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Director's Report to the National Advisory Council on Drug Abuse
February, 2002

Research Findings

Research on AIDS and Other Medical Consequences of Drug Abuse

Neural Correlates of Attention and Working Memory Deficits in HIV Patients

Dr. Linda Chang and colleagues evaluated the neural correlates of attention and working memory deficits in patients with HIV-1. Functional magnetic resonance imaging (fMRI) was used with the blood oxygen level dependent (BOLD) contrast to evaluate regional brain activity in HIV-positive (HIV+) and HIV-negative (HIV-) controls while performing a battery of tasks that required different levels of attention for working memory. Results revealed that those HIV+ individuals showed greater brain activation in the parietal regions when performing simple tasks compared with seronegative controls, but those HIV+ individuals also showed task difficulty-dependent increases in frontal activation. Reaction times were slower, but accuracy was similar in the HIV+ individuals compared with controls. Thus, neuronal injury caused by HIV infection may necessitate greater attentional modulation reflected by a greater use of brain reserve in general and more specifically excessive attentional modulation due to frontostriatal brain injury. Chang L., et al., Neurology, 57(6), pp. 1001-1007, 2001.

Sex-related HIV Risk Reduction Behavior Among Adolescents in DATOS-A

This study examines changes in levels of HIV-related risky sexual behaviors pre- and post- treatment in relation both to patient characteristics and treatment services, received among 796 adolescents entering drug treatment programs in four cities in the United States. More than half of the adolescents (54%) reported reductions in risky sex behavior after treatment or sustained low levels of risk. Conduct-disordered adolescents with abuse history, unmet physical and emotional needs, and low commitment to school were associated with lack of improvement. Furthermore, conduct-disordered adolescents who perceived treatment to be effective were more likely to show posttreatment improvement, with the exceptions that those who scored high on hostility or low in self-perception were not likely to improve. Among adolescents without conduct disorder, receipt of mental health services was associated with improvements in their risky sex behavior The effect of drug treatment on HIV risk reduction can be increased when attention is focused on adolescents' pretreatment risk factors, service needs, in treatment responses, and key personality characteristics. Joshi, V., Hser, Y.I., Grella, C.E., and Houlton, R. Journal of Adolescent Research, 16(6), pp. 642-660, 2001.

A Cluster Analysis of HIV Risk Among Felony Drug Offenders

HIV risk profiles were investigated using cluster analysis with 247 male felony drug offenders. Two clusters were produced, distinguishable by high frequency of sex behaviors that were largely unprotected, or high frequency drug use. Exploratory analysis examining latent HIV predictors by risk type found older age, troubled feelings over drug problems, memory and concentration difficulties, higher frequency of burglary charges, and physical abuse history were predictive of drug-related HIV risk. Family problems, spending free time with family or friends, troubled feelings over medical problems, driving under the influence of drugs, anxiety, high risk-taking, polysubstance use, and using wages for drugs were predictive of sex-related HIV risk. Findings suggest intervention efforts for felony drug offenders need to address differential risk behaviors. Lang, M.A., and Belenko, S. Criminal Justice and Behavior, 28(1), pp. 24-61, 2001.

Meta-Analysis of HIV Risk-Reduction Interventions Within Drug Abuse Treatment Programs

A meta-analysis was conducted on studies using a treatment-comparison group design to evaluate HIV/AIDS risk-reduction interventions for clients enrolled in drug abuse treatment programs. Overall, the interventions studied were found to have a reliable positive (weighted) effect size (d = 0.31), and this was unlikely to be due to publication bias. Effect sizes for specific categories of outcome variables were 0.31 for knowledge, attitudes, and beliefs; 0.26 for sexual behavior; 0.62 for risk-reduction skills; and 0.04 for injection practices. A number of potential moderators were examined. Effect sizes were negatively correlated with the presence of predominantly ethnic minority samples and positively correlated with the number of intervention techniques used, the intensity of the intervention, intervention delivery at a later stage of drug treatment or within methadone treatment, and the presence of a number of specific intervention techniques. Prendergast, M.L., Urada, D., and Podus, D. J Consult Clin Psychol., 69(3), pp. 389-405, 2001.

