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1.  Chronic kidney disease at presentation is not an independent risk factor for AIDS-defining events or death in HIV-infected persons 
Clinical nephrology  2013;79(2):93-100.
Studies have documented an association between chronic kidney disease (CKD) and increased risk of end-stage renal disease (ESRD), death and comorbidities, including cardiovascular disease and metabolic syndrome, in the general population. However, there is little data on the relationship between CKD and ADE (AIDS defining event), and to our knowledge, no studies have analyzed death as a competing risk for ADE among HIV-infected persons. An observational cohort study was performed to determine the incidence and risks for developing an ADE or death among HIV-infected persons with and without CKD from 1998 – 2005. CKD was defined as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 using the CKD-Epidemiology Collaboration (CKD-EPI) equation. Log rank test and Cox regression which determined time to development of ADE and/or death as combined and separate outcomes, and competing risk models for ADE versus mortality, were performed. Among the 2,127 persons that contributed to the 5,824 person years of follow-up: 22% were female, 34% African-American, 38% on HAART, and 3% had CKD at baseline. ADE occurred in 227 (11%) persons and there were 80 (4%) deaths. CKD was not significantly associated with ADE/death (HR 1.3, 95% CIs: 0.5, 3.2), ADE (HR 1.0, 95% CIs: 0.4, 3.1), or death (HR 1.6, 95% CIs: 0.4, 3.1). Competing risk analyses confirmed no statistically significant associations between CKD and these outcomes. CKD was uncommon in HIV-infected persons presenting for care in this racially diverse cohort, and was not independently associated with risk of developing an ADE or dying during follow-up.
doi:10.5414/CN107390
PMCID: PMC3726221  PMID: 23270930
HIV; CKD; AIDS defining event (ADE); mortality
2.  An Optimal Body Mass Index Range Associated With Improved Immune Reconstitution Among HIV-Infected Adults Initiating Antiretroviral Therapy 
In a cohort of human immunodeficiency virus–infected adults beginning antiretroviral therapy, CD4+ lymphocyte recovery at 12 months was highest among overweight patients (body mass index, 25–30 kg/m2). Similar results were observed in the subgroups with virologic suppression and minimal weight change.
Background. Higher body mass index (BMI) was associated with slower human immunodeficiency virus (HIV) disease progression before the availability of effective antiretroviral therapy (ART), but the relationship between pretreatment BMI and CD4+ lymphocyte recovery on ART is not well described.
Methods. We conducted an observational cohort study of HIV-infected, ART-naive adults starting treatment at a clinic affiliated with Vanderbilt University in Nashville, Tennessee. We assessed the relationship between pretreatment BMI and CD4+ lymphocyte count change from baseline to 12 months in all subjects, among those with plasma HIV-1 RNA levels <400 copies/mL for ≥6 months and those with <10% change in weight during follow-up. Linear regression models were adjusted for age, sex, race, protease inhibitor usage, year of ART initiation, and baseline CD4+ lymphocyte count and HIV-1 RNA level.
Results. A total of 915 patients met inclusion criteria; 78% were male, and their median age, BMI, and CD4+ lymphocyte count were 39 years, 24 kg/m2, and 171 cells/μL, respectively. The CD4+ lymphocyte increase at 12 months was greatest among patients with a pretreatment BMI of ∼25–30 kg/m2 and diminished above and below this range (P = .03). Similar patterns were observed in the subgroup analyses. Among patients with a pretreatment CD4+ lymphocyte count <200 cells/μL, a BMI of ∼25 kg/m2 was associated with the highest odds of reaching a CD4+ lymphocyte count >350 cells/μL at 12 months (P = .05).
Conclusions. 12-month immune reconstitution on ART was highest among patients commonly classified as overweight, suggesting there may be an optimal BMI range for immune recovery on ART.
doi:10.1093/cid/cir606
PMCID: PMC3189168  PMID: 21946189
3.  Hemoglobin May Contribute to Sex Differences in Mortality among HIV-Infected Persons in Care 
PLoS ONE  2012;7(9):e44999.
Background
Some retrospective studies have found that HIV-infected women have a higher mortality risk than men after adjusting for baseline characteristics, while others have not. Anemia is a known predictor of HIV-related mortality. We assessed whether anemia contributed to the sex difference in mortality in our cohort.
Methods
We conducted a retrospective cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between 1998 and 2009. Cox proportional hazards models compared time from first clinic visit to death and AIDS-defining events (ADE), adjusted for baseline characteristics with and without baseline hemoglobin.
