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1.  PREVALENCE AND CORRELATES OF STREET-OBTAINED BUPRENORPHINE USE AMONG CURRENT AND FORMER INJECTORS IN BALTIMORE, MARYLAND 
Addictive behaviors  2013;38(12):2868-2873.
Objectives
There are few systematic assessments of street-obtained buprenorphine use from community-based samples in the United States. The objective of this study was to characterize the prevalence, correlates, and reasons for street-obtained buprenorphine use among current and former injection drug users (IDUs) in Baltimore, Maryland.
Methods
In 2008, participants of the ALIVE (AIDS Linked to the IntraVenous Experience) study, a community-based cohort of IDUs, were administered a survey on buprenorphine. Street-obtained buprenorphine represented self-reported use of buprenorphine obtained from the street or a friend in the prior three months.
Results
602 respondents were predominantly male (65%), African-American (91%), and 30% were HIV-positive. Overall, nine percent reported recent street-obtained buprenorphine use, and only 2% reported using to get high. Among active opiate users, 23% reported recent use of street-obtained buprenorphine. Use of buprenorphine prescribed by a physician, injection and non-injection drug use, use of street-obtained methadone and prescription opiates, homelessness, and opioid withdrawal symptoms were positively associated, while methadone treatment, health insurance, outpatient care, and HIV-infection were negatively associated with recent street-obtained buprenorphine use in univariate analysis. After adjustment, active injection and heroin use were positively associated with street-obtained buprenorphine use. Ninety-one percent reported using street-obtained buprenorphine to manage withdrawal symptoms.
Conclusions
While 9% reported recent street-obtained buprenorphine use, only a small minority reported using buprenorphine to get high, with the majority reporting use to manage withdrawal symptoms. There is limited evidence of diversion of buprenorphine in this sample and efforts to expand buprenorphine treatment should continue with further monitoring.
doi:10.1016/j.addbeh.2013.08.008
PMCID: PMC3805723  PMID: 24018232
buprenorphine; injection drug use; drug treatment; diversion
2.  Beyond Surveillance: A Role for Respondent-driven Sampling in Implementation Science 
American Journal of Epidemiology  2013;178(2):260-267.
We are now in the fourth decade of the human immunodeficiency virus (HIV) pandemic. Several novel prevention tools have been identified, and prevalence and incidence have declined in many settings. A remaining challenge is the delivery of preventive interventions to hard-to-reach populations, including men who have sex with men and injection drug users. Leaders in the field of HIV have called for a new focus on implementation science, which requires a shift in thinking from individual randomized controlled trials to cluster-randomized trials. Multiple challenges need to be addressed in the conduct of cluster-randomized trials, including: 1) generalizability of the study population to the target population, 2) potential contamination through overlap/exchange of members of control and intervention clusters, and 3) evaluation of effectiveness at multiple levels of influence. To address these key challenges, we propose a novel application of respondent-driven sampling—a chain-referral strategy commonly used for surveillance—in the recruitment of participants for the evaluation of a cluster-randomized trial of a community intervention. We illustrate this application with an empirical example of a cluster-randomized trial that is currently under way to assess the effectiveness of men's wellness centers in improving utilization of HIV counseling and testing among men who have sex with men in India.
doi:10.1093/aje/kws432
PMCID: PMC3712656  PMID: 23801014
HIV; implementation science; men who have sex with men; randomized controlled trial; respondent-driven sampling
3.  Limited Uptake of Hepatitis C Treatment among Injection Drug Users 
Journal of community health  2008;33(3):126-133.
We characterized 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.
doi:10.1007/s10900-007-9083-3
PMCID: PMC3800027  PMID: 18165889
Hepatitis C virus; Injection drug use; Antiviral therapy; Health care access
4.  Assessment of liver disease (non-invasive methods) 
Current opinion in HIV and AIDS  2011;6(6):465-471.
Purpose of review
The purpose of this review is to highlight new findings published in 2010-11 related to noninvasive fibrosis assessment in HIV/HCV co-infected patients. Overall, in 2010-11, 15 papers were published, of which two were excluded because they were published in languages other than English.
Recent findings
11 papers focused on serum marker panels. Papers sought to either 1) validate established panels in HIV/HCV co-infected patients often by comparing multiple serum marker panels in the same population; 2) establish new marker panels using combinations of markers used in previously validated panels; and 3) develop new marker panels using novel methodology. Overall, all panels performed within similar ranges of diagnostic accuracy as measured by the area under the receiver operating characteristic curve (AUROC) but the Fibrometer panel and its derivations achieved the highest performance. Four studies focused on transient elastography (TE). Two papers confirmed its accuracy for identifying fibrosis and cirrhosis and two papers confirmed that misclassification rates are higher in the presence of elevated triglycerides and steatosis.