Association of Alcohol Consumption with HIV Sex- and Drug-Risk Behaviors Among Drug Users

The relationship between alcohol use and HIV transmission is well recognized but not fully understood. In particular, the role of alcohol abuse as a mediator of HIV risk behavior among drug users is not well documented. We hypothesized that alcohol use in drug users will result in greater HIV risk-taking behavior. Participants were 354 drug users, of whom 105 were recent injection drug users. Multiple regression models were used to characterize the association between alcohol use, sexual risk behavior and injection drug use. HIV risk behavior was related to alcohol consumption, controlling for other potentially associated factors. We found that sexual HIV risk-taking behavior is associated with increased alcohol consumption among women (p = 0.02), with women having more risky sexual behavior than males. However, contrary to our hypothesis, there was no significant association of alcohol consumption with risky injection drug behavior. Addressing alcohol problems among drug users, particularly women, may be an important opportunity to reduce HIV sexual risk behavior among this high-risk population. Rees, V., Saitz, R., Horton, N.J. and Samet, J. Journal of Substance Abuse Treatment, 21(3), pp. 129-134, 2001.

Specific Drug Use Patterns Associated with Different Health Outcomes, HIV

A study in Baltimore assessed types of drugs used and routes of administration among 672 street-recruited drug users, and explored correlations of drug use patterns with social affiliation, HIV status, and lifestyle stability. Participants reported 63 patterns of drug use, which were categorized into five groups, including: sniff heroin only, smoke crack and snort cocaine, sniff heroin and smoke crack, inject heroin and cocaine, and inject heroin and cocaine, smoke crack, and may snort heroin. Social network analysis revealed that heroin sniffers and crack smokers both tended to associate with those with similar drug use pattern. Non-injecting drug use, particularly heroin sniffing, appeared to have the lowest risk of HIV infection, but high symptoms of drug dependence were observed among heroin users irrespective of mode of administration. Drug injectors who smoke crack are a bridge population to crack smokers who do not inject, and crack smoking compared to non-crack smoking was associated with higher sexual risk behaviors in terms of numbers of sex partners and drug-using sex partners. Specific drug use patterns may be more likely than others to facilitate HIV transmission, suggesting that, for example, HIV prevention interventions that target subgroups of cocaine and opiate users based on drug use patterns may be more effective in controlling HIV and preventing transitions from non-injecting to injecting drug use. Differential affiliation by drug use patterns suggests caution in snowball sampling for recruiting drug users, since some studies have found that interventions that bring together high-risk individuals may lead to unanticipated negative outcomes. Mixing groups of heroin sniffers or crack users with injectors, especially if they use both heroin and cocaine, may increase the risks of HIV transmission for the non-injectors and may facilitate injection of drugs. Latkin, C.A., Knowlton, A.R., and Sherman, S. Routes of Drug Administration, Differential Affiliation, and Lifestyle Stability Among Cocaine and Opiate Users: Implications to HIV Prevention. J Subst Abuse, 13, pp. 89-102, 2001.

Relationships and Diseases Among Drug Users and Non-Users

HIV and syphilis are relationship-based diseases that are typically transmitted by the cooperative activities (sex or drug injection) of two persons. In this study, researchers sampled 215 drug users and 52 socio-demographically matched nonusers to examine the behaviors and relationships related to HIV and syphilis transmission. They found that, although drug users had more risk opportunities (more sex partners and more injection partners) than nonusers, actual sex risk behaviors (never using condoms) did not differ appreciably among drug users and nonusers or with opposite-sex partners and same-sex partners. Similarity in sexual risk was evidenced by the similar levels of syphilis between drug users and nonusers. The unique risk to drug users (i.e., higher risk of exposure to disease than nonusers) was drug injection, although drug users were found to engage in fewer risky injection behaviors (sharing of drug injection equipment) than the risky sexual behaviors in which all participants engaged. Although drug users interacted as frequently with partners as nonusers, nonuser relationships were longer lasting and emotionally closer. Bell, D.C., Lee, D., Yang, S., and Health, V. Relationships and Diseases Among Drug Users and Nonusers. J Urban Health, 78(2), pp. 313-326, 2001.