Results
Of 3,633 persons, 879 (24%) were women. Women had lower median baseline hemoglobin compared to men: 12.4 g/dL (inter-quartile range (IQR) 11.3–13.4) vs. 14.4 (IQR 13.1–15.5), respectively (P<0.001). In multivariable models without hemoglobin, the risk of death was higher among women: hazard ratio (HR) 1.46 (95% confidence interval (CI) 1.17, 1.82; P = 0.001). In multivariable models with hemoglobin, the risk of death in women was diminished and no longer statistically significant: HR 1.2 (95% CI 0.93, 1.55; P = 0.17). The risk of ADE was higher among women in both models, but not statistically significant: HR 1.1 (95% CI 0.85–1.42; P = 0.46) in the model without hemoglobin and 1.11 (95% CI 0.82–1.48; P = 0.50) in the model with hemoglobin. Hemoglobin was a strong predictor of death: HR 0.88 per 1 g/dL increase (95% CI 0.83, 0.93; P<0.001).
Conclusion
In our study population of HIV-infected persons in care, women had lower baseline hemoglobin, and lower hemoglobin contributed to their higher risk of ADE and death.
doi:10.1371/journal.pone.0044999
PMCID: PMC3441736  PMID: 23028732
4.  Tuberculosis Risk Before and After Highly Active Antiretroviral Therapy Initiation: Does HAART Increase the Short-term TB Risk in a Low Incidence TB Setting? 
Objective
To evaluate the short- and long-term effects of highly active antiretroviral therapy (HAART) on tuberculosis (TB) risk, compared to risk without HAART in a low TB incidence setting.
Design
An observational cohort study among HIV-infected persons in care at the Comprehensive Care Center (Nashville, TN) between January 1998 and December 2008.
Methods
A marginal structural model was used to estimate the effect of HAART on short- (≤180 days) and long-term (>180 days) TB risk, with CD4+ lymphocyte count incorporated as a time-updated covariate.
Results
Of 4,534 HIV-infected patients, 34 developed TB (165/100,000 p-y; 20,581 person-years [p-y] of follow-up). Seventeen cases occurred among persons not on HAART or >30 days after HAART discontinuation (212/100,000 p-y; 8,019 p-y of follow-up). Seventeen occurred among persons on HAART (135/100,000 p-y; 12,562 p-y of follow-up); ten in the first 180 days (402/100,000 p-y; 2,489 p-y of follow-up) and 7 after more than 180 days (69/100,000 p-y; 10,073 p-y of follow-up). After adjusting for the most recent CD4+ lymphocyte count, the risk of TB in the first 180 days of HAART exposure relative to no HAART was 0.68 (0.14–3.22, p=0.63).
Conclusions
In this low TB incidence setting, the TB rate in the first 180 days of HAART was almost twice as high as persons not on HAART. However, after adjusting for most recent CD4+ count there was no significant difference in TB risk between these two groups. This suggests that low recent CD4+ lymphocyte count influences TB risk during the first 180 days of HAART.
doi:10.1097/QAI.0b013e3182182e2d
PMCID: PMC3141096  PMID: 21423024
tuberculosis; M. tuberculosis infection; tuberculosis risk; human immunodeficiency virus; highly active antiretroviral therapy
5.  The Relationships between Injection and Non-injection Drug Use and HIV Disease Progression 
Background
Injection drug use is associated with poor HIV outcomes even among persons receiving highly active antiretroviral therapy (HAART), but there are limited data on the relationship between non-injection drug use and HIV disease progression.
Methods
We conducted an observational study of HIV-infected persons entering care between January 1, 1999 and December 31, 2004, with follow-up through December 31, 2005.
Results
There were 1,712 persons in the study cohort: 262 with a history of injection drug use (IDU), 785 with a history of non-injection drug use, and 665 with no history of drug use; 56% were white, and 24% were females. Median follow-up was 2.1 years, 33% had HAART prior to first visit, 40% initiated first HAART during the study period, and 306 (17.9%) had an AIDS-defining event or died. Adjusting for sex, age, race, prior antiretroviral use, CD4 cell count, and HIV-1 RNA, patients with a history of injection drug use were more likely to advance to AIDS or death than non-users (adjusted hazard ratio (HR) = 1.97, 95% confidence interval (CI) 1.43-2.70, P<0.01). There was no statistically significant difference of disease progression between non-injection drug users and non-users (HR=1.19, 95% CI 0.92-1.56, P=0.19). An analysis among the subgroup who initiated their first HAART during the study period (n=687) showed a similar pattern (IDUs: 1.83, 1.09-3.06, P=0.02; non-IDUs: 1.21, 0.81-1.80, P=0.35). Seventy-four patients had active IDU during the study period, 768 active non-IDU, and 870 no substance use. Analyses based on active drug use during the study period did not substantially differ from those based on history of drug use.