Summary
Overall, performance of TE appeared superior to the majority of serum marker panels for the detection of significant fibrosis and cirrhosis in HIV/HCV co-infected patients. Challenges of widespread application of TE remain high misclassification in some subgroups, lack of standardized cutpoints and lack of widespread availability. Panels that were newly developed in 2010-11 specifically for HIV/HCV appeared to perform better than existing panels such as APRI and FIB-4; however additional external validation will be needed to confirm their accuracy.
doi:10.1097/COH.0b013e32834b55c7
PMCID: PMC3784022  PMID: 21857222
hepatitis C virus; liver fibrosis; HIV; elastography; serum markers
5.  Factors associated with injection cessation, relapse and initiation in a community-based cohort of injection drug users in Chennai, India 
Addiction (Abingdon, England)  2011;107(2):349-358.
Aims
To characterize factors associated with injection cessation, relapse and initiation.
Design
MIDACS is a prospective cohort of injection drug users (IDUs) recruited in 2005–06 with semi-annual follow-up through 2009. Discrete-time survival models were used to characterize predictors of time to first injection cessation and relapse.
Setting
Chennai, India
Participants
855 IDUs who reported injecting in the six months prior to baseline and had > 1 follow-up visit.
Measurements
Cessation was defined as the first visit where no injection drug use was reported (prior six months) and relapse as the first visit where drug injection (prior six months) was reported after first cessation.
Findings
All participants were male; median age was 35. Over three years, 92.7% reported cessation (incidence rate [IR]: 117 per 100 person-years). Factors positively associated with cessation included daily injection and incarceration and factors negatively associated with cessation included marriage, alcohol and homelessness. Of those who reported cessation, 24% relapsed (IR: 19.7 per 100 person-years). Factors positively associated with relapse included any education, injection in the month prior to baseline, sex with a casual partner, non-injection drug use, incarceration and homelessness. Alcohol was negatively associated with relapse. The primary reasons for cessation were medical conditions (36%) and family pressure (22%). The majority initiated with non-injection drugs, transitioning to injection after a median 4 years.
Conclusions
Injection drug users in Southern India demonstrate a high rate of injection cessation over three years, but relapse is not uncommon. Compensatory increases in alcohol use indicate that cessation of injection does not mean cessation of all substance use. Family pressure, concerns about general health, fear of HIV infection, and a history of non-injection drug use are important correlates of cessation.
doi:10.1111/j.1360-0443.2011.03602.x
PMCID: PMC3222716  PMID: 21815960
natural history; drug use; India; injection drug users; cohort
6.  Correlates of non-medical prescription drug use among a cohort of injection drug users in Baltimore City 
Addictive behaviors  2011;36(12):1282-1287.
Despite reports of increasing non-medical prescription drug use, relatively few studies have systematically evaluated the prevalence and correlates of non-medical prescription drug use, particularly in populations that might be especially vulnerable (e.g., injection drug users [IDUs]). We examined factors associated with non-medical prescription drug use among a community-based cohort of current and former IDUs in Baltimore (The ALIVE Study). We conducted a cross-sectional analysis of data from cohort participants that responded to a survey that included questions on non-medical prescription drug use between 2005–06 (n=1320). Non-medical prescription drug use was considered to be use of any of the following: Opiates (Oxycontin, Percocet), Benzodiazepines or Clonidine, purchased on the street and taken orally within the last six months. Data on other covariates of interest (e.g., demographics, substance use, general health) was obtained through a standardized interview. The median age was 46 years; 66% were male, 85% were African-American. Twenty one percent reported any non-medical prescription drug use; 12% reported using more than one drug. Non-medical use of opiates was most common (17%). In multivariate analysis, non-medical prescription drug use was significantly associated with Caucasian race (prevalence ratio [PR]: 1.79), self-reported bodily pain (PR: 1.58), hazardous alcohol use (PR: 1.47), marijuana use (PR: 1.65), non-injection cocaine/heroin use (PR: 1.70), diverted use of buprenorphine (PR: 1.51) or methadone (PR: 2.51), and active injection drug use (PR: 3.50; p<0.05 for all). The association between bodily pain and non-medical prescription drug use was stronger among persons that were not using substances (marijuana, injecting drugs, snorting/smoking heroin, cocaine, using crack) as compared to those using these substances. The high prevalence of non-medical prescription drug use among this population warrants further research and action. Information on the risks of nonmedical prescription drug use especially overdose, should be incorporated into interventions targeted at IDUs.
doi:10.1016/j.addbeh.2011.07.046
PMCID: PMC3179799  PMID: 21868170
non-medical prescription drug use; poly-drug use; injection drug users; substance abuse; Baltimore
7.  Changes in Blood-borne Infection Risk Among Injection Drug Users 
The Journal of Infectious Diseases  2011;203(5):587-594.
(See the editorial commentary by Grebely and Dore, on pages 571–4.)