Drug Use, Sex Partners, and Behaviors of 18-24 Year-Olds in a High Risk Neighborhood

Researchers sought to determine how stigmatized drug use is related to sexual risk behaviors and network characteristics among youth. They conducted in-person interviews with a probability household sample (n=363) and a targeted, street-recruited sample of cocaine, heroin, crack, or injecting drug users comprising 18-24 year-olds in an inner city neighborhood. Drug use in the preceding 12 months was scaled hierarchically on the basis of lowest to highest social stigma, from none, to marijuana, non-injected cocaine, non-injected heroin, crack, and injected drugs. Findings indicate that users of the more stigmatized drugs had more sex partners. They were more likely to report a history of concurrent sex partners, sex with someone who also had engaged in sex with a network member, commercial sex work, and unprotected sex. Findings also showed crack use and drug injection to be associated more strongly with increased sex risk among women than among men. Young users of the more stigmatized drugs are at much greater network and behavior risk for sexually transmitted diseases. Drug use prevention and treatment programs can help to reduce sex risk because young people who use drugs engage in more sex risk behaviors and are more likely to have concurrent or shared partners than those who do not use drugs. Risk reduction interventions that address sex risk of drug users can also help to encourage condom use and fewer sex partners, and to refer drug users to screening and treatment services for sexually transmitted infections. Flom, P., Friedman, S., Kottiri, B., Neaigus, A., Curtis, R., Des Jarlais, D., Sandoval, M., and Zenilman, J. Stigmatized Drug Use, Sexual Partner Concurrency, and Other Sex Risk Network and Behavior Characteristics of 18- to 24-Year Old Youth in a High-Risk Neighborhood. Sexually Transmitted Diseases, 28(10), pp. 598-607, 2001.

Crack Cocaine Users, Predictors of Change, and Condom Use

Researchers examined whether sexual activity and partner characteristics differentiate people in different stages of change. Behavior change, primarily the reduction of high-risk sexual activity through the promotion of condom use, is the best method of reducing the incidence of new HIV infections. Many interventions attempt to reach people who are ready to make a behavior change, and miss those who are only beginning to think about it or not thinking about it at all. In this study, factors expected to distinguish people in different stages of change were partner type, drug use during sex, and HIV status. Three discriminant functions emerged from the data: partner type was the strongest predictor that distinguished people in the pre-contemplation stage from those in the preparation, action, and maintenance stages; when controlling for partner type, HIV status was the best predictor for distinguishing between the people in the maintenance stage and those in the other stages. The overall classification results indicate that individuals using crack cocaine and engaging in high-risk sexual behaviors can be classified into the stages of change for condom use based on these variables. Timpson, S., Pollak, K., Williams, M., Ross, M., Kapadia, A., Bowen, A., McCoy, C., and McCoy, V. Predictors of Stages of Change for Condom Use in Crack Cocaine Users. AIDS and Behavior, 5(1), pp. 65-74, 2001.

Residential Status and HIV Risk Behaviors Among Puerto Rican IDUs in NY and PR

Researchers investigated the association between residential status and HIV risk behaviors among island and New York Puerto Rican (PR) IDUs. They assigned 561 participants from New York City and 312 from Puerto Rico to 5 residential status categories: living in parents’ home, living in own home, living in others’ home, living in temporary housing, and homeless. Dependent variables were injection- and sex-related risk behaviors (sharing syringes, sharing other injection paraphernalia, shooting gallery use, and having paid sex). Chi square, t tests, and multivariate logistic analysis tests were performed separately by site. About 25% of the participants at each site were homeless. Island PRs were more likely to live with parents (44% vs 12%, p<. 001) and more NY IDUs lived in their own home (30% vs 14%, p<. 001). In NY, gallery use and paid sex were associated with living in other’s home, living in parent’s home, and being homeless. Sharing paraphernalia was related to living in other’s home, living in temporary housing, and being homeless. In Puerto Rico, having paid sex was associated with homelessness. High-risk behaviors were more likely among homeless IDUs in both sites. Programs to provide housing and target outreach and other prevention programs for homeless IDUs are recommended to help reduce HIV risk. Andia, J., Deren, S., Kang, S., Robles, R., Colon, H., Oliver-Velez, D., Finlinson, A., Beardsley, M., and Friedman, S. Residential Status and HIV Risk Behaviors Among Puerto Rican Drug Injectors in New York and Puerto Rico. Am J Drug Alcohol Abuse, 27(4), pp. 719-735, 2001.

