HIV and TB in children Why do we worry? Sharon Nachman IMPAACT - - PowerPoint PPT Presentation

HIV and TB in children Why do we worry?

Sharon Nachman IMPAACT

Address the impact of TB/HIV co-infection

• What are the numbers?
• How do kids get infected
• And how can we diagnose them
• How can we prevent TB infection
• How do we treat these children?

WHO focus

• Reduce the burden of TB in people living with HIV and initiate early

antiretroviral therapy

• WHO guidance: the three I’s for TB/HIV
• Intensify TB case finding and ensure high-quality antituberculosis treatment
• Initiate TB prevention with isoniazid preventive therapy and early antiretroviral

therapy

• Ensure control of TB infection in health care facilities and congregate settings
• Reduce the burden of HIV in patients with presumptive and diagnosed TB
• Provide HIV testing and counselling to patients with presumptive and diagnosed TB
• Provide HIV prevention interventions for patients with presumptive and diagnosed

TB

• Provide co-trimoxazole preventive therapy for TB patients living with HIV
• Ensure HIV prevention interventions, treatment and care for TB patients living with

HIV

• Provide antiretroviral therapy for TB patients living with HIV

Where are we now?

• 2 billion people are infected with MTB
• 9 million new active TB cases a year
• 2 million people die/year; 1/15 sec
• ~ 400,000 new cases of MDR-TB a year
• 12 million persons are TB/HIV co-infected
• Biggest killer of women of childbearing age
• Economic toll: $12 billion a year

How big is the problem in children?

• It is estimated that there are more than half a million

cases of tuberculosis (TB) in children occurring globally each year.

• In settings with a high overall incidence of TB, children

can account for a large proportion (up to one-third) of all TB cases.

• As a consequence, TB is an important cause of morbidity

and mortality in children in TB endemic countries.

Global burden…are the number real?

• Difficult to assess TB cases in children, based on AFB smears
• Estimated that 11% of the 8 million new cases per year are in

children under 15 years of age

• 75% occurred in 22 highest burden countries
• South Africa has an annual case load of 200 per 100,000 population
• TB HIV co-infection burden even harder to estimate
• Children rarely transmit disease and contribute little to

maintenance of infection in the population

• So don’t get counted or studied

Burden of MDR-TB in children

• WHO estimates 500,000 new cases of MDR-TB in 2013: 60% in

Brazil, China, India, the Russian Federation and South Africa alone

• Poor pediatric estimates DR-TB
• >1,000,000 children potentially exposed to MDR-TB each

year

• Rollout of rapid molecular diagnostic tools including Xpert

MTB/RIF: number of adult MDR-TB cases diagnosed increasing with associated increasing numbers of child contacts identified

• Infants and HIV-infected children
• high risk of TB disease progression

Data on drug resistance?

• Still not available in over 100

countries…

• Over 400,000 cases of drug

resistance in world in 2004

• 62% from China, India and

Russian Federation Map of XDR TB

Where is the burden of disease in children?

Country Total Cases Cases in Children < 15 % in Children Myanmar 78,489 8,007 10.2 Nigeria 261,404 32,310 12.4 Pakistan 244,736 61,905 25.3 Philippines 230,217 12,167 5.3 Russian Fed. 183,373 7,778 4.2 South Africa 220,486 35,449 16.1 Thailand 85,928 2,317 2.7 Uganda 75,250 12,099 16.1 Tanzania 117,489 18,890 16.1 Viet Nam 143,023 7,559 5.3 Zimbabwe 76,296 12,267 16.1 Total 6,678,188 630,722 9.4

Some misperceptions…

• Children rarely get severe disease
• Autopsy study in Zambia: TB rivals pneumonia as a

leading cause of death in children

• If smear is negative, no TB
• Can’t do sputum in children very easily
• No data in kids…
• Many pre-therapy studies in the old literature, none of

which are electronic all describe the natural history of TB

Pathogens found in autopsy study in SA children

Causes of pneumonia HIV infected N=473 HIV uninfected N=338 Total N=811 Bacterial 238 (50%) 132 (39%) 370 (46%) PCP 145 (31%) 11 (3%) 156 (19%) CMV 121 (26%) 7 (2%) 128 (16%) TB 50 (11%) 27 (8%) 77 (9%) Co-infection 98 (21%) 5 (1.5%) 103 (13%)

14

10 20 30 40 50 %

<1 1to2 2to5 5to10 10to15

Age in Years

PTB Disseminated

Age-related risk of TB disease

Ben Marais. Int J Tubercul Lung Dis 2004, 8: 278 - 85

The challenge of co-occurring HIV and TB

• Greater difficulty with diagnosis
• Perhaps poorer response to therapy
• Drug drug interactions

Risk factors for child acquisition of TB infection

• HIV+ environment
• Sicker contact
• More AFB in sputum
• TB in contact not recognized
• Malnutrition

TB Disease transition is a continuum from infection to disease

TB exposure TB infection TB disease Disease severity

• HIV affects each step

Death Risk factors for disease are young age, malnutrition and HIV

Risk stratification

• Age is the most critical determinant of disease progression

Age@ primary Risk to progress to disease <1

No disease 50%, pulmonary disease 30-40%, disseminated 10-20%

1-2

No disease 75-80%, pulmonary disease 10-20%, disseminated 2-5%

2-5

No disease 95%, pulmonary 5%, disseminated 0.5%

5-10

No disease 98%, pulmonary 2%, disseminated. <0.5%

>10 No disease 80-90%, pulmonary 10-20%, disseminated disease <0.5%

Child TB and TB/HIV

• In HIV endemic Africa, 40-60% of child TB cases are HIV infected
• Jeena PM, Int J Tuber Lung 2002
• Schaaf HA BMC 2008
• 20x higher risk of culture confirmed TB in HIV+ children vs HIV uninfected

children

• Madhi CID 2000, Hesseling CID 2008
• TB risk 4 fold higher in HIV+ with low CD4 cell count
• Elenga N PIDJ 2005
• TB related mortality significantly higher in HIV+
• Madhi COD 2000

