Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.

OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.

Vitamin D deficiency is common among HIV-infected breastfeeding mothers in Pune, India, but is not associated with mother-to-child HIV transmission.

A recent report from Tanzania demonstrated an increased risk of being HIV infected or of dying at birth among children born to breastfeeding mothers with low baseline vitamin D levels. We conducted a nested case-control study among HIV-infected pregnant women in western India to confirm the association between maternal vitamin D levels and mother-to-child transmission (MTCT) of HIV. Vitamin D insufficiency and deficiency were common among HIV-infected pregnant women, but were not associated with mother to child HIV transmission at 1 year postpartum (adjusted odds ratio [AOR], 0.66; 95% CI, 0.30-1.45; P = .30).

Maternal tuberculosis: a risk factor for mother-to-child transmission of human immunodeficiency virus.

BACKGROUND: Maternal human immunodeficiency virus (HIV) RNA load, CD4 cell count, breast-feeding, antiretroviral use, and malaria are well-established factors associated with mother-to-child transmission (MTCT) of HIV; the role of maternal tuberculosis (TB), however, has not been well established. METHODS: The study population was 783 HIV-infected Indian mother-infant pair participants in randomized and ancillary HIV-infected cohorts of the Six Week Extended-Dose Nevirapine (SWEN) Study, a study comparing extended nevirapine versus single-dose nevirapine, to reduce MTCT of HIV among breast-fed infants. Using multivariable logistic regression, we assessed the impact of maternal TB occurring during pregnancy and through 12 months after delivery on risk of MTCT. RESULTS: Of 783 mothers, 3 had prevalent TB and 30 had incident TB at 12 months after delivery. Of 33 mothers with TB, 10 (30%) transmitted HIV to their infants in comparison with 87 of 750 mothers without TB (12%; odds ratio [OR], 3.31; 95% confidence interval [CI], 1.53-7.29; P = .02). In multivariable analysis, maternal TB was associated with 2.51-fold (95% CI, 1.05-6.02; P = .04) increased odds of HIV transmission adjusting for maternal factors (viral load, CD4 cell count, and antiretroviral therapy) and infant factors (breast-feeding duration, infant nevirapine administration, gestational age, and birth weight) associated with MTCT of HIV. CONCLUSIONS: Maternal TB is associated with increased MTCT of HIV. Prevention of TB among HIV-infected mothers should be a high priority for communities with significant HIV/TB burden.

Symptom screening among HIV-infected pregnant women is acceptable and has high negative predictive value for active tuberculosis.

We evaluated tuberculosis (TB) screening among 799 human immunodeficiency virus (HIV)-infected pregnant women in India. Eleven (1.4%) had active TB. The negative predictive value of screening using cough, fever, night sweats, or weight loss was 99.3%. Tuberculin skin test and targeted chest radiography provided no substantial benefit. TB symptom screening, as recommended by the World Health Organization, is effective for ruling out TB in HIV-infected pregnant women.

Impact of maternal human immunodeficiency virus infection on pregnancy and birth outcomes in Pune, India.

Little is known about birth outcomes for HIV-infected women in India. We examine maternal and neonatal birth outcomes in HIV-infected women within the context of enhanced pre-natal care associated with a randomized clinical trial conducted in Pune, India. Birth outcomes of 212 HIV-infected pregnant women were compared with those of 130 HIV-uninfected pregnant women attending a government tertiary care hospital between 2002 and 2004. These women and children were participating in the Six Week Extended-Dose Nevirapine (SWEN) study. Birth outcomes and maternal morbidity data were collected at delivery. We found no differences between HIV-infected and uninfected pregnant women with respect to the proportion with elevated intrapartum blood pressure, eclampsia, oligohydramnios, intrauterine growth restriction (IUGR), preterm delivery, or caesarean section (p>0.05). HIV-infected women were more likely to have peri-partum fever (3% versus 0%, p=0.04). There were no differences in neonatal parameters such as low birth weight (LBW), infants who were small for gestational age, or those having congenital anomalies (p>0.05). Compared with infants of HIV-infected women enrolled antenatally, infants of HIV-infected women enrolled in the post-partum ward had a higher risk of pre-term delivery (20% versus 8%, p=0.02) and LBW (41% versus 22%, p=0.002). HIV-infected women in this cohort in India were not found to have significant negative birth outcomes. Antenatal care was important as those not having received any antenatal care prior to deliver were at increased risk of having a pre-term delivery or an infant with LBW. Based on these data, regular antenatal care provided to HIV-infected women can reduce risk of adverse birth outcomes for their infants.

Pregnancy differentially impacts performance of latent tuberculosis diagnostics in a high-burden setting.

BACKGROUND: Targeted screening for latent TB infection (LTBI) in vulnerable populations is a recommended TB control strategy. Pregnant women are at high risk for developing TB and likely to access healthcare, making pregnancy an important screening opportunity in developing countries. The sensitivity of the widely-used tuberculin skin test (TST), however, may be reduced during pregnancy. METHODS: We performed a cross-sectional study comparing the TST with the QuantiFERON Gold In-tube (QGIT) in 401 HIV-negative women presenting antepartum (n = 154), at delivery (n = 148), or postpartum (n = 99) to a government hospital in Pune, India. A subset of 60 women enrolled during pregnancy was followed longitudinally and received both tests at all three stages of pregnancy. RESULTS: The QGIT returned significantly more positive results than the TST. Of the 401 women in the cross-sectional study, 150 (37%) had a positive QGIT, compared to 59 (14%) for the TST (p<0.005). Forty-nine (12%) did not have their TST read. Of 356 who had both results available, 46 (13%) were concordant positive, 91 (25%) were discordant (12 (3%) TST+/QGIT-; 79 (22%) TST-/QGIT+), and 206 (57%) concordant negative. Comparison by stage of pregnancy revealed that QGIT percent positivity remained stable between antepartum and delivery, unlike TST results (QGIT 31-32% vs TST 11-17%). Median IFN-γ concentration was lower at delivery than in antepartum or postpartum (1.66 vs 2.65 vs 8.99 IU/mL, p = 0.001). During postpartum, both tests had significantly increased positives (QGIT 31% vs 32% vs 52%, p = 0.01; TST 17% vs 11% vs 25%, p<0.005). The same trends were observed in the longitudinal subset. CONCLUSIONS: Timing and choice of LTBI test during pregnancy impact results. QGIT was more stable and more closely approximated the LTBI prevalence in India. But pregnancy stage clearly affects both tests, raising important questions about how the complex immune changes brought on by pregnancy may impact LTBI screening.