Effect of Gestational Age at Tenofovir-Emtricitabine-Efavirenz Initiation on Adverse Birth Outcomes in Botswana.
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SUBMITTER: Zash R
PROVIDER: S-EPMC6097579 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Effect of Gestational Age at Tenofovir-Emtricitabine-Efavirenz Initiation on Adverse Birth Outcomes in Botswana.
Zash Rebecca R Rough Kathryn K Jacobson Denise L DL Diseko Modiegi M Mayondi Gloria G Mmalane Mompati M Essex Max M Petlo Chipo C Lockman Shahin S Makhema Joseph J Shapiro Roger L RL
Journal of the Pediatric Infectious Diseases Society 20180801 3
Among human immunodeficiency virus-positive women in Botswana on the recommended first-line antiretroviral therapy regimen, tenofovir-emtricitabine-efavirenz, initiated within the first or early second trimester, we found no increased risk of stillbirth, neonatal death, preterm/very preterm delivery, or the infant being born small or very small for gestational age. Treatment with tenofovir-emtricitabine-efavirenz <1 year before conception increased the risk of preterm delivery slightly over late ...[more]
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Project description:BACKGROUND:We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex. METHODS:We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1-infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII). RESULTS:Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex. CONCLUSIONS:This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential. CLINICAL TRIALS REGISTRATION:NCT00118898.
| S-EPMC3905755 | biostudies-literature
Project description:BackgroundIn a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r).MethodsUsing data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding.ResultsThere were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight.ConclusionsThe risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).
| S-EPMC5984044 | biostudies-literature
Project description:ObjectivesEvaluate long-term rates of virological failure and treatment interruption for people living with HIV (PLWHIV) with viral suppression on first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine/lamivudine (EFV + TDF + FTC/3TC), and compare these according to patient characteristics.MethodsPLWHIV enrolled in the Collaboration of Observational HIV Epidemiological Research Europe cohort collaboration, who started first-line EFV + TDF + FTC/3TC at age at least 16 years and had viral suppression (<200 copies/ml) within 9 months were included. Rates of virological failure (≥200 copies/ml) and (complete) treatment interruption were estimated according to years since initial suppression. We used Poisson regression to examine associations of baseline characteristics with rates of virological failure or treatment interruption.ResultsAmong 19 527 eligible PLWHIV with median (interquartile range) follow-up 3.7 (2.0-5.6) years after initial viral suppression, the estimated rate of the combined incidence of virological failure or treatment interruption fell from 9.0/100 person-years in the first year to less than 4/100 person-years beyond 3 years from suppression; considering only those remaining on EFV + TDF + FTC/3TC, the combined rate dropped from 8.2/100 person-years in the first year to less than 3.5/100 person-years beyond 3 years. PLWHIV with injecting drug-related or heterosexual transmission were at higher risk of virological failure or treatment interruption, as were those of Black ethnicity. PLWHIV aged less than 35 years were at higher risk of virological failure and treatment interruption.ConclusionPLWHIV starting first-line EFV + TDF + FTC/3TC had low rates of virological failure and treatment interruption up to 10 years from initial suppression. Demographic characteristics can be used to identify subpopulations with higher risks of these outcomes.