How to make the diagnosis

• TST
• Cold storage issue
• Testing in
• BCG+ populations
• Infants
• HIV+
• IGRA
• Specialized lab
• Correct interpretation
• Can’t use in infants and young children

Yield of Mycobacterium tuberculosis in Culture Using Various Specimen Collection Methods

Swaminathan S , and Rekha B Clin Infect Dis. 2010;50:S184-S194

What about symptoms?

• Among 1397 children without TB
• In prior 3 months: 26% had cough, 10% had night sweats,

11% had fever and 5% had chest pain

• Only weight loss was helpful
• 50% of children with newly diagnosed TB had no symptoms

at all

Marais, BJ. Arch Dis Child 2005;90:1166–1170. doi: 10.1136/adc.2004.060640

What about Prevention?

Variable Efficacy of BCG vs. Pulmonary TB

Efficacy of BCG vaccination in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994; 271:698-702.

Efficacy of BCG vs. Disseminated TB

Summary Efficacy: Miliary Tuberculosis 77% (58 to 87) Summary Efficacy Tuberculous Meningitis 73% (67 to 79)

How do we treat children with TB?

• LTBI:
• INH for 6 months
• But does it work in all ages?
• IMPAACT study 1041 suggests that it doesn't
• Intrathoracic TB:
• Typical 2 months/4 month regimens
• MDR TB
• Difficult
• Nothing much is new…
• Not good!

UDPATE ON PAEDIATRIC TB TREATMENT TRIALS

Anneke C. Hesseling Professor in Paediatrics Desmond Tutu TB Centre Stellenbosch University HANC webinar 27 May 2015

Disclosures: I like children

Susceptible Exposed Infected Diseased Infectious Sick Accessed care Recognized Diagnosed Treated Completed Cured Mortality

Young age, HIV, malnutrition, recent exposure

Don Enarson, The Union

KEY TRANSITIONS IN TUBERCULOSIS

AGE RELATED DISEASE RISK

Marais et al. Int J Tuberc Lung Dis. 2004

PRINCIPLES OF TB TREATMENT

Intensive phase

• Rapidly kill most bacilli to:
• prevent disease progression
• prevent transmission of infection
• prevent development of drug resistance

Continuation phase

• To effect cure and prevent relapse (eliminate dormant bacilli)

All of the above with minimal adverse effects

TREATMENT CONSIDERATIONS: CHILDEN

• Wide spectrum of disease; more EPTB
• >75% pulmonary TB
• Severe and disseminated TB (TBM and miliary TB) especially in young (<3

years)

• Paucibacillary disease compared to adult pulmonary TB (fewer lung cavities)
• Treatment outcome in children generally good provided initiated early

(paucibacillary)

• Bacillary load and type of TB may influence effectiveness of regimens

TRIAL DESIGN CONSIDERATIONS

• Case definitions: end points, entry points approximately 30%

confirmed cases; subset with bacteriological end points

• Disease spectrum
• New drugs given against background of existing regimens (toxicity,

MDR-TB)

• Need for efficacy data?
• PK: the recommended dose of anti-TB drugs in children should lead to

a PK profile that approximates the adult exposures associated with efficacy and safety

• Target population: risk/benefit
• Strategies for earlier inclusion children: adolescents, flexible use adult

formulations

PRAGMATIC CONSIDERATIONS

• Ethics of studies in children

– FDA, EMA, other national ethics boards – ‘prevent harm to children’ – Risk/benefit: MDR, XDR, IPT – Ethics of not doing research in children

• Implementation of trials in children

– Timing in relation to adult trials – Recruitment, sampling for drug assay, adverse effect monitoring and data interpretation – End points: infection, death, TB disease - age specific: neonates to adolescents

• Where are children with TB?

– NICU, general paediatric services, hospitals to NTP

• Formulations

Area Gaps for children Priority studies

DS-TB

• PK/safety first-line drugs at higher

doses, esp. infants, HIV+

• Optimal treatment for TB meningitis
• Treatment shortening DS-TB
• FDC of FLD (2015)

PK studies first-line drugs at higher dose: DAtiC, NICHD PK/efficacy study in children: TBM-KIDS, NICHD SHINE (nested PK)

36

Area Gaps for children Priority studies Co-treatment TB/HIV

• Super boosting LPV/r in young children

taking HRZE

• EFV-based regimen in children < 3 years
• INSTI-based ART with standard TB drugs

(HRZE) Super-boosted PI with HRZE (DnDI) EFV+HRZE in slow CYP2B6 genotype RAL or DTG-based ART with TB drugs (PENTA, IMPAACT P1101)

37

• Parallel group, non-inferiority trial
• 4 vs. 6 months, open label
• Children aged 0-16 years
• Non-severe TB
• WHO-recommended doses first-line drugs
• N=1200 children
• New FDC; 75, 50, 150

INH: Early bactericidal activity, rapid reduction in

• rganism burden

Rifampicin: Unique sterilizing activity against “persisters”, key contributor to cure without relapse Pyrazinamide: Sterilizing activity in acidic environments over the first 2 months, allowing for shortening of treatment Ethambutol: Prevents resistance to other antibiotics

ROLE OF INDIVIDUAL DRUGS

Developmental pharmacology: A Moving Target

40

Kearns, NEJM 2003 349: 1157.