Evaluation of a Brief HIV Risk Reduction Intervention in a Community Setting

Researchers evaluated a brief educational intervention strategy designed to reduce the risks of HIV infection associated with injecting drug use and risky sexual behaviors. Participants (N=7,733) were not-in-treatment drug users at high risk for HIV infection or transmission in multiple sites in the US and Puerto Rico. Multi-item needle and sex risk measures were developed to assess the efficacy of the intervention. Behavioral change was assessed within 6 empirically derived homogenous risk groups. Drug users in all 6 groups reduced their needle use and sexual risks after participating in the brief intervention. Sexual risks were reduced to a greater extent than were risks associated with needle use, both in relative terms and when measured as a percentage of risk exhibited at intake. Brief educational interventions may be more effective in reducing sexual risk behaviors than it was previously believed. Needle risk, on the other hand, appears to be more resistant to change, especially among high frequency cocaine injectors. These findings suggest that HIV prevention strategies may be more effective and more efficient if drug users are triaged into an intervention appropriate to their level of needle risk. Williams, M., McCoy, V., Bowen, A., Saunders, L., Freeman, R., and Chen, D. An Evaluation of a Brief HIV Risk Reduction Intervention Using Empirically Derived Drug Use and Sexual Risk Indices. AIDS and Behavior, 5(1), pp. 31-43, 2001.

HIV Risk in Men who Abuse their Spouses

This study examines the relationship between perpetrating intimate partner violence and HIV risk behavior among a sample of men in methadone maintenance treatment programs (MMTPs). Data were collected on 273 sexually active men, who were recruited from four inner-city MMTP clinics. More than a third of the sample reported perpetrating intimate physical abuse and 15% reported severe physical abuse in the past 12 months. Results from multiple logistic regression analyses indicate that after adjusting for demographic, poverty, and drug-use factors, men who abused an intimate partner were almost 4 times more likely to have more than one intimate partner, almost 3 times more likely to have unprotected anal sex, and 2.6 times more likely to have sex with a drug-injecting sexual partner than their counterparts. This study showed that men who perpetrated partner violence were at higher risk for HIV transmission. HIV prevention interventions need to consider the complex relationship between partner violence and HIV risk. El-Bassel, N., Fontdevila, J., Gilbert, L., Voisin, D., Richman, B.L., and Pitchell, P. J Subst Abuse, 13(1-2), pp. 29-43, 2001.

Additional Cost of Enhanced Prevention Intervention is Small, While Benefit is Large

An important objective of the NIDA Cooperative Agreement (CA) for AIDS Community-Based Outreach/Intervention Research Program was to develop and evaluate innovative interventions to reduce drug and sexual risk-taking behaviors. Findings from the multi-site CA suggest that NIDA’s brief standard intervention has a positive effect in reducing HIV risk behaviors. Researchers evaluated the costs, effectiveness, and cost-effectiveness of outreach-based HIV prevention interventions for out-of-treatment drug users at risk for HIV in North Carolina, as part of the NIDA CA. Participants in the study were given the NIDA standard intervention and randomly assigned to either a longer, more personalized enhanced intervention or no additional intervention. The cost of each intervention was estimated using simple means analysis and multiple regression models; the incremental effectiveness of the enhanced intervention was also estimated relative to the standard intervention; and cost-effectiveness ratios were computed for several drug use outcomes and compared to a general estimate of the benefit of reducing drug use. Findings indicate that the estimated cost of implementing the standard intervention is $187.52 per person, and the additional cost of the enhanced intervention is $124.17 per person. Cost-effectiveness ratios range from $35.68 to $139.52 per reduced day of drug use, which is less than an estimate of the benefit per reduced drug day. The additional cost of implementing the enhanced intervention is relatively small and compares favorably to a rough estimate of the benefits of reduced days of drug use. Thus, the enhanced intervention strategy should be considered an important additional component for out-of-treatment drug users. Zarkin, G., Lindrooth, R., Demiralp, B., and Wechsberg, W. The Cost and Cost-Effectiveness of an Enhanced Intervention for People with Substance Abuse Problems at Risk for HIV. Health Services Research, 36(2), pp. 335-355, 2001.

