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Director's Report to the National Advisory Council on Drug Abuse - September, 2006

Research Findings - Research on Medical Consequences of Drug Abuse and Infections

Abnormal Glucose Metabolism Among Older Men with or at Risk of HIV Infection

The aim of this study was to determine factors associated with diabetes, insulin resistance, and abnormal glucose tolerance in older men with or at risk of HIV infection. Diabetes was assessed by self-report in 643 men >/=49 years old with or at risk of HIV infection. In a subset of 216 men without previously diagnosed diabetes [including 90 HIV-uninfected men, 28 HIV-infected, antiretroviral- naive men, 28 HIV-infected men taking non-protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART), and 70 HIV-infected men taking PI-containing HAART], an oral glucose tolerance test with insulin levels was performed. HIV serology, CD4 cell count, weight, height and waist circumference were measured. Antiretroviral use, drug use, family history of diabetes, physical activity and sociodemographic data were obtained using standardized interviews. Of 643 participants, 116 (18%) had previously diagnosed diabetes. With the oral glucose tolerance test, 15 of 216 men (7%) were found to have undiagnosed diabetes and 40 (18%) impaired glucose tolerance. Factors independently associated with previously diagnosed diabetes included use of non-PI-containing HAART, methadone treatment, positive CAGE test for alcoholism, obesity and family history of diabetes. Factors independently associated with greater insulin resistance included waist circumference and heroin use. Factors independently associated with abnormal glucose tolerance (impaired glucose tolerance or diabetes) included age >/=55 years and Hispanic ethnicity. HIV-infected men with diabetes risk factors should undergo screening for diabetes regardless of HAART use. Interventions targeting modifiable risk factors, including overweight and physical inactivity, are warranted. The potential impact of opiate and alcohol abuse on glucose metabolism should be recognized in clinical care, and addressed in future research studies of HIV-infected persons. Howard, A., Floris-Moore, M., Lo, Y., Arnsten, J., Fleischer, N., Klein, R., HIV Med. 7(6), pp. 389-396, September 2006.

Neurocognitive Aspects of Medication Adherence in HIV-positive Injecting Drug Users

Cognitive deficits are associated with nonadherence to HIV medications. HIV-positive injecting drug users (IDUs) are at particular risk for nonadherence and cognitive barriers to adherence specific to this population should therefore be identified. The present study assessed the relation of three domains of cognitive functioning, executive functions, memory, and psychomotor speed, to self-reported antiretroviral adherence in a sample of HIV-positive IDUs. Depression, use of alcohol, heroin, cocaine/crack, or marijuana in the last week were also included in the models. Logistic regression analyses showed that only psychomotor slowing was significantly associated with nonadherence. Executive functions, memory, depression, and active alcohol and substance use were unrelated to adherence. No other studies to date have exclusively linked psychomotor slowing to nonadherence in HIV infection. Psychomotor slowing among our study sample was severe and suggests that when evident, such slowing may be a valuable determinant for antiretroviral adherence among IDUs. Waldrop-Valverde, D., Ownby, R.L., Wilkie, F.L., Mack, A., Kumar, M., and Metsch, L., AIDS Behav. 10(3), pp. 287-297, May 2006.

Resistance to HIV Infection

The biological correlates of an effective immune response that could contain or prevent HIV infection remain elusive despite substantial scientific accomplishments in understanding the interactions among the virus, the individual and the community. The observation that some individuals appear to possess resistance to HIV infection or its consequences has generated a host of epidemiologic investigations to identify biological or behavioral characteristics of these individuals. These data might hold the keys to developing appropriate strategies for mimicking the effective responses of those who appear immune. In this paper authors review genetic mechanisms including the role of chemokines and their receptors, cytokines, host genetic immune response to HIV infection, local immune response correlating with behavioral variables, co-infection and immune based mechanisms that have been elucidated so far. The authors offer suggestions for how to use these observations as platforms for future research to further understand natural resistance to HIV infection through cohort studies, population genotype sampling, mathematical modeling of virus-host interactions and behavioral analyses. Marmor, M., Hertzmark, K., Thomas, S.M., Halkitis, P.N., and Vogler, M., J Urban Health. 83(1), pp. 5-17, January 2006.

