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Director's Report to the National Advisory Council on Drug Abuse - September, 2008

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


Early Retinal Vascular Abnormalities in African-American Cocaine Users

The purpose of this study was to investigate whether cocaine use is associated with early retinal vascular abnormalities. The design used was a population-based cross-sectional study. The study setting comprised inner-city neighborhoods in Baltimore, Maryland. Sixty-eight participants were recruited from an ongoing observational study, investigating cardiovascular complications of human immunodeficiency virus (HIV) infection and cocaine use in African Americans aged between 25 and 54 years. Those with hypertension and known cardiovascular/cerebrovascular diseases were excluded. Ophthalmoscopic examinations and fundus photography of the retinas of these subjects were performed after papillary dilation. The largest angle of arterial bifurcation (LAAB), central retinal artery equivalent (CRAE), and central retinal vein equivalent (CRVE) were measured by single-masked fundus image examiners. Main outcome measures studied were: LAAB, CRAE, and CRVE. Among the 68 study subjects, 52 (76.5%) were chronic cocaine users and 16 (23.5%) were non-cocaine users. Univariate and multivariate analyses indicated that the LAAB was associated with age and duration of cocaine use of more than 10 years. The LAAB was also inversely associated with very low-density lipoproteins levels. Multivariate analysis indicated a positive association between CRVE and cocaine use. CRAE was also associated with intravenous injection. The authors confirmed that CRAE was inversely associated with age. HIV infection was not found to be associated with any retinal vascular parameters. The authors concluded that cocaine use is associated with increased retinal arterial branching angle and venular caliber. The retinal vascular changes provided the first evidence that cocaine use has an effect on the retinal vascular system. Leung, I.Y., Lai, S., Ren, S., Kempen, J., Klein, R., Tso, M.O., and Lai, H.C. Am. J. Ophthalmol. Jul 26, 2008.

C-reactive Protein: A Poor Marker of Cardiovascular Disease Risk in HIV+ Populations with a High Prevalence of Elevated Serum Transaminases

Blood lipids and high-sensitivity C-reactive protein (hsCRP) are used to assess cardiovascular disease (CVD) risk. The authors evaluated in a cross-sectional design the relationship of hsCRP to markers of liver function (aspartate and alanine transaminases [AST and ALT, respectively]), CVD risk factors and HIV-disease progression markers in 226 HIV-1 sero-positive drug users. hsCRP showed a significant inverse relationship with ALT and high-density lipoprotein, independent of age, gender, viral load, CD4 cell-count and antiretroviral (ARV) use, and was not significantly associated with HIV-disease progression markers. Serum markers of liver damage, AST and ALT, were associated with lower hsCRP, total cholesterol, low-density lipoproteins and triglycerides. Elevated liver enzymes (> or =40 IU/L) were predictive of hsCRP levels that are considered a low risk for CVD. In conclusion, hsCRP may not be a reliable marker of CVD risk in populations with HIV at-risk for elevated liver enzymes due to high hepatitis B virus/hepatitis C virus prevalence and ARV use. Baum, M.K., Rafie, C., Sales, S., Lai, S., Duan, R., Jayaweera, D.T., Page, J.B., Campa, A. Int. J. STD AIDS. 19(6), pp. 410-413, 2008.

A Pilot Survey of Attitudes and Knowledge about Opioid Substitution Therapy for HIV-Infected Prisoners

A majority of inmates in the state of Connecticut Department of Corrections use opioids or are opioid dependent before incarceration. None of the state's prisons offer opioid substitution therapy other than for detoxification or maintenance therapy for women during pregnancy. On release to the community, most prisoners relapse to drug use and this has been associated with higher recidivism rates, and less adherence to antiretroviral medications for HIV-infected persons. Nationally and internationally, methadone (METH) and buprenorphine (BUP) have been found to decrease relapse to drug use, decrease recidivism rates, improve adherence to antiretroviral medications, decrease HIV-risk taking behaviors, and improve mortality. However, the general knowledge about opioid substitution therapy among correctional facility staff has been reported as substandard. This pilot study compiled results of answers to anonymous surveys from 27 individuals who work directly with inmates in a patient-care capacity for the Connecticut Department of Corrections (CT DOC) and CT DOC case-management referral program (Project TLC) in the year 2006. The surveys included questions regarding current attitudes and knowledge about opioid substitution therapy for prisoners. A minority of respondents refer released prisoners with a history of opioid dependency to METH or BUP treatment. The majority of correctional workers and case-management referral workers did not have knowledge about BUP or METH's ability to improve health and decrease HIV risk taking behaviors. This study found that more education of individuals treating and caring for HIV-infected opioid dependent prisoners is needed. Springer, S.A., and Bruce, R.D. J. Opioid Manag. 4(2), pp. 81-86, 2008.

