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Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.

ABSTRACT: While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy.Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review.Among 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1-1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3-1.1 and 1.8, 95% CI 0.9-3.6, resp.).Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.

SUBMITTER: Taylor AW

PROVIDER: S-EPMC3606726 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.

Taylor Allan W AW Mosimaneotsile Barudi B Mathebula Unami U Mathoma Anikie A Moathlodi Ritah R Theebetsile Irene I Samandari Taraz T

Infectious diseases in obstetrics and gynecology 20130307

<h4>Objective</h4>While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy.<h4>Design</h4>Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial ...[more]

PMID: 23533318

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Project description:BackgroundThe dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period.MethodsWe randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization.ResultsAntiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups.ConclusionsPrimary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).

Project description:This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

Project description:BackgroundThe World Health Organization recommends isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) to prevent tuberculosis (TB), including pregnant women. Recent trial results suggest increased adverse pregnancy outcomes associated with IPT during pregnancy. Data are limited regarding programmatic IPT use in pregnant PLHIV.MethodsWe assessed previous programmatic IPT during pregnancy among HIV-infected mothers on enrollment to an infant TB prevention trial in Kenya. Pregnancy IPT use was assessed by the estimated conception date assuming 38 weeks of gestation. Correlates of initiation and completion were analyzed by relative risk regression, using generalized linear models with log link and Poisson family adjusted for IPT initiation year.ResultsBetween August 15, 2016, to June 6, 2018, 300 HIV-infected women enrolled at 6 weeks postpartum. Two hundred twenty-four (74.7%) women reported previous IPT, of whom 155/224 (69.2%) had any pregnancy IPT use. Forty-five (29.0%) initiated preconception extending into early pregnancy, 41 (26.5%) initiated and completed during pregnancy, and 69 (44.5%) initiated in pregnancy and extended into early postpartum. The median gestational age at IPT pregnancy initiation was 15.1 weeks (interquartile range 8.3-28.4). Pregnancy/early postpartum IPT initiation was associated with new pregnancy HIV diagnosis [adjusted relative risk 1.9 95% confidence interval (CI): 1.6 to 2.2, P < 0.001]. Six-month IPT completion rates were high [147/160 (91.9%)] among women with sufficient time to complete before trial enrollment and similar among preconception or during pregnancy initiators [adjusted relative risk 0.93 (95% confidence interval: 0.83 to 1.04, P = 0.19)].ConclusionsProgrammatic IPT use was high in pregnant PLHIV, with frequent periconception and early pregnancy initiation. Programmatic surveillance could provide further insights on pregnancy IPT implementation and maternal and infant safety outcomes.

Project description:BackgroundIntermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).Methods and findingsA total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p=0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p=0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p=0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p=0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p=0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.ConclusionsAn effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.Trial registrationClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary.

Project description:BackgroundWomen living with HIV (WLHIV) are at higher risk of micronutrient deficiencies and adverse health outcomes. There are limited data on the burden or sequelae of micronutrient deficiencies among pregnant WLHIV receiving antiretroviral therapy (ART).ObjectivesWe aimed to examine anemia and vitamin B-12, folate, and vitamin D deficiencies, and their associations with obstetric and infant outcomes, among pregnant WLHIV initiating combination antiretroviral therapy (cART) in rural Uganda.MethodsThis was a prospective analysis among pregnant WLHIV (12-28 weeks of gestation) in PROMOTE-Pregnant Women and Infants (PIs), a randomized trial comparing the effects of protease inhibitor (PI)-based ART with those of a non-PI-based ART on placental malaria risk. We conducted a substudy on the burden of anemia [trimester 1/3: hemoglobin (Hb) <11.0 g/dL; trimester 2: Hb <10.5 g/dL; n = 367] and micronutrient deficiencies (n = 127) in pregnant WLHIV and their associations with obstetric and infant outcomes. Hb was measured by cyanmethemoglobin, vitamin B-12 and folate were measured via electrochemiluminescence, and vitamin D was measured by ELISA. Linear and binomial regression were used to evaluate associations between micronutrient status during pregnancy and perinatal outcomes.Results26.8% women were anemic, 30.2% were vitamin B-12 insufficient (<221.0 pmol/L), 66.1% were folate insufficient (<13.5 nmol/L), and 65.4% were vitamin D insufficient (<30.0 ng/mL) at enrollment. Anemia during pregnancy was associated with a greater risk of small for gestational age (SGA) (RR: 1.88; 95% CI: 1.28, 2.77; P = 0.001); each 1-g/dL decrease in Hb was associated with greater risk of SGA (RR: 0.76; 95% CI: 0.65, 0.90; P = 0.001). Multivariate models showed that increased vitamin D concentrations predicted lower risk of infant wasting (WLZ < -2; RR: 0.94; 95% CI: 0.89, 0.99; P = 0.04). Multivariate models also indicated that maternal vitamin B-12 and folate concentrations at enrollment predicted maternal (P < 0.001) and infant (P = 0.02) concentrations postpartum.ConclusionsAnemia and micronutrient deficiencies are associated with a variety of adverse obstetric and infant outcomes and are an important public health concern in perinatal WLHIV on cART and their children.This trial was registered at clinicaltrials.gov as NCT00993031.

Project description:ImportanceAntiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined.ObjectiveTo assess pregnancy incidence and outcomes among women using PrEP during the periconception period.Design, setting, and participantsRandomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda.InterventionsDaily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected.Main outcomes and measuresPregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth.ResultsA total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% CI, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, -5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, -4.6%; 95% CI, -18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, -16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo.Conclusions and relevanceAmong HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant.Trial registrationclinicaltrials.gov Identifier: NCT00557245.

Dataset Information

Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.

Publications

Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.

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