Effects of combination antiretroviral therapy and nutritional rehabilitation on growth in children aged 6-36 months with severe acute malnutrition in IMPAACT protocol P1092.

BACKGROUND: Antiretroviral therapy (ART) is known to improve child survival and growth in children living with HIV (CLHIV). We investigated growth outcomes in children with severe non-edematous acute malnutrition (SAM) and without-SAM (mild malnutrition and normal nutrition) after initiation of ART in both groups and nutritional support. MATERIAL AND METHODS: IMPAACT P1092 enrolled CLHIV aged 6 to <36 months with WHO-defined SAM or without-SAM across 5 sites in Sub-Saharan Africa and followed them for 48 weeks. The enrollment was conducted in 4 countries Malawi, Tanzania, Uganda, and Zimbabwe. Weight, height, and mid-upper-arm circumference (MUAC) were measured at baseline through 48 weeks. WHO weight-for-length/height Z-scores (WFL/H Z-score) were calculated. SAM children received readily available therapeutic food per WHO guidelines. All participants were initiated on a triple-ART regimen. SAM children entered the study after initial nutritional rehabilitation. RESULTS: Fifty-two CLHIV, 25 in the SAM cohort and 27 in the without-SAM cohort, were enrolled. WFL/HZ-scores and MUAC in the SAM cohort increased significantly at weeks 24 and 48 (WFL/HZ-scores: mean change [95% CI] 2.34 [1.77, 2.91] and 2.73 [2.09, 3.37], both p< 0.001; MUAC: mean change [95% CI] 2.63 [1.98, 3.28] and 3.53 [2.83, 4.24] cm, p<0.001). At Week 48, mean SAM height was 4cm shorter and mean weight 1kg lighter than without SAM (post hoc mean differences -4.11 (95% CI -8.60, 0.38) cm and -0.92 (95% CI -2.22, 0.39) kg). CONCLUSION: CHLHIV with SAM who undergo WHO nutritional rehabilitation can achieve significant growth and WFL/HZ score improvements but continued intensive anthropometric monitoring is needed as SAM will still be behind those without SAM.

Effects of preterm birth, maternal ART and breastfeeding on 24-month infant HIV-free survival in a randomized trial.

BACKGROUND: IMPAACT 1077BF/FF (PROMISE) compared the safety/efficacy of two HIV antiretroviral therapy (ART) regimens to zidovudine (ZDV) alone during pregnancy for HIV prevention. PROMISE found an increased risk of preterm delivery (<37 weeks) with antepartum triple ART (TDF/FTC/LPV+r or ZDV/3TC/LPV+r) compared with ZDV alone. We assessed the impact of preterm birth, breastfeeding, and antepartum ART regimen on 24-month infant survival. METHODS: We compared HIV-free and overall survival at 24 months for liveborn infants by gestational age, time-varying breastfeeding status, and antepartum ART arm at 14 sites in Africa and India. Kaplan-Meier survival probabilities and Cox proportional hazards ratios were estimated. RESULTS: Three thousand four hundred and eighty-two live-born infants [568 (16.3%) preterm and 2914 (83.7%) term] were included. Preterm birth was significantly associated with lower HIV-free survival [0.85; 95% confidence interval (CI) 0.82-0.88] and lower overall survival (0.89; 95% CI 0.86-0.91) versus term birth (0.96; 95% CI 0.95-0.96). Very preterm birth (<34 weeks) was associated with low HIV-free survival (0.65; 95% CI 0.54-0.73) and low overall survival (0.66; 95% CI 0.56-0.74). Risk of HIV infection or death at 24 months was higher with TDF-ART than ZDV-ART (adjusted hazard ratio 2.37; 95% CI 1.21-4.64). Breastfeeding initiated near birth decreased risk of infection or death at 24 months (adjusted hazard ratio 0.05; 95% CI 0.03-0.08) compared with not breastfeeding. CONCLUSION: Preterm birth and antepartum TDF-ART were associated with lower 24-month HIV-free survival compared with term birth and ZDV-ART. Any breastfeeding strongly promoted HIV-free survival, especially if initiated close to birth. Reducing preterm birth and promoting infant feeding with breastmilk among HIV/antiretroviral drug-exposed infants remain global health priorities.

Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age.

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months. RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months. CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

Micronutrients and nutritional status among children living with HIV with and without severe acute malnutrition: IMPAACT P1092.

