LTBI Treatment in Pregnancy

Sylvia LaCourse MD, MPHUniversity of Washington

End TB 2019: Union-NAR ConferenceFebruary 22, 2019

DeLuca JAIDS 2009

Majority of TB cases in women occur during years of child-bearing potential

Global TB in Women

Global TB in Pregnancy

Sugarman Lancet Glob Health 2014

Data not routinely collected:Based on total population, crude birth rates, age distribution, case notification by age/sex

26.6 cases/100,000 pregnancies?!?

El-Messidi AJOG 2016

US TB Epidemiology in Pregnancy (?)

• Retrospective review of hospital discharge diagnoses 2003-2011

26.6 cases/100,000

“personal h/o TB”

After removing “personal h/o TB”

Salemi AJOG 2017

US TB Epidemiology in Pregnancy (?)

5.9 TB cases/100,000 pregnancies after removing personal h/o TB cases

Improved estimates needed

US TB Surveillance Form Updates• CDC piloting addition of questions to capture pregnancy status

– Report of Verified Case of Tuberculosis (RVCT)– TB Latent Infection Surveillance System (TBLISS)

• Opportunity to improve our understanding of TB risk, burden, and outcomes among pregnant women using surveillance data

Pregnancy

Postpartum

Gestational age

Infant outcome

UK cohort: TB incidence 2x higher postpartum vs non-pregnancy times

Peripartum risk of TB

Zenner AJRCCM 2012

Jonnalagadda IJTLD 2015Jonnalagadda JID 2010

12% HIV+ pregnant w/ IGRA+ conversion

Peripartum increased risk of Mtb infection?

Peripartum risk of MTB infection and disease progression

• Cohort Kenyan pregnant HIV+ women pre-ART roll-out

IGRA+ assoc w/• 5x maternal TB/death• 3x infant TB/death

IGRA-

IGRA+

Peripartum increased risk of TB progression?

Jonnalagadda IJTLD 2015Jonnalagadda JID 2010

12% HIV+ pregnant w/ IGRA+ conversion

Peripartum increased risk of Mtb infection?

Peripartum risk of MTB infection and disease progression

• Cohort Kenyan pregnant HIV+ women pre-ART roll-out

IGRA+ assoc w/• 5x maternal TB/death• 3x infant TB/death

IGRA-

IGRA+

Peripartum increased risk of TB progression?

Maternal HIV/TB associated with poor maternal/infant outcomes

Despite maternal ART, TB treatment, and infant IPTMathad 2012, Salazar-Austin CID 2017

Pregnancy-related immunologic and physiologic changes

Do pregnancy-related immunologic changes increase risk of TB?

Kourtis NEJM 2014 Frederiksen Sem Perinatol 2001 Anderson Clin PK 2005Adapted from Jyoti Mathad, Cornell

Implications for TB/LTBI treatment?

Mathad AJRCCM 2016Mathad PLOS One 2014 LaCourse JAIDS 2017

Pregnancy impacts LTBI test results

QFT identified 2x more women with LTBI vs. TST

Mean Mitogen and Mtb antigen lower in pregnancy vs. postpartum

LTBI testing and treatment in pregnancy

• Pregnancy itself not indication for LTBI testing• LTBI diagnostic cut-offs same for non-pregnant• A decision to test, is a decision to treat…

– but timing of treatment depends on risk

– Women at higher risk for of TB (HIV+, recent converter, recent contact)• Recommend to treat now even in first trimester

– Women with lower risk of TB• Recommend to wait until after delivery or 3 months postpartum due to

concerns for hepatotoxicity

ATS AJRCCM 2000Canadian TB Standards 2014

Risk vs BenefitMother and fetus/infant

ATS AJRCCM 2000Canadian TB Standards 2014WHO 2018AAP RedBook 2018

Low Burden (US, Canada) High Burden (WHO)

RegimenPreferred

Alternative*

INH 300mg daily x 9 mo ORINH 900mg twice weekly x 9 mo

RIF 600mg daily x 4 months

INH 300mg daily x 6 or 36 mo

RIF 600mg daily x 4 months

Treatment timing

Defer 2-3 mo postpartum unless: HIV+, recent TB contact, recent conversion

Treatment for all HIV+, including pregnancy (TST+ or unknown)

MonitoringBaseline LFTs Baseline LFTs (if feasible)

LTBI treatment guidelines in pregnancy

* RIF considered as a first line option in Canada

Administer INH w/ pyroxidine (vit B6) in pregnancy or breastfeeding

Not currently recommended: INH/RPT

Routine monitoring for signs/symptoms of possible adverse effects

ATS AJRCCM 2000Canadian TB Standards 2014WHO 2018AAP RedBook 2018

Low Burden (US, Canada) High Burden (WHO)

