TB PREVENTIVE THERAPY IN CHILDREN · TB PREVENTIVE THERAPY IN HIV-INFECTED PATIENTS >11 randomized control trials of IPT 73,375 patients Mixed exposure risk Reduction in active TB

A N N E K E C . H E S S E L I N G

D E S M O N D T U T U T B C E N T R E

1 1 T H I N T E R N A T I O N A L C H I L D H O O D T B C O U R S E

1 3 S E P T E M B E R 2 0 1 7

G O U D I N I

TB PREVENTIVE THERAPY IN CHILDREN

Key transitions in tuberculosis

SusceptibleExposed

InfectedDiseased

InfectiousSick

Accessed careRecognized

DiagnosedTreated

CompletedCuredMortality

Each transition has a measurable probability

Probability varies with the situation= childhood TB

Don Enarson, The Union

PRINCIPLES

M. tuberculosis infection

Relevant disease in young children

Relevant disease in immune compromised children

Effectively contained through preventive therapy

The successful delivery of preventive therapy is dependent on numerous interrelated mediators

RISK OF PROGRESSION IN CHILDREN

Young age

43% of infants (children < 1year)

25% of children aged one to five years

15% of adolescents

Recent infection (1-2 years) children with close contact

Malnutrition

HIV

Marais et al. Int J Tuberc Lung Dis. 2004

Age Related Risk

Marais et al. Int J Tuberc Lung Dis. 2004, 8(4):392–402

IMMUNE COMPROMISED CHILDREN

HIV-infected women have an increased risk of TB

Kali, et al. J Acquir Immune Defic Syndr 2006;42(3):379-81

Gupta, et al. Clin Infect Dis. 2007 Jul 15;45(2):241-9.

10% of 766 HIV-exposed, uninfected infants had contact with a TB source case

Cotton, et al. Int J Tuberc Lung Dis 12(2):225–227

HIV-infected children: 5 fold increased relative risk with ART

Contact management

• The overall yield for all TB (bacteriologically confirmed and clinically diagnosed) was 4.5% (95% CI 4.3-4.8, I(2)=95.5%) of contacts investigated; for cases with bacteriological confirmation the yield was 2.3% (95% CI 2.1-2.5, I(2)=96.6%).

• Latent tuberculosis infection was found in 51.4% of contacts investigated.

• “Contact investigation merits serious consideration as a means to improve early case detection and decrease transmission of M tuberculosis in high-incidence areas”.

Morrison, Lancet Infect Dis 2008

“More evidence to support screening of child contacts of tuberculosis cases: if not now, then when?”

Jaganath D, Clin Infec Dis 2013 Graham SM, Triasih R. Clin Infect Dis. 2013

• 761 children from 351 households

• 79 TB cases

• 10% prevalent TB

• 71% bacteriologically confirmed

Using TB contact management as quantification of paediatric disease burden

Quantify number at-risk children (community, facility) –indirect estimate of childhood TB burden

Estimate number infected and diseased (who should be attending)

Document who attended and TB prevention offered Quantify missing cases Earlier diagnosis and less severe disease

“Contact investigation study (TB-and neighbouring households): children with a documented TB source case less likely to have severe disease than those without (21% vs. vs. 44%; OR: 0.34, 95%CI: 0.12; 1.01, p=0.025)”

Wiseman, IJTLD 2015

Isoniazid for preventing tuberculosis in HIV-negative persons

Smeja MJ, eta al.Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.CD001363.

2/3

1/3

~50%

Thirty years after INHIts impact on TB in children & adolescents

30 year observational study of IPT in children

2,494 children WHO COMPLETED TREATMENT

15,943 patient-years

IPT most effective in children < 4 years of age

None experienced overt disease

*Hsu KH. JAMA. 1984 Mar 9;251(10):1283-5.

TB PREVENTIVE THERAPY IN HIV-INFECTED PATIENTS

>11 randomized control trials of IPT 73,375 patients Mixed exposure risk

Reduction in active TB over 2+ years Relative risk reduction: 0.40 (95% CI 0.31 to 0.52) Absolute risk reduction: 0.01 ~ NNT 100 No significant difference between 6 & 12 month course Most benefit in TST+ individuals

Reduction in TB deaths No reduction in all-cause mortality INH hepatotoxicity

6 month regimen: 0.36% 12 month regimen: 0.52%

Smeja MJ. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001363.