Conclusions
This study shows no relationship between non-injection drug use and HIV disease progression. This study is limited by using history drug use and lumping together different types of drugs. Further studies ascertaining specific type and extent of non-injection drug use in a prospective way, and with longer follow-up, are needed.
doi:10.1016/j.jsat.2011.01.007
PMCID: PMC3110534  PMID: 21349679
Injection drug use; non-injection drug use; CD4 cell count; HIV viral load; HIV disease progression; antiretroviral therapy
6.  Non-AIDS-defining events among HIV-1-infected adults receiving combination antiretroviral therapy in resource-replete versus resource-limited urban setting 
AIDS (London, England)  2011;25(12):1471-1479.
Objective
To compare incidence and distribution of non-AIDS-defining events (NADEs) among HIV-1-infected adults receiving combination antiretroviral therapy (cART) in urban sub-Saharan African versus United States settings.
Design
Retrospective cohort analysis of clinical trial and observational data.
Methods
Compared crude and standardized (to US cohort by age and sex) NADE rates from two urban adult HIV-infected cART-initiating populations: a clinical trial cohort in Gaborone, Botswana (Botswana) and an observational cohort in Nashville, Tennessee (USA).
Results
Crude NADE incidence rates were similar: 10.0 [95% confidence interval 6.3–15.9] per 1000 person-years in Botswana versus 12.4 [8.4–18.4] per 1000 person-years in the United States. However, after standardizing to an older, predominantly male US population, the overall NADE incidence rates were higher in Botswana [18.7 (8.3–33.1) per 1000 person-years]. Standardized rates differed most for cardiovascular events (8.4 versus 5.0 per 1000 person-years) and non-AIDS-defining malignancies (8.0 versus 0.5 per 1000 person-years) – both higher in Botswana. Conversely, hepatic NADE rates were higher in the United States (4.0 versus 0.0 per 1000 person-years), whereas renal NADE rates [3.0 per 1000 person-years (United States) versus 2.4 per 1000 person-years (Botswana)] were comparable.
Conclusion
Crude NADE incidence rates were similar between cART-treated patients in a US observational cohort and a sub-Saharan African clinical trial. However, when standardized to the US cohort, overall NADE rates were higher in Botswana. NADEs appear to be a significant problem in our sub-Saharan African setting, and the monitoring, prevention, and treatment of NADEs should be a critical component of care in resource-limited settings.
doi:10.1097/QAD.0b013e328347f9d4
PMCID: PMC3188442  PMID: 21572309
combination antiretroviral therapy; HIV/AIDS; non-AIDS-defining events; urban sub-Saharan Africa; urban United States
7.  Estimating the Optimal CD4 Count for HIV-infected Persons to Start Antiretroviral Therapy 
Epidemiology (Cambridge, Mass.)  2010;21(5):698-705.
Background
Optimal timing of antiretroviral therapy in HIV-infected persons is unclear, although two recent large observational studies have improved our understanding of the best CD4 threshold for initiation. These studies compared the effect of starting HAART on mortality and mortality/AIDS between strata defined using broad ranges of CD4 counts. We sought to expand this understanding using a novel statistical approach proposed by Robins and colleagues.
Methods
Using observational data from 1034 antiretroviral-naïve HIV-infected patients from Nashville, Tennessee, we directly estimated the optimal CD4 count for initiation of HAART to maximize patient health 6, 12, 24, and 36 months after the first instance of CD4 falling below 750. We measured health using two outcome metrics, one based on CD4 counts at the end of follow-up and the other based on a published quality-of-life scale; both metrics incorporated death, AIDS-defining events, serious non-AIDS events, and CD4 at the end of follow-up if asymptomatic.
Results
The CD4-based metric estimated that to maximize health 6, 12, 24, and 36 months after study entry, HAART should be initiated within 3 months of CD4 first dropping below 495 (95% confidence interval [CI] = 468 – 522), 554 (459 – 750), 489 (427 – 750), and 509 (460 – 750), respectively. The quality-of-life-based metric produced CD4 initiation threshold estimates of 337 (95% CI = 201–442), 354 (288 – 386), 358 (294 – 750), and 475 (287 – 750) for the same time points.
