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Relationship Between Alcohol Use Categories and Noninvasive Markers of Advanced Hepatic Fibrosis in HIV-Infected, Chronic Hepatitis C Virus-Infected, and Uninfected Patients....findings suggest a little alcohol in HCV/HIV coinfected increased risk for advanced liver fibrosis, and among HCV or HIV monoinfected as well.
 
 
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Clinical Infectious Diseases May 15 2014
Joseph K. Lim,1,2 Janet P. Tate,1,2 Shawn L. Fultz,3 Joseph L. Goulet,1,2 Joseph Conigliaro,4 Kendall J. Bryant,5
Adam J. Gordon,6 Cynthia Gibert,7 Dav 1Veterans Affairs (VA) Connecticutid Rimland,8 Matthew Bidwell Goetz,9 Marina B. Klein,10 David A. Fiellin,2,11
Amy C. Justice,1,2,11 and Vincent Lo Re III12
 
Healthcare System, West Haven; 2Yale University School of Medicine, New Haven, Connecticut; 3Center for Tobacco Products, US Food and Drug Administration, Washington D.C.; 4Hofstra North Shore-LIJ School of Medicine and North Shore-LIJ Health System, Lake Success, New York; 5National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland; 6University of Pittsburgh and Pittsburgh VA Medical Center, Pennsylvania; 7Washington, DC, VA Medical Center and George Washington University Medical Center; 8Atlanta VA Medical Center and Emory University School of Medicine, Georgia; 9VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, Los Angeles, California; 10Chronic Viral Illness Service, McGill University Health Centre, Montreal, Canada; 11Yale Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, Connecticut; and 12Philadelphia VA Medical Center and Perelman School of Medicine, University of Pennsylvania
 
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"There may be no "safe" level of alcohol consumption among HIV+ and HCV+.....Advanced hepatic fibrosis was present at low levels of alcohol consumption, increased with alcohol use categories, and was greater in HIV-infected than uninfected individuals...... (Figure 2) for HCV mono infected advanced hepatic fibrosis was present ....in 1.3% "non-hazardous' drinkers ....... Among HCV/HIV connected: 14.2% "non-hazardous" drinkers had advanced liver fibrosis...... 'Co-infected individuals with nonhazardous drinking were 13 times more likely to have advanced liver fibrosis than uninfected persons who reported non-hazardous drinking'...... for HIV+ only 2.5% of "non-hazardous" drinkers......had advanced fibrosis...... Both HIV and HCV increased the strength of association between alcohol use and advanced hepatic fibrosis with strongest associations seen in HIV/HCV-coinfected patients with non-hazardous drinking (OR, 13.7"....... HIV and HCV can each induce hepatocyte apoptosis.... addition of alcohol may accelerate this process...... hepatic inflammation and fibrosis induced by alcohol may be additive in the setting of HIV-associated immune dysfunction/dysregulation and HCV-related liver inflammation....... Alternatively, the hepatotoxicity of antiretroviral and nonantiretroviral drugs may be exacerbated by alcohol consumption in the setting of HIV or chronic HCV infection"
 
CROI/2014 (same study): Level of Alcohol Use and Advanced Hepatic Fibrosis in HIV-Infected and Uninfected Patients...."there may be no safe level of alcohol use among HIV+ & HCV+"........http://www.natap.org/2014/CROI/croi_130.htm
 
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"Our study found that advanced hepatic fibrosis by FIB-4 was present at low levels of alcohol consumption across groups stratified by HIV/HCV status.
For each alcohol use category, advanced hepatic fibrosis was more common among HIV-infected than -uninfected and chronic HCV-infected than -uninfected patients. In addition, increasing categories of alcohol use were associated with a higher prevalence of advanced hepatic fibrosis among HIV/HCV-coinfected, HCV-monoinfected, HIV-monoinfected, and HIV/HCV-uninfected persons.......The strongest associations with advanced hepatic fibrosis were observed among HIV/HCV-coinfected patients with nonhazardous drinking (OR, 14.2; 95% CI, 5.91-34.0), hazardous/binge drinking (OR, 18.9; 95% CI, 7.98-44.8), and alcohol-related diagnoses (OR, 25.2; 95% CI, 10.6-59.7) compared with uninfected nonhazardous drinkers......Knowledge of the alcohol use category and its potential effects on various organ systems, such as the liver, might motivate patients to reduce or discontinue alcohol consumption. Second, given the strong associations between all alcohol use categories and advanced hepatic fibrosis among HIV/HCV-coinfected patients, clinicians should particularly counsel these patients to decrease their alcohol use, even with low levels of consumption. Finally, any patient with a FIB-4 >3.25 should be counseled to reduce or avoid alcohol consumption."
 
