A GUIDE TO RESEARCH ISSUES AND OPPORTUNITIES

NAAA Research Priorities NIAAA Mission Statement Introduction: The Intersection of the Alcohol and HIV/AIDS Epidemics  EPIDEMIOLOGIC RESEARCH     Epidemiology and Natural History     High Risk Groups     Comorbidity     Future Directions BEHAVIORAL RESEARCH     Developing Comprehensive Models     Primary Prevention Among Adolescents     Alcohol Use and Risks among Women     Alcohol Use and Adherence to Treatment     Future Directions BIOMEDICAL RESEARCH     Alcohol and the Immune System and Disease Susceptibility     Alcohol, HIV Infection and Opportunistic Infections     Alcohol and HIV Viral Replication     Alcohol Research and Animal Models of HIV/AIDS     Alcohol and HIV Pharmacotherapy     Alcohol, HIV Infection and the Central Nervous System ACKNOWLEDGMENTS/CONTACTS

This pamphlet identifies areas of future research on interactions between alcohol abuse and HIV/AIDS. These areas offer promise for improving prevention and treatment strategies and reducing the spread of HIV/AIDS. Such strategies require the timely application of both behavioral and biological knowledge.

Studying the epidemiology of alcohol use, abuse and dependence in HIV infection and AIDS will help to identify high-risk groups and promote the targeting of effective HIV prevention and treatment efforts. This knowledge will also improve the medical management of HIV/AIDS disease. Specific studies are needed to:

• further an understanding of the alcohol-HIV/AIDS relationship through population-based studies which describe the alcohol consumption patterns of groups at risk for HIV infection;
• identify and model the impact of patterns of alcohol consumption on the spread of HIV infection and opportunistic infections over time;
• describe alcohol use and alcohol use disorders in high-risk groups with HIV/AIDS and co-occurring medical and psychiatric complications; and
• more fully describe the role of gender, race/ethnicity and cultural factors in the intersection of the alcohol and HIV/AIDS epidemics.

Alcohol prevention and treatment interventions are effective in reducing HIV risk behaviors and preventing HIV infection. Development and testing of new interventions are needed at various levels (e.g., community, dyadic, individual, organizational, and social network). Specific interventions are needed to:

• motivate drinkers—including those who perceive themselves to be at low risk for HIV infection—to decrease risky sexual and substance use behaviors;
• integrate HIV risk reduction goals into alcohol abuse treatment settings—including psychosocial and pharmacological interventions;
• develop community-based interventions (e.g., bar-based server training, altering alcohol availability, and improving linkage of alcohol and HIV preventive services); and
• target and retain the highest risk drinkers (including those from difficult-to-reach groups) in HIV/STD prevention and treatment interventions—including trials for prophylactic vaccines.

Behavioral, affective, and cognitive factors affect the risk for HIV infection and the efficacy of HIV prevention and treatment among alcohol users and abusers. Models should be developed for interrelating these individual factors with contextual and social factors that influence alcohol misuse, sexual risk-taking, and other HIV risk behaviors. Models are needed to increase the understanding of:

• the relationship of alcohol consumption, alcohol-related sexual expectancies, social norms, and decision-making on HIV risk behaviors for different at-risk groups;
• the relationship between alcohol use and abuse and adherence to HIV therapeutic regimens, including delivery and cost of services;
• social dynamics and environmental characteristics of high-risk alcohol-related settings (bars, parties, "wet" neighborhoods) and the impact of alcohol regulations and policies on HIV transmission; and
• improving methods for assessing and analyzing the complex relationships between alcohol use and abuse, specific situations and settings, and HIV-related risk behaviors.

Alcohol use may be a key determinant in adherence to therapeutic regimens among HIV-infected individuals. Research is needed on interventions to improve treatment adherence and to ameliorate negative physical, behavioral, affective, cognitive, and social consequences of HIV infection in alcohol-using and -abusing populations. Research efforts are needed to:

• improve medication adherence in alcohol-using and -abusing HIV+ patients;
• prevent alcohol relapse and related HIV risk behaviors among HIV+ individuals;
• enhance linkage of primary medical care with alcohol prevention and treatment services for HIV-infected alcohol abusers; and
• develop and test interventions to improve quality of life for alcohol-using and -abusing HIV-infected persons (e.g., ameliorating the interaction of alcohol use and medical sequelae of AIDS progression).

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Biomedical research is important in the prevention and treatment of HIV/AIDS among alcohol users. Biomedical research focuses on basic, applied, and preclinical studies to promote the understanding of biological interactions between alcohol and HIV pathogenesis, including:

• effects of alcohol on viral burden, immune function, organ pathogenesis and neuropsychological function in HIV infected individuals and appropriate animal models;
• effects of alcohol consumption on seroconversion and progression of disease in defined cohorts including biological endpoints which relate to both alcohol abusing populations (e.g., MCV, CDT, liver function enzymes) and AIDS-specific measures (e.g., viral load, CD4+ and CD8+ levels);
• mechanisms of enhanced progression of liver disease by alcohol consumption in individuals infected with HIV or co-infected with both HIV and hepatitis C (HCV);
• drug-drug interactions between alcohol and antiretroviral drugs (and possibly vaccines) and altered pharmacology due to either chronic or acute alcohol consumption;
• alcohol-related host defense impairment and opportunistic infection caused by pathogens such as M. tuberculosis, S. pneumoniae, P. carinii and HCV;

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) supports and conducts epidemiologic, behavioral and biomedical research on the causes, consequences, treatment, and prevention of alcoholism and alcohol-related problems. NIAAA is one of 18 institutes that comprise the National Institutes of Health (NIH), the principal biomedical research agency of the Federal Government. NIH is a component of the Public Health Service within the Department of Health and Human Services. The NIAAA supports a comprehensive program of epidemiologic, behavioral and biomedical research within the HIV/AIDS research arena and actively participates in the planning process of the Office of AIDS, Office of the Director, NIH, in determining the National Institutes of Health Fiscal Year Plan for HIV-Related Research. In addition, the NIAAA collaborates with other research institutes and Federal programs relevant to alcohol abuse and HIV/AIDS; providing coordination for Federal alcohol abuse and HIV/AIDS research activities; and dissemination of these research findings to health care providers, researchers, policymakers, and the public.

The purpose of this pamphlet is to provide a foundation for expanded discussions among research scientists, clinicians and NIAAA staff to promote new innovative research on alcohol and HIV/AIDS. The Institute recognizes the importance of fostering ongoing dialogue and supporting research partnerships between experts on HIV / AIDS and experts on alcohol research. It is our intention that this pamphlet will facilitate these interactions.

