A randomized trial of therapy shortening for minimal tuberculosis with new WHO-recommended doses and FDC drugs in African/indian HIV+/HIV- children. (360G-Wellcome-102225_Z_13_Z)

1) To determine whether treatment of minimal TB disease in children for 4 months results in 18-month disease-free survivalthat is non-inferior to treatment for 6 months, both with standard, but recently increased doses (WHO recommendation) ofanti-TB regimens of isoniazid and rifampicin supplemented by pyrazinamide for the first 2 months and ethambutol in areasof high HIV prevalence.2) To determine via nested PK substudies:a) The plasma PK of Isoniazid, rifampicin and pyrazinamide taken as daily new paediatric fixed-dose dispersible tabletcombinations in African and Indian HIV-infected and uninfected children across different ages according to weight-baseddosing tables. Results would be compared to values following administration of single drugs (within child) and to historicaldata in adults and children.b) To describe the effect of rifampicin on the PK of key antiretroviral drugs (efavirenz at standard doses in children olderthan 3 years; ritonavir-boosted lopinavir (with additional ritonavir boosting), nevirapine in fixed dose combinations withadded neviripine; zidovudine and abacavir in triple nucleoside regimens.c) to evaluate the association between PK and adverse drug effects and to response to anti-TB drugs.d) Using PK modeling, to simulate dosing approaches in different groups of children (race, age, nutritional status, cotreatmentwith ART).