"Co-infected individuals with nonhazardous drinking were 13 times more likely to have advanced liver fibrosis than uninfected persons who reported non-hazardous drinking. Co-infected patients with a history of hazardous/binge drinking were 17 times more likely, whereas those who had alcohol-related diagnosis were 21 times more likely, to have advanced liver fibrosis compared to their uninfected non-hazardous drinking counterparts."
 
"The reasons for the higher prevalence of advanced hepatic fibrosis at each category of alcohol use among HIV-infected or chronic HCV-infected patients compared to uninfected persons remain unclear. In vitro data have demonstrated that HIV and HCV can each induce hepatocyte apoptosis [48], and the addition of alcohol may accelerate this process. Moreover, the hepatic inflammation and fibrosis induced by alcohol may be additive in the setting of HIV-associated immune dysfunction/dysregulation and HCV-related liver inflammation [49-51]. Alternatively, the hepatotoxicity of antiretroviral and nonantiretroviral drugs may be exacerbated by alcohol consumption in the setting of HIV or chronic HCV infection [52]."
 
'Participants reporting alcohol use on the AUDIT-C within the 12 months prior to enrollment were assigned, in a hierarchical manner, to 3 mutually exclusive alcohol consumption categories: (1) alcohol-related diagnosis, defined by an ICD-9 diagnosis for alcohol dependence/abuse recorded between 12 months before and 6 months after VACS enrollment; (2) hazardous or binge drinking in those without an alcohol-related diagnosis, defined as an AUDIT-C score ≥4 or report of consumption of ≥6 drinks on any 1 occasion in the past year; and (3) nonhazardous drinking, defined as an AUDIT-C score <4 [37-39]."
 
"Advanced fibrosis was more prevalent among HIV-infected than -uninfected (210 [9.9%] vs 61 [4.2%]"
 
Figure 1. Prevalence of advanced hepatic fibrosis (defined by FIB-4 index >3.25) according to category of alcohol use (ie, nonhazardous drinking, hazardous or binge drinking, alcohol-related diagnosis), by human immunodeficiency virus (HIV) and chronic hepatitis C virus (HCV) infection status, in patients reporting current alcohol use at enrollment in the Veterans Aging Cohort Study (N = 3565). *χ2 test for trend over categories of alcohol use for HIV/HCV-uninfected, P = .019. ^χ2 test for trend over categories of alcohol use for HCV-monoinfected, P < .001. †χ2test for trend over categories of alcohol use for HIV-monoinfected, P = .0025. ŗχ2 test for trend over categories of alcohol use for HIV/HCV-coinfected, P = .060.
 

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Figure 2. Odds ratio of advanced hepatic fibrosis (defined by FIB-4 index >3.25) for category of alcohol use (ie, nonhazardous drinking, hazardous or binge drinking, alcohol-related diagnosis), by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status, in patients reporting current alcohol use at enrollment in the Veterans Aging Cohort Study (N = 3565). Model adjusted for hepatitis B virus infection. Reference category is HIV/HCV-uninfected nonhazardous drinkers.

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Drinking poses greater risk for advanced liver disease in HIV/hep C patients
 
May 2 2014
http://medicalxpress.com
 
........Even light ("nonhazardous") drinking—which typically poses a relatively low risk for uninfected persons—was linked to an increased risk of liver fibrosis in the co-infected group.
 
Reasons for this are not fully understood, but preclinical studies have shown that the two viruses can induce liver cell death and that adding alcohol may accelerate that process and more quickly lead to severe liver fibrosis. Toxicity to the liver from antiretroviral drugs may also be exacerbated by alcohol.
 