| S-EPMC6410964 | biostudies-literature
Project description:OBJECTIVE:To evaluate the association between gestational weight gain in twin pregnancies and small-for-gestational-age (SGA) and large-for-gestational-age (LGA) birth, preterm birth before 32 weeks of gestation, cesarean delivery, and infant death within each prepregnancy body mass index (BMI) category. METHODS:Data in this population-based study came from Pennsylvania-linked infant birth and death records (2003-2013). We studied 54,836 twins born alive before 39 weeks of gestation. Total pregnancy weight gain (kg) was converted to gestational age-standardized z scores. Multivariable modified Poisson regression models stratified by prepregnancy BMI were used to estimate associations between z scores and outcomes. A probabilistic bias analysis, informed by an internal validation study, evaluated the effect of BMI and weight gain misclassification. RESULTS:Gestational weight gain z score was negatively associated with SGA and positively associated with LGA and cesarean delivery in all BMI groups. The relation between weight gain and preterm birth was U-shaped in nonobese women. An increased risk of infant death was observed for very low weight gain among normal-weight women and for high weight gain among women without obesity. Most excess risks of these outcomes were observed at weight gains at 37 weeks of gestation that are equivalent to less than 14 kg or more than 27 kg in underweight or normal-weight women, less than 11 kg or more than 28 kg in overweight women, and less than 6.4 kg or more than 26 kg in women with obesity. The bias analysis supported the validity of the conventional analysis. CONCLUSION:Very low or very high weight gains were associated with the adverse outcomes we studied. If the associations we observed are even partially reflective of causality, targeted modification of pregnancy weight gain in women carrying twins might improve pregnancy outcomes.
| S-EPMC6814560 | biostudies-literature
Project description:IntroductionSub-Saharan Africa has the largest number of people with HIV, one of the most severe burdens of adverse birth outcomes globally and particular vulnerability to climate change. We examined associations between seasonality and adverse birth outcomes among women with and without HIV in a large geographically representative birth outcomes surveillance study in Botswana from 2015 to 2018.MethodsWe evaluated stillbirth, preterm delivery, very preterm delivery, small for gestational age (SGA), very SGA, and combined endpoints of any adverse or severe birth outcome. We estimated the risk of each outcome by month and year of delivery, and adjusted risks ratios (ARRs) of outcomes during the early wet (1 November-15 January), late wet (16 January-31 March) and early dry (1 April-15 July) seasons, compared with the late dry (16 July-31 October) season. Analyses were conducted overall and separately by HIV status.ResultsAmong 73 178 women (24% with HIV), the risk of all adverse birth outcomes peaked in November-January and reached low points in September. Compared with the late dry season, the ARRs for any adverse birth outcome were 1.03 (95% CI 1.00 to 1.06) for the early dry season, 1.08 (95% CI 1.04 to 1.11) for the early wet season and 1.07 (95% CI 1.03 to 1.10) for the late wet season. Comparing the early wet season to the late dry season, we found that ARRs for stillbirth and very preterm delivery were higher in women with HIV (1.23, 95% CI 0.96 to 1.59, and 1.33, 95% CI 1.10 to 1.62, respectively) than in women without HIV (1.07, 95% CI 0.91 to 1.26, and 1.19, 95% CI 1.04 to 1.36, respectively).ConclusionsWe identified a modest association between seasonality and adverse birth outcomes in Botswana, which was greatest among women with HIV. Understanding seasonal patterns of adverse birth outcomes and the role of HIV status may allow for mitigation of their impact in the face of seasonal extremes related to climate change.
| S-EPMC8420660 | biostudies-literature
Project description:BackgroundIn the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration.MethodsRetrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ?20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression.ResultsOf 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively.ConclusionsTFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.
| S-EPMC7409985 | biostudies-literature
Project description:Gestational age estimation by last menstrual period (LMP) vs. ultrasound (or best obstetric estimate in the US) may result in discrepant classification of preterm vs. term birth. We investigated whether such discrepancies are associated with adverse infant outcomes.We studied singleton livebirths in the Medical Birth Registries of Norway, Sweden and Finland and US live birth certificates from 1999 to the most recent year available. Risk ratios (RR) with 95% confidence intervals (CI) by discordant and concordant gestational age estimation for infant, neonatal and post-neonatal mortality, Apgar score <4 and <7 at 5 min, and neonatal intensive care unit (NICU) admission were estimated using generalised linear models, adjusting for maternal age, education, parity, year of birth, and infant sex. Results were presented stratified by country.Compared to infants born at term by both methods, infants born preterm by ultrasound/best obstetric estimate but term by LMP had higher infant mortality risks (range of adjusted RRs 3.9 to 7.2) and modestly higher risks were obtained among infants born preterm by LMP but term by ultrasound/best obstetric estimate (range of adjusted RRs 1.6 to 1.9). Risk estimates for the other outcomes showed the same pattern. These findings were consistent across all four countries.Infants classified as preterm by ultrasound/best estimate, but term by LMP have consistently higher risks of adverse outcomes than those classified as preterm by LMP but term by ultrasound/best estimate. Compared with ultrasound/best estimate, use of LMP overestimates the proportion of births that are preterm.
