MAJOR ARTICLE

HIV/AIDS

Antiretroviral Therapy Reduces the Rate of Hepatic Decompensation Among HIV- and Hepatitis C Virus–Coinfected Veterans Jeffrey P. Anderson,1 Eric J. Tchetgen Tchetgen,1,2 Vincent Lo Re III,3,4 Janet P. Tate,5,6 Paige L. Williams,2 George R. Seage III,1 C. Robert Horsburgh,7,8 Joseph K. Lim,5,6 Matthew Bidwell Goetz,9,10 David Rimland,11,12 Maria C. Rodriguez-Barradas,13,14 Adeel A. Butt,15,16 Marina B. Klein,17 and Amy C. Justice5,6 Departments of 1Epidemiology and 2Biostatistics, Harvard School of Public Health, Boston, Massachusetts; 3Philadelphia Veterans Affairs Medical Center, and 4Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia; 5Veterans Affairs Connecticut Healthcare System, West Haven, and 6Yale School of Medicine, New Haven, Connecticut; 7Department of Epidemiology, Boston University School of Public Health, and 8Section of Infectious Diseases, Boston Medical Center, Boston University School of Medicine, Massachusetts; 9Veterans Affairs Greater Los Angeles Healthcare System, and 10David Geffen School of Medicine at UCLA, Los Angeles, California; 11Atlanta Veterans Affairs Medical Center, and 12Emory University School of Medicine, Atlanta, Georgia; 13Michael E. DeBakey Veterans Affairs Medical Center, and 14Baylor College of Medicine, Houston, Texas; 15University of Pittsburgh School of Medicine, Pennsylvania; 16Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates; and 17Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada

Background. Human immunodeficiency virus (HIV) coinfection accelerates the rate of liver disease outcomes in individuals chronically infected with hepatitis C virus (HCV). It remains unclear to what degree combination antiretroviral therapy (ART) protects against HCV-associated liver failure. Methods. We evaluated 10 090 HIV/HCV-coinfected males from the Veterans Aging Cohort Study Virtual Cohort, who had not initiated ART at entry, for incident hepatic decompensation between 1996 and 2010. We defined ART initiation as the first pharmacy fill date of a qualifying ART regimen of ≥3 drugs from ≥2 classes. Hepatic decompensation was defined as the first occurrence of 1 hospital discharge diagnosis or 2 outpatient diagnoses for ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage. To account for potential confounding by indication, marginal structural models were used to estimate hazard ratios (HRs) of hepatic decompensation, comparing initiation of ART to noninitiation. Results. We observed 645 hepatic decompensation events in 46 444 person-years of follow-up (incidence rate, 1.4/100 person-years). Coinfected patients who initiated ART had a significantly reduced rate of hepatic decompensation relative to noninitiators (HR = 0.72; 95% confidence interval [CI], .54–.94). When we removed individuals with HIV RNA ≤400 copies/mL at baseline from the analysis (assuming that they may have received undocumented ART at entry), the hazard ratio became more pronounced (HR = 0.59; 95% CI, .43–.82). Conclusions. Initiation of ART significantly reduced the rate of hepatic decompensation by 28%–41% on average. These results suggest that ART should be administered to HIV/HCV-coinfected patients to lower the risk of end-stage liver disease. Keywords.

HIV; hepatitis C; coinfection; hepatic decompensation; marginal structural model.

Liver complications, particularly those due to chronic hepatitis C virus (HCV) infection, have emerged as Received 22 May 2013; accepted 2 November 2013; electronically published 27 November 2013. Correspondence: Janet P. Tate, MPH, VA Connecticut Healthcare System, 950 Campbell Ave, West Haven, CT 06516 ([email protected]). Clinical Infectious Diseases 2014;58(5):719–27 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/cid/cit779

leading non-AIDS-related causes of morbidity and mortality among patients infected with human immunodeficiency virus (HIV) [1, 2]. HIV coinfection accelerates progression to clinical HCV-related liver outcomes, although the mechanisms have yet to be fully characterized [3]. Given the high prevalence of HIV/HCV coinfection in the United States (250 000–300 000 individuals) and the rapid HCV-associated fibrosis progression rate among coinfected patients, therapies to reduce the incidence of advanced liver disease are needed [4, 5].