"We've shown a much greater risk for coinfected compared to uninfected persons at all levels of alcohol consumption—from nonhazardous drinking up to hazardous/binge drinking and abuse/dependence," said senior author Vincent Lo Re III, MD, MSCE, assistant professor of Medicine and Epidemiology in the division of Infectious Diseases and department of Biostatistics and Epidemiology at Penn and an infectious disease physician at the Veteran Affairs Medical Center in Philadelphia. "This highlights how important it is for clinicians to be counseling co-infected patients on reducing alcohol consumption. More communication and education about the risks of alcohol may prompt patients to reduce drinking or quit altogether, which will help reduce the incidence of complications."
 
For the study, researchers, which included first author Joseph K. Lim, MD, of the Yale University School of Medicine and the Veterans Affairs Connecticut Healthcare System, conducted a cross-sectional study among 7,270 participants from the Veterans Aging Cohort Study: 701 HIV/HCV co-infected; 1,410 HIV-mono-infected; 296 HCV-mono-infected; and 1,158 uninfected. Alcohol use was determined by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire and diagnoses of alcohol abuse/dependence and classified as nonhazardous drinking, hazardous/binge drinking, and alcohol-related diagnosis.
 
The team found that regardless of HIV or HCV status, the prevalence of advanced hepatic fibrosis increased as alcohol use category increased. However, the strongest associations were observed in co-infected patients across all alcohol categories compared with uninfected non-hazardous drinkers.
 
Co-infected individuals with nonhazardous drinking were 13 times more likely to have advanced liver fibrosis than uninfected persons who reported non-hazardous drinking. Co-infected patients with a history of hazardous/binge drinking were 17 times more likely, whereas those who had alcohol-related diagnosis were 21 times more likely, to have advanced liver fibrosis compared to their uninfected non-hazardous drinking counterparts.
 
"The difference between co-infected and uninfected groups was stark. Given the prevalence of drinking in co-infected individuals, it is important to determine the patterns of alcohol use, such as nonhazardous drinking and even binge drinking, which are not traditionally thought to contribute to liver fibrosis," said Lo Re.
 
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Relationship Between Alcohol Use Categories and Noninvasive Markers of Advanced Hepatic Fibrosis in HIV-Infected, Chronic Hepatitis C Virus-Infected, and Uninfected Patients
 
Abstract
 
Background.
It is unclear if the risk of liver disease associated with different levels of alcohol consumption is higher for patients infected with human immunodeficiency virus (HIV) or chronic hepatitis C virus (HCV). We evaluated associations between alcohol use categories and advanced hepatic fibrosis, by HIV and chronic HCV status.
 
Methods. We performed a cross-sectional study among participants in the Veterans Aging Cohort Study who reported alcohol consumption at enrollment (701 HIV/HCV-coinfected; 1410 HIV-monoinfected; 296 HCV-monoinfected; 1158 HIV/HCV-uninfected). Alcohol use category was determined by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire and alcohol-related diagnoses and was classified as nonhazardous drinking, hazardous/binge drinking, or alcohol-related diagnosis. Advanced hepatic fibrosis was defined by FIB-4 index >3.25.
 
Results. Within each HIV/HCV group, the prevalence of advanced hepatic fibrosis increased as alcohol use category increased. For each alcohol use category, advanced hepatic fibrosis was more common among HIV-infected than uninfected (nonhazardous: 6.7% vs 1.4%; hazardous/binge: 9.5% vs 3.0%; alcohol-related diagnosis: 19.0% vs 8.6%; P < .01) and chronic HCV-infected than uninfected (nonhazardous: 13.6% vs 2.5%; hazardous/binge: 18.2% vs 3.1%; alcohol-related diagnosis: 22.1% vs 6.5%; P < .01) participants. Strong associations with advanced hepatic fibrosis (adjusted odds ratio [95% confidence interval]) were observed among HIV/HCV-coinfected patients with nonhazardous drinking (14.2 [5.91-34.0]), hazardous/binge drinking (18.9 [7.98-44.8]), and alcohol-related diagnoses (25.2 [10.6-59.7]) compared with uninfected nonhazardous drinkers.
 