WHO/IUATLD dosing guidelines for children <12 years of age

Rifampicin (R): 15 (10-20) mg/kg  50% Isoniazid (H): 10 (7-15) mg/kg  100% Pyrazinamide: 35 (Z) (30-40) mg/kg  40% Evidence needed to support MINIMUM requirement - drug formulations and doses that achieve comparable PK to adults

WHO/HTM/TB/2014.03; Burman et al. PLoS Med. 2008

Characteristics: n= 47 children

n median IQR range Age (years) 47 2.9 (1.4, 6.4) 0.2, 10.1 Weight (kg) 47 13.4 (10.1, 18.4) Girls 18/47 (38%) HIV-infected 3/47 (6%) WFH -score 41 (0, 1) C-reactive protein (mg/L) 46 1.85 (1, 6.5) Albumin (g/L) 46 40 (38, 42) Rifampicin dose (mg/kg) 47 15.8 (13.4, 17.8) Isoniazid dose (mg/kg) 47 12.0 (11.1, 13.5) Pyrazinamide dose (mg/kg) 47 34.4 (32.1, 36.9)

H McIlleron: NIH/NICHD R01HD069175 (DATiC study)

Isoniazid

weight (kg) <8 8-11.9 12-15.9 >16 n 5 13 14 15 median age (y) (range) 1.1 (0.4,1.4) 1.3 (0.2,3.8) 2.6 (1.5,5.4) 7.1 (4.1,10.1) median dose (mg/kg) 13.9 13.5 11.4 11.2 median for reference adult population

Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants

• LBW infants receiving 10 mg/kg of INH had desirable blood drug

concentrations

• Prolonged half-life and reduced elimination of INH noted in smaller and

younger infants, especially in slow acetylators.

• Caution against exceeding a dosage of 10 mg/kg here

Bekker et al. AAC 2014;58:2229

weight (kg) <8 8-11.9 12-15.9 >16 n 5 13 14 15 median age (y) (range) 1.1 (0.4,1.4) 1.3 (0.2,3.8) 2.6 (1.5,5.4) 7.1 (4.1,10.1) median dose (mg/kg) 11.3 15.8 15.4 14.5 8 children (17%) have median AUC > a reference adult population

Rifampicin AUC0-24

median AUC =28.3 mg.h/L

MDR-TB TREATMENT

Area Gaps for children Priority studies DR-TB

• PK/dosing second-line drugs (FQ,

aminoglycosides, linezolid, clofazamine, PAS)

• New drugs PK and safety (bedaquiline,

delamanid, PA-824, sutezolid)

• Injectable sparing shorter regimen

Modeling existing data, testing doses predicted to achieve PK targets,

• ptimal use, DDI

PK/safety studies bedaquiline, PA- 824, DLM, BDQ and combinations Non-inferiority

MDR-TB TREATMENT OUTCOMES

Outcome N = 149 (%) Cure 36 (24.2) Probable cure* 101 (67.8) Transferred out 1 (0.7) Lost to follow up 8 (5.4) Died 3 (2.0)

Includes 8 patients who stopped their therapy before indicated but whoe were clinically well at follow up

Seddon, Clin Infect Dis 2013

Grade of AE Gr 0 Gr 1 Gr 2 Gr 3-4 Any AE (%) Joint, muscle or bone pain 122 11 2 2 (1.5) 15 (10.9) Skin rashes 104 30 2 1 (0.7) 33 (24.1) Itchy skin 110 24 2 1 (0.7) 27 (19.7) Headache 120 16 1 17 (12.4) Sleep/mood problem 124 9 3 1 (0.7) 13 (9.5) Lethargy 118 17 1 1 (0.7) 19 (13.9) Visual problem 132 5 5 (3.6) Vomiting 113 20 3 1 (0.7) 24 (17.5) Diarrhoea 125 10 1 1 (0.7) 12 (8.8) Jaundice 133 1 2 1 (0.7) 4 (2.9) ↓Appetite/nausea 118 14 3 1 (0.7) 18 (13.1) Hearing loss (n=142) 25 (17.6) Thyroxine supplementation (n=142; ↑TSH & ↓ fT4) 32 (22.5)

MDR-TB: ADVERSE EVENTS (n = 137)

Seddon, Clin Infect Dis 2013

LEVOFLOXACIN IN CHILDREN 15 mg/kg daily

Parameter Median (IQR) PK value (n=23) Cmax (μg/ml) 6.71 (4.69 - 8.06) AUC0-8 (μg∙h/ml) 29.89 (23.81 - 36.39)

Thee, Antimicrob Agents Chemother, 2013

Parameter Target value Mean (sd) PK value/MIC if MIC is 0.5 Mean (sd) PK value/MIC if MIC is 1.0

Cmax /MIC

8-10 13.1 (4.0) 6.5 (2.0)

AUC/MIC

100 65.3 (18.4) 32.6 (9.2)

No QTc prolongation, no significant clinical AE

MOXIFLOXACIN PK IN CHILDREN 7-15 years (n=23)

Mean AUC0-24/MIC: 56.1 Target: 100 Mean Cmax/MIC: 6.5: Target: 8-10 MIC90= 0.5 mg/L

Thee, Clin Infect Dis 2015 Sirgel et al. JAC 2012

NOVEL MDR-TB REGIMENS

• Given good outcome, lower bacillary load, toxicities: injectable

sparing shorter regimen

• Optimizing role of safe and effective SLD: FQN, clofazamine, PAS,

linezolid

• Adult PK targets? PK/PD
• Inclusion of novel drugs: DMD, BDQ
• DDI data needed (also ARVs)
• 9 months
• Non-inferiority?