| S-EPMC5576505 | biostudies-literature
Project description:BACKGROUND: Increased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)? vitamin D is uncertain. METHODS: We performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)? vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor ?B ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)? vitamin D were also evaluated. RESULTS: Seventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)? vitamin D remained stable, though a seasonality variation was demonstrated. CONCLUSIONS: These data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.
| S-EPMC3296645 | biostudies-literature
Project description:BackgroundDrug choice and metabolic changes with antiretroviral therapy contribute to cardiovascular risk in persons with HIV-1 infection.MethodsA randomized, 12 week, open-label, comparative study of the impact on lipids of continuation of abacavir/lamivudine (ABC/3TC) plus efavirenz (EFV) or replacement with the single tablet regimen of EFV/emtricitabine/tenofovir DF (EFV/FTC/TDF) in hypercholesterolaemic subjects on successful antiretroviral therapy, with a 12-week extension with all subjects on EFV/FTC/TDF.Results157 subjects received study drug, 79 switched to EFV/FTC/TDF and 78 subjects continued ABC/3TC+EFV. At Week 12, 73 subjects on ABC/3TC+EFV switched to EFV/FTC/TDF. The switch was well tolerated and no subject experienced viral rebound. Median baseline fasting total cholesterol was 6.32 mmol/L. 12 weeks following switch, the difference in the means (LSM) between treatment groups (EFV/FTC/TDF minus ABC/3TC+EFV) in total cholesterol change from baseline was -0.74 mmol/l (95% CI -1.00, -0.47, p < 0.001). The median change from baseline in total cholesterol following switch in the EFV/FTC/TDF arm was -0.86 mmol/l (p < 0.001) compared with +0.01 mmol/l (p = 0.45) in the continuation arm at Week 12. Significant (p < 0.001) differences between treatment groups following switch were seen for all lipid fractions from baseline to Week 12: LDL cholesterol (-0.47 mmol/L [-0.70, -0.25]), HDL cholesterol (-0.15 mmol/L [-0.21, -0.08]), triglycerides (-0.43 mmol/L [-0.75, -0.11]), and non HDL cholesterol (-0.56 mmol/L [-0.80, -0.31]). In the extension phase, similar declines in total cholesterol were observed with a median change from Week 12 to Week 24 of -0.73 mmol/L (p < 0.001).ConclusionsSwitching from ABC/3TC+EFV to EFV/FTC/TDF in persons with hypercholesterolemia maintains virological control and significantly improves key lipid parameters.Trial registrationClinicalTrials.gov NCT00615810.
| S-EPMC4319732 | biostudies-literature
Project description:ObjectivesTo determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.DesignObservational cohort study of HIV-infected adults initiating efavirenz-based regimens in Botswana.MethodsThe primary endpoint was a composite of death or loss to care or HIV RNA more than 25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured by using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.ResultsA total of 801 individuals included 406 (51%) men, median age 37 years, median baseline CD4 cell count 195 cells/μl, and plasma HIV RNA 4.9 log10 copies/ml. 288 (36%) reached the endpoint, including 34 (4%) deaths, 151 (19%) lost to care, 11 (1%) lost to the study, but alive and in care, and 92 (11%) with plasma HIV RNA more than 25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences.ConclusionSlow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate central nervous system toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.
| S-EPMC5612381 | biostudies-literature