Longitudinal Predictors of Depressive Symptoms Among Low Income IDUs

In this study, researchers assessed the effects of changes in physical health status and drug use, and prior social support on depressive symptoms in low income IDUs. Data are from 503 participants enrolled at baseline who remained at 1-year follow up (393 IDUs, or 79%); 37% were HIV+ and 36% female. Physical health was measured by HIV symptoms, AIDS, CD4 count and functional limitation. One third scored high on depressive symptoms at 1-year follow up, representing no statistically significant change from baseline (38%). In multiple logistic regression, after controlling for baseline depression scores (OR=6.11, p<0.001) and drug use (OR=1.20, p=0.192), baseline functional limitation (OR=3.28, p<0.001) and declining functioning (OR=3.60, p<0.001) were positively, and quitting drug use was negatively, associated with depressive symptoms at follow-up. Low social support at baseline (OR=0.58), p<0.10) was marginally predictive of depressive symptoms. Depressive symptoms did not differ by gender. For HIV-positive respondents, functional limitation was predictive of depressive symptoms, but HIV illness and drug use were not. Facilitating drug treatment and preventive medical care may aid in reducing depression in this population. For HIV-positive drug users, drug treatment prior to AIDS may help reduce depressive symptoms, with potential implications for HIV service utilization and medical adherence. Knowlton, A., Latkin, C., Schroeder, J., Hoover, D., Ensminger, M., and Celentano, D. Longitudinal Predictors of Depressive Symptoms Among Low Income IDUs. AIDS Care, 13(5), pp. 549-559, 2001.

Study Examines Intention to Practice Safer Sex Among High-Risk Crack Smokers

Crack cocaine smokers are at particularly high risk for HIV due to heterosexual exposure with HIV-infected partners. In this study, researchers investigated predictors of intention to use condoms and related therapy processes among 586 heterosexual crack users in Washington, DC, Miami, and Collier County, Florida who reported having primary and casual sex partners. Participants responded to questionnaire items derived from the theory of reasoned action, the theory of planned behavior, and the trans-theoretical model of behavior change. Condom use beliefs and therapy processes used to initiate and maintain condom use were assessed. Outcome expectancies and normative beliefs were the strongest predictors of intention to use condoms with a primary partner. In turn, beliefs that condoms inhibit sexual romance and decrease sexual pleasure strongly predicted outcome expectancies. Therapy processes found to be associated with these constructs include: self-liberation, counter conditioning, and stimulus control/reinforcement. Results suggest that HIV risk reduction interventions using a group format and targeting condom beliefs related to sexual romance and pleasure will decrease negative outcome expectancies about condom use. Reinforcing attempts to use condoms with intimate partners should increase positive outcome expectancies and intention to initiate or maintain condoms with a primary partner. Bowen, A., Williams, M., McCoy, H., and McCoy, C. Crack Smokers’ Intention to Use Condoms with Partners: Intention Development Using the Theory of Reasoned Action, Condom Beliefs, and Processes of Change. AIDS Care, 13(5), pp. 579-594, 2001.

Drug-Drug Interactions Between AZT and Opioid Dependence Pharmacotherapies

Dr. McCance-Katz and her colleagues (Albert Einstein College of Medicine, NY) had previously reported that methadone increased zidovudine (AZT) concentrations. Now they report that other opioid dependence pharmacotherapies such as LAAM, buprenorphine, or naltrexone have no significant effect on AZT levels. The investigators studied the pharmacokinetics of AZT in 69 patients (25 women, 44 men; 18-65 years of age) treated with LAAM (21 patients), buprenorphine (16 patients), naltrexone (15 patients), and controls (17 patients). They found no significant differences in AZT concentrations in patients treated with any of the medications. They conclude that, although methadone maintenance may result in AZT toxicity and possibly require dose adjustments, other opioid pharmacotherapies are not associated with AZT toxicity. McCance-Katz, E., Rainey, P.M., Friedland, G., Kosten, T.R., Jatlow, P. Effect of Opioid Dependence Pharmacotherapeutics on Zidovudine Disposition. Am. J. Addictions, 10(4), pp. 296-307, 2001.

Risk Factors for Skin and Soft Tissue Abscess Among Injection Drug Users: A Case Control Study

