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Director's Report to the National Advisory Council on Drug Abuse - September, 2007

Research Findings - Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV)

The 2004 Australian Prison Entrants' Blood-borne Virus and Risk Behavior Survey

The objective of this study was to assess the prevalence of blood-borne viruses and associated risk factors among prison entrants at seven Australian prisons across four States. For this work a consecutive cross-sectional design was employed. Voluntary confidential testing of all prison entrants for serological markers of human immunodeficiency virus (HIV), hepatitis C (HCV) and hepatitis B (HBV) was carried out over 14 consecutive days in May 2004. Demographic data and data related to risks for blood-borne virus transmission, such as sexual activity, body piercing, tattooing, and injecting drug use, were collected. National prevalence for HIV was 1%, hepatitis B core antibody 20%, and hepatitis C antibody 34%. Fifty-nine per cent of participants had a history of injecting drug use. Among injecting drug users, the prevalence of HIV was 1%, hepatitis C antibody 56%, and hepatitis B core antibody 27%. Forty-one per cent of those screened reported a previous incarceration. In the multivariate model, Queensland and Western Australian (WA) prison entrants were significantly less likely to test positive for HCV than those in New South Wales (NSW). Amphetamine was the most commonly injected drug in Queensland, Tasmania and WA. In NSW, heroin was the most common drug injected. In the multivariate analysis a history of injecting drug use, being aged 30 years or more, and a prior incarceration were positively associated with hepatitis C infection. For hepatitis B core antibody, age over 30 years and a history of injecting drug use were associated with an increased risk. The findings support the view that prisoner populations are vulnerable to blood-borne virus infection, particularly hepatitis B and C. Prisoner populations should be included in routine surveillance programs so as to provide a more representative picture of blood-borne virus epidemiology in Australia. Butler, T., Boonwaa, L., Hailstone, S., Falconer, T., Lems, P., Ginley, T., Read, V., Smith, N., Levy, M., Dore, G., and Kaldor, J. Aust N Z J Public Health. Feb;31(1), pp. 44-50, 2007.

CD4+ T Cell-Dependent Reduction in Hepatitis C Virus-specific Humoral Immune Responses After HIV Infection

Human immunodeficiency virus (HIV) infection adversely affects all stages of hepatitis C virus (HCV) infection, leading to increased rates of viral persistence, higher levels of HCV viremia, and accelerated progression of HCV-related liver disease. These disease interactions may result in part from impairment of B cell function, which is CD4(+) T cell dependent. To determine the effect of HIV infection on B cell function, authors compared HCV antibody levels and specificities in 29 HCV-infected persons before and after they acquired HIV and assessed the temporal correlation of these changes with overall CD4(+) T lymphocyte counts. The pre-HIV infection HCV antibody titer was a predictor of the subsequent titer for all antigens, and decreasing CD4(+) T cell numbers was strongly associated with a decrease in anti-HCV titers for several antigens. CD4(+) T cells counts of <500 cells/mm(3) were significantly associated with lower HCV antibody end-point titers. Higher HCV end-point titers were associated with fewer years from HIV infection and, for Core antigen, current drug use. HCV-specific antibody production is impaired by HIV infection, and loss of antibody production depends on CD4(+) T cell depletion. However, the decrease in titers is less significant in those who continue to actively inject drugs. Netski, D.M., Mosbruger, T., Astemborski, J., Mehta, S.H., Thomas, D.L., and Cox, A.L. J Infect Dis. 2007 Mar 15;195(6):857-63. Epub February 7, 2007.

Effect of Exposure to Injection Drugs or Alcohol on Antigen-Specific Immune Responses in HIV and Hepatitis C Virus Coinfection

Ongoing substance use is a potential confounder for immunological studies on hepatitis C virus (HCV), but there is little in the literature regarding the effects of injection drug use (IDU) or alcohol on HCV-specific immune responses. The authors wanted to determine whether IDU or alcohol affected immune responses in HCV-infected and human immunodeficiency virus (HIV)/HCV coinfected subjects. Eighty-four subjects with HIV/HCV and 57 with HCV were classified as either injection drug users, drinkers, or nonusers based on questionnaire results. Immune responses were studied with enzyme-linked immunosorbent spot assay for interferon (IFN)- gamma, interleukin (IL)-10, and tumor necrosis factor (TNF)- alpha against HCV proteins Core, NS3, and NS5 and recall antigens. Subjects with HIV/HCV, in aggregate, had significantly lower HCV-specific IFN- gamma and TNF- alpha responses than subjects with HCV. However, HIV/HCV injection drug users had HCV-specific IFN- gamma and IL-10 responses that were similar to those of HCV injection drug users and were significantly higher than in nonusers with HIV/HCV. Conversely, subjects who drank alcohol had similar immune responses to those who were abstinent, among both subjects with HIV/HCV and subjects with HCV. Studies that examine IFN- gamma or IL-10 immune responses in HIV/HCV-coinfected or HCV-infected persons need to consider current IDU. Alcohol, at levels consumed in this cohort, does not appear to have as much of an effect on antigen-specific immune responses. Graham, C.S., Wells, A., Edwards, E.M., Herren, T., Tumilty, S., Stuver, S.O., Samet, J.H., Nunes, D., Horsburgh, C.R., and Koziel, M.J. J Infect Dis. 2007 Mar 15;195(6), pp. 847-856. Epub February 2, 2007.