Conclusions. Advanced hepatic fibrosis was present at low levels of alcohol consumption, increased with higher alcohol use categories, and was more prevalent among HIV-infected and chronic HCV-infected patients than uninfected individuals. All alcohol use categories were strongly associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients.
 
Alcohol consumption is prevalent among human immunodeficiency virus (HIV)-infected [1-3] and chronic hepatitis C virus (HCV)-infected [4] patients and is an important contributor to progression of liver fibrosis in these groups [5, 6]. Excessive alcohol intake is associated with a range of hepatic manifestations, including hepatic inflammation, fibrosis, and steatosis, which can lead to cirrhosis and hepatic decompensation [7].
 
Despite the acknowledged impact of alcohol on the liver, few studies have evaluated the effects of different patterns of alcohol consumption on liver disease, particularly among persons with HIV or chronic HCV. Furthermore, it is unclear if the risk of liver disease associated with each level of alcohol use is higher for those with HIV or chronic HCV. Given the prevalence of alcohol consumption in these groups [1, 2, 4], it is important to determine if certain patterns of alcohol use—such as nonhazardous and binge drinking, which are traditionally not thought to contribute to hepatic fibrosis—are harmful to the liver, and more so for those infected with HIV or chronic HCV.
 
Although biopsy has been the gold standard for staging liver disease, it is not feasible to perform liver biopsies in large cohort studies because of the costs and risks to patients [8]. Noninvasive markers of hepatic fibrosis have been valuable for evaluating liver disease in population-based studies [9], particularly in HIV-infected cohorts [10-12]. The FIB-4 index (based on liver aminotransferases, platelet count, and age) is a noninvasive, validated measure of advanced hepatic fibrosis in patients with chronic liver disease, including alcoholic liver disease [13], viral hepatitis [14-17], and HIV/viral hepatitis coinfection [18], and can predict liver-related mortality among HCV-monoinfected [19-21] and HIV/HCV-coinfected patients [20, 21].
 
Our objective was to evaluate the association between alcohol use categories and advanced hepatic fibrosis, determined by FIB-4 index, by HIV and chronic HCV status among participants in the Veterans Aging Cohort Study (VACS), an ongoing cohort established to examine the effects of alcohol and comorbidities on health outcomes [22]. We hypothesized that for each category of alcohol use, the prevalence of advanced fibrosis would be greater in persons infected with HIV or chronic HCV compared with uninfected persons. We also examined associations between alcohol use categories and advanced hepatic fibrosis among HIV/HCV-coinfected, HIV-monoinfected, HCV-monoinfected, and HIV/HCV-uninfected patients, to gain insights into the effects of HIV, chronic HCV, and alcohol use on significant liver fibrosis.
 
DISCUSSION
 
Our study found that advanced hepatic fibrosis by FIB-4 was present at low levels of alcohol consumption across groups stratified by HIV/HCV status. For each alcohol use category, advanced hepatic fibrosis was more common among HIV-infected than -uninfected and chronic HCV-infected than -uninfected patients. In addition, increasing categories of alcohol use were associated with a higher prevalence of advanced hepatic fibrosis among HIV/HCV-coinfected, HCV-monoinfected, HIV-monoinfected, and HIV/HCV-uninfected persons. Alcohol use category remained independently associated with advanced hepatic fibrosis in both HIV-infected and -uninfected persons. Finally, when we evaluated associations between alcohol use categories and advanced hepatic fibrosis across groups stratified by HIV/HCV status, the strongest associations were observed among those with HIV/HCV coinfection. These results provide new data that suggest that there is a stepwise increased risk of advanced liver fibrosis with greater severity of alcohol use. They also demonstrate that all alcohol use categories are strongly associated with advanced hepatic fibrosis in HIV/HCV-coinfected patients.
 
