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1.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, 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. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | 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 | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
doi:10.1093/cid/cit003
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
2.  Failure to Initiate Antiretroviral Therapy, Loss to Follow-up and Mortality among HIV-infected Patients during the Pre-ART period in Uganda 
Background
Delays and failures in initiation of antiretroviral therapy (ART) among treatment eligible patients may compromise the effectiveness of HIV care in Africa. An accurate understanding, however, of the pace and completeness of ART initiation and mortality during the waiting period is obscured by frequent losses to follow-up.
Methods
We evaluated newly ART-eligible HIV-infected adults from 2007 to 2011 in a prototypical clinic in Mbarara, Uganda. A random sample of patients lost to follow-up was tracked in the community to determine vital status and ART initiation after leaving the original clinic. Outcomes among the tracked patients were incorporated using probability weights, and a competing risks approach was used in analyses.
Results
Among 2,633 ART-eligible patients, 490 were lost to follow-up, of whom a random sample of 132 was tracked and 111 (84.0%) had outcomes ascertained. After incorporating the outcomes among the lost, the cumulative incidence of ART initiation at 30, 90 and 365 days after eligibility was 16.0% (95% CI: 14.2–17.7), 64.5% (95% CI: 60.9–68.1), and 81.7% (95% CI: 77.7–85.6). Death prior to ART was 7.7% at one year. Male sex, higher CD4 count, and no education were associated with delayed ART initiation. Lower CD4 level, malnourishment and travel time to clinic were associated with mortality.
Conclusions
Using a sampling-based approach to account for losses to follow-up revealed that both the speed and completeness of ART initiation were sub-optimal in a prototypical large clinic in Uganda. Improving the kinetics of ART initiation in Africa is needed to make ART optimally effective.
doi:10.1097/QAI.0b013e31828af5a6
PMCID: PMC3654002  PMID: 23429504
Antiretroviral therapy; Africa; loss to follow-up; mortality
3.  Delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among HIV-infected adults in Africa 
AIDS (London, England)  2014;28(14):2097-2107.
Objective
Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa.
Design
A cohort.
Methods
We examined patients with confirmed virologic failure on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4+ T-cell count and HIV RNA.
Results
Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27–33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1 –4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99–5.8) to that of the entire cohort, although of borderline statistical significance.
Conclusion
Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality.
doi:10.1097/QAD.0000000000000349
PMCID: PMC4317283  PMID: 24977440
antiretroviral; cohort studies; HIV; HIV RNA level; inverse probability weight; marginal structural model; time-dependent confounding; treatment failure; viral load
4.  Treatment as long-term prevention: Sustained reduction in HIV sexual transmission risk with use of antiretroviral therapy in rural Uganda 
AIDS (London, England)  2014;28(2):267-271.
Objectives
Suppressive anti-retroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda.
Design
Observational cohort study
Methods
We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was > 400 copies/mL and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with ≥1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days.
Results
We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5,293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4 count, low household asset ownership and increased internalized stigma.
Conclusions
Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to six years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.
doi:10.1097/QAD.0000000000000136
PMCID: PMC4038415  PMID: 24361683
HIV/AIDS; Anti-retroviral therapy; sub-Saharan Africa; treatment as prevention; Uganda
5.  Self-reported alcohol abstinence associated with ART initiation among HIV-infected persons in rural Uganda 
Drug and alcohol dependence  2013;134:10.1016/j.drugalcdep.2013.09.025.
BACKGROUND
There is limited data on the impact of anti-retroviral treatment (ART) initiation on alcohol consumption. We characterized predictors of abstaining from alcohol among HIV-infected individuals following ART initiation.
METHODS
We analyzed data from a prospective cohort of HIV-infected adults in Mbarara, Uganda with quarterly measures of self-reported alcohol consumption, socio-demographics, health status, and blood draws. We used pooled logistic regression to evaluate predictors of becoming abstinent from alcohol for at least 90 days after baseline.
RESULTS
Among the 502 participants, 108 (21.5%) were current drinkers who consumed alcohol within 90 days of baseline, 206 (41.0%) were former drinkers, and 188 (37.5%) were lifetime abstainers at baseline. Among current drinkers, 67 (62.0%) drank at hazardous levels. 90 of current drinkers (83.3%) abstained from alcohol at least for 90 days over 3.6 median years of follow-up [IQR 2-4.8]; of those 69 (76.7%) remained abstinent for a median duration of follow-up of 3.25 years [1.6-4.5]. Becoming abstinent was independently associated with lower baseline AUDIT score (adjusted odds ratio [AOR] 0.95[95%CI 0.91-0.99]), baseline physical health score (AOR 0.92[0.87-0.97]), and decreases in physical health score at follow-up visits (AOR 0.92[0.88-0.97)). Alcohol abstinence was most likely to start immediately after ART initiation (AORs for 6 month versus 3 month visit: 0.25[0.10-0.61]; 9 month visit or later versus 3 month visit: 0.04[0.02-0.09]).
CONCLUSIONS
We found that a large majority of drinkers starting ART reported that they became and remained abstinent from alcohol. ART initiation may be an opportune time to implement interventions for alcohol consumption and other health behaviors.
doi:10.1016/j.drugalcdep.2013.09.025
PMCID: PMC3885244  PMID: 24169501
Alcohol; HIV; alcohol abstinence; hazardous drinking; ART-initiation; antiretroviral treatment; Uganda; Africa
6.  The Immunologic Effects of Mesalamine in Treated HIV-Infected Individuals with Incomplete CD4+ T Cell Recovery: A Randomized Crossover Trial 
PLoS ONE  2014;9(12):e116306.
The anti-inflammatory agent, mesalamine (5-aminosalicylic acid) has been shown to decrease mucosal inflammation in ulcerative colitis. The effect of mesalamine in HIV-infected individuals, who exhibit abnormal mucosal immune activation and microbial translocation (MT), has not been established in a placebo-controlled trial. We randomized 33 HIV-infected subjects with CD4 counts <350 cells/mm3 and plasma HIV RNA levels <40 copies/ml on antiretroviral therapy (ART) to add mesalamine vs. placebo to their existing regimen for 12 weeks followed by a 12 week crossover to the other arm. Compared to placebo-treated subjects, mesalamine-treated subjects did not experience any significant change in the percent CD38+HLA-DR+ peripheral blood CD4+ and CD8+ T cells at week 12 (P  = 0.38 and P  = 0.63, respectively), or in the CD4+ T cell count at week 12 (P  = 0.83). The percent CD38+HLA-DR+ CD4+ and CD8+ T cells also did not change significantly in rectal tissue (P  = 0.86, P  = 0.84, respectively). During the period of mesalamine administration, plasma sCD14, IL-6, D-dimer, and kynurenine to tryptophan ratio were not changed significantly at week 12 and were similarly unchanged at week 24. This study suggests that, at least under the conditions studied, the persistent immune activation associated with HIV infection is not impacted by the anti-inflammatory effects of mesalamine.
Trial Registration
ClinicalTrials.gov NCT01090102
doi:10.1371/journal.pone.0116306
PMCID: PMC4283685  PMID: 25545673
7.  Internalized stigma, social distance, and disclosure of HIV seropositivity in rural Uganda 
Background
HIV is highly stigmatized, compromising both treatment and prevention in resource-limited settings.
Purpose
To study the relationship between internalized HIV-related stigma and serostatus disclosure and to determine the extent to which this association varies with the degree of social distance.
Methods
We fit multivariable Poisson regression models, with cluster-correlated robust estimates of variance, to data from 259 persons with HIV enrolled in an ongoing cohort study in rural Uganda.
Results
Persons with more internalized stigma were less likely to disclose their seropositivity. The magnitude of association increased with social distance such that the largest association was observed for public disclosures and the smallest association was observed for disclosures to sexual partners.
Conclusions
Among persons with HIV in rural Uganda, internalized stigma was negatively associated with serostatus disclosure. The inhibiting effect of stigma was greatest for the most socially distant ties.
doi:10.1007/s12160-013-9514-6
PMCID: PMC3795853  PMID: 23690283
HIV; social stigma; disclosure; Uganda
8.  Comparison of Self-Reported Alcohol Consumption to Phosphatidylethanol Measurement among HIV-Infected Patients Initiating Antiretroviral Treatment in Southwestern Uganda 
PLoS ONE  2014;9(12):e113152.
Background
Alcohol consumption among HIV-infected patients may accelerate HIV disease progression or reduce antiretroviral therapy adherence. Self-reported alcohol use is frequently under-reported due to social desirability and recall bias. The aim of this study was to compare self-reported alcohol consumption to phosphatidylethanol (PEth), a biomarker of alcohol consumption, and to estimate the correlation between multiple measures of self-reported alcohol consumption with PEth.
Methods
The Uganda AIDS Rural Treatment Outcomes (UARTO) cohort is located in southwestern Uganda and follows patients on ART to measure treatment outcomes. Patients complete standardized questionnaires quarterly including questions on demographics, health status and alcohol consumption. Baseline dried blood spots (DBS) were collected and retrieved to measure PEth.
Results
One hundred fifty samples were tested, and 56 (37.3%) were PEth positive (≥8 ng/mL). Of those, 51.7% did not report alcohol use in the past month. Men were more likely to under-report compared to women, OR 2.9, 95% CI = 1.26, 6.65) and those in the higher economic asset categories were less likely to under-report compared to those in the lowest category (OR = 0.41 95% CI: 0.17, 0.94). Among self-reported drinkers (n = 31), PEth was highly correlated with the total number of drinking days in the last 30 (Spearman R = 0.73, p<0.001).
Conclusions
Approximately half of HIV infected patients initiating ART and consuming alcohol under-report their use of alcohol. Given the high prevalence, clinicians should assess all patients for alcohol use with more attention to males and those in lower economic asset categories who deny alcohol use. Among those reporting current drinking, self-reported drinking days is a useful quantitative measure.
doi:10.1371/journal.pone.0113152
PMCID: PMC4249861  PMID: 25436894
9.  Increase in 2–Long Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial 
The Journal of Infectious Diseases  2013;208(9):1436-1442.
Background. The degree to which human immunodeficiency virus (HIV) continues to replicate during antiretroviral therapy (ART) is controversial. We conducted a randomized, double-blind, placebo-controlled study to assess whether raltegravir intensification reduces low-level viral replication, as defined by an increase in the level of 2–long terminal repeat (2-LTR) circles.
Methods. Thirty-one subjects with an ART-suppressed plasma HIV RNA level of <40 copies/mL and a CD4+ T-cell count of ≥350 cells/mm3 for ≥1 year were randomly assigned to receive raltegravir 400 mg twice daily or placebo for 24 weeks. 2-LTR circles were analyzed by droplet digital polymerase chain reaction at weeks 0, 1, 2, and 8.
Results. The median duration of ART suppression was 3.8 years. The raltegravir group had a significant increase in the level of 2-LTR circles, compared to the placebo group. The week 1 to 0 ratio was 8.8-fold higher (P = .0025) and the week 2 to 0 ratio was 5.7-fold higher (P = .023) in the raltegravir vs. placebo group. Intensification also led to a statistically significant decrease in the D-dimer level, compared to placebo (P = .045).
Conclusions. Raltegravir intensification resulted in a rapid increase in the level of 2-LTR circles in a proportion of subjects, indicating that low-level viral replication persists in some individuals even after long-term ART. Intensification also reduced the D-dimer level, a coagulation biomarker that is predictive of morbidity and mortality among patients receiving treatment for HIV infection.
doi:10.1093/infdis/jit453
PMCID: PMC3789577  PMID: 23975885
HIV; raltegravir intensification; 2-LTR circles; ongoing viral replication; D-dimer
11.  Programmed death-1 expression on CD4+ and CD8+ T cells in treated and untreated HIV disease 
AIDS (London, England)  2014;28(12):1749-1758.
Background
There is intense interest in the role of programmed death 1 (PD-1) in causing persistent T-cell dysfunction in HIV infection. However, the impact of HIV infection and antiretroviral treatment (ART) on the expression of PD-1 on T cells is still poorly defined.
Methods
PD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (<6 months after infection) vs. later (≥2 years after infection). PD-1 was also measured cross-sectionally in a diverse cohort of chronically HIV-infected adults (n = 206).
Results
PD-1 expression levels were high on CD8+ T cells during early HIV infection. PD-1 levels increased on both CD4+ and CD8+ T cells populations in those who delayed therapy (11 and 10%/year, respectively). PD-1 levels declined and were similar in those treated early vs. late after 1 year of ART. In both cohorts, PD-1 expression on CD4+ T cells was associated with CD4+ T-cell activation (CD38+HLA-DR+) and inversely with CD4+ cell count. In contrast, PD-1 expression on CD8+ T cells was most strongly associated with CD8+ T-cell activation and with plasma viral load in viremic individuals.
Conclusion
Across two large cohorts of untreated and treated individuals, we found consistent associations between HIV RNA levels, CD8+ T-cell activation and PD-1 expression on CD8+ T cells. In contrast, CD4+ T-cell counts and CD4+ T-cell activation were more consistent correlates of PD-1 expression on CD4+ T cells. PD-1 expression appears to be driven by both direct antigen and homeostatic pathways.
doi:10.1097/QAD.0000000000000314
PMCID: PMC4206412  PMID: 24871455
CD4+ lymphocyte count; early antiretroviral therapy; HIV antiretroviral therapy; HIV-1/immunology/*physiology; humans; programmed death-1; T-cell activation; T lymphocytes/immunology/*physiology; virus replication/physiology
12.  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
13.  How does antiretroviral treatment attenuate the stigma of HIV? Evidence from a cohort study in rural Uganda 
AIDS and behavior  2013;17(8):2725-2731.
Program implementers and qualitative researchers have described how increasing availability of HIV antiretroviral therapy (ART) is associated with improvements in psychosocial health and internalized stigma. To determine whether, and through what channels, ART reduces internalized stigma, we analyzed data from 262 HIV-infected, treatment-naïve persons in rural Uganda followed from ART initiation over a median of 3.4 years. We fitted Poisson regression models with cluster-correlated robust estimates of variance, specifying internalized stigma as the dependent variable, adjusting for time on treatment as well as socio-demographic, clinical, and psychosocial variables. Over time on treatment, internalized stigma declined steadily, with the largest decline observed during the first two years of treatment. This trend remained statistically significant after multivariable adjustment (χ2=28.3; p=0.03), and appeared to be driven by ART-induced improvements in HIV symptom burden, physical and psychological wellbeing, and depression symptom severity.
doi:10.1007/s10461-013-0503-3
PMCID: PMC3773278  PMID: 23670710
social stigma; depression; antiretroviral therapy; highly active; HIV; Uganda
14.  HIV-infected women on antiretroviral treatment in Uganda have increased mortality during pregnant and postpartum periods 
AIDS (London, England)  2013;27(0 1):S105-S112.
Objective
To assess the impact of pregnancy on mortality among HIV-infected Ugandan women initiating antiretroviral therapy (ART).
Design
Prospective cohort study.
Methods
HIV-infected women initiating ART in the Uganda AIDS Rural Treatment Outcomes study were assessed quarterly for self-reported pregnancy. The association between pregnant/postpartum (“pregnancy-related”) follow-up periods and mortality was assessed with Cox proportional hazards models adjusted for age, CD4 cell count, plasma HIV-1 RNA levels, and ART duration.