Methamphetamine Modulates Gene Expression Patterns in Monocyte Derived Mature Dendritic Cells: Implications for HIV-1 Pathogenesis

The US is currently experiencing a grave epidemic of methamphetamine use as a recreational drug, and the risk for HIV-1 infection attributable to methamphetamine use continues to increase. Recent studies show a high prevalence of HIV infection among methamphetamine users. Dendritic cells (DCs) are potent antigen presenting cells that are the initial line of defense against HIV-1 infection. In addition, DCs also serve as reservoirs for HIV-1 and function at the interface between the adaptive and the innate immune systems, which recognize and internalize pathogens and subsequently activate T cells. Exposure to methamphetamine results in modulation of immune functional parameters that are necessary for host defense. Chronic methamphetamine use can cause psychiatric co-morbidity, neurological complications, and can alter normal biological processes and immune functions. Limited information is available on the mechanisms by which methamphetamine may influence immune function. This study explores the effect of methamphetamine on a specific array of genes that may modulate immune function. Authors hypothesize that methamphetamine treatment results in the immunomodulation of DC functions, leading to dysregulation of the immune system of the infected host. This suggests that methamphetamine has a role as a cofactor in the pathogenesis of HIV-1. Authors used the high-throughput technology of gene microarray analysis to understand the molecular mechanisms underlying the genomic changes that alter normal biological processes when DCs are treated with methamphetamine. Additionally, they validated the results obtained from microarray experiments using a combination of quantitative real-time PCR and Western blot analysis. These data are the first evidence that methamphetamine modulates DC expression of several genes. Methamphetamine treatment alters categories of genes that are associated with chemokine regulation, cytokinesis, signal transduction mechanisms, apoptosis, and cell cycle regulation. This report focuses on a selected group of genes that are significantly modulated by methamphetamine treatment and that have been associated with HIV-1 pathogenesis. The purpose of this study was to identify genes that are unique and/or specific to the complex immunomodulatory mechanisms that are altered as a result of methamphetamine abuse in HIV-1-infected patients. These studies will help to identify the molecular mechanisms that underlie methamphetamine toxicity, and several functionally important classes of genes have emerged as targets in methamphetamine-mediated immunopathogenesis of HIV-1. Identification of novel DC-specific and methamphetamine-responsive genes that modulate several biological, molecular, and signal transduction functions may serve as methamphetamine- and/or HIV-1-specific drug targets. Mahajan, S.D., Hu, Z., Reynolds, J.L., Aalinkeel, R., Schwartz, S.A., and Nair, M.P., Mol Diagn Ther. 10(4), pp. 257-269, 2006.

Pharmacokinetic Drug Interactions Between Opioid Agonist Therapy and Antiretroviral Medications: Implications and Management for Clinical Practice

Opioid dependence and HIV/AIDS are 2 of the most serious yet treatable diseases worldwide. Global access to opioid agonist therapy and HIV treatment is expanding but when concurrently used, problematic pharmacokinetic drug interactions can occur. Authors reviewed English, Spanish, French, and Italian language articles from 1966 to 2005 in Medline using the following keywords: HIV, AIDS, HIV therapy, antiretroviral therapy, HAART, drug interactions, methadone, and buprenorphine. Additionally, authors reviewed abstracts from national and international meetings and conference proceedings. Selected references from these articles were reviewed as well. Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone and most approved antiretroviral therapies. Important pharmacokinetic drug interactions have been demonstrated within each class of agents, affecting either methadone or antiretroviral agents. Few studies, however, have been conducted with buprenorphine. The metabolism of both therapies, description of the known interactions, and clinical implications and management of these interactions are reviewed. Authors conclude that certain interactions between methadone and antiretroviral medications are known and may have important clinical consequences. To optimize care, clinicians must be alert to these interactions and have a basic knowledge regarding their management. Bruce, R.D., Altice, F.L., Gourevitch, M.N., and Friedland, G.H., J Acquir Immune Defic Syndr. 41(5), pp. 563-572, April 2006.