Support and direction for Alcohol and HIV/AIDS research within NIAAA is through the Division of Epidemiology and Prevention Research, the Division of Treatment and Recovery Research, the Division of Neuroscience and Behavior and the Division of Metabolism and Health Effects. NIAAA scientists and administrators are available to discuss research ideas and eligibility requirements for each grant or training opportunity. For more information, please contact:

Kendall Bryant, Ph.D., NIAAA AIDS Coordinator, Alcohol and AIDS Research, NIAAA, 5635 Fishers Lane, Bethesda, MD 20892-9304. Tel: 301-402-9389

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INTRODUCTION

Intersecting Alcohol and HIV/AIDS Epidemics

Alcohol is the most frequently used and abused substance in United States and its misuse results in approximately 100,000 deaths each year through accidents and alcohol-related diseases. Forty-four percent of the population, aged 18 and over, have consumed at least 12 drinks in the preceding year. Of these individuals, approximately 14 million (7.4 percent of the adult population) meet the diagnostic criteria for alcohol abuse or alcoholism. Individuals with hazardous drinking patterns may cause harm to themselves or others and represent a disproportionate number of primary care and emergency room patients.

HIV and sexually transmitted diseases (STDs) are among the most common infectious diseases. There are an estimated 50,000 new cases of HIV infection per year in the United States. These new cases include a large proportion of adolescents and young adults (approximately 40% aged 13-29) almost half of whom are women (47%). Although deaths from AIDS are beginning to decline in the United States, this still represents about 40,000 deaths per year. AIDS is the leading cause of death among men and women between the ages of 25 and 44, many of whom became infected as young adults.

The activities that transmit AIDS—unprotected sexual intercourse with an HIV-infected individual, use of HIV-contaminated injection drug equipment, vertical transmission—may interact directly and indirectly with alcohol use and abuse. How alcohol use affects specific HIV risk behaviors at an individual level is not precisely understood; investigation is ongoing. Studies of cross-sectional samples, however, have consistently shown that heavy alcohol use predicts increased rates of HIV risk behaviors and infection. Longitudinal multisite AIDS studies have reported that baseline heavy alcohol consumption is associated with seroconversion. However, risk reduction interventions among alcoholics have significantly reduced HIV risk behaviors, and interventions among young adults show promise. Treatment of seropositive (HIV+) alcoholics presents additional challenges in the delivery of appropriate services.

There is an overlap between individuals at risk for alcohol abuse and individuals at risk for HIV infection. Dual risk groups include, for example, gay men, runaway and homeless youth, injecting drug users, and victims of sexual coercion. These groups are often at risk because of vulnerable lifestyles and share similar ages for onset of heavy drinking and HIV/STD infection. In a national probability study, men and women who reported a history of problem drinking were three times more likely to have an STD than those without such a history. Certain personality characteristics associated with both drinking and sexual risk-taking have been identified (e.g., impulsive decision making, stimulus seeking, and poor socialization), particularly among young adults.

Drinking and HIV risk behaviors may often occur together in the same physical location (e.g., high-risk bars) or during a particular activity (e.g., exchange of drugs and alcohol for sex.) Multiple HIV risks are often shared by individuals and the social network to which they belong. The general riskiness of the social network may be indexed by alcohol use among its members. Community-level variables are also important. The distribution of liquor outlets may impact the spread of STDs. Enforcement of laws that control the availability of alcohol may also affect the incidence of STDs.

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Examination of the social and cultural contexts for alcohol use and HIV risk offers another level of understanding of these dual risks. For example, research on gay culture and the development of gay identity poses important behavioral research questions about the relationship between alcohol use and HIV transmission. Gay bars, which provide opportunities for gay men to socialize, also represent a high-risk context for excessive alcohol use. Alcohol use is the most frequent precipitant of relapse to unsafe sex among gay and bisexual men, and locations that combine sexual opportunities and alcohol availability pose the greatest risk for populations vulnerable to HIV. Similarly, understanding how acculturation patterns and social norms emerge for drinking among new immigrants, migrant workers, or individuals in new settings such as colleges, improves our understanding of how patterns of alcohol and HIV risk coalesce.

Chronic abusive alcohol use can lead to life threatening organ damage. Light to moderate consumption can induce organ system changes which may influence HIV pathogenesis. Regardless of the level consumed, alcohol is likely to influence the health status of persons infected with HIV and those whose behaviors place them at risk for acquiring the infective agent. To date, there is no conclusive evidence that acute or chronic alcohol consumption increases susceptibility to HIV infection or accelerates progression to AIDS. However, clinical findings have associated increased levels of chronic alcohol consumption with diminished immune function as evidenced by reduced levels of CD4 and CD8 activity. Strain variations of HIV, individual differences in susceptibility, long incubation time following seroconversion and varying patterns of adherence to HIV medications are some of the difficulties in studying this disease progression. Whether alcohol consumption increases susceptibility to opportunistic infections in HIV+ patients and whether alcohol-induced immunosuppression exacerbates disease pathogenesis remain important questions.

Lack of knowledge on the influence of alcohol on HIV infectivity and viral replication is a major impediment to understanding HIV-related morbidity and mortality. Therefore, research that provides detailed knowledge of how alcohol and HIV, each in its own way or acting in concert, degrade host defense mechanisms and usurp vital cellular machinery to enhance viral replicative success, is urgently needed. Biomedical research that delineates the multiple dimensions of alcohol and HIV on host defense mechanisms will provide a rational basis for the development of new methods of therapeutic interdiction.

NIAAA supports a prevention science agenda that aims to be comprehensive and multidisciplinary in understanding the role of alcohol in the spread of HIV from both biomedical and behavioral sciences perspectives. Informative Epidemiology is also necessary to target interventions (both behavioral and biological) to the highest risk groups, situations, and settings. Development of this knowledge base is essential to promote both domestic and international programs of prevention research.

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Knowledge gained from studying the epidemiology of the alcohol/AIDS intersection may contribute to the amelioration of the HIV/AIDS epidemic by identifying high risk groups, promoting the development of more effective and finely tuned prevention efforts and contributing to improved management of HIV/AIDS patients.

HIV infection rates are high among frequent and/or heavier drinkers and among those who are alcohol abusers or in alcohol treatment. Assessments of male and female alcohol inpatients and outpatients from varying racial/ethnic backgrounds have indicated infection rates from about 3% to 12% among heterosexuals without a substantial comorbid drug use history. This is several times higher than rates found in similar community based heterosexual non-treatment samples. Conversely, rates of alcohol problems are high among HIV/AIDS patients. Lifetime prevalence rates of alcohol use disorders ranging from 29% to 60% have been found among HIV positive populations. This is 2 to 4 times higher than in the general population.

Drinkers, especially heavy and more frequent drinkers, tend to engage in more impulsive and risky behavior, such as having more sex partners, using injection drugs and having unprotected sex. Although sexual risk and protective behaviors are not consistently associated with severity of alcohol problems, studies among the general adult population, among adolescents and among gay men have found that heavier drinkers tend to use condoms less frequently. Although there is less research among minorities, women and alcohol populations, heavier drinking appears to be related to less condom use in these groups as well. In studies of alcohol treatment samples, which included blacks, Hispanics, and whites, males and females and individuals in gay treatment settings, approximately 30% reported failure to use condoms and multiple sex partners.

