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BackgroundPregnancy 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.Methods944 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.ResultsFrom 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.ConclusionsDecreased 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.

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.

Introduction Western-constructed neuropsychological tests have been used in low- and middle-income countries to assess the impact of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and other chronic illnesses. We explore using such instruments cross-culturally in a sub-Saharan African setting. Methods IMPAACT P1104S was a 2-year observational study performed at six clinical sites (South Africa—three sites, Malawi, Uganda, and Zimbabwe) to assess and compare neuropsychological outcomes in three cohorts of children between the ages of 5 and 11 years: HIV-infected (HIV), HIV-exposed but uninfected (HEU), and HIV unexposed and uninfected (HU). Descriptive statistics compared sociodemographic characteristics among children at sites. Instruments included the Kaufman Assessment Battery for Children, 2nd edition (KABC-II) cognitive ability, Test of Variables of Attention (TOVA) attention/impulsivity, Bruininks–Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2) motor proficiency tests, and Behavior Rating Inventory for Executive Function (BRIEF) executive function problems. Test characteristics were assessed using intraclass and Spearman's nonparametric correlations, linear regression, and principal factor analyses. Results Of the 611 participants, 50% were males and mean age ranged from 6.6 to 8 years. In Malawi, Uganda, and Zimbabwe, substantial proportions of families lived in rural settings in contrast to the South African sites. Intraclass correlation coefficients between weeks 0 and 48 were highest for the KABC scores, ranging between 0.42 and 0.71. Correlations among similar test domains were low to moderate but significant, with positive correlation between KABC sequential and TOVA scores and negative correlation between BRIEF and KABC scores. TOVA response time scores correlated negatively with the BOT-2 total points score. Strong and significant associations between individual measures of growth, disability, and development with all test scores were observed. Performance-based measures were markedly lower for HIV compared with HEU and HU participants, even after controlling for age, sex, and site. Factor analyses confirmed the underlying theoretical structure of the KABC scaled item scores. Conclusion The KABC, TOVA, BRIEF, and BOT-2 were valid and reliable tools for assessing the neuropsychological impact of HIV in four sub-Saharan African countries.

Background. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial. Methods. Human immunodeficiency virus (HIV)–infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring. Results. As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3–6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37–2.65) but not death alone (aHR, 1.65; 95% CI, .72–3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses. Conclusions. These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00307151","term_id":"NCT00307151"}}NCT00307151.