RegimenPreferred

Alternative*

INH 300mg daily x 9 mo ORINH 900mg twice weekly x 9 mo

RIF 600mg daily x 4 months

INH 300mg daily x 6 or 36 mo

RIF 600mg daily x 4 months

Treatment timing

Defer 2-3 mo postpartum for TST+ or IGRA+ unless: HIV+, recent TB contact, recent conversion

Treatment for all HIV+, including pregnancy (TST+ or unknown)

MonitoringBaseline LFTs Baseline LFTs (if feasible)

LTBI treatment guidelines in pregnancy

* RIF considered first line option in Canada

Administer INH w/ pyroxidine (vit B6) in pregnancy or breastfeeding

Not currently recommended: INH/RPT

Routine monitoring for signs/symptoms of possible adverse effects

Many experts prefer RIF to avoid hepatotoxicity risk

Hepatotoxicity and INH in pregnancy

• 3681 women who initiated INH Franks Public Health Reports 1989

– 5 pregnant women developed hepatitis, 2 died

• 20 INH-associated deaths in California Moulding Am Rev Resp Disease 1989

– 4 initiated INH in pregnancy

• IPT implementation in HIV+ pregnant women in Lesotho Tiam JAIDS 2014

– 124 women who initiated IPT, none reported side effects– 3/99 mildly elev ALT--> 0/20 repeat LFT testing without significant elevation

Concern initially based primarily on US-based retrospective studies

In implementation studies in pregnant PLHIV appeared safe

Pregnancy and infant outcomes in LTBI tx trials

PREVENT TB or iAdhere trials (3HP vs. 9H) Moro Annals ATS 2018

‒ 126 pregnancies during treatment or f/u‒ 87 exposed to study drugs ‒ Fetal loss similar 3HP (15%) vs 9H (13%) (all <20 weeks)‒ Congenital anomalies similar 3HP (3%) vs 9H (4%)

Fetal loss/congenital anomsimilar between arms and baseline US estimates

BOTUSA (6 vs. 36H) Taylor IDOBGYN 2013

‒ 196 pregnancies during treatment or f/u‒ 103 exposed to INH during pregnancy‒ IPT exposure during pregnancy not assoc with

adverse pregnancy outcomes aOR 0.6 95%CI 0.3-1.1

Long-term INH + ART not assoc with adverse pregnancy outcomes

TB prevention in PLHIV (3HP vs. 3HR vs. 6H) Martinson NEJM 2011

– 235 pregnancies during treatment or f/u– 26 women became pregnant on INH– 10 chose to continue, no toxicities

LTBI tx exposure in pregnancy not assoc with toxicity

>40 trials listed here that are planned, ongoing or recently completed

At least 8 are Phase III trialsAll exclude pregnant women

More than 13 trials of preventive therapy in HIV-infected adults

INH for 6, 9, 12, 36 monthsINH+ rifampin

INH+ rifapentineINH+ ART

All excluded pregnant womenAkolo Cochrane metanalysis 2010; Sterling NEJM 2011; Martinson NEJM 2011; Samandari Lancet 2011; Rangaka Lancet ID 2014

Slide Courtesy of Amita Gupta, Johns Hopkins

https://www.nichd.nih.gov/About/Advisory/PRGLAC

Inclusion of peripartum women in TB trials

“Of 213 new pharmaceuticals receivingFDA approval 2003-2012, only 5% includedany data from pregnant women.”

http://www.treatmentactiongroup.org

LTBI/TB treatment in pregnancy trials

• P1078: phase IV RCT to evaluate the safety of antepartum versus postpartum 6H among HIV-infected women

• P2001: Phase I/II PK and tolerability of 3HP in HIV-infected and HIV-uninfected pregnant and postpartum women

• P1026: Phase IV prospective PK study of 1st line ARVs and TB drugs in HIV-infected pregnant and postpartum women

• 1HP in pregnancy IMPAACT capsule in development

Phase IV multicenter, double-blind, randomized placebo-controlled, non-inferiority trial of antenatal vs. postpartum safety of INH

HIV+ Pregnant women14- 34 weeks gestation

End of follow-up: 48 weeks postpartum

Arm AImmediate INH (ANTENATAL)Pregnancy: INH 300mg daily x

28 weeks Postpartum: Placebo

Arm BDeferred INH (POSTPARTUM)

