IMPAACT 2001 STUDY Mhembere T.P. (B. Pharm (Hons), MPH) A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and Postpartum Women with Latent Tuberculosis Infection IMPAACT 2001 STUDY Mhembere T.P. (B. Pharm (Hons), MPH)

GLOBAL TB BURDEN In 2015, there were an estimated 10.4 million new (incident) TB cases worldwide, of which 5.9 million (56%) were among men, 3.5 million (34%) among women and 1.0 million (10%) among children. People living with HIV accounted for 1.2 million (11%) of all new TB cases in 2015.

LATENT TB Latent Tuberculosis Infection (LTBI) is defined as a state of persistent immune response to Mycobacterium tuberculosis without clinically-manifested evidence of active TB disease 2016 WHO Global TB Report

LATENT TB

RISK FACTORS FOR DEVELOPING TB DISEASE FROM LTBI Risk factors for developing TB disease from LTBI include: •HIV infection •Infection with TB bacteria in the last 2 years •Children under 5years •Diabetes mellitus •Immune suppression •Previous incomplete treatment for TB in the past

LATENT TB & PREGNANCY Physiological changes during pregnancy and the postpartum period may increase risk of LTBI reactivation Prevention of active TB in mother = prevention of TB in children Negative sequalae on maternal-child health Increased maternal and infant mortality Adverse pregnancy outcomes (LBW, SGA) Infant TB, increased maternal-infant HIV transmission Singh CID 2007; Zenner AJRCCM 2011 Gomes Thorax 2011; Anderson Clin Pharmacokinet 2005; Wadelius Clin Pharmacokinet 1997; Jana NEJM 1999; Chih H-C BJOG 2010; Khan AIDS 2001; Pillay Lancet ID 2000; Gupta CID 2007; Gupta JID 2011;

LATENT TB REACTIVATION PREVENTION WHO: 6-month isoniazid 9-month isoniazid 3-month regimen of weekly rifapentine plus isoniazid 3–4 months isoniazid plus rifampicin, 3–4 months rifampicin alone. Zimbabwe National TB Guidelines 2016: 6-month isoniazid

LATENT TB TREATMENT: INH & RPT TB Trials Consortium (TBTC) Study 26/ ACTG 5259: 3mo of directly observed once-weekly rifapentine (RPT) (900mg) plus INH (900mg) (3HP) VS 9mo of self-administered daily INH (300mg) (9H) 3HP (3mo Rifapentine + Isoniazid) was as effective as standard 9H regimen and was associated with a higher completion rate (82% versus 69%) and less drug-related hepatotoxicity (0.4% versus 2.7%). 3HP regimen better tolerated in HIV-1- infected participants compared to HIV-1-uninfected participants.

LATENT TB TREATMENT: INH & RPT 2.TB Trials Consortium (TBTC) Study 26 [Paediatric Cohort]: Trial in children and adolescents to assess safety and efficacy of 3HP versus 9H regimen. 3HP resulted in higher adherence rates (88% in 3HP vs81% in 9H). Importantly, neither arm exhibited any hepatotoxicity, Grade 4 adverse events or treatment-attributed deaths. 0 of the children in the 3HP arm developed active TB versus 3 (0.74%) of the children in the 9H arm.

IMPAACT 2001 QUESTION Rifapentine + Isoniazid 3months to prevent LTB reactivation: i) How do pregnancy induced physiological changes affect metabolism, function and disposition ? ii) Is it safe in pregnancy ? iii) Is it safe during breastfeeding?

STUDY DESIGN Prospective, open-label, multi- centre study HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants, enrolled in two cohorts based on gestation: • Cohort 1: Enrolled in second trimester (14 to <28 weeks) • Cohort 2: Enrolled in third trimester (28 to ≤34 weeks) 82 pregnant women (and their infants) will be enrolled to yield a minimum of 25 evaluable women in each cohort 12 DOT once-weekly doses of RPT (900mg) and INH (900mg) taken with pyridoxine 50mg. Each woman will be followed through pregnancy up to 24 weeks postpartum.

STUDY DRUGS Rifapentine (RPT) 900 mg (6 x 150 mg tablets) under directly observed therapy once-weekly for 12 weeks Isoniazid (INH) 900 mg (3 x 300 mg tablets) under directly observed therapy once-weekly for 12 weeks Pyridoxine 50mg once-weekly in conjunction with RPT+ INH

PRIMARY OBJECTIVES To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the second trimester and third trimester who are receiving once-weekly RPT To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once weekly for 12 weeks in pregnant women. To describe the infant safety outcomes among infants born to women receiving once-weekly RPT + INH.

INCLUSION CRITERIA ≥ 18 years, Informed Consent Pregnancy with estimated gestational age ≥ 14 through ≤ 34 weeks. Has at least one of the following risk factors for LTB: (1)Participant is a household contact of known active pulmonary TB patient (2)Confirmed HIV-1 infection and positive Tuberculin Skin Test

EXCLUSION CRITERIA Evidence of confirmed or probable active TB disease History of active TB in the past 2 years Previous treatment for LTBI. Documentation of multi-drug resistant (MDR) or extensively drug resistant (XDR) TB (history/ contact) Known major fetal abnormality as detected on ultrasound

SUMMARY TB disease is problematic globally and locally Pregnant/ postpartum women with LTBI have ↑risk of developing TB Standard LTBI regimen of 6-9 months daily INH has low completion rates and some hepatotoxicity Regimen of 3 months weekly INH + RPT has shown ↑completion rates, ↓hepatotoxicity and safety in HIV-1-infected populations. IMPAACT 2001 will provide data needed to extend use of 3 months weekly Isoniazid+ Rifapentine to pregnant women.

CURRENT STUDY STATUS 7 International Sites participating. Harare Site to enrol 10 of 82 participants. Approval from all IRBs received Protocol registered with sponsor Received activation from protocol team (02 May 17)

ACKNOWLEDGEMENTS IMPAACT NETWORK UZ-UCSF SITE LEADERSHIP HARARE FAMILY CARE CRS STAFF IMPAACT COMMUNITY ADVISORY BOARD