This study is being done because TB is a major cause of illness and death in women of reproductive age. In countries where TB is common, up to half of all women are infected with TB. There are two types of TB that may occur when exposed to TB. In one type, people may become sick with symptoms such as cough and fever and these people are also contagious, meaning they can pass TB to other people. This type of TB is known as active TB disease. In the other type, people do not become sick or contagious, but they still have TB in an inactive form. This inactive form is known as latent TB. If latent TB is not treated, it can become active TB, and this often happens for women around the time of pregnancy. Maternal TB can be passed on to the babies causing illness or death. There are medicines that help prevent latent TB from becoming active TB. These medicines, Rifapentine and Isoniazid are widely used by people who are not pregnant. The purpose of this study is to test how these medicines are taken up in the body also called pharmacokinetic tests (PK), how they are tolerated and the safety of the medicines for pregnant women and their babies.

This is a multi-center study that will enroll HIV-1-infected and HIV-1- uninfected pregnant women with latent TB infection and their infants. Women will be enrolled into two cohorts based on gestation and started on RPT and INH once weekly for 12 weeks (at Entry and 11 weekly follow-up visits). Women in Cohort 1 will be enrolled at a pregnancy gestation between 14 and < 28 weeks; women in Cohort 2 will be enrolled at a pregnancy gestation between 28 to 34 weeks. In total across all study sites, up to 82 pregnant women will be enrolled to yield 50 evaluable women (a minimum of 25 evaluable women in each cohort) and their infants. Women are considered evaluable if they contribute any data to the PK sampling collections or complete the study drug regimen. The Kericho site will recruit up to 20 participants and after completing the study drug regimen, participants will be followed until 24 weeks postpartum then they are transitioned to the primary health care providers. The study will benefit the society by informing practice on appropriate use of these medicines in pregnant and postpartum women for prevention of active TB disease. It is anticipated that this study will generate useful data to help inform next steps for an amendment to this protocol or a separate future study.

Participants will be informed of all potential risks from the treatment that they will receive which involve the side effects of medicine to be given. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection. Taking TB preventative medicine, as well as vitamin B6, may provide a benefit to the mother and her infant. Furthermore, early detection of TB may be a benefit and would help prevent transmission of TB to the infant. Participants will receive clinical examination, laboratory testing, and TB signs and symptoms counseling. For other medical conditions identified as part of the study screening and/or follow-up procedures, participants will be managed at KEMRI WRP CRC or referred to other sources of care available in the community

Tuberculosis (TB) is one of the most important global health problems. Kenya is ranked 15th among the 22 high TB burden countries that account for 80% of the global TB burden. An estimated two billion persons carry latent Mycobacterium tuberculosis (MTB). Treatment of latent tuberculosis infection (LTBI) is critical to global tuberculosis control and elimination. Pregnant women are at increased risk of progressing from latent LTBI to active tuberculosis because pregnancy suppresses the immune response. Symptoms of active TB may not be seen until after delivery, when the immune suppression reverses and symptoms are exacerbated. The World Health Organization (WHO) currently recommends treating LTBI with daily isoniazid (INH) for all HIV- infected pregnant women, but few programs have implemented this policy. Adherence and toxicity concerns remain the main barriers to treatment. Pregnancy and infant outcomes of women taking isoniazid for active TB treatment are comparable to normal pregnant women not receiving TB treatment, but toxicity concerns persist due to the suboptimal quality of existing studies. The US Centers for Disease Control and Prevention (CDC) recommends the use of either nine months of daily isoniazid monotherapy or a newer regimen of three months of weekly isoniazid and rifapentine (RPT) which is recommended in otherwise healthy patients over the age of 12 years who have LTBI. Though the CDC states that the regimen can be considered in other populations when it offers “practical advantages,” the regimen is not recommended in pregnant women, because the safety of the regimen in pregnancy is unknown. This study aims to address this gap in knowledge. This study aims to evaluate the pharmacokinetics, safety and tolerability of RPT and INH dosed once weekly for 12 doses in HIV-1 infected and HIV-1 uninfected pregnant women with latent TB infection at high risk for development of TB. The study will also describe the safety infant outcomes among infants born to women receiving once weekly RPT/INH. HIV-1 infected and HIV-1 uninfected pregnant women with latent TB and their infants will be enrolled into two cohorts based on gestation and started on RPT and INH once weekly for 12 weeks. Women in Cohort 1 will be enrolled in the second trimester of pregnancy (≥14 to <28 weeks); women in Cohort 2 will be enrolled in the third trimester of pregnancy (≥28 to ≤34 weeks). The Kericho site will recruit up to 20 participants and after completing the study drug regimen, participants will be followed until 24 weeks postpartum. This study is to inform practice on appropriate use of this regimen in pregnant and postpartum women that achieves concentrations similar to non-pregnant adults, in whom efficacy has been established. It is anticipated that this study will generate useful PK data to help inform next steps for an amendment to this protocol or a separate future study.