Pregnancy: Placebo 12 weeks postpartum: INH 300

mg daily x 28 weeks

APPRISE (P1078) Antenatal vs. Postpartum 6H in PLHIV

Gupta CROI 2018

Primary Endpoints

1st Maternal Tx-related Grade ≥ 3 AE or

drug discontinuation due to toxicity

All cause Grade ≥ 3 AE

Secondary Endpoints

Maternal: hepatotoxicity, TB, death

Infant: Grade ≥ 3 AE, TB, death

Pregnancy: fetal demise, LBW,

preterm delivery, congenital anomalies

APPRISE (P1078) Antenatal vs. Postpartum 6H in PLHIV

Primary: Antenatal INH safety non-inferior to postpartum (met NIM 5/100 PY)High rates Grade >3AE both arms

Secondary: No significant differences in maternal/infant safety or TB incidencePostpartum INH arm: increased Grade >2 ALT and symptomatic hepatitis

Antenatal INH arm: Increased composite adverse pregnancy outcomes (fetal demise, LBW)Signal with earlier gestation initiationGupta CROI 2018

DeliveryWeek 12 Postpartum

Median ALT by INH arm and EFV regimens

Higher LFTs after delivery in both armsNo difference by INH arm or ART regimen

Immediate vs. Deferred INH

EFV vs. No EFV

Gupta CROI 2018

Maternal Deaths, n=6Immediate IPT Deferred IPT

1 2 3 4 5 6

Location Zimbabwe Botswana Zimbabwe Tanzania Tanzania Tanzania

Age (yrs) 34 38 27 35 24 33

CD4 459 469 402 609 431 553

GA at entry (weeks)

33 21 31 26 26 30

Postpartum (PP) week at death

12 weeks 40 weeks 5 weeks 19 weeks 7.5 weeks 5.5 weeks

Time on INH

13 weeks(4 AP & 9 PP)

28 weeks(20 AP, 8 PP)

Never started 1 week PP Never started Never started

ART regimen initiated

TDF/3TC/EFV Started 1

week prior to entry

TDF/FTC/EFVStarted 2.5

years prior to entry

TDF/3TC/EFV for 4 months prior to entry

TDF/3TC/EFV+ COT 14

months prior to entry

TDF/3TC/EFV started 3

weeks before entry

TDF/3TC/EFV started 1

month before entry

Deathcause

Fulminant hepatitisRelated

Bacterial sepsis

Not related

Fulminanthepatitis

Not related

Fulminant hepatitisRelated

HepatitisNot related

PneumoniaNot related

4 deaths due to hepatotoxicity, 2 deaths related to INH and 2 not (? Efavirenz or other culprit)

Gupta CROI 2018

More data to come: PK ART + TB treatment/preventive therapy in pregnancy (1078 and Tshepiso)

Breastfeeding during LTBI treatment in pregnancy

ATS IDSA CDC CID 2016

• Breastfeeding not contraindicated• LTBI meds typically small concentrations in breastmilk

– Non-toxic to infant– Not effective treatment for infant

https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

For women who wish to avoid pregnancy

• Important to counsel potential drug interactions with contraception (esp. rifamycins)

• Nonhormonal contraception recommended

For women undergoing assisted reproductive treatment

• Female genital TB likely greater contribution to infertility than previously thought

• Growing number of IVF-related congenital TB case reports

Fisher NAR IUATLD 2018

Take home points

• Pregnancy (and postpartum!) status – important addition to routine TB/LTBI surveillance data‒ Can improve our understanding of TB and LTBI risk, burden, and outcomes

• INH (or RIF) can be used to treat LTBI in pregnancy • Some experts prefer RIF to decrease risk of hepatotoxicity

• Timing of LTBI treatment in pregnancy based on risk/benefit‒ Low risk of TB - reasonable to wait to treat postpartum (concern for hepatotoxicity)‒ High risk of TB - treat during pregnancy

• Impact of recent trial results on LTBI pregnancy treatment guidelines remain unclear…• Illustrate the importance of greater inclusion of pregnant women in TB treatment

and prevention trials

Key gaps in our knowledge

• Best ways to screen to TB pregnant women?

• Best practices for implementing TB prevention in maternal child health settings?

• Immune correlate of TB risk associated with pregnancy?

• What is the safest regimen and timing (role of 1HP and 3HP)?

• What to do in case of MDR exposure in pregnancy?

AcknowledgementsUniversity of WashingtonGrace John-StewartDavid Horne

Emory UniversityLisa Cranmer

Johns Hopkins UniversityAmita Gupta

Cornell UniversityJyoti Mathad

TAGLindsay McKenna

CDCNeela GoswamiElvin Magee

Funding/support

NIH/NIAID T32 AI007140 K23 AI 120793

NIH P30 AI027757 UW CFARFirland Foundation

UW Global Center for Integrated Health of Women, Adolescents and Children (Global WACh)Kizazi Working GroupUW Kenya Research & Training Center (KRTC)

Thank you.