Drug Use and Other Risk Factors Related to Lower Body Mass Index Among HIV-Infected Individuals

Malnutrition is associated with morbidity and mortality in HIV-infected individuals. Little research has been conducted to identify the roles that clinical, illicit drug use and socioeconomic characteristics play in the nutritional status of HIV-infected patients. This cross-sectional analysis included 562 HIV-infected participants enrolled in the Nutrition for Healthy Living study conducted in Boston, MA and Providence, RI. The relationship between body mass index (BMI) and several covariates (type of drug use, demographic, and clinical characteristics) were examined using linear regression. Overall, drug users had a lower BMI than non-drug users. The BMI of cocaine users was 1.4 kg/m(2) less than that of patients who did not use any drugs, after adjusting for other covariates (p=0.02). The BMI of participants who were over the age of 55 years was 2.0 kg/m(2) less than that of patients under the age of 35, and BMI increased by 0.3 kg/m(2) with each 100 cells/mm(3) increase in CD4 count. HAART use, adherence to HAART, energy intake, AIDS status, hepatitis B and hepatitis C co-infections, cigarette smoking and depression were not associated with BMI in the final model. In conclusion, BMI was lower in drug users than non-drug users, and was lowest in cocaine users. BMI was also directly associated with CD4 count and inversely related to age more than 55 years old. HIV-infected cocaine users may be at higher risk of developing malnutrition, suggesting the need for anticipatory nutritional support. Quach, L.A., Wanke, C.A., Schmid, C.H., Gorbach, S.L., Mwamburi, D.M., Mayer, K.H., Spiegelman, D., and Tang, A.M. Drug Alcohol Depend. 95(1-2), pp. 30-36, 2008.

Relationship between T cell Activation and CD4+ T cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Untreated human immunodeficiency virus (HIV)-infected patients maintaining undetectable plasma HIV RNA levels (elite controllers) have high HIV-specific immune responses; however it is unclear whether they experience abnormal levels of T cell activation, potentially contributing to immunodeficiency. The authors found that controllers had higher CD4(+) and CD8(+) cell activation levels (P < .001 for both) than HIV-negative subjects and higher CD8(+) cell activation levels than the antiretroviral therapy suppressed (P = .048). In controllers, higher CD4(+) and CD8(+) T cell activation was associated with lower CD4(+) cell counts (P = .009 and P = .047). These findings suggest that HIV controllers have abnormally high T cell activation levels, which may contribute to progressive CD4(+) T cell loss even without measurable viremia. Hunt, P.W., Brenchley, J., Sinclair, E., McCune, J.M., Roland, M., Page-Shafer, K., Hsue, P., Emu, B., Krone, M., Lampiris, H., Douek, D., Martin, J.N., and Deeks, S.G. J. Infect. Dis.197(1), pp. 126-133, 2008.

Linkage to Treatment and Supportive Services among HIV-Positive Ex-Offenders in Project Bridge

Access to supportive services is important for HIV-positive inmates upon release to improve continuity of medical care. Through Project Bridge, a federally funded demonstration project,18 months of intensive case management by teams of a professional social worker and an outreach worker between May 2003 and December 2005 provided 12 weekly followed by at least monthly client contacts thereafter. Most clients (95%) received medical care throughout their enrollment. Of all clients, 45.8% secured housing, 71% were linked to mental health care, and 51% were linked to addiction services. Despite high levels of addiction (97%) and mental health disorders (34% on medication), ex-offenders were retained in health care for a year after being released from incarceration. Zaller, N.D., Holmes, L., Dyl, A.C., Mitty, J.A., Beckwith, C.G., Flanigan, T.P., and Rich J.D. J. Health Care Poor Underserved 19(2), pp. 522-531, 2008.

Status Epilepticus Resulting from Severe Efavirenz Toxicity in an HIV-infected Patient

The case of an HIV-infected patient with cirrhosis in whom severe neuropsychiatric signs and symptoms developed with significantly elevated plasma efavirenz level. Although mild neuropsychiatric symptoms are a well-known adverse effect of this medication, this was a first reported status epilepticus with routine efavirenz dosing. The case raised several significant questions regarding adverse effects and dosing of the medication, including which patient characteristics predispose to efavirenz toxicity, the relevance of the CYP2B6 mutation, and indications for therapeutic drug monitoring. Nijhawan, A.E., Zachary, K.C., Kwara, A., and Venna, N. AIDS Read. 18(7), pp. 386-388, C3, 2008.


Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. The authors hypothesized that HIV promotes liver disease by enhancing microbial translocation. They studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. Results indicated that HIV-related CD4(+) lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the alpha-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), e.g., LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. The authors conclude that microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease. Balagopal, A., Philp, F.H., Astemborski, J., Block, T.M., Mehta, A., Long, R., Kirk, G.D., Mehta, S.H., Cox, A.L., Thomas, D.L., and Ray, S.C. Gastroenterology, 135(1), pp. 226-233, 2008.

The Challenge of Hepatitis C in the HIV-Infected Person

Hepatitis C virus (HCV) coinfection occurs in an estimated one quarter of HIV-infected persons in Europe, Australia, and the United States. As use of highly active antiretroviral drugs has markedly reduced opportunistic infections, HCV-related liver disease has emerged as a leading cause of death. HIV infection adversely affects both the natural history and the treatment of hepatitis C. Because there are no experimental models of coinfection and because the pathogenesis of each infection is incompletely understood, how HIV infection alters hepatitis C is not clear. This review considers the epidemiology, natural history, treatment, and pathogenesis of hepatitis C in HIV-infected persons. Thomas, D.L. Ann. Rev. Med. 59, pp. 473-485, 2008.

Comprehensive Genetic and Epigenetic Analysis of Occult Hepatitis B from Liver Tissue Samples

Occult infection with hepatitis B virus (HBV) is a type of chronic HBV infection that is characterized by the absence of a detectable hepatitis B surface antigen in the blood and by very low levels of HBV DNA in the blood and liver. The mechanisms leading to occult HBV infection remain poorly understood but include possible genetic mutations and deletions. Recently, it has been shown that HBV has CpG islands that are methylated, raising the possibility that epigenetic changes may also be important. The full-length genomes of isolates from 5 cases of occult HBV infection were cloned and analyzed for mutations and deletions. Additional studies were performed to examine for APOBEC3G (1 member of a family of deaminating proteins that are part of the innate immune system's defense against viral infection) hyperediting and methylation of viral DNA. Numerous mutations and deletions were found in the genomes of occult HBV. However, similar types and locations of polymorphisms were also noted in the genome sequences of HBV isolated from control liver tissue samples obtained from individuals with nonoccult HBV infection. Evidence of APOBEC3G hyperediting was found in 1 case of occult HBV infection, but hyperedited sequences made up only a small proportion of the viral sequences. Methylation of HBV CpG islands 1 and 2 was evident in both occult and nonoccult HBV sequences, with island 2 more densely methylated in occult HBV sequences and island 1 more densely methylated in nonoccult HBV sequences. The authors conclude that deletions and mutations are common in occult HBV but are also found in control nonoccult HBV, and no unique genetic signature for occult HBV was found. Methylation patterns differ between cases of occult and nonoccult HBV infection, suggesting that epigenetic changes may be relevant to occult HBV. Together, these findings suggest that multiple mechanisms can contribute to occult HBV infection. Vivekanandan, P., Kannangai, R., Ray, S.C., Thomas, D.L., and Torbenson, M. Clin. Infect. Dis. 46(8), pp. 1227-1236, 2008.


A Randomized Intervention Trial to Reduce the Lending of Used Injection Equipment among Injection Drug Users Infected with Hepatitis C

The authors evaluated the efficacy of a peer-mentoring behavioral intervention designed to reduce risky distributive injection practices (e.g., syringe lending, unsafe drug preparation) among injection drug users with hepatitis C virus (HCV) infection. A randomized trial with a time-equivalent attention-control group was conducted among 418 HCV-positive injection drug users aged 18 to 35 years in 3 US cities. Participants reported their injection-related behaviors at baseline and at 3- and 6-month follow-ups. Compared with the control group, intervention-group participants were less likely to report distributive risk behaviors at 3 months (odds ratio [OR]=0.46; 95% confidence interval [CI]=0.27, 0.79) and 6 months (OR=0.51; 95% CI=0.31, 0.83), a 26% relative risk reduction, but were no more likely to cite their HCV-positive status as a reason for refraining from syringe lending. Effects were strongest among intervention-group participants who had known their HCV-positive status for at least 6 months. Peer mentoring and self-efficacy were significantly increased among intervention-group participants, and intervention effects were mediated through improved self-efficacy. The authors concluded that this behavioral intervention reduced unsafe injection practices that may propagate HCV among injection drug users. Latka, M.H., Hagan, H., Kapadia, F., Golub, E.T., Bonner, S., Campbell, J.V., Coady, M.H., Garfein, R.S., Pu, M., Thomas, D.L., Thiel, T.K., and Strathdee, S.A. Am. J. Public Health. 98(5), pp. 853-861, 2008.

