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

Munya* In December HIV negative Active TB

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

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

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

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

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

ii) TB Treatment Shortening Regimens

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)

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

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

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.

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

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

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

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.

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

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

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

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

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

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

Munya* Tindo*

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

Prevention of MDRTB in Household contacts

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

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

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

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

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

Munya* Tindo*

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