P1078: A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid Preventive Therapy Among HIV-Infected Women in High TB Incidence Settings

This is a clinical trial conducted under the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network and funded by the U.S. National Institutes of Health.

Dr. Amita Gupta is Protocol Chair for this multinational clinical trial being conducted in Botswana, Haiti, South Africa, Tanzania, Thailand, Uganda, and Zimbabwe, and in India by the Baltimore-Washington-India Clinical Trials Unit, of which CCGHE is a member.

Background

Tuberculosis (TB) is the most important cause of morbidity and mortality among HIV-infected persons residing in high TB burden settings such as sub-Saharan Africa and India. TB predominantly affects women of reproductive age, and when it occurs during pregnancy or early postpartum, it can result in adverse maternal outcomes and infant TB and death. Infant TB is very challenging to diagnose. It is estimated that up to a half of infant TB cases are due to maternal TB disease. While there is no controversy about the need and benefit of treating active TB during pregnancy or benefit of isoniazid (INH) preventive therapy (IPT) to HIV-infected adults, particularly those who are tuberculin skin test (TST) positive, data on the safety and efficacy of administering IPT to HIV-infected pregnant women in the era of antiretroviral therapy (ART) are not available. 

There have been a number of clinical trials involving IPT in HIV-infected adults and HIV-infected or HIV-exposed children. Current guidelines from the World Health Organization (WHO) recommend that all HIV-infected persons residing in low- and middle-income regions where TB is endemic receive at least 6 months of IPT. The guidelines have removed the prior requirement of a positive TST due to difficulties in implementation and have now included a recommendation of IPT to pregnant women and children. However, none of the more than 13 adult IPT trials has included HIV-infected pregnant women, a population that may have a higher risk of adverse events (AEs) and drug-induced liver injury. There remains limited data regarding highly active antiretroviral therapy (HAART) initiation in close approximation with INH but a pragmatic trial conducted in South Africa suggested IPT + HAART was beneficial irrespective of TST status. Pregnant women, however, were excluded from this trial as well.

The optimal timing of IPT in pregnancy remains unknown and this knowledge gap is acknowledged in the WHO guidelines. The US Centers for Disease Control and Prevention (CDC) guidelines and literature to date acknowledge that there is increased toxicity risk of IPT in pregnancy and within 3 months postpartum. Pregnant women also have increased risk of adverse antiretroviral drug toxicity and increased risk of hepatic dysfunction from pregnancy itself. Currently the US Food and Drug Administration (FDA) categorizes INH as category C, meaning that animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Although the WHO guidelines recommend use of IPT in HIV-infected pregnant women, in the absence of safety data, it is unclear if this recommendation will be followed. Furthermore, safety data specific to IPT initiation among pregnant women also initiating HAART are lacking but needed. Small studies have observed that continuing IPT when women become pregnant or initiating IPT in pregnancy is not associated with severe adverse events. However, the Lesotho study, for example, had only liver function test data for 20 of 160 women of whom only a small number were on HAART. HAART is known to have an independent effect on reducing TB incidence but prospective data on the risks and benefits of combining IPT with HAART in pregnancy is unknown. Since some HIV-infected pregnant women may not have latent TB infection (LTBI) and, therefore, may not have significant benefit from IPT, it is important to evaluate the safety of IPT in pregnancy, the optimal timing of IPT in this population, as well as overall efficacy, risk and benefits

Goal

The goal of IMPAACT P1078 is to evaluate whether initiating IPT is safe in HIV-infected pregnant women who may be receiving HAART. This study will also assess the tolerability of IPT in the context of HAART during pregnancy and as secondary objectives include assessment of efficacy of INH, pregnancy and infant outcomes, adherence to INH and ART via hair sampling, pharmacology of INH/HAART and performance of latent TB diagnostics. In addition, the data and samples from this study may allow for novel and important immunologic studies that will provide insights into Mycobacterium tuberculosis (M.tb)-specific responses, LTBI, risk of maternal disease, and risk of infection and disease among infants born to women who have received INH antepartum versus postpartum.