Models for Integrating Buprenorphine Therapy into the Primary HIV Care Setting

Opiate dependence among human immunodeficiency virus (HIV)-infected patients has been associated with negative clinical outcomes, yet few affected patients receive appropriate and coordinated treatment for both conditions. The introduction of buprenorphine maintenance therapy into HIV care settings provides an opportunity for providers to integrate treatment for opiate dependence into their practices. Buprenorphine maintenance therapy has been associated with reductions in opiate use, increased social stability, improved adherence to antiretroviral therapy, and lowered rates of injection drug use. Authors describe the following 4 models for the integration of buprenorphine maintenance therapy into HIV care: (1) a primary care model, in which the highly active antiretroviral therapy-administering clinician also prescribes buprenorphine; (2) a model that relies on an on-site specialist in addiction medicine or psychiatry to prescribe the buprenorphine; (3) a hybrid model, in which an on-site specialist provides the induction (with or without stabilization phases) and the HIV care provider provides the maintenance phase; and (4) a drug treatment model that provides buprenorphine maintenance therapy services with HIV services in the substance abuse clinic setting. The key barriers against effective integration of buprenorphine maintenance therapy and primary HIV services are discussed, and we suggest several mechanisms to overcome such obstacles. Basu, S., Smith-Rohrberg, D., Bruce, R.D., and Altice, F.L., Clin Infect Dis. 42(5), pp. 716-721, March 1, 2006.

Predictors of Hepatitis C Virus RNA Levels in a Prospective Cohort Study of Drug Users

High levels of hepatitis C virus (HCV) RNA are associated with a poor response to treatment of chronic hepatitis C, and a substantial reduction in HCV RNA levels predicts a favorable treatment response. Authors prospectively studied time-dependent and time-independent predictors of HCV RNA levels in 264 drug users with chronic HCV infection. Interviews on medical history and high-risk behaviors, phlebotomy for HIV viral load, serum HCV RNA levels as measured by the COBAS Amplicor HCV Monitor (Roche Diagnostics, Branchburg, NJ), and a lymphocyte subset assay were performed. Factors associated with HCV RNA levels over time were analyzed using a linear mixed model. Nearly 70% of the participants were men, two thirds were Hispanic, and the mean age was 46 years. HCV RNA levels increased over time. Older age (P < 0.001), HIV seropositivity (P = 0.03), and HCV nongenotype 1 (P = 0.05) were predictors of higher HCV RNA levels on multivariate analysis. Among 142 HIV-seropositive participants, a detectable HIV-1 viral load (P < 0.001) and recent alcohol use (P = 0.02) were predictors of higher HCV RNA levels. The predictors of higher HCV RNA levels found in this longitudinal study are consistent with those of prior cross-sectional studies. Further studies are warranted to determine if treatment of alcohol use affects HCV RNA levels. Fishbein, D.A., Lo, Y., Netski, D., Thomas, D.L., Klein, R.S., J Acquir Immune Defic Syndr. 41(4), pp. 471-476, April 1, 2006.

Identification of a Specific Gene Expression Pattern Associated with HCV-Induced

Pathogenesis in HCV- and HCV/HIV-Infected Individuals Gene expression profiling was performed on liver biopsies from 28 patients (12 HCV and 16 HCV/HIV infected) in an attempt to understand the mechanisms of HCV liver disease in the presence and absence of HIV coinfection. The data were compared with clinical observations and a gene expression database obtained for transplant HCV-infected samples. This is the first report of functional genomics being used to compare intrahepatic gene expression profiles of HCV- and HCV/HIV-infected individuals. Significantly, the intrahepatic global gene expression profiles do not differ between HCV- and HCV/HIV-infected individuals. However, a subset of patients was identified who share a specific pattern of gene expression, termed the enhanced gene expression (EGE) pattern. Specifically, the EGE (+) patients show a dramatic decreased expression of multiple genes associated with the FAS-apoptosis pathway and increased expression of lymphocyte adhesion molecules and lymphocyte-specific genes. The EGE (+) patients also have partially impaired Type I and II IFN-mediated antiviral responses, including a lack of induction of the anti-fibrogenic cytokine IFN-gamma. Importantly, the pattern of gene expression observed in EGE (+) patients has similarities to patients who developed fibrosis within 1 year of receiving a liver transplant. Walters, K.A., Smith, M.W., Pal, S., Thompson, J.C., Thomas, M.J., Yeh, M.M., Thomas, D.L., Fitzgibbon, M,, Proll, S., Fausto, N., Gretch, D.R., Carithers, R.L. Jr., Shuhart, M.C., and Katze, M.G., Virology. 350(2), pp.453-464. Epub 2006 Mar 30, July 5, 2006.

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 study 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. Authors 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 was 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); anaemia (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). 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., Skanderson, M., Good, C., and Kwoh, C.K. Aliment Pharmacol Ther. 24(4), pp. 585-591, August 15, 2006.