Conclusions
Our results support early initiation of antiretroviral therapy, although the criterion for starting therapy depends on the choice of health outcome.
doi:10.1097/EDE.0b013e3181e97737
PMCID: PMC3086582  PMID: 20585252
8.  Postpartum Discontinuation of Antiretroviral Therapy and Risk of Maternal AIDS-Defining Events, Non-AIDS–Defining Events, and Mortality Among a Cohort of HIV-1–Infected Women in the United States 
AIDS Patient Care and STDs  2010;24(5):279-286.
Abstract
This retrospective cohort study of HIV-infected women receiving highly active antiretroviral therapy (HAART) while pregnant assessed the effect of postpartum HAART discontinuation on maternal AIDS-defining events (ADEs), non-AIDS–defining events (non-ADEs), and death 1997–2008 in Nashville, Tennessee. Cox proportional hazards models compared rates of ADE or all-cause death and non-ADE or all-cause death, and competing risks analyses compared rates of ADE or ADE-related death and non-ADE or non-ADE–related death across the groups. There were two groups: women who stopped HAART postpartum (discontinuation, n = 54) and women who continued HAART postpartum (continuation, n = 69). Fifty percent were African American, 40% had prior non-HAART antiretroviral therapy (ART) use, and 38% had a history of illicit drug use. Median age was 27.5 years, baseline CD4(%) was 532 (34%) and CD4 nadir was 332 cells/mm3, baseline and peak HIV-1 RNA were 2.6 and 4.32 log10 copies per milliliter, respectively. Women in the continuation group were older, had lower baseline CD4, CD4%, and CD4 nadir, and had higher peak HIV-1 RNA. In multivariable proportional hazards models, the hazard ratios [95% confidence interval (CI)] of ADE or all-cause death and non-ADE or all-cause death were lower in the continuation group, but not statistically significantly: 0.50 (0.12, 2.12; p = 0.35) and 0.69 (0.24, 1.95; p = 0.48), respectively. The results were similar in competing risks analyses. Despite having characteristics associated with worse prognosis, women who continued HAART postpartum had lower hazard ratio point estimates for ADEs or death and non-ADEs or death than women who discontinued HAART. Larger studies with longer follow-up are indicated to assess this association.
doi:10.1089/apc.2009.0283
PMCID: PMC2875979  PMID: 20438375
9.  Drug Use and Receipt of Highly Active Antiretroviral Therapy among HIV-Infected Persons in Two U.S. Clinic Cohorts 
PLoS ONE  2011;6(4):e18462.
Objective
Drug use and receipt of highly active antiretroviral therapy (HAART) were assessed in HIV-infected persons from the Comprehensive Care Center (CCC; Nashville, TN) and Johns Hopkins University HIV Clinic (JHU; Baltimore, MD) between 1999 and 2005.
Methods
Participants with and without injection drug use (IDU) history in the CCC and JHU cohorts were evaluated. Additional analysis of persons with history of IDU, non-injection drug use (NIDU), and no drug use from CCC were performed. Activity of IDU and NIDU also was assessed for the CCC cohort. HAART use and time on HAART were analyzed according to drug use category and site of care.
Results
1745 persons were included from CCC: 268 (15%) with IDU history and 796 (46%) with NIDU history. 1977 persons were included from JHU: 731 (35%) with IDU history. Overall, the cohorts differed in IDU risk factor rates, age, race, sex, and time in follow-up. In multivariate analyses, IDU was associated with decreased HAART receipt overall (OR = 0.61, 95% CI: [0.45–0.84] and OR = 0.58, 95% CI: [0.46–0.73], respectively for CCC and JHU) and less time on HAART at JHU (0.70, [0.55–0.88]), but not statistically associated with time on HAART at CCC (0.78, [0.56–1.09]). NIDU was independently associated with decreased HAART receipt (0.62, [0.47–0.81]) and less time on HAART (0.66, [0.52–0.85]) at CCC. These associations were not altered significantly whether patients at CCC were categorized according to historical drug use or drug use during the study period.
