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3.  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
4.  HIV Incidence Determination in the United States: A Multiassay Approach 
The Journal of Infectious Diseases  2012;207(2):232-239.
Background. Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys.
Methods. We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4+ T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BED-CEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort.
Results. The MAA had a window period of 141 days (95% confidence interval [CI], 94–150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%–1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .51%–1.71%).
Conclusions. The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination.
doi:10.1093/infdis/jis659
PMCID: PMC3532826  PMID: 23129760
HIV; incidence testing; United States; epidemiology
5.  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
6.  Sensitivity Changes over the Course of Infection Increases the Likelihood of Resistance Against Fusion but Not CCR5 Receptor Blockers 
AIDS Research and Human Retroviruses  2012;28(12):1584-1593.
Abstract
As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers.
doi:10.1089/aid.2011.0319
PMCID: PMC3505054  PMID: 22650962
7.  Association between U.S. State AIDS Drug Assistance Program (ADAP) Features and HIV Antiretroviral Therapy Initiation, 2001–2009 
PLoS ONE  2013;8(11):e78952.
Background
U.S. state AIDS Drug Assistance Programs (ADAPs) are federally funded to provide antiretroviral therapy (ART) as the payer of last resort to eligible persons with HIV infection. States differ regarding their financial contributions to and ways of implementing these programs, and it remains unclear how this interstate variability affects HIV treatment outcomes.
Methods
We analyzed data from HIV-infected individuals who were clinically-eligible for ART between 2001 and 2009 (i.e., a first reported CD4+ <350 cells/uL or AIDS-defining illness) from 14 U.S. cohorts of the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Using propensity score matching and Cox regression, we assessed ART initiation (within 6 months following eligibility) and virologic suppression (within 1 year) based on differences in two state ADAP features: the amount of state funding in annual ADAP budgets and the implementation of waiting lists. We performed an a priori subgroup analysis in persons with a history of injection drug use (IDU).
Results
Among 8,874 persons, 56% initiated ART within six months following eligibility. Persons living in states with no additional state contribution to the ADAP budget initiated ART on a less timely basis (hazard ratio [HR] 0.73, 95% CI 0.60–0.88). Living in a state with an ADAP waiting list was not associated with less timely initiation (HR 1.12, 95% CI 0.87–1.45). Neither additional state contributions nor waiting lists were significantly associated with virologic suppression. Persons with an IDU history initiated ART on a less timely basis (HR 0.67, 95% CI 0.47–0.95).
Conclusions
We found that living in states that did not contribute additionally to the ADAP budget was associated with delayed ART initiation when treatment was clinically indicated. Given the changing healthcare environment, continued assessment of the role of ADAPs and their features that facilitate prompt treatment is needed.
doi:10.1371/journal.pone.0078952
PMCID: PMC3832515  PMID: 24260137
8.  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
9.  Longitudinal changes in engagement in care and viral suppression for HIV-infected injection drug users 
AIDS (London, England)  2013;27(16):2559-2566.
Objective
To examine temporal trends and predictors of linkage to HIV care, longitudinal retention in care and viral suppression among injection drug users (IDUs) infected with HIV.
Design
Community-based, prospective cohort study
Methods
We prospectively studied 790 HIV-infected IDUs participating in the AIDS Linked to the Intravenous Experience (ALIVE) study from 1998 through 2011. IDUs were considered linked to care if they attended any HIV care visit during follow-up and retained in care if they reported HIV clinic attendance at every semiannual study visit. We used logistic regression to identify predictors of poor retention in care and failure to achieve sustained viral suppression in response to ART.
Results
Of 790 HIV-infected IDUs studied, 740 (93.6%) were ever linked to care. The majority of IDUs (76.7%) received ART at some point during observation and of these, most (85.4%) achieved viral suppression. However, over a median of 8.7 years of follow-up, only 241 (30.5%) IDUs were continuously retained with no 6-month lapses in HIV care and only 63 (10.2%) had sustained viral suppression at every study visit after first receiving ART. Suboptimal engagement in care was associated with poor access to medical care, active drug use, and incarceration.
Conclusion
Compared with national estimates of retention in care and virologic suppression in the United States, IDUs are substantially less likely to remain fully engaged in HIV care. Strategies to optimize HIV care should acknowledge the elevated risk of poor engagement in care among IDUs.
doi:10.1097/QAD.0b013e328363bff2
PMCID: PMC3795966  PMID: 23770493
antiretroviral therapy; drug users; human immunodeficiency virus; primary care; retention in care
10.  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
11.  Ethical Issues in mHealth Research Involving Persons Living with HIV/AIDS and Substance Abuse 
AIDS Research and Treatment  2013;2013:189645.
