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Director's Report to the National Advisory Council on Drug Abuse - September, 2009

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


Medication Assisted Treatment in the Treatment of Drug Abuse and Dependence in HIV/AIDS Infected Drug Users

Drug use and HIV/AIDS are global public health issues. The World Health Organization (WHO) estimates that up to 30% of HIV infections are related to drug use and associated behaviors. The intersection, of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the health care providers and researchers who work in the expanding global HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens, and concomitant drug - drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer sigma and discrimination creating additional barriers to care and treatment for their drug abuse and dependence as well as HIV infection. In an increasing number of studies, medication assisted treatment of drug abuse and dependence has been shown to be an important HIV prevention intervention. Controlling the global transmission of HIV will require further investment in evidence-based interventions and programs to enhance access to care and treatment of individuals who abuse illicit drugs and alcohol. In this review, the authors present the cumulative evidence of the importance of medication assisted treatment in the prevention, care, and treatment of HIV infected individuals who also abuse drugs and alcohol. Kresina T, Bruce D, McCance-Katz E. Curr HIV Res. 2009; Jul7(4):354-364.

Tubular Cell HIV-1 gp120 Expression Induces Caspase 8 Activation and Apoptosis

Renal biopsy data indicate that tubular epithelial cells serve as a reservoir for HIV-1 infection. The authorss studied the effect of HIV-1 gp120 envelope gene expression on tubular cell apoptosis. HIV-1 gp120 was expressed in a lentiviral vector pHR-CMV-IRES2-EGFP-ΔB. This plasmid construct was used to produce pseudotyped virus using VSV-G envelope to enhance the tropism for efficient viral transduction. Human proximal tubular (HK-2) cells were transduced and assayed for cellular injury by trypan blue exclusion, Hoechst and PI staining, TUNEL, and cell cycle staging. HIV-1 gp120-transduced HK-2 cells showed cellular injury in a time-dependent manner. Gp120-transduced cells showed 2.5-fold greater apoptosis when compared with vector-transduced cells. Cell cycle analysis did not reveal any alteration between gp120-transduced cells and vector-transduced cells. Gp120-transduced cells showed higher expression of both Fas and FasL, whereas pretreatment with anti-FasL antibody partially inhibited gp120-induced tubular cell apoptosis. Similarly, pretreatment with caspase-8 inhibitor attenuated gp120-induced HK2 cell apoptosis. Moreover, gp120-transduced cells showed activation of caspase 8. These results suggest that HIV-1 gp120 expression induces tubular cell apoptosis through the extrinsic pathway by enhancing Fas and FasL expression and activation of caspase-8. Vashistha H, Husain M, Kumar D, Singhal P. Ren Fail. 2009;1(4):303-312.

AZT 5'-triphosphate Nanoformulation Suppresses Human Immunodeficiency Virus Type 1 Replication in Peripheral Blood Mononuclear Cells

Inefficient cellular phosphorylation of nucleoside and nucleotide analog reverse transcriptase inhibitors (NRTIs) to their active nucleoside 5'-triphosphate (NTPs) form is one of the limitations for human immunodeficiency virus (HIV) therapy. Reported herein is direct binding of 3'-azido-3'-deoxythymidine-5'-triphosphate (AZTTP) onto magnetic nanoparticles (Fe3O4; magnetite) due to ionic interaction. This magnetic nanoparticle bound AZTTP (MP-AZTTP) completely retained its biological activity as assessed by suppression of HIV-1 replication in peripheral blood mononuclear cells. The developed MP-AZTTP nanoformulation can be used for targeting active NRTIs to the brain by application of an external magnetic force and thereby eliminate the brain HIV reservoir and help to treat NeuroAIDS. Saiyed Z, Gandhi N, Nair M. J Neurovirol. 2009; Jul 2:1-5.

Drug Use and Weight Loss in HIV-infected Hispanic Men

Weight loss is an independent risk factor for mortality in HIV but the role of drug use in HIV-related weight loss is not well described. This study was conducted to determine the role of drug use in HIV-related weight loss. Men (n=304), all of whom were Hispanic, were recruited into one of three groups: HIV-infected drug users; HIV-non-infected drug users; and HIV-infected non-drug users. Body mass index (BMI) was measured at successive visits. The groups were re-categorized based on self-reported drug use at the current visit into: (1) users of cocaine alone; (2) users of cocaine and opiates; (3) users of opiates alone; (4) former drug users; and (5) those who denied ever using drugs (all HIV-infected). The effect on BMI of the duration of use of the specific drug types was evaluated using repeated-measures analyses. Longer duration of exclusive opiate use or mixed cocaine and opiate use did not affect BMI in the men, regardless of HIV status. Exclusive cocaine use was associated with a decline in BMI among HIV-infected men (-0.070 kg/m2 per month duration of use; SE=0.033; p=0.037) but not among HIV-uninfected men (0.024 kg/m2 per month; SE=0.023; p=0.29). Adjustment for marijuana, cigarette and alcohol use in all men, or for CD4 count, viral load or HIV medication use in the HIV-infected men, did not alter the conclusions. In conclusion, the use of opiates or combined opiates and cocaine does not increase the risk of weight loss in the presence or absence of HIV infection. Exclusive cocaine use may exacerbate weight loss in HIV-infection. Forrester JE, Tucker KL, Skinner S, Terrin N. AIDS Care. 2009; August; 20(7):868- 875.