Tenofovir for Chronic Hepatitis B Virus Infection in HIV-Coinfected Patients

Tenofovir has significant activity against hepatitis B virus (HBV), but clinical data about its utility for treatment of hepatitis B in patients coinfected with HBV and HIV are limited. Authors report the long-term safety and efficacy of tenofovir in 6 HBV-HIV-coinfected persons who received tenofovir as part of their antiretroviral regimen and were followed up for an average of 26.8 months (range, 19 to 33 months). Four of 6 patients were positive for hepatitis B e antigen (HBeAg), and all 6 had initial HBV DNA levels greater than 7 log10 copies/mL. HBV DNA levels dropped by a mean (median) of 2.83 (3.40) and 3.92 (4.63) log10 after 12 and 24 months of treatment, respectively. After 24 months, 3 patients had HBV DNA levels below the limit of detection and 5 had HIV RNA levels below the limit of detection (less than 400 copies/mL). The sixth patient had stopped treatment and had a 0.14-log10 decrease in HIV RNA level at 36 months of follow-up. The CD4+ lymphocyte count increased by a mean (median) value of 47/microL (177/microL). No significant adverse events attributable to tenofovir therapy were reported. Butt, A.A. AIDS Read. 16(4), pp. 219-222, April 2006.

Comorbid Medical and Psychiatric Conditions and Substance Abuse in HCV Infected Persons on Dialysis

The burden of comorbidity in the Hepatitis C virus (HCV) infected persons on dialysis is unknown. Authors identified all HCV infected and uninfected subjects in the United States Renal Data System in the years 1997-1998 using ICD-9 codes. Controls were matched on the date of first dialysis. ICD-9 codes and claims data was used to identify medical and psychiatric comorbidities. Authors identified 5,737 HCV infected persons and 11,228 HCV uninfected subjects. HCV infected subjects were younger, more likely to be black race and male and more likely to have the following comorbidities: hypertension; hepatitis B; cirrhosis; wasting; anemia; human immunodeficiency virus (HIV) infection; major depression; mild depression; bipolar disorder; schizophrenia; post-traumatic stress disorder; drug use; alcohol use; smoking and less likely to have the following comorbidities: coronary artery disease; stroke; peripheral vascular disease; diabetes; cancer; erythropoietin use. After adjusting for age, gender and race, HCV infected subjects were more likely to have hypertension, hepatitis B, cirrhosis, wasting, anemia and HIV infection and less likely to have coronary artery disease and stroke. Authors concluded that HCV infected persons on dialysis are more likely to have psychiatric comorbidities and substance abuse, as well as certain medical comorbidities. These factors should be considered when developing future intervention strategies. Butt, A.A., Evans, R., Skanderson, M., and Shakil, A.O. J Hepatol. 44(5), pp. 864-868, May 2006.

HIV/Hepatitis C Virus-Coinfected Patients with Normal Alanine Aminotransferase Levels

The significance of normal alanine aminotransferase (ALT) levels in patients with HIV/hepatitis C virus (HCV) coinfection is not well understood. Authors performed a cross-sectional retrospective analysis on consecutive HIV/HCV-coinfected patients (n = 89) who underwent a liver biopsy during a 2-year period. Similar data were also collected on HCV-monoinfected patients (n = 117). Mean ALT levels and the percentage of patients with normal ALT (< or =40 U/L) levels were similar in HIV/HCV-coinfected (mean +/-SD, 81.7 +/- 56.1 U/L; 21%) and HCV-monoinfected patients (97.3 +/- 100.7 U/L; 18%; P = 0.19 and 0.54, respectively). Coinfected patients, however, had significantly advanced necroinflammation (P= 0.001) and fibrosis (P = 0.02) compared with monoinfected patients. The percentage of patients with advanced necroinflammation (grades 3 or 4) was lower in HCV-monoinfected patients with normal ALT levels compared with those with elevated ALT (5% vs 20%, respectively). In contrast, the percentage of coinfected patients with advanced necroinflammation was similar whether the patient had normal or elevated ALT levels (32% vs 37%, respectively). In coinfected patients, normal ALT levels are not an indicator of mild necroinflammation and may not portend a more benign disease course. Gonzalez, S.A., Liu, R.C., Edlin, B.R., Jacobson, I.M., and Talal, A.H. J Acquir Immune Defic Syndr. 41(5), pp. 582-589, April 15, 2006.