BACKGROUND: Micronutrient deficiencies from malabsorption, gut infections, and altered gut barrier function are common in children living with the human immunodeficiency virus (CLHIV) and may worsen with severe acute malnutrition (SAM). Exploratory data of baseline zinc and selenium levels and changes over 48 weeks in children living with HIV by nutritional status are presented. METHODS: Zinc, selenium, serum protein and albumin levels measured at study entry and over 48 weeks were compared between children aged 6 to < 36 months who were living with HIV and had SAM or mild malnutrition-normal nutrition. Children with SAM were enrolled after 10-18 days of nutritional rehabilitation. Two-sided t-tests were used to compare levels and changes in levels of micronutrients and proteins by nutritional status. RESULTS: Fifty-two participants, 25 with and 27 without SAM, of median (Q1,Q3) age 19 (13,25) and 18 (12,25) months respectively, were enrolled. Zinc deficiency was present at entry in 2/25 (8%) of those who had SAM. Mean (SD) baseline zinc levels were [52.2(15.3) and 54.7(12.0) µg/dL] for the SAM and non-SAM cohorts respectively while selenium levels were similar [92.9(25.0), 84.3(29.2) µg/L]. Mean changes of zinc and selenium from study entry to week 48 were similar between the children with and without SAM. There was no significant difference between baseline protein levels [75.2(13.2), 77.3(9.4) g/L] and the mean change from study entry to 48 weeks was also similar between the two groups; with a mean difference of 4.6 g/L [95% CI, (-2.4,11.6)]. Children with SAM compared to those without had significantly lower serum albumin levels at study entry with similar levels at 48 weeks. CONCLUSIONS: Children with severe malnutrition who were initiated/switched to zidovudine/lamivudine/boosted lopinavir following 10 to 18 days of nutritional rehabilitation showed normal baseline levels of selenium and zinc, and had comparable selenium levels after 48 weeks. There was a strong positive correlation in entry and week 48 selenium levels within each cohort and for zinc in the non-SAM cohort. These data support the current WHO recommended approach to management of severe malnutrition in CLHIV who are initiated on combination antiretroviral treatment. TRIAL REGISTRATION: Registered with ClinicalTrials.gov Identifier NCT01818258 26/03/2013.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

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 AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 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 AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial.

BACKGROUND: We assessed bone and kidney outcomes in infants randomized postdelivery as mother-infant pairs within the IMPAACT PROMISE trial to maternal tenofovir disoproxil fumarate-based antiretroviral treatment (mART) or infant nevirapine prophylaxis (iNVP) to prevent breastfeeding HIV transmission. METHODS: Infants were coenrolled in the P1084s substudy on randomization day and followed through Week 74. Lumbar spine bone mineral content (LS-BMC) was assessed at entry (6-21 age days) and Week 26 by dual-energy x-ray absorptiometry. Creatinine clearance (CrCl) was calculated at entry; Weeks 10, 26, and 74. Student t tests compared mean LS-BMC and CrCl at Week 26 and mean change from entry between arms. RESULTS: Of 400 enrolled infants, the mean (SD; n) for entry LS-BMC was 1.68 g (0.35; n = 363) and CrCl was 64.2 mL/min/1.73 m 2 (24.6; n = 357). At Week 26, 98% of infants were breastfeeding and 96% on their assigned HIV prevention strategy. The mean (SD) Week 26 LS-BMC was 2.64 g (0.48) for mART and 2.77 g (0.44) for iNVP; mean difference (95% confidence interval [CI]) -0.13 g (-0.22 to -0.04), P = 0.007, n = 375/398 (94%). Mean absolute (-0.14 g [-0.23 to -0.06]) and percent (-10.88% [-18.53 to -3.23]) increase in LS-BMC from entry was smaller for mART than iNVP. At Week 26, the mean (SD) CrCl was 130.0 mL/min/1.73 m 2 (34.9) for mART vs. 126.1 mL/min/1.73 m 2 (30.0) for iNVP; mean difference (95% CI) 3.8 (-3.0 to 10.7), P = 0.27, n = 349/398 (88%). CONCLUSION: Week 26 mean LS-BMC was lower in infants in the mART group compared with the iNVP group. However, this difference (∼0.23 g) was less than one-half SD, considered potentially clinically relevant. No infant renal safety concerns were observed.

HIV-1 remission and possible cure in a woman after haplo-cord blood transplant.

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s.

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.

Influence of NAT2 Genotype and Maturation on Isoniazid Exposure in Low-Birth-Weight and Preterm Infants With or Without Human Immunodeficiency Virus (HIV) Exposure.

BACKGROUND: Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention. METHODS: This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using 2 targets: Cmax at 3-6 mg/L and area under the curve (AUC) ≥ 10.52 mg h/L. RESULTS: We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7-39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2-7.3) months and weight (WT) was 3.7 (0.9-9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age, and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis. CONCLUSIONS: In LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, because NAT2 genotype highly impacts INH pharmacokinetic variability.

