Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB. Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20–26 weeks’ and 30–38 weeks’ gestation and at 2–8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4–6 months after birth. A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55

Background: Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout. Setting: Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants. Methods: Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed. Cord blood and infant washout samples were collected. Total and free bictegravir concentrations were measured by validated liquid chromatography with tandem mass spectrometry methods. Within- participant geometric mean ratios (GMR) with 90% confidence intervals (CI) were calculated to compare pharmacokinetics between second and third trimester versus postpartum. Infant HIV testing results were obtained. Results: Twenty-seven maternal-infant pairs were enrolled. Bictegravir area under the concentration-time curve from time 0 through 24 hours post-dose was 46% lower in the second trimester (n = 12; P = 0.002; GMR 0.54; 90% CI: 0.43 to 0.69) and 52% lower in the third trimester (n = 24; P < 0.0001; GMR 0.48; 90% CI: 0.43 to 0.55), compared with postpartum. C24 concentrations were above the estimated bictegravir protein-adjusted 95% effective concentration of 0.162 mg/mL. The median ratio of cord-to-maternal blood concentration was 1.38 (n = 17; quartiles: 1.17-1.63). Median T1/2 for infant bictegravir washout was 33.2 hours (quartiles: 25.7-45.9) with a Cmax of 2.06 mg/mL (quartiles: 1.37-2.72). Overall, 88%-92% of participants maintained suppression <40 copies/mL throughout pregnancy and postpartum. All available infant HIV testing results were negative. The safety profile for pregnant PWH and infants was acceptable. Conclusions: Bictegravir exposure was lower during pregnancy compared with postpartum, yet C24 concentrations were greater than the bictegravir protein-adjusted 95% effective concentration.

The pharmacokinetics (PK) of antituberculosis drugs may be altered by both pregnancy-induced physiological changes and drug interactions in individuals living with HIV who develop tuberculosis. Within the multicenter International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study, we assessed the PK of rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum (PP) in women on efavirenz-based antiretroviral therapy (ART). Results were compared to a previously published non-HIV group and described minimum targets. World Health Organization-recommended daily doses of antituberculosis and ART medications were administered, followed by PK sampling of all antituberculosis drugs over 24 h during the second trimester (2T), third trimester (3T), and 2-8 weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made among stages of pregnancy and between groups using geometric mean ratios with 90% confidence intervals. Twenty-two participants were enrolled, and PK data were available for 12, 20, and 13 participants in 2T, 3T, and PP, respectively. While no significant difference in rifampin exposure between pregnancy and postpartum was detected, the median area-under-the-plasma-concentration-time-curve up to 24 h post-dose (AUC0-24) and Cmax were below target during each period and were 42% and 35% lower in 3T than the non-HIV group. No significant difference in isoniazid exposure was found between pregnancy and PP or between the groups. Ethambutol and pyrazinamide AUC0-24 and Cmax in 2T and 3T were similar between the groups. In both groups, pyrazinamide Cmax was above target in all periods. The clinical relevance of lower rifampin exposure in pregnant women requiring tuberculosis treatment while on efavirenz should be determined.

Background Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy.Methods IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated.Results Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35-3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected.Conclusions Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.Clinical Trials Registration NCT04582266. The plasma PK of remdesivir and its major metabolites were comparable between hospitalized pregnant and nonpregnant women with COVID-19, suggesting no dose adjustments are needed for intravenous remdesivir in pregnancy.