Proteomic Analyses of Methamphetamine (METH)-induced Differential Protein Expression by Immature Dendritic Cells (IDC)

In the US, the increase in methamphetamine (METH) use has been associated with increased human immunodeficiency virus (HIV-1) infection. Dendritic cells (DC) are the first line of defense against HIV-1. DC plays a critical role in harboring HIV-1 and facilitates the infection of neighboring T cells. However, the role of METH on HIV-1 infectivity and the expression of the proteome of immature dendritic cells (IDC) have not been elucidated. Authors hypothesize that METH modulates the expression of a number of proteins by IDC that foster the immunopathogenesis of HIV-1 infection and utilized LTR amplification, p24 antigen assay and the proteomic method of difference gel electrophoresis (DIGE) combined with protein identification through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the effects of METH on HIV-1 infectivity (HIV-1 IIIB; CXCR4-tropic, X4 strain) and the proteomic profile of IDC. Results demonstrate that METH potentiates HIV-1 replication in IDC. Furthermore, METH significantly differentially regulates the expression of several proteins including CXCR3, protein disulfide isomerase, procathepsin B, peroxiredoxin and galectin-1. Identification of unique, METH-induced proteins may help to develop novel markers for diagnostic, preventive and therapeutic targeting in METH using subjects. Reynolds, J.L., Mahajan, S.D., Sykes, D.E., Schwartz, S.A., and Nair, M.P. Biochim Biophys Acta. 2007 Apr;1774(4), pp. 433-442. Epub February 13, 2007.

Heroin-Induces Differential Protein Expression by Normal Human Astrocytes (NHA)

Heroin use is postulated to act as a cofactor in the neuropathogenesis of human immunodeficiency virus (HIV-1) infection. Astrocytes, integral components of the CNS, are reported to be susceptible to HIV-1 infection. Upon activation, astrocytes release a number of immunoregulatory products or modulate the expression of a number of proteins that foster the immunopathogenesis of HIV-1 infection. However, the role of heroin on HIV-1 infectivity and the expression of the proteome of normal human astrocytes (NHA) have not been elucidated. Authors hypothesize that heroin modulates the expression of a number of proteins by NHA that foster the neuoropathogenesis of HIV-1 infection and utilized LTR amplification and the p24 antigen assay to quantitate the effect of heroin on HIV-1 infectivity while difference gel electrophoresis (DIGE) combined with protein identification through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the effects of heroin on the proteomic profile of NHA. Results demonstrate that heroin potentiates HIV-1 replication in NHA. Furthermore, heroin significantly increased protein expression levels for protein kinase C (PKC), reticulocalbin 1 precursor, reticulocalbin 1, tyrosine 3-monooxgenase/tryptophan 5-monooxgenase activation protein, chloride intracellular channel 1, cathepsin D preproprotein, galectin 1 and myosin light chain alkali. Heroin also significantly decreased protein expression for proliferating cell nuclear antigen, proteasome beta 6 subunit, tropomyosin 3, laminin receptor 1, tubulin alpha 6, vimentin, EF hand domain family member D2, Tumor protein D54 (hD54), ATP synthase, H+ transporting, mitochondrial F1 complex and ribosomal protein S14. Identification of unique, heroin-induced proteins may help to develop novel markers for diagnostic, preventative and therapeutic targeting in heroin using subjects. Reynolds, J.L., Mahajan, S.D., Sykes, D., and Nair, M.P. Am J Infect Dis. 2(2), pp. 49-57, 2006.

Suppression of Human Immunodeficiency Virus Type 1 Viral Load with Selenium Supplementation: A Randomized Controlled Trial

Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking. High selenium yeast supplementation (200 mug/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean +/- SD. Of the 450 HIV-1-seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% +/- 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (Delta) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (Delta = 32.2 +/- 24.5 vs 0.5 +/- 8.8 microg/L; P<.001), and greater levels predicted decreased HIV-1 viral load (P<.02), which predicted increased CD4 count (P<.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection. Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 microg/L displayed poor treatment adherence (56.8% +/- 29.8%), HIV-1 viral load elevation (Delta = +0.29 +/- 1.1 log(10) units), and decreased CD4 count (Delta = -25.8 +/- 147.4 cells/microL). In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 microg/L evidenced excellent treatment adherence (86.2% +/- 13.0%), no change in HIV-1 viral load (Delta = -0.04 +/- 0.7 log(10) units), and an increase in CD4 count (Delta = +27.9 +/- 150.2 cells/microL). The authors conclude that daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease. Trial Registration Identifier: ISRCTN22553118. Hurwitz, B.E., Klaus, J.R., Llabre, M.M., Gonzalez, A., Lawrence, P.J., Maher, K.J., Greeson, J.M., Baum, M.K., Shor-Posner, G., Skyler, J.S., and Schneiderman, N. Arch Intern Med. 167(2), pp. 148-154, 2007.

