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

Micronutrient Levels and HIV Disease Status in HIV-Infected Patients on Highly Active Antiretroviral Therapy in the Nutrition for Healthy Living Cohort

Low serum micronutrient levels were common before widespread use of highly active antiretroviral therapy (HAART) and were associated with adverse outcomes. Few data are available on micronutrient levels in subjects taking HAART. This cross-sectional study was conducted to determine the prevalence of low serum retinol, alpha-tocopherol, zinc, and selenium in HIV-infected subjects taking HAART and to assess the association of micronutrient levels with HIV disease status. Participants were HIV-infected subjects on HAART in an ongoing Nutrition for Healthy Living (NFHL) study at Tufts. Retinol, alpha-tocopherol, zinc, and selenium were determined in frozen serum samples from 171 men and 117 women. Low serum levels were defined as retinol <30 mug/dL, selenium <85 mug/L, alpha-tocopherol <500 mug/dL, and zinc <670 mug/L. Association of micronutrient quartiles with CD4 cell count, CD4 count <200 cells/mm, HIV viral load (VL), and undetectable VL was assessed using adjusted multivariate regression. Results indicated that 5% of men and 14% of women had low retinol, 8% of men and 3% of women had low selenium, and 7% of men and no women had low alpha-tocopherol. Forty percent of men and 36% of women had low zinc, however. Subjects in the upper quartiles of zinc had lower log VL levels than those in the lowest quartile (significant for women). Subjects in the upper quartiles of selenium also tended to have lower VL levels compared with those in the lowest quartile. Surprisingly, women in the upper quartiles of retinol had higher log VLs than those in the lowest quartile. There was no significant association of any micronutrient with CD4 cell count or likelihood of CD4 count <200 cells/mm. The level of CD4 cell count influenced the association of retinol with log VL in men, however. In men with CD4 counts >350 cells/mm, those with higher retinol had higher log VLs compared with the lowest quartile, whereas in men with CD4 counts <350, those with higher retinol levels had lower log VLs compared with the lowest quartile. The authors concluded that low retinol, alpha-tocopherol, and selenium are uncommon in HIV-infected subjects on HAART. Zinc deficiency remains common, however. Jones, C.Y., Tang, A.M., Forrester, J.E., Huang, J., Hendricks, K.M., Knox, T.A., Spiegelman, D., Semba, R.D., and Woods, M.N. J Acquir Immune Defic Syndr. 43(4), pp. 475-482, December 1, 2006.

Increased Serum Lipids are Associated with Higher CD4 Lymphocyte Count in HIV-Infected Women

Highly active antiretroviral therapy (HAART) has been associated with dyslipidaemia; however, the roles of immune status and non-HIV-disease risk factors remain unclear. A cross-sectional analysis of fasting lipids was carried out for 231 women, of whom 132 were HIV-infected and 99 were uninfected. The concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B (apo B) were measured. CD4 lymphocyte count, hepatitis C status, demographics, diet, and anthropometrics were also assessed. A total of 132 women were HIV-infected [30 were antiretroviral-naive, 68 were on protease inhibitors (PIs), and 34 were on non-PI HAART]. HIV infection was associated with higher triglycerides, lower HDL-C, and, among obese women, higher total cholesterol and LDL-C. Non-PI and PI HAART were each independently associated with higher total cholesterol, LDL-C, and apo B, compared with being ART-naive. Among HIV-infected women, after adjustment for HAART use, women with a CD4 lymphocyte count > or =500 cells/microL had total cholesterol 41.8 mg/dL (P = 0.002) and LDL-C 28.8 mg/dL (P = 0.01) higher, on average, than women with a CD4 count <200 cells/microL. Women with a CD4 count of 200-499 cells/microL had total cholesterol 26.31 mg/dL higher, on average, than those with a CD4 count <200 cells/microL (P = 0.04), although differences in LDL-C did not reach significance (15.51 mg/dL; P = 0.12). A higher CD4 count was also associated with higher apo B (P < 0.001). Active hepatitis C infection was associated with lower total cholesterol, LDL-C, triglycerides, and apo B. The authors concluded that higher CD4 ymphocyte counts were associated with higher lipid levels, suggesting that immune competence may independently affect the dyslipidaemia seen in the HAART era. In addition, it is important that hepatitis C status be assessed in studies of dyslipidaemia in the HIV-infected population. Floris-Moore, M., Howard, A.A., Lo, Y., Arnsten, J.H., Santoro, N., and Schoenbaum, E.E. Increased Serum Lipids are Associated with Higher CD4 Lymphocyte Count in HIV-infected Women. HIV Med. 7(7), pp. 421-430, 2006.