Research also indicates that the amount of alcohol consumed per drinking occasion correlates more strongly with inconsistent condom use than does drinking frequency and that alcohol is associated with relapse to unsafe sexual practices following a period of practicing safer sex.

Over the past 15 years, rates of HIV infection and AIDS among adolescents, women, minorities, drug users and heterosexuals have increased, while rates among homosexual and bisexual men have decreased. These differences in rates may be in part a reflection of the fact that relationships between alcohol consumption and sexual risk taking practices differ by age, sex, race-ethnicity, sexual orientation and level of acculturation. Type of partner, alcohol expectancy effects and certain personality characteristics associated with both drinking and sexual risk-taking (e.g., impulsive decision making, stimulus seeking and poor socialization) are other important factors to consider.

Teens acquire HIV infection through unprotected sex at a much higher rate than adults. AIDS has been cited as a leading cause of death among adolescents and young adults who, in many cases, became infected as teenagers. Among adolescents, risk-taking behavior, including sexual risk taking, is more common than in the general population. . Studies indicate that alcohol plays an important role in sexual risk taking among young people, particularly among heterosexual women. According to a nationally representative survey, of the 38% of students in grades 9 to 12 who are currently sexually active, 25% reported that they had used alcohol or drugs at last sexual intercourse and 42% reported not using a condom at last intercourse. College students report rates of 15% to 65% rates of condom use following drinking. Adolescents with alcohol use disorders are more likely than other drinkers to be sexually active, to have greater numbers of partners and to initiate sexual activity at slightly younger ages.

Among women, especially minority women, the incidence of HIV/AIDS is increasing. The number of HIV infections and AIDS cases that can be attributed to heterosexual contact have steadily increased and heterosexual contact is the predominant mode of HIV transmission among women diagnosed with AIDS. Sexual practices among heterosexuals, which increase risk of exposure to HIV include: sex with multiple partners; sex with a partner of unknown sexual history or HIV status; and failure to use condoms. The likelihood of engaging in these practices may be influenced by alcohol consumption. Most studies have shown that overall frequency of drinking is associated with the frequency of unsafe sex, but many studies do not link the two within the same event. Some studies have indicated that alcohol and substance use may have the greatest effect on condom use not among women who know they engage in risky sex, but among those who are not sufficiently cognizant that every sexual encounter is risky.

Rates of HIV infection and AIDS among minorities, particularly African Americans and Hispanics, are high relative to their representation in the general population, and increasing. Studying the relationship of alcohol and HIV related risk factors, which has been shown to vary by race/ethnicity, may offer some insight into these trends. Studies have indicated that the role of race/ethnicity in alcohol related HIV/AIDS risk is complex and that other variables such as gender, age and socioeconomic status need to be considered simultaneously. Findings also indicate that the complex interplay of alcohol, and personal, situational and behavioral factors with risky sex is ethnically and culturally related and that level of acculturation may be an important variable to consider. Additional studies are needed to more fully describe the role of race/ethnicity and cultural factors at the intersection of the alcohol and HIV epidemics.

Although the rate of new HIV infection among gay and bisexual men has decreased, this is not the case in some younger birth cohorts, and overall this group remains at high risk. Among gay men, as in other populations, the relationship between alcohol and unprotected sex is complex and inconsistent findings have been reported with respect to alcohol as a predisposing factor. In this population, situational factors such as partner type (steady or non-steady), setting and other drug use appear to be important modifiers. Among gay men, those who are alcohol dependent are more likely to have unsafe sex with non-steady partners after drinking. Further epidemiologic investigations can provide additional information about the specific role of alcohol.

Drug users are another group at high risk for HIV/AIDS disease. Much of the risk in this group accrues from their drug use, particularly if they use drugs intravenously and share needles. However, alcohol may also be a factor as research indicates an association between alcohol and risky sex in samples of injection drug users, and crack smokers. Among drug users, as in the other populations already discussed, situational and personality factors need to be considered when attempting to understand the intersection of alcohol and HIV/AIDS risk.

The co-occurrence of alcohol problems or alcohol use disorders in people with AIDS may lead to medical and psychiatric complications, which may impact HIV medication compliance and treatment outcomes. It is well known that alcohol consumption suppresses immune responses and therefore may increase susceptibility to initial HIV infection. Alcohol consumption may also affect the risk of subsequent opportunistic infection and disease progression, including the course of HIV associated dementia, even for those who do not drink very heavily. Data relating alcohol use and the progression from asymptomatic HIV to symptomatic HIV and poorer neurological status is mixed, however. Further epidemiologic study will help clarify alcohol’s role in HIV disease progression and better delineate medical and psychiatric comorbidity.

Available studies have provided a valuable initial understanding of the epidemiology of alcohol and HIV infection and progression to AIDS. These studies have begun to characterize the prevalence of HIV/AIDS, as well as HIV/AIDS related risk and protective factors, among those with various alcohol-drinking patterns and have also begun to elucidate drinking patterns among those with HIV/AIDS disease. These studies have also begun to describe the relationship of alcohol and HIV/AIDS risk by age, gender, race/ethnicity and sexual preference.

However, studies to date have rarely used samples representative of the entire population; their generalizability is therefore limited. More population-based studies are needed to further our understanding of the alcohol-HIV/AIDS intersection and better describe the extent of the problem. For example, large-scale studies of general risk behavior are needed so population information is available against which to evaluate what is found in smaller studies of more specific populations. In specific groups where rates of infection are disproportionately high, there is a need to investigate the role of alcohol related factors by group. In addition, more epidemiologic studies among groups at increasing risk such as women, ethnic minorities and the young are needed to inform the fine-tuning of prevention efforts for these groups.

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At present, the most effective way to slow the spread of HIV/AIDS is through changing the sexual and injecting drug risk behaviors that transmit HIV from individual to individual. Drinking alcohol significantly increases the risk of these behaviors in complex ways. The availability and abuse of alcohol increases the difficulty of preventing initiation of these risk behaviors and the difficulty of maintaining protective behaviors once they have been adopted. In addition, continued abuse of alcohol by HIV infected individuals increases the negative impact of the disease on the individuals, their families, and the health care system. Interventions to reduce alcohol abuse and treat alcohol dependence significantly improve the success of HIV preventive and treatment interventions. Developing combined alcohol/HIV interventions for groups at significant risk for both of these problems has been identified as a priority for future research by the Office on AIDS Research (OAR), NIH in both domestic and international settings:

OAR Objectives: Priorities for Future Research

OAR Strategies

While the need for preventing the transmission of HIV in alcohol and substance abuse risk groups is a pressing public health concern, the development and testing of interventions in these groups should be informed by sound scientific research. A number of theoretical perspectives have been proposed to explain the relationship between alcohol consumption and sexual risk-taking. Direct causal explanations have focused on the disinhibiting properties of alcohol use. These psychophysiological explanations have been modified to include cognitive factors such as alcohol-related sexual expectancies, alterations in risk judgments, and memory processes. Other explanations have also been advanced that identify specific personality characteristic -- such as stimulus seeking or impulsive decisionmaking styles, or more general risk-prone dispositions -- as determinants of alcohol-related sexual risk taking. Beliefs about the potential positive or negative consequences of an activity have been shown to predict risk-taking behavior. In addition, experimental research is clarifying the role of alcohol use in specific sexual risk-taking situations. This research examines how alcohol intoxication influences participation in dangerous activities.