Rates and Predictors of Hepatitis C Virus Treatment in HCV-HIV-Coinfected Subjects

True treatment rates and the impact of comorbidities on treatment rates for hepatitis C virus in the HCV-HIV-coinfected subjects are unknown. The aim of this research was to quantify the rates of treatment prescription and the effect of comorbidities on hepatitis C virus treatment rates in HCV-HIV-coinfected veterans. The Veterans Affairs National Patient Care Database was used to identify all hepatitis C virus-infected subjects between 1999 and 2003 using ICD-9 codes. Demographics, comorbidities and pharmacy data were retrieved. Authors used logistic regression to compare the predictors of hepatitis C virus treatment in hepatitis C virus-monoinfected and HCV-HIV coinfected subjects and identified 120 507 hepatitis C virus-infected subjects, of which 6502 were HIV coinfected. 12% of the hepatitis C virus-monoinfected and 7% of the -coinfected subjects were prescribed hepatitis C virus treatment (P < 0.0001). Those not prescribed treatment were older (48.6 years vs. 47.7 years, P _ 0.007) and more likely to be black (52% vs. 32%, P < 0.0001). HIV coinfected subjects were less likely to be prescribed hepatitis C virus treatment (OR 0.74, 95% CI: 0.67-0.82). Among the coinfected subjects, the following were associated with non-treatment (OR, 95% CI): black race (0.45, 0.35-0.57); Hispanic race (0.56, 0.38-0.82); drug use (0.68, 0.53-0.88); anemia (0.17, 0.11-0.26); bipolar disorder (0.63, 0.40-0.99); major depression (0.72, 0.53-0.99); mild depression (0.47, 0.35-0.62). The authors conclude that a small number of HCV-HIV-coinfected veterans are prescribed treatment for hepatitis C virus. Non-treatment is associated with increasing age, minority race, drug use and psychiatric illness. Further studies are needed to determine the eligibility for treatment and reasons for non- treatment for hepatitis C virus. Butt, A.A., Justice, A.C., Sakanderson, M., Good, C., and Kwoh, C.K. Aliment Pharmacol Ther 24(4), pp. 585-591, 2006.

Biochemical and Virologic Parameters in Patients Co-infected with Hepatitis C and HIV Versus Patients with Hepatitis C Mono-infection

Previous studies of patients with hepatitis C virus (HCV) infection looking at the effect of human immunodeficiency virus (HIV) co-infection on biochemical parameters and HCV RNA level have shown conflicting results. Accurate characterization of the effect of HIV is important for evaluation and treatment of HCV in co-infected persons. The authors studied 315 HCV mono-infected and 75 HCV-HIV co-infected subjects to determine the effect of HIV on biochemical parameters and HCV RNA and to determine the predictors of elevated serum alanine aminotransferase (ALT) levels and HCV RNA levels. The co-infected subjects were more likely to be African-American (55% vs 26%, P < 0.0005), have used injection drugs (68% vs 60%, P = 0.02), have detectable HCV RNA (84% vs 70.5%, P = 0.018), have HCV RNA levels >6 log10 IU/mL (60% vs 38%, P = 0.001), and have lower mean serum ALT levels (50.4 IU/mL vs 73.7 IU/mL, P = 0.006). In multivariable analyses, the following factors predicted an ALT level >50 IU/mL: log10 HCV RNA (OR, 1.15; 95% CI, 1.00 to 1.32); HIV co-infection (OR, 0.48; 95% CI, 0.25 to 0.89); and having ever been treated for HCV (OR, 1.92; 95% CI, 1.16 to 3.18). The only significant predictor of HCV RNA level >6 log10 IU/mL was HIV co-infection (OR, 2.75; 95% CI, 1.46 to 5.15). Significant predictors of having a detectable HCV RNA level were female sex (OR, 3.81; 95% CI, 1.18 to 12.25); HIV co-infection (2.45; 95% CI, 1.14 to 5.26); and ever being treated for HCV (OR, 1.96; 95% CI, 1.10 to 3.48). The authors conclude that HCV-HIV co-infected persons have higher HCV RNA levels but lower serum ALT levels than HCV mono-infected patients. Criteria for performing liver biopsy and treating HCV infection in co-infected patients may need to be revisited. Butt, A.A., Tsevat, J., Ahmad, J., Shakil, A.O., and Mrus, J.M. Am J Med Sci. 333(5), pp. 271-275, 2007.

