Browsing by Author "Sterling, Timothy R."

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    Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens
    (Oxford University Press, 2021) Leonard, Michael A.; Cindi, Zinhle; Bradford, Yuki; Bourgi, Kassem; Koethe, John; Turner, Megan; Norwood, Jamison; Woodward, Beverly; Erdem, Husamettin; Basham, Rebecca; Baker, Paxton; Rebeiro, Peter F.; Sterling, Timothy R.; Hulgan, Todd; Daar, Eric S.; Gulick, Roy; Riddler, Sharon A.; Sinxadi, Phumla; Ritchie, Marylyn D.; Haas, David W.; Medicine, School of Medicine
    Background: Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. Methods: We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. Results: In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex. Conclusions: Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.
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    Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy
    (Oxford, 2019-05) Bourgi, Kassem; Rebeiro, Peter F.; Turner, Megan; Castilho, Jessica L.; Hulgan, Todd; Raffanti, Stephen P.; Koethe, John R.; Sterling, Timothy R.; Medicine, School of Medicine
    Background Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)–based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. Methods Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)–, and nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. Results Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. Conclusions Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.
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    Mortality Among People With HIV Treated for Tuberculosis Based on Positive, Negative, or No Bacteriologic Test Results for Tuberculosis: The IeDEA Consortium
    (Oxford University Press, 2020-01-10) Humphrey, John M.; Mpofu, Philani; Pettit, April C.; Musick, Beverly; Carter, E. Jane; Messou, Eugène; Marcy, Olivier; Crabtree-Ramirez, Brenda; Yotebieng, Marcel; Anastos, Kathryn; Sterling, Timothy R.; Yiannoutsos, Constantin; Diero, Lameck; Wools-Kaloustian, Kara; Medicine, School of Medicine
    Background In resource-constrained settings, many people with HIV (PWH) are treated for tuberculosis (TB) without bacteriologic testing. Their mortality compared with those with bacteriologic testing is uncertain. Methods We conducted an observational cohort study among PWH ≥15 years of age initiating TB treatment at sites affiliated with 4 International epidemiology Databases to Evaluate AIDS consortium regions from 2012 to 2014: Caribbean, Central and South America, and Central, East, and West Africa. The exposure of interest was the TB bacteriologic test status at TB treatment initiation: positive, negative, or no test result. The hazard of death in the 12 months after TB treatment initiation was estimated using a Cox proportional hazard model. Missing covariate values were multiply imputed. Results In 2091 PWH, median age 36 years, 53% had CD4 counts ≤200 cells/mm3, and 52% were on antiretroviral therapy (ART) at TB treatment initiation. The adjusted hazard of death was higher in patients with no test compared with those with positive test results (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.08–2.26). The hazard of death was also higher among those with negative compared with positive tests but was not statistically significant (HR, 1.28; 95% CI, 0.91–1.81). Being on ART, having a higher CD4 count, and tertiary facility level were associated with a lower hazard for death. Conclusions There was some evidence that PWH treated for TB with no bacteriologic test results were at higher risk of death than those with positive tests. Research is needed to understand the causes of death in PWH treated for TB without bacteriologic testing.
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    The relationship between adverse neighborhood socioeconomic context and HIV continuum of care outcomes in a diverse HIV clinic cohort in the Southern United States
    (Taylor & Francis, 2018-11) Rebeiro, Peter F.; Howe, Chanelle J.; Rogers, William B.; Bebawy, Sally S.; Turner, Megan; Kheshti, Asghar; McGowan, Catherine C.; Raffanti, Stephen P.; Sterling, Timothy R.; Medicine, School of Medicine
    Retention in care and viral suppression are critical to delaying HIV progression and reducing transmission. Neighborhood socioeconomic context (NSEC) may affect HIV care receipt. We therefore assessed NSEC's impact on retention and viral suppression in a diverse HIV clinical cohort. HIV-positive adults with ≥1 visit at the Vanderbilt Comprehensive Care Clinic and 5-digit ZIP code tabulation area (ZCTA) information between 2008 and 2012 contributed. NSEC z-score indices used neighborhood-level socioeconomic indicators for poverty, education, labor-force participation, proportion of males, median age, and proportion of residents of black race by ZCTA. Retention was defined as ≥2 HIV care visits per calendar year, >90 days apart. Viral suppression was defined as an HIV-1 RNA <200 copies/mL at last measurement per calendar year. Modified Poisson regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI). Among 2272 and 2541 adults included for retention and viral suppression analyses, respectively, median age and CD4 count at enrollment were approximately 38 (1st and 3rd quartile: 30, 44) years and 351 (176, 540) cells/μL, respectively, while 24% were female, and 39% were black. Across 243 ZCTAs, median NSEC z-score was 0.09 (-0.66, 0.48). Overall, 79% of person-time contributed was retained and 74% was virally suppressed. In adjusted models, NSEC was not associated with retention, though being in the 4th vs. 1st NSEC quartile was associated with lack of viral suppression (RR = 0.88; 95% CI: 0.80-0.97). Residing in the most adverse NSEC was associated with lack of viral suppression. Future studies are needed to confirm this finding.