FDA approved 2012 EMA approved 2014

BEDAQUILINE PAEDIATRIC EVALUATION : P1108

• Delayed
• Paediatric PK and safety studies (no efficacy)
• Inclusion HIV-infected children: DDI
• PK targets adults?
• Risk/benefit
• Long-term safety
• Long half life, tissue bound
• Confirmed and probable MDR-TB targeted
• Need for age de-escalation?
• Adaptive design, real-time PK assaying

and modeling, dose adjustments

• Formulation issues

EMA APPROVED 2014

DELAMANID

• Trial 232: Phase 1 PK Age De-escalation study

– Define dose of delamanid in children resulting in AUC comparable to the effective AUC

• bserved in adult MDR-TB trials
• Trial 233: Phase 2 Safety Study

– Investigate the safety, tolerability, and PK of delamanid administered for six months in a pediatric population receiving concomitant OBR – Enrolling: Phillipines, South Africa; age de-escalation, HIV- IMPAACT P2005 in development: Delamanid PK and safety in HIV-co-infected children with MDR-TB : DDI

LTBI

• Safety/tolerability/PK once-weekly INH/RPT

regimen for youngest children, DDI with ART

• MDR LTBI
• RPT dose for children under 2 for

weekly INH/RPT: Study 35 , child- friendly formulation

• Efficacy and safety of long-term use
• f fluoroquinolones, novel drugs:

Phoenix, TB-CHAMP, V-QUIN

No WHO-recommended regimen given absence of trial data: MDR- TB prevention regimen

Q1 2014: Initiate discussions with GDF, Global Fund,

• ther donors

Q4 2014: Countries quantify cases

• f child TB

Q2 2016: All first-line products WHO pre- qualified and available in the market 2013: Project Launch Q2/3 2015: First-line FDC products available to procure through GDF and/or Importation waivers Q2 2015: Dosage guidelines for children <5kg Q2 2014:Three manufacturing partners secured Q1 2015: Manufacturers submit for WHO PQ and local registration

Timeline for New First-Line Pediatric Formulations:

SUMMARY

• Significant research gaps in DS-TB, DR-TB
• Special populations: LBW, adolescents, HIV c-infected
• Multiple interventional trials planned or ongoing
• Need for earlier inclusion of children in evaluating novel

drugs and regimens

• Significant gains made
• Need for child-friendly approaches

ACKNOWLEDGEMENTS

Simon Schaaf Tony Garcia-Prats Steffi Thee Peter Donald Heather Draper Helen McIlleron Jennifer Norman Lubbe Wiesner Peter Smith Marianne Willemse Sharon Nachman James Seddon Kelly Dooley Rada Savic Elin Svensson Mats Karlson Study participants and their parents/care-givers!

M)—

–

Tuberculosis in Pregnancy

Amita Gupta MD MHS Associate Professor of Medicine and International Health Johns Hopkins University HANC Webinar May 27, 2015

Disclosures

• Amita Gupta has no financial relationships with commercial entities to

disclose

• Amita Gupta receives research grant funding from the

– US NIH (NIAID, NICHD, Fogarty, CFAR) – US CDC – Indian Department of Biotechnology and Indian Council of Medical Research – Foundations (Gilead, Wyncote, Ujala)

• Any opinions expressed are my own and not of any of my sponsors.

Overview

• Global TB burden and epidemiology
• Impact on maternal-child health
• utcomes
• Screening for active and latent TB

infection (LTBI) in pregnancy/ postpartum

• Treatment

What is the burden of TB in pregnancy?

• 2014

– >500,000,000 latently infected – 3.3 million with active TB (37% of global burden) – 510,000 died (180,000 HIV-infected) – 50% of HIV-related TB deaths – 67% of cases Africa and SE Asia – More than 50% of female TB cases went undetected – >216,000 cases in pregnancy estimated

TUBERCULOSIS IN WOMEN

WHO Global TB Report 2014 Sugarman, Lancet Global Health 2014

Peak TB incidence in women of reproductive age irrespective of HIV

TB Cases per 100,000

Age, years

Sub-Saharan African Women

Deluca JAIDS 2009

TB Cases per 100,000

Indian women

RNTCP: Gender differentials in TB control 2004

Prevalence of TB in pregnancy

Mathad & Gupta, CID 2012

Study Site HIV-negative HIV-positive Low burden countries 0.06-0.25% 1% High-burden countries 0.07-0.53% 0.69-11%

Active TB

Study Site HIV-negative HIV-positive Low burden countries 10-23% 11-26% High-burden countries 18-34% 21-49%

Latent TB

• No national reporting for high burden countries
• Data based on individual screening studies

Prevalence of TB disease in HIV-infected pregnant women in high burden settings

Pillay Kalli TiPs* Hoffman* Jonnalagadda Gupta Modi* (unpub) Gounder Leroy Sheriff Nachega Study 2001 2006 2014 2013 2010 2007 2014 2011 1995 2010 2003 Year

