Prevalence of neurotoxicity symptoms among postpartum women on isoniazid preventive therapy and efavirenz-based treatment for HIV: an exploratory objective of the IMPAACT P1078 randomized trial.

BACKGROUND: This exploratory analysis investigates the prevalence and risk factors of neurocognitive toxicity in postpartum women on HIV treatment in response to a concern of an Isoniazid Preventive Therapy (IPT)/Efavirenz interaction. TRIAL DESIGN: Pregnant women on HIV treatment from countries with high TB prevalence were randomized in IMPAACT P1078 to 28 weeks of IPT started either during pregnancy or at 12 weeks postpartum. Partway through study implementation, the Patient Health Questionnaire 9, the cognitive complaint questionnaire, and the Pittsburg Sleep Quality Index were added to evaluate depression, cognitive function, and sleep quality at postpartum weeks. Screening for peripheral neuropathy was conducted throughout the study. METHODS: We summarized percentages of women with depression symptoms, cognitive dysfunction, poor sleep quality and peripheral neuropathy and assessed the association of 11 baseline risk factors of neurotoxicity using logistic regression, adjusted for gestational age stratum. RESULTS: Of 956 women enrolled, 749 (78%) had at least one neurocognitive evaluation. During the postpartum period, the percentage of women reporting at least mild depression symptoms, cognitive complaint and poor sleep quality peaked at 13%, 8% and 10%, respectively, at 12 weeks, and the percentage of women reporting peripheral neuropathy peaked at 13% at 24 weeks. There was no evidence of study arm differences in odds of all four neurotoxic symptoms. CONCLUSIONS: Timing of IPT initiation and EFV use were not associated with symptoms of neurotoxicity. Further study is advised to formally assess risk factors of neurotoxicity.

Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.

BACKGROUND: Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy. METHODS: IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics. RESULTS: Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants. CONCLUSIONS: 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT02651259.

Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women.

BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).

Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women.

BACKGROUND: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions. METHODS: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. RESULTS: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53). CONCLUSIONS: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).

Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus.

BACKGROUND: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors' associations and effect modifications with IPT and pregnancy outcomes were examined. METHODS: Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed. RESULTS: This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15-2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14-2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22-2.49). CONCLUSIONS: We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes.

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.

A framework for considering the risk-benefit trade-off in designing noninferiority trials using composite outcome approaches.

When a new treatment regimen is expected to have comparable or slightly worse efficacy to that of the control regimen but has benefits in other domains such as safety and tolerability, a noninferiority (NI) trial may be appropriate but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize composite risk-benefit outcomes that combine elements from domains of importance (eg, efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can be used as a tool at the design stage of a NI trial for selecting an NI margin for efficacy that balances changes in risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable decrease in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given an assumed distribution for the composite outcome. We observe that MADE: (1) is larger when the safety improvement for the experimental arm is larger, (2) depends on the association between the efficacy and safety outcomes, and (3) depends on the control arm efficacy rate. We use a numerical example for power comparisons between a superiority test for the composite outcome vs a noninferiority test for efficacy using the MADE as the NI margin, and apply the methods to a TB treatment trial.

Applying a Risk-benefit Analysis to Outcomes in Tuberculosis Clinical Trials.

Although it is common to analyze efficacy and safety separately in clinical trials, this could yield a misleading study conclusion if an increase in efficacy is accompanied by a decrease in safety. A risk-benefit analysis is a systematic approach to examine safety and efficacy jointly. Both the "rank-based" and "partial-credit" methods described in this paper allow researchers to create a single, composite outcome incorporating efficacy, safety, and other factors. The first approach compares the distribution of rankings between arms. In the second approach, a score can be assigned to each outcome category, considering its severity and comparing the mean or median scores of arms. The methods were applied to the A5279/Brief Rifapentine-Isoniazid Efficacy for TB Prevention study, and design considerations for future clinical trials are discussed, including the challenge of arriving at a consensus on rankings/scorings. If well designed, a risk-benefit analysis may allow for a superiority comparison and, therefore, avoid setting a noninferiority margin. Clinical Trials Registration. NCT01404312 (A5279).

Viral hepatitis B and C in HIV-exposed South African infants.

BACKGROUND: Whilst much attention is given to eliminating HIV mother-to-child transmission (MTCT), little has been done to ensure the same for hepatitis B virus (HBV) transmission. The introduction of HBV immunization at six weeks of age has reduced HBV horizontal transmission in South Africa. However, in order to eliminate HBV MTCT, further interventions are needed. The risk of hepatitis C virus (HCV) MTCT in HIV-infected (HIV+) African women is not yet well described. This study aimed to determine the rate of HBV and HCV vertical transmission in HIV-exposed infants in South Africa. METHODS: Serum samples from infants enrolled in an isoniazid prevention study (P1041) were screened for HBV and HCV serology markers; screening was performed on samples collected at approximately 60 weeks of age of the infants. HBV DNA was quantified in HBsAg positive samples and HBV strains characterized through gene sequencing. All HCV antibody samples with inconclusive results underwent molecular testing. RESULTS: Three of 821 infants were positive for both HBsAg and HBV DNA. All HBV strains belonged to HBV sub-genotype A1. The rtM204I mutation associated with lamivudine resistance was identified in one infant, a second infant harboured the double A1762T/G1764A BCP mutation. Phylogenetic analysis showed clustering between mother and infant viral genomic sequences. Twenty-one of 821 HIV-exposed infants tested had inconclusive HCV antibody results, none were HCV PCR positive. CONCLUSIONS: This study suggests that HBV vertical transmission is likely to be occurring in HIV-exposed infants in South Africa.. A more robust strategy of HBV prevention, including birth dose vaccination, is required to eradicate HBV MTCT. HCV infection was not detected.

Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis.

BACKGROUND: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. METHODS AND FINDINGS: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. CONCLUSION: Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.

Optimizing the design of a pharmacokinetic trial to evaluate the dosing scheme of a novel tuberculosis drug in children living with or without HIV.

Pharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often, population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel tuberculosis drug delamanid, and show how applications of optimal design methodology can result in highly efficient and model-robust designs in children for estimating PK parameters using a limited number of sampling measurements. Using developed population PK models based on available data from adults living with and without HIV, and limited data on children without HIV, competing designs for children living with HIV were derived and assessed based on robustness to model uncertainty.

Impact of in-utero exposure to HIV and latent TB on infant humoral responses.

Introduction: Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Methods: Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. Results: In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. Discussion: The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination.

Social ecological predictors of longitudinal HIV treatment adherence in youth with perinatally acquired HIV.

OBJECTIVE: To apply a social ecological model to explore the psychosocial factors prospectively associated with longitudinal adherence to antiretroviral treatment in youth perinatally infected with HIV. METHODS: Randomly selected youth, age 8 to <19 years old, completed cognitive testing and psychosocial questionnaires at baseline as part of a multisite protocol (N = 138). A validated caregiver-report measure of adherence was completed at baseline and 24 and 48 weeks after baseline. RESULTS: In multivariate analysis, youth awareness of HIV status, caregiver not fully responsible for medications, low caregiver well-being, adolescent perceptions of poor caregiver-youth relations, caregiver perceptions of low social support, and African American ethnicity were associated with nonadherence over 48 weeks. CONCLUSIONS: Interventions focusing on caregivers and their interactions with the individual youth and extrafamilial system should be prioritized for prevention and treatment efforts to address nonadherence during the transition into adolescents.

Evaluation of tuberculosis diagnostics in children: 2. Methodological issues for conducting and reporting research evaluations of tuberculosis diagnostics for intrathoracic tuberculosis in children. Consensus from an expert panel.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.

Timing of maternal isoniazid preventive therapy on tuberculosis infection among infants exposed to HIV in low-income and middle-income settings: a secondary analysis of the TB APPRISE trial.

BACKGROUND: Infants born to women with HIV in settings with a high tuberculosis burden are at risk of tuberculosis infection and rapid progression to active disease. Maternal isoniazid preventive therapy might mitigate this risk, but optimal timing of therapy remains unclear. The TB APPRISE trial showed that initiation of isoniazid during pregnancy resulted in more frequent adverse pregnancy outcomes than when initiated postpartum. We aimed to determine the proportion of infants testing positive for tuberculosis infection born to mothers who initiated isoniazid therapy antepartum compared with postpartum using two commonly used tests, the test agreement, and predictors of test positivity. METHODS: TB APPRISE was a randomised, double-blind, placebo-controlled, non-inferiority trial done at 13 study sites across eight countries (Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda, and Zimbabwe). Pregnant women with HIV on antiretroviral therapy were randomly assigned to receive immediate isoniazid preventive therapy (28 weeks isoniazid [300 mg daily], then placebo until week 40 after delivery) or deferred treatment (placebo until week 12 after delivery, then isoniazid [300 mg daily] for 28 weeks). Mother-infant pairs were followed up until 48 weeks after delivery. We included all liveborn infants with a tuberculin skin test or interferon-γ release assay (IGRA) at 44 weeks. The outcomes assessed in this secondary analysis were tuberculosis test positivity by study group, test agreement, and predictors of test positivity. This study was registered with ClinicalTrials.gov, NCT01494038. FINDINGS: Between Aug 19, 2014, and April 4, 2016, 956 mothers were randomly assigned, and 749 mother-child pairs were included in this secondary analysis. Of 749 infants, 694 (93%) received Bacille Calmette-Guérin (BCG) vaccination, 675 (90%) were born to mothers who had completed isoniazid treatment, 20 (3%) were exposed to tuberculosis, seven (1%) became HIV positive, and one (<1%) developed probable tuberculosis. 43 (6%; 95% CI 4-8]) of 732 infants had a positive IGRA test result and 55 (8%; 6-10) of 727 infants had a positive tuberculin skin test result. Test positivity did not differ by study group (p=0·88 for IGRA; p=0·44 for tuberculin skin test). Test agreement was poor (κ=0·107 [95% CI 0·002-0·212]). Infant tuberculin skin test positivity was associated with breastfeeding (adjusted odds ratio 6·63 [95% CI 1·57-27·9]), BCG vaccination (4·97 [1·50-16·43]), and maternal tuberculin skin test positivity at delivery (3·28 [1·70-6·33]); IGRA positivity was associated with female sex (2·09 [1·06-4·14]). INTERPRETATION: Deferral of maternal isoniazid preventive therapy to early postpartum had no effect on infant tuberculosis acquisition in our trial population, regardless of the diagnostic test used; however, tuberculosis test agreement is poor during infancy. FUNDING: US National Institutes of Health.

