Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women

Breslow (1981, Biometrika 68, 73-84) has shown that the Mantel-Haenszel odds ratio is a consistent estimator of a common odds ratio in sparse stratifications. For cohort studies, however, estimation of a common risk ratio or risk difference can be of greater interest. Under a binomial sparse-data model, the Mantel-Haenszel risk ratio and risk difference estimators are consistent in sparse stratifications, while the maximum likelihood and weighted least squares estimators are biased. Under Poisson sparse-data models, the Mantel-Haenszel and maximum likelihood rate ratio estimators have equal asymptotic variances under the null hypothesis and are consistent, while the weighted least squares estimators are again biased; similarly, of the common rate difference estimators the weighted least squares estimators are biased, while the estimator employing "Mantel-Haenszel" weights is consistent in sparse data. Variance estimators that are consistent in both sparse data and large strata can be derived for all the Mantel-Haenszel estimators.

Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The effect of pregnancy on transport proteins is unknown. Drugs eliminated by non-CYP or non-UGT pathways or multiple pathways will need to be evaluated individually. In conclusion, by evaluating the pharmacokinetic data of a variety of drugs during pregnancy and using a mechanistic-based approach, we can start to predict the effect of pregnancy for a large number of clinically used drugs. However, because of the limitations, more clinical, evidence-based studies are needed to fully elucidate the effects of pregnancy on the pharmacokinetics of drugs.

In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per μL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups. In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. US Centers for Disease Control and Prevention and US Agency for International Development. Copyright © 2011 Elsevier Ltd. All rights reserved.