The reasons for the higher prevalence of advanced hepatic fibrosis at each category of alcohol use among HIV-infected or chronic HCV-infected patients compared to uninfected persons remain unclear. In vitro data have demonstrated that HIV and HCV can each induce hepatocyte apoptosis [48], and the addition of alcohol may accelerate this process. Moreover, the hepatic inflammation and fibrosis induced by alcohol may be additive in the setting of HIV-associated immune dysfunction/dysregulation and HCV-related liver inflammation [49-51]. Alternatively, the hepatotoxicity of antiretroviral and nonantiretroviral drugs may be exacerbated by alcohol consumption in the setting of HIV or chronic HCV infection [52]. Future studies should evaluate the mechanisms by which alcohol contributes to liver disease progression in HIV-monoinfected, HCV-monoinfected, and HIV/HCV-coinfected patients.
 
Our results have several clinical implications. First, the 3-item AUDIT-C questionnaire could be administered by HIV practitioners during routine practice to ascertain and categorize patients' alcohol consumption [38]. Knowledge of the alcohol use category and its potential effects on various organ systems, such as the liver, might motivate patients to reduce or discontinue alcohol consumption. Second, given the strong associations between all alcohol use categories and advanced hepatic fibrosis among HIV/HCV-coinfected patients, clinicians should particularly counsel these patients to decrease their alcohol use, even with low levels of consumption. Finally, any patient with a FIB-4 >3.25 should be counseled to reduce or avoid alcohol consumption.
 
Our results extend the observations of 2 prior studies examining the relationship between alcohol consumption and advanced liver fibrosis in HIV-infected patients. Chaudhry et al [6] conducted a cross-sectional study within the Johns Hopkins HIV Clinical Cohort and observed that hazardous drinking was associated with an APRI >1.5 in HIV-monoinfected, but not HIV/HCV-coinfected, patients. Fuster et al [53] performed a cross-sectional analysis among HIV-infected patients with current or past alcohol problems enrolled in the HIV-Longitudinal Interrelationships of Viruses and Ethanol (HIV-LIVE) study. No association was observed between lifetime alcohol use and either FIB-4 >3.25 or APRI >1.5, regardless of HCV status. Differences in the way that alcohol use was categorized and the smaller samples of patients who reported alcohol consumption in those studies might account for the disparate results. Neither study included HIV-uninfected patients, as was done in the present analysis.
 
Our study has several potential limitations. First, because cross-sectional studies evaluate exposure and disease status simultaneously, our analysis is limited in its ability to determine whether alcohol use category preceded or resulted from advanced hepatic fibrosis. Being informed about the presence of hepatic fibrosis, either through invasive or noninvasive modalities, may prompt patients to decrease or cease alcohol consumption. Because of this phenomenon of sick abstainers, we chose to exclude participants who did not report current alcohol use. Among current drinkers, reverse causality seems less likely. The cross-sectional design also did not permit us to evaluate changes in hepatic outcomes over time.
 
Second, we cannot exclude the possibility that some individuals were misclassified by FIB-4 due to conditions that can decrease the platelet count or that transiently increase liver aminotransferase levels. However, FIB-4 has been validated to identify advanced hepatic fibrosis among individuals with alcoholic liver disease [13], viral hepatitis [14-17], and HIV/viral hepatitis coinfection [18]. Further, we conducted parallel analyses evaluating APRI, liver inflammation, and hepatic decompensation and observed consistent results and relationships. Hepatic fibrosis would ideally be assessed with liver biopsy, but the acceptability, cost, and risk of liver biopsy in large cohorts of patients make such a study impractical. Further, liver biopsy itself is an imperfect measure as it is subject to sampling error and interobserver variability in histological assessment [54, 55]. Future studies could use other noninvasive modalities, such as transient elastography, to assess the degree of hepatic fibrosis [56].
 
Third, as with any observational study, there is the possibility of residual confounding. We were unable to account for lifetime history of alcohol consumption [57], but such measures are currently unable to classify patterns of alcohol use [58]. We also did not have durations of HIV or HCV infections and did not collect all potential hepatotoxic medications.
 