EVIDENCE FOR IPT AND HIV IN CHILDEN

Among 277 HIV-infected children (median 2.1 y) not receiving cART, IPT decreased TB by 72% and mortality by 54%

Zar, BMJ 2007

HIV-infected

HIV-exposed uninfected

TotalN=547

INHN=273

PlaceboN=274

TotalN=804

INHN=403

PlaceboN=404

TB disease or death

105 (19.2%)

52 (19%)

53 (19.3%)

84 (10.4%)

39 (9.7%)

45 (11.2%)

Madhi, NEJM, 2011

Evidence synthesis: IPT and HIV

3 trials: 991 participants < 13 years (South Africa and Botswana)

Children randomized to isoniazid prophylaxis or placebo, given daily or three times weekly.

Median length of follow-up: 5.7 -34 months

In HIV-positive children not on ART, IPT reduces the risk of active TB (HR) 0.31, 95% CI)0.11 to 0.87 and death (HR 0.46, 95% CI 0.22 to 0.95)

In HIV-positive children on ART, no clear benefit of isoniazid (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72)

Zunza, Zar, 2017, Cochrane

Database Syst Rev. 2017

cART reduces TB in 1st year of life by >3 fold (per 100 patient years)

0

5

10

15

20

25

Early

Deferred

cART

The CHER Trial: Violari, N Engl J Med 2008

EFFECT OF ART ON TB INCIDENCE

Isoniazid: 10-15 mg/kg per day, 30 mg max dailyWHO 2010

Operational challenges surrounding contact management in children

Van Wyk, IJTLD, 2012

India: Poor uptake of screening (14%), and poor uptake of IPT initiation (19%) (Rekha, et al. IJTLD, 2009)

Laos: Poor uptake of IPT (0/148), and poor knowledge of infectiousness amongst TB patients (Nguyen, et al. BMC Infect Dis,

2009)

Malawi: only 9% of TB-exposed children were screened for TB and initiated on IPT (Claessens, et al. IJTLD, 2002) AND despite education of TB patients about the benefits and importance of contact screening, only 8% attended the hospital-based clinic (Nyirenda, et al. IJTLD, 2006)

Botswana: 1/3 of community screened contacts who were symptomatic, did not attend the clinic for further

investigations. (Ghandi , et al. IJTLD, 2011)

POOR UPTAKE OF IPT IS COMMON

BARRIERS

Knowledge, understanding and perception amongst TB patients and NTP staff

Lack of management / monitoring structure and tools

Treatment side-effects

Transport and cost difficulties

Hill, et al. Plos Medicine 2011

IMPLEMENTATION & EVALUATION

(Hill, et al. Plos Medicine, 2011)

Comprehensive implementation strategy

Monitoring and evaluation strategy

Measurable indicators (IPT register)

Incorporated into routine audits

Key components:

• Sustainability

• Capacity building

IPT Register

IPT register designed for a pilot implementation project

Design based on the current TB Register model

Records

TB case identifier

Paediatric contact demographic information

HIV status

Date for every follow-up visit to collect IPT

Number and dose of IPT issued

Number of returned tablets

Reason for stopping IPT before 6 months

Van Soelen, IJTLD 2013

RATIONAL IPT DELIVERY STRATEGIES

Prioritization of a CCM-friendly healthcare environment with improved CCM processes and tools; health education; and active, evidence-based strategies can decrease barriers.

A focused approach toward every aspect of the CCM cascade will likely diminish losses throughout the CCM cascade and ultimately decrease TB related morbidity and mortality in children.