Nutrition Issues in Chronic Drug Users Living With HIV Infection

Human immunodeficiency virus (HIV) infection and chronic drug abuse both compromise nutritional status. For individuals with both disorders, the combined effects on wasting, the nutritional consequence that is most closely linked to mortality, appear to be synergistic. Substance abuse clinicians can improve and extend patients' lives by recommending healthy diets; observing and assessing for food insecurity, nutritional deficits, signs of weight loss and wasting, body composition changes, and metabolic abnormalities; and providing referrals to food programs and nutritionists. More studies are needed on the nutritional consequences of using specific illicit drugs, the impact on health of specific micronutrient and metabolic deficiencies seen in people with HIV, and the causes and clinical implications of body fat changes associated with HIV. Hendricks K, Gorbach S. Add Sci & Clin Prac. 2009;Apr 5(1):16-23.

Latently-infected CD4+ T cells are Enriched for HIV-1 Tat Variants with Impaired Transactivation Activity

The ability of HIV to establish latent infection in CD4+ lymphocytes represents a major barrier to the eradication of HIV. It is not clear what mechanisms favor latent over productive infection, but prior studies have suggested a role for the viral transcription factor Tat or its RNA target, TAR. Using samples from five individuals who were started on ART within 6 months of infection and achieved a viral load < 50 (suppressed), one- and two-exon tat RNA from HIV propagated ex vivo from baseline plasma and from co-cultures of CD4+ T cells obtained at baseline and suppressed time points were isolated. Compared to virus from the baseline plasma (mostly from productively-infected CD4+ T cells), virus from the baseline and suppressed co-cultures (mostly from latently-infected cells) had more Tat variants with impaired transactivation activity. These findings suggest that impaired activity in the Tat-TAR axis may contribute to the establishment of latent infection in CD4+ T cells. Yukl S, Pillai S, Li P, Chang K, Pasutti W, Ahlgren C, Havlir D, Strain M, GŸnthard H, Richman D, Rice A, Daar E, Little S and Wong J. Virology. 2009;387:98-108.

Diagnosis of Acute HIV Infection in Connecticut

Acute HIV infection (AHI) is the earliest stage of HIV disease, when plasma HIV viremia, but not HIV antibodies, can be detected. Acute HIV infection often presents as a nonspecific viral syndrome. However, its diagnosis, which enables linkage to early medical care and limits further HIV transmission, is seldom made. The study describes the experience of Yale's Center for Interdisciplinary Research on AIDS with AHI diagnosis in Connecticut, as a participating center in the National Institute of Mental Health Multisite AHI Study. The team sought to identify AHI cases by clinical referrals and by screening for AHI at two substance abuse care facilities and an STD clinic. One case by referral and one through screening of 590 persons were identified. Screening for AHI is feasible and probably cost effective. Primary care providers should include AHI in the differential diagnosis when patients present with a nonspecific viral syndrome. Dubrow R, Sikkema KJ, Mayer KH, Bruce RD, Julian P, Rodriguez I, Beckwith C, Roome A, Dunne D, Boeving A, Kidder TJ, Jenkins H, Dobson M, Becker J, Merson MH. Conn Med. 2009; Jun-Jul;73(6):325-331.

Pregnancy Among HIV-infected Refugees in Rhode Island

In 1999, immigration laws lifted previous barriers, allowing more HIV-infected refugees entrance to the US. Many of these refugees are women of reproductive age. At this center in Providence, RI, a significant number of HIV-infected refugees have become pregnant since resettling in the US. The pregnancies seen among these predominantly West African HIV-infected refugees are described. A retrospective chart review was conducted on all HIV-infected female refugees who established care from 2000-2006. During this period 28 HIV-infected female refugees entered from Liberia. Of these, 79% (22) women entered during 2000- 2006, with 20 pregnancies among 14 women between the median time from resettlement in the US to first pregnancy of 16 (<1-69) months. The median age at time of first pregnancy was 29 years (19-39). At time of pregnancy, the median CD4 count was 506 cells/mL and median plasma viral load (PVL) was 3.36 log10 copies/ml. There were nine deliveries, one current pregnancy and one loss to follow-up. Other pregnancy outcomes included five terminations and three spontaneous abortions. All women received antiretroviral therapy during their pregnancy. At the time of delivery the median PVL was <1.88 log. There was one HIV transmission from mother to child. Two women became pregnant while on efavirenz, which was subsequently discontinued. One of the women delivered a normal term infant; the other relocated and transferred her care. Among this cohort of HIV-infected refugees, there is a high rate of pregnancy, highlighting the need for timely initiation of medical care including comprehensive preconception counseling, upon resettlement in the US. Blood E, Beckwith C, Bazerman L, Cu-Uvin S, Mitty J. AIDS Care. 2009; Feb;21(2):207-211.

