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Item Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s(Oxford Academic, 2017-07-01) Gupta, Samir K.; Yeh, Eunice; Kitch, Douglas W.; Brown, Todd T.; Venuto, Charles S.; Morse, Gene D.; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A.; Medicine, School of MedicineBackground: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.Item Case 27-2021: A 16-Year-Old Boy Seeking Human Immunodeficiency Virus Prophylaxis(NEJM Group, 2021-09) Neilan, Anne M.; Salvant Valentine, Sheila; Knopf, Amelia S.; School of NursingItem Changes in proteinuria and albuminuria with initiation of antiretroviral therapy: data from a randomized trial comparing tenofovir disoproxil fumarate/emtricitabine versus abacavir/lamivudine(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-09-01) Wyatt, Christina M.; Kitch, Douglas; Gupta, Samir K.; Tierney, Camlin; Daar, Eric S.; Sax, Paul E.; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A.; AIDS Clinical Trials Group Study A5224s Team; Department of Medicine, IU School of MedicineBACKGROUND: Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. METHODS: We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. RESULTS: At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. CONCLUSIONS: In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.Item Comprehensive evaluation of caregiver-reported antiretroviral therapy adherence for HIV-infected children(Springer-Verlag, 2015-04) Vreeman, Rachel C.; Nyandiko, Winstone M.; Liu, Hai; Tu, Wanzhu; Scanlon, Michael L.; Slaven, James E.; Ayaya, Samuel O.; Inui, Thomas S.; Department of Pediatrics, IU School of MedicineFor HIV-infected children, adherence to antiretroviral therapy (ART) is often assessed by caregiver report but there are few data on their validity. We conducted prospective evaluations with 191 children ages 0-14 years and their caregivers over 6 months in western Kenya to identify questionnaire items that best predicted adherence to ART. Medication Event Monitoring Systems(®) (MEMS, MWV/AARDEX Ltd., Switzerland) electronic dose monitors were used as external criterion for adherence. We employed a novel variable selection tool using the LASSO technique with logistic regression to identify items best correlated with dichotomized MEMS adherence (≥90 or <90 % doses taken). Nine of 48 adherence items were identified as the best predictors of adherence, including missed or late doses in the past 7 days, problems giving the child medicines, and caregiver-level factors like not being present at medication taking. These items could be included in adherence assessment tools for pediatric patients.Item Immune reconstitution in ART treated, but not untreated HIV infection, is associated with abnormal beta cell function(Public Library of Science, 2018-05-24) Sims, Emily K.; Park, Grace; Mather, Kieren J.; Raghavendra, G. Mirmira; Liu, Ziyue; Gupta, Samir K.; Pediatrics, School of MedicineHIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts <350 cells/μL, PI:C ratios were lower than in HIV- controls (p<0.01), suggesting a reduction in intrinsic beta cell stress among this group. By contrast, HIV+ participants on ART had higher fasting glucose (p<0.0001) and lower HOMA%B (p<0.001) compared to HIV- controls. Among the entire HIV+ population, higher HIV RNA correlated with lower fasting glucose (r = -0.57, p<0.001), higher HOMA%B (r = 0.40, p = 0.001), and lower PI:C ratios (r = -0.42, p<0.001), whereas higher CD4 counts correlated with higher PI:C ratios (r = 0.2, p = 0.00499). Our results suggest that HIV seropositivity in the absence of ART does not worsen beta cell function or glucose homeostasis, but immune reconstitution with ART may be associated with worsened beta cell function.Item The Need for Pediatric Formulations to Treat Children with HIV(Hindawi Publishing Corporation, 2016) Schlatter, Adrienne F.; Deathe, Andrew R.; Vreeman, Rachel C.; Department of Pediatrics, IU School of MedicineOver 3.2 million children worldwide are infected with HIV, but only 24% of these children receive antiretroviral therapy (ART). ART adherence among children is a crucial part of managing human-immunodeficiency virus (HIV) infection and extending the life and health of infected children. Important causes of poor adherence are formulation- and regimen-specific properties, including poor palatability, large pill burden, short dosing intervals, and the complex storage and transportation of drugs. This review aims to summarize the various regimen- and formulation-based barriers to ART adherence among children to support the need for new and innovative pediatric formulations for antiretroviral therapy (ART). Detailing the arguments both for and against investing in the development of pediatric HIV medications, as well as highlighting recent advances in pediatric ART formulation research, provides a synopsis of the current data related to pediatric ART formulations and adherence.Item Point-of-care CD4 testing to inform selection of antiretroviral medications in south african antenatal clinics: a cost-effectiveness analysis(PLoS, 2015-03-10) Ciaranello, Andrea L.; Myer, Landon; Kelly, Kathleen; Christensen, Sarah; Daskilewicz, Kristen; Doherty, Katie; Bekker, Linda-Gail; Hou, Taige; Wood, Robin; Francke, Jordan A.; Wools-Kaloustian, Kara; Freedburg, Kenneth A.; Walensky, Rochelle P.; Department of Medicine, IU School of MedicineBACKGROUND: Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. METHODS: We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO "Option A"): antenatal zidovudine (CD4 ≤350/μL) or ART (CD4>350/μL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved). RESULTS: In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. CONCLUSIONS: In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection.Item A randomized, controlled trial of the effect of rilpivirine versus efavirenz on cardiovascular risk in healthy volunteers.