IMPAACT P1078 Chair: Amita Gupta Vice Chairs: Adriana Weinberg, Timothy Sterling (TBTC), Gerhard Theron Statisticians:

1. TB APPRISE: A 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 IMPAACT P1078 Chair: Amita Gupta Vice Chairs: Adriana Weinberg, Timothy Sterling (TBTC), Gerhard Theron Statisticians: Grace Montepiedra, Lisa Aaron Sponsors: NIAID, NICHD Complications Committee Chair: Sharon Nachman

2. TB: a major global problem for maternal child health and HIV morbidity • Globally 9.2 million new cases of TB, with women accounting for 3.6 million cases and 700,000 deaths • TB most common HIV-1 related illness and cause of mortality in women of reproductive age (15-49 years) in Asia and Africa • Women account for up to 70% of HIV-infected adults in sub-Saharan Africa • HIV and TB are independent risk factors for maternal mortality • Maternal TB/HIV important risk factor for poor pediatric birth outcomes, TB and all-cause mortality • Research on optimal methods for early detection and prevention of TB in HIV-infected women needed as it will benefit both maternal and child health (WHO global report 2009 Pillay 2004; Khan 1999; Cotton 2007; Gupta 2007, 2010)

3. INH preventive therapy in HIV-infected adults • 12 TB prevention trials: 5 trials INH vs placebo and 3 trials INH vs. other TB preventive regimens • TB preventive therapy associated with lower incidence of active TB • Overall: RR 0.68 (95% CI 0.54 to 0.85) • TST+ individuals RR 0.38 (95% CI 0.25 to 0.57) • TST - individuals RR 0.89 (95% CI 0.64 to 1.24) • No reduction in overall all cause-mortality but reduction in mortality in TST+ RR 0.74 • NONE INCLUDED PREGNANT WOMEN AT ENTRY AND NONE INCLUDED HAART Akolo Cochrane meta-analysis 2010

4. New WHO guidelines for HIV-infected persons • INH 300mg daily for at least 6 months to all HIV-infected persons in TB endemic countries, NOW INCLUDES PREGNANT WOMEN • Tuberculin skin testing not required • Recommend pyridoxine (vitamin B6) 25mg daily with INH http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf WHO December 2010

5. TB screening • No longer uses TST… • Screening includes: • History of fever • Night sweats • Weight loss (self reported) • Cough • The protocol has been updated to include these screening measures plus: • Failure of adequate weight gain in pregnancy • Duration of symptoms

6. 2010 WHO IPT Guidelines Statement for Pregnant Women Living with HIV • Pregnant women living with HIV are at risk of TB • impact to maternal and perinatal outcomes • The guideline group stressed the importance of screening pregnant women living with HIV for TB using clinical algorithm.   • …concluded that existing evidence and experience in the pre-HIV and HIV era suggest that IPT is safe in pregnant women.   • Therefore, the guideline group strongly recommend that pregnancy should not exclude women living with HIV from symptom based TB screening and receiving IPT. WHO December 2010

7. Unanswered Questions • What is optimal timing of IPT in pregnant and postpartum women • Urgent need for prospective data on: • Safety • Tolerability • Adherence • And effectiveness in combination with ARVs

8. INH safety in pregnancy and post-partum • FDA category C • INH data from pre-HIV and pre-HAART era • Teratogenicity: none based on existing human data • Association of INH and hemorrhagic disease in newborn suggested in one study but not confirmed in other reports (some recommend prophylactic vitamin K recommended at birth but generally not done) • Hepatotoxicity • Abnormal liver enzymes (AST/ALT) :1-25% • Symptomatic liver disease 5.2 per 1000 patients in a study where 20,838 given INH for 12 mo. • 20 deaths in CA, 4 were in women who had started INH in pregnancy (Mouldings 1989) • 2.5 fold increased hepatoxicity and 4-fold increased death in pregnant women but not statistically significant (Francks 1989) • Risk factors pregnancy, first 3 months postpartum, possibly HIV, alcohol, underlying liver disease including chronic Hep B, age, ?HAART • Breast milk: safe. Concentration 6.4-25% Francks 1989; Mouldings 1989; Brost 1995; Ouyang 2009; Singh 2008

9. Pros More likely to prevent maternal and infant TB Compliance and follow-up may be better Cons Potential increased toxicities for mother and fetus/infant when started in antepartum Antepartum INH EVIDENCE NEEDED TO CONVINCE PROVIDERS AND PROGRAMS