Neurocognitive Consequences of HIV in Southern India: A Preliminary Study of Clade C Virus

The neurocognitive impact of the clade C viral strain of human immunodeficiency virus (HIV) has not been determined. The purpose of this study was to examine neurocognitive function in southern India among individuals with the clade C virus with advanced HIV. A battery of cognitive tasks sensitive to the effects of HIV on brain function was translated and administered in Tamil and Telegu, two widely spoken languages in southern India. A sample of 30 treatment-naïve HIV-positive individuals with a median CD4 cell count of 97, and 30 age and education matched healthy controls obtained from the same region of India, were included in the study. Results revealed significant differences on most cognitive tests, with lower performances obtained by the HIV-positive individuals. These results suggest that cognitive difficulties are present among individuals with the clade C virus in India, with as many as 56% of the patients with advanced HIV meeting the criterion for impairment in two cognitive domains. Additional study is needed to determine if clade C HIV infection is more or less prone to cause neurocognitive deficit than the clade B virus. Furthermore, the impact of antiretroviral therapy on neurocognitive dysfunction in clade C virual infection needs to be determined. Yepthomi, T., Paul, R., Vallabhaneni, S., Kumarasamy, N., Tate, D.F., Solomon, S., and Flanigan, T. J Int Neuropsychol Soc.12(3), pp. 424-430, May 2006.

(C2) Saliva, Breast Milk, and Mucosal Fluids in HIV Transmission

The oral environment has received various amounts of attention in association with HIV infection and pathogenesis. Since HIV infection occurs through mucosal tissue, oral factors-including tissue, fluids, and compartments-are of interest in furthering our understanding of the diagnosis, infectivity, transmission, and pathogenesis of disease. This report reviews: (1) HIV testing and diagnoses with oral fluids; (2) post-natal acquisition of HIV in association with breast-feeding from HIV-positive mothers; and (3) oral sex and HIV transmission. In the first, authors examine how oral fluids are used to detect HIV infection and review current consensus on the role of salivary molecules as markers for immunosuppression. Second, lactation-associated HIV acquisition is reviewed, with special consideration of emerging issues associated with the impact of anti-retroviral therapies. Last, authors consider current data on the risk of HIV infection in association with oral sex. Investigation of these diverse topics has a common goal: understanding how HIV presents in the oral environment, with an aim to rapid and accessible HIV diagnosis, and improved prevention and treatment of infection. Page-Shafer, K., Sweet, S., Kassaye, S., and Ssali, C. Adv Dent Res. 19(1), pp. 152-157, April 1, 2006.

Commercial Sex Work and Risk of HIV Infection Among Young Drug-Injecting Men Who Have Sex with Men in San Francisco

The objective of this study was to investigate the relationship between sex work and HIV infection among young injection drug-using men who have sex with men (MSM-IDU). This study was a cross-sectional analysis of behavioral and serologic data collected from 227 street-recruited MSM-IDU in San Francisco, California, between January 2000 and November 2001. Sixty-eight percent of participants reported being paid by another man for sex. HIV prevalence was 12% (95% confidence interval, 8-16%); 42% of seropositive participants were unaware of their infection. HIV was independently associated with higher number of paying male partners and history of gonorrhea and inversely associated with number of female partners, education, and syringe-sharing. Consistent condom use overall was 41%, but varied significantly by type of partner. Among MSM-IDU in San Francisco, sex work with men is strongly associated with HIV infection and the prevalence of condom use is low. HIV prevention among MSM-IDU must be tailored to address the excess risk associated with sex work. Bacon, O., Lum, P., Hahn, J., Evans, J., Davidson, P., Moss, A., Page-Shafer, K. Sex Transm Dis. 33(4), pp. 228-234, April 2006.

Treatment Algorithm for the Management of Hepatitis C in HIV-Coinfected Persons

In the era of highly effective antiretroviral therapy (ART), HCV-related liver disease has emerged as a significant cause of morbidity and mortality. Accordingly, expert panels have recommend that coinfected patients undergo medical evaluation for HCV-related liver disease, consideration for HCV treatment and, if indicated, orthotopic liver transplantation. While the treatment of such patients is complicated by medical, and psychiatric comorbidities, HIV disease, and concurrent antiretroviral therapy, randomized controlled trials support the safety, tolerability and efficacy of HCV treatment with peginterferon alfa (PEG-IFN) plus ribavirin (RBV) in HIV-infected persons. Although, the available data has led to consensus among experts regarding the need to medically manage HCV disease in HIV-infected persons, uncertainty remains regarding the best treatment algorithm for coinfected patients. Sulkowski, M.S. J Hepatol.44(1 Suppl):S49-55, 2006.

