Generating Evidence

A critical pillar of the IMPAACT4TB project is the ongoing generation of evidence to ensure that decisions about the use of short-course preventive therapies – including 3HP – are based on the latest available scientific knowledge. Consortium members are carrying out ongoing implementation research to evaluate RPT/DTG drug-drug interactions, models of delivery, and the feasibility, impact and cost-effectiveness of implementing 3HP for PLHIV and child contacts.

Study 1: 3HP/dolutegravir safety and pharmacokinetics study.

Study 2: Phase I/II dose finding and safety study of rifapentine in HIV-infected and HIV-uninfected children with latent TB infection (Tuberculosis Trials Consortium (TBTC) Study 35 (S35)). The study is being supported by the US Centers for Disease Control and Prevention (CDC) for one site at Desmond Tutu TB Centre at Stellenbosch University and IMPAACT4TB will be supporting an additional site at Perinatal HIV Research Unit (PHRU), in Soweto, South Africa, to accelerate the completion of the trial. The study will evaluate the pharmacokinetics (PK), safety and tolerability of rifapentine given in a new fixed dose combination once-weekly, in combination with isoniazid for 12 weeks, in HIV-infected and HIV-uninfected children aged 0-12 years in whom latent TB infection treatment is indicated. The study utilizes a modified age de-escalation approach given the extensive PK and safety data already available in children older than two years of age. The study will identify new PK and safety data for children under two years of age. The protocol allows for parallel enrolment of children into cohorts 1 and 2, simultaneously, using a predetermined modelled initial dose for each cohort, separately. Similarly, cohorts 3 and 4 will be enrolled in parallel, using modelled doses for each cohort, based on data from cohorts 1 and 2 and historical data from TBTC trials.

Study 3: Compare contact investigation models for increasing 3HP uptake among children under the age of five who are exposed to TB.

Study 4: Compare health system models of 3HP delivery to increase proportion of eligible participants initiating 3HP among PLHIV.

Study 5: Impact and cost effectiveness modelling: The impact and cost-effectiveness modelling will include a general (“global”) model, as well as specific models to represent the epidemic and economic contexts in at least three key implementing countries (to be determined). Primary outcomes will include the projected reductions in TB incidence and mortality over a ten-year time period, as well as the incremental cost-effectiveness (in terms of cost per DALY averted), associated with scale-up of 3HP for TB prevention among children and PLHIV.

India is strategically important to IMPAACT4TB due to the potential high volume market for 3HP, the large public health impact of scaling up 3HP, and the generic manufacturers that could potentially produce RPT. A demonstration project will be undertaken in India to generate evidence to support adoption of 3HP. Part of the transition strategy in our IMPAACT4TB countries is to build evidence by strengthening Monitoring & Evaluation and evaluating innovative, affordable, delivery models and communicating lessons learnt in scaling up 3HP. This will encourage other donors to fund and non-project countries to adopt and scale-up 3HP.