Testing the mediating role of alcohol in HIV/AIDS preventive interventions requires multicomponent interventions with well-measured outcomes. Advances in the understanding of alcohol-related outcomes are dependent on improved measurement of co-occurring alcohol and HIV risk behaviors, and the application of alcohol-focused theories. The ideal methodological approach is to obtain global, situational, and event-specific measures of drinking behavior and unsafe sexual behavior in conjunction with partner characteristics, use of other substances, and frequency of these encounters. These improvements in data collection methodologies are producing important insights into the relationship between alcohol use and unsafe sexual behavior. However, models for both analyzing the data and explaining the influence of alcohol in these complex results are in need of further development.

The combination of drinking and early sexual intercourse places adolescents at risk for sexually transmitted diseases and HIV infection. Given the long incubation period for AIDS, many individuals diagnosed with AIDS today probably became infected as teenagers. In 1997, more than 100,000 cases of AIDS were diagnosed in the age group 20 to 29—individuals who likely became infected as teenagers.

The misuse of alcohol in this age group may lead to risky behaviors such as unprotected sex. The 1995 Youth Risk Behavior survey by the Centers for Disease Control and Prevention (CDC) found that 53% of males and 50% of females in grades 9 to 12 reported using alcohol in the last month. Similarly, 36% of males and 29% of females reported heavy episodic drinking in the last month. CDC reports that 25% of ninth graders in the U.S. have engaged in recent heavy episodic drinking. A similar percentage is currently sexually active. Approximately one third to one half consumed alcohol at last sexual intercourse.

Alcohol is readily accessible and clearly the primary substance of abuse in this age group. Fatal driving accidents and other serious injuries are among the many easily identified consequences of alcohol misuse. Early initiation of alcohol use may serve as a marker for increased risk of later alcohol-related problems—including unprotected sex. Use of alcohol in new situations by inexperienced young adults may lead to unsafe sex. Even if individuals intend to enact safer behaviors, peer social norms or the specific context of the relationship may make this difficult. Adolescents who report a lack of norms for safe sex among their peers are less likely to use condoms. In addition, the male partner’s alcohol use significantly increases risky sex irrespective of the level of alcohol use by the female partner.

Delaying the initiation of sexual activity and dissuading young adults from using alcohol and drugs are important HIV prevention strategies. Interventions among adolescents seek to reduce the use of alcohol and other substances both before and during sexual encounters. These interventions often focus on high-risk youth who are likely to use alcohol in the context of sexual behavior. These include runaway or homeless youth, incarcerated youth, or adolescents who have characteristics associated with risk-taking (e.g., high sensation seekers, impulsive decisionmakers, and individuals with pessimistic outlook.) These interventions are carried out in a variety of school-based, family, and public health settings, such as STD clinics. Multicomponent interventions may seek to change individual knowledge about alcohol-related HIV risks, perceived susceptibility to these risks, and normative beliefs about health consequences. Interventions may also target peer and family social networks or may include other sources of social influence such as physicians.

Unfortunately, an increasing number of adolescents are being identified who not only misuse alcohol on particular occasions, such as parties, but also are chronic drinkers in need of alcoholism treatment. The lifestyles of these individuals, many of whom are from broken families, put them at especially high risk for HIV infection. These individuals—who may be runaway or homeless, victims of early sexual abuse, or participants in sex for money or drugs—are often difficult to engage in interventions. Addressing the substance abuse and health care needs of this population calls for the development of innovative interventions.

The urgency for interventions focused on women is highlighted by the rapidly increasing rates of HIV infection among urban minority women. AIDS is the leading cause of death among women of color ages 25 to 44. This group constitutes 75% of all AIDS-infected women, and almost half of the infections are contracted through heterosexual contact. Almost 90% of children with AIDS contracted the virus perinatally as a result of being born to an infected mother. African-American women account for 40% of AIDS cases among heterosexuals and 60% of pediatric AIDS. Deaths attributed to AIDS are increasing among African American women while declining for other risk groups.

Many socioeconomic factors such as availability of treatment for HIV or substance abuse, changing social norms, and enforcement of laws influence local variations in HIV prevalence rates. Rapid increases in HIV infection can occur among women in specific neighborhoods, particularly among alcohol and drug users. State agencies have concluded that reductions in alcohol and drug abuse are critical in controlling rapid changes in HIV-infection. They have recommended a significant increase in substance abuse interventions as part of comprehensive prevention strategies.

Researchers need to incorporate what they have learned about problem drinking and alcoholism into interventions among HIV at-risk populations. Male-oriented intervention models may not be appropriate for alcohol-abusing women. A variety of factors need to be considered. These include: understanding women's perceptions of their susceptibility to AIDS; the actual severity of exposure to HIV in women's lives; barriers to enacting safer behaviors with partners; and the perceived benefits of changing high-risk behaviors.

Interventions need to address the interactive role of alcohol use and abuse and sexual risk taking. Harm reduction strategies may be of particular importance for low-income women who may have limited personal control over decisions that affect their lives. These strategies focus on reducing the negative consequences of alcohol abuse by encouraging consistent condom use, reduction of number of sex partners, treatment for STDs and developing realistic drinking goals. Women in alcohol treatment settings are at particularly high risk for both HIV infection and transmission. Efforts should be made to monitor alcohol dependent women both in and out of alcohol and substance abuse treatment settings. Effective interventions need to consider lifestyle issues, such as child care, family and partner roles, and other potential barriers to receiving health care.

Recent advances in antiviral therapies for HIV infection have resulted in the treatment of HIV/ AIDS as a chronic disease. To be successful, however, these HIV treatments require access and strict adherence to drug regimens. Long-term HIV treatment with these new drug therapies is particularly difficult for alcohol-abusing populations. Research is needed to identify issues that compromise access to HIV treatment and adherence to treatment among alcohol-using and -abusing seropositive populations. Special populations of interest include HIV-infected gay men, pregnant women, and underserved minorities. In addition, the impact of treatment settings and services needs to be identified, particularly for alcoholics in institutional (e.g., prisons) and self-help (e.g., Alcoholics Anonymous) treatment settings.

Studies also indicate that alcohol drinkers, especially heavy drinkers are less compliant with treatment regimens. Some studies have reported that HIV patients use alcohol to cope with their disease while others have reported that patients claim to have stopped or reduced their alcohol consumption after diagnosis. Newer antiretroviral therapies require high levels of adherence to be effective and studies have indicated that alcohol use is associated with decreased adherence.