• S. Africa
• S. Africa

Kenya

• S. Africa

Kenya India Kenya

• S. Africa

Rwanda Tanzania

• S. Africa

Country 14650 370 288 1415 393 715 134 1427 211 396 120 N

0.8 (0.6, 0.9) 2.2 (0.9, 4.2) 2.4 (0.1, 4.2) 2.5 (1.7, 3.4) 2.8 (1.4, 4.9) 3.4 (2.2, 4.9) 6.0 (2.6, 11.4) 0.6 (0.4, 0.7) 7.9 (4.8, 12.6) 10.0 (1.2, 31.7) 11.0 (5.9, 17.8)

Prevalence (95% CI) 5 10 15 20

Prevalence: 0.6-11% *culture obtained independent of symptoms Slide courtesy of Sylvia LaCourse, Univ of Washington

Impact of Maternal TB on maternal-infant

• utcomes?

Risk of complications in pregnancy TB vs. no TB

Maternal complications

• Pre-eclampsia & eclampsia (2 fold)
• Vaginal bleeding (2 fold)
• Hospitalization (12 fold)
• Miscarriage (10 fold)

Jana Int J Gyn Obstet 1994 Jana NEJM 1999 Chin HC BJOG 2010 Bjerkedal 1975 Bothalmley 2001 Pillay Lancet ID 2000; Mathad CID 2012

Risk of complications in pregnancy TB vs. no TB

Fetal and infant complications

• Fetal death (increased)
• Low birth weight (2 fold)
• Lower Apgar scores
• Prematurity (2 fold)
• Small for gestational age (2 fold)
• Perinatal death (increased)
• congenital TB (rare)
• Increased HIV transmission (2 fold)

Jana Int J Gyn Obstet 1994 Jana NEJM 1999 Chin HC BJOG 2010 Khan AIDS 2001; Pillay Lancet ID 2000; Gupta JID 2011

Postpartum TB important causes maternal and infant mortality in HIV infected women

• HIV-infected mothers have 10-fold increase in TB.
• Maternal TB/HIV increased risk of postpartum mortality by 2.2 fold and probability of

infant death by 3.4 fold.

2 4 6 8 10 Mother Infant 0.9 8.5 0.4 2.5 Mortality Incidence, #/100/pt-yr Materal TB No Maternal TB

Maternal death aIRR 2.2 p=0.006 Infant death aIRR = 3.4 p=0.02

Gupta A et al. Clin Infect Dis 2007;45:241-9 715 HIV-infected pregnant women in Pune, India TB incidence 5/100 pt-yr (24 of 715 HIV+ women)

Does pregnancy or the postpartum period increase the risk of TB acquisition? reactivation? severity?

Pregnancy-associated immune changes are biologically significant

• Systemic immunomodulation that simultaneously embraces cellular immunosuppression,

immunotolerance to various antigens, and enhanced inflammatory response.

Adapted from Kourtis NEJM 2014 Improved course of multiple sclerosis and rheumatic arthritis Aggravated systemic lupus erythematosus  risk of plasmodium falciparum malaria, listeriosis, HIV  severity of influenza, hepatitis E, HSV, malaria, measles, smallpox, varicella, coccidiomycosis

Confavreux N Engl J Med 1998;Gordon Best Pract Res Clin Rheumatol 2004;Lindsay. Am J Epidemiol 2006;

• Diagne. Trans R Soc Trop Med Hyg 1997;Kumar. J Reprod Med 1997; Kourtis NEJM 2014

Risk of TB in Pregnancy: UK primary care cohort

• 192,801 women enrolled 1996-2008
• with 264,136 pregnancies
• Mean f/up 9.1 years, 1,745,834 PY
• 177 TB events; postpartum
• 15.4 vs 9.1/100,000 PY

Zenner AJRCCM 2011

Impact on TB reactivation and severity debated

Clinical data limited and were not consistent or convincing (Good Am. J. Obstet. Gynecol 1981, Carter Chest 1994, Espinal 1996;Sterling 2007)

IRR 1.95 Postpartum TB

Does pregnancy impact performance of screening for active or latent TB?

TB diagnostic sensitivity of WHO 4-symptom screen in pregnancy

28% 43% 54% 80% 1.40% 0% 50% 43% 79% 34% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Hoffman LaCourse Gupta PLWHIV WHO Sx screen Smear Xpert Urine LAM

At least one WHO 4-symptom in 9-19% of women Compared to non-pregnant HIV infected adults

• Lower sensitivity observed but not clear if that is due to pregnancy alone
• High negative predictive value (NPV) BUT
• High prevalence of undiagnosed asymptomatic TB (HoffmanPLOS One 2013, #822)

TIPS data courtesy of LaCourse and Cranmer, UW

Current recommendations LTBI screening

Low-burden countries1:

• TST or IGRA for “high risk”

– TB contacts – HIV – Anti-TNF treatment – Dialysis, silicosis, or transplant patients – Foreign birth, IVDA, congregate settings2

High-burden countries:

• WHO does not recommend

routine LTBI screening

– Exceptions:

• HIV+3,
• TB contacts < 5yo4

– IGRA not recommended5

1WHO LTBI Guidelines 2015;2CDC 2013; 3WHO Intensified Case finding 2011 4WHO Contact tracing Recs 2012 5WHO IGRA Policy 2011

Screen for latent TB?