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    Risk of Incident Diabetes Mellitus, Weight Gain, and Their Relationships With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among Persons With Human Immunodeficiency Virus in the United States and Canada
    (Oxford University Press, 2021) Rebeiro, Peter F.; Jenkins, Cathy A.; Bian, Aihua; Lake, Jordan E.; Bourgi, Kassem; Moore, Richard D.; Horberg, Michael A.; Matthews, W. Christopher; Silverberg, Michael J.; Thorne, Jennifer; Mayor, Angel M.; Lima, Viviane D.; Palella, Frank J., Jr.; Saag, Michael S.; Althoff, Keri N.; Gill, M. John; Wong, Cherise; Klein, Marina B.; Crane, Heidi M.; Marconi, Vincent C.; Shepherd, Bryan E.; Sterling, Timothy R.; Koethe, John R.; Medicine, School of Medicine
    Background: Integrase strand transfer inhibitor (INSTI)-based combination antiretroviral therapy (cART) is associated with greater weight gain among persons with human immunodeficiency virus (HIV), though metabolic consequences, such as diabetes mellitus (DM), are unclear. We examined the impact of initial cART regimen and weight on incident DM in a large North American HIV cohort (NA-ACCORD). Methods: cART-naive adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from January 2007 through December 2017 who had weight measured 12 (±6) months after treatment initiation contributed time until clinical DM, virologic failure, cART regimen switch, administrative close, death, or loss to follow-up. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DM by cART class. Mediation analyses, with 12-month weight as mediator, similarly adjusted for all covariates. Results: Among 22 884 eligible individuals, 47% started NNRTI-, 30% PI-, and 23% INSTI-based cART with median follow-up of 3.0, 2.3, and 1.6 years, respectively. Overall, 722 (3%) developed DM. Persons starting INSTIs vs NNRTIs had incident DM risk (HR, 1.17 [95% CI, .92-1.48]), similar to PI vs NNRTI initiators (HR, 1.27 [95% CI, 1.07-1.51]). This effect was most pronounced for raltegravir (HR, 1.42 [95% CI, 1.06-1.91]) vs NNRTI initiators. The INSTI-DM association was attenuated (HR, 1.03 [95% CI, .71-1.49] vs NNRTIs) when accounting for 12-month weight. Conclusions: Initiating first cART regimens with INSTIs or PIs vs NNRTIs may confer greater risk of DM, likely mediated through weight gain.
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    The Tuberculosis Sentinel Research Network (TB-SRN) of the International epidemiology Databases to Evaluate AIDS (IeDEA): protocol for a prospective cohort study in Africa, Southeast Asia and Latin America
    (BMJ, 2024-01-09) Enane, Leslie A.; Duda, Stephany N.; Chanyachukul, Thida; Bolton-Moore, Carolyn; Navuluri, Neelima; Messou, Eugène; Mbonze, Nana; McDade, LaQuita R.; Figueiredo, Marina Cruvinel; Ross, Jeremy; Evans, Denise; Diero, Lameck; Akpata, Robert; Zotova, Natalia; Freeman, Aimee; Pierre, Marie Flore; Rupasinghe, Dhanushi; Ballif, Marie; Byakwaga, Helen; de Castro, Nathalie; Tabala, Martine; Sterling, Timothy R.; Sohn, Annette H.; Fenner, Lukas; Wools-Kaloustian, Kara; Poda, Armel; Yotebieng, Marcel; Huebner, Robin; Marcy, Olivier; International epidemiology Databases to Evaluate AIDS; Pediatrics, School of Medicine
    Introduction: Tuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity and mortality. Following TB treatment, surviving individuals may be at risk for post-TB lung disease. The TB Sentinel Research Network (TB-SRN) provides a platform for coordinated observational TB research within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. Methods and analysis: This prospective, observational cohort study will assess treatment and post-treatment outcomes of pulmonary TB (microbiologically confirmed or clinically diagnosed) among 2600 people aged ≥15 years, with and without HIV coinfection, consecutively enrolled at 16 sites in 11 countries, across 6 of IeDEA's global regions. Data regarding clinical and sociodemographic factors, mental health, health-related quality of life, pulmonary function, and laboratory and radiographic findings will be collected using standardised questionnaires and data collection tools, beginning from the initiation of TB treatment and through 12 months after the end of treatment. Data will be aggregated for proposed analyses. Ethics and dissemination: Ethics approval was obtained at all implementing study sites, including the Vanderbilt University Medical Center Human Research Protections Programme. Participants will provide informed consent; for minors, this includes both adolescent assent and the consent of their parent or primary caregiver. Protections for vulnerable groups are included, in alignment with local standards and considerations at sites. Procedures for requesting use and analysis of TB-SRN data are publicly available. Findings from TB-SRN analyses will be shared with national TB programmes to inform TB programming and policy, and disseminated at regional and global conferences and other venues.