Background. Population-level hepatitis C virus (HCV) infection incidence is a surrogate for community drug-related risk.
Methods. We characterized trends in human immunodeficiency virus (HIV) and HCV infection incidence and HCV infection prevalence among injection drug users (IDUs) recruited over 4 periods: 1988–1989, 1994–1995, 1998, and 2005–2008. We calculated HIV and HCV infection incidence within the first year of follow-up among IDUs whose test results were negative for these viruses at baseline (n = 2061 and n = 373, respectively). We used Poisson regression to compare trends across groups.
Results. HIV infection incidence declined significantly from 5.5 cases/100 person-years (py) in the 1988–1989 group to 2.0 cases/100 py in the 1994–1995 group to 0 cases/100 py in the 1998 and 2005–2008 groups. Concurrently, HCV infection incidence declined but remained robust (22.0 cases/100 py in the 1988–1989 cohort to 17.2 cases/100 py in the 1994–1995 cohort, 17.9 cases/100 py in the 1998 cohort, and 7.8 cases/100 py in the 2005–2008 cohort; P = .07). Likewise, HCV infection prevalence declined, but chiefly in younger IDUs. For persons aged <39 years, relative to the 1988–1989 cohort, all groups exhibited significant declines (adjusted prevalence ratio [PR] for the 2005–08 cohort, .73; 95% confidence interval [CI], .65–.81). However, for persons aged ≥39 years, only the 2005–2008 cohort exhibited declining prevalence compared with the 1988–1989 cohort (adjusted PR, .87; 95% CI, .77–.99).
Conclusions. Although efforts to reduce blood-borne infection incidence have had impact, this work will need to be intensified for the most transmissible viruses, such as HCV.
doi:10.1093/infdis/jiq112
PMCID: PMC3072736  PMID: 21282191
8.  Low Incidences of Human Immunodeficiency Virus and Hepatitis C Virus Infection and Declining Risk Behaviors in a Cohort of Injection Drug Users in Chennai, India 
American Journal of Epidemiology  2010;172(11):1259-1267.
The authors characterized human immunodeficiency virus (HIV) and hepatitis C virus (HCV) incidence and prospective changes in self-reported risk behavior over 2 years among 1,158 injection drug users (IDUs) recruited in Chennai, India, in 2005–2006. At baseline, HIV prevalence was 25.3%, and HCV prevalence was 54.5%. Seropositive persons with prevalent HIV infection were used to estimate baseline HIV incidence by means of the Calypte HIV-1 BED Incidence EIA (Calypte Biomedical Corporation, Portland, Oregon). Longitudinal HIV and HCV incidence were measured among 865 HIV-negative IDUs and 519 HCV antibody-negative IDUs followed semiannually for 2 years. Participants received pre- and posttest risk reduction counseling at each visit. Estimated HIV incidence at baseline was 2.95 per 100 person-years (95% confidence interval (CI): 1.21, 4.69) by BED assay; observed HIV incidence over 1,262 person-years was 0.48 per 100 person-years (95% CI: 0.17, 1.03). HCV incidence over 645 person-years was 1.71 per 100 person-years (95% CI: 0.85, 3.03). Self-reported risk behaviors declined significantly over time, from 100% of participants reporting drug injection at baseline to 11% at 24 months. In this cohort with high HIV and HCV prevalence at enrollment, the authors observed low incidence and declining self-reported risk behavior over time. While no formal intervention was administered, these findings highlight the potential impact of voluntary counseling and testing in a high-risk cohort.
doi:10.1093/aje/kwq288
PMCID: PMC3025630  PMID: 20935070
cohort studies; hepacivirus; HIV; India; risk-taking; substance abuse, intravenous
9.  Admixture Analysis of Spontaneous Hepatitis C Virus Clearance in Individuals of African-Descent 
Genes and immunity  2014;15(4):241-246.
Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75–85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African-descent have lower rates of clearance compared to individuals of European-descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 SNPs from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18×10−8) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.
doi:10.1038/gene.2014.11
PMCID: PMC4308959  PMID: 24622687
Hepatitis C; Chronic Infection; Admixture; African Ancestry
10.  Hepatitis C Virus Infection Is Not An Independent Risk Factor For Obstructive Lung Disease 
COPD  2013;11(1):10-16.