• Goal of Latent TB screening

– Identify those at highest risk for reactivation disease – Target preventive therapy

• Implementation challenges
• Little attention paid to performance of latent TB diagnostics in pregnant/postpartum

women in era of HIV

• Mixed data

– Two US studies of IGRA (Quantiferon) test positivity was lower than TST (older age, foreign birth associated with positivity) (Worjohol et al Obstet Gynecol 2011; Chebab Kansas J Med 2010) – India, more Quantiferon positive than TST and discordance QGIT+/TST- was higher (Mathad, PLOS One

2014)

• Positive IGRA predictive of active TB postpartum (Jonalagadda JID 2010, IJTLD 2013

TST vs IGRA positivity rates: When women screened and which latent TB diagnostic test used matters

Mathad et al PLOS One 2014

17% 31% 10% 32% 25% 52%

N=450 HIV-negative women in India

Does pregnancy impact TB treatment and prevention?

Physiology Changes of Pregnancy Can Significantly Impact Drug Metabolism, Safety and Efficacy

• Increased body fat
• Increased total body weight
• Decreased albumin
• Hepatic metabolism

– Increased CYP3A4 – Decreased CYP1A2 and CYP2C19

Decreased lung capacity Decreased gastric emptying Increased cardiac

• utput

Changes in hepatic metabolism Increased GFR Decreased stomach pH Frederiksen, Sem Perinatol 2001; Anderson, Clin Pharmacokinetics 2005

Importance of studying TB/HIV drugs in pregnancy: INH and EFV example

*Median (IQR) The population PK model post-hoc estimates were used to predict individual Cmin

Pre/intrapartum (n=73) 6 weeks Post-partum (n=75) Cmin (mg/L)* 1.35 (0.90-2.07) 2.00 (1.40-3.59) % with Cmin<1 mg/L 27% 13%

Dooley et al., JID 2014 TSHIEPO study

• Pregnancy modestly reduces EFV exposures, even after adjusting for weight, and proportion
• f women with EFV Cmin<1 mcg/mL higher in pregnancy than postpartum

– especially in extensive CYP2B6 metabolizers

• TB treatment that includes INH and RIF doesn’t reduce EFV concentrations, but EFV

exposures higher in patients with slow NAT2 genotype taking INH

• No increased HIV MTCT noted

Drug-Drug Interactions HIV/TB and contraception

• Rifamycins and antiretrovirals

– IMPAACT P1026s first line TB drugs with and without ARVs (EFV, LPV/r, NVP) now underway – Need data for

• Protease inhibitors and rifabutin
• Raltegravir and rifampin
• Rifamycins and hormonal contraceptives

– Rifampin reduces OCP mean AUC but did not reverse suppression of

• vulation (Barditch-Crovo Clin Pharm & Therap 1999)

– Interaction with Depo-Provera, Implanon, ARVs? (ACTG 5338)

www.fda.gov

First line drugs for TB in pregnancy

Drug FDA Crosses placenta Breast- feeding Issues in pregnant women

INH C Yes Yes Hepatotoxicity Rifampin C Yes Yes Drug interactions with NVP, PIs, OCPs; may require Vit K Rifabutin B Unk Unk Drug interactions with PIs, limited experience EMB B Yes Yes PZA C Unk Unk Different guidance

Brost Obstet Gyn Clin 1997;Bothamley Drug Safety 2001;Shin CID 2003; Micromedex; Mathad & Gupta CID 2012

Treatment of Active Pulmonary TB in Pregnancy

Low Burden1 High Burden2 HIV negative INH 5mg/kg/d x 9 mo RIF 10mg/kg/d x 9mo EMB wt-based x 2 mo B6 25mg/d x 9 mo INH 5 mg/kg/d × 6 mo RIF 10 mg/kg/d × 6 mo EMB 15mg/kg/d x 2 mo PZA 25mg/kg/d x 2 mo B6 10-25mg/d x 6 mo HIV positive INH 300 mg/d × 6 mo RIF 600 mg/d × 6 mo EMB wt-based x 2mo PZA wt-based × 2 mo B6 25mg/d x 6 mo INH 5 mg/kg/d × 6 mo RIF 10 mg/kg/d × 6 mo EMB 15mg/kg/d x 2 mo PZA 25mg/kg/d x 2 mo B6 10-25mg/d x 6 mo

1 CDC, ATS, IDSA guidelines 2 WHO, British thoracic Society, RNTCP and IUATLD guidelines

Treatment of EPTB involves same drugs but most experts recommend 9-12 mo for TBM (but include PZA plus steroids) or bone/joint infections

DIFFERENCE IN PZA guidance

LACTATION CDC encourages breastfeeding if no longer infectious; WHO once smear negative

Drug-resistant TB in pregnancy?