Limited Uptake of Hepatitis C Treatment among Injection Drug Users

Authors characterized hepatitis C virus (HCV) treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs. Mehta, S.H., Genberg, B.L., Astemborski, J., Kavasery, R., Kirk, G.D., Vlahov, D., Strathdee, S.A., and Thomas, D.L. J Community Health. 33(3), pp. 126-133, 2008.

Progression of Fibrosis during Chronic Hepatitis C is Associated with Rapid Virus Evolution

Hepatic fibrosis is the primary mediator of disease due to chronic infection with hepatitis C virus (HCV). HCV exists as a quasispecies in each infected individual, and longitudinal viral sequence changes may reveal viral dynamics and the selection pressures applied by the host immune system. Thus, the authors hypothesized that patterns of sequence change might reveal the immunopathogenesis of fibrosis progression. They tested this hypothesis by studying individuals enrolled in a prospective study of chronic HCV-related hepatic fibrosis with little or no fibrosis at first biopsy (stage 0 or 1) and a second planned liver biopsy sample obtained 4 years later. Serum was obtained from five individuals with fast progression (FP; defined as a >2-stage change between visits) and 10 carefully matched individuals with slow progression (SP; defined as a <2-stage change between visits). The authors sequenced multiple cloned hemigenomic cDNAs from each person spanning six genes (core through NS3). Phylogenetic analysis revealed temporal shifts in phylogenetic clustering over time, suggesting frequent quasispecies replacement rather than simple diversification. In addition, mixed infections were detected in three subjects, with coexistence in two subjects (one FP, one SP) of subtypes 1a and 1b throughout the 4-year biopsy interval. Subjects with FP had a higher rate of evolution than subjects with SP, with a preponderance of synonymous changes, suggesting purifying selection, except in hypervariable region 1, where positive selection pressure is frequently detected. Thus, in a small but carefully matched cohort the authors found evidence for rapid neutral evolution of HCV in persons with rapid progression of hepatic fibrosis, suggesting higher turnover of infected cells. Wang, X.H., Netski, D.M., Astemborski, J., Mehta, S.H., Torbenson, M.S., Thomas, D.L., and Ray, S.C. J. Virol. 81(12), pp. 6513-6522, 2007.

Immune Responses during Acute and Chronic Infection with Hepatitis C Virus

Hepatitis C virus (HCV) induces persistent infection and causes chronic liver disease in most infected patients. Vigorous HCV-specific CD4+ and CD8+ T cell responses against HCV multiple epitopes are necessary for spontaneous viral clearance during the acute phase, but the virus appears to have multiple strategies to evade these defenses. There are relatively few studies on the role of immune responses during the chronic phase of infection. CD4+ T cell responses appear to protect against liver injury and may be important to clearance during interferon and ribavirin based therapy. Classic cytotoxic T cells (CTL) may primarily damage the liver in chronic HCV, but there may be subpopulations of T cells that protect against liver inflammation. Resolution of these outstanding questions is important to the development of a prophylactic vaccine as well as improving therapeutic options for those with chronic infection. Ishii, S., and Koziel, M.J. Clin. Immunol. 128(2), pp. 133-147, 2008.

Hepatitis C Virus-specific T-cell Immune Responses in Seronegative Injection Drug Users

T-cell responses to hepatitis C virus (HCV) antigens reported in high-risk HCV seronegative persons suggest that an effective cellular immune response might be able to clear infection without the development of antibodies. Such findings, however, could be explained by waning antibody or cross-reactivity to other antigens. The authors therefore evaluated HCV-specific T-cell responses in 26 young (age 18-33 years) aviremic, seronegative injection drug users (IDUs) (median duration of injection, 6 years) by interferon-gamma enzyme-linked immunospot (ELISpot) assay using 429 overlapping HCV peptides pooled in 21 mixes. Seventeen aviremic, seropositive IDUs (spontaneous resolvers) and 15 healthy people were used as positive and negative controls, respectively. Findings suggested that HCV-specific T-cell responses are common among high-risk, seronegative IDUs. Zeremski, M., Shu, M.A., Brown, Q., Wu, Y., Des Jarlais, D.C., Busch, M.P., Talal, A.H., and Edlin B.R. J. Viral Hepat. 2008 Jul 17.