Murphy and his colleagues (UCSF) report that subcutaneous (sc) or intramuscular (im), instead of intravenous (iv), injection is a major risk factor for soft tissue abscess among IDUs. The investigators conducted a case control study where they enrolled 151 IDU cases with new diagnoses of abscess requiring incision and drainage, and 267 IDU controls without abscess or other bacterial infection during the previous year. They matched the controls to cases by age, sex, and race. Data were obtained from the medical record and a questionnaire, and antibodies to viruses such as HIV, HTLV-I and II subtypes were measured in blood samples. Results showed abscess diagnosis was associated with sc or im injection or “skin popping” (OR=6.13, 95% CI 3.51-10.70); use of dirty needles (OR=3.34, 95% CI 1.75-6.82); injection of “speedball” (OR=3.31, 95% CI 1.37-7.95), and drawing blood into the syringe prior to injection or “booting” in those who did not “skin pop” (OR=2.33, 95% CI 1.46-3.70). Cleaning the skin with alcohol prior to injection was protective (OR=0.48, 95% CI 0.32-0.74). Neither HIV nor HTLV-II seropositivity was significantly associated with abscess. It was concluded that sc or im injection was associated with abscess among IDUs, and that injection of “speedball” may predispose to abscess by inducing soft tissue ischemia. Murphy, E.L., Liu, H., Leung, P., Edlin, B.R., DeVita, D., Vittinghoff, E., and Ciccarone, D.H. Clinical Infectious Disease, 33(1), pp. 35-40, 2001.

How Injection Drug Users Coped with Testing HIV-Seropositive: Implications for Subsequent Health-Related Behaviors

Margolin and his colleagues (Yale) find that IVUs have coping problems after testing positive for HIV that result in poor health and risky behaviors. The team assessed a group of 94 HIV+ IDUs entering a methadone treatment program. The instrument (Coping Responses Inventory) asked them to describe their feelings and experiences when they first learned that they were positive for HIV. Results showed that avoidance of coping was highly correlated with high levels of recent HIV risk behaviors at entry into the treatment program. Other independent predictors of continued risk behavior were poor health, lack of social support, and low levels of HIV/AIDS knowledge. The authors identify a strong need for interventions to help IDUs cope subsequent to testing HIV seropositive. Avants, S.K, Warburton, L.A., and Margolin, A. AIDS Education and Prevention, 13(3), pp, 207-218, 2001.

Opioid Modulation of HIV Infection

Kappa opioids have been observed to inhibit HIV growth in special cell cultures. The present study demonstrates that delta opioids are immunosuppressive in cultured human lymphocytes of HIV growth. Thus drugs of this type would appear to be an even more important adjunctive treatment for AIDS in humans. However, no delta ligand is presently available for studies in humans. The delta opioid receptors (DORs) modulate T cell proliferation, IL-2 production, chemotaxis, and intracellular signaling. Moreover, in DOR-transfected Jurkat cells, delta opioids have been shown to suppress HIV-1 p24 Ag expression. These observations led investigators to characterize the expression of DORs by human peripheral blood T cells and to determine whether a specific DOR agonist, SNC-80, can suppress p24 Ag expression by HIV-1-infected CD4(+) T cells obtained from normal donors. By immunofluorescence flow cytometry, PHA stimulated the expression of DOR of the peripheral blood mononucleocytes (PBMC) population by 48 h. To determine whether activated DORs suppress HIV-1 expression, PBMC were prestimulated with PHA, and then CD4+ T cells were purified, pretreated with SNC-80, and infected with HIV-1. In a concentration-dependent manner, SNC-80 inhibited production of the p24 Antigen of HIV. SNC-80 maximally suppressed both lymphocytotropic and monocytotropic strains of HIV. Naltrindole, a selective DOR antagonist, abolished the inhibitory effects of SNC-80. Kinetic studies indicated that 24-h pre- or postincubation with SNC-80, relative to infection with HIV-1, eliminated its suppressive effects. Thus, stimulating the DORs expressed by activated CD4+ T cells significantly suppressed the expression of HIV-1. These findings suggest that opioid immunomodulation directed at host T cells may be adjunctive to standard antiviral approaches to HIV-1 infection. Sharp, B.M., McAllen, K., Gekker, G., Shahabi, N.A., and Peterson, P.K. Immunofluorescence Detection of Delta Opioid Receptors (DOR) on Human Peripheral Blood CD4(+) T cells and DOR-dependent Suppression of HIV-1 expression. J Immunology, 167, pp. 1097-1102, 2001.