Research is needed to identify how successful alcohol intervention strategies and HIV risk reduction strategies can be modified to become more effective in HIV-infected alcohol-abusing populations. Theoretically grounded, yet practical, multicomponent interventions need to be developed that include accurate assessment of patterns of alcohol use, facilitation of medication with antiretrovirals, changing expectancies for effects of alcohol use on medication efficacy, and tailoring of pill-taking to individual patients’ daily living circumstances. In addition, recent pharmacological advances in the treatment of alcohol abuse (e.g., the advent of Naltrexone) suggest that enhanced pharmacotherapies should be tested along with behavioral therapies for alcohol abuse.

Preliminary research indicates that alcohol use is a key determinant of adherence to new regimens of antiretrovirals. Research in this area is focused on answering several key questions:

Although these questions have not yet been answered, it is clear that routine HIV testing with counseling should be strongly considered for alcohol treatment populations and that interventions should call for enhanced linkage of alcohol treatment services to primary medical care—to include HIV testing, initiation of therapy, treatment of tuberculosis and STDs, and prevention/cessation of other substance use.

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Alcohol abusers often delay entering medical settings where they could be identified as needing appropriate interventions and are often difficult to retain in controlled clinical trials. Such difficulties in attracting and retaining alcohol-abusing individuals may have particular significance for the testing and evaluation of HIV vaccines and therapeutics. New interventions need to be developed to attract and retain individuals at extremely high risk for alcohol abuse and HIV infection. New research designs and analytic strategies need to be developed to evaluate these interventions adequately in settings where high rates of attrition may occur. Intervention strategies might, for example, include more informal and culturally relevant drop-in clinics. Different analytic procedures—such as case-control or case-based designs— may be necessary to test the effects of these interventions on such variables as HIV exposure, alcohol abuse, and retention in vaccine or therapeutics trials.

Increasing attention is being paid to the role of healthcare systems and professionals in preventing alcohol-related problems before they occur, in facilitating early detection of alcohol-related high-risk behaviors, and in providing appropriate treatment. Experimental and quasi-experimental designs may be used within healthcare settings to test the efficacy of preventive strategies. These strategies may include risk assessment, brief and more extensive advice, case monitoring, and improved linkage to services for alcoholics in treatment or for HIV-infected individuals with alcohol problems.

Ongoing research is needed to assess the efficacy of media strategies—alone or combined with other strategies—to prevent alcohol-related risky sexual behavior. Researchers are encouraged to develop and test promising media messages, new communications technologies, and special media for cultural subgroups to determine the most effective media/communications approaches for varied target audiences. Of particular interest are communication strategies that reach audiences at highest risk for alcohol abuse and HIV infection, which include impoverished youth and women, selected ethnic minorities, gay and bisexual men, and male and female partners of HIV-infected individuals.

Research suggests that family involvement, broadly defined, can enhance the effectiveness of school-based and clinic-based alcohol prevention programs among youth at risk for alcohol problems. Research on homeless and runaway youth indicates a high rate of co-occurring alcohol abuse and unsafe sexual behavior—often resulting in the spread of sexually transmitted diseases and HIV. Research needs to be expanded in this area to develop effective interventions among group or family members to reduce the risk for HIV infection.

As behavioral researchers focus on problems of substance abuse and AIDS, they are increasingly involved in the communities that are most affected. Urban ethnic and racial minority neighborhoods are particularly affected and often hard to access. Community characteristics such as density and location of liquor outlets, or community organization of health services may significantly effect the spread of STDs including HIV. To overcome barriers to access, behavioral scientists have formed productive collaborative alliances with organizations within these community environments, including nongovernment organizations.

Substantial changes in alcohol use and HIV-related risk behaviors can be achieved through substance abuse treatment. Changes in alcohol use were associated with reduced use of other drugs, decreased HIV risk behaviors, and increased attendance at AA meetings. However, variation exists in the ability of men and women to reduce sexual risk-taking during substance abuse treatment. In general, greater risk at intake, more sexual activity, and a tendency to combine alcohol use/other substance use and sexual behavior were associated with continued sexual risk during the year after entry into treatment. Current investigations include integrated behavioral interventions that promote alcohol abstinence or controlled drinking and improve consistency in safer sex behaviors among both HIV- and HIV+ men and women. These studies aim to reduce the sexual transmission of HIV and to improve the quality of life for infected individuals. Further research is needed to evaluate individuals in need of alcohol treatment who are at-risk of HIV infection.

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Both alcohol abuse and the HIV / AIDS are major public health burdens in the Western world. As the two epidemics converge, there are increasing numbers of individuals at risk for alcohol abuse, HIV infection and progression to AIDS. For instance, in a Pulmonary AIDS Complications Study (PACS) cohort, 41% of the individuals met the criteria for alcoholism. Thus, the burden of AIDS and alcoholism may be prevalent during end-stage HIV disease. However, limited data are available regarding alcohol consumption and any stage of HIV infection, including the acute stage of HIV infection as well as the asymptotic period of HIV infection. It is clear that alcohol consumption alters the natural history, disease manifestations and disease progression of HIV infection, thereby complicating patient management issues. Use of antiretroviral therapy to manage HIV infection has reduced morbidity and mortality due to chronic HIV infection. Immune reconstitution is observed at some level in patients managed with HAART- Highly Active Antiretroviral Therapy. Thus, profound changes can be observed systemically during the course of HIV infection and treatment.

Research on alcohol consumption and the immune system has taken two approaches: investigations of alcohol consumption on immune function modulation and the manifestation of this immunomodulation , increased susceptibility to infectious diseases. Research of both areas explores the reduced host immune defense due to alcohol consumption. Both acute and chronic consumption of alcohol results in marked alterations of host immunity. Frequency and duration of the exposure to alcohol in relation to infection is also important. For example, acutely exposing human monocytes to alcohol results in reduced antigen presentation and subsequent decreased antigen-dependent T-cell proliferation . In a chronic alcohol-consuming animal model, a defect in presentation occurred during the cognitive phase of the immune response when antigen presenting cells (APC) engage uncommitted T helper CD4⁺ cells. But, this defect could not be reproduced when alcohol exposure occurred after the presentation and recognition steps. The nature of the APC-T helper cell interaction helps to determines the effector response, i.e., cell- mediated (Th1 ) or humoral (Th2 ). Cytokine expression after alcohol exposure of normal human monocytes and murine splenic cells are shifted toward Th2 dominance. These experimental observations, taken together, suggest that the immune abnormalities observed in alcoholics stem from the polarization of the immune response to Th2 cytokine excess. This polarization to Th2 is further enhanced in alcoholics since pro-oxidant levels, such as glutathione, are depleted in alcoholics and play an integral role in determining the Th1/Th2 maturational pathway of an immune response.