Alimentary Pharmacology & Therapeutics Awareness of Hepatitis C Diagnosis is Associated with Less Alcohol Use Among Persons Co-infected with HIV

It is unknown whether testing HIV-infected individuals for hepatitis C virus (HCV) and informing them of their HCV status impacts subsequent alcohol use. The authors hypothesized that HIV-infected individuals with current or past alcohol problems who reported being told they had HCV were more likely to 1) abstain from alcohol and 2) not drink unhealthy amounts compared to individuals who had not been told. Data from a prospective, observational cohort study (HIV-Longitudinal Interrelationships of Viruses and Ethanol) were used to assess the association between awareness of having HCV at baseline and subsequent abstinence and not drinking unhealthy amounts as reported at 6-month follow-up intervals. General estimating equations logistic regression was used to account for the correlation from using repeated observations from the same subject over time. The authors adjusted for age, sex, race, homelessness, injection drug use, depressive symptoms, and having abnormal liver tests. Participants who reported being told they had HCV were more likely to report abstaining from alcohol (AOR = 1.60; 95% CI: 1.13 to 2.27) and not drinking unhealthy amounts (AOR = 1.46; 95% CI: 1.01 to 2.11). The authors conclude that among patients infected with HIV who had a history of alcohol problems, reporting being told one had HCV was associated with greater abstinence from alcohol and less unhealthy amounts of drinking. Tsui, J.I., Saitz, R., Cheng, D.M., Nunes, D., Libman, H., Alperen, J.K., and Samet, J.H. J Gen Intern Med. 22(6), pp. 822-825, 2007. Epub February 23, 2007.

Impact of Hepatitis C on HIV Progression in Adults with Alcohol Problems

Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a substantial medical and public health concern due to its increasing prevalence and complex patient management. Alcohol use may worsen HCV-related liver disease and interfere with adherence to antiretroviral therapy (ART) and medical care. The authors therefore studied the association between HCV infection and markers of HIV disease progression in adults with alcohol problems. This is a longitudinal study of 396 HIV-infected persons with alcohol problems, 199 (50%) of whom were coinfected with HCV (positive HCV RNA test). CD4 cell counts and HIV RNA levels were assessed at baseline and then every 6 months for up to 42 months. Hepatitis C virus RNA status was determined at study enrollment. The authors examined the relationship between HCV infection and laboratory markers of HIV progression (CD4 cell count and log10 HIV RNA) by fitting multivariable longitudinal regression models for each outcome. Among subjects who were adherent to ART, the presence of HCV infection was associated with a lower CD4 cell count (adjusted mean difference -46.0 cells/microL, p=0.03). There was no association observed between HCV infection and CD4 cell count among those not adherent to ART or those not taking ART. No significant association was observed between HCV infection and HIV RNA regardless of ART status. The authors concluded that Hepatitis C virus infection has an adverse effect on CD4 cell count in patients with alcohol problems who are adherent to ART. Addressing HCV coinfection among these patients may confer additional immunologic benefit for this patient population. Cheng, D.M., Nunes, D., Libman, H., Vidaver, J., Alperen, J.K., Saitz, R., and Samet, J.H. Alcohol Clin Exp Res. 31(5), pp. 829-836, 2007. Epub March 31, 2007.

HIV Infection is Associated with an Increased Risk for Lung Cancer, Independent of Smoking

HIV-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. The ALIVE or AIDS Link to the Intravenous Experience Study has prospectively observed a cohort of IDU in Baltimore, MD since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables. Among 2086 ALIVE participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. These findings indicate that HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status, but specifically how or why this is so remains as yet unknown. Kirk, G., Merlo, C., O'Driscoll, P., Mehta, S., Galai, N., Vlahov, D., Samet, J., and Engels, E. HIV Infection is Associated with an Increased Risk for Lung Cancer, Independent of Smoking. Clin Infect Dis, 45(1), pp. 103-110, 2007.

Injection Drug Use and Patterns of Highly Active Antiretroviral Therapy Use: An Analysis of ALIVE, WIHS, and MACS Cohorts