HIV Infection in Refugees: A Case-Control Analysis of Refugees in Rhode Island

The number of HIV-infected refugees entering the USA is increasing. There is little data describing the HIV-infected refugee population and the challenges encountered when caring for them. A retrospective case-control analysis of HIV-infected refugees in order to characterize their co-morbidities, baseline HIV characteristics, and longitudinal care compared to HIV-infected non-refugees was conducted. A retrospective chart review was performed of HIV-infected refugees and non-refugees who were matched for gender, age, and time of establishment of initial HIV care. The refugee population studied was largely from West Africa. Refugees were more likely than non-refugees to have heterosexual risk for HIV infection, latent tuberculosis infection, and active hepatitis B. Refugees were less likely than non-refugees to have a history of substance use, start antiretrovirals, and be enrolled in a clinical study. The baseline CD4 counts and HIV plasma viral loads were similar between the two groups. Clinicians caring for West African HIV-infected refugees should be knowledgeable about likely co-morbidities and the impact of cultural differences on HIV care. Further studies are needed to develop culturally competent HIV treatment, education, and prevention programs for refugees who are beginning a new life in the USA. Beckwith CG, DeLong AK, Desjardins SF, Gillani F, Bazerman L, Mitty JA, Ross H, Cu-Uvin S. Int J Infect Dis. 2009; Mar;13(2):186-192.

Lessons Learned from a Training Collaboration Between An Ivy League Institution and a Historically Black University

The Miriam Hospital, Brown Medical School, and Jackson State University developed a joint training program for predoctoral, Black psychology students under the auspices of a training grant funded by the National Institutes of Health. The development and success of this collaboration between two institutions with federally funded training programs for HIV/AIDS research are rooted in the individual commitment of key investigators who shared a common goal that transcended institutional allegiances and a program official at the National Institute on Drug Abuse. The students in the program at Jackson State University had unlimited access to the clinical research resources and mentoring expertise at Brown Medical School. This innovative program began in 2001 and addresses the need for Black leaders in clinical research and academia who will focus on HIV and other infections that disproportionately affect the Black community. This collaboration has served as a bridge between an Ivy League institution and a historically Black university for training in clinical research to develop successful minority academicians. Flanigan TP, Payne N, Simmons E, Hyde J, Sly K, Zlotnick C. Am J Public Health. 2009; Apr;99 Suppl 1:S57-60.

Low-Abundance HIV Drug-Resistant Viral Variants in Treatment-Experienced Persons Correlate with Historical Antiretroviral Use

It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure were obtained from a specimen bank. The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing. The additional low abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects. When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug resistant mutations correlated with the failing antiretroviral drugs in 21% of subjects and correlated with historical antiretroviral use in 79% of subjects. Low-abundance HIV drug-resistant mutations in antiretroviral-experienced subjects at time of virologic failure can increase a subject's overall burden of resistance, yet commonly go unrecognized by conventional genotyping. The majority of unrecognized resistant mutations correlate with historical antiretroviral use. Ultra-deep sequencing can provide important historical resistance information for clinicians when planning subsequent antiretroviral regimens for highly treatment-experienced patients, particularly when their prior treatment histories and longitudinal genotypes are not available. Le T, Chiarella J, Simen BB, Hanczaruk B, Egholm M, Landry ML, Dieckhaus K, Rosen MI, Kozal MJ. Low-abundance HIV drug-resistant viral variants in treatment-experienced persons correlate with historical antiretroviral use. PLoS One. 2009 Jun 29;4(6):e6079.


Assessment of Liver Fibrosis by Transient Elastography in Persons with Hepatitis C Virus

Infection or HIV-Hepatitis C Virus Coinfection Transient elastography is a novel, noninvasive method for staging liver fibrosis. Eelastography with histologic methods among hepatitis C virus (HCV)-infected and human immunodeficiency virus (HIV)-HCV-coinfected participants in an urban, predominantly black study population were compared. Participants recruited from the AIDS Linked to the Intravenous Experience and the Johns Hopkins HIV Clinical Cohort studies underwent elastography to determine liver stiffness measurements. Liver biopsy specimens were staged F0-F4 in accordance with the Metavir score. Diagnostic accuracy and determination of liver stiffness cutoff values, compared with histologic methods, were determined by receiver operating characteristic analysis. Logistic regression methods identified parameters associated with discordant classification status. Of 192 participants, 139 (72%) were coinfected with HIV and HCV, 121 (63%) had insignificant fibrosis, and 48 (25%) had cirrhosis. Overall, the area-under-the-curve receiver operating characteristic was 0.87 for detection of both significant fibrosis (95% confidence interval, 0.82-0.92) and cirrhosis (95% confidence interval, 0.81-0.93). With use of cutoff values of _9.3 kPa for fibrosis and _12.3 kPa for cirrhosis, 79%-83% of participants were correctly classified by liver stiffness measurement (compared with histologic methods); accuracy appeared to be higher among HIV-uninfected participants than among HIV-infected participants. Most discordance occurred when liver stiffness measurements indicated liver disease and histologic examination did not (in 16% of participants); the patients with these discordant results were more likely to have attributes that increased the odds of significant fibrosis, such as elevated serum fibrosis markers or HIV-related immunosuppression, compared with persons in whom low fibrosis was predicted by both examination of a biopsy specimen and elastography. For most HCV-infected persons, fibrosis stage predicted by elastography is similar to that predicted by examination of a biopsy specimen. Elastography-based measurement of liver stiffness holds promise to expand liver disease screening and monitoring, particularly among injection drug users. Kirk G, Astemborski J, Mehta S, Spoler C, Fisher C, Allen D, et al., Clin Infect Dis. 2009; Apr 1;48(7):963-972.