Hepatitis C Virus (HCV)-Specific Immune Responses of Long-Term Injection Drug Users Frequently Exposed to HCV

Successful clearance of hepatitis C virus (HCV) among IDUs is associated with a reduced risk of developing chronic reinfection, despite continuing exposure to the virus. Immunological correlates for this apparent protection were studied via HCV-specific immune responses in long-term IDUs (duration, >10 years). HCV-specific T cell responses were assessed in proliferation, enzyme-linked immunospot (ELISPOT), interferon (IFN)-gamma secretion, and cytotoxicity assays, whereas HCV-specific antibodies were assessed in enzyme immunoassays (EIAs), chemiluminescent assays, and in vitro neutralization assays. Findings suggest HCV-specific T cell proliferation and IFN-gamma production were more common in nonviremic EIA-positive IDUs (16 [94%] of 17 IDUs) than in viremic EIA-positive IDUs (9 [45%] of 20 IDUs). They were also noted in 16 (62%) of 26 nonviremic EIA-negative IDUs. In contrast, 19 (90%) of 21 viremic IDUs displayed neutralizing antibodies, compared with 9 (56%) of 16 nonviremic EIA-positive IDUs. Overall, the reduced risk of HCV persistence in IDUs previously recovered from HCV infection correlated with T cell responses, and prolonged antigenic stimulation appeared to be required to maintain humoral responses. Mizukoshi, E., Eisenbach, C., Edlin, B.R., Newton, K.P., Raghuraman, S., Weiler-Normann, C., Tobler, L.H., Busch, M.P., Carrington, M., McKeating, J.A., O'Brien, T.R., and Rehermann B. J. Infect. Dis. 198(2), pp. 203-212, 2008.

Testing Strategy to Identify Cases of Acute Hepatitis C Virus (HCV) Infection and to Project HCV Incidence Rates

Surveillance for hepatitis C virus (HCV) is limited by the challenge of differentiating between acute and chronic infections. This study identified a cross-sectional testing strategy to determine individuals with acute HCV infection and estimate HCV incidence. Anti-HCV-negative persons from four populations with various risks, i.e., blood donors, Veterans Administration (VA) patients, young injection drug users (IDU), and older IDU, were screened for HCV RNA by minipool or individual sample nucleic acid testing (NAT). The number of detected viremic seronegative infections was combined with the duration of the preseroconversion NAT-positive window period (derived from analysis of frequent serial samples from plasma donors followed from NAT detection to seroconversion) to estimate annual HCV incidence rates. Projected incidence rates were compared to observed incidence rates. Projected HCV incidence rates per 100 person-years were 0.0042 (95% confidence interval [95% CI], 0.0025 to 0.007) for blood donors, 0.86 (95% CI, 0.02 to 0.71) for VA patients, 39.8 (95% CI, 25.9 to 53.7) for young IDU, and 53.7 (95% CI, 23.4 to 108.8) for older IDU. Projected rates were most similar to observed incidence rates for young IDU (33.4; 95% CI, 28.0 to 39.9). This study demonstrates the value of applying a cross-sectional screening strategy to detect acute HCV infections and to estimate HCV incidence. Page-Shafer, K., Pappalardo, B.L., Tobler, L.H., Phelps, B.H., Edlin, B.R., Moss, A.R., Wright, T.L., Wright, D.J., O'Brien, T.R., Caglioti, S., and Busch, M.P. J. Clin. Microbiol. 46(2), pp. 499-506, 2008.

MBL2 and Hepatitis C Virus Infection among Injection Drug Users

Genetic variations in MBL2 that reduce circulating levels and alter functional properties of the mannose binding lectin (MBL) have been associated with many autoimmune and infectious diseases. MBL2 variants were examined as to their influence on the outcome of hepatitis C virus (HCV) infection. Participants were enrolled in the Urban Health Study of San Francisco Bay area injection drug users (IDU) during 1998 through 2000. The analysis included 198 study subjects who were positive for HCV antibody, but negative for HCV RNA, and 654 IDUs who were positive for both antibody and virus. There was no significant association between any of the genetic variants that cause MBL deficiency and the presence of HCV RNA. Unexpectedly, the MBL2 -289X promoter genotype, which causes MBL deficiency, was over-represented among European Americans who were HCV RNA negative (OR = 1.65, 95% CI 1.05-2.58), although not among the African Americans. This study found no association between genetic variants that cause MBL deficiency and the presence of HCV RNA. The observation that MBL2 -289X was associated with the absence of HCV RNA in European Americans requires validation. Brown, E.E., Zhang, M., Zarin-Pass, R., Bernig, T., Tseng, F.C., Xiao, N., Yeager, M., Edlin, B.R., Chanock, S.J., and O'Brien, T.R. BMC Infect. Dis. 8, pp. 57, 2008.