Sustained use of antiretroviral therapy has been consistently shown to be one of the primary predictors of long-term effectiveness. Switching and discontinuation reflect patient and provider decisions that may limit future treatment options. In this study, researcher's utilized data reported at semi-annual study visits from three prospective cohort studies, the AIDS Link to IntraVenous Exposure (ALIVE), the Women's Interagency HIV Study (WIHS), and the Multicenter AIDS Cohort Study (MACS), to investigate determinants of HAART modification with a particular focus on reported injection drug use (IDU). Longitudinal data collected between 1996 and 2004 contributed from 2,266 participants (37% with a reported history of IDU) who reported initiating their first HAART regimen during follow-up were utilized. Separate proportional-hazards models were used to identify factors measured prior to HAART-initiation associated with the time to first HAART discontinuation and first switch of components of HAART among continuous HAART users. The use of PI- vs. NNRTI-based regimens among HAART users with and without any history of IDU was similar over follow-up. The median time to a first report of discontinuation of HAART was 1.1 years for individuals with a history of IDU but 2.5 years for those without a history of IDU and multivariate analyses confirmed overall that individuals with a history of IDU were at greater risk for HAART discontinuation (adj RH = 1.24, 95% CI: 1.03-1.48). However, when restricting to data contributed after 1999, there was no longer any significant increased risk (adj RH = 1.05, 95% CI: 0.81-1.36). After adjusting for pre-HAART health status and prior ARV exposure, individuals who were ethnic/racial minorities, reported an annual income < $10,000/year, and were not employed were at significantly greater risk for HAART discontinuation. The median time to a first change in HAART regimen was approximately 1.5 years after first HAART report and was not elevated among those with a history of IDU (adj RH = 1.09, 95% CI: 0.89-1.34). The researchers analyses demonstrate that injection drug use by itself does not appear to be an independent risk factor for HAART switching or discontinuation in more recent years. However, as continued HAART use is of paramount importance for long-term control of HIV infection, efforts to improve maintenance to therapy among disadvantaged and minority populations remain greatly needed. Morris, J., Golub, E., Mehta, S., Jacobson, L., and Gange, S. Injection Drug Use and Patterns of Highly Active Antiretroviral Therapy Use: An Analysis of ALIVE, WIHS, and MACS Cohorts. AIDS Res Ther, 4, pp. 12-20, 2007.

HIV Seropositive Drug Users' Attitudes towards Partner Notification (PCRS): Results from the SHIELD Study in Baltimore, Maryland

Researchers assessed the attitudes of HIV seropositive current or former drug users towards HIV partner counseling and referral services (PCRS) and determined if opinion varies by partner type. They used a cross-sectional survey using structured and semi-structured questions to measure attitudes towards PCRS. The majority of the sample was African-American (97%), male (63%) and had been diagnosed with HIV for a mean of 7.9 years. Most agreed that PCRS would help stop the spread of HIV and AIDS (87%). A range of reactions to scenarios of their drug and sex partners being informed were observed and included positive reactions (e.g. PCRS as a means to facilitate testing of their partners and early treatment) to negative (e.g. feelings about guilt, shame and concern about partner responses). Data from this study indicate that HIV positive drug users view PCRS as a viable practice for preventing the spread of HIV, though barriers exist to engaging clients to identify partners. The range of reactions noted in this study underscore the importance of providing flexible options for PCRS based on partner type. Additional training for counselors, time for case-management and meetings with sex and drug partners and fieldwork for locating contacts are important considerations for providers. Tobin, K., Muessig, K., and Latkin, C. HIV Seropositive Drug Users' Attitudes towards Partner Notification (PCRS): Results from the SHIELD Study in Baltimore, Maryland. Patient Educ Couns, 67(1-2), pp. 137-142, 2007.

Sexual and Other Noninjection Risks for HBV and HCV Seroconversions among Noninjecting Heroin Users

Many heroin users do not inject drugs but may still be at risk of infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV), via sexual or other non-injection related activity. Non-injecting heroin users (NIUs) in New York City who were recruited and prospectively followed during March 1996-February 2003 were tested for anti-HIV, anti-hepatitis B core antigen, and anti-HCV and were interviewed about their sexual and other non-injecting risk. A seroconversion is represented by the first positive test result after the last negative test result. Hazard ratios (HRs) (P<.05) were estimated by use of Cox proportional hazards regression. Of 253 HIV-negative participants, 2 seroconverted (0.29/100 person-years at risk [pyar]); of 184 HBV-negative participants, 16 (3.3/100 pyar); and, of 219 HCV-negative participants, 16 (2.7/100 pyar). Independent predictors of seroconversion were, for HBV, being a female who engages in unprotected receptive anal sex (HR, 6.8), having short-term sex partners (HR, 6.2), and being a male with male sex partners (HR, 5.7); for HCV, being a male who receives money/drugs for sex (HR, 5.6) and sharing non-injecting crack-use equipment (HR, 4.5). These findings suggest that NIUs are at considerable risk of HBV infection via high-risk sex; and, for HCV, via high-risk sexual activity and the sharing of non-injecting crack-use equipment. Interventions for NIUs should seek to reduce high-risk sexual activity and the sharing of non-injecting drug-use equipment. Neaigus, A., Gyarmathy, V., Zhao, M., Miller, M., Friedman, S., and Des Jarlais, D. Sexual and Other Non-injection Risks for HBV and HCV Seroconversions among Non-injecting Heroin Users. J Infect Dis, 195(7), pp. 1052-1061, 2007.