Finally, our study sample was predominantly comprised of male US veterans of black race, potentially limiting the generalizability of our results. Because liver fibrosis progression may differ by sex and race [59-61], future epidemiologic analyses should evaluate the relations between alcohol use categories and hepatic outcomes among women and persons of other races. In summary, our findings suggest that increased category of alcohol use is associated with a correspondingly higher risk of advanced hepatic fibrosis. In addition, for each category of alcohol use, advanced hepatic fibrosis was more common among persons infected with HIV or chronic HCV than among uninfected individuals. Strong associations between all categories of alcohol use and advanced hepatic fibrosis were observed among HIV/HCV-coinfected patients. Future longitudinal studies should evaluate the mechanisms for the increased liver injury associated with alcohol consumption in the setting of HIV and chronic HCV infection and characterize the impact of nonhazardous alcohol consumption and binge drinking on liver fibrosis progression over time to help determine whether there is a safe level of alcohol exposure.
 
PATIENTS AND METHODS
 
Study Design and Data Source

 
We conducted a cross-sectional study among participants receiving medical care at 1 of 8 VACS sites (Veterans Health Administration [VA] facilities in Atlanta, Georgia; Baltimore, Maryland; Bronx, New York; Houston, Texas; Los Angeles, California; Manhattan, New York; Pittsburgh, Pennsylvania; Washington, D.C.) [22]. VACS follows HIV-infected patients group matched in a 1:1 ratio to uninfected patients by age, sex, race/ethnicity, and clinical site. At enrollment, participants complete a standardized questionnaire that collects demographic information, alcohol use (determined using the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] questionnaire [23-25]), and other self-reported behaviors. VACS also extracts VA electronic medical record data, including body mass index (BMI), diagnoses (recorded using International Classification of Diseases, Ninth Revision [ICD-9] diagnostic codes), procedures, laboratory results, and VA-dispensed medications [26]. Approval was obtained by the institutional review boards at each participating VA medical center.
 
Study Participants
 
Patients enrolled in the VACS between 1 June 2002 and 30 September 2010 and reporting alcohol consumption on the AUDIT-C at enrollment were eligible for inclusion. Participants were excluded if they (1) denied alcohol use in the prior 12 months or (2) did not have laboratory results available to determine FIB-4 index at enrollment. We excluded patients who did not consume alcohol to avoid inclusion of sick abstainers (ie, persons who avoid drinking alcohol because of former alcohol abuse, knowledge of the presence of advanced hepatic fibrosis, or concerns regarding alcohol's interactions with prescribed medications), which could bias results [27].
 
Main Study Outcomes
 
The primary outcome was advanced hepatic fibrosis, determined by FIB-4 index. FIB-4 is calculated using aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, and age as follows: (age [years] x AST [U/L])/((platelet count [109/L]) x (ALT [U/L])1/2) [18]. A FIB-4 index >3.25 has been shown to identify advanced hepatic fibrosis (Metavir stage F3 or F4) with a high degree of accuracy in patients with alcoholic liver disease (area under the receiver-operating characteristic curve [AUROC], 0.70-0.80) [13], viral hepatitis (AUROC, 0.85-0.91) [14-17], and HIV/viral hepatitis coinfection (AUROC, 0.77) [18]. FIB-4 was calculated using age at VACS enrollment and AST, ALT, and platelet count results measured closest to, but between 12 months before and 6 months after, enrollment. We used the established cutoff of FIB-4 index >3.25 to define advanced hepatic fibrosis [14-16, 18].
 
To further examine the relationship between alcohol use categories and liver disease, we evaluated 3 secondary outcomes: (1) significant liver fibrosis determined by AST-to-platelet ratio index (APRI) >1.5, (2) hepatic inflammation, and (3) hepatic decompensation. APRI is calculated using AST and platelet count: ([AST [U/L]/upper limit of normal [considered as 40 U/L])/platelet count (109/L)] x 100 [28]. An APRI >1.5 accurately identifies significant liver fibrosis (Metavir stage F2-F4) in chronic liver diseases [13, 14, 17, 28-32]. Hepatic inflammation was defined by serum levels of either AST or ALT >40 U/L, as this cutoff reflects a clinically meaningful level of hepatocellular injury [33, 34]. Hepatic decompensation was defined by medical record-confirmed diagnoses of ascites, spontaneous bacterial peritonitis, esophageal variceal hemorrhage, or hepatic encephalopathy [35, 36].
 