Management of Hepatic Complications in HIV-Infected Persons

Liver disease-related deaths mostly result from chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and are the 2nd most common cause of death from HIV. Management issues among HIV-infected persons require careful consideration, balancing potential benefits of therapy with the potential for significant treatment-related adverse effects (HCV infection) and viral resistance and/or hepatitis flares (HBV infection). Several antiretroviral agents are active against HBV infection, including lamivudine, emtricitabine, tenofovir, and, more recently, entecavir. Despite the complexity and potential for antiretroviral-associated hepatotoxicity, ART usually is safe for patients with viral hepatitis coinfection, and, in some cases, treatment for HIV infection may be beneficial for the liver. Sulkowski, M.S. J. Infect. Dis. 197 Suppl 3:S279-293, 2008.

Traveling Young Injection Drug Users at High Risk for Acquisition and Transmission of Viral Infections

A cross-sectional study of young highly mobile (under age 30) injection drug users (IDU) in San Francisco (2004-2006) were interviewed and tested for hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV infection. Travel was independently associated with heavy alcohol consumption, drinking to blackout, poly-substance use, more sexual risk behaviors and injection partners and receptive needle/syringe sharing, backloading syringes and pooling money to buy drugs; and infection status, after adjusting for demographic characteristics and years injecting. Two-thirds (62%) reported past (3 months) travel outside of San Francisco (n=355). Travelers, as compared to non-travelers, were more likely to be under age 20, female, and planned to leave San Francisco in the coming months. In an analysis of interactions with travel, younger travelers were more likely to be HCV positive than younger non-travelers. Findings showed that traveling young IDU are at exceptionally high risk for acquiring and transmitting viral infections, while their mobility makes it challenging to effectively deliver interventions. Hahn, J.A., Page-Shafer, K., Ford, J., Paciorek, A., and Lum, P.J. Drug Alcohol Depend. 93(1-2), pp. 43-50, 2008. Epub 2007 Nov 5.

Other Infections

Risk Factors Associated with Life-Threatening Rickettsial Infections

The authors retrospectively analyzed 92 cases of severe rickettsial infections in patients (median age = 49 years, 57% male, 37.0% with scrub typhus) in Hong Kong. Immunofluorescence assay was used for diagnostic confirmation. Identification of > or = 1 diagnostic sign (exposure history, rash, or eschar) was possible in 94.6% of the cases. Multivariate analysis suggested that pulmonary infiltrates (odds ratio [OR] = 25.2, 95% confidence interval [CI] = 3.9-160.9, P = 0.001) and leukocytosis (OR = 1.3, 95% CI = 1.0-1.5 per unit increase, P = 0.033) were independent predictors of admission to an intensive care unit (14.1%). Delayed administration of doxycycline was independently associated with major organ dysfunction (23.9%; oxygen desaturation, renal failure, severe jaundice, encephalopathy, cardiac failure) (OR = 1.2, 95% CI = 1.0-1.5 per day delay, P = 0.046; adjusted for age and rickettsia biogroup) and prolonged hospitalization > 10 days (25%) (OR = 1.4, 95% CI = 1.1-1.9 per day delay, P = 0.014). Treatment with fluoroquinolone/clarithromycin did not correlate with clinical outcomes (P > 0.05). Early empirical doxycycline therapy should be considered if clinico-epidemiologic signs of rickettsial infections are present. Lee, N., Ip, M., Wong, B., Lui, G., Tsang, O.T., Lai, J.Y., Choi, K.W., Lam, R., Ng, T.K., Ho, J., Chan, Y.Y., Cockram, C.S., and Lai, S.T. Am. J. Trop. Med. Hyg. 78(6), pp. 973-997, 2008.