We aim to raise awareness and stimulate dialogue among investigators and research ethics committees regarding ethical issues that arise specifically in the design and conduct of mHealth research involving persons living with HIV/AIDS and substance abuse. Following a brief background discussion of mHealth research in general, we offer a case example to illustrate the characteristics of mHealth research involving people living with HIV/AIDS and substance abuse. With reference to a well-established systematic general ethical framework for biomedical research with human participants, we identify a range of ethical issues that have particular salience for the protection of participants in mHealth research on HIV/AIDS and substance abuse.
doi:10.1155/2013/189645
PMCID: PMC3792525  PMID: 24171110
13.  Vitamin D Deficiency and Persistent Proteinuria among HIV-infected and –uninfected Injection Drug Users 
AIDS (London, England)  2012;26(3):295-302.
Objective
Proteinuria occurs commonly among HIV-infected and -uninfected injection drug users (IDUs) and is associated with increased mortality risk. Vitamin D deficiency, highly prevalent among IDUs and potentially modifiable, may contribute to proteinuria. To determine whether vitamin D is associated with proteinuria in this population, we conducted a cross-sectional study in the AIDS Linked to the IntraVenous Experience (ALIVE) Study.
Methods
25(OH)-vitamin D levels were measured in 268 HIV-infected and 614 HIV-uninfected participants. The association between vitamin D deficiency (<10 ng/mL) and urinary protein excretion was evaluated by linear regression. The odds of persistent proteinuria (urine protein-to-creatinine ratio >200 mg/g on two occasions) associated with vitamin D deficiency was examined using logistic regression.
Results
One-third of participants were vitamin D-deficient. Vitamin D deficiency was independently associated with higher urinary protein excretion (P<0.05) among HIV-infected and diabetic IDUs (P-interaction<0.05 for all). Persistent proteinuria occurred in 18% of participants. Vitamin D deficiency was associated with >6-fold odds of persistent proteinuria among diabetic IDUs (odds ratio [OR]=6.29, 95% confidence interval [CI]: 1.54, 25.69) independent of sociodemographic characteristics, co-morbid conditions, body mass index, and impaired kidney function (estimated GFR <60 mL/min|1.73 m2); no association, however, was observed among non-diabetic IDUs (OR=1.06, 95% CI: 0.64, 1.76) (P-interaction<0.05).
Conclusions
Vitamin D deficiency was associated with higher urinary protein excretion among those with HIV infection and diabetes. Vitamin D deficiency was independently associated with persistent proteinuria among diabetic IDUs, although not in non-diabetic persons. Whether vitamin D repletion ameliorates proteinuria in these patients requires further study.
doi:10.1097/QAD.0b013e32834f33a2
PMCID: PMC3766727  PMID: 22156964
Vitamin D deficiency; proteinuria; HIV; injection drug use; diabetes
14.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
Background
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
Objective
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Design
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Setting
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
Participants
1176 current and former injection drug users with antibodies to HCV.
Measurements
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Results
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
Limitation
The process of liver fibrosis began before the study in most persons.
Conclusion
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
doi:10.7326/0003-4819-158-9-201305070-00604
PMCID: PMC3708651  PMID: 23440167
15.  Stability of liver fibrosis among HCV-infected injection drug users 
Antiviral therapy  2012;17(5):813-821.
Background
There are few published data characterizing patterns of liver stiffness measurements (LSMs) among HCV-infected persons and their potential impact on clinical decisions (for example, deferring treatment and hepatocellular carcinoma surveillance).
Methods
A total of 591 HCV-infected injection drug users (IDUs) in a community-based cohort had four LSMs. We used semi-parametric latent class growth modelling to identify patterns, which then became a gold standard against which we characterized validity of information from the initial measurements.
Results
Median age was 49, 68% were male, 92% African-American and 33% HIV-coinfected. The median LSM at visit 1 was 6.7 kPa (IQR 5.3–8.8). Over a median 1.75 years, LSM measures were stable; median change between visits was 0 kPa (IQR -1.4–1.7). Only 3% had evidence of fibrosis progression. Other groups included stable patterns of 1) no fibrosis (59%), 2) moderate fibrosis (21%), 3) severe fibrosis (7%) and 4) cirrhosis (9%). Individuals with fibrosis progression were more likely to be HIV-infected than those with stable low fibrosis (P<0.001). The diagnostic accuracy of the first LSM for identification of need for cancer surveillance (cirrhosis ≥12.3 kPa) was high (positive predictive value = 97%). Although no single low LSM had high negative predictive value for significant fibrosis (metavir <2), individuals with two or more low results rarely had progression.