Progression of Liver Fibrosis Among Injection Drug Users with Chronic Hepatitis C

Although most hepatitis C virus (HCV) infections are acquired by injection drug use, prospective data on the progression of liver fibrosis are sparse. Baseline liver biopsies were obtained (1996-1998) on a random sample of 210 out of 1667 HCV-positive injection drug users (IDUs). Subjects were followed biannually, with a second biopsy offered to those eligible. Paired biopsies were scored 0 to 6 (modified Ishak score), significant fibrosis was defined as score 3 or greater, and progression of fibrosis was defined as an increase 2 or more units or clinical evidence of end-stage liver disease. Predictive values of blood markers [FibroSURE, aspartate aminotransferase-to-platelet-ratio index (APRI) and alanine aminotransferase (ALT)] were assessed for detection of contemporaneous and future liver fibrosis. Among 119 prospectively followed IDUs, 96% were African American; 97% HCV genotype 1a/b; 27% HIV-infected, and median age was 42 years. Most (90.7%) did not have significant liver fibrosis at first biopsy. Although predictive value for detecting insignificant fibrosis at first biopsy was greater than 95% for FibroSURE, APRI, and ALT, specificities were 88.9%, 72.7%, and 72.7%, respectively. After 4.2 years median follow-up, 21% had progression of fibrosis, which was significantly associated with serum level of HCV RNA and ALT. No serological test had predictive value greater than 40% for contemporaneous or future significant fibrosis. Even initial biopsy result had only a 30.4% value for predicting future significant fibrosis. In conclusion, significant liver fibrosis and progression were detected in some, but not most, IDUs in this cohort. In this setting with low fibrosis prevalence, FibroSURE, ALT, and APRI tests predict insignificant fibrosis; however, further work is needed to find noninvasive markers of significant liver fibrosis. Wilson, L.E., Torbenson, M., Astemborski, J., Faruki, H., Spoler, C., Rai, R., Mehta, S., Kirk, G.D., Nelson, K., Afdhal, N., and Thomas, D.L. Hepatology. 43(4), pp. 788-795, April 2006.

The Cannabis Withdrawal Syndrome

The demand for treatment for cannabis dependence has grown dramatically. The majority of the people who enter treatment have difficulty in achieving and maintaining abstinence from cannabis. Understanding the impact of cannabis withdrawal syndrome on quit attempts is of obvious importance. Cannabis, however, has long been considered a 'soft' drug, and many continue to question whether one can truly become dependent on cannabis. Skepticism is typically focused on whether cannabis use can result in 'physiological' dependence or withdrawal, and whether withdrawal is of clinical importance. The neurobiological basis for cannabis withdrawal has been established via discovery of an endogenous cannabinoid system, identification of cannabinoid receptors, and demonstrations of precipitated withdrawal with cannabinoid receptor antagonists. Laboratory studies have established the reliability, validity, and time course of a cannabis withdrawal syndrome and have begun to explore the effect of various medications on such withdrawal. Reports from clinical samples indicate that the syndrome is common among treatment seekers. In summary, a clinically important withdrawal syndrome associated with cannabis dependence has been established. Additional research must determine how cannabis withdrawal affects cessation attempts and the best way to treat its symptoms. Budney, A.J. and Hughes, J.R., Curr Opin Psychiatry. 19(3), pp. 233-238, May 2006.

Oral Delta-9-tetrahydrocannabinol Suppresses Cannabis Withdrawal Symptoms

This study assessed whether oral administration of delta-9-tetrahydrocannbinol (THC) effectively suppressed cannabis withdrawal in an outpatient environment. The primary aims were to establish the pharmacological specificity of the withdrawal syndrome and to obtain information relevant to determining the potential use of THC to assist in the treatment of cannabis dependence. Eight adult, daily cannabis users who were not seeking treatment participated in a 40-day, within-subject ABACAD study. Participants administered daily doses of placebo, 30mg (10mg/tid), or 90mg (30mg/tid) oral THC during three, 5-day periods of abstinence from cannabis use separated by 7-9 periods of smoking cannabis as usual. Comparison of withdrawal symptoms across conditions indicated that (1) the lower dose of THC reduced withdrawal discomfort, and (2) the higher dose produced additional suppression in withdrawal symptoms such that symptom ratings did not differ from the smoking-as-usual conditions. Minimal adverse effects were associated with either active dose of THC. This demonstration of dose-responsivity replicates and extends prior findings of the pharmacological specificity of the cannabis withdrawal syndrome. The efficacy of these doses for suppressing cannabis withdrawal suggests oral THC might be used as an intervention to aid cannabis cessation attempts. Budney, A.J., Vandrey, R.G., Hughes, J.R., Moore, B.A., Bahrenburg, B., Drug Alcohol Depend., June 10, 2006.