Abacavir dosing in neonates from birth to 3 months of life: a population pharmacokinetic modelling and simulation study.

BACKGROUND: No evidence-based optimal dosing guidance is available for abacavir liquid formulation use from birth. We used abacavir pharmacokinetic data from neonates and infants to determine an exact abacavir dosing strategy (mg/kg) for infants aged 0-3 months and to propose dosing by WHO weight band for neonates. METHODS: Abacavir pharmacokinetic and safety data were pooled from three completed studies (1997-2020): PACTG 321 (USA), the Tygerberg Cohort (South Africa), and IMPAACT P1106 (South Africa). PACTG 321 and the Tygerberg Cohort were performed in neonates exposed to HIV receiving a single dose of abacavir. IMPAACT P1106 included predominantly low birthweight (<2500 g) infants on antiretroviral therapy enrolled when they were younger than 3 months. We developed a population pharmacokinetic model and performed simulations to achieve abacavir exposures (area under the curve for 0-12 h) within the target range of 3·2-25·2 µg·h/mL, previously reported in older children. FINDINGS: 45 infants contributed 308 abacavir concentrations; 21 neonates were younger than 15 days. At first pharmacokinetic assessment, median postnatal age for PACTG 321 was 1 day and median bodyweight was 3·1 kg; for the Tygerberg Cohort it was 10 days and 3·3 kg; and for IMPAACT P1106 it was 73 days and 3·8 kg. Our model predicted a slow abacavir clearance of 2·51 mL/min per kg at birth, which doubled by 4 weeks of age. Therapeutic targets were achieved with exact abacavir doses of 2·0 mg/kg twice daily from 0 weeks to 4 weeks and 4·0 mg/kg twice daily from 4 weeks to 12 weeks. A fixed weight-band dosing strategy of 8 mg (for 2-3 kg), 10 mg (3-4 kg), and 12 mg (4-5 kg) abacavir twice daily achieved target exposures throughout the first 4 weeks of life without the need for dose adjustment due to age or bodyweight changes. No adverse events of grade 3 or higher were related to abacavir. INTERPRETATION: Integration of these dosing strategies into national and international guidelines for the abacavir liquid formulation will expand antiretroviral options from birth and simplify the clinical management of neonates with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, and the Collaborative Initiative for Paediatric HIV Education and Research Programme.

Pharmacokinetics of Atazanavir Boosted With Cobicistat in Pregnant and Postpartum Women With 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.

Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial.

BACKGROUND: Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. METHODS AND FINDINGS: We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). CONCLUSIONS: In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01061151.

Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial.

OBJECTIVES: We set out to evaluate the effect of postnatal exposure to tenofovir-containing antiretroviral therapy on bone mineral density among breastfeeding women living with HIV. DESIGN: IMPAACT P1084s is a sub-study of the PROMISE randomized trial conducted in four African countries (ClinicalTrials.gov number NCT01066858). METHODS: IMPAACT P1084s enrolled eligible mother-infant pairs previously randomised in the PROMISE trial at one week after delivery to receive either maternal antiretroviral therapy (Tenofovir disoproxil fumarate / Emtricitabine + Lopinavir/ritonavir-maternal TDF-ART) or administer infant nevirapine, with no maternal antiretroviral therapy, to prevent breastmilk HIV transmission. Maternal lumbar spine and hip bone mineral density were measured using dual-energy x-ray absorptiometry (DXA) at postpartum weeks 1 and 74. We studied the effect of the postpartum randomization on percent change in maternal bone mineral density in an intention-to-treat analysis with a t-test; mean and 95% confidence interval (95%CI) are presented. RESULTS: Among 398/400 women included in this analysis, baseline age, body-mass index, CD4 count, mean bone mineral density and alcohol use were comparable between study arms. On average, maternal lumbar spine bone mineral density declined significantly through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference (95%CI) -2.86 (-4.03, -1.70) percentage points (p-value <0.001). Similarly, maternal hip bone mineral density declined significantly more through week 74 in the maternal TDF-ART compared to the infant nevirapine arm; mean difference -2.29% (-3.20, -1.39) (p-value <0.001). Adjusting for covariates did not change the treatment effect. CONCLUSIONS: Bone mineral density decline through week 74 postpartum was greater among breastfeeding HIV-infected women randomized to receive maternal TDF-ART during breastfeeding compared to those mothers whose infants received nevirapine prophylaxis.

Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092.