10. HIV-infected pregnant woman, ≥14 through ≤34 weeks gestation TB Screening, Rule out active TB YES Refer to local TB program for evaluation and TB treatment; not eligible for study Active TB Suspected OR Documented NO Woman meets other eligibility criteria ARM B: Deferred INH Placebo for INH until week 12 postpartum, then INH x 28 weeks ARM A: Immediate INH INH x 28 weeks, then Placebo for INH Enrollment and Randomization Study drugs (INH/Placebo for INH), open label Pyridoxine (vitamin B6) and open label prenatal multivitamin terminated at 40 weeks postpartum End of study, 48 weeks postpartum All women and their infants will receive local standard of care for HIV, PMTCT WHO TB symptom screen on all women at each visit

11. Study Schema cont’d • Sample Size • 950 pregnant women (475/arm) • Allows for 10% loss to follow up • Stratification: • Gestational age • Ia: 14 wks to <24 wks (at least 30%) • Ib: 24 wks to ≤34 wks • HAART • IIa:on HAART at study entry • IIb: not on HAART at entry • Randomization balanced at each CRS

12. Primary Objective and Endpoint • To compare safety of immediate vs. deferred INH preventive therapy in HIV-infected pregnant women enrolled at 14 to ≤34 weeks gestation. Safety of INH will be assessed by comparing rates of Grade ≥3 events possibly, probably, definitely related to INH/placebo or permanent drug discontinuation between women in the immediate and deferred arms by 48 weeks postpartum

13. Secondary Objectives • Safety and toxicity of INH on fetus and infants • Compare TB incidence and all-cause mortality in HIV-infected women and their infants • Evaluate INH resistance • Assess INH and ART PK and pharmacogenomic variants • Performance characteristics of IGRA (Quantiferon Gold in Tube, enhanced ELISPOT) with TST in women and infants • Assess adherence to INH/placebo during pregnancy and postpartum

14. Key Inclusion criteria • HIV+ • Pregnant ≥18 years • if IRB approves and appropriate consent ≥ 13 years • 14-34 weeks gestation • AST (SGOT), ALT (SGPT), and total bilirubin below 1.25 times the upper limit of normal (ULN)

15. Key Exclusion criteria • Positive TB symptom screen or suspected active TB • Acute hepatitis within 90 days prior to entry • Grade ≥1 peripheral neuropathy using BPNS tool • Known active TB exposure within past 12 weeks • INH>30 days in past year • Heavy alcohol exposure • AIDS defining illness treated less than 14 days • Any clinical significant diagnosis that site investigator feels would compromise participation

16. Schedule of evaluations Mothers • Screening • Assess for eligibility and active TB with WHO TB symptom screen, targeted physical, risk exposure • CD4 and screening labs • Entry (after randomization) • start INH/placebo, open label prenatal MVI and Vitamin B6 • PBMC collection for TB ELISPOT • Blinded QGIT • Sample for Hep B and C testing • Q4 week visit until delivery • Delivery (TST and abstraction of delivery data) • Q4 week post partum until week 48 postpartum (week 12 visit important) • Suspected active TB Infants • Birth • Week 4, 8, 12, 24, 36, 48 of life • Suspected active TB or mom diagnosed with TB

17. Details of study evaluations • Entry will occur within 30 days of screening • TB screen at each visit • Safety labs: ALT at every scheduled visit until week 40 postpartum • At approved sites • Stored cells at entry, 12 and 44 weeks postpartum for immunology studies • Intensive PK for 36 women (restricted to women on HAART) • Sample collection for population PK during pregnancy and pharmacogenomic variant associated with toxicity risk (nested case-control) • Urine sample at suspected TB visit and end of study • Infant PBMC and plasma stored samples at 12, 24, 44 weeks and at TB visit, urine at 24, 48 and suspected TB

18. Stage of development • Undergoing Regulatory and budget rereview in response to April 2011 DSMB recommendations • Anticipate Version 1.0 by July 1st • 13 Interested sites:8052 - Soweto (Johannesburg, South Africa) • 8950 - Stellenbosch University (Cape Town, South Africa) • 12701 - Gaborone Prevention / Treatment Trials (Gaborone, Botswana) • 12702 - Molepolole Prevention/Treatment Trials (Molepolole, Botswana) • 20201 - Durban Pediatric (Durban, South Africa) • 30301 - Blantyre College of Medicine (Blantyre, Malawi) • 30303 - St. Mary's (Chitungwiza, Zimbabwe) • 30306 - Seke North (Chitungwiza, Zimbabwe) • 30313 - UZ-Parirenyatwa (Harare, Zimbabwe) • 30273 - George Clinic (Lusaka, Zambia) • 30293 - Makerere University (Kampala, Uganda) • 31441 - BJ Medical College (Pune, India) • 12901- KCM (Moshi, Tanzania)