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2.  The Exposure Assessment in Current Time Study: Implementation, Feasibility, and Acceptability of Real-Time Data Collection in a Community Cohort of Illicit Drug Users 
AIDS Research and Treatment  2013;2013:594671.
Objective. We describe the study design and evaluate the implementation, feasibility, and acceptability of an ecological momentary assessment (EMA) study of illicit drug users. Design. Four sequential field trials targeting observation of 30 individuals followed for a four week period. Participants. Participants were recruited from an ongoing community-cohort of current or former injection drug users. Of 113 individuals enrolled, 109 completed study procedures during four trials conducted from November 2008 to May 2013. Methods. Hand-held electronic diaries used in the initial trials were transitioned to a smartphone platform for the final trial with identical data collection. Random-prompts delivered five times daily assessed participant location, activity, mood, and social context. Event-contingent data collection involved participant self-reports of illicit drug use and craving. Main Outcome Measures. Feasibility measures included participant retention, days of followup, random-prompt response rates, and device loss rate. Acceptability was evaluated from an end-of-trial questionnaire. Sociodemographic, behavioral, clinical, and trial characteristics were evaluated as correlates of weekly random-prompt response rates ≥80% using logistic regression with generalized estimating equations. Results. Study participants were a median of 48.5 years old, 90% African American, 52% male, and 59% HIV-infected with limited income and educational attainment. During a median followup of 28 days, 78% of 11,181 random-prompts delivered were answered (mean of 2.8 responses daily), while 2,798 participant-initiated events were reported (30% drug use events; 70% craving events). Self-reported acceptability to study procedures was uniformly favorable. Device loss was rare (only 1 lost device every 190 person-days of observation). Higher educational attainment was consistently associated with a higher response rate to random-prompts, while an association of HIV infection with lower response rates was not observed after accounting for differences in trial recruitment procedures. Conclusion. Near real-time EMA data collection in the field is feasible and acceptable among community-dwelling illicit drug users. These data provide the basis for future studies of EMA-informed interventions to prevent drug relapse and improve HIV treatment outcomes in this population.
doi:10.1155/2013/594671
PMCID: PMC3836292  PMID: 24307943
3.  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
4.  Effect of a Liver Cancer Education Program on Hepatitis B Screening Among Asian Americans in the Baltimore–Washington Metropolitan Area, 2009–2010 
Introduction
Asian Americans have the highest incidence of hepatocellular carcinoma (HCC), the major form of primary liver cancer, of all ethnic groups in the United States. Chronic hepatitis B virus (HBV) infection is the most common cause of HCC, and as many as 1 in 10 foreign-born Asian Americans are chronically infected with HBV. We tested the effectiveness of a culturally tailored liver cancer education program for increasing screening for HBV among Chinese, Korean, and Vietnamese Americans residing in the Baltimore–Washington metropolitan area, from November 2009 through June 2010.
Methods
We used a cluster randomized controlled trial to recruit volunteer participants from community-based organizations (CBOs) in the Baltimore–Washington metropolitan area. We selected 877 participants by using a pretest survey. People were eligible to participate if they had not attended a hepatitis B–related education program in the past 5 years. The intervention group (n = 441) received a 30-minute educational program, and the control group (n = 436) received an educational brochure. After attending the educational program, the intervention group completed a post-education survey. Six months later, participants in both groups were followed up by telephone. Receipt of HBV screening was the outcome measure.
Results
Approximately 79% (n = 688) of participants completed the 6-month follow-up telephone survey. Among those who had not had HBV screening at baseline (n = 446), the adjusted odds of self-reported receipt of HBV screening at the 6-month follow-up to the educational program were significantly higher for the intervention group than for the control group (odds ratio = 5.13; 95% confidence interval, 3.14–8.39; P < .001). Chinese Americans and Vietnamese Americans had significantly higher odds of having HBV screening in the 6-month period than Korean Americans.
Conclusion
Culturally tailored education programs that increase liver cancer awareness can be effective in increasing HBV screening among underserved Asian American populations.
doi:10.5888/pcd11.130258
PMCID: PMC3921910  PMID: 24503341
5.  Discordance Between CD4+ T-Lymphocyte Counts and Percentages in HIV-Infected Persons With Liver Fibrosis 
In cross-sectional analysis of 287 human immunodeficiency virus–infected persons with high hepatitis C virus prevalence, liver fibrosis defined by elastography was associated with higher CD4+ T-cell percentages relative to absolute CD4+ number; this discordance was most apparent in persons with marked lymphopenia.
Background. Cirrhosis of the liver can induce splenic sequestration of peripheral blood cells, recently suggested to reduce the number but not percentage of circulating CD4+ T cells in persons uninfected with human immunodeficiency virus (HIV). We investigated whether earlier stages of liver fibrosis prior to cirrhosis were associated with discordance between CD4 count (CD4N) and CD4 percentage (CD4%) in HIV-infected patients.