Clinical Trial of Abstinence-based Vouchers and Cognitive-Behavioral Therapy for Cannabis Dependence

Ninety cannabis-dependent adults seeking treatment were randomly assigned to receive cognitive-behavioral therapy, abstinence-based voucher incentives, or their combination. Treatment duration was 14 weeks, and outcomes were assessed for 12 months posttreatment. Findings suggest that (a) abstinence-based vouchers were effective for engendering extended periods of continuous marijuana abstinence during treatment, (b) cognitive-behavioral therapy did not add to this during-treatment effect, and (c) cognitive-behavioral therapy enhanced the posttreatment maintenance of the initial positive effect of vouchers on abstinence. This study extends the literature on cannabis dependence, indicating that a program of abstinence-based vouchers is a potent treatment option. Discussion focuses on the strengths of each intervention, the clinical significance of the findings, and the need to continue efforts toward development of effective interventions. Budney, A.J., Moore, B.A., Rocha, H.L., and Higgins, S.T. J Consult Clin Psychol. 74(2), pp. 307-316, April 2006.

Ritonavir has Minimal Impact on the Pharmacokinetic Disposition of a Single Dose of Bupropion Administered to HumanVolunteers

A drug-drug interaction study was conducted to determine whether ritonavir (200 mg; 4 doses over 2 days) alters the pharmacokinetic disposition of bupropion (75 mg; once) coadministered to 7 healthy volunteers in a placebo-controlled 2-way crossover study. Serum samples collected from 0 to 24 hours after bupropion administration were assayed for concentrations of bupropion and metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Derived pharmacokinetic parameters were compared between placebo/bupropion and ritonavir/bupropion trials by paired t test. The effect of ritonavir on most pharmacokinetic parameters was minimal (<20% mean change). The only parameters that showed a statistically significant effect were threohydrobupropion area under the blood concentration curve (14% +/- 5% decrease, mean +/- SE; P = .04) and erythrohydrobupropion time-to-maximal serum concentration (161% +/- 92% increase, P = .03), suggesting that ritonavir may inhibit the carbonyl reductase enzyme responsible for formation of these metabolites. These findings indicate that short-term ritonavir dosing has only minimal impact on the pharmacokinetic disposition of a single dose of bupropion in healthy volunteers. Hesse, L.M., Greenblatt, D.J., von Moltke, L.L., Court, M.H., J Clin Pharmacol. 46(5), pp. 567-576, May 2006.

Cardiovascular Function in Multi-Ethnic Study of Atherosclerosis: Normal Values by Age, Sex, and Ethnicity

MRI provides accurate and high-resolution measurements of cardiac anatomy and function. The purpose of this study was to describe the imaging protocol and normal values of left ventricular (LV) function and mass in the Multi-Ethnic Study of Atherosclerosis (MESA). Eight hundred participants (400 men, 400 women) in four age strata (45-54, 55-64, 65-74, 75-84 years) were chosen at random. Participants with the following known cardiovascular risk factors were excluded: current smoker, systolic blood pressure > 140 mm Hg, diastolic blood pressure > 90 mm Hg, fasting glucose > 110 mg/dL, total cholesterol > 240 mg/dL, and high-density lipoprotein (HDL) cholesterol < 40 mg/dL. Cardiac MR images were analyzed using MASS software (version 4.2). Mean values, SDs, and correlation coefficients in relationship to patient age were calculated. There were significant differences in LV volumes and mass between men and women. LV volumes were inversely associated with age (p < 0.05) for both sexes except for the LV end-systolic volume index. For men, LV mass was inversely associated with age (slope = -0.72 g/year, p =0.0021), but LV mass index was not associated with age (slope = -0.179 g/m2/year, p = 0.075). For women, LV mass (slope = -0.15 g/year, p = 0.30) and LV mass index (slope = 0.0044 g/m2/year, p = 0.95) were not associated with age. LV mass was the largest in the African-American group (men, 181.6 +/- 35.8 [SD] g; women, 128.8 +/- 28.1 g) and was smallest in the Asian-American group (men, 129.1 +/- 20.0 g; women, 89.4 +/- 13.3 g). The normal LV differs in volume and mass between sexes and among certain ethnic groups. When indexed by body surface area, LV mass was independent of age for both sexes. Studies that assess cardiovascular risk factors in relationship to cardiac function and structure need to account for these normal variations in the population. Natori, S., Lai, S., Finn, J.P., Gomes, A.S., Hundley, W.G., Jerosch-Herold, M., Pearson, G., Sinha, S., Arai, A., Lima, J.A., and Bluemke, D.A., AJR Am J Roentgenol. 186(6 Suppl 2):S357-365, June 2006.