Effect of pregnancy versus postpartum maternal isoniazid preventive therapy on infant growth in HIV-exposed uninfected infants: a post-hoc analysis of the TB APPRISE trial.

Background: Isoniazid preventive therapy (IPT) initiation during pregnancy was associated with increased incidence of adverse pregnancy outcomes in the TB APPRISE trial. Effects of in utero IPT exposure on infant growth are unknown. Methods: This post-hoc analysis used data from the TB APPRISE trial, a multicentre, double-blind, placebo-controlled trial, which randomised women to 28-week IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT) in eight countries with high tuberculosis prevalence. Participants were enrolled between August 2014 and April 2016. Based on modified intent-to-treat analyses, we analysed only live-born babies who had at least one follow-up after birth and compared time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum in overall and sex-stratified multivariable Cox proportional hazards regression. Factors adjusted in the final models include sex of infant, mother's baseline BMI, age in years, ART regimen, viral load, CD4 count, education, and household food insecurity. Results: Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in pregnancy-IPT had a 1.47-fold higher risk of becoming underweight by 12 weeks (aHR 1.47 [95% CI: 1.06, 2.03]) than infants in the postpartum-IPT; increased risk persisted to 48 weeks postpartum (aHR 1.34 [95% CI: 1.01, 1.78]). Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of low birth weight (LBW) (aRR 2.04 [95% CI: 1.16, 3.68), preterm birth (aRR 1.81 [95% CI: 1.04, 3.21]) and becoming underweight by 12 weeks (aHR 2.02 [95% CI: 1.29, 3.18]) and 48 weeks (aHR 1.82 [95% CI: 1.23, 2.69]). Maternal IPT timing did not influence growth in female infants. Interpretation: Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, particularly male infants. These data add to prior TB APPRISE data, suggesting that IPT during pregnancy impacts infant growth, which could inform management, and warrants further examination of mechanisms. Funding: The TB APPRISE study Supported by the National Institutes of Health (NIH) (award numbers, UM1AI068632 [IMPAACT LOC], UM1AI068616 [IMPAACT SDMC], and UM1AI106716 [IMPAACT LC]) through the National Institute of Allergy and Infectious Diseases, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract number, HHSN275201800001I) and the National Institute of Mental Health.

Coordination of inflammatory responses in children with perinatally acquired HIV infection.

OBJECTIVE: We investigated dynamics of inflammatory biomarkers in children with perinatally acquired HIV (PHIV) who started antiretrovirals at age less than 3 years and achieved sustained virologic control (HIV plasma RNA <400 copies/ml). DESIGN: This was a retrospective analysis of inflammatory biomarkers in children enrolled in a randomized trial of early (<3 years of age) PI-based versus NNRTI-based regimens (P1060), who achieved sustained virologic control and participated in a neurodevelopmental follow-up study (P1104s) between ages 5 and 11 years. METHODS: We measured 20 inflammatory biomarkers using ELISA or chemiluminescence at onset of sustained virologic control (Tc) and at P1104s entry (Te). RESULTS: The 213 participants had median ages of 1.2, 1.9, and 7 years at antiretroviral initiation, Tc, and Te, respectively, with 138 on protease inhibitor-based and 74 on NNRTI-based regimens at Tc. Eighteen markers decreased and two increased from Tc to Te (Te-Tc). Biomarker subsets, particularly cytokines, the chemokine IP-10, and adhesion molecules sICAM-1 and sVCAM-1, correlated at Tc, Te, and Te-Tc. At Tc, higher biomarker levels were associated with younger age, female sex, HIV plasma RNA at least 750 000 copies/ml, lower nadir CD4 + %, lower nadir weight z scores, and NNRTI-based treatment. Greater Te-Tc biomarker declines were associated with younger age, male sex, higher Tc biomarker levels, lower nadir CD4 + %, and NNRTI-based treatment. Duration of controlled viremia and nadir height z scores showed mixed associations. CONCLUSION: Biomarker expression showed substantial coordination. Most markers decreased after virologic control. Demographic and clinical variables associated with biomarker patterns were identified. Mechanistic studies of these biomarker patterns are needed to inform interventions to control inflammation.

Acylcarnitines and Genetic Variation in Fat Oxidation Genes in HIV-infected, Antiretroviral-treated Children With and Without Myopathy.

BACKGROUND: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO). METHODS: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated. RESULTS: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter ( SLC22A5 ), were associated with the cardiomyopathy phenotype. CONCLUSION: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable.