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