Hypertension and Smoking are Associated with Reduced Regional Left Ventricular

Function in Asymptomatic: Individuals the Multi-Ethnic Study of Atherosclerosis This study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals. Coronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals. The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression. Higher diastolic blood pressure (DBP) was associated with lower Ecc (p < or = 0.002). The Ecc's in the LAD territory of participants with DBP <80, 80 to 84, 85 to 89, and > or =90 mm Hg were -15.6%, -14.8%, -14.2%, and -13.7%, respectively (p < 0.001). Similar results were documented in other territories and after multivariable analysis. Smokers had lower Ecc in the LAD and RCA regions compared with nonsmokers. Furthermore, dose response relationship between cigarette consumption measured in pack-years and regional LV dysfunction by Ecc was noted (p < or = 0.01 in LAD and RCA territories). Finally, combined diastolic hypertension and smoking was associated with a greater reduction of regional LV function. Authors conclude that higher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals. Rosen, B.D., Saad, M.F., Shea, S., Nasir, K., Edvardsen, T., Burke, G., Jerosch-Herold, M., Arnett, D.K., Lai, S., Bluemke, D.A., and Lima, J.A., J Am Coll Cardiol. 47(6), pp. 1150-1158, March 26, 2006.

Caffeine Metabolites in Umbilical Cord Blood, Cytochrome P-450 1A2 Activity, and Intrauterine Growth Restriction

Studies investigating antenatal caffeine consumption and reproductive outcomes show conflicting results, and most studies have used maternal self-reported caffeine consumption to estimate fetal exposure. This study (n=1,606) was specifically designed to test the association of caffeine and its primary metabolites in umbilical cord blood with intrauterine growth restriction (IUGR). Pregnant women were recruited from 56 obstetric practices and 15 clinics affiliated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000. In an adjusted model including caffeine only, levels in all quartiles were associated with reduced risk of IUGR. In adjusted analyses including paraxanthine and caffeine, serum paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective. These conflicting findings suggest that cytochrome P-450 1A2 (CYP1A2) metabolic activity may be associated with IUGR, so the ratio of paraxanthine to caffeine was then modeled. The likelihood of IUGR increased 21% for every one standard deviation change in the ratio (adjusted odds ratio=1.21, 95% confidence interval: 1.07, 1.37), suggesting that CYP1A2 activity, and not the absolute levels of paraxanthine, influences fetal growth. No associations were observed between caffeine or any metabolites and preterm delivery. Grosso, L.M., Triche, E.W., Belanger, K., Benowitz, N.L., Holford, T.R., and Bracken, M.B. Am J Epidemiol. 163(11), pp. 1035-1041, June 1, 2006.

Caffeine Metabolism, Genetics, and Perinatal Outcomes: A Review of Exposure Assessment Considerations During Pregnancy

The purpose of this study was to review the methodologic issues complicating caffeine exposure assessment during pregnancy; to discuss maternal and fetal caffeine metabolism, including genetic polymorphisms affecting caffeine metabolism; and to discuss the endogenous and exogenous risk factors known to influence caffeine metabolism. Methods consisted of a review of the relevant literature. Results indicated that there is wide inter-individual variation in caffeine metabolism, primarily due to variations in CYP1A2 enzyme activity. Some variability in CYP1A2 activity is due to genetic polymorphisms in the CYP1A2 gene that can cause increased or decreased inducibility of the enzyme. Considerable evidence exists that maternal caffeine metabolism is influenced by a variety of endogenous and exogenous factors and studying the genetic polymorphisms may improve understanding of the potential effects of caffeine and its metabolites on perinatal outcomes. There is substantial evidence that measurement of maternal, fetal, and neonatal caffeine metabolites may allow for a more precise measure of fetal caffeine exposure. Authors conclude that research on the genetic polymorphisms affecting caffeine metabolism may further explain the potential effects of caffeine and its metabolites on perinatal outcomes. Grosso, L.M. and Bracken, M.B. Ann Epidemiol. 15(6), pp. 460-466, July 2006.


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