Acute Hepatitis C Virus Infection in an HIV Clinic and in Community Settings

Recent European, Australian, and US reports of clusters of sexually transmitted acute HCV infection among HIV-infected men who have sex with men (MSM) have led to a call for regular screening of at-risk individuals. Acute HCV among HIV-infected persons is underrecognized and alanine aminotransferase (ALT) elevations often attributed to hepatotoxicity due to highly active antiretroviral therapy, leading to unwarranted treatment interruptions. In Rhode Island, at Brown University, the authors are prospectively studying a low-cost screening strategy to identify acute HCV with routine blood tests in an HIV clinic. Fifty-nine HIV-infected, HCV antibody-negative individuals receiving primary HIV care at a Ryan White-funded clinic who were ³18 years of age, with drug and/or sexual HCV risk behavior within the prior 6 months, were prospectively enrolled. At quarterly routine clinic visits, ALT levels are measured and a Behavioral Risk Questionnaire completed. ALT rise prompts HCV RNA testing: For normal baseline, if ALT becomes abnormal (>45 IU/ml) or increases by ³20 IU/ml; and for elevated baseline, if ALT increases by 50%. Risk reduction counseling, testing for sexually transmitted infections, and drug treatment are provided. Acute HCV is classified as either a baseline incident infection (anti-HCV negative but HCV RNA positive with an elevated ALT and subsequent HCV antibody seroconversion) or a prospective incident infection (baseline HCV antibody and RNA negative, but with newly detectable HCV RNA after a rise in ALT followed by HCV antibody seroconversion). Individuals with acute HCV are interviewed about risk behaviors leading to acquisition, followed to determine treatment candidacy, educated about potential benefits of early therapy, and provided with on-site evaluation and HCV treatment. The study is ongoing. At baseline, 1 incident acute HCV infection was identified. Traumatic sexual and drug practices that may transmit HCV were prevalent, although more than half of participants rated their risk for acute HCV as low. A smaller number of HIV-infected individuals who were identified clinically were also followed. Risk factors include sexual transmission for 1 (MSM with genotype 1 who achieved sustained virologic response with 6 months of HCV therapy) and drug injection for 3 (1 spontaneously resolved infection; 2 declined therapy and developed chronic HCV). Screening for acute HCV at one of Rhode Island's gay bathhouses, the largest MSM sex club in New England, with >15,000 members is also being explored. Development of this study has led to routine availability of HCV antibody testing at the bathhouse with facilitated referral into care for HCV antibody-positive individuals. HIV/HCV coinfected individuals may have the most to lose with later diagnosis and the most to gain from earlier therapy and preventive intervention. Thus, although many questions remain regarding biology, precise modes of transmission, and predictors of acute HCV, the authors endorse a more aggressive approach to acute HCV surveillance and diagnosis among HIV-infected individuals as per the European AIDS Clinical Society's recent Coinfection Guidelines. Recommendations include serologic testing for HCV on initial physician visit and then annually thereafter, plus HCV RNA for patients with risk factors (eg, injection drug use, mucosal traumatic sex) who have an unexplained increase in transaminases and negative HCV antibody. Taylor L, Mayer K. Correspondence 2411. 2009; May 3 Available online.

HCV/ HBV, Liver Disease:

Role of Molecular Mimicry of Hepatitis C Virus Protein with Platelet GPIIIa in Hepatitis C-Related

Immunologic Thrombocytopenia Patients with HIV-1 immune-related thrombocytopenia (HIV-1-ITP) have a unique Ab against platelet GPIIIa49-66 capable of inducing oxidative platelet fragmentation in the absence of complement. HIV-1-seropositive drug abusers are more prone to develop immune thrombocytopenia than non-drug abusers and have a higher coinfection with hepatitis C virus (HCV) than non-drug abusers (90% vs 30%). Molecular mimicry was sought by screening a phage peptide library with anti-GPIIIa49-66 antibody as bait for peptides sharing homology sequences with HCV. Several phage peptide clones had 70% homology with HCV protein. Sera from dually infected thrombocytopenic patients with HCV and HIV-ITP reacted strongly with 4 nonconserved peptides from HCV core envelope 1. Reactivity correlated inversely with platelet count (r2 = 0.7, P < .01). Ab raised against peptide PHC09 in GPIIIa-/- mice induced thrombocytopenia in wild-type mice. Affinity-purified IgG against PHC09 induced oxidative platelet fragmentation in vitro. Drug abusers dually infected with HCV and HIV-1 had a greater incidence and severity of thrombocytopenia as well as titer of anti-GPIIIa49-66/PHC09 Ab. NZB/W F1 mice injected with recombinant core envelope 1 developed Ab versus PHC09 and significantly decreased their platelet count (P < .001). Thus, HCV core envelope 1 can induce thrombocytopenia by molecular mimicry with GPIIIa49-66. Zhang W, Nardi M, Borkowsky W, Li Z, and Karpatkin S. Blood. 2009; April 23; 113(17): 4086-4093.