Several epidemiological studies have suggested that hepatitis C virus (HCV) infection is associated with the presence of obstructive lung disease (OLD). However, there is a strong link between HCV infection and tobacco abuse, a major risk factor for the development of OLD. In this study we analyzed clinical, laboratory and spirometric data from 1068 study participants to assess whether HCV infection, viremia, or HCV-associated end organ damage were associated with OLD. Demographics, risk behavior, serologic status for HCV and HIV, and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome (AIDS) Linked to the IntraVenous Experience (ALIVE) study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Of 1,068 participants, 890 (83%) were HCV positive and 174 (16%) met spirometric criteria for OLD. Factors independently associated with OLD were age and BMI. HCV infection, viral load and HCV-associated end organ damage were similar in participants with and without OLD. In summary, there was no independent association between markers of HCV exposure, chronicity, viremia, or HCV-associated end-organ damage with OLD. Our findings support the strong correlation between HCV status, injection drug use, and smoking. These data suggest that HCV may not be a sole contributor to the increased prevalence of OLD described in previous studies of HCV-infected individuals.
doi:10.3109/15412555.2013.800854
PMCID: PMC4302731  PMID: 23862666
chronic viral infections; injection drug users; HIV; Obstructive Lung Disease
11.  Temporal trends in HAART initiation among injection drug users in Baltimore, MD, 1996–2008 
Background
We characterized temporal trends in HAART initiation (1996–2008) among treatment eligible persons in a community-based cohort of current and former injection drug users (IDUs) in Baltimore.
Methods
The AIDS Linked to the IntraVenous Experience (ALIVE) cohort has been following HIV positive IDUs since 1988. HAART eligibility was defined as the first visit after January 1, 1996 where CD4 was <350 cells/µl. Temporal trends and predictors of HAART initiation were examined using chi-square tests for trend and lognormal survival models.
Results
The median age of 582 HAART-eligible IDUs was 41; 75% were male, 97% African American and 60% active injectors. 345 initiated HAART over 1803 person-years (19.2 per 100 person-years, 95% CI, 17.2–21.3); there was no significant temporal trend in HAART initiation. Independent predictors of delayed initiation included heavy injection and higher CD4 count; prior AIDS diagnosis, usual source of care and health insurance were predictors of more rapid initiation. The delay between eligibility and initiation decreased among those becoming eligible most recently (2003–07) compared with those in earlier calendar periods (1996–2003); however, a substantial number initiated HAART in recent calendar years either after substantial delay or not at all.
Conclusions
We failed to observe substantial improvement in HAART initiation among current and former IDUs over 12 years; heavy drug injection remains the major barrier to HAART initiation and consistent HIV care. The fact that many IDUs initiate HAART after significant delay or not at all raises concern that disparities in HIV care for IDUs remain at a time of simplified antiretroviral regimens and increasing adoption of earlier treatment.
doi:10.1086/652867
PMCID: PMC2874101  PMID: 20450418
HIV/AIDS; injection drug users; highly active antiretroviral therapy; temporal trends
12.  Epidemiology of hepatitis C virus infection & liver disease among injection drug users (IDUs) in Chennai, India 
Background & Objectives:
We characterized HCV antibody prevalence, viral persistence, genotype and liver disease prevalence among IDUs in Chennai, India as the study of the association of HIV with each of these states is important and there are no data available.
Methods:
Between 2005-2006, 1158 IDUs were recruited and followed semi-annually. All were tested for HCV antibodies at baseline; a random sample of 400 antibody positives (200 HIV-positive and 200 HIV-negative) were tested for HCV RNA; 13 of these were sequenced. Assessment of asparate amino transferase (AST)-to-platelet ratio index (APRI) was done on 557 IDUs. Prevalence ratios of each outcome were examined.
Results:
Median age was 35 yr; 99 per cent were male. HCV antibody prevalence was 55 per cent and was associated with older age, being unmarried, longer injection history, tattoo and injecting at a dealer’s place. Of the 400 HCV antibody positive IDUs, 281 (70.3%) had persistent infection which was less common among hepatitis B-infected persons but not associated with HIV. Of the 13 samples sequenced, 11 (85%) were HCV genotype 3a. Fibrosis prevalence according to APRI was: HIV/HCV-uninfected, 4 per cent; HIV mono-infected, 3 per cent; HCV mono-infected, 11 per cent; HIV/HCV co-infected, 12 per cent (P<0.001). In addition to being associated with HCV and HIV/HCV, fibrosis prevalence was higher among those drinking alcohol frequently; daily marijuana use was protective.
Interpretation & Conclusions:
Our findings show that IDUs in Chennai have high HCV prevalence and associated disease burden. The burden will increase as access to antiretroviral therapy improves particularly given the high prevalence of HIV, HCV and alcohol use.
PMCID: PMC3102459  PMID: 21245619
APRI; HCV genotype; hepatitis C virus; HIV; injection drug users; liver disease
13.  The Profile of Injection Drug Users in Chennai, India: Identification of Risk Behaviours and Implications for Interventions 
Substance use & misuse  2010;45(3):354-367.