Drug FDA Category

Aminoglycosides D Capreomycin C Fluoroquinolones C Ethionamide/Prothionamide C Cycloserine C PAS C Linezolid C Clofazamine C Bedaquiline B

Delaminid EMA approved no teratogenicity but use with great caution

MDR TB in pregnancy

• Treatment guidelines similar to non-pregnant adults

– Individualized treatment vs public health approach – At least 4 new agents – Favor injectable after delivery – Lactation little to no data so often not recommended

• >57 published case reports (Gach 1999;Shin 2003; Nitta 1999;Lessnau 2003;Tabarsi 2007; Khan

2007; Palacios 2009; Toro 2011)

– 3 case series describes 4 cases HIV+ (Khan 2007; Palacios 2009, Toro 2011) – US, Italy, Peru, Iran, South Africa

• Regimens: variable
• Outcomes: case series suggest treatment success possible

Treatment as Prevention: The Case for Latent TB Treatment in Pregnancy

Guidelines for Preventive TB Treatment in Pregnant Women

Low Burden (US CDC) High Burden (WHO) Regimen INH 300mg/d x 9 mo B6 25-50mg/d x 9 mo OR INH 900mg twice weekly x 9 mo B6 25-50mg/d x 9 mo INH 300mg/d x 6 or 36 mo B6 10-25mg/d x 6 or 36 mo HIV-negative Defer for TST+ or IGRA+ until 2-3 mo postpartum unless known recent TB contact No recommendations HIV-positive Immediate treatment for TST+ or IGRA+ Treatment for all HIV+ without active TB

>40 trials listed here that are planned, ongoing or recently completed At least 8 are Phase III trials All exclude pregnant women

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

INH for 6, 9, 12, 36 months INH+ rifampin INH+ rifapentine INH+ ART

All excluded pregnant women

Akolo Cochrane metanalysis 2010; Sterling NEJM 2011; Martinson NEJM 2011; Samandari Lancet 2011; Rangaka Lancet ID 2014

Some TB trials and studies underway in pregnant women!

Treatment

• IMPAACT P1026s

– PK/Safety of 1st line TB drugs with or without ARVs

• THSIEHPO (NICHD- Chaisson)

– PK/safety of EFV/RIF, EFV/INH

Prevention

• IMPAACT P1078

– TB APPRISE: Phase IV double blind RCT of antepartum vs postpartum INH for HIV+ pregnant women in high TB burden settings

• IMPAACT P2001

– PK/safety of INH/rifapentine weekly for 12 weeks in HIV+ and HIV-

• ACTG/IMPAACT PHOENIX

MDR contact prophylaxis

Filling the gaps for maternal TB

Epidemiology of latent and active TB

NICHD TSHIEPO TIPS, India, Haiti studies, IMPAACT PROMISE

Immunology and pathogenesis of TB

IMPAACT P1078 NICHD Pregnancy Immune Changes/TB

Cost-effectiveness studies for TB screening/treatment

PK, safety, and outcome studies of:

• LTBI regimens
• 1st and 2nd line TB medications

IMPAACT Pregnancy studies P1078 (RCT of antepartum vs postpartum INH) P2001 (PK, safety INH/rifapentine weekly) P1026s (PK 1st line TB drugs and ARVs) A5300/P2003 PHOENIX MDR contact Implementation Science

• PMTCT/TB screening &IPT

MOHs Lesotho, Kenya, South Africa CDC, USAID, JHPIEGO, ICAP ARVs /ATT drug interactions A5388 (PK ARV, Rifampin, contraception) NICHD TSHIEPO

Summary

• Peak incidence of TB during reproductive age
• Maternal TB associated with adverse pregnancy outcomes, maternal mortality

and infant TB and mortality

• Immune and physiological changes may be of importance to screening diagnostic

yield, TB drug disposition

• Best approaches of integrated TB screening and prevention needed
• Need to include pregnant women in trials of diagnostics and drugs whenever

feasible

• Several studies now ongoing that will help to fill in the knowledge gap

Acknowledgements

NIAID R01AI080417, UM1AI069465, R01A1I097494 NICHD R01HD081929, R01HD074944 Fogarty D43TW000010, CFAR 1P30AI094189 Foundations: Ujala, Wyncote, Gilead

JHU-CCGHE-BJMC India Bob Bollinger Jyoti Mathad (Cornell) Vidya Mave Nikhil Gupte Rupak Shivakoti Akshay Gupte Natasha Chida Nishi Suryavanshi Jane McEnzie-White Ramesh Bhosale Renu Bharadwaj Ajay Chandanwale Sameer Joshi Aarti Kinikar Sandesh Patil Charles Flexner JHU Center for TB Research Richard Chaisson Kelly Dooley Jonathan Golub NIRT/ICER Soumya Swaminathan Subhash Babu UW Sylvia Lacourse Lisa Cramner Grace John Stewart

• U. Colorado

Adriana Weinberg Stellenbosch Anneke Hesseling Gerhard Theron WHO Haileyesus Getahun ACTG and IMPAACT investigators Women and children participants

COMMUNITY ENGAGEMENT —AND COLLABORATION— IN TB/HIV RESEARCH

Lindsay McKenna, MPH Project Officer, TB/HIV Treatment Action Group May 27, 2015

Who We Are & Where We Are Going

• About the Community Research Advisors Group (CRAG) and the Tuberculosis

Trials Consortium (TBTC)

• About Community Partners (CP) and the National Institutes of Health (NIH)

HIV/AIDS clinical trials networks

• About TB and TB/HIV research
• Why CRAG and CP are working together
• The issues in TB/HIV research we’re thinking about

About the CRAG

• an international, community-based advisory body;
• ensures the meaningful engagement of TB-affected communities in research conducted

by the TBTC;

• supports a TBTC research agenda that is responsive to community needs and scientific

priorities. 8 members from TBTC sites in 6 countries:

• United States;
• South Africa;
• Uganda;
• Vietnam;
• Spain;
• Peru

About the TBTC

Tuberculosis Trials Consortium

• Research network at US Centers for Disease Control Department of TB

Elimination;

• Conducts drug research for TB infection and TB disease;
• Mission to conduct programmatically-relevant research;

8 U.S. sites (Texas, New York, Tennessee, California, Washington, D.C.); 8 International sites (Spain, Peru, South Africa, Vietnam, Uganda, Kenya, Hong Kong).

