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Alcohol & HIV Progression
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Article follows press release.
Study shows link between alcohol consumption and HIV disease progression
(Release from BU) - Researchers from Boston University School of Medicine (BUSM) have found a link between alcohol consumption and HIV disease progression in HIV-infected persons. The study appears online in the August issue of the Journal of Acquired Immune Deficiency Syndromes.
Alcohol use is common among HIV-infected persons, and its impact on HIV disease progression has been examined in in-vitro, animal and human studies. Alcohol may adversely affect immunologic function in HIV-infected persons by various mechanisms, including increased HIV replication in lymphocytes.
Researchers assessed CD4 cell counts, HIV RNA levels [viral load], and alcohol consumption in 595 HIV-infected persons with alcohol problems. The relation of HIV disease progression to alcohol consumption was studied using longitudinal regression models controlling for known prognostic factors, including adherence and depressive symptoms, and stratified by antiretroviral therapy (ART) use. Among subjects who were not on ART, heavy alcohol consumption was associated with a lower CD4 cell count. Among subjects who were on ART, heavy alcohol consumption was not associated with a lower CD4 cell count or higher HIV viral load. "
Alcohol use in patients with a prevalent disease such as HIV, can have important public health consequences," said lead author Jeffrey Samet, MD, MPH, a professor of medicine at BUSM and chief of General Internal Medicine at Boston Medical Center. "HIV-infected persons who drink alcohol heavily and are not on ART might decrease their risk of disease progression if they abstain from alcohol use."
Researchers further noted that there is extensive evidence about the efficacy of a brief intervention for unhealthy alcohol use in nondependent drinkers in medical settings and of the efficacy of psychosocial and pharmacologic treatments for alcohol dependence. "Although limited evidence demonstrates the effectiveness of intervention for alcohol problems specifically in people with HIV, its implementation among HIV-infected populations seems to be a worthwhile goal," according to senior author Richard Saitz, MD, MPH, professor of medicine at BUSM, director of the Clinical Addiction Research and Education Unit at Boston Medical Center, and associate director of the Boston University School of Public Health Youth Alcohol Prevention Center.
Alcohol Consumption and HIV Disease Progression
J Acquir Immune Defic Syndr Epub 2007
Jeffrey H. Samet, MD, MA, MPH,* Debbie M. Cheng, ScD,* Howard Libman, MD, David P. Nunes, MD,k Julie K. Alperen, DrPh,* and Richard Saitz, MD, MPH*
Objective: To assess the relation between alcohol consumption and
laboratory markers of HIV disease progression.
Methods: We prospectively assessed CD4 cell counts, HIV RNA levels, and alcohol consumption for up to 7 years in 595 HIV-infected persons with alcohol problems recruited between 1997 and 2003. We investigated the relation of these markers of HIV disease progression to alcohol consumption using longitudinal regression models controlling for known prognostic factors, including adherence and depressive symptoms, and stratified by antiretroviral therapy (ART) use.
Results: Among subjects who were not on ART, heavy alcohol consumption was associated with a lower CD4 cell count (adjusted mean decrease of 48.6 cells/mL compared with abstinence; P = 0.03) but not with higher log10 HIV RNA. Among subjects who were on ART, heavy alcohol consumption was not associated with a lower CD4 cell count or higher log10 HIV RNA.
Conclusions: Heavy alcohol consumption has a negative impact on the CD4 cell count in HIV-infected persons not receiving ART. In addition to the known deleterious effects of alcohol on ART adherence, these findings suggest that avoiding heavy alcohol consumption in patients not on ART may have a beneficial effect on HIV disease progression.
Alcohol use is common among HIV-infected persons,5-7 and its impact on HIV disease progression has been examined in in vitro, animal, and human studies. Alcohol can adversely affect immunologic function in HIV-infected persons by
various mechanisms,8 including increased HIV replication in lymphocytes.9,10 Research on the impact of alcohol on simian immunodeficiency virus (SIV) demonstrates increased viral loads in infected rhesus monkeys given intoxicating levels of alcohol at the time of viral inoculation compared with controls that received no alcohol.11-16 These data indicate that the viral set point is increased and clinical deterioration is more rapid in alcohol-exposed monkeys.
In humans, the literature shows mixed effects of alcohol. Evidence from a large observational cohort of homosexual men, the Multicenter AIDS Cohort Study (MACS), before the advent of highly active ART, found no association between alcohol use and HIV disease progression.17 We previously published
cross-sectional data suggesting a negative impact of alcohol use on HIV disease progression in the era of highly active ART.18 Alcohol consumption was associated with lower CD4 cell counts and higher HIV viral loads among those receiving ART. No comparable association was found for similar patients not on ART, however.
In this study, we report on the impact of alcohol use among HIV-infected persons with current or past alcohol problems prospectively assessed for up to 7 years to test the following hypothesis: alcohol consumption is independently associated with more rapid HIV disease progression as measured by the CD4 cell count and HIV viral load (HIV RNA).