Background: Primary results of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) 2002 trial showed that cognitive behavioural therapy (CBT) and medication management algorithm (MMA) (COMB-R) significantly improved depression in youth with HIV (YWH) compared with enhanced standard care (ESC). Acceptability and satisfaction were examined among study participants and clinicians.Method: Between March 2017 and March 2019, 13 U.S. sites enrolled YWH, aged 12-24, diagnosed with nonpsychotic depression. Sites were randomised to either COMB-R (CBT by a therapist and licensed prescriber) or ESC (standard psychotherapy and medication management). After the intervention (week 24), participants, prescribers, and therapists rated acceptability and satisfaction. We compared site-level means using Wilcoxon tests.Results: Both COMB-R (n = 69) and ESC (n = 71) participants had a mean age of 21.4 years, with 53% female, and 54% having acquired HIV perinatally. Baseline age, sex, depression levels, RNA viral load, and CD4 count were comparable between arms. The distribution of site-level mean participant acceptability was greater in COMB-R compared with ESC (p = 0.04). The distribution of site-level mean prescriber satisfaction was greater in COMB-R (p = 0.01). The was no evidence that the site-level mean therapist satisfaction did not differ between arms (p = 0.52).Discussion: Acceptability and satisfaction for participants and licensed prescribers were higher at COMB-R sites compared with standard of care, indicating that this tailored, manual-guided, collaborative, measured care intervention was less burdensome in terms of the number of visits. Patient and medication provider satisfaction rates were higher than standard of care.Conclusion: While these results support the use of CBT and MMA in treating depression among YWH, further research is required to determine generalisability.

This is a secondary analysis of a multi-site, cluster (site) randomized trial of the efficacy of a combined Health and Wellness Cognitive Behavior Therapy (H W CBT) and medication management approach for depression in youth with HIV (YWH) compared to standard care. In this study, we explored the association between H W CBT factors and depression outcomes after 24 weeks of treatment to discover treatment elements associated with symptom reduction. Participants (12–24 years of age) were YWH in the United States (US) diagnosed with moderate to severe depression [Quick Inventory of Depressive Symptomatology (QIDS), Clinician-Rated score ≥ 11]. Thirteen US sites were randomly assigned to either the combination treatment approach or standard care. For site-level analyses, site-specific summary scores were used to account for the within site correlation. The number of depressive symptoms [QIDS-Self Reported (QIDS-SR) score] after 24 weeks of H W CBT was significantly negatively correlated with the mean total session duration (ρ = − 0.94), the total homework assigned (ρ = − 0.83), the total number of practice modules used (ρ = − 0.83), and the mean total booster sessions given (ρ = − 0.82). Specific elements of the H W CBT (e.g., dose, assignment of homework, greater skills practice, and use of booster sessions) were associated with improvement of depression outcomes in YWH. A focus on these elements in treatment may improve symptom reduction for YWH with depression.

Introduction: Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal–infant health. Setting: Fourteen sites in 7 countries within sub-Saharan Africa and India. Methods: The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother–infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. Results: Two thousand four hundred thirty-one mother–infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553–869), and the median mVL was 322 copies/mL (IQR 40–1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL (P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). Conclusions: Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. Clinical Trial Number: ClinicalTrials.gov: NCT01061151; closed to follow-up.

ABSTRACT Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2–8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC 0–24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC 0–24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC 0–24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC 0–24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Background: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. Methods: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6–12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5–9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. Results: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. Conclusion: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Background: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12–24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. Methods: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. Results: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). Conclusions: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

Background: Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs. Setting: NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. Methods: Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal–Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs. Results: Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m2/wk versus 0.11 kg/m2/wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) (P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs. Conclusions: A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.

Objectives: Long-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics. Study Design: We enrolled postpartum women using etonogestrel implants and receiving ritonavirboosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression. Results: We collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boostedatazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (C (min)) of ritonavir-boosted-atazanavir and ritonavirboosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion. Conclusions: Unlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations. (C) 2021PublishedbyElsevierInc.

Objective To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual’s viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. Design A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. Methods HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. Results PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases’ median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). Conclusions We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.

