Can community-wide active case finding for tuberculosis and universal testing and treatment for HIV control the African tuberculosis epidemic?

Tuberculosis (TB) is an infectious disease, which is spread when the bacteria causing TB is released into the air by TB cases when they cough. Globally one third of the worlds population is infected with TB and 9 million new cases of disease, with 1.5 million deaths occurred in 2013.

Only 1 in 10 individuals infected with TB goes on to develop disease but the risk is much higher in individuals who have a weakened immune system such as those infected with HIV. Because of the overlap between HIV and TB, sub-Saharan Africa has the highest rate of TB disease. But, with increasing globalisation and travel, this has also translated into increasing rates in other parts of the world such as the UK. Therefore preventing TB in sub-Saharan Africa helps countries devastated by this disease, and also decreases the risk of TB worldwide. To control TB a consistent decrease in the number of new cases and improved TB case outcomes (e.g. less deaths) are needed in the whole population.

There is no effective vaccine against TB. However, if TB cases are identified earlier and started on effective treatment, before they normally present to healthcare, TB spread to others could be reduced. Active case finding for TB (ACF) involves systematically screening the whole population for TB disease and starting cases on treatment. This benefits the individual and should decrease the number of new cases by decreasing the spread of TB. Antiretroviral therapy (ART) improves a HIV-infected person's immune function and decreases their susceptibility to TB. Therefore if rolled-out widely to those who need it, ART should decrease the number of new TB cases. However to date, we don't have any strong evidence to show that ACF and ART can control TB in populations.

HPTN071 is a large trial being conducted in 21 Zambian and South African communities, two countries devastated by TB and HIV, by the London School of Hygiene and Tropical Medicine in the UK, Zambart in Zambia and the Desmond Tutu TB Centre in South Africa. In this trial 14 intervention communities receive a HIV prevention package administered to the entire population and 7 control communities receive usual care. In the intervention communities, from 2014-2018, all adults and children are tested annually for HIV ("universal testing"). ART is started immediately in 7 communities ("universal treatment") and according to national guidelines in 7 communities. The trial will determine if new HIV infections can be decreased by this strategy of universal test and treat. To measure this, the study will follow 52500 adults aged 18-44 years for 3 years from all 21 communities, and compare the number of new HIV infections in the intervention and control communities. Given the TB problem in these communities, all individuals in the intervention communities are also asked about TB symptoms (e.g. cough, night sweats etc). If symptoms are reported, sputum is collected and tested for TB, with referral to local TB clinics for treatment.

HPTN071 therefore combines community-wide ACF for TB and ART for HIV. It provides a unique opportunity to study if these interventions together can decrease the number of new TB cases and improve the clinical outcomes of TB cases. This proposed project will use information from the HPTN071 trial as well as the national TB records for these communities to see if the number of new TB cases have reduced in the intervention communities compared to the control communities, and also what the clinical outcomes for these patients are. A mathematical model will be used to better understand and tease out the effects of the two interventions.

This project has the potential to change our approach to TB prevention in sub-Saharan Africa. It is an important study, which will make a major contribution in the fight against one of the most important diseases in the world.

Current strategies are failing to control the HIV-driven African TB epidemic. Two important control measures are active case finding for TB (ACF) and antiretroviral therapy (ART). ACF involves systematic TB screening, to identify and treat infectious cases early and prevent the onward spread of TB. ART decreases the susceptibility to TB among people living with HIV. However, their effect on TB epidemiology is unclear.

In HPTN071 a three armed (2 intervention and a control arm) cluster randomised controlled (CRT) HIV-prevention trial in 21 Zambian and South African communities, a community-wide intervention package (including universal testing and treatment for HIV [UTT] and ACF) is being implemented in the intervention arms from 2014-2018. The control arm receives the current standard of care. Intervention effects on HIV incidence will be measured among an adult (18-44 years) cohort (N=52500), followed-up for 36 months from all 21 communities.

HPTN071 provides an unprecedented opportunity to determine the combined effect of community-wide ACF and UTT on TB epidemiology (incidence and outcomes). The objectives of this project nested in HPTN071 are to:
1. Determine ACF and UTT effects on population-level TB incidence: effect on TB incidence in the adult cohort (N=52500) and on routine TB case notification rates
2. Determine ACF and UTT effects on TB case characteristics, fatality rates and treatment outcomes
3. Use mathematical modelling to describe the current and projected ACF and UTT effects on TB prevalence and incidence

This project involves secondary data analysis using routine and HPTN071 research data. Statistical methods for CRTs will be used. The HPTN071 TB model that has been developed will be refined, parameterised with all study data and used to estimate and project intervention effects on TB epidemiology. This study will provide data to a pressing Global Health question and inform the TB prevention landscape in sub-Saharan Africa.

This research will produce high quality evidence on whether community-wide active case finding for TB and universal testing and treatment for HIV can change TB epidemiology in sub-Saharan Africa.

Direct/immediate beneficiaries
The general population in the HPTN071 communities will directly benefit from this project. TB is a major cause of morbidity and mortality in these communities, where the epidemic predominantly affects young people in the prime of their lives. The health and economic costs associated with TB are significant. Therefore an intervention that prevents TB and improves patient outcomes will contribute towards both individual and national health and wealth.

Indirect/long-term beneficiaries
Key stakeholders and the wider research and policy sectors will benefit from the research findings over a 1-3 year period. While the study is conducted in Zambia and South Africa, findings will be relevant to other sub-Saharan African countries with generalised HIV-driven TB epidemics. Therefore the potential scale of impact of the project is large. The beneficiaries include:

1) National Governments
The Ministry of Health in Zambia and Department of Health in South Africa are key policy makers for these countries. The HPTN071 team work closely with these partners and all results from this project and the parent HPTN071 trial will be disseminated to them, aiming to change policy and practice in the countries. TB prevention is a priority area for these countries and therefore research findings will be of interest to them. A combined intervention that targets both TB and HIV, two of the biggest Public Health problems in the region, is likely to be much more feasible, efficient and cost saving than a single disease approach. The process data from this project will inform programme roll-out and further operational research needs.

2) Wider public
The results will be disseminated widely in Zambia and South Africa and presented to key policy makers, aiming to benefit the country's general population. TB control is a priority area across sub-Saharan Africa and the findings of this project has the potential to change the TB epidemics in these countries. Therefore research findings will be widely relevant in sub-Saharan Africa and can benefit the general population in the region.

3) Public Health and clinicians
Results are relevant to Public Health practitioners and clinicians working in sub-Saharan Africa. The finding will inform their knowledge and changes in TB prevention practices which may result as a consequence of this project will be relevant to their day to day function.

4) Non-governmental organisations
In sub-Saharan Africa, non-governmental organisations such as Médecins Sans Frontières work in close partnership with national governments to provide TB prevention, treatment and care services. The project results will be relevant to them and could change their TB prevention policy, approach and practice in the region.

5) International policy and funding agencies (World Health Organization, the United States Presidents Emergency Plan for AIDS Relief, The Global Fund to Fight AIDS, Tuberculosis and Malaria, the Bill and Melinda Gates Foundation and the Joint United Nations Programme on HIV/AIDS)
TB is a major priority area for international policy and funding agencies. The findings can help guide international policy on TB prevention in sub-Saharan Africa. It can provide strategic direction for major implementation funders in the region.

6) Academics
Findings will inform academics in the field of TB, HIV and Global Health. It will inform future work on TB prevention, epidemiology and areas for operational research to optimise intervention coverage/uptake. It will add to the expertise and profile of the Clinical Research Department at the London School of Hygiene and Tropical Medicine, which could attract future grants.