Naltrexone Potentiates anti-HIV-1 Activity of Antiretroviral Drugs in CD4(+) Lymphocyte Cultures

Another study focused on the amplification of anti-HIV drug treatment. The addition of naltrexone in vitro to lymphocytes enhanced the inhibition of HIV growth in the presence of either of the major types of anti-viral drugs now in therapy. Clinical studies are envisioned by this group to see if the in vitro effects observed here relate to treatment of this disease in humans. CD4(+) T lymphocytes are the primary cell target for human immunodeficiency virus-1 (HIV-1), and these cells are known to express opioid receptors. Due to the need for new treatment approaches to HIV-1 infection, we sought to determine whether the non-selective opioid receptor antagonist naltrexone would affect HIV-1 expression in CD4(+) lymphocyte cultures and whether naltrexone would alter the antiviral properties of zidovudine (AZT) or indinavir. Activated CD4(+) lymphocytes were infected with a monocytotropic or T-cell tropic HIV-1 isolate, and p24 antigen levels were measured in supernatants of drug-treated or untreated (control) cultures. While naltrexone alone did not affect HIV-1 expression, naltrexone increased the antiviral activity of AZT and indinavir 2-3-fold. Similar findings with a Kappa-opioid receptor (KOR) selective antagonist supported the possible involvement of KOR in naltrexone's potentiation of the antiretroviral drugs. The results of this in vitro study suggest that treatment of alcohol or opiate dependent HIV-1-infected patients with naltrexone is unlikely to interfere with the activity of antiretroviral drugs. Also, based upon naltrexone's safety profile and its synergistic activity in vitro, these findings suggest clinical trials should be considered of naltrexone as an adjunctive therapy of HIV-1 infection. Gekker, G., Lokensgard, J.R., and Peterson, P.K. Naltrexone Potentiates anti-HIV-1 Activity of Antiretroviral Drugs in CD4(+) Lymphocyte Cultures. Drug Alcohol Depend, 64, pp. 457-463, 2001.

HIV Infection Requires Integration of the Virus into the Host Genome or DNA

This integration takes place by DNA strand breaks and subsequent repair of these breaks. One enzyme activated by DNA strand breaks and involved in the repair process is Poly (ADP-ribose) polymerase-1 (PARP-1), an enzyme that is expressed mostly in the nucleus. It has been hypothesized that PARP-1 mediates the integration of HIV into the host genome. However, studies using benzamide derivatives and benzopyrone inhibitors, weak inhibitors of PARP, have not been conclusive in showing reduction of viral infection. To more definitively demonstrate the role of PARP-1 in HIV integration and infection, Dr. Snyder and his colleague at Johns Hopkins University Medical School attempted to infect mouse fibroblast derived from a genetically engineered mouse that is deficient in PARP-1. In the March 13, 2001 issue of the Proceedings of the National Academy Science, Dr. Snyder reports a profound reduction of HIV infection in mouse fibroblasts lacking PARP-1 and results from an inhibition of viral integration. These results suggest that potent and selective inhibitors of PARP-1 may prove useful in the treatment of HIV infection. In animal models, these inhibitors have already been shown to be effective in treating stroke, myocardial infarction, diabetes, sepsis, and inflammation. Ha, H.C., Juluri, K., Zhou, Y., Leung, S., Hermankova, M. and Snyder, S.H. Poly(ADP-ribose) polymerase-1 (PARP-1) is Required for Efficient HIV-1 Integration. Proceedings of the National Academy of Sciences, 98, pp. 3364-3368, 2001.

HIV Transmission and the Cost Effectiveness of Methadone Maintenance

This project determined the cost effectiveness of expanding methadone maintenance treatment for heroin addiction, particularly its effect on the HIV epidemic. The investigators developed an epidemic model to study the effects of increased methadone maintenance capacity on health-care costs and survival, measured as quality-adjusted life years (QALYs). The investigators considered communities with HIV prevalence among injection drug users (IDUs) of 5% and 40%. Results included: additional methadone maintenance capacity costs $8,200 per QALY gained in the high-prevalence community and $10,900 per QALY gained in the low-prevalence community. Individuals who do not inject drugs gain more than half of the benefits. Even if the benefits realized by treated and untreated IDUs are ignored, methadone maintenance expansion costs between $14,100 and $15,200 per QALY gained. Additional capacity remains cost effective even if it is twice as expensive and half as effective as current methadone maintenance slots. Importantly, expansion of methadone maintenance is cost effective based on commonly accepted criteria for medical interventions. Barriers to methadone maintenance deny IDUs access to a cost-effective intervention that generates significant health benefits for the general population. Zaric, G., Barnett, P., and Brandeau, M. American Journal of Public Health, 90, pp. 1100-1111, 2000.