BACKGROUND: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. MATERIALS AND METHODS: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC0-12h) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. RESULTS: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) -3.4 (IQR -4.0, -3.0) and 27 non-SAM had median WHZ -1.0 (IQR -1.8, -0.1). No significant differences in mean AUC0-12h or CL/F were observed (P ≥ 0.09) except for lower 3TC AUC0-12h (GMR, 0.60; 95% CI, 0.4-1.0; P = 0.047) at week 12, higher ZDV AUC0-12h (GMR, 1.52; 1.2-2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). CONCLUSION: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.

Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV.

BACKGROUND: Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity. METHODS: 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. RESULTS: From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. CONCLUSIONS: Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.

Pregnancy Outcomes of Women Conceiving on Antiretroviral Therapy (ART) Compared to Those Commenced on ART During Pregnancy.

BACKGROUND: Globally, the number of infected women of childbearing age living with human immunodeficiency virus (HIV) and conceiving on antiretroviral therapy (ART) is increasing. Evidence of ART safety at conception and during pregnancy and adverse pregnancy outcomes remains conflicting. The Promoting Maternal and Infant Survival Everywhere (PROMISE) 1077 breastfeeding (BF) and formula feeding (FF) international multisite trials provide an opportunity to examine the impact of ART at conception on pregnancy outcomes with subsequent pregnancies. METHODS: The PROMISE 1077BF/1077FF trials were designed to address key questions in the management of HIV-infected women who did not meet clinical guidelines for ART treatment during the time of the trials. After the period of risk of mother-to-child transmission was over, women were randomized to either continue or discontinue ART. We compared subsequent pregnancy outcomes of nonbreastfeeding women randomized to continue ART following delivery, or breastfeeding women randomized to continue ART following breastfeeding cessation who conceived while on ART to women randomized to discontinue ART, who restarted ART after pregnancy was diagnosed. RESULTS: Pregnancy outcomes of 939 subsequent pregnancies of 826 mothers were recorded. The intention-to-treat analyses showed increased incidence of low birth weight (<2500 g) for women who conceived while on ART (relative risk, 2.65 [95% confidence interval {CI}, 1.20-5.81]), and also a higher risk of spontaneous abortion, stillbirth, or neonatal death (hazard ratio, 1.40 [95% CI, .99-1.98]) compared to women who restarted ART after they were found to be pregnant during trial follow-up. CONCLUSIONS: We found an increased risk for adverse pregnancy outcomes in women conceiving on ART, emphasizing the need for improved obstetric and neonatal care for this group. CLINICAL TRIALS REGISTRATION: NCT01061151.

Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

Brief Report: Impact of ART on Maternal Health After Cessation of Breastfeeding.

ABSTRACT: IMPAACT PROMISE 1077BF/FF was a sequentially randomized study of pregnant and postpartum women living with HIV to investigate the efficacy and safety of antiretroviral therapy (ART). This Maternal Health Component investigated efficacy for the risk of developing AIDS or death; and safety among women randomized to continue ART (CTART: N = 289) or discontinue ART (N = 268) after cessation of breastfeeding or after confirmation of infant infection. No AIDS-defining illnesses were reported during follow-up in either arm. Adverse events of grade 3 or higher were more frequent in the CTART arm [hazard ratio = 1.78, 95% confidence interval: (1.05 to 3.02), P-value = 0.03]. The difference in adverse events in the 2 groups was mostly driven by moderate weight loss for women on the CTART arm.

Advanced imaging tools for childhood tuberculosis: potential applications and research needs.

Tuberculosis is the leading cause of death globally that is due to a single pathogen, and up to a fifth of patients with tuberculosis in high-incidence countries are children younger than 16 years. Unfortunately, the diagnosis of childhood tuberculosis is challenging because the disease is often paucibacillary and it is difficult to obtain suitable specimens, causing poor sensitivity of currently available pathogen-based tests. Chest radiography is important for diagnostic evaluations because it detects abnormalities consistent with childhood tuberculosis, but several limitations exist in the interpretation of such results. Therefore, other imaging methods need to be systematically evaluated in children with tuberculosis, although current data suggest that when available, cross-sectional imaging, such as CT, should be considered in the diagnostic evaluation for tuberculosis in a symptomatic child. Additionally, much of the understanding of childhood tuberculosis stems from clinical specimens that might not accurately represent the lesional biology at infection sites. By providing non-invasive measures of lesional biology, advanced imaging tools could enhance the understanding of basic biology and improve on the poor sensitivity of current pathogen detection systems. Finally, there are key knowledge gaps regarding the use of imaging tools for childhood tuberculosis that we outlined in this Personal View, in conjunction with a proposed roadmap for future research.