Results
354 women with median age 33 years (IQR: 27-37) and CD4 142 cells/mm3 (IQR: 82-213) were followed for a median of 4.0 years (IQR: 2.5-4.8) after ART initiation, with 3% and 6% loss-to-follow-up at years 1 and 3. 109 women experienced pregnancy. Five deaths occurred during pregnancy-related follow-up and 16 during non-pregnancy-related follow-up, for crude mortality rates during the first year after ART initiation of 12.57/100 PYs and 3.53/100 PYs (Rate Ratio 3.56, 95% CI: 0.97-11.07). In adjusted models, the impact of pregnancy-related follow-up on mortality was highest at ART initiation (aHR: 21.48, 95% CI: 3.73 - 123.51), decreasing to 13.44 (95% CI 3.28 – 55.11) after 4 months, 8.28 (95% CI 2.38 – 28.88) after 8 months, 5.18 (95% CI: 1.36 - 19.71) after one year, and 1.25 (95% CI: 0.10 - 15.58) after two years on ART. Four of five maternal deaths occurred postpartum.
Conclusions
Pregnancy and the postpartum period were associated with increased mortality in HIV-infected women initiating ART, particularly during early ART. Contraception proximate to ART initiation, earlier ART initiation, and careful monitoring during the postpartum period may reduce maternal mortality in this setting.
doi:10.1097/QAD.0000000000000040
PMCID: PMC4142689  PMID: 24088676
HIV; maternal health; maternal mortality; immune reconstitution; pregnancy; postpartum; antiretroviral therapy; mortality; Africa; women
15.  Comparison of HIV DNA and RNA in Gut-Associated Lymphoid Tissue of HIV-Infected Controllers and Non-controllers 
AIDS (London, England)  2013;27(14):2255-2260.
Objectives
HIV-infected controllers have provided novel insights into mechanisms of viral control. We investigated the degree to which HIV DNA and RNA are present in gut-associated lymphoid tissue (GALT) of controllers.
Design
Cross-sectional cohort study.
Methods
Colorectal biopsy pieces were obtained from 5 untreated non-controllers, 5 ART-suppressed subjects, and 9 untreated controllers.
Results
Rectal HIV DNA was lower in controllers (median 496 copies/106 CD4+ T cells) than in untreated non-controllers (117483 copies/106 CD4+ T cells, p=0.001) and ART-suppressed subjects (6116 copies/106 CD4+ T cells, p=0.004). Similarly, rectal HIV RNA was lower in controllers (19 copies/106 CD4+ T cells) than in non-controllers (15210 copies/106 CD4+ T cells, p=0.001) and ART-suppressed subjects (1625 copies/106 CD4+ T cells, p=0.0599). Rectal HIV RNA/DNA ratios were not statistically different between the 3 groups.
Conclusions
Despite being able to maintain very low plasma HIV RNA levels in the absence of antiretroviral therapy, HIV-infected controllers have readily measurable levels of HIV DNA and RNA in GALT. As expected, controllers had lower rectal HIV DNA and RNA compared to untreated non-controllers and ART-suppressed individuals. Compared to the mechanisms of “natural” viral control of controllers, long-term antiretroviral therapy does not reduce the total HIV reservoir to the level of controllers.
doi:10.1097/QAD.0b013e328362692f
PMCID: PMC4143147  PMID: 24157906
HIV; controllers; gut-associated lymphoid tissue; GALT; viral reservoir
17.  Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection 
AIDS (London, England)  2014;28(4):511-519.
Objective
To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH).
Design
HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality.
Methods
We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL-6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC.
Results
Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 μmol/l, P =0.0049 and 3.9% per doubling, P =0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 μmol/l, P =0.0014 and 5.8% per doubling, P =0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio =1.74, P =0.029).
Conclusion
Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH.
doi:10.1097/QAD.0000000000000124
PMCID: PMC4149286  PMID: 24469026
asymmetric dimethylarginine; endothelial dysfunction; HIV; nitric oxide; pulmonary arterial hypertension
18.  Limited HIV Infection of Central Memory and Stem Cell Memory CD4+ T Cells Is Associated with Lack of Progression in Viremic Individuals 
PLoS Pathogens  2014;10(8):e1004345.
A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated (“putative progressors”, PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = −0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.
Author Summary
Here we assessed correlates of protection from disease progression in a rare subset of HIV-infected individuals, viremic non-progressors (VNP). These individuals have high viral load for several years. In contrast to the majority of infected individuals, however, these individuals do not progress to AIDS. Here we found this lack of progression was associated with selective preservation of two critical subsets of memory CD4+ T cells, central memory (TCM) and stem-cell memory (TSCM) cells. Compared to HIV-infected putative progressors, VNPs had higher proliferation of these indispensable subsets of memory cells. In addition, the long-lived CD4+ TCM and TSCM cells in VNPs had decreased HIV infection compared to the less critical effector memory CD4+ T cells, which indicates a possible mechanism by which VNPs maintain their CD4+ T cell pool after several years of infection, and remain free from AIDS progression.
doi:10.1371/journal.ppat.1004345
PMCID: PMC4148445  PMID: 25167059
19.  Real-time Adherence Monitoring of Antiretroviral Therapy Among HIV-infected Adults and Children in Rural Uganda 
AIDS (London, England)  2013;27(13):10.1097/QAD.0b013e328363b53f.
A real-time wireless electronic adherence monitor(EAM) and weekly self-report of missed doses via interactive voice response (IVR) and short message service (SMS) queries were used to measure ART adherence in 49 adults and 46 children in rural Uganda. Median adherence was 89.5% among adults and 92.8% among children by EAM, and 99–100% for both adults and children by IVR/SMS self-report. Loss of viral suppression was significantly associated with adherence by EAM (OR 0.58 for each 10% increase), but not IVR/SMS. Wireless EAM creates an exciting opportunity to monitor and potentially intervene with adherence challenges as they are happening.
doi:10.1097/QAD.0b013e328363b53f
PMCID: PMC3868644  PMID: 23751260
20.  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.  Empiric Deworming and CD4 Count Recovery in HIV-Infected Ugandans Initiating Antiretroviral Therapy 
Background
There is conflicting evidence on the immunologic benefit of treating helminth co-infections (“deworming”) in HIV-infected individuals. Several studies have documented reduced viral load and increased CD4 count in antiretroviral therapy (ART) naïve individuals after deworming. However, there are a lack of data on the effect of deworming therapy on CD4 count recovery among HIV-infected persons taking ART.
Methodology/Principal Findings
To estimate the association between empiric deworming therapy and CD4 count after ART initiation, we performed a retrospective observational study among HIV-infected adults on ART at a publicly operated HIV clinic in southwestern Uganda. Subjects were assigned as having received deworming if prescribed an anti-helminthic agent between 7 and 90 days before a CD4 test. To estimate the association between deworming and CD4 count, we fit multivariable regression models and analyzed predictors of CD4 count, using a time-by-interaction term with receipt or non-receipt of deworming. From 1998 to 2009, 5,379 subjects on ART attended 21,933 clinic visits at which a CD4 count was measured. Subjects received deworming prior to 668 (3%) visits. Overall, deworming was not associated with a significant difference in CD4 count in either the first year on ART (β = 42.8; 95% CI, −2.1 to 87.7) or after the first year of ART (β = −9.9; 95% CI, −24.1 to 4.4). However, in a sub-analysis by gender, during the first year of ART deworming was associated with a significantly greater rise in CD4 count (β = 63.0; 95% CI, 6.0 to 120.1) in females.
Conclusions/Significance
Empiric deworming of HIV-infected individuals on ART conferred no significant generalized benefit on subsequent CD4 count recovery. A significant association was observed exclusively in females and during the initial year on ART. Our findings are consistent with recent studies that failed to demonstrate an immunologic advantage to empirically deworming ART-naïve individuals, but suggest that certain sub-populations may benefit.
Author Summary
It is estimated that up to half of all people infected with HIV in sub-Saharan Africa are co-infected with one or more gastrointestinal parasites. These parasitic infections may negatively impact the ability of the immune system to combat the HIV virus, leading to worse clinical outcomes in people with HIV. Therefore, routine, universal, empiric treatment of gastrointestinal parasite infections (“deworming”) has been suggested as one strategy for optimizing HIV outcomes in this region. Previous studies have provided conflicting results on whether empiric deworming positively impacts markers of HIV disease progression such as CD4 count and viral load, but all of these studies were performed in HIV-infected individuals not yet on antiretroviral therapy. In this study, we measured the association between receipt of empiric deworming and CD4 count over time in HIV-infected adults taking antiretroviral therapy in southwestern Uganda, an area with a high parasite burden. We found that, overall, there was no significant association between deworming and change in CD4 count; however, when we performed a sub-analysis looking exclusively at females during the first year of ART, deworming was associated with significantly increased CD4 count. These results suggest that empiric deworming may not be an effective generalized strategy for improving HIV treatment outcomes in sub-Saharan Africa; however, the possibility of targeted benefit in specific sub-populations deserves further investigation.
doi:10.1371/journal.pntd.0003036
PMCID: PMC4125278  PMID: 25101890
23.  Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4+ T cell recovery after the initiation of antiretroviral therapy for HIV disease 
The level (or frequency) of circulating monocyte subpopulations such as classical (CD14hiCD16-) and non-classical (CD14dimCD16+) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4+ T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL]. A longitudinal analysis of ART-treated subjects was also performed along with regression analysis to determine which biomarkers were associated with and/or predictive of CD4+ T cell recovery. Suppressive ART was associated with increased levels of classical monocyte subpopulations (CD14hiCD16-) and decreased levels of non-classical monocyte populations (CD14dimCD16+). Among peripheral blood mononuclear cells (PBMCs), HO-1 was found to be most highly up-regulated in CD14+ monocytes after ex vivo stimulation. Neither the levels of monocyte subpopulations nor of HO-1 expression in CD14+ monocytes were significantly associated with the degree of CD4+ T cell recovery. Monocyte subpopulations and HO-1 gene expression were, however, restored to normal levels by suppressive ART. These results suggest that the level of circulating monocyte subpopulations and their expression of HO-1 have no evident relationship to CD4+ T cell recovery after the initiation of ART.
doi:10.1186/1742-6405-11-27
PMCID: PMC4150425  PMID: 25180041
HIV; HO-1; Immune activation; Monocytes; CD4+ T cell recovery
24.  Cutting Edge: An Antibody Recognizing Ancestral Endogenous Virus Glycoproteins Mediates Antibody-Dependent Cellular Cytotoxicity on HIV-1–Infected Cells 
The failure of antiviral vaccines is often associated with rapid viral escape from specific immune responses. In the past, conserved epitope or algorithmic epitope selections, such as mosaic vaccines, have been designed to diversify immunity and to circumvent potential viral escape. An alternative approach is to identify conserved stable non–HIV-1 self-epitopes present exclusively in HIV-1–infected cells. We showed previously that human endogenous retroviral (HERV) mRNA transcripts and protein are found in cells of HIV-1–infected patients and that HERV-K (HML-2)–specific T cells can eliminate HIV-1–infected cells in vitro. In this article, we demonstrate that a human anti–HERV-K (HML-2) transmembrane protein Ab binds specifically to HIV-1–infected cells and eliminates them through an Ab-dependent cellular cytotoxicity mechanism in vitro. Thus, Abs directed against epitopes other than HIV-1 proteins may have a role in eliminating HIV-1–infected cells and could be targeted in novel vaccine approaches or immunotherapeutic modalities.
doi:10.4049/jimmunol.1302108
PMCID: PMC4120895  PMID: 25024383
25.  Cell-Based Measures of Viral Persistence Are Associated With Immune Activation and Programmed Cell Death Protein 1 (PD-1)–Expressing CD4+ T cells 
Background. Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure.
Methods. We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy.
Results. The median CD4+ T cell count was 523 cells/mm3, and the median duration of viral suppression was 31 months. Cell-associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4+ and CD8+ T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 [PD-1]) (P < .05). Having a low CD4+ T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4+ T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001).
Conclusions. Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1–expressing CD4+ T cells. Treated patients with a low CD4+ T-cell count had higher frequencies of PD-1–expressing CD4+ T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions.
doi:10.1093/infdis/jis630
PMCID: PMC3666131  PMID: 23089590
HIV; raltegravir intensification; 2-LTR circles; ongoing viral replication; D-dimer

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