We characterize the demographics, injection practices and risk behaviours of 1158 injection drug users (IDUs) in Chennai, the capital of Tamil Nadu in southern India who were recruited in 2005–2006 by community outreach. The median age was 35 years; the majority of IDUs were male, of Tamil ethnicity and married, earning less than USD 75 per month. Most (76%) had injected in the prior month. The median age at first injection was 25 years; the most common drug injected was heroin (80%) followed by buprenorphine. High risk behaviours were common and included needle sharing, unsafe disposal and inappropriate cleaning of needles as well as limited condom use. IDUs in India need to be educated on harm reduction and safe-injection practices; Pharmacies could serve as potential venues for HIV prevention interventions among IDUs in India as most IDUs obtain their needles from pharmacies without prescription.
doi:10.3109/10826080903452447
PMCID: PMC2924430  PMID: 20141452
Injection drug use; India; risk behaviour; HIV
14.  Mortality among injection drug users in Chennai, India (2005–2008) 
AIDS (London, England)  2009;23(8):997-1004.
Background
Injection drug users (IDUs) have estimated mortality rates over 10 times higher than the general population; much of this excess mortality is HIV associated. Few mortality estimates among IDUs from developing countries, including India, exist.
Methods
IDUs (1158) were recruited in Chennai from April 2005 to May 2006; 293 were HIV positive. Information on deaths and causes was obtained through outreach workers and family/network members. Mortality rates and standardized mortality ratios were calculated; multivariate Poisson regression was used to identify predictors of mortality.
Results
We observed 85 deaths over 1998 person-years (p-y) of follow-up [incidence rate (IR) 4.25 per 100 p-y; 95% confidence interval (CI) 3.41, 5.23]. The overall standardized mortality ratio was 11.1; for HIV-positive IDUs, the standardized mortality ratio was 23.9. Mortality risk among HIV-positive IDUs (IR 8.88 per 100 p-y) was nearly three times that of negative IDUs (IR 3.03 per 100 p-y) and increased with declining immune status (CD4 cells > 350: 5.44 per 100 p-y vs. CD4 cells ≤ 200: 34.5 per 100 p-y). This association persisted after adjustment for potential confounders. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n = 22), AIDS (n = 14), tuberculosis (n = 8) and accident/trauma (n = 9).
Conclusion
Substantial mortality was observed in this cohort with the highest rates among HIV-positive IDUs with CD4 cells less than 350. Although in these 2 years, non-AIDS deaths outnumbered AIDS-related deaths, the relative contribution of AIDS-associated mortality is likely to increase with advancing HIV disease progression. These data reinforce the need for interventions to reduce the harms associated with drug use and increase HAART access among IDUs in Chennai.
doi:10.1097/QAD.0b013e32832a594e
PMCID: PMC2697391  PMID: 19367155
HIV; India; injection drug users; mortality; overdose
15.  Non-structured treatment interruptions (NTIs) among injection drug users in Baltimore, MD 
Background
We characterized patterns of highly active antiretroviral therapy (HAART) use and predictors of non-structured treatment interruptions (NTIs) among injection drug users (IDUs) in Baltimore, MD.
Methods
335 IDUs who initiated HAART from 1996-2006 were studied. NTIs were defined as any subsequent six-month interval where HAART was not reported. Predictors of the first NTI and subsequent restart of HAART were examined using Cox regression.
Results
260 (78%) reported ≥1 NTI. Of 215 with ≥1 follow-up visit after the NTI, 44 (20%) never restarted HAART, 62 (29%) restarted and remained on HAART and 109 (51%) reported multiple NTIs. NTIs were less likely among those who initiated HAART in later calendar years and hada recent outpatient visit and more likely among women, persons with detectable HIV RNA at the prior visit and those who reported injecting daily. Among those with NTIs, interuptions occurred earlier in persons who were younger, did not have a prior AIDS diagnosis and were actively injecting; NTIs lasted longer in persons who had higher HIV RNA levels, were incarcerated and drinking alcohol. A recent outpatient visit and not actively injecting were associated with restarting HAART.
Conclusions
NTIs were common in this population and occurred most frequently in the setting of active drug use and disruption of health care. Effective linkages between primary care for HIV and substance abuse treatment may improve HAART outcomes in this population.
doi:10.1097/QAI.0b013e318198a800
PMCID: PMC2782439  PMID: 19214124
Highly active antiretroviral therapy; injection drug users; treatment interruptions
16.  Cross-clade simultaneous HIV drug resistance genotyping for reverse transcriptase, protease, and integrase inhibitor mutations by Illumina MiSeq 
Retrovirology  2014;11(1):122.
Background
Viral resistance to antiretroviral therapy threatens our best methods to control and prevent HIV infection. Current drug resistance genotyping methods are costly, optimized for subtype B virus, and primarily detect resistance mutations to protease and reverse transcriptase inhibitors. With the increasing use of integrase inhibitors in first-line therapies, monitoring for integrase inhibitor drug resistance mutations is a priority. We designed a universal primer pair to PCR amplify all major group M HIV-1 viruses for genotyping using Illumina MiSeq to simultaneously detect drug resistance mutations associated with protease, nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, and integrase inhibitors.