Primary Independent Variable
The main independent variable, alcohol consumption in the past 30 days, which was categorized as heavy, moderate, or abstinent, was assessed using a validated calendar method.25 The ''heavy'' category was derived from the National Institute on Alcohol Abuse and Alcoholism definition of amounts that
risk consequences (>14 drinks per week or >/=5 drinks on a single occasion for men <66 years old and >7 drinks per week or >/=4 drinks on a single occasion for men >/=66 years old and all women).26 ''Moderate'' alcohol use was defined as any drinking less than heavy amounts.
RESULTS
Characteristics for the cohort (n = 595) at study entry and stratified by level of alcohol consumption are listed in Table 1. The cohort included 25% women, 66% nonwhites, and 27% homeless persons, with a mean age of 41 years. Injection drug use was the HIV risk behavior in more than half of the subjects; for the remainder, the risk behavior was divided between MSM and heterosexual sex. Assessment of alcohol use in the past 30 days revealed heavy consumption in 30% of subjects and moderate consumption in 10%; 59% of subjects were
abstinent. One quarter (128 of 595) of all subjects used alcohol and illicit drugs (heroin or cocaine), 19% used alcohol alone, and 15% used heroin or cocaine alone. The average daily alcohol consumption of subjects drinking in the past 30 days was 5.4 drinks. Of subjects with a history of injection drug use, 32% (114 of 354) had injected drugs in the previous 6 months.
The median number of assessment time points per subject was 9, and the maximum was 15. The number of observations included in the analyses for CD4 cell count was 1475 for the on ART group and 384 for the not-on-ART group (1273 and 350 respectively for the CD4% secondary outcome). The number of
observations included in the analyses for HIV RNA was 1808 and 603 for the on ART group and for the not-on-ART group, respectively. The number of outcomes in the CD4 analyses was less than that in the HIV RNA analyses, because the former adjusted for baseline CD4 cell count. Thus, CD4 analyses only included outcome data from follow-up assessments. Seventy-three percent (1360 of 1859) of the CD4 test results and 71% (1710 of 2411) of the HIV RNA test results were collected within 1 month of the interview.
The results of the 6 regression analyses are presented in Table 2. Among those subjects not on ART, CD4 cell counts averaged 48.6 cells/mL lower for those with heavy alcohol use compared with abstinence (P = 0.03). Note that this difference does not represent change over time within individual subjects
but, instead, the average difference between subjects with heavy alcohol use compared with abstinence across all time points, adjusting for baseline CD4 cell count among other covariates. There was not a significant association, however, between heavy alcohol consumption and viral load for subjects not on ART. No association was observed for moderate drinking and any of the outcomes in the not-on-ART group.
For subjects on ART, no significant association was found for the primary outcomes at any level of alcohol consumption. Because depressive symptoms have been shown to be associated with HIV disease progression, we controlled for the CES-D score in our main analyses as a potential confounder. Because depression may be in the causal pathway between alcohol and HIV disease progression, however, we fit additional models without the CES-D score. In these analyses, among subjects not on ART, similar results were found (CD4 cell counts were an average of 58.4 cells/mL lower for those with heavy alcohol use compared with abstinence; P = 0.02).
Among subjects on ART, nonsignificantly higher log10 HIV RNA was found in those with heavy alcohol consumption compared with those who abstained (adjusted mean increase = 0.13; P = 0.09).
The secondary outcome, CD4%, did not show any significant relation with alcohol consumption in either group (in the analyses adjusted for depressive symptoms; see Table 2).
DISCUSSION
The findings demonstrate a clinically and statistically significant effect of heavy alcohol consumption on the CD4 cell count among persons not on ART. Controlling for medication adherence, this effect was not observed in those receiving ART.
Previous efforts to examine this relation in HIV-infected persons have been limited by the study design (eg, crosssectional) 18 or timing (eg, before the advent of highly active ART).17,31 The current study prospectively examined alcohol consumption at 6-month intervals among HIV-infected persons selected on the basis of alcohol use. Use of a cohort with past or current alcohol problems was chosen, because a hypothesized modest effect of alcohol on HIV disease
progression would require a relatively large study population, careful alcohol measurement, and subjects with heavier levels of alcohol consumption. Other factors, including psychosocial issues, known to be associated with HIV disease progression were measured and controlled for in the multivariable analyses
to assess the independent effect of heavy or moderate alcohol consumption on markers of HIV disease progression. This study comprehensively assessed alcohol consumption using validated self-report instruments;25 extended follow-up; and inclusion of multiple time-varying covariates in the regression analyses, including measures of ART adherence and depressive symptoms.