Szkwarko D, Mandalakas.PLoS One. 2017

Tuberculous Infection Among Children by Type of Contact and Bacteriologic Status of Index Case, British Columbia and Saskatchewan, 1966 - 1971

0

5

10

15

20

25

30

35

40

Smear + Smear -

Pe

rc

en

t in

fec

ted

Grzybowski S. Bull Int Union Tuberc 1975

Risk of infection

Age Related Risk

Marais et al. Int J Tuberc Lung Dis. 2004, 8(4):392–402

IPT DELIVERY STRATEGIES

1. More pragmatic approaches: Smear+ and <3 years of age?

2. Shorter regimens?

3. Implementation tools, recording and reporting

4. Community-supported models of care

5. Integration with HIV and maternal care

6. Science under-explored – research needed

Sterling, NEJM, 2011

TBTC STUDY 26: EFFICACY OF 12 WEEKS RIFAPENTINE AND ISONIAZID

Safety End Points Among Children Who Received at Least 1 Dose of Study drug: Study 26

CHILD-FRIENDLY RPT FORMULATIONS

Water-dispersible FDC tablet: 150 mg RPT/150 mg INH

Water-dispersible RPT-only tablet

FAMILY- BASED APPROACHES TO IPT DELIVERY

Integration

EPI

IMCI

Intensified Case

Finding

IPT

Infection Control

CHALLENGING QUESTIONS

Repeat exposure – repeat screening – repeat IPT? How long does the protective effect of IPT last?

Need & feasibility of toxicity monitoring?

Preventive therapy in the context of MDR/XDR?

Cost-effectiveness of targeted IPT and role of screening

IPT in HIV-infected children without TB exposure/infection? 36 months regimen

IPT in HIV-infected pregnant women: IMPAACT P1078, P2001

Risk of infection, disease and MDR-TB preventive therapy in children

228 MDR-TB-exposed children <5 years of age enrolled (May 2010- April 2011)

45% were TST positive and 6.6% had prevalent TB at enrolment.

Children without TB received a routine regimen of INH (15-20mg/kg), ofloxacin (15-20mg/kg) and ethambutol (20-25mg/kg) daily for 6 months. Ofloxacin was available at the time; LFX now used in children < 8 years.

Children were monitored for clinical outcomes and adverse events, resulting in >200 patient years of follow-up.

Seddon. Clin Infect Dis. 2013

Micronesia MDR-TB outbreak

• MDR TB outbreak in the Federated States of Micronesia, HH contacts treated with 12 months moxi or LVF, with or without ethambutol or ethionamide

Bamrah S, IJTLD 2014

• Of 119 infected contacts, 15 refused; 104 began treatment• Of the 104 who initiated treatment, 93 (89%) completed

treatment, while 4 contacts discontinued due to adverse effects.

• None of the 104 contacts who undertook treatment of any duration developed MDR-TB disease

• 3 of 15 contacts who refused and 15 unidentified contacts developed MDR-TB disease.

• The regimens were safe and well tolerated, and no TB cases occurred among persons treated for MDR LTBI.

TB-CHAMP V-QUIN PHOENIx

Intervention LVF (novel paediatric dispersible formulation) vs. placebo daily for 6 months

LVF vs. placebo daily for 6 months

DLM vs standard dose INH daily for 26 weeks

Design Cluster randomized; superiorityCommunity-based

Cluster randomized; superiorityCommunity-based

Cluster randomized; superiorityCommunity-based

Target Population 0-5 y regardless of TST/IGRA or HIV status

• All ages • Paediatric enrolment

currently on hold (not treated)

• TST +

• HIV +• Children 0-5 yrs• TST/IGRA + > 5 y

Assumptions LVF decreases TB incidence from 7 to 3.5%80% power

LVF decreases TB incidence by 70% from 3% untreated 80% power

DLM decreases TB incidence by 50% from 5% to 2.5%90% power

Sample size 778 Households1556 contacts

1326 Households2785 contacts

1726 Households3452 contacts

Sites South Africa Viet NamNTP

ACTG & IMPAACT sites

Timelines to open Q1 2017 Open (Q1 2016) Q1 2018

Funder, PI BMRC/WellcomeTrust/DFID, SA MRC SHIP; Hesseling

Australian MRCFox, Nguyen

DAIDS, ACTH/IMPAACTChurchyard, Gupta, Hesseling, Swindells

3 sites 24 sites incl .SA

TB-CHAMP

Cluster randomised phase III superiority trial of Levofloxacin for the prevention of TB in child contacts of DR-TB index cases

Double-blinded; placebo-controlled

Levofloxacin 15-20 mg/kg vs. placebo, 6 months

3 SA sites:

1. Cape Town Metro (N=750): DTTC

2. Matlosana, Klerksdorp (n=500) : PHRU

3. Shandukani, Johannesburg (n=2500): WHRI