Methods. In cross-sectional analysis of 287 HIV-infected participants of the AIDS Linked to the Intravenous Experience cohort, we evaluated CD4N, CD4%, and transient elastography staging of liver fibrosis. High CD4+ lymphocyte discordance was defined as higher CD4% relative to CD4N based on accepted clinical cutoffs; multivariable logistic regression was used to determine covariates associated with discordance.
Results. Of 287 participants, 99 (34.4%) had high CD4+ discordance, which increased to 76% of 114 participants with marked lymphopenia (total lymphocyte count [TLC] ≤1200 cells/μL). In multivariable analysis, the odds of having high CD4+ discordance was increased in persons with significant liver fibrosis compared to those without fibrosis (odds ratio, 1.69; 95% confidence interval [CI], .95–2.96); the odds ratio of discordance increased to 2.66 (95% CI, 1.11–6.40) among the subset of participants with TLC ≤1200 cells/μL. The odds for discordance associated with cirrhosis were of similar magnitude as those observed with significant fibrosis.
Conclusions. In HIV-infected persons, liver fibrosis is associated with discordant peripheral CD4+ lymphocyte results, especially in the setting of marked lymphopenia. Clinicians should also consider CD4% when interpreting absolute CD4+ counts of HIV-infected persons with known or suspected liver disease, particularly if TLC is <1200 cells/μL.
doi:10.1093/cid/cis294
PMCID: PMC3404711  PMID: 22460963
6.  Changes in sexual and drug-related risk behavior following antiretroviral therapy initiation among HIV-infected injection drug users 
AIDS (London, England)  2012;26(18):2383-2391.
Objective
To evaluate whether HAART is associated with subsequent sexual and drug-related risk behavior compensation among injection drug users (IDUs).
Design
A community-based cohort study of 362 HIV-infected IDUs initiating HAART in Baltimore, Maryland.
Methods
HAART use and risk behavior was assessed at 8316 biannual study visits (median 23). Using logistic regression with generalized estimating equations (GEE), we examined the effect of HAART initiation on changes in risk behavior while adjusting for sociodemographics, alcohol use, CD4+ cell count, year of initiation and consistency of HAART use.
Results
At HAART initiation, participants were a median of 44.4 years old, 71.3% men and 95.3% African–American. In multivariable analysis, HAART initiation was associated with a 75% reduction in the likelihood of unprotected sex [adjusted odds ratio (aOR) 0.25; 95% confidence interval (CI), 0.19–0.32] despite no change in overall sexual activity (aOR 0.95; 0.80–1.12). Odds of any injecting decreased by 38% (aOR 0.62; 0.51–0.75) after HAART initiation. Among the subset of persistent injectors, needle-sharing increased nearly two-fold (aOR 1.99; 1.57–2.52). Behavioral changes were sustained for more than 5 years after HAART initiation and did not differ by consistency of HAART use. Reporting specific high-risk behaviors in the year prior to initiation was a robust predictor of engaging in those behaviors subsequent to HAART.
Conclusion
Overall, substantial declines in sexual risk-taking and active injecting argue against significant behavioral compensation among IDUs following HAART initiation. These data also provide evidence to support identifying persons with risky pre-HAART behavior for targeted behavioral intervention.
doi:10.1097/QAD.0b013e32835ad438
PMCID: PMC3678983  PMID: 23079804
antiretroviral therapy; HIV prevention; injecting; injection drug users; risk compensation; sexual behavior
7.  HIV Infection in the Etiology of Lung Cancer 
Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations.
doi:10.1513/pats.201009-061WR
PMCID: PMC3132793  PMID: 21653536
HIV infection; lung cancer; smoking
8.  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
9.  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
10.  High Frequency of False-Positive Hepatitis C Virus Enzyme-Linked Immunosorbent Assay in Rakai, Uganda 
The prevalence of hepatitis C virus (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai, Uganda, with the Ortho version 3.0 HCV enzyme-linked immunosorbent assay. All serologically positive samples were tested for HCV RNA. Seventy-six of the 1000 (7.6%) participants were HCV antibody positive; none were confirmed by detection of HCV RNA.