The finding of an impact on the CD4 cell count in subjects not on ART supports the study hypothesis that alcohol consumption has a direct effect on HIV disease progression. The impact seems to be relatively modest, however, and was
not observed for moderate drinking or among persons on ART after controlling for adherence and other known associations with HIV disease progression. It may be difficult to detect a modest effect of heavy drinking on CD4 cell count among those on ART, because the large beneficial effect of ART on CD4 cell count may overcome any deleterious effect of alcohol. Only 10% of the cohort reported moderate levels of alcohol consumption. Such a low prevalence of moderate alcohol use is not surprising, given the fact that most of the subjects in this cohort met criteria for lifetime alcohol dependence. Individuals with current or past alcohol dependence are likely to abstain or drink heavily.32 The modest number of moderate drinkers in the cohort limited our ability to assess the impact of moderate alcohol consumption on HIV disease progression, however. In particular, among subjects not on ART, we are unable to conclude that there is no effect of moderate drinking because it is likely that the study was underpowered to detect effects of the observed magnitude. Nevertheless, it is noteworthy that the magnitude and direction of the CD4 cell count change among those on ART with moderate drinking suggest that a larger study would be unlikely to find a detrimental effect.
The mechanism of alcohol's impact on the CD4 cell count is unclear. Attributing it to decreased medication adherence or to likelihood of receiving ARTwould not explain the finding of lower CD4 cell counts in persons not on ART. Attributing lower CD4 cell counts to a decreased likelihood of receiving ART should be adequately addressed by controlling for baseline CD4 cell count. Evidence from Bagby et al16 in macaque monkeys demonstrating clinical deterioration of immune function in SIV-infected animals with chronic alcohol exposure suggests a more direct effect on immune function.
The absence of a correlation of heavy alcohol use with HIV viral load in our study contrasts with the findings of an increased viral set point associated with heavy drinking in these animal studies. This difference may be attributable to the fact that under experimental conditions, the monkeys were all intoxicated at the time of SIV inoculation, a scenario that was not likely the case for all subjects in this observational cohort of persons with chronic HIV infection. The absence of impact on HIV viral load among those not on ART also suggests that the decrement in CD4 cell count is not mediated by an increased viral load, which is an important determinant of the trajectory of CD4 cell count decline. Findings from this cohort raise the possibility that the effect of alcohol on the CD4 cell
count is CD4 cell specific or related to the nonspecific lymphopenia associated with alcohol use.33 The absence of a significant association of alcohol consumption on CD4% suggests that the alcohol effect observed may relate to a decrease of lymphocytes overall as opposed to a selective decrement of cells.
The observation that heavy alcohol consumption has an effect on the CD4 cell count in HIV-infected patients not receiving ART is in contrast to that previously described in the medical literature. One of the earliest reports on this subject
was by Kaslow et al,17 in which MACS participants were examined every 6 months to assess the relation between alcohol and AIDS-defining illnesses. No effect was found among the 1706 HIV-infected men; however, the level of alcohol exposure was unclear. The highest alcohol consumption considered was 2 or more drinks per day, and mean consumption was not described. This level of consumption contrasts with an average of 7 drinks per day in the current study's heavy drinkers.
In the analyses excluding depressive symptoms, the finding of an association of borderline significance between heavy drinking and a modest increase of HIV viral load among subjects on ART is consistent with the findings of Chander et al,34 in which heavy alcohol consumption correlated with significantly less viral suppression in cross-sectional analyses. These authors attributed this finding to the poorer adherence expected among heavy drinkers on ART. This is a possibility, and such an association in the current study may have been attenuated by the inclusion of ART adherence as a covariate in the regression analysis.
One limitation of this study was that we did not enroll HIV-infected persons in a cohort at the time of seroconversion (ie, an inception cohort) and follow their alcohol use, CD4 cell counts, and viral loads over time. To address this limitation,
analyses controlled for baseline CD4 cell count. Lack of an inception cohort also allows the possibility that participants in the not-on-ART group may have been exposed to ART in the past but were no longer receiving it at the time of study
enrollment. It is unclear how such exposure would alter the current findings. As in any observational study, the effects of heavy alcohol use could be confounded. It is possible that we did not adequately control for all potential contributing factors
to HIV disease progression. Multiple characteristics known to be associated with HIV disease progression were included as covariates in the multivariable analyses, however. Another limitation is the fact that alcohol use was assessed 30 days before the interview and CD4 cell counts and HIV RNA levels, by study design, could have been obtained up to 4 months before the interview. Most of these outcomes were within 1 month of the subject interview, however.
Although alcohol consumption in HIV-infected persons is common,5,7,35 heavy consumption in US cohorts is less frequent than in countries in which HIV infection and high per capita alcohol consumption coexist (eg, Russia, South Africa).36,37 A modest impact of a common problem (heavy alcohol use) in patients with a prevalent disease (HIV infection) can have major public health consequences. Heavy alcohol use is a potentially modifiable factor that seems to have a modest impact on HIV disease progression. Based on our findings, we believe that HIV-infected persons who drink alcohol heavily and are not on ART might decrease their risk of disease progression if they abstain from alcohol use. There is extensive evidence of the efficacy of a brief intervention for unhealthy alcohol use in nondependent drinkers in medical settings and of the efficacy of psychosocial and pharmacologic treatments for alcohol dependence.38,39 Although limited evidence demonstrates that intervention for alcohol problems
in people with HIV is effective, its implementation among HIV-infected populations seems to be a worthwhile goal.40 In addition to the known deleterious effects of alcohol on ART adherence, these findings suggest that avoiding heavy alcohol consumption in patients not on ART may have a beneficial effect on HIV disease progression.
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