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Although the benefits of combination antiretroviral therapy (ART) on the course of HIV disease have been well established, the effects of ART on the course of chronic HCV–related liver outcomes remain less clear. ART could help reduce the risk of HCV-associated hepatic decompensation by controlling HIVmediated immune dysfunction and dysregulation through CD4 T-lymphocyte recovery. This mechanism is consistent with prior studies suggesting that CD4 count gain and suppression of HIV RNA are associated with reduced rates of advanced hepatic fibrosis, cirrhosis, hepatic decompensation, and/or death due to end-stage liver disease [6–11], although not with others [12–14]. In contrast, immune reconstitution due to ART could exacerbate host-mediated hepatic inflammation and chronic antiretroviral-associated hepatotoxicity and subsequently increase the risk of hepatic decompensation [11, 15– 17]. Results from previous studies assessing the direct impact of ART on liver-related outcomes have been inconclusive [6, 18– 23]. Most have relied on cross-sectional analyses of liver biopsies, which can be susceptible to bias. Generally these studies have evaluated the stage or rate of fibrosis as the outcome of interest, and not clinical liver disease progression events. Given that HIV coinfection hastens liver disease progression in individuals with chronic HCV, elucidation of the impact of treating HIV on hepatic decompensation events in this population is warranted. However, studies using longitudinal data to evaluate the effects of clinical interventions on health outcomes are in general susceptible to biases. This is primarily because patient factors that predict the likelihood of treatment are also correlates of poor outcomes, and may in turn be affected by treatment (confounding by indication). Whereas standard regression methods will be inherently biased in this context, marginal structural models can be used to account for these biases and are preferred when confounding by indication may be present [24]. Thus, the primary goal of this study was to estimate the effect of ART initiation on the rate of hepatic decompensation in a large cohort of HIV/HCV-coinfected veterans, using marginal structural model methods.

METHODS Study Population

We evaluated HIV/HCV-coinfected patients in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC), an electronic medical records database of HIV-infected adults enrolled in the US Department of Veterans Affairs (VA) healthcare system from 1996 to the present [25]. This database contains demographic information, laboratory results, pharmacy data, clinical diagnoses (recorded using International Classification of Diseases, Ninth Revision [ICD-9] diagnostic codes), and dates of death. The pharmacy database includes information on

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medication fill dates, dosages, numbers dispensed, and dosing frequency. Dates of death were available from the VA vital status file, which records information from the Social Security Administration death master file, the Beneficiary Identification and Records Locator subsystem, and the VA medical Statistical Analysis Systems inpatient data sets. Patients were included in the analysis if they (1) had laboratory evidence of HIV infection (HIV antibody and RNA positive); (2) had a recorded diagnosis of HCV infection [26], a positive HCV antibody [27], and/or quantifiable HCV RNA; and (3) had not initiated ART at or prior to entry in the VA healthcare system. Patients were excluded if they (1) were female (given the small sample size and possible sex-based differences in HCV-associated liver disease progression rates); (2) had a baseline diagnosis of hepatic decompensation; (3) were on ART at VACS-VC entry; or (4) lacked follow-up visits (Figure 1). The VACS-VC has been granted a waiver of informed consent and has been approved by the institutional review boards (IRBs) of the VA Connecticut healthcare system and Yale University; this analysis was additionally approved by the IRB at the Harvard School of Public Health. Data Collection