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

The objective 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 >or=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 >or=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.A., Floris-Moore, M., Lo, Y., Arnsten, J.H., Fleischer, N., and Klein, R.S. HIV Med. 7(6), pp. 389-396, 2006.

CCR5 Expression and Duration of High Risk Sexual Activity among HIV-Seronegative Men Who have Sex with Men

The objectives of this study were to test the hypothesis that in comparison with those with shorter risk duration, individuals with longer HIV risk duration would have reduced susceptibility to HIV-1 infection as measured by CCR5 expression, and to evaluate whether variation in CCR5 expression could be explained by known genetic polymorphisms. Methodology involved a cross-sectional study of HIV-1 exposed but uninfected men who have sex with men. The risk duration was estimated from self-reported years since first receptive anal intercourse. CCR5 expression on peripheral blood CD4+ monocytes and T cells was determined by flow cytometry. The CCR5-Delta32 mutation and polymorphisms in the CCR5 promoter and CCR2 as well as the copy number of CCL3L1 were analyzed by polymerase chain reaction. Plasma levels of MIP-1alpha (CCL3), MIP-1beta (CCL4) and RANTES (CCL5) were also measured. As risk duration varied with age, analyses were restricted to 67 individuals aged 30-49 years. Multiple linear regression analyses, adjusted for age and race, showed a significant negative association between HIV risk duration and CCR5 expression on monocytes (P = 0.01), and in a separate model, a similar negative association with CCR5 expression on T cells (P = 0.03). Low CCR5 expression was attributable mainly to CCR5-Delta32 heterozygosity and the CCR5-59029G allele. Authors confirmed a role for reduced CCR5 expression in HIV-1 resistance. CCR5-Delta32 heterozygosity and the CCR5-59029G allele were significant predictors of low CCR5 expression. Individuals with high CCR5 expression who resisted infection despite long HIV risk duration form an interesting group within which to search for additional mechanisms of resistance to HIV infection. Thomas, S.M., Tse, D.B., Ketner, D.S., Rochford, G., Meyer, D.A., Zade, D.D., Halkitis, P.N., Nadas, A., Borkowsky, W., and Marmor, M. AIDS. 20(14), pp. 1879-1883, 2006.

Pharmacokinetic Interactions between Buprenorphine and Antiretroviral Medications

Buprenorphine is used for the treatment of opioid dependence. As the number of persons receiving buprenorphine treatment and antiretroviral therapy continues to grow, so too does the existence and clinical impact of drug interactions between buprenorphine and medications for treating human immunodeficiency virus (HIV) infection. Awareness that such interactions exist may deter some patients and physicians from initiating potentially lifesaving therapy or lead to complications among patients whose treatment is already under way. Complications include nonadherence to antiretroviral therapy and the development of viral resistance. Illicit drug use is a frequent consequence of adverse drug effects experienced by injection drug users. The occurrence of unrecognized drug interactions can lead to unsuccessful therapy for HIV infection and the treatment of substance dependence. The present review is organized to provide a working background of buprenorphine pharmacology. Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions. Bruce, R.D., McCance-Katz, E., Kharasch, E.D., Moody, D.E., and Morse, G.D. Clin Infect Dis. 43 Suppl 4, pp. S216-223, 2006.

Interactions between Buprenorphine and Antiretrovirals. II. The Protease Inhibitors Nelfinavir, Lopinavir/Ritonavir, and Ritonavir

Authors examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease. McCance-Katz, E.F., Moody, D.E., Smith, P.F., Morse, G.D., Friedland, G., Pade, P., Baker, J., Alvanzo, A., Jatlow, P., and Rainey, P.M. Clin Infect Dis. 43 Suppl 4. pp. S235-246, 2006.

Interactions between Buprenorphine and Antiretrovirals. I. The Nonnucleoside Reverse-Transcriptase Inhibitors Efavirenz and Delavirdine

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease. McCance-Katz, E.F., Moody, D.E., Morse, G.D., Friedland, G., Pade, P., Baker, J., Alvanzo, A., Smith, P., Ogundele, A., Jatlow, P., and Rainey, P.M. Clin Infect Dis. 43 Suppl 4, pp. S224-234, 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. The 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.