(Oxford UP, 2015-10) Gupta, Samir K.; Slaven, James E.; Kamendulis, Lisa M.; Liu, Ziyue; Department of Medicine, IU School of MedicineObjectives: The HIV NNRTI rilpivirine is being evaluated as a possible agent for HIV pre-exposure prophylaxis. We have recently shown that the NNRTI efavirenz may impair endothelial function assessed as flow-mediated dilation (FMD), but whether this impairment is also found with rilpivirine is unknown. We sought to compare cardiovascular risk profiles between efavirenz and rilpivirine in healthy volunteers. Methods: We performed a prospective, randomized, open-label trial in 40 HIV-uninfected healthy volunteers who were randomized 1: 1 to either efavirenz or rilpivirine. Vascular indices, metabolic parameters, inflammatory biomarkers and oxidative stress were measured before and after 4 weeks of treatment. This study is registered at ClinicalTrials.gov (NCT01585038). Results: There were no significant differences in 4 week mean (SD) changes in FMD between efavirenz and rilpivirine [0.089 (3.65)% versus 0.63 (2.42)%; P = 0.77]. There were also no significant differences in 4 week changes in high-sensitivity C-reactive protein,Item Sexual Communication Self-Efficacy and PrEP Literacy Helps to Meet HIV Prevention Outcomes Among Black and Latinx Individuals(Sage Journals, 2022) Carter, Gregory; Brown, Lucy; Mahnke, Brianna; Ohmit, Anita; Woodward, BrennanBackground: Ending the HIV Epidemic is a campaign dedicated to reducing new HIV infections in the United States by 90% by 2030. Preexposure prophylaxis (PrEP) holds significant promise as a prevention tool. However, uptake has not improved much since then. As a result, this research looked at how PrEP literacy relates to sexual communication self-efficacy. Methods: Between August 4 and 21, 2020, we performed a community-informed cross-sectional study of Black and Latino residents in Indiana. We collected demographic information as well as PrEP literacy, sexual communication self-efficacy, and awareness of HIV status. Results: Being unaware of one's own HIV status and being unsure of one's sexual identity were both linked to reduced self-efficacy in the domain of sex communication. Those who had a greater level of PrEP literacy felt more confident in their ability to communicate with others about sexually related topics. People living in rural areas showed a significantly lower degree of sexual communication self-efficacy than participants in urban settings. Conclusion: Providing information about PrEP to those at risk of acquiring the virus may help them connect with treatment or prevention services. Healthcare professionals should take the time to understand their patients' levels of PrEP literacy and communication self-efficacy regarding sexual health.Item Time Preferences Predict Mortality among HIV-Infected Adults Receiving Antiretroviral Therapy in Kenya(Public Library of Science (PLoS), 2015) Thirumurthy, Harsha; Hayashi, Kami; Linnemayr, Sebastian; Vreeman, Rachel C.; Levin, Irwin P.; Bangsberg, David R.; Brewer, Noel T.; Department of Pediatrics, IU School of MedicineBACKGROUND: Identifying characteristics of HIV-infected adults likely to have poor treatment outcomes can be useful for targeting interventions efficiently. Research in economics and psychology suggests that individuals' intertemporal time preferences, which indicate the extent to which they trade-off immediate vs. future cost and benefits, can influence various health behaviors. While there is empirical support for the association between time preferences and various non-HIV health behaviors and outcomes, the extent to which time preferences predict outcomes of those receiving antiretroviral therapy (ART) has not been examined previously. METHODS: HIV-infected adults initiating ART were enrolled at a health facility in Kenya. Participants' time preferences were measured at enrollment and used to classify them as having either a low or high discount rate for future benefits. At 48 weeks, we assessed mortality and ART adherence, as measured by Medication Event Monitoring System (MEMS). Logistic regression models adjusting for socio-economic characteristics and risk factors were used to determine the association between time preferences and mortality as well as MEMS adherence ≥90%. RESULTS: Overall, 44% (96/220) of participants were classified as having high discount rates. Participants with high discount rates had significantly higher 48-week mortality than participants with low discount rates (9.3% vs. 3.1%; adjusted odds ratio 3.84; 95% CI 1.03, 14.50). MEMS adherence ≥90% was similar for participants with high vs. low discount rates (42.3% vs. 49.6%, AOR 0.70; 95% CI 0.40, 1.25). CONCLUSION: High discount rates were associated with significantly higher risk of mortality among HIV-infected patients initiating ART. Greater use of time preference measures may improve identification of patients at risk of poor clinical outcomes. More research is needed to further identify mechanisms of action and also to build upon and test the generalizability of this finding.