Studies in human volunteers who consume moderate levels of alcohol confirm both the animal and in vitro data by showing changes in cytokine production in peripheral blood monocytes. Furthermore, alcohol-induced malnutrition can further compromise the human immune. Heavy alcohol abuse is associated with high caloric intake derived form alcohol and inadequate intake of protein, vitamins and minerals creating a "malnutrition/wasting –type syndrome". Thus, alcoholics may not ingest adequate levels of trace elements, such as zinc, iron, selenium and magnesium, and micronutrients as well as vitamins necessary for a competent immune response .

The clinical manifestation of the immune changes caused by alcohol consumption is clearly seen in the susceptibility of these individuals to infectious diseases, such as pneumonia, tuberculosis or sepsis. Infections that may lead to septicemia in the alcoholic include pneumonia, urinary tract infections and bacterial peritonitis. Thus, studies are needed in the context of disease susceptibility and HIV infection including: alcohol-related host defense impairment and opportunistic infection caused by pathogens such as Mycobacterium tuberculosis, Streptococcus pneumonia, Pneumocystis carinii and hepatitis C (HCV).

The incidence and natural history of AIDS-associated opportunistic infections (OI’s) are changing as a result of the use of potent antiretroviral therapy. Although the incidence of OI’s is reduced, these infections are still an important clinical and pathophysiological manifestation of HIV disease. Individuals with immune deficiencies, that respond to therapy and thereby obtain near or undetectable serum viral loads, are still at risk for organ-specific infections due to the newly described immune reconstitution syndrome. Only specific components of the immune system are reconstituted by HAART, resulting in an exaggerated immune response on exposure to a pathogen or activation of autoimmunity. In addition, there is an increasing appearance of drug -resistance strains of OI's as well as the recent report of alcohol consumption increasing the progression of liver disease in patients co-infected with HIV and HCV.

HCV infection is a major worldwide cause of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). In the United States, nearly 4 million people are infected with HCV. Although acute HCV infection may resolve possibly through induced or innate immunity, the most likely path of infection results in chronic hepatitis infection. Liver cirrhosis occurs in a minority of chronically infected individuals (ranging from approximately 5- 20% of individuals). Chronic HCV infection is now the number one cause of end stage liver disease requiring orthotopic liver transplantation in the United States.

Alcohol intake at any level as well as alcohol abuse may increase the severity of HCV-induced liver injury by promoting viral replication, inhibiting clearance of the virus, promoting virulence, or enhancing host susceptibility to HCV infection of the liver through malnutrition or other unknown changes in the liver. Little data are available regarding HIV, HCV and alcohol consumption. What is clear is that the population at high risk for drug/alcohol abuse is also at high risk for HCV infection and HIV infection. With the focus on HIV infection, there is emerging evidence that HIV infection possibly through immunosuppression, alters the natural history of hepatitis C infection. Studies have found increased concentrations of HCV RNA in individuals that undergo HIV seroconversion or that progress in their HIV infection . However, it must be noted that unlike HIV, HCV viral loads do not correlate or predict disease progression. In addition, HIV co-infection appears to promote hepatic pathology (liver fibrosis, cirrhosis) increasing the progression to liver failure due to HCV. Alcohol use is now being studied in co-infected populations. In HIV/HCV co-infected individuals, alcohol consumption was determined to be a crucial cofactor in progression of liver disease. In a comparison of liver disease progression between coinfected and HCV-infected cohorts, a low CD4 count, greater than 50g/day of alcohol consumption and young age at the time of infection were associated with progression of liver fibrosis. In addition, in this cohort, alcohol consumption reduced the time to cirrhosis from 30-40 years to 15-20 years. These and other data suggest that hepatitis C should be treated as an opportunistic infection in co-infected individuals and that alcohol withdrawal/therapy be a required part of pharmacotherapy of the viral infections.

The issue of liver transplantation of individuals with end-stage liver disease and HIV/HCV co-infection is also beginning to be addressed and is an area for further research At this early point, regardless of whether the donor liver is obtained from a seropositive or negative individuals, the use of HAART postransplantation appears to control HIV infection. Thus, the patient is at risk for complications of immunosuppression and recurrent liver disease either through re-emergence of the hepatitis C infection or resumption of alcohol consumption.

The resurgence of tuberculosis throughout the world during the late 1980’s resulted from several factors, including the emergence of drug resistant Mycobacterium tuberculosis and an increasing highly susceptible HIV-infected population. As an AIDS defining event, TB ranks fourth behind immunodeficiency, pneumocystsis and wasting syndrome. TB comprises 3% or 1,552 case of AIDS reporting cases in 1998. But the question for alcohol researchers is- What role does alcohol consumption play in the resurgence of TB as observed in the HIV infected population? What is the role of alcohol-related nutritional problems in this population? Recent data indicate that alcohol consumption maybe an important factor in TB disease progression and confirm previous epidemiologic data that show a significant association between alcoholism and TB.

Alcohol predisposes to pulmonary infection by alterations in pulmonary cellular and humoral host defense mechanisms. Critical components of the host’s ability to contain intracellular pathogens, such as M. tuberculosis, include regulation of proximal proinflammatory cytokine production or function (such as interleukin-12, tumor necrosis factor, and interferon-g), and generation of specific immune effector cell populations. The loss of recruitment to the lung of effector populations due to ethanol exposure, such as neutrophils, may be a critical factor in loss of immune function. However, effective containment of M. tuberculosis and other intracellular pathogens can be mediated by Th1 subsets of CD4+ lymphocytes. Alcohol consumption, through disruption of early proinflammatory cytokine networks, may prevent development of an effective Th1 CD4+ lymphocyte-mediated immune response, which may contribute to an inability to control M. tuberculosis infection. Other potential adverse effects of alcohol may include alterations in lymphocyte populations due to neutrophil apoptosis, which would further compromise the host’s ability to contain these intracellular pathogens.

An emerging area of research related to bacterial pathogenesis and alcohol, is the role of alcohol-induced micronutrient deficiency in increased microbial virulence through genetic mutation. Recent studies have shown an inverse correlation between total dietary energy intake and an elevated genetic mutation rate in normal human volunteers. Noting that alcohol consumption modifies dietary intake and micronutrient deficiencies may arise due to alcohol or HIV infection, an interrelationship may exist among alcohol-HIV - and increased pathogen virulence. For the case of M. tuberculosis possible mutations may occur in the genome involved in drug resistance/ susceptibility which appear to be less well conserved. Further forces involved in such mutagenesis may be related to adherence to therapeutic drug regimens.

HIV infection predisposes to infection with M. tuberculosis by inexorable depletion of functional CD4+ lymphocytes. Although there is no specific CD4 count that predicts an increased risk to tuberculosis, HIV –infected individuals are at increased risk for initial TB infection, reactivation of TB and re-infection at any stage of HIV infection. TB, on the other hand, mediates cytokine activity that influences HIV replication. Active tuberculosis, as opposed to latent infection, leads to cellular activation and cytokine release, resulting in enhanced viral replication . TNF is synthesized in increasing amounts during active TB and permits granuloma formation to contain the infection. In latent infection, alcohol abuse or chronic alcohol consumption can contribute to reactivation of TB by exacerbating an immune system already compromised by HIV disease.