doi:10.1093/cid/cit602
PMCID: PMC3840403  PMID: 24051866
hepatitis C virus; ELISA; Africa
11.  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
12.  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
13.  Effect of Cigarette Smoking on HIV Acquisition, Progression, and Mortality 
Cigarette smoking is more common among those with HIV compared to the general population. However, it remains unclear whether smoking alters the natural history of HIV infection or if unique health consequences related to smoking occur in the context of HIV. In this article, we review the literature on the effect of smoking on acquisition of HIV, progression of HIV to AIDS, and mortality. While there was significant heterogeneity in the study populations evaluated, we found little evidence that cigarette smoking increases the risk for acquiring HIV. Although two studies observed that smoking was associated with more rapid CD4 cell count declines, most data suggest that smoking does not accelerate progression to clinical AIDS. The most consistent finding was an increased risk for respiratory infections in smokers. While no effect of smoking was seen with AIDS-related mortality, findings related to all-cause mortality were inconclusive. Due to an increase in chronic non-AIDS outcomes in the post-HAART era, smoking is likely an increasingly important contributor to morbidity and mortality in HIV-infected populations. Future investigation of the biological and clinical effects of smoking, and of preventive approaches to reduce the heavy burden, in individuals with HIV is warranted.
doi:10.1521/aeap.2009.21.3_supp.28
PMCID: PMC2774230  PMID: 19537952
HIV infection; smoking; tobacco; HAART
14.  Characterization of HIV-1 envelopes in acutely and chronically infected injection drug users 
Retrovirology  2014;11(1):106.
Background
Mucosally acquired human immunodeficiency virus type 1 (HIV-1) infection results from a limited number of variants, and these infecting strains potentially have unique properties, such as increased susceptibility to entry blockers, relative interferon-alpha (IFN-α) resistance, and replication differences in some primary cells. There is no data about the phenotypic properties of HIV-1 envelope variants found early after acquisition among subjects infected through injection drug use (IDU). For the first time, we compared the characteristics of virus envelopes among injection drug users sampled prior to seroconversion (HIV RNA+/Ab-), within 1 year (early), and more than 2 years (chronic) after estimated acquisition.
Results
Virus envelopes from 7 HIV RNA+/Ab- subjects possessed lower genetic diversity and divergence compared to 7 unrelated individuals sampled during the chronic phase of disease. Replication competent recombinant viruses incorporating the HIV RNA+/Ab- as compared to the chronic phase envelopes were significantly more sensitive to a CCR5 receptor inhibitor and IFN-α and showed a statistical trend toward greater sensitivity to a fusion blocker. The early as compared to chronic infection envelopes also demonstrated a statistical trend or significantly greater sensitivity to CCR5 and fusion inhibitor and IFN- α. The HIV RNA+/Ab- as compared to chronic envelope viruses replicated to a lower extent in mature monocyte derived dendritic cells – CD4+ T cell co-cultures, but there were no significant replication differences in other primary cells among the viruses with envelopes from the 3 different stages of infection.
Conclusions
Similar to mucosal acquisition, HIV-1 envelope quasispecies present in injection drug users prior to seroconversion have unique phenotypic properties compared to those circulating during the chronic phase of disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12977-014-0106-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12977-014-0106-8
PMCID: PMC4253609  PMID: 25430652
HIV-1; Envelope; Transmission; Receptor; Replication; Injection drug use; Dendritic cells; Selection; Interferon
15.  “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
16.  HIV Infection is associated with reduced pulmonary diffusing capacity 
Journal of acquired immune deficiency syndromes (1999)  2013;64(3):10.1097/QAI.0b013e3182a9215a.
Rationale:
Prior studies comparing abnormalities in pulmonary function between HIV-infected and HIV-uninfected persons in the current era are limited.
Objectives:
To determine the pattern and severity of impairment in pulmonary function in HIV-infected compared to HIV-uninfected individuals.
Methods:
Cross-sectional analysis of 300 HIV-infected and 289 HIV-uninfected men enrolled from 2009-2011 in two clinical centers of the Lung HIV Study. Participants completed pre- and post-bronchodilator spirometry, diffusing capacity (DLCO) measurement, and standardized questionnaires.
Results:
Most participants had normal airflow; 18% of HIV-infected and 16% of HIV-uninfected men had airflow obstruction. The mean percent predicted DLCO was 69% in HIV-infected vs. 76% in HIV-uninfected men (p<0.001). A moderately to severely reduced DLCO of ≤60% was observed in 30% of HIV-infected compared to 18% of HIV-uninfected men (p<0.001), despite the fact that 89% of those with HIV were on antiretroviral therapy. A reduced DLCO was significantly associated with HIV and CD4 cell count in linear regression adjusting for smoking and other confounders. The DLCO was lowest in HIV-infected men with CD4 cell counts <200 compared to those with CD4 cell counts ≥200 and to HIV-uninfected men. Respiratory symptoms of cough, phlegm and dyspnea were more prevalent in HIV-infected patients particularly those with abnormal pulmonary function compared to HIV-uninfected patients.