The Cost Effectiveness of Buprenorphine Maintenance Therapy for Opiate Addiction in the United States

The aims of this project were to determine the cost-effectiveness of buprenorphine maintenance therapy (BMT) for opiate addiction in the United States, particularly its effect on the HIV epidemic. The researchers developed a model to capture the effects of adding buprenorphine maintenance to the current opiate dependence treatment system. The evaluated incremental costs, including all health care costs, and incremental effectiveness, measured as quality-adjusted life years (QALYs) of survival. The investigators considered communities with HIV prevalence among injection drug users of 5% and 40%. Because no price has been set in the United States for a dose of buprenorphine, the investigators considered three prices per dose: $5, $15, and $30. Authors found that if buprenorphine increases the number of individuals in maintenance treatment by 10%, but does not affect the number of individuals receiving methadone maintenance, the cost-effectiveness ratios for BMT are less than $45,000 per QALY gained for all prices, in both the low-prevalence and high-prevalence communities. If the same number of individuals enter buprenorphine maintenance (10% of the number currently in methadone), but half are injection drug users newly entering maintenance, and half are individuals who switched from methadone to buprenorphine, the cost-effectiveness ratios in both communities are less than $45,000 per QALY gained for the $5 and $15 prices, and greater than $65,000 per QALY gained for the $30 price. The authors conclude that at a price of $5 or less per dose, buprenorphine maintenance is cost-effective under all scenarios considered. At $15 per dose, it is cost-effective if its adoption does not lead to a net decline in methadone use, or if a medium to high value is assigned to the years of life lived by injection drug users and those in maintenance therapy. At $30 per dose, buprenorphine will be cost-effective only under the most optimistic modeling assumptions. Barnett, P., Zaric, G., and Brandeau, M. Addiction, 96, pp. 1267-1278, 2001.

Prenatal Cocaine Exposure and Intrauterine Growth

Researchers at the University of Miami, with collaborators at Johns Hopkins University, have recently reported findings of a specific cocaine-related deficit in fetal growth and gestational age. The analyses in this report involved a high degree of covariate control (e.g., prenatal substance exposures other than cocaine, maternal age, maternal education), using structural equations and multiple regression models. The findings support previously reported research regarding influences of prenatal cocaine on fetal growth and gestational age, and call into question the notion that head circumference is disproportionately affected compared to overall somatic growth. Head circumference was affected, but not disproportionately. There was also evidence that some of the cocaine effects on fetal growth were direct and some were indirect, mediated by a cocaine influence on gestational age. The study sample was drawn from the Miami Prenatal Cocaine Study, which involved 476 full-term infants born to inner-city, African-American women. Bandstra, E.S., Morrow, C.E., Anthony, J.C., et al. Intrauterine Growth of Full-Term Infants: Impact of Prenatal Cocaine Exposure. Pediatrics, 108, pp. 1309-1319, 2001.

Neuropsychological Performance in Long-term Cannabis Users

Pope and his colleagues (Harvard/McLean Hospital) have found that in long-term heavy cannabis using adults, some cognitive deficits are detectable on days 0, 1, 7, and not on days 28, after cannabis use is discontinued. The team recruited individuals aged 30 to 55 in 3 groups: 63 current heavy users who had smoked cannabis at least 5000 times in their lives and who were smoking daily at study entry; 45 former heavy smokers who had also smoked at least 5000 times but fewer than 12 times in the last 3 months; and 72 control subjects who had smoked no more than 50 times in their lives. Subjects underwent a 28-day washout from cannabis use, monitored by observed urine toxicology. On days 0, 1, 7, and 28, the subjects were administered a neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Test results were analyzed by repeated-measures regression analysis, adjusting for potentially confounding variables. Results showed that at days 0, 1, and 7, current heavy users scored significantly below control subjects on recall of word lists, and this deficit was associated with users’ urinary 11-nor-9-carboxy-THC (THC metabolite) concentrations at study entry. By day 28, there were virtually no deficits that could be associated with cumulative lifetime cannabis use. The authors concluded that cognitive deficits were reversible and related to recent cannabis use rather than irreversible and related to cumulative lifetime use. Pope, H., Gruber, A.J., Hudson, J.I., Huestes, M.A., and Yurgelum-Todd, D. Arch. Gen. Psychiatry, 58, pp. 909-915, 2001.

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