Conclusions
These data underscore the stability of liver fibrosis in a cohort of predominantly African-American HCV-infected persons over 1.75 years, support using LSMs to monitor untreated persons at risk for progression and assess need for hepatocellular carcinoma surveillance.
doi:10.3851/IMP2085
PMCID: PMC3699312  PMID: 22418880
16.  Estimating the effects of multiple time-varying exposures using joint marginal structural models: alcohol consumption, injection drug use, and HIV acquisition 
Epidemiology (Cambridge, Mass.)  2012;23(4):574-582.
The joint effects of multiple exposures on an outcome are frequently of interest in epidemiologic research. In 2001, Hernán, Brumback, and Robins (JASA 2001; 96: 440–448) presented methods for estimating the joint effects of multiple time-varying exposures subject to time-varying confounding affected by prior exposure using joint marginal structural models. Nonetheless, the use of these joint models is rare in the applied literature. Minimal uptake of these joint models, in contrast to the now widely used standard marginal structural model, is due in part to a lack of examples demonstrating the method. In this paper, we review the assumptions necessary for unbiased estimation of joint effects as well as the distinction between interaction and effect measure modification. We demonstrate the use of marginal structural models for estimating the joint effects of alcohol consumption and injection drug use on HIV acquisition, using data from 1,525 injection drug users in the AIDS Link to Intravenous Experience cohort study. In the joint model, the hazard ratio (HR) for heavy drinking in the absence of any drug injections was 1.58 (95% confidence interval= 0.67–3.73). The HR for any drug injections in the absence of heavy drinking was 1.78 (1.10–2.89). The HR for heavy drinking and any drug injections was 2.45 (1.45–4.12). The P values for multiplicative and additive interaction were 0.7620 and 0.9200, respectively, indicating a lack of departure from effects that multiply or add. However, we could not rule out interaction on either scale due to imprecision.
doi:10.1097/EDE.0b013e31824d1ccb
PMCID: PMC3367098  PMID: 22495473
17.  APOBEC3B Deletion and Risk of HIV-1 Acquisition 
The Journal of infectious diseases  2009;200(7):1054-1058.
The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from five HIV-1 natural history cohorts. The hemizygous genotype had no effect on either infection or progression. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (OR=7.37, P=0.024), progression to AIDS (RH = 4.01, P=0.03), and viral set-point (P=0.04). These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1/AIDS and warrant further study.
doi:10.1086/605644
PMCID: PMC3690486  PMID: 19698078
18.  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
19.  TP53 R249S mutation, genetic variations in HBX and risk of hepatocellular carcinoma in The Gambia 
Carcinogenesis  2012;33(6):1219-1224.
In regions with high prevalence of chronic hepatitis B virus (HBV) infection and dietary aflatoxin B1 (AFB1) exposure, hepatocellular carcinomas (HCCs) often contain TP53 mutation at codon 249 (R249S). Furthermore, a C-terminal truncated HBx protein expressed from hepatocyte integrated HBV is associated with HCC development. This study evaluates the association between R249S and HBX status in relation to HCC in West African population. HBX (complete or 3′-truncated) and HBS genes were assessed by PCR in cell-free DNA (CFDNA) from plasma of subjects recruited in a hospital-based case–control study (325 controls, 78 cirrhotic patients and 198 HCC cases) conducted in The Gambia. These samples had been previously analyzed for R249S and HBV serological status. Complete HBX sequence was frequently detected in CFDNA of HCC-R249S positive (77%, 43/56) compared with HCC-R249S-negative cases (44%, 22/50). Conversely, the proportion of 3′-truncated HBX gene was significantly higher in HCC-R249S negative than positive cases (34%, 17/50, compared with 12%, 7/56) (χ2 = 12.12; P = 0.002; distribution of R249S negative and positive according to HBX status). Occult HBV infection (detected by PCR) was present in 24% of HCC previously considered as negative by HBV serology. Moreover, HBV mutation analysis revealed that double mutation at nucleotides 1762T/1764A was associated with diagnosis of cirrhosis or HCC {cirrhosis: odds ratio (OR): 9.50 [95% confidence interval (CI) 1.50–60.11]; HCC: OR: 11.29 [95% CI 2.07–61.47]}. These findings suggest that in HCC from The Gambia, complete HBX sequences are often associated with the presence of TP53 R249S mutation.
doi:10.1093/carcin/bgs135
PMCID: PMC3388490  PMID: 22759751
20.  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
21.  Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America 
In a large North American cohort study, anal cancer incidence rates were substantially higher for HIV-infected men who have sex with men, other men, and women compared with HIV-uninfected individuals. Rates increased from 1996–1999 to 2000–2003 but plateaued by 2004–2007.
Background. Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends.
Methods. In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men).
Results. Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7–151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5–61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8–6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5–2.2). In comparison with the period 2000–2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3–.9) in 1996–1999 and 0.9 (95% CI, .6–1.2) in 2004–2007.
Conclusions. Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.
doi:10.1093/cid/cir1012
PMCID: PMC3297645  PMID: 22291097
22.  Frailty, HIV Infection, and Mortality in an Aging Cohort of Injection Drug Users 
PLoS ONE  2013;8(1):e54910.
Background
Frailty is associated with morbidity and premature mortality among elderly HIV-uninfected adults, but the determinants and consequences of frailty in HIV-infected populations remain unclear. We evaluated the correlates of frailty, and the impact of frailty on mortality in a cohort of aging injection drug users (IDUs).
Methods
Frailty was assessed using standard criteria among HIV-infected and uninfected IDUs in 6-month intervals from 2005 to 2008. Generalized linear mixed-model analyses assessed correlates of frailty. Cox proportional hazards models estimated risk for all-cause mortality.
Results
Of 1230 participants at baseline, the median age was 48 years and 29% were HIV-infected; the frailty prevalence was 12.3%. In multivariable analysis of 3,365 frailty measures, HIV-infected IDUs had an increased likelihood of frailty (OR, 1.66; 95% CI, 1.24–2.21) compared to HIV-uninfected IDUs; the association was strongest (OR, 2.37; 95% CI, 1.62–3.48) among HIV-infected IDUs with advanced HIV disease (CD4<350 cells/mm3 and detectable HIV RNA). No significant association was seen with less advanced disease. Sociodemographic factors, comorbidity, depressive symptoms, and prescription drug abuse were also independently associated with frailty. Mortality risk was increased with frailty alone (HR 2.63, 95% CI, 1.23–5.66), HIV infection alone (HR 3.29, 95% CI, 1.85–5.88), and being both HIV-infected and frail (HR, 7.06; 95%CI 3.49–14.3).
Conclusion
Frailty was strongly associated with advanced HIV disease, but IDUs with well-controlled HIV had a similar prevalence to HIV-uninfected IDUs. Frailty was independently associated with mortality, with a marked increase in mortality risk for IDUs with both frailty and HIV infection.
doi:10.1371/journal.pone.0054910
PMCID: PMC3561408  PMID: 23382997
23.  HIV Infection, Immune Suppression, and Uncontrolled Viremia Are Associated With Increased Multimorbidity Among Aging Injection Drug Users 
Human immunodeficiency virus (HIV)-infected persons, especially those with advanced immune suppression or uncontrolled viremia, experienced increased numbers of multimorbid non-AIDS-defining conditions compared with epidemiologically comparable HIV-uninfected persons. Many of these clinically identified chronic diseases were unrecognized and untreated.
Background. Despite an increasing burden of age-associated non-AIDS outcomes, few studies have investigated the prevalence or correlates of multimorbidity among aging human immunodeficiency virus (HIV)–infected and epidemiologically comparable at-risk populations.
Methods. Among 1262 AIDS Linked to the IntraVenous Experience (ALIVE) study participants followed in a community-based observational cohort, we defined the prevalence of 7 non-AIDS-defining chronic conditions (diabetes, obstructive lung disease, liver disease, anemia, obesity, kidney dysfunction, and hypertension) using clinical and laboratory criteria. Ordinal logistic regression was used to model the odds of increased multimorbidity associated with demographic, behavioral, and clinical factors. Self-reported prevalence was compared with clinically defined prevalence.
Results. Participants were a median of 48.9 years of age; 65.1% were male, 87.5% were African-American, and 28.7% were HIV infected. In multivariable analysis, HIV infection (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.13–1.99) was positively associated with increased multimorbidity. Among HIV-infected participants, multimorbidity was increased with lower nadir CD4 T-cell count (OR, 1.14 per 100-cell decrease; 95% CI, 1.00–1.29) and higher current HIV RNA (OR, 1.32 per log10 increase; 95% CI, 1.08–1.60). Older age, being female, not using cigarettes or drugs, and having depressive symptoms were also associated with increased multimorbidity. A substantial proportion of multimorbid conditions in HIV-infected and HIV-uninfected participants were unrecognized and untreated.
Conclusions. HIV-infected participants experienced increased numbers of multimorbid conditions; risk increased with advanced immunosuppression and higher viremia. These results underscore the heavy burden of multimorbidity associated with HIV and highlight the need for incorporating routine assessment and integrated management of chronic diseases as part of comprehensive healthcare for aging, HIV-infected persons.
doi:10.1093/cid/cir673
PMCID: PMC3214585  PMID: 21976463
24.  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
25.  A Novel Variant Marking HLA-DP Expression Levels Predicts Recovery from Hepatitis B Virus Infection 
Journal of Virology  2012;86(12):6979-6985.
Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3′ untranslated regions (3′UTRs) in 662 individuals of European-American and African-American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3′UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3′UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection.
doi:10.1128/JVI.00406-12
PMCID: PMC3393572  PMID: 22496224

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