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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.