Alcohol Use Categories
 
Alcohol use at enrollment was categorized using responses to AUDIT-C questions and diagnoses of alcohol-related conditions [37, 38]. AUDIT-C is a 3-item screening test evaluating alcohol consumption within the prior year (ie, frequency of alcohol use, quantity of alcohol consumed, and consumption of ≥6 drinks on 1 occasion [binge drinking]) [23]. This instrument has good operating characteristics for the detection of nonhazardous, hazardous, and binge drinking, but not for the diagnosis of alcohol abuse or dependence [23-25]. Diagnoses of alcohol-related conditions (defined by ICD-9 codes 291.x, 303.x, and 305.0) have been shown to accurately identify active alcohol dependence/abuse [39]. Because neither AUDIT-C nor alcohol-related diagnoses can individually capture all levels of alcohol consumption, we used both measures to categorize alcohol use. The need, feasibility, and validity of using both psychometric and diagnostic measures of alcohol consumption have previously been established [40-43], and this methodology minimizes exposure misclassification. Participants reporting alcohol use on the AUDIT-C within the 12 months prior to enrollment were assigned, in a hierarchical manner, to 3 mutually exclusive alcohol consumption categories: (1) alcohol-related diagnosis, defined by an ICD-9 diagnosis for alcohol dependence/abuse recorded between 12 months before and 6 months after VACS enrollment; (2) hazardous or binge drinking in those without an alcohol-related diagnosis, defined as an AUDIT-C score ≥4 or report of consumption of ≥6 drinks on any 1 occasion in the past year; and (3) nonhazardous drinking, defined as an AUDIT-C score <4 [37-39].
 
Demographic and Clinical Data
 
Demographic data collected at VACS enrollment included age, sex, and race/ethnicity. Clinical data collected between 12 months before and 6 months after enrollment included BMI, chronic HCV infection (detectable HCV RNA); active hepatitis B virus (HBV) infection (positive HBV surface antigen and/or detectable HBV DNA); history of other chronic liver diseases (ICD-9 diagnosis of nonalcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis, α-1 antitrypsin deficiency, or Wilson disease); diabetes mellitus (random glucose ≥200 mg/dL, diabetes ICD-9 diagnosis, or antidiabetic medication use [44, 45]); HIV-related data (CD4 count; HIV RNA level; use of antiretroviral therapy [ART], defined as at least 3 antiretrovirals from 2 different classes [46]; and ART regimen); ALT; AST; and platelet count. Laboratory results measured closest to but between 12 months before and 6 months after enrollment were used in analyses. We evaluated for the presence of hepatic decompensation at VACS enrollment as previously described [47].
 
Statistical Analysis
 
Differences in characteristics by HIV and chronic HCV status were assessed using χ2 tests for categorical data and t tests or Wilcoxon rank-sum tests, as appropriate, for continuous data. We determined differences in the prevalence of outcomes for each category of alcohol use, by HIV and chronic HCV status. Next, we used logistic regression to determine the adjusted odds ratio (OR) and 95% confidence interval (CI) of advanced hepatic fibrosis associated with alcohol use categories, stratified by HIV status. Models were adjusted for sex, race, BMI, diabetes, HBV infection, chronic HCV, and CD4 count and HIV RNA level (HIV-infected stratum). We did not control for age because age is a component of the FIB-4 index.
 
We then evaluated the prevalence of advanced fibrosis for each alcohol use category among HIV/HCV-coinfected, HIV-monoinfected, HCV-monoinfected, and HIV/HCV-uninfected participants. We determined adjusted ORs of advanced hepatic fibrosis associated with the alcohol use categories in these 4 groups. Associations were assessed with a 12-level HIV/HCV and alcohol use category variable (4 HIV/HCV groups x 3 alcohol levels). HIV/HCV-uninfected nonhazardous drinkers served as the reference group for all comparisons. Analyses were performed using SAS software, version 9.2 (SAS Institute, Cary, North Carolina).
 
