2. The story of Munya* (and us)
* Not his real name

4. Munya*
In December
HIV negative
Active TB

5. TB disease for Munya What??!! But how? What will people say?
Will I die?
Treatment for how long?
Will it work?

7. TB Treatment Shortening Regimens & Prevention of MDRTB in Household Contacts
Wilfred T. Gurupira MPH
ACTG Pharmacist of Record, Parirenyatwa CRS
UZ-UCSF Annual Research Day
05 May 2017

8. TB Disease Monitoring Disease burden Diagnosis and Treatment
Prevention
Social determinants
Financing
Research and development

9. A WORLD FREE OF TB Post-2015 strategy to end TB ZERO TB DEATHS ZERO
VISION
A WORLD FREE OF TB
TOWARDS
ZERO
TB DEATHS
ZERO
TB CASES
ZERO
TB SUFFERING

10. TB Transformative Science Group (TB TSG) Agenda
Treatment & prevention of TB with or without HIV co-infection
Anti-TB new drugs & combinations
Develop shorter Rx regimens
Rx for MDR/XDR TB
Optimal Rx of latent TB
Optimal Rx for TB in patients on ART
Evaluation of drug-drug interactions (anti-TB & ART)
Improved TB diagnostic assays & biomarkers to predict & detect disease

11. ii) TB Treatment Shortening Regimens

12. Current TB regimen: 6 months of treatment
2-month intensive phase with four drugs
rifampin, isoniazid, pyrazinamide, and ethambutol
(R) (H) (Z) (E)
4-month continuation phase with two drugs
isoniazid and rifampin
(H) (R)

13. Current TB Treatment Shortening Studies
Study
Description
Status
A5289
Phase 2 trial of Sutezolid for improving sputum conversion at 8 weeks
Protocol on hold
TBTC S31/A5349
Phase 3 trial of rifapentine + moxifloxacin to shorten TB therapy to 4 months
Enrolling
A5362
Phase 2 trial of clofazamine in drug susceptible TB
Protocol in development

14. TBTC S31/A5349: Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis

15. A5349/TBTC S31 International, multicenter trial
Randomized to one of 3 arms
AIM: To determine if one or two four-month regimens of TB treatment are as effective as a standard six-month regimen for treatment of pulmonary TB.

16. Primary Objectives
1. Does a high dose rifapentine-containing regimen work?
single substitution of Rifapentine for Rifamycin makes it possible to reduce treatment to 4 months (17 weeks)
2. Does double substitution work? Substitutes
high dose Rifapentine for Rifamycin and
Moxifloxacin for Ethambutol
determine whether reduction to 4 months (17 weeks) is possible

17. Study Intensive phase CONTROL REGIMEN (8 WEEKS)
INVESTIGATIONAL REGIMEN 1 (8 WEEKS)
INVESTIGATIONAL REGIMEN 2 (8 WEEKS)

18. Study Continuation phase
CONTROL REGIMEN (18 WEEKS)
INVESTIGATIONAL REGIMEN 1 (9 WEEKS)
INVESTIGATIONAL REGIMEN 2 (9 WEEKS)

19. Secondary Objectives safety of the regimens
tolerability of the regimens
Drug action (PK/PD)
all the drugs
efavirenz-based ARV treatment among patients with TB/HIV co-infection.

20. Study Population
Male & Female participants > 18 yr suspected to have pulmonary TB
diagnosis: AFB smear positive OR is Xpert positive
Target enrollment is 2,500 participants (TBTC and 13 ACTG International sites)
Harare site target 200 participants
Duration per participant is approximately 18 months

21. Study status Open to accrual Jan 2016
424/2500 enrolled ( as at 01 May 2017)
Harare Site started enrollment December 2016
25/200 currently enrolled

22. D.O.T. directly observed therapy
ALL three regimens administered daily, SEVEN days each week
Direct observation of each dose by a health-care worker at least FIVE of the SEVEN days
Rifapentine-containing regimen: take drugs within one hour after eating
Rifampin-containing regimen: drugs on an empty stomach

23. A5349 DOT
Ongoing
10 sites: City centre, Highfield (2), Glen View, Budiriro, Kuwadzana, Dzivarasekwa, Hopely, Caledonia, Mabvuku
Maintained 5/7 days – including weekend and holiday DOT

24. Munya* Started treatment and responded very well
Didn’t like DOT but never missed a day
A few months ago . . .

25. Tindo* Started coughing Initially ignored it but cough persisted
Diagnosed with active TB

26. Munya* Tindo*

27. TB Transformative Science Group (TB TSG) Agenda
Treatment & prevention of TB with or without HIV co-infection

28. Prevention of MDRTB in Household contacts

29. MDR TB in household (HH) contacts
Household (HH) contacts of MDR TB patients who become infected have a high risk of progressing to active TB and possibly death
Vast majority of MDR TB in children arises from HH transmission
TB among adolescents and adults may be also due to infections acquired within the community

30. How do we protect HH contacts of MDR cases?
No randomized controlled trials (RCTs)
guide the management of HH contacts exposed to MDR-TB patients
Inconsistent international and national guidelines
management of MDR TB contacts
WHO recommends follow-up. No drug regimen (based on limited evidence)
Urgent need for trials of TB preventive therapy for HH contacts of MDR TB patients

31. A5300B/I2003B/PHOENIx
Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (PHOENIx MDR-TB)

32. Phoenix Interventional trial ACTG study A5300B
Design
Multi-center trial comparing 26 weeks of delamanid to 26 weeks of Isoniazid
Aim: prevention of TB among high-risk adult and child HH contacts of MDR TB patients

33. A5300B Phoenix trial Sample size & duration
3,452 high-risk HH contacts (from 1,726 HH)
Follow-up: 96 weeks for each participating HH contact
Total study duration: 304 weeks (5.9 years)
Protocol still in development

34. Munya* Tindo*

36. Acknowledgements A5349 participants including Munya* and Tindo*
UZ-UCSF ACTG CAB
Sponsors: NIAID,NIH, CDC, TBTC, ACTG
UZ-UCSF leadership
Prof JG Hakim, Parirenyatwa CRS Leader
Dr W Samaneka, A5349 site PI
ACTG site staff especially Pharmacists and DOT workers