Conclusions:
HIV infection is an independent risk factor for reduced DLCO, particularly in individuals with a CD4 cell count below 200. Abnormalities in pulmonary function among HIV-infected patients manifest clinically with increased respiratory symptoms. Mechanisms accounting for the reduced DLCO require further evaluation.
doi:10.1097/QAI.0b013e3182a9215a
PMCID: PMC3845879  PMID: 23979001
Pulmonary function; FEV1; DLCO; gas exchange; COPD; HIV/AIDS
17.  Assessment of Liver Fibrosis by Transient Elastography in Persons with Hepatitis C Virus Infection or HIV–Hepatitis C Virus Coinfection 
Background
Transient elastography is a novel, noninvasive method for staging liver fibrosis. We compared elastography with histologic methods among hepatitis C virus (HCV)–infected and human immunodeficiency virus (HIV)–HCV-coinfected participants in an urban, predominantly black study population.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1086/597350
PMCID: PMC2715996  PMID: 19236273
18.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
doi:10.1093/infdis/jit373
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
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.  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
21.  Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1 
Nature genetics  2007;39(6):733-740.
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
doi:10.1038/ng2035
PMCID: PMC4135476  PMID: 17496894
22.  A randomized study of contingency management and spirometric lung age for motivating smoking cessation among injection drug users 
BMC Public Health  2014;14(1):761.
Background
Even after quitting illicit drugs, tobacco abuse remains a major cause of morbidity and mortality in former injection drug users. An important unmet need in this population is to have effective interventions that can be used in the context of community based care. Contingency management, where a patient receives a monetary incentive for healthy behavior choices, and incorporation of individual counseling regarding spirometric “lung age” (the age of an average healthy individual with similar spirometry) have been shown to improve cessation rates in some populations. The efficacy of these interventions on improving smoking cessation rates has not been studied among current and former injection drug users.
Methods
In a randomized, factorial design study, we recruited 100 active smokers from an ongoing cohort study of current and former injection drug users to assess the impact of contingency management and spirometric lung age on smoking cessation. The primary outcome was 6-month biologically-confirmed smoking cessation comparing contingency management, spirometric lung age or both to usual care. Secondary outcomes included differences in self-reported and biologically-confirmed cessation at interim visits, number of visits attended and quit attempts, smoking rates at interim visits, and changes in Fagerstrom score and self-efficacy.
Results
Six-month biologically-confirmed smoking cessations rates were 4% usual care, 0% lung age, 14% contingency management and 0% for combined lung age and contingency management (p = 0.13). There were no differences in secondary endpoints comparing the four interventions or when pooling the lung age groups. Comparing contingency management to non-contingency management, 6-month cessation rates were not different (7% vs. 2%; p = 0.36), but total number of visits with exhaled carbon monoxide-confirmed abstinence were higher for contingency management than non-contingency management participants (0.38 vs. 0.06; p = 0.03), and more contingency management participants showed reduction in their Fagerstrom score from baseline to follow-up (39% vs. 18%; p = 0.03).
Conclusions
While lung age appeared ineffective, contingency management was associated with more short-term abstinence and lowered nicotine addiction. Contingency management may be a useful tool in development of effective tobacco cessation strategies among current and former injection drug users.
Trial registration
Clinicaltrials.gov NCT01334736 (April 12, 2011).
doi:10.1186/1471-2458-14-761
PMCID: PMC4132916  PMID: 25074396
Contingency management; Spirometry; Lung age; Smoking cessation
23.  HIV-associated obstructive lung diseases: insights and implications for the clinician 
The lancet. Respiratory medicine  2014;2(7):583-592.
The effectiveness of antiretroviral therapy to control HIV infection has led to the emergence of an older HIV population who are at risk of chronic diseases. Through a comprehensive search of major databases, this Review summarises information about the associations between chronic obstructive pulmonary disease (COPD), asthma, and HIV infection. Asthma and COPD are more prevalent in HIV-infected populations; 16–20% of individuals with HIV infection have asthma or COPD, and poorly controlled HIV infection worsens spirometric and diffusing capacity measurements, and accelerates lung function decline by about 55–75 mL/year. Up to 21% of HIV-infected individuals have obstructive ventilatory defects and reduced diffusing capacity is seen in more than 50% of HIV-infected populations. Specific pharmacotherapy considerations are needed to care for HIV-infected populations with asthma or COPD–protease inhibitor regimens to treat HIV (such as ritonavir) can result in systemic accumulation of inhaled corticosteroids and might increase pneumonia risk, exacerbating the toxicity of this therapy. Therefore, it is essential for clinicians to have a heightened awareness of the increased risk and manifestations of obstructive lung diseases in HIV-infected patients and specific therapeutic considerations to care for this population. Screening spirometry and tests of diffusing capacity might be beneficial in HIV-infected people with a history of smoking or respiratory symptoms.
doi:10.1016/S2213-2600(14)70017-7
PMCID: PMC4111094  PMID: 24831854
24.  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
25.  NPHS2 Variation in Sporadic Focal Segmental Glomerulosclerosis 
Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3′ untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
doi:10.1681/ASN.2007030319
PMCID: PMC4096868  PMID: 17942957

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