Adherence to Medication for Chronic Hepatitis C - Building on the Model of Human Immunodeficiency Virus Antiretroviral Adherence Research

Treatment of hepatitis C virus (HCV) infection with pegylated interferon/ribavirin achieves sustained virological response in up to 56% of HCV mono-infected patients and 40% of HCV/human immunodeficiency virus (HIV)-co-infected patients. The relationship of patient adherence to outcome warrants study. The aim of this study was to review comprehensively research on patient-missed doses to HCV treatment and discuss applicable research from adherence to HIV antiretroviral therapy. Publications were identified by PubMed searches using the keywords: adherence, compliance, hepatitis C virus, interferon and ribavirin. The term 'non-adherence' differs in how it is used in the HCV from the HIV literature. In HCV, 'non-adherence' refers primarily to dose reductions by the clinician and early treatment discontinuation. In contrast, in HIV, 'non-adherence' refers primarily to patient-missed doses. Few data have been published on the rates of missed dose adherence to pegylated interferon/ribavirin and its relationship to virological response. As HCV treatment becomes more complex with new classes of agents, adherence will be increasingly important to treatment success as resistance mutations may develop with suboptimal dosing of HCV enzyme inhibitors. HIV adherence research can be applied to that on HCV to establish accurate methods to assess adherence, investigate determinants of non-adherence and develop strategies to optimize adherence. Weiss JJ, Brau N, Stivala A, Swan T, Fishbein T. Aliment Pharmacol Ther. 2009; Jul 30(1):14-27.

Student Volunteers Screen Drug Users for Viral Hepatitis

The Viral Hepatitis Integration Project (VHIP) provides injection drug users with viral hepatitis vaccination, screening and treatment referral services. These services are co-located with a streetside, mobile syringe exchange in a neighborhood in which illicit drug use is highly prevalent. Year 1 and 2 students from the Albert Einstein Medical School volunteer to perform phlebotomy, vaccinate and counsel syringe exchange clients about viral hepatitis. The VHIP was developed to meet the needs of both students and syringe exchange clients. Substance abuse disorders are common among patients, yet few medical students have exposure to drug users prior to their clinical rotations. Little time is devoted to formal teaching about these complex disorders in medical school. Medical students attend the VHIP in pairs; each pair includes one experienced and one novice volunteer. Students are accompanied by the VHIP program coordinator and a health care provider (doctor or Physician Assistant) with expertise in addiction medicine. The medical providers deliver ongoing supervision and support of the students, both on-site and in quarterly meetings. Additionally, medical providers model professional and compassionate behavior in caring for active drug users. To date, 36 medical students have participated in the VHIP. Students have provided vaccinations, viral hepatitis screening, and health counseling to over 200 syringe exchange clients. A self-administered, open-ended survey of student volunteers revealed that they valued learning about the lives of drug users, practicing skills in vaccination and phlebotomy, and having the chance to work with underserved patients. All the students found the experience enjoyable, and many expressed a wish to have more opportunities to volunteer in similar settings. Stein MR, Soloway I, Litwin AH. Student volunteers screen drug users for viral hepatitis. Student Medical Education. 2009 May;43:481-482.

In Vitro Characterization of a miR-122-Sensitive Double-helical Switch Element in the 5' Region of Hepatitis C Virus RNA

It has been proposed that the hepatitis C virus (HCV) internal ribosome entry site (IRES) resides within a locked conformation, owing to annealing of its immediate flanking sequences. In this study, structure probing using Escherichia coli dsRNA-specific RNase III and other classical tools showed that this region switches to an open conformation triggered by the liver-specific microRNA, miR-122. This structural transition, observed in vitro, may be the mechanistic basis for the involvement of downstream IRES structural domain VI in translation, as well as providing a role of liver-specific miR-122 in HCV infection. In addition, the induced RNA switching at the 5' untranslated region could ultimately represent a new mechanism of action of micro-RNAs. D’az-Toledano R, Ariza-Mateos A, Birk A, Mart’nez-Garc’a, B and G—mez J. Nucleic Acids Res. 2009; Jul 3 available on line.