Functional Studies of an HIV-1 Encoded Glutathione Peroxidase

In an alternate reading frame overlapping the viral envelope gene, HIV-1 has been shown to encoded a truncated glutathione peroxidase (GPx) module. Essential active site residues of the catalytic core regions of mammalian GPx sequences are conserved in the putative viral GPx (vGPx, encoded by the env-fs gene). Cells transfected with an HIV-1 env-fs construct show up to a 100% increase in GPx enzyme activity, and are protected against the loss of mitochondrial transmembrane potential and subsequent cell death induced by exogenous oxidants or mitochondrial reactive oxygen species. An intact vGPx gene was observed to be more common in HIV-1-infected long-term non-progressors, as compared to HIV-1 isolates from patients developing AIDS. An antioxidant/ antiapoptotic protective role of the vGPx is also consistent with the observation that -1 frameshifting induced by the HIV-1 env-fs sequence AAAAAGA (which contains a potential "hungry" arginine codon, AGA) increases during arginine deficiency, which has been associated with increased oxidative stress. Under arginine-limited conditions, nitric oxide synthase generates superoxide, which rapidly combines with NO to form peroxynitrite, which can cause activated T-cells to undergo apoptosis. Thus, biosynthesis of the HIV-1 GPx as an adaptive response to low arginine conditions might delay oxidant-induced apoptotic cell death, providing an enhanced opportunity for viral replication. Zhao, L., Olubajo, B., and Taylor, E.W. Biofactors. 27(1-4), pp. 93-107, 2006.

Limited Effectiveness of Antiviral Treatment for Hepatitis C in an Urban HIV Clinic

The objective of this study was to evaluate predictors and trends of referral for hepatitis C virus (HCV) care, clinic attendance and treatment in an urban HIV clinic. Methodology for this study comprised a retrospective cohort analysis in which 845 of 1318 co-infected adults who attended the Johns Hopkins HIV clinic between 1998 and 2003 after an on-site viral hepatitis clinic was opened, attended regularly (>/= 1 visit/year for >/= 2 years). Logistic regression was used to examine predictors of referral. A total of 277 (33%) of 845 were referred for HCV care. Independent predictors of referral included percentage elevated alanine aminotransferase levels [adjusted odds ratio (AOR) for 10% increase,1.16; 95% confidence interval (CI), 1.10-1.22] and CD4 cell count > 350 cells/mul (AOR, 3.20; 95% CI, 2.10-4.90), while injection drug use was a barrier to referral (AOR, 0.26; 95% CI, 0.11-0.64). Overall referral rate increased from < 1% in 1998 to 28% in 2003; however, even in 2003, 65% of those with CD4 cell count > 200 cells/mul were not referred. One hundred and eighty-five (67%) of 277 referred kept their appointment, of whom 32% failed to complete a pre-treatment evaluation. Of the remaining 125, only 69 (55%) were medically eligible for treatment, and 29 (42%) underwent HCV treatment. Ninety percent of 29 were infected with genotype 1 and 70% were African American; six (21%) achieved sustained virologic response (SVR). Only 0.7% of the full cohort achieved SVR. Authors concluded that although the potential for SVR and the recent marked increase in access to HCV care are encouraging, overall effectiveness of anti-HCV treatment in this urban, chiefly African American, HCV genotype 1 HIV clinic is extremely low. New therapies and treatment strategies are an urgent medical need. Mehta, S.H., Lucas, G.M., Mirel, L.B., Torbenson, M., Higgins, Y., Moore, R.D., Thomas, D.L., and Sulkowski, M.S. AIDS. 20(18), pp. 2361-2369, 2006.

A Success Story: HIV Prevention for Injection Drug Users in Rhode Island

New HIV diagnoses related to injection drug use (IDU) have declined in the United States. Decreasing HIV transmission among IDUs and clean syringe access have been HIV prevention priorities of the Rhode Island (RI) HIV community. To examine trends in IDU-related new HIV diagnoses in RI, a retrospective analysis of new HIV diagnoses according to HIV risk factors from 1990-2003 was performed. An 80% absolute reduction in IDU-related new HIV diagnoses was found in RI coincident with IDU-specific prevention efforts. A greater decline was found in IDU-related new HIV diagnoses in Rhode Island compared to reported national data from the Centers for Disease Control and Prevention. The dramatic decline in Rhode Island is hypothesized to be related to extensive HIV prevention efforts targeting IDUs. Further research is needed to examine the impact of specific HIV prevention interventions for IDUs. Beckwith, C.G., Moreira, C.C., Aboshady, H.M., Zaller, N., Rich, J.D., and Flanigan, T.P. Subst Abuse Treat Prev Policy. 1(1):34 [Epub ahead of print], 2006.