Trends in Hepatitis B Virus, Hepatitis C Virus, and Human Immunodeficiency Virus Prevalence, Risk Behaviors, and Preventive Measures among Seattle Injection Drug Users Aged 18-30 Years, 1994-2004

Injection drug users (IDUs) are at risk for infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Information on time trends in prevalence of these viruses among IDUs and in behaviors influencing their transmission can help define the status of these epidemics and of public health efforts to control them. Researchers conducted a secondary data analysis combining cross-sectional data from IDUs aged 18-30 years enrolled in 4 Seattle-area studies from 1994 to 2004. Participants in all 4 studies were tested for antibody to HIV (anti-HIV), hepatitis B core antigen (anti-HBc), and HCV (anti-HCV), and completed behavioral risk assessments. Logistic regression was used to investigate trends in prevalence over time after controlling for sociodemographic, drug use, and sexual behavior variables. Between 1994 and 2004, anti-HBc prevalence declined from 43 to 15% (p < 0.001), anti-HCV prevalence fell from 68 to 32% (p < 0.001) and anti-HIV prevalence remained constant at 2-3%. Declines in anti-HBc and anti-HCV prevalence were observed within the individual studies, although not all these declines were statistically significant. The declines in anti-HBc and anti-HCV prevalence remained significant after control for confounding. Although coincident declines in injection equipment sharing practices were not observed, there were increases in self-reported needle-exchange use, condom use, and hepatitis B vaccination. These findings suggest that a substantial and sustained reduction in prevalence rates for HBV and HCV infection among young Seattle IDUs, while HIV rates have remained low and stable. Burt, R., Hagan, H., Garfein, R., Sabin, K., Weinbaum, C., and Thiede, H. Trends in Hepatitis B Virus, Hepatitis C Virus, and Human Immunodeficiency Virus Prevalence, Risk Behaviors, and Preventive Measures among Seattle Injection Drug Users Aged 18-30 Years, 1994-2004. J Urban Health, 84(3), pp. 436-454, 2007.

Non-injection Drug Use and Hepatitis C Virus: A Systematic Review

This systematic review examined the evidence on the prevalence of the Hepatitis C Virus (HCV) in non-injecting drug users (NIDUs) who sniff, smoke or snort drugs such as heroin, cocaine, crack or methamphetamine. The search included studies published from January 1989 to January 2006. Twenty-eight eligible studies were identified and the prevalence of HCV in these NIDU populations ranged from 2.3 to 35.3%. There was substantial variation in study focus and in the quality of the NIDU data presented in the studies. The results of the researchers systematic review suggested that there are important gaps in the research of HCV in NIDUs. The researchers identified a problem of study focus; much of the research did not aim to study HCV in users of non-injection drugs. Instead, NIDUs were typically included as a secondary research concern, with a principal focus on the problem of transmission of HCV in IDU populations. Despite methodological issues, HCV prevalence in this population is much higher than in a non-drug using population, even though some IDUs might have inadvertently been included in the NIDU samples. These studies point to a real problem of HCV in NIDU populations, but the causal pathway to infection remains unclear. Scheinmann, R., Hagan, H., Lelutiu-Weinberger, C., Stern, R., Des Jarlais, D., Flom, P., and Strauss, S. Non-injection Drug Use and Hepatitis C Virus: A Systematic Review. Drug Alcohol Depend, 89(1), pp. 1-12, 2007.

Individual and Couple-Level Risk Factors for Hepatitis C Infection among Heterosexual Drug Users: A Multilevel Dyadic Analysis

Hepatitis C virus (HCV) is the most common blood borne pathogen in the United States and is a leading cause of liver-related morbidity and mortality. Although it is known that HCV is most commonly transmitted among IDUs, the role of sexual transmission in the spread of HCV remains controversial because of inconsistent findings across studies involving heterosexual couples. A novel multilevel modeling technique designed to overcome the limitations of previous research was performed to assess multiple risk factors for HCV while partitioning the source of risk at the individual and couple level. The analysis was performed on risk exposure and HCV screening data obtained from 265 drug-using couples in East Harlem, New York City. In multivariable analysis, significant individual risk factors for HCV included a history of injection drug use, tattooing, and older age. At the couple level, HCV infection tended to cluster within couples, and this interdependence was accounted for by couples' drug-injection behavior. Individual and couple-level sexual behavior was not associated with HCV infection. These results are consistent with prior research indicating that sexual contact plays little role in HCV transmission. Rather, couples' injection behavior appears to account for the clustering of HCV within heterosexual dyads. McMahon, J., Pouget, E., and Tortu, S. Individual and Couple-Level Risk Factors for Hepatitis C Infection among Heterosexual Drug Users: A Multilevel Dyadic Analysis. J Infect Dis, 195(11), pp. 1572-1581, 2007.

Reasons for Condom Use or Non-use Among Drug Users

In this study, Rosengard, Anderson, and Stein, interviewed two hundred and seventy-seven drug using adults regarding details of their most recent sexual encounter. Demographic, attitudinal, and context variables were associated with condom use and non-use. Greater perceived risk of STDs/HIV and positive attitudes toward condoms effect on sexual pleasure were associated with greater likelihood of reporting condom use. Common reasons for not using condoms included lower perceived risk of contracting HIV/STDs, negative attitudes toward condoms effect on pleasure, and lack of condom availability. Tailoring messages to modifiable perceptions of risk and condom attitudes may be useful in reducing sexual risk among drug-using individuals. Rosengard, C., Anderson, B., and Stein, M. Correlates of Condom Use and Reasons for Condom Non-use Among Drug Users. Am J Drug Alcohol Abuse, 32(4), pp. 637-644, 2006.