More Rare Birds, and the Occasional Swan

The Urban Health Study recruited semiannual cross-sections of persons who injected illicit drugs from the streets and other natural settings in inner-city neighborhoods in the San Francisco Bay area. Of nearly 14,000 persons enrolled from 1986 through 2002, nearly 5000 participated more than once (mean, 4.5 visits), comprising a passive, embedded cohort. Participants were interviewed, tested for HIV antibody, and given harm reduction counseling and referrals to needed services. Data from the interviews, blood samples, and add-on studies were used to study health and illness among persons who inject illicit drugs and evaluate interventions. Findings from this cohort have been published in >100 articles, describing basic biological, clinical, immunologic, and epidemiologic investigations; social and behavioral studies; and research on health services, health policy, and legal policy. From 1998 through 2002, 4018 study participants received hepatitis B and C serologic testing, of whom 3548 (88%) tested positive for antibodies to the hepatitis C virus (HCV). Of those testing negative, 84 returned for a subsequent visit, and 24 tested positive for HCV antibody, representing prospectively identified seroconversions. Retrospective testing of stored serum identified an additional 43 seroconversions from 1986 through 1998. Ongoing analyses are examining HCV prevalence, incidence, and risk factors, and genetic factors associated with resistance to viral infection and persistence. The Swan Project began recruiting injection drug users (IDUs) aged 18-35 on the Lower East Side of Manhattan in 2005; >500 IDUs have been interviewed and tested for HIV and HCV antibody, and 150 who have tested HCV antibody negative have enrolled in a prospective cohort. Cohort members undergo biweekly risk behavior interviews and HCV RNA testing to detect new HCV infections as soon as possible after they are acquired, along with counseling and referrals to needed services. Biweekly interviewing and testing has proved feasible, reveals more risk behavior than quarterly or semiannual interviewing, and identifies the timing of risk behavior and infections more precisely, providing increased power to detect associations between specific injection practices and contexts and HCV acquisition. Identifying these risk factors is urgent because HCV still spreads rapidly among IDUs, even where access to sterile syringes has dramatically reduced transmission. The incidence of new infections in Swan participants during follow-up fell 3-fold from 2005 to 2007, whereas the incidence during the period immediately preceding enrollment, calculated using data on window period infections, did not fall, suggesting that the reduction might have resulted from our intervention. The authors are prospectively studying the clinical features, immunology, and virology of acute infection, and comparing those who clear infection, those who develop chronic infection, and those who remain uninfected. They have found HCV-specific cellular responses in nearly 50% of seronegative, HCV RNA-negative persons in this cohort. This study provides the rare opportunity to analyze blood specimens collected before infection and then from the same person weekly during acute infection. Participants who do not clear infection within 90 days are offered antiviral treatment through a unique, multidisciplinary program. To date, the authors have identified 21 prospectively observed infections, 18 persons in the seronegative window period on enrollment, 3 recent seroconverters, and 12 possible reinfections. Edlin B, Shu M, Winkelstein E, Des Jarlais D, Busch M, Rehermann B, O'Brien T, Talal A, Tobler L, Zeremski M and Beeder A. Gastroenterology. 2009; June 136(7):2412-2414.

Methylation Regulates Hepatitis B Viral Protein Expression

Hepatitis B virus (HBV)DNA has been shown to contain CpGislands that are methylated in human tissue, which suggests a role for methylation in regulating viral protein production. However, data are lacking about whether methylation regulates viral gene expression. To investigate the hypothesis that methylation of viral DNA regulates viral gene expression, unmethylated, partially methylated, and fully methylated viral DNA was transfected into HepG2 cells. In addition, a new assay was designed that specifically identifies methylated covalently closed circular DNA (cccDNA) in human liver tissue. Transfection of methylated HBV DNA led to reduced HBV mRNA levels in HepG2 cells, decreased surface and core protein expression in these cells, and decreased secretion of HBV viral proteins into the cell supernatant. These data provide direct evidence that CpG islands regulate gene transcription of HBV. Furthermore, methylated cccDNA was found in tumor and nonneoplastic human liver tissues. Finally, an in vitro equivalent of cccDNA showed decreased viral protein production in HepG2 cells after DNA methylation. Taken together, these data demonstrate that methylation of viral CpG islands can regulate viral protein production. Vivekanandan P, Thomas D, and Torbenson M . J Infect Dis. 2009; May 1;199(9):1286-1291.

Predictors of Injection Drug Use Cessation and Relapse in a Prospective Cohort of Young Injection Drug Users in San Francisco, CA (UFO Study)

Studies of injection drug use (IDU) cessation have largely sampled adults in drug treatment settings. Little is known about injection cessation and relapse among young IDU in the community. A total of 365 HCV-negative IDU under age 30 years were recruited by street outreach and interviewed quarterly for a prospective cohort between 1/2000 and 2/2008. Participants were followed for a total of 638 person-years and 1996 visits. Survival analysis techniques to identify correlates of injection cessation (> or =3 months) and relapse to injection were used. 67% of subjects were male, median age was 22 years and median years injecting was 3.6, 28.8% ceased injecting during the follow-up period. Among those that ceased injecting, nearly one-half resumed drug injection on subsequent visits, one-quarter maintained injecting cessation, and one-quarter were lost to follow-up. Participating in a drug treatment program in the last 3 months and injecting less than 30 times per month were associated with injection cessation. Injecting heroin or heroin mixed with other drugs, injecting the residue from previously used drug preparation equipment, drinking alcohol, and using benzodiazepines were negatively associated with cessation. Younger age was associated with relapse to injection. These results suggest that factors associated with stopping injecting involve multiple areas of intervention, including access to drug treatment and behavioral approaches to reduce injection and sustain cessation. The higher incidence of relapse in the younger subjects in this cohort underscores the need for earlier detection and treatment programs targeted to adolescents and transition-age youth. In conclusion, young IDU remain at high risk of blood-borne infections and other negative health outcomes. Understanding of longitudinal patterns of injection drug use cessation and relapse and their determinants is critical for guiding public health interventions to reduce morbidity and mortality. Evans JL, Hahn JA, Lum PJ, Stein ES, Page K. Drug Alc Dep 2009;101(3): 152-157.