HIV infection is also a major risk factor for reactivation of latent tuberculosis through the loss of CD4+ T cells. Alcohol abuse or chronic alcohol consumption can contribute to reactivation of tuberculosis by exacerbating an immune system compromised by HIV. There is a need for research studies using directly observed therapy (DOT) in this cohort. Through the use of DOT, as well as attention to pharmacotherapy regimens and community screening, a resurgence of TB is being prevented in alcohol-abusing patients who comprise a substantial segment of noncompliant patients.

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The pathologic consequences of HIV are a function of the completion of the life cycle of the virus. HIV-1 has a complex viral life cycle that utilizes 15 distinct proteins in specific functions, some of which may interact with alcohol. They are: Gag and Env structural proteins, capsid proteins, nucleocapsid, SU and transmembrane proteins, Pol enzymes, reverse transcriptase, integrate, gene regulatory proteins Tat and Rev and accessory proteins Nef, Vif, Vpr and Vpu. Interventions to reduce viral transmission engage those stages in the HIV life cycle that can reduce viral shedding which correlates with reductions in serum and seminal viral load. Thus, efforts to reduce viral replication represent secondary interventions to reduce viral transmission augmenting primary behavioral prevention measures.

A potential prevention intervention is the direct modulation of specific regulatory genes of the viral life cycle. For example, functions provided by Tat and Rev or structural gene products such as Gag or Pol, when defective, can render the HIV-1 virus replication incompetent. High level HIV-1 transcription is regulated by Tat and functionally dependent on a Tat activation region designated TAR. TAR also serves as the binding site for the Tat protein, thereby providing a target for intervention. Alternatively, one can target the HIV promoter, regulating, in part, viral protein expression. Promoter activity is a function of the activation of the non-HIV, Sp1-binding site and the transcription factors, Sp1,and NF-k B. Thus, cell activities, unrelated to HIV infection inducing signal transduction pathways, and ultimately upregulating transcriptions factors, can enhance HIV transcription. A specific cell activity unrelated to HIV infection is cell activation via alcohol exposure. As observed in alcoholics, elevated levels of TNF contribute to the activation of NF-k B. NF-K B, on the other had, influences HIV promoter activity.

The questions for alcohol/HIV researchers are, "Does alcohol modify expression of HIV proteins or the cellular biology of infected cells to promote or inhibit HIV replication, via NF-K B or any other mechanism? Is alcohol a viral "adapter" that can influence and/or modify cellular functions to enhance the replicative capacity the virus? Conflicting results have been obtained by those studying HIV replication in isolated peripheral blood mononuclear cells (PBMC). An increase HIV rate of replication after prior exposure to alcohol has been reported while, in a differing experimental design, no consistent increase in HIV replication after exposure to alcohol was shown . Further studies are needed to solve the controversy in the field.

Differing research approaches could be used to resolve whether alcohol consumption enhances HIV replication. The first could be a clinical study of alcohol consumption and viral load over time. A positive correlation, or direct relationship would provide important clinical data for patient management. Determining the mechanism of a correlation would likely involve molecular studies of the HIV genome to determine the presence of alcohol binding and/or inducible response elements. Such genomic sequences, on exposure to ethanol or its metabolites, could enhance viral replication. This enhancement could be through the recently described NF-k b activation/ augmentation of the HIV promoter, LTR or other regulatory gene (s), such as Tat or Rev.

A second approach for alcohol/HIV replication is to address whether HIV replication could be enhanced through the action of alcohol or its metabolites on tissue specific cellular metabolism.

Two animal models of HIV/AIDS have been utilized to address the difficult issues related to alcohol-induced immune dysregulation and alcohol-induced pathogenesis in HIV infection and AIDS. A murine model of retroviral infection, murine AIDS (MAIDS), where immune deficiency is induced by LP-BM5 murine leukemia virus, has been intensely investigated. More recently, a primate model using Simian Immunodeficiency Virus (SIV) is being used.

The etiology of MAIDS does not replicate HIV infection. LP-BM5 is B-cell tropic while HIV is T cell/macrophage trophic. But, from a pathogenesis point of view there are similarities in pathogensis; lymphadenopathy, splenomegaly, hypergammaglobulinemia, defects in B and T cell function, impaired cytokine release, enhanced susceptibility to carcinogenesis and opportunistic infections. Retrovirus infection in the mouse inhibits the release of T helper 1 (Th1) cytokines, stimulates secretion of Th2 cytokines, increases hepatic lipid peroxidation, and induces vitamin E deficiency. These events pattern the biological processes that can occur due to alcoholic liver disease: a dominance of a Th2 cytokine response, an increase in oxidative stress in the liver and a reduction in anti-oxidant compounds. Thus, studies of ethanol in MAIDS may elucidate the interplay between retroviral-induced pathogenesis and alcohol-induced pathogenesis

An animal model that more closely resembles the etiology of HIV infection is SIV infection of rhesus monkeys. SIV is a lentivirus that is genetically related to HIV. SIV is T cell tropic and infects both lymphocytes and macrophages inducing an immunodeficient state that correlates with the depletion of CD4⁺ lymphocytes. Infection with SIV results in three stages comparable to HIV human infections: (a) acute infection characteristic of high viremia, fever, lethargy and dermal rash; (b) asymptomatic stage with anti-SIV antibody and a decline in CD4 cell count and (c) AIDS, characteristic of substantial CD4 cell depletion and opportunistic infections. Beyond these similarities, an additional advantage of the use of the primate animal model is the ability to establish and monitor specific parameters related to alcohol consumption and HIV infection . These include time and route of infection, timing and quantity of alcohol consumption, assessment of nutritional and behavioral variables as well as characterization of systemic and organ specific pathogenesis. Limited data are available using this model and studies are needed to determine the interactions among alcohol, immune function, patent SIV infection and disease progression in nonhuman primate infection.

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Two genetic characteristics are relevant when considering a patient's response to drug therapy and drug metabolism. They are pharmacogenomics and pharmacogenetics. Pharmacogenomics, a function of the human genome, is the emerging field that uses genetic information to predict a patient's response to a drug. Examples of genes that influence a patient's response are genes regulating the enzymes and proteins involved in drug(s) metabolism and transport, genes that code for specific drug targets or genes that influence the expression of a disease. Pharmacogenetics is the field of science that identifies and characterizes polymorphic expression of genes related to drug metabolism. Most important for alcohol detoxification is alcohol and aldehyde dehydrogenases and the cytochrome P450 systems in phase I biotransformation and glutathione-S-transferase for phase II biotransformation. For the metabolism of drugs used for the control of HIV infection, the cytochrome P450 system and glutathione-S-transferases are important. Polymorphisms in the genes that encode for enzymes in phase I or phase II biotransformation result in differing enzyme kinetics, with relatively slower or faster than normal rates of metabolism. Thus, based on the expression of polymorphic genes, ethanol metabolites and toxic intermediates could build -up or be quickly biotransformed based on the nature of the kinetics. This could change the bioavailability of the drug in question and present dosing difficulties for drugs with narrow therapeutic ranges. The question "How does individual patient pharmacokinetic profiles contribute to HIV treatment failure?" is now being addressed through the elucidation of an individual pharmacogenetics. Subsequent individualized drug regimens can then be contemplated to include alcohol consumption and metabolism to maximize treatment success.

Highly Active Antiretroviral Therapy (HAART)

The activity level of CYP3A4 is important in the metabolism of drugs comprising

HAART. Orally administered drugs comprising HAART regimens are rapidly converted to inactive metabolites via first-pass oxidative metabolism by the P450 cytochrome system. including CYP3A4. HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir and the non-nucleoside reverse transcriptase inhibitors efavirenz, nevirapine and delavirdine are susceptible to drug-drug interactions resulting in either enhanced or decreased metabolism. Drugs that are inhibitors of specific cytochromes reduce clearance and extend the serum concentration half-life of drugs. Inducers of cytochromes, enhance oxidative metabolism and reduce serum concentrations of drugs. Additional inducers of CYP3A4 modify (reduce) HAART pharmacokinetics. Isopentanol has been shown to be a more potent and effective inducer of CYP3A4 than ethanol in human liver cells in vitro. In animals, the administration of isopentanol/ethanol mixtures results in increases in CYP3A greater than that induced by either agent alone. An elevation in CYP3A4 activity in these individuals may result in enhanced drug metabolism and reduced therapeutic drug levels. Thus, HAART may not be as effective in some individuals who consume alcoholic beverages. Individuals consuming alcoholic beverages may place themselves at risk for developing drug resistant HIV strains due to subtherapeutic levels of protease inhibitors, as a consequence of enhanced protease inhibitor metabolism. Therapeutic drug monitoring studies, stratified by alcohol consumption levels, are needed in HIV patients who consume any alcoholic beverages to confirm this hypothesis.

With regard to HAART, drug deposition may be altered due to reduced liver function from drug-induced hepatotoxicity, hepatitis -infection or cirrhotic liver disease. A standard strategy for evaluating drug metabolism in individuals with liver impairment is to conduct single-dose studies in patients with alcoholic cirrhosis and a control group comprised of healthy volunteers. Individuals with liver disease are graded and stratified by the severity of liver disease usually by the Child-Pugh scoring classification. Drug dosing recommendations from the studies are based on the comparative results of the liver-impaired groups versus controls. Such a study has recently been performed with Amprenavir, showing a 2.5 fold increase in area under the curve (drug serum concentration) for the moderate cirrhosis group and a 4.5 fold increase for the severe cirrhosis group compared to healthy controls. The study indicated reduced oral concentrations of drug that should be given to HIV-infected individuals with liver cirrhosis since drug accumulation can lead to further toxicity. Dosage reductions have also been recommended for zidovudine and indinavir.

In addition to causing major dysregulation of the immune system, HIV infection profoundly affects the CNS. Viral invasion of the brain has been documented as early as two weeks postinfection, a time well before seroconversion can be determined. Autopsy reports have confirmed neuropathological abnormalities in as many as 90% of patients with AIDS. Consistent with these observations of CNS damage, HIV-associated cognitive/motor complex-characterized by psychomotor slowing, memory deficits and behavior changes- is thought to afflict between 15% and 40% of AIDS patients and to be the histopathologic correlate of HIV encephalities.

Despite the widespread recognition of the devastating effects of HIV on neural tissue and brain function, the mechanism(s) underlying these pathologies remain unclear. Penetration of the virus into the CNS arena appears to be critical, however, as neurobehavioral deficits correlate with viral load. Mounting evidence points to the ability of HIV or HIV-infected mononuclear cells to penetrate the blood-brain barrier (BBB) as the means by which the virus gains access to the CNS compartment. The cerebral microvessel endothelium is the major cellular element of the BBB and comprises the primary limitation to passage of substances from the blood to the brain. Brain microvessel endothelial cells (BMECs) possess unique features that distinguish them from cells of peripheral endothelium, and these may significantly limit the paracellular flux through the BBB and that are thought to be a major impediment to invasion of the brain by both microorganisms and circulating leukocytes. The lack of fenestrae in BMECs, as well as the presence of specific membrane-associated transport systems, further restricts the transcellular movement of materials from blood to brain. It stands to reason that modulation of any of these BBB properties could significantly impact the ability of HIV to enter the CNS and cause neurodestruction.

While many factors could potentially alter BBB integrity and function-and thus foster HIV access to brain environs-particular attention should be given to alcohol. Alcohol has been linked to heightened susceptibility to and progression of HIV infection and HIV-related CNS disease. Potential routes by which alcohol might facilitate HIV entry into the brain include augmented expression of proinflammatory cytokines, modulation of membrane permeability and interendothelial junctions, and stimulation of viral replication.

Research studies are needed to elucidate the influence of alcohol use and abuse on the systemic biological changes observed during the course of HIV infection and treatment. Data from these studies are of particular clinical significance because alcohol consumption can change the physiology of virtually every cell in the body. Alcohol can modify the function of the digestive tract, immune system, cardiovascular system, endocrine system, reproductive system, brain and central nervous system, and musculoskeletal system. Thus, the biomedical consequences of alcohol use and abuse on HIV infection, transmission, pathogenesis and treatment are important research priorities.

Clinical management of HIV infected alcohol abusers is dependent on understanding the combined role of HIV and alcohol in damaging specific organs and systems and how to prevent continuing damage. Given the widespread use of alcohol and rapidly growing HIV-infected population, the need to delineate the role of alcohol in the development of HIV-related CNS disease has reach urgent status. In addition, more studies are needed in the medical management of HIV-infected patients determining the interrelationship between HIV and the liver disease, the diversity and duration of antiviral therapeutic regimens, drug-drug interactions, differing etiologies of hepatic cirrhosis (alcohol, hepatitis C, hepatitis B) and determination of liver disease.

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ACKNOWLEDGEMENTS

The National Institute on Alcohol Abuse and Alcoholism is grateful to the following individuals for their various contributions to the ideas and content of this pamphlet.

Charles W. Flexner, MD, Johns Hopkins Medical Institutions, Baltimore

Craig McClain, MD, University of Kentucky, Lexington

Joel Pachter, PhD, University of Connecticut Health Science Center, Farmington

Judd Shellito, MD, Louisiana State University Medical Center, New Orleans

Jack T. Stapleton, MD, University of Iowa, Iowa City

Carl Waltenbaugh, PhD, Northwestern University, Chicago

Some parts of this pamphlet have been previously published. A previous version of the pamphlet entitled Alcohol & AIDS was published in 1998. The Behavioral section was adapted from a presentation Alcohol and AIDS Behavioral Research, delivered by Dr. Kendall Bryant, NIAAA AIDS Coordinator at a meeting of the Research Society on Alcoholism, Hilton Head, South Carolina, 1998.

Updated: December 2004