Incidence of, Risk Factors for, Clinical Presentation, and 1-Year Outcomes of Infective Endocarditis in an Urban HIV Cohort

Previous studies described infective endocarditis (IE) in the era before highly active antiretroviral therapy (HAART); however, IE has not been well studied in the current HAART era. The incidence of, risk factors for, clinical presentation, and 1-year outcomes of IE in HIV-infected patients were evaluated. All cases of IE diagnosed between 1990 and 2002 in patients followed at the Johns Hopkins Hospital outpatient HIV clinic were evaluated. To identify factors associated with IE in the current era of HAART, a nested case-control analysis was employed for all initial episodes of IE occurring between 1996 and 2002. Logistic regression analyses were used to assess risk factors for IE and factors associated with 1-year mortality. IE incidence decreased from 20.5 to 6.6 per 1000 person years (PY) between 1990 and 1995 and 1996 and 2002. The majority of IE cases were male (66%), African American (90%), and injection drug users (IDUs) (85%). In multivariate regression, an increased risk of IE occurred in IDUs (AOR, 8.71), those with CD4 counts, 50 cells/mm3, and those with HIV-1 RNA .100,000 copies/mL (AOR, 3.88). Common presenting symptoms included fever (62%), chills (31%), and shortness of breath (26%). The most common etiologic organism was Staphylococcus aureus (69%; of these 11 [28%] were methicillin resistant).Within 1 year, 16% had IE recurrence, and 52% died. Age over 40 years was associated with increased mortality. IE rates have decreased in the current HAART era. IDUs and those with advanced immunosuppression are more likely to develop IE. In addition, there is significant morbidity and 1-year mortality in HIV-infected patients with IE, indicating the need for more aggressive follow-up, especially in those over 40 years of age. Future studies investigating the utility of IE prophylaxis in HIV patients with a history of IE may be warranted. Gebo, K.A., Burkey, M.D., Lucas, G.M., Moore, R.D., and Wilson, L.E. Incidence of, Risk Factors for, Clinical Presentation, and 1-Year Outcomes of Infective Endocarditis in an Urban HIV Cohort. J Acquir Immune Defic Syndr, 43(4), pp. 426-432, 2006.

HIV Risk Behaviors Among Rural Stimulant Users: Variation By Gender and Race/Ethnicity

Data were examined from a community sample of rural stimulant users (n = 691) in three diverse states to identify gender and racial/ethnic differences in HIV risk behaviors. Bivariate and logistic regression analyses were conducted with six risk behaviors as dependent variables: injecting drugs, trading sex to obtain money or drugs, trading money or drugs to obtain sex, inconsistent condom use, multiple sex partners, and using drugs with sex. Controlling for state, income, age, heavy drinking, and type of stimulant used, men had lower odds than women for trading sex to obtain money or drugs (adjusted odds ratio [AOR] =0.4, confidence interval [CI] = 0.28-0.59; p < .0001), greater odds than women for trading money or drugs to obtain sex (AOR = 44.4, CI = 20.30-97.09; p < .0001), greater odds than women of injecting drugs (adjusted odds ratio (AOR =1.6, CI = 1.11-2.42; p = .01), and lower odds than women of using condoms inconsistently (AOR = 0.6, CI = 0.35-0.92; p = .02); African Americans had lower odds than Whites of injecting drugs (AOR = .08, CI = 0.04-0.16; p < .0001), greater odds than Whites for trading sex to obtain money or drugs (AOR = 1.7, CI = 1.01-2.85; p = .04) and for trading money or drugs to obtain sex (AOR = 2.9,CI = 1.53-5.59; p = .001), and greater odds than Whites of using drugs with sex (AOR = 3.9, CI = 1.47-10.09; p = .006). These findings indicate HIV prevention efforts should be tailored to address gender and racial/ethnic differences in risk behaviors among rural stimulant users. Booth, B.M., Wright, P.B., Stewart, K.E., Fischer, E.P., Carlson, R.G., Falck, R., Wang, J., and Leukefeld, C.G. HIV Risk Behaviors Among Rural Stimulant Users: Variation by Gender and Race/Ethnicity. AIDS Educ Prev, 12(2), pp. 137-150, 2007.