Risk Behaviors after Hepatitis C Virus Seroconversion in Young Injection Drug Users in San Francisco

The rationale for screening populations at risk for hepatitis C virus infection (HCV) includes the possibility of altering risk behaviors that impact disease progression and transmission. This study prospectively examined young injection drug users (IDU) to determine if behaviors changed after they were made aware of HCV seroconversion. The effects of HCV seroconversion coupled with post-test counseling on risk behaviors (alcohol use, non-injection and injection drug use, lending and sharing injecting equipment, and having sex without a condom) and depression symptoms were estimated using conditional logistic regression, fitting odds-ratios for immediately after disclosure and 6 and 12 months later, and adjusting for secular effects. 112 participants met inclusion criteria, i.e. they were documented HCV seronegative at study onset and subsequently seroconverted during the follow-up period, with infection confirmed by HCV RNA testing. HCV seroconversion was independently associated with a decreased likelihood of consuming alcohol (OR=0.52; 95% CI: 0.27-1.00, p=0.05) and using non-injection drugs (OR=0.40; 95% CI: 0.20-0.81, p=0.01) immediately after disclosure, however, results were not sustained over time. There were significant (p<0.05) declines in the use of alcohol, injection and non-injection drugs, and sharing equipment associated with time that were independent from the effect of seroconversion. Making young IDU aware of their HCV seroconversion may have a modest effect on alcohol and non-injection drug use that is not sustained over time. Tsui JI, Vittinghoff E, Hahn JA, Evans JL, Davidson PJ, Drug Alc Depend. 2009; Jul 30.


Impact of South American Heroin on the US Heroin Market 1993-2004

The past two decades have seen an increase in heroin-related morbidity and mortality in the United States. Trends in US heroin retail price and purity, including the effect of entry of Colombian-sourced heroin on the US heroin market were reported. The average standardized price ($/mg-pure) and purity (% by weight) of heroin from 1993 to 2004 was obtained from US Drug Enforcement Agency retail purchase data for 20 metropolitan statistical areas. Univariate statistics, robust Ordinary Least Squares regression and mixed fixed and random effect growth curve models were used to predict the price and purity data in each metropolitan statistical area over time. Over the 12 study years, heroin price decreased 62%. The median percentage of all heroin samples that are of South American origin increased an absolute 7% per year. Multivariate models suggest percent South American heroin is a significant predictor of lower heroin price and higher purity adjusting for time and demographics. These analyses reveal trends to historically low-cost heroin in many US cities. These changes correspond to the entrance into and rapid domination of the US heroin market by Colombian-sourced heroin. The implications of these changes are discussed. Ciccaronea D, Unickb G, Kraus A. International Journal of Drug Police. 2009; Sept 20(5):392-401.

Depression and Anxiety in Adolescent Females: The Impact of Sleep Preference and Body Mass Index

To examine the differences in depressive symptoms and anxiety between (a) normal weight and overweight, and (b) morning type and evening type (sleep chronotype) adolescent girls. The interaction of sleep chronotype and weight and depressive symptoms and anxiety were also examined. The design consisted of a cross-sectional study of 264 adolescent females (mean age = 14.9 ± 2.2, range 11-17 years). Sleep chronotype, depressive symptoms, and anxiety were obtained by self-report questionnaire. The mean of three measurements of height and weight was used to calculate the body mass index (BMI). BMI was plotted on the CDC BMI-for-age growth charts to obtain percentile ranking. Participants were categorized into two groups according to BMI percentile: normal weight (<85th percentile) and overweight (³85th percentile). Compared with normal-weight females, overweight females were more likely to be non-Caucasian, lower socioeconomic status, have more advanced pubic hair and breast stages, and earlier age at menarche. No differences were observed with respect to sleep chronotype, depressive symptoms, and trait anxiety between normal weight and overweight females. Evening chronotype was associated with more depressive symptoms (Β = -.65, p < .01) and higher trait anxiety (Β = -.22, p < .05). Evening chronotype was associated with more depressive symptoms in both normal-weight and overweight females. However, the association was stronger in overweight females. Individually, sleep and weight impact physical and mental health during adolescence. The combination of evening chronotype and overweight appears to have the strongest association on the emotional health of adolescent females. Further investigations are needed to provide potential biological mechanisms for this relationship. Negriff S, Dorn L, Susman E, Huand B. J Adolesc Health. 2009; Jun 44(6):554-560.

Thrombin Induces Tumor Cell Cycle Activation and Spontaneous Growth by Down-regulation of p27Kip1, in Association with the Up-regulation of Skp2 and MiR-222

The effect of thrombin on tumor cell cycle activation and spontaneous growth was examined in synchronized serumstarved tumor cell lines and a model of spontaneous prostate cancer develop-ment in TRAMP mice. BrdUrd incorporation and propidium iodide staining of prostate LNCaP cells arrested in G0 and treated with thrombin or serum revealed a 48- and 29-fold increase in S phase cells, respectively, at 8 hours. Similar results were obtained with TRAMP cells and a glioblastoma cell line, T98G. Cell cycle kinases and inhibitors in synchronized tumor cells revealed high levels of p27Kip1 and low levels of Skp2 and cyclins D1 and A. Addition of thrombin, TFLLRN, or serum down-regulated p27Kip1 with concomitant induction of Skp2, Cyclin D1, and Cyclin A with similar kinetics. LNCaP p27Kip1-transfected cells or Skp2 knockdown cells were refractory to thrombin-induced cell cycle activation. MicroRNA 222, an inhibitor of p27Kip1, was robustly up-regulated by thrombin. The in vitro observations were tested in vivo with transgenic TRAMP mice. Repetitive thrombin injection enhanced prostate tumor volume 6- to 8-fold (P < 0.04). Repetitive hirudin, a specific potent antithrombin, decreased tumor volume 13- to 24-fold (P < 0.04). Thus, thrombin stimulates tumor cell growth in vivo by down-regulation of p27Kip1. Hu L, Ibrahim S, Liu C, Skaar K, Pagano M, Karpatkin S. Cancer Res. 2009; Apr 15;69(8):3374-3381.