Conclusions
Persons with IDU history from both clinic populations were less likely to receive HAART and tended to have less cumulative time on HAART. Effects of NIDU were similar to IDU at CCC. NIDU without IDU is an important contributor to HAART utilization.
doi:10.1371/journal.pone.0018462
PMCID: PMC3081810  PMID: 21541016
10.  Antiretroviral Therapy Initiation Before, During, or After Pregnancy in HIV-1-Infected Women: Maternal Virologic, Immunologic, and Clinical Response 
PLoS ONE  2009;4(9):e6961.
Background
Pregnancy has been associated with a decreased risk of HIV disease progression in the highly active antiretroviral therapy (HAART) era. The effect of timing of HAART initiation relative to pregnancy on maternal virologic, immunologic and clinical outcomes has not been assessed.
Methods
We conducted a retrospective cohort study from 1997–2005 among 112 pregnant HIV-infected women who started HAART before (N = 12), during (N = 70) or after pregnancy (N = 30).
Results
Women initiating HAART before pregnancy had lower CD4+ nadir and higher baseline HIV-1 RNA. Women initiating HAART after pregnancy were more likely to receive triple-nucleoside reverse transcriptase inhibitors. Multivariable analyses adjusted for baseline CD4+ lymphocytes, baseline HIV-1 RNA, age, race, CD4+ lymphocyte count nadir, history of ADE, prior use of non-HAART ART, type of HAART regimen, prior pregnancies, and date of HAART start. In these models, women initiating HAART during pregnancy had better 6-month HIV-1 RNA and CD4+ changes than those initiating HAART after pregnancy (−0.35 vs. 0.10 log10 copies/mL, P = 0.03 and 183.8 vs. −70.8 cells/mm3, P = 0.03, respectively) but similar to those initiating HAART before pregnancy (−0.32 log10 copies/mL, P = 0.96 and 155.8 cells/mm3, P = 0.81, respectively). There were 3 (25%) AIDS-defining events or deaths in women initiating HAART before pregnancy, 3 (4%) in those initiating HAART during pregnancy, and 5 (17%) in those initiating after pregnancy (P = 0.01). There were no statistical differences in rates of HIV disease progression between groups.
Conclusions
HAART initiation during pregnancy was associated with better immunologic and virologic responses than initiation after pregnancy.
doi:10.1371/journal.pone.0006961
PMCID: PMC2734183  PMID: 19742315
11.  Increased Detectability of Plasma HIV-1 RNA after Introduction of a New Assay and Altered Specimen-Processing Procedures 
After changes to assay and specimen-processing methods, plasma human immunodeficiency virus type 1 (HIV-1) RNA was frequently detectable in patients who previously had well-suppressed HIV-1 RNA levels. This artifact is attributable to shipping frozen plasma in primary plasma preparation tubes and is not caused by the HIV-1 RNA detection assay; it can be avoided by shipping plasma in a secondary tube.
doi:10.1086/592693
PMCID: PMC2605467  PMID: 18922071
12.  Virologic, Immunologic and Clinical Responses in Foreign-Born versus US-Born HIV-1 Infected Adults Initiating Antiretroviral Therapy: An Observational Cohort Study 
PLoS ONE  2012;7(12):e52336.
Introduction
Mortality rates within the first year of combination antiretroviral therapy (cART) initiation are several-fold higher in resource-limited countries than in resource-replete settings. However studies in western countries examining virologic, immunologic and clinical responses after cART initiation in indigenous versus non-indigenous populations have shown mixed results. This study aimed to determine whether there is a difference in these outcomes in a United States setting between foreign-born and US-born patients.
Methods
This retrospective observational cohort study of HIV-1 infected adults in one urban clinic in the United States compared virologic suppression, immune recovery and rates of AIDS defining events (ADEs) within the first year of cART using linear mixed effect models, log rank tests and Cox proportional hazard models. Data were analyzed for 94 foreign-born and 1242 US-born patients.
Results
Foreign-born patients were younger (31.7 years versus 38.5 years), more often female (38.3% versus 27.1%), less often injection drug users (3.2% versus 9.5%) or men who have sex with men (19.0% versus 54.5%), and had higher loss to follow-up rates (14.9% versus 6.2%). No significant differences were detected between the groups in suppression of plasma HIV-1 RNA, CD4+ cell recovery or development of ADEs.
Conclusions
During the first year on cART, virologic suppression, immune recovery and development of ADEs were comparable between foreign-born and US-born patients in care in a US clinic. Differential rates of loss to follow-up warrant further investigation in the foreign-born population.
doi:10.1371/journal.pone.0052336
PMCID: PMC3526482  PMID: 23284994

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