Cytoplasmic Vacuolization Responses to Cytopathic Bovine Viral Diarrhoea Virus

Bovine Viral Diarrhea Virus (BVDV) is a positive sense, single-stranded RNA virus which exhibits two biotypes in standard cell culture systems. The cytopathic strains of this virus (cpBVDV) induce dramatic cytoplasmic vacuolization in cell cultures, while infection with the non-cytopathic (NCP-BVDV) strains produces no overt changes in the host cells. The authors results show that extensive cytoplasmic vacuolization is the earliest morphological change in response to cpBVDV infection in MDBK cells. Cells with extensive vacuolization showed no co-existing chromatin condensation, caspase activation, or loss of membrane integrity. In addition, the caspase inhibitor (zVAD-fmk), although improving cell viability of infected cells from 6.7+/-2.2% to 18.8+/-2.2%, did not prevent vacuolization. On the ultrastructural level, the virus-induced cytoplasmic vacuoles are single membrane structures containing organelles and cellular debris, which appear capable of fusing with other vacuoles and engulfing surrounding cytoplasmic materials. LysoTracker Red which marks lysosomes did not stain the virus-induced cytoplasmic vacuoles. In addition, this lysosomal dye could be observed in the cytoplasm of vacuolized cells, suggesting a lysosomal abnormality. These data demonstrate that cpBVDV induced a novel cell death pathway in MDBK cells that is primarily associated with lysosomal dysfunction and the formation of phagocytic cytoplasmic vacuoles, and this mode of cell death is different from apoptosis and necrosis. Birk, A.V., Dubovi, E.J., Cohen-Gould, L., Donis, R., and Szeto, H.H. Virus Res. 132(1-2), pp. 76-85, 2008.

Antiviral Activity of Geneticin against Bovine Viral Diarrhoea Virus

Aminoglycoside G418 is commonly used to generate stable replicons for RNA viruses, such as hepatitis C virus, West Nile virus, and bovine viral diarrhoea virus (BVDV). This precludes testing 6418's own antiviral activities against those viruses. Here, the authors report antiviral activity of 6418 against BVDV. Cell viability and virus yield reduction assays were used to investigate antiviral effects of G418 against BVDV. The expression of viral proteins and RNA were determined by western blot and real-time quantitive PCR, respectively. The authors demonstrated that G418 (50% cytotoxicity concentration of 400 microg/ml) improved cell viability of Madin-Darby bovine kidney cells infected with a cytopathic strain of BVDV (NADL) in a dose-dependent manner with 50% effective concentration of 4 microg/ml. Interestingly, close structural analogues with known properties as translation inhibitors similar to G418 - kanamycin and gentamicin - had no antiviral activity against BVDV. In addition, 6418 inhibits virus yield of two different strains of BVDV (NADL and NY-1) without affecting viral RNA replication and translation or viral NS3 protein processing. The data indicate that antiviral activity of G418 could result from interference with either the assembly or release of active virus, rather than the regulation of viral translation and replication. Thus, the authors propose the use of chemical analogues of G418 as antiviral therapeutics for treatment of viral diseases associated with the Flaviviridae family, such as hepatitis C virus, dengue virus, yellow fever virus, West Nile virus and others. Birk, A.V., Dubovi, E.J., Zhang, X., Szeto, H.H. Antivir. Chem. Chemother. 19(1), pp. 33-40, 2008.

Non-Infection Drug Abuse Medical Consequences

Case Series of Buprenorphine Injectors in Kuala Lumpur, Malaysia

Diversion of buprenorphine has been described in settings where it is legally prescribed and has become an increasing concern in Malaysia; it resulted in banning of buprenorphine in Singapore where unsubstantiated case reports suggested that buprenorphine injection was associated with particularly poor outcomes. The authors therefore conducted a case series of qualitative interviews with buprenorphine injectors in Kuala Lumpur, Malaysia to examine further the issues surrounding buprenorphine injection as well as the abuse of midazolam in combination with buprenorphine. Interviews with 19 men do not suggest significant adverse health consequences from buprenorphine injection alone and injectors have adapted diverted buprenorphine as a treatment modality. A subset of these injectors, however, combined buprenorphine and midazolam for euphoric effects with resultant symptoms of a possible pharmacological interaction. Prospective cohort studies, rather than hospital-derived samples, are needed to better understand the safety of buprenorphine injection. Bruce, R.D., Govindasamy, S., Sylla, L., Haddad, M.S., Kamarulzaman, A., and Altice, F.L. Am. J. Drug Alcohol Abuse. 34(4), pp. 511-517, 2008.