RESULTS
 
Participant Characteristics

 
Among the 7270 participants enrolled in VACS through September 2010, 4611 (63%; 2311 HIV-infected vs 2300 HIV-uninfected; P = .7) reported alcohol consumption within the 12 months prior to enrollment, and 5784 (80%; 3312 HIV-infected vs 2472 HIV-uninfected; P < .001) had laboratory data available to calculate FIB-4. The final study sample included 3565 current drinkers with available FIB-4 data (701 HIV/HCV-coinfected; 1410 HIV-monoinfected; 296 HCV-monoinfected; 1158 HIV/HCV-uninfected), of whom 1479 (41.5%) met criteria for nonhazardous drinking, 1232 (34.6%) for hazardous/binge drinking, and 854 (24.0%) for an alcohol-related diagnosis (Table 1). Compared with those excluded due to lack of FIB-4 data, patients included in the study sample were older; more commonly black, Hispanic, and infected with HIV or viral hepatitis; and less frequently obese (BMI > 30 kg/m2). The groups were similar for all other characteristics listed in Table 1.
 
Compared to HIV-uninfected persons, those with HIV were younger (median, 48 vs 50 years), more commonly black (66.2% vs 62.4%), and more frequently infected with HBV (4.3% vs 1.8%) or chronic HCV (30.6% vs 18.9%), but less commonly had diabetes mellitus (10.6% vs 16.9%) or obesity (14.1% vs 37.6%). Twenty-three percent of HIV-infected patients had a CD4 count <200 cells/ĶL, and 83% received ART. As alcohol use category increased, the mean CD4 count decreased (nonhazardous: 417 cells/ĶL; hazardous/binge: 402 cells/ĶL; alcohol-related diagnosis: 384 cells/ĶL; test for trend, P = .04) and mean HIV RNA level increased (nonhazardous: 3.1 log copies/mL; hazardous/binge: 3.2 log copies/mL; alcohol-related diagnosis: 3.3 copies/L; test for trend, P = .01).
 
Advanced Hepatic Fibrosis, by HIV and Chronic HCV Status
 
Overall, 271 (7.6%) participants had advanced hepatic fibrosis (FIB-4 >3.25). Advanced fibrosis was more prevalent among HIV-infected than -uninfected (210 [9.9%] vs 61 [4.2%]; P < .001) and chronic HCV-infected than -uninfected (182 [18.3%] vs 89 [3.5%]; P < .001) patients. Among HIV-infected and -uninfected (Table 2) and chronic HCV-infected and -uninfected (Table 2) participants, the prevalence of advanced hepatic fibrosis increased as the category of alcohol use increased, with the lowest prevalence among nonhazardous drinkers, an increased prevalence among participants who reported hazardous/binge drinking, and the highest prevalence among those with an alcohol-related diagnosis. For each category of alcohol use, HIV-infected (Table 2) or chronic HCV-infected (Table 2) patients more commonly had advanced hepatic fibrosis than uninfected patients. Similar patterns were observed for significant liver fibrosis, hepatic inflammation, and hepatic decompensation (Table 2).
 
In multivariable analyses, category of alcohol use remained independently associated with advanced hepatic fibrosis in HIV-infected (P = .001) and -uninfected (P = .003) persons (Table 3). Results were similar when the outcome was significant liver fibrosis (APRI >1.5; Supplementary Appendix 1).
 
The prevalence of advanced hepatic fibrosis increased with higher alcohol use category among HIV/HCV-coinfected, HIV-monoinfected, HCV-monoinfected, and HIV/HCV-uninfected patients (Figure 1). For each alcohol use category, the prevalence of advanced hepatic fibrosis was highest among HIV/HCV-coinfected participants. In multivariable analysis, the ORs of advanced hepatic fibrosis increased with greater severity of alcohol use categories within each of the 4 groups (Figure 2; Supplementary Appendix 2). The strongest associations with advanced hepatic fibrosis were observed among HIV/HCV-coinfected patients with nonhazardous drinking (OR, 14.2; 95% CI, 5.91-34.0), hazardous/binge drinking (OR, 18.9; 95% CI, 7.98-44.8), and alcohol-related diagnoses (OR, 25.2; 95% CI, 10.6-59.7) compared with uninfected nonhazardous drinkers.
 
 
 
 
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