About Community Partners

Group established to promote effective representation and communication among many communities globally working with NIH HIV/AIDS clinical trials networks. Comprised of representatives from each of the NIH-funded networks’ community groups, including:

• ACTG
• HVTN
• HPTN
• IMPAACT
• MTN

About the NIH HIV/AIDS Networks

• Sits within the U.S. National Institute of Allergy and Infectious Diseases

(NIAID);

• Supports global research portfolio on HIV/AIDS, its related co-infections, and

co-morbidities.

• Mission to enable innovative approaches aimed at:
• Prevention of HIV;
• Treatment and cure of HIV;
• Prevention and treatment for HIV co-infections and co-morbidities; and
• Partnering with scientific and community stakeholders to implement effective interventions.

Priorities issues in TB research

• Long duration

(6 months for DS-TB; 2 years for MDR-TB;

• High pill burden

(up to 12 pills/day for DS-TB; up 15,000 pills for full course of MDR-TB treatment)

• Toxic side-effects

(irreversible deafness; neuropathy; skin discoloration; psychosis; vomiting)

• Painful injectables

(for early stage of MDR-TB treatment)

Why integrate TB and HIV in research and practice? 2014 WHO Report:

• 9 million people developed TB, 1.5

million TB deaths

• 1.1 million PLHIV developed TB (4/5
• f these in Africa)
• 360,000 people with HIV died of TB
• 510,000 women died from TB; 1/3 of

these were women with HIV

• 70% of PLHIV with TB are on ARVs
• 40% of TB patients know their HIV

status

TB/HIV: One disease…

“The reality is that in sub-Saharan Africa, TB and HIV are one

• disease. We must treat them together.”

––Mark Dybul, Global Fund “We need to integrate TB and HIV and treat these as one disease.” ––Jarbas Barbosa, Brazil “Life is forcing us to put TB and HIV together.” ––Aaron Moatsaledi, South Africa

…with two research agendas?

• 1. Money spent on research:

HIV: US 2.6 billion, (drug R&D, 2011) TB: US 676.6 million, (all R&D, 2013)

• 3. Number of clinical trials behind the newest drugs:

HIV: Dolutegravir, 61 trials TB: Delamanid, 6 trials

• 2. Number of new drugs approved by FDA since 1987:

HIV: 36 drugs TB: 2* drugs

Where are people with HIV in TB R&D?

• PLHIV often in phase IIb and III studies, but at higher CD4 counts

(≥250);

• PLHIV on ARVs less frequently included in phase IIb and III trials;
• People with extra-pulmonary TB, including many PLHIV, are

almost always excluded from trials

• Children with HIV often not included in trials

What needs to change?

• Having HIV shouldn’t be an exclusion criteria for TB drug research;
• Taking ARVs shouldn’t be an exclusion criteria, either;
• DDI studies between TB and HIV drugs need to happen sooner—

preferably by time TB drug enters phase IIa trials;

• TB investigators need to become more comfortable enrolling

PLHIV;

• HIV investigators need to become better acquainted with TB

research;

• HIV community groups need to become better acquainted with TB

research and issues and vice versa

Why are CRAG and CP collaborating?

• The incidence and impact of TB/HIV co-infection is significant and

growing

• Integration of TB and HIV education and research
• treatment shortening regimens
• Trial site overlap
• TB is an emerging focus within DAIDS
• Overall need for more co-infection work and integration at the

community level

• TBTC & ACTG are working together on Study 31– phase III study
• f rifapentine-containing

What we are working on

Research literacy: community engagement should start early in the research process.

Inclusion:

• People living with HIV (& taking ARVs)
• Adolescents
• Children

Post-trial access considerations:

• Results dissemination
• Registration
• Pricing and other access considerations

Promoting “good participatory practice”:

GPP-HIV: http://www.avac.org/resource/good-participatory-practice-guidelines-biomedical-hiv-prevention-trials-second-edition. GPP-TB: http://www.cptrinitiative.org/downloads/resources/GPP-TB%20Oct1%202012%20FINAL.pdf. Recommendations for CE in HIV/AIDS Research: https://www.hanc.info/cp/resources/Documents/Recommendations%202014%20FINAL%206-5-

14%20rc.pdf.

Retiring stigmatizing language:

• CP memo to investigators re: “participant” vs. “subject”;
• CP advocacy for HHS to replace “mother to child transmission” with

“perinatal transmission” in Pediatric ARV Guidelines. Terms in TB are different, but the issue is the same– carry overtones of criminalization and transgression… “defaulter” “suspect”

Where do we go from here?

• Greater collaboration between TB and HIV research networks (and their community groups);
• Progressive inclusion of people with HIV (including those taking ARVs) in TB clinical trials;
• Earlier inclusion of adolescents and children (including those with HIV) in TB clinical trials;
• Earlier and more comprehensive drug-drug interaction studies: between TB/TB drugs; and TB/HIV drugs;
• More research designed to address key challenges facing TB/HIV treatment and prevention (pill burden;

drug-drug interactions; long treatment duration; patient-friendly delivery systems; extra-pulmonary TB);

• Increased joint TB/HIV research activities and funding commitments for these activities.

THANK YOU

Lindsay.McKenna@treatmentactiongroup.org http://crag-tb.tumblr.com/

**Special thanks to Mike Frick, TAG for letting me borrow his slides!