C-Terminal ADAMTS-18 Fragment Induces Oxidative Platelet Fragmentation, Dissolves Platelet Aggregates, and Protects Against Carotid Artery Occlusion and Cerebral Stroke

Anti-platelet integrin GPIIIa49-66 antibody (Ab) induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385-amino acid fragment of ADAMTS-18 (a disintegrin metalloproteinase with thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP or collagen and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCI3-induced carotid artery thrombosis as well as cerebral infarction in a postischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18. Li Z, Nardi M, Li YS, Zhang W, Pan R, Dang S, et al., Blood. 2009; Jun 11;113(24):6046-6047.

Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market

Diversion of buprenorphine (BPN) has been described in settings where it is legally prescribed and has resulted in increasing concern. To address this concern, co-formulation of buprenorphine/naloxone (BPN/NLX) replaced buprenor-phine alone in Malaysia in December 2006. To assess the significance of BPN/NLX introduction, 41 BPN/NLX injectors in Kuala Lumpur, Malaysia were recruited using a modified snowball recruitment technique. In January 2007, all subjects had previously injected BPN alone. During the transition from injecting BPN alone to co-formulated BPN/NLX, the mean daily BPN injection dose increased from 1.88 mg (range 1.0-4.0 mg) to 2.49 mg/day ( p <.001). Overall, 18 (44%) subjects increased their daily amount of injection while 22 (54%) had no change in dose; only one subject reduced the amount of injection. Development of opioid withdrawal symptoms was the primary outcome, however the only symptom that was significantly associated with BPN/NLX dosage was the report of "stomach pains" ( p = .01). In logistic regression analysis, the development of opioid withdrawal symptoms was associated with increased benzodiazepine injection and increased syringe sharing. These data suggests that the introduction of BPN/NLX did not reduce injection related risk behaviors such as syringe sharing and was associated with increased benzodiazepine use. Evidence-based approaches to treat BPN injection are urgently needed. Bruce D, Govindasamy S, Sylla L, Kamarulzaman A, Altice F. The American Journal of Drug and Alcohol Abuse. 2009; March;35(2):68-72.

Contemporary Clinical Opioid Use: Opportunities and Challenges

Opiate analgesics have been used by humans for thousands of years and are the longest continuously used class of medications. The recent increased interest in opiates (drugs derived from opium) and opioids (more generally, any natural or synthetic drug that binds to an opioid receptor) has evolved largely from 5 directions: (1) advances in the design of new opioid receptor agonist and antagonist drugs; (2) expansion and innovation in methods of drug delivery; (3) increased public awareness of pain management options and the appropriateness of aggressively treating pain (eg, declaration of pain as the "fifth vital sign" and pain relief as a fundamental human right); (4) growing recognition of the serious consequences of opioid misuse, misadventure, and addiction; and (5) medicolegal aspects of practitioners' prescribing practices and legal prosecution for "overprescribing." These and related issues are addressed in 4 articles and 1 additional editorial in the current issue of Mayo Clinic Proceedings. Specifically, Passik discusses long-term prescription opioid therapy; Argoff and Silvershein address the use of long- vs short-acting opioids for treating chronic noncancer pain; Smith reviews opioid metabolism; and Berge et al discuss chemical dependency in physicians, with a focus on opioids. In their editorial, Oreskovich and Caldeiro discuss whether select groups of health care professionals, such as anesthesiologists, have unacceptably poor outcomes after initial opioid addiction and whether this should dictate policies of rehabilitation and possible return to clinical practice. Lanier WL, Kharasch ED. Mayo Clin Proc. 2009; Jul 84(7):572-575.

Serum IL-6 Levels are Associated with Significant Coronary Stenosis in Cardiovascularly Asymptomatic Inner-city Black Adults in the US

The objective of this study was to explore whether increased levels of inflammatory cytokines are associated with the risk of clinically silent coronary artery disease. Three-hundred-fifty-six black adults aged 25-54 residing in inner city of Baltimore, Maryland, United States were included in this study. Sociodemographics were assessed as were lipid profiles, IL-6, tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1), and high-sensitivity C-reactive protein (hs-CRP) levels. Computed tomography (CT) coronary angiography was performed. Coronary calcification was identified in 22.5 % participants and 14 % had significant (³50 %) coronary stenosis. Multiple logistic regression analyses suggested that IL-6 levels were independently associated with the presence of coronary calcification and significant coronary stenosis, while TNF-alpha, sICAM-1 and hs-CRP levels were not. This study underscores a critical role for IL-6 in atherosclerosis and suggests that IL-6 may be a marker for significant coronary stenosis in cardiovascularly asymptomatic individuals. Lai S, Fishman E, Lai H, Pannu H, Detrick B. Inflamm Res. 2009;58:15-21.


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