Results
A universal primer pair targeting the HIV pol gene was used to successfully PCR amplify HIV isolates representing subtypes A, B, C, D, CRF01_AE and CRF02_AG. The universal primers were then tested on 62 samples from a US cohort of injection drug users failing treatment after release from prison. 94% of the samples were successfully genotyped for known drug resistance mutations in the protease, reverse transcriptase and integrase gene products. Control experiments demonstrate that mutations present at ≥ 2% frequency are reliably detected and above the threshold of error for this method. New drug resistance mutations not found in the baseline sample were identified in 54% of the patient samples after treatment failure. 86% of patients with major drug resistance mutations had 1 or more mutations associated with drug resistance to the treatment regimen at the time point of treatment failure. 59% of the emerging mutations were found at frequencies between 2% and 20% of the total sequences generated, below the estimated limit of detection of current FDA-approved genotyping techniques. Primary plasma samples with viral loads as low as 799 copies/ml were successfully genotyped using this method.
Conclusions
Here we present an Illumina MiSeq-based HIV drug resistance genotyping assay. Our data suggests that this universal assay works across all major group M HIV-1 subtypes and identifies all drug resistance mutations in the pol gene known to confer resistance to protease, reverse transcriptase and integrase inhibitors. This high-throughput and sensitive assay could significantly improve access to drug resistance genotyping worldwide.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-014-0122-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12977-014-0122-8
PMCID: PMC4302432  PMID: 25533166
Human immunodeficiency virus; Antiretroviral therapy; HIV drug resistance; Drug resistance genotyping; Illumina MiSeq; Integrase inhibitor genotyping; Deep sequencing
17.  Correlates of elevated interleukin-6 and C-reactive protein in persons with or at high-risk for HCV and HIV infections 
Journal of acquired immune deficiency syndromes (1999)  2013;64(5):10.1097/QAI.0b013e3182a7ee2e.
Background
HIV and HCV infections may increase interleukin-6 (IL-6) and C-reactive protein (CRP). However, relationships between inflammatory biomarkers, chronic viral infections, clinical factors, and behavioral factors remain poorly understood.
Methods
Using linear regression, we modeled cross-sectional associations between loge IL-6 or loge CRP levels and HCV, HIV, injection drug use, and comorbidity among 1191 injection drug users.
Results
Mean age was 47 years, 46.0% reported currently injecting drugs, 59.0% were HCV-monoinfected, and 27% were HCV/HIV-coinfected. In multivariable models, higher loge IL-6 was associated with HCV monoinfection (β=0.191, 95%CI: 0.043 to 0.339) and HCV/HIV coinfection (β=0.394, 95% CI: 0.214 to 0.574). In contrast, HCV monoinfection (β=−0.523, 95%CI: −0.275 to −0.789) and HCV/HIV coinfection (β=−0.554 95%CI: −0.260 to −0.847) were associated with lower CRP. Lower CRP with HCV infection was independent of liver fibrosis severity, synthetic function, or liver injury markers; CRP decreased with higher HCV RNA. Increased injection intensity was associated with higher IL-6 (p=0.003) and CRP (p<0.001); increasing comorbidity (p<0.001) and older age (p=0.028) were associated with higher IL-6; older age was associated with higher CRP among HCV-uninfected participants (p=0.021).
Conclusion
HIV and HCV infections contribute to chronic inflammation; however, reduced CRP possibly occurs through HCV-virally-mediated mechanisms. Findings highlight potentially modifiable contributors to inflammation.
doi:10.1097/QAI.0b013e3182a7ee2e
PMCID: PMC3848037  PMID: 23978997
inflammation; interleukin-6; C reactive protein; HCV; HIV; injection drug use; comorbidities
18.  “Everything that looks good ain’t good!”: Perspectives on Urban Redevelopment among Persons with a History of Injection Drug Use in Baltimore, Maryland 
Background
While urban redevelopment is intended to ameliorate urban decay, some studies demonstrate that it can negatively impact some residents. Few studies have considered its impact on persons with a history of drug use.
Methods
A convenience sample of 25 current or former injection drug users from Baltimore, Maryland, enrolled in the AIDS Linked to the Intravenous Experience study, and reporting residence in or bordering a redeveloping neighborhood participated in 1-2 semi-structured in-depth interviews from July, 2011-February, 2012. Interviews explored personal experiences with redevelopment and perceptions of community-wide impact. Data were analyzed using the constant comparison method.
Results
Respondents rarely described urban redevelopment as solely negative or positive. Revitalization and increased security in the redeveloping area were reported as positive consequences. Negative consequences included the lack of redevelopment-related employment opportunities, disruption of social ties, and housing instability among relocated residents. Respondents also said that urban redevelopment led to the displacement of drug markets to adjacent neighborhoods and outlying counties. Residential relocation and displacement of drug markets were reported as beneficial for persons in contemplative and later stages of recovery.
