A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine - PowerPoint Presentation

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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 BURDENIn 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.

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LATENT TBLatent Tuberculosis Infection (LTBI)

is defined as a state of persistent immune response to Mycobacterium tuberculosis without clinically-manifested evidence of active TB disease2016 WHO Global TB Report

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LATENT TB4

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 past5

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;

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LATENT TB REACTIVATION PREVENTIONWHO:6-month isoniazid

9-month isoniazid3-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

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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.

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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.

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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)

I

s it safe during breastfeeding?

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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

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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. 11

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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 weeksPyridoxine 50mg once-weekly in conjunction with RPT+ INH13

PRIMARY OBJECTIVESTo 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.14

INCLUSION CRITERIA≥ 18 years,

Informed ConsentPregnancy with estimated gestational age ≥ 14 through ≤ 34 weeks.

Has at least one of the following risk factors for L

TB

:

(1)Participant

is a household

contact of known active pulmonary TB patient

(2)

Confirmed

HIV-1 infection

and positive Tuberculin Skin Test

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EXCLUSION CRITERIAEvidence of confirmed or probable active TB disease

History of active TB in the past 2 yearsPrevious 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

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SUMMARYTB 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 R

egimen 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

.

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CURRENT STUDY STATUS7 International Sites participating. Harare Site to enrol

10 of 82 participants.Approval from all IRBs receivedProtocol registered with sponsorReceived activation from protocol team (02 May 17)18

ACKNOWLEDGEMENTSIMPAACT NETWORKUZ-UCSF SITE LEADERSHIP

HARARE FAMILY CARE CRS STAFFIMPAACT COMMUNITY ADVISORY BOARD19

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