Platelet Fragmentation Requires a Specific Structural Conformation of Human Monoclonal Antibody against Beta3 Integrin

The authors have described an autoantibody against beta3 (GPIIIa49-66), a region of platelet integrin alphaIIbbeta3 that is unique. It induces platelet fragmentation in the absence of complement via antibody activation of platelet NADPH oxidase and 12-lipoxygenase to release reactive oxygen species, which destroy platelets. To study the mechanism of anti-GPIIIa antibody-induced platelet fragmentation, we screened a human single chain Fv antibody library with the GPIIIa49-66 peptide. Nine monoclonal antibodies were identified that were capable of binding to GPIIIa49-66. Surprisingly, binding avidity for GPIIIa49-66 did not correlate with activity of induction of platelet fragmentation. The authors therefore investigated the requirements for platelet fragmentation. Mutations were introduced into the heavy chain complementary-determining region-3 of clones 11, 43, and 54 by site-directed mutagenesis. The capability of these clones to induce platelet fragmentation or bind to GPIIIa49-66 subsequently changed. Molecular modeling of these clones with their mutants revealed that the ability to induce platelet fragmentation is affected by the side chain orientation of positively charged amino acids in the heavy chain of residues 99-102. Thus, a structural change in the conformation of anti-GPIIIa49-66 antibody contributes to its binding to the beta3 integrin and subsequent antibody-induced platelet fragmentation and aggregate dissolution. Li, Z., Nardi, M.A., Wu, J., Pan, R., Zhang, W., and Karpatkin, S. J. Biol. Chem. 283(6), pp. 3224-3230, 2008.

Barriers to Seeking Mental Health Care after Treatment for Orofacial Injury at a Large, Urban Medical Center: Concordance of Patient and Provider Perspectives

Patients with orofacial injury in a large, urban medical center meeting screening criteria for probable mental health disorder (n = 25) and trauma service providers (n = 35) were queried regarding psychosocial aftercare and identified factors that impeded or facilitated aftercare participation. Bivariate analyses and Fisher's exact tests were used to describe and compare patient and provider responses. Although patient participants expressed interest in receiving aftercare services for psychological problems; lack of information about services, financial cost, and availability of transportation emerged as the most salient barriers to care, indicating potentially substantial unmet psychosocial needs after facial trauma. Providers were not necessarily aware of either the extent of patient interest in psychosocial services or the nature of the barriers that would impede care utilization. Chandra, A., Marshall, G.N., Shetty, V., Paddock, S.M., Wong, E.C., Zatzick, D., Luo, G., and Yamashita, D.D. J. Trauma 65(1), pp. 196-202, 2008.

Arrested on Heroin: A National Opportunity

Arrestee drug-testing data, total number of arrests, an estimate of the mean annual number of arrests in a drug-using population, estimates of arrestees incarcerated, and estimates of heroin use and addiction in the U.S. population were derived to determine potential impact of interventions designed to link heroin-using individuals to addiction treatment. The authors found that a conservative estimate of 24 to 36 percent of all heroin addicts pass through the corrections system each year, representing more than 200,000 individuals, and offering a public health opportunity for effective linkages to addiction treatment, health care, prevention of disease transmission, criminality and recidivism. Boutwell, A.E., Nijhawan, A., Zaller, N., and Rich, J.D. J. Opioid Manag. 3(6), pp. 328-332, 2007.

Trends in Methamphetamine Use in Young Injection Drug Users in San Francisco from 1998 to 2004: the UFO Study

Secondary analysis of cross-sectional baseline data collected for a longitudinal study of young IDU from 1998 to 2004 were examined to describe temporal trends in methamphetamine use among young injection drug users (IDU) in San Francisco. Median age was 22 years [interquartile range (IQR) 20-25], 30.3% were women and median duration of injecting was 4.4 years (IQR 2-7). Prevalence of methamphetamine use was high, with 50.1% reporting recent injection, but overall there were no temporal increases in reported 'ever' injected use. Recent methamphetamine injection (past 30 days) increased significantly, and peaked at 60% in 2003. MSM-IDU had higher methamphetamine injection ever (92.3%) and recently (59.5%) compared to heterosexual male (non-MSM) IDU (81.6% and 47.3%, respectively) and to female IDU (78.4% and 46.1%, respectively). Findings disclosed that despite reports of ubiquitous increases in methamphetamine use, there were no significant increases in 6 years in ever injecting methamphetamine overall among young IDU. Further, the methamphetamine 'epidemic' appeared to have been under way among young IDU earlier than in other populations. Inglez-Dias, A., Hahn, J.A., Lum, P.J., Evans, J., Davidson, P., and Page-Shafer, K. Drug Alcohol Rev. 27(3), pp. 286-291, 2008.


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