Conclusion
These findings support a holistic approach to urban redevelopment that increases access to employment opportunities and affordable housing and ensures equitable coverage of public services such as law enforcement.
doi:10.1016/j.drugpo.2013.03.015
PMCID: PMC3896568  PMID: 23647924
urban planning; urban redevelopment; substance use; drug markets
19.  The longitudinal association between homelessness, injection drug use, and injection-related risk behavior among persons with a history of injection drug use in Baltimore, MD 
Drug and alcohol dependence  2013;132(3):457-465.
Background
Few studies have assessed the temporal association between homelessness and injection drug use, and injection-related risk behavior.
Methods
Among a cohort of 1,405 current and former injection drug users in follow-up from 2005–2009, we used random intercept models to assess the temporal association between homelessness and subsequent injection drug use, and to determine whether the association between homelessness and sustained injection drug use among active injectors differed from the association between homelessness and relapse among those who stopped injecting. We also assessed the association between homelessness and subsequent injection-related risk behavior among participants who injected drugs consecutively across two visits. Homelessness was categorized by duration: none, <1 month, and ≥1 month.
Results
Homelessness was reported on at least one occasion by 532 (38%) participants. The relationship between homelessness and subsequent injection drug use was different for active injectors and those who stopped injecting. Among those who stopped injecting, homelessness was associated with relapse [<1 month: AOR=1.67, 95% CI (1.01, 2.74); ≥1 month: AOR=1.34 95% CI (0.77, 2.33)]. Among active injectors, homelessness was not associated with sustained injection drug use [<1 month: AOR=1.03, 95% CI (0.71, 1.49); ≥1 month: AOR=0.81 95% CI (0.56, 1.17)]. Among those injecting drugs across two consecutive visits, homelessness ≥1 month was associated with subsequent injection-related risk behavior [AOR=1.61, 95% CI (1.06, 2.45)].
Conclusion
Homelessness appears to be associated with relapse and injection-related risk behavior. Strengthening policies and interventions that prevent homelessness may reduce injection drug use and injection-related risk behaviors.
doi:10.1016/j.drugalcdep.2013.03.009
PMCID: PMC3926693  PMID: 23578590
unstable housing; homelessness; relapse; injection drug use; injection-related risk behavior; random intercept models
20.  Universal Antiretroviral Therapy for HIV Infection: Should US Treatment Guidelines Be Applied to Resource-Limited Settings? 
US guidelines recommending antiretroviral therapy (ART) for all patients should not yet be universally applied to resource-limited settings because of disparities in regimens used, monitoring, and access to uninterrupted ART. We discuss ethical implications of applying US guidelines in resource-limited settings.
US treatment guidelines now recommend antiretroviral therapy (ART) for all persons infected with human immunodeficiency virus (HIV), regardless of CD4 count, both for the benefit of infected individuals and to prevent HIV transmission. In an effort to meet the critical goal of treating all HIV-infected persons worldwide, there is movement toward extrapolating these guidelines and the data supporting them to resource-limited settings. While economic and practical barriers to universal ART are widely recognized, there has been little discussion of the ethical considerations resulting from global disparities in the safety and efficacy of universal ART in these settings. We argue that the risk-benefit considerations for initiating ART are not the same worldwide due to limitations in the ART regimens used, laboratory monitoring, and consistent availability of ART, which raises ethical questions about universally applying US guidelines in resource-limited settings at the present time.
doi:10.1093/cid/cit382
PMCID: PMC3749746  PMID: 23759345
HIV; antiretroviral therapy; ethics; guidelines; resource-limited settings
21.  Association between obstructive lung disease and markers of HIV infection in a high-risk cohort 
Thorax  2011;67(4):309-314.
Background
Evidence suggests an association between HIV infection and the presence of obstructive lung disease (OLD). However, the associations between specific markers of HIV infection and OLD remain unclear. A study was undertaken to determine the independent associations of HIV infection, CD4 cell count and plasma HIV viral load with the presence of OLD in an urban cohort.
Methods
Clinical, laboratory and spirometric data from the AIDS Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, were analysed. Multivariable logistic regression models were generated to identify HIV infection indices independently associated with OLD.
Results
Of 1077 participants (mean±SD age 48±8 years), 89% were African-American, 65% were men and 86% were current smokers. A total of 303 (28%) were HIV infected and 176 (16%) had spirometry-defined OLD. Higher viral load was independently associated with OLD. HIV-infected individuals with viral load >200 000 copies/ml had a 3.4-fold increase in the odds of OLD compared with HIV-negative participants (95% CI 1.24 to 9.39; p=0.02). The association between higher HIV viral load and OLD persisted after accounting for antiretroviral therapy use (OR 4.06, 95% CI 1.41 to 11.7; p=0.01). No association was observed between HIV serostatus or CD4 cell count and the presence of OLD.
Conclusion
In a cohort at risk for OLD and HIV infection, high viral load but not CD4 cell count was associated with an increased prevalence of spirometry-defined OLD. These findings suggest that higher viral load may contribute mechanistically to the increased risk of OLD in patients with HIV infection.
doi:10.1136/thoraxjnl-2011-200702
PMCID: PMC4135473  PMID: 22090038
22.  Survival during Renal Replacement Therapy among African Americans Infected with HIV Type 1 in Urban Baltimore, Maryland 
Background
African Americans with human immunodeficiency virus type 1 (HIV-1) infection and kidney disease are at increased risk of end-stage renal disease requiring renal replacement therapy (RRT), particularly in urban areas with high rates of poverty and injection drug use. It is unknown how the widespread use of highly active antiretroviral therapy (HAART) has affected survival during RRT in this vulnerable population.
Methods
African American patients infected with HIV-1 who required RRT were identified from 2 cohorts that included 4509 Africans Americans infected with HIV-1 who were recruited during the period 1988–2004 in Baltimore, Maryland. Survival after initiation of RRT was compared for those who initiated treatment in the pre-HAART and the HAART eras using Kaplan-Meier curves. Cox proportional hazards regression analysis was used to adjust for potential confounders.
Results
RRT was initiated in 162 patients (3.6%) during 10.6 years of follow-up (119 during the HAART era). Compared with patients who started RRT in the pre-HAART era, those in the HAART era were older (P< .001) and more likely to have CD4 cell counts of ≥200 cells/mm3 (P = .01). A total of 126 patients (78%) died during follow-up; among those who initiated RRT during the HAART era, 87 deaths occurred (73%). Median survival time in the pre-HAART era was 22.4 months (95% confidence interval [CI], 9.3–30.7); during the HAART era, it was 19.9 months (95% CI, 14.7–26.5; P = .94). In the multiple Cox regression model, factors independently associated with increased mortality included age (hazard ratio [HR], 1.30; 95% CI, 1.06–1.60; P = .01), lower serum albumin level (HR, 0.72; 95% CI, 0.57–0.91; P< .007), lower CD4 cell count (HR, 0.90; 95% CI, 0.82–0.99; P< .03), and the lack of HAART (HR, 0.52; 95% CI, 0.33–0.82; P = .005).
Conclusions
Older age, lower serum albumin level, lower CD4 cell count, and the lack of HAART are independent predictors of poor survival among African Americans infected with HIV-1 undergoing RRT in a resource-limited urban area. RRT survival was similar in the pre-HAART and HAART eras, likely reflecting inadequate HIV treatment in this population.
doi:10.1086/523728
PMCID: PMC4096866  PMID: 18190325
23.  HIV and COPD: impact of risk behaviors and diseases on quality of life 
Purpose
Smoking worsens quality of life among HIV-infected individuals, but it remains unclear if this association is related simply to smoking or to chronic obstructive pulmonary disease (COPD), the end-organ disease caused by smoking.
Methods
Using cross-sectional data from the AIDS Linked to the Intravenous Experience study, we determined the independent effects of smoking, HIV and COPD assessed using the Medical Outcome Studies-HIV questionnaire.
Results
Of 973 participants, 287 (29.5%) were HIV infected and 151 (15.5%) had spirometry-defined obstruction. Eight hundred and thirty-four (85.7%) were current smokers with 23.3 mean pack-years history. HIV infection was independently associated with reduced physical and mental health. COPD was associated with a trend toward worse physical health (−1.48 units; 95%CI −3.33 to 0.38; p = 0.12) and was independently associated with worse mental health (−2.43 units; 95%CI −4.22 to −0.64; p < 0.01). After accounting for COPD and other covariates, smoking was not associated with changes in physical or mental health.
Conclusions
The presence of COPD, rather than smoking, is associated with worse quality of life independent of HIV infection. Diagnosis and management of COPD in former or current smokers with or at risk for HIV may further improve quality of life.
doi:10.1007/s11136-010-9701-x
PMCID: PMC4097077  PMID: 20617387
Quality of life; Chronic obstructive pulmonary disease; Human immunodeficiency virus; Injection drug use; Smoking; Tobacco use
24.  HIV Infection Is Associated with an Increased Risk for Lung Cancer, Independent of Smoking 
Background
Human immunodeficiency virus (HIV)–infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question.
Methods
The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables.
Results
Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre–highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7–16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6–7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant.
Conclusions
HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.
doi:10.1086/518606
PMCID: PMC4078722  PMID: 17554710
25.  HIV Diversity as a Biomarker for HIV Incidence Estimation: Including a High-Resolution Melting Diversity Assay in a Multiassay Algorithm 
Journal of Clinical Microbiology  2014;52(1):115-121.
Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data.
doi:10.1128/JCM.02040-13
PMCID: PMC3911463  PMID: 24153134

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