OBJECTIVE To evaluate the pharmacokinetics of tenofovir alafenamide (TAF) 10 mg with cobicistat and 25 mg without boosting in pregnant and postpartum women with HIV and to characterize TAF placental transfer and infant washout pharmacokinetics. DESIGN Open-label, multicenter phase IV prospective study of TAF pharmacokinetics during pregnancy, postpartum, delivery and infant washout. METHODS Pregnant women receiving TAF 10 mg with cobicistat or TAF 25 mg without boosting as part of clinical care had intensive pharmacokinetic assessments performed during the second and third trimesters, and 6-12 weeks postpartum. Maternal and infant blood samples were collected at delivery, and washout pharmacokinetic samples were collected in infants. TAF concentrations were quantified using LC/MS. Comparisons between pregnancy and postpartum were made using geometric mean ratios (90% confidence intervals) and Wilcoxon signed-rank tests. RESULTS Thirty-one pregnant women receiving TAF 10 mg with cobicistat-boosting and 27 women receiving TAF 25 mg without boosting were enrolled. TAF exposures did not significantly differ between pregnancy and postpartum when administered as 10 mg with cobicistat. Antepartum TAF exposures with the 25 mg dose were 33-43% lower in comparison to postpartum, but comparable to those measured in non-pregnant adults. TAF was below the lower limit of quantitation in 43/44 cord blood, 41/45 maternal blood at delivery, and all infant washout samples. CONCLUSIONS TAF exposures were comparable or higher than those measured in non-pregnant adults during pregnancy and postpartum. These findings provide reassurance on adequate TAF exposures during pregnancy, and support efforts to expand the use of TAF in pregnant women with HIV.

Background: Breastfeeding mothers with HIV infection not qualifying for antiretroviral therapy (ART) based on country-specific guidelines at the time of the Promoting Maternal-Infant Survival Everywhere trial and their uninfected neonates were randomized to maternal ART (mART) or infant nevirapine prophylaxis (iNVP) postpartum. HIV transmission proportions were similar (<1%) in the 2 arms. We assessed whether maternal viral load (MVL) and CD4 cell counts were associated with breastfeeding HIV transmission. Methods: MVL was collected at entry (7–14 days postpartum) and at weeks 6, 14, 26, and 50 postpartum. CD4 cell counts were collected at entry and weeks 14, 26, 38, and 50 postpartum. Infant HIV-1 nucleic acid test was performed at weeks 1 and 6, every 4 weeks until week 26, and then every 12 weeks. The associations of baseline and time-varying MVL and CD4 cell counts with transmission risk were assessed using time-to-event analyses by randomized treatment arm. Results: Two thousand four hundred thirty-one mother–infant pairs were enrolled in the study. Baseline MVL (P = 0.11) and CD4 cell counts (P = 0.51) were not significantly associated with infant HIV-1 infection. Time-varying MVL was significantly associated with infant HIV-1 infection {hazard ratio [95% confidence interval (CI)]: 13.96 (3.12 to 62.45)} in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 1.04 (0.20 to 5.39)]. Time-varying CD4 cell counts were also significantly associated with infant HIV-1 infection [hazard ratio (95% CI): 0.18 (0.03 to 0.93)] in the mART arm but not in the iNVP arm [hazard ratio (95% CI): 0.38 (0.08 to 1.77)]. Conclusions: In women receiving mART, increased MVL and decreased CD4 cell counts during breastfeeding were associated with increased risk of infant HIV-1 infection.