A Within-subject Comparison of Withdrawal Symptoms During Abstinence from Cannabis, Tobacco, and Both Substances

A cannabis withdrawal syndrome has been characterized, but its clinical significance remains uncertain. One method of assessing the significance of cannabis withdrawal is to compare it directly to an established withdrawal syndrome. The present study was a within-subject comparison of cannabis, tobacco, and combined cannabis and tobacco withdrawal among users of both substances. Participants (N=12) completed three 5-day periods of abstinence in a randomized order, separated by 9-day periods of usual substance use. Overall withdrawal severity associated with cannabis alone and tobacco alone was of a similar magnitude. Withdrawal during simultaneous cessation of both substances was more severe than for each substance alone, but these differences were of short duration and substantial individual differences were noted. These results are consistent with other evidence suggesting cannabis withdrawal is clinically important and warrants detailed description in the DSM-V and ICD-11. Additional research is needed to replicate these findings and to further investigate the effects of abstaining from multiple drugs simultaneously. Vandrey, R.G., Budney, A.J., Hughes, J.R., and Liguori, A. Drug Alcohol Depend. July 21, 2007 [Epub ahead of print].

Effects of Pregnancy on Nicotine Self-administration and Nicotine Pharmacokinetics in Rats

Dr. Pentel's group at Minneapolis Medical Research Foundation developed an animal model of smoking during pregnancy by initially characterizing nicotine self-administration (NSA) in pregnant rats. In addition, they also began to explore the effects of pregnancy on nicotine pharmacokinetics in rats. NSA decreased over the course of pregnancy with NSA significantly lower in the third trimester compared to nonpregnant controls. NSA remained suppressed for up to 10 days into lactation. Locomotor behavior was also significantly suppressed during the second and third trimesters and throughout lactation. Nicotine elimination was slower in pregnant females compared to nonpregnant females only in the third trimester. In conclusion, NSA, locomotor behavior, and nicotine elimination in rats are decreased during late pregnancy. The present study is the first to characterize NSA during pregnancy in animals, providing a potential model of maternal smoking in humans. Lesage, M.G., Keyler, D.E., Burroughs, D., and Pentel, P.R. Effects of Pregnancy on Nicotine Self-administration and Nicotine Pharmacokinetics in Rats. Psychopharmacology (Berl), July 7, 2007 [Epub ahead of print].

Maternal Separation Alters Drug Intake Patterns in Adulthood in Rats

Dr. Kuhar's group at Emory University, Atlanta, Georgia, examined the effects of maternal separation and drug intake patterns in adulthood in rats. Maternal separation/handling (MS/H) is an animal model of early life stress that causes profound neurochemical and behavioral alterations in pups that persist into adulthood. Many recent studies have used the MS/H model to study changes in drug effects in adulthood that are linked to behavioral treatments and stressors in the perinatal period. The drug effects focused on in this review are the reinforcing properties of the abused drugs, cocaine and alcohol. A striking finding is that variations in maternal separation and handling cause changes in ethanol and cocaine self-administration. Further, these changes indicate that various manipulations in the perinatal period can have long lasting effects of interest to biochemical pharmacologists. This article reviewed recent studies on ethanol and cocaine self-administration using the MS/H model and the neurochemical alterations that may play a role in the effects of MS/H on ethanol and cocaine self-administration. Studying the MS/H model can provide important clues into the vulnerability to drug abuse and perhaps identify a crucial window of opportunity for therapeutic intervention. Moffett, M.C., Vicentic, A., Kozel, M., Plotsky, P., Francis, D.D. and Kuhar, M.J. Maternal Separation Alters Drug Intake Patterns in Adulthood in Rats. Biochem Pharmacology, 73(3), pp. 321-330, 2007.

Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse

When generating monoclonal antibodies (mAb) against small molecules, the chemical composition and molecular orientation of the drug-like hapten on the antigen is a crucial determinant. This is especially important when attempting to discover therapeutic mAb against the drugs of abuse (+)-methamphetamine [(+)-METH], (+)-amphetamine [(+)-AMP], and the related compound (+)-3,4-methylenedioxymethamphetamine [(+)-MDMA, the plus isomer in the racemic mixture known as MDMA or ecstasy]. The goal of these studies was to design and synthesize (+)-METH-like haptens with structural attributes that could make them effective for generating monoclonal antibodies for treating medical problems associated with these stimulant drugs of abuse. Five prototype (+)-METH-like haptens were synthesized and used to generate mAb. After screening for anti-(+)-METH IgG antibodies in more than 25,000 potential mouse hybridoma cell lines, one prototype mAb from each of the five haptens was selected and studied in detail for molecular properties and preclinical efficacy. One antibody (designated mAb4G9) exhibited high affinity and specificity to (+)-METH, (+)-MDMA, and (+)-AMP, without significant cross-reactivity against other METH-like ligands, over-the-counter medications, or endogenous neurotransmitters. Considered together, discovery of mAb4G9 and the other antibodies in this report represent an important step in understanding the process for custom design of drug class-specific therapeutic antibodies for the treatment of drug addiction. Peterson, E.C., Gunnell, M., Che, Y., Goforth, R.L., Carroll, F.I., Henry, R., Liu, H., and Owens, S.M. Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse. J Pharmacol Exp Ther. 322(1), pp. 30-39, 2007.


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