Tuberculosis (TB) is a highly stigmatized disease, and approximately one-third of the Cambodian population living with TB are undetected. Therefore, it is vital to find these missing cases and promptly link them to care to reduce disease progression and interrupt further transmission. The integration of community-based, peer-driven intervention in TB active case finding (ACF) is relatively novel. In partnership with KHANA