To evaluate the frequency and associated characteristics of chronic comorbid conditions and obstetrical complications among pregnant women living with HIV on antiretroviral therapy, and in comparison to those without HIV. We assessed two concurrent U.S cohorts of pregnant women with and without HIV: 1) International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1025, 2002-2013; and 2) Consortium for Safe Labor Study, 2002-2008. The primary outcomes were ≥2 chronic comorbid conditions per the WHO, and obstetrical complications. For women with HIV, we assessed whether a detectable viral load at delivery (≥400 copies/mL), starting ART earlier (less effective era, 2002-2008), and late entry to prenatal care (≥14 weeks) were associated with study outcomes. We assessed 2,868 deliveries (n=2,574 women) with HIV on antiretroviral therapy, and 211,910 deliveries (n=193,170 women) without HIV. Women with HIV were more likely to have ≥2 chronic comorbid conditions versus those without (10 vs. 3%; AOR: 2.96), including the most frequent comorbid groups, psychiatric (16 vs. 4%; AOR: 5.13), pulmonary (12 vs. 8%; AOR: 1.66), and cardiovascular (9 vs. 5%; AOR: 1.27). Women with HIV were slightly less likely to have obstetrical complications versus those without (both 17%; AOR: 0.84), including preeclampsia (both 6%; AOR: 0.80), very preterm birth <34 weeks (4 vs. 5%; AOR: 0.76), and gestational diabetes (both 4%; AOR: 0.70), but not preterm birth <37 weeks (17 vs. 13%; AOR: 1.31). Late entry to prenatal care and starting antiretroviral therapy earlier were associated with a lower likelihood of ≥2 chronic comorbidities (AORs: 0.65 and 0.72) and obstetrical complications (AORs: 0.76 and 0.76), and detectable viral load with a higher likelihood of obstetrical complications (AOR: 1.32). Chronic comorbid conditions were more frequent among pregnant women with HIV in an era of antiretroviral therapy, but not most obstetrical complications, compared to those without HIV, reinforcing the continued importance of high-risk interdisciplinary pregnancy care for this population.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Background. To evaluate the frequency and associated characteristics of chronic comorbid conditions and obstetrical complications among pregnant women with human immunodeficiency virus (HIV) and receiving antiretroviral therapy (ART) in comparison to those without HIV. Methods. We compared 2 independent concurrent US pregnancy cohorts: (1) with HIV (International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1025, 2002-2013) and (2) without HIV (Consortium for Safe Labor Study, 2002-2007). Outcomes were >= 2 chronic comorbid conditions and obstetrical complications. For women with HIV, we assessed whether late prenatal care (>= 14 weeks), starting ART in an earlier era (2002-2008), and a detectable viral load at delivery (>= 400 copies/mL) were associated with study outcomes. Results. We assessed 2868 deliveries (n = 2574 women) with HIV and receiving ART and 211 910 deliveries (n = 193 170 women) without HIV. Women with HIV were more likely to have >= 2 chronic comorbid conditions versus those without HIV (10 vs 3%; adjusted OR [AOR]: 2.96; 95% CI: 2.58-3.41). Women with HIV were slightly less likely to have obstetrical complications versus those without HIV (both 17%; AOR:.84; 95% CI:.75-.94), but secondarily, higher odds of preterm birth <37 weeks. Late entry to prenatal care and starting ART in an earlier era were associated with a lower likelihood of >= 2 chronic comorbidities and obstetrical complications; detectable viral load at delivery was associated with a higher likelihood of obstetric complications. Conclusions. Pregnant women with HIV receiving ART have more chronic comorbid conditions, but not necessarily obstetrical complications, than their peers without HIV.

Background: This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples. Setting: A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children. Methods: Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons. Results: A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0 –24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 μg/mL (0.16–0.28) in the second trimester, 0.21 μg/mL (0.11–0.56) in the third trimester, and 0.61 μg/mL (0.42–1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited. Conclusions: Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.

Background: Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL). Methods: This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission. Results: A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants. Conclusions: Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.

Supplemental Digital Content is Available in the Text. Background: Depression is frequent among youth living with HIV (YLWH). Studies suggest that manualized treatment guided by symptom measurement is more efficacious than usual care. Setting: This study evaluated manualized, measurement-guided depression treatment among YLWH, aged 12–24 years at 13 US sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network. Methods: Using restricted randomization, sites were assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB-R) tailored for YLWH or to enhanced standard of care, which provided standard psychotherapy and medication management. Eligibility included diagnosis of nonpsychotic depression and current depressive symptoms. Arm comparisons used t tests on site-level means. Results: Thirteen sites enrolled 156 YLWH, with a median of 13 participants per site (range 2–16). At baseline, there were no significant differences between arms on demographic factors, severity of depression, or HIV status. The average site-level participant characteristics were as follows: mean age of 21 years, 45% male, 61% Black, and 53% acquired HIV through perinatal transmission. At week 24, youth at COMB-R sites, compared with enhanced standard of care sites, reported significantly fewer depressive symptoms on the Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR score 6.7 vs. 10.6, P = 0.01) and a greater proportion in remission (QIDS-SR score ≤ 5; 47.9% vs. 17.0%, P = 0.01). The site mean HIV viral load and CD4 T-cell level were not significantly different between arms at week 24. Conclusions: A manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH significantly reduced depressive symptoms compared with standard care at HIV clinics.