Individuals were considered to have initiated ART on the filled prescription date of their first treatment regimen consisting of ≥3 antiretroviral medications from at least 2 different drug classes, or 3 nucleoside analogues. Until the first documented date these criteria were fulfilled, individuals were considered to be noninitiators. To account for the possibility that patients may have received undocumented antiretrovirals prior to entry in the VACS-VC, we repeated the primary analyses after removing from consideration patients with a baseline HIV RNA of ≤400 copies/mL yet no record of ART initiation. In a recent validation study within the VACS, this algorithm correctly identified 86% as truly ART-naive based on medical records review [28]. For all analyses, we assumed that patients stayed on ART once having initiated, for ease in interpretation and to parallel the intent-to-treat approach of a hypothetical clinical trial. Covariates included age at enrollment (years); calendar year at enrollment; race/ethnicity (white non-Hispanic, black nonHispanic, Hispanic, other/unknown); hepatitis B virus (HBV) coinfection; history of alcohol abuse; history of drug abuse; CD4 cell count (cells/µL); HIV RNA level (copies/mL); diabetes; FIB-4 score; pegylated interferon therapy for HCV; and AIDS-defining conditions. HBV coinfection status was determined by a positive test for HBV surface antigen at any time under observation. Alcohol and/or drug abuse were considered to be present if an individual had documented alcohol- and/or drug-related ICD-9 diagnosis codes [29]. FIB-4, a noninvasive index used to identify advanced hepatic fibrosis, was calculated

Figure 1. Study population flow diagram. Abbreviations: ART, antiretroviral therapy; HCV, hepatitis C virus; HD, hepatic decompensation; HIV, human immunodeficiency virus.

and categorized as described by Sterling et al [30]. Individuals were considered to have initiated HCV therapy at the filled prescription date for their first regimen of pegylated interferon lasting at least 28 days. AIDS-defining conditions were identified using ICD-9 diagnoses and established criteria [31]. HCV genotype (1, other) and HCV RNA (IU/mL) were additionally evaluated in preliminary analyses but removed from primary models due to a large proportion of missing data (61% and 60%, respectively) and a lack of observed associations of these factors with both ART initiation and hepatic decompensation. Outcome

The outcome under study was incident hepatic decompensation, defined as a primary hospital discharge diagnosis or ≥2 outpatient diagnoses for ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage. Determination of hepatic decompensation using this diagnostic algorithm was found to be highly valid in a previous study, with 91% of events confirmed via medical records [32]. The decompensation date was determined by the hospital admission date (if identified by discharge diagnosis) or initial outpatient diagnosis date (if identified by outpatient diagnoses). We did not include hepatic encephalopathy or nonobstructive jaundice, which might also indicate decompensation, as these diagnoses often identified unrelated conditions [32].

Statistical Analysis

The baseline date for analysis was considered to be the first visit on record with available values for both CD4 count and HIV RNA. Study patients were followed and considered to be at risk from the baseline date until the first occurrence of hepatic decompensation, death, censoring, or 30 September 2010. Individuals were conservatively considered to be lost to follow-up if there was any gap in observations of at least 1 year; these individuals were censored at their last prior visit. Values for CD4 count and HIV RNA were carried forward until a new measure was available but not for more than 1 year. Values for FIB-4 were carried forward indefinitely until an updated value was available. To reflect the reality that the clinical decision to initiate ART is based on previously available (and not simultaneous) values of covariates (ie, CD4 count precedes and informs treatment status), we lagged covariate values to ensure the proper sequence for analysis. To appropriately account for time-dependent confounding by indication, marginal structural (weighted Cox) models were constructed as previously described with minor modifications [33–35]. First, logistic regression models were constructed to calculate the likelihood of initiating ART at each time point, given an individual’s covariate history. Models for probabilities of death and censoring were similarly constructed to account for potential biases due to competing risks and/or differential loss to follow-up [33, 35]. These predicted probabilities were

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Table 1. Baseline Distributions of Selected Patient Characteristics and Time-Dependent Unadjusted Associations With Hepatic Decompensation

Table 1 continued.

Characteristic Characteristic

No. (%)a

Total patients Age, y

10 090 (100)

Unadjusted HR (95% CI)

20–39

1459 (14.5)

Referent

40–49 50–59

5364 (53.2) 2718 (26.9)

1.55 (1.19–2.00) 1.72 (1.30–2.27)

60–89

549 (5.4)

1.35 (.86–2.10)

Year at baseline 1996–2000

6780 (67.2)

Referent

2001–2009

.007

3310 (32.8)

0.82 (.68–1.00)

2703 (26.8)

Referent

Black non-Hispanic

6135 (60.8)

.048

0.69 (.58–.83)

9789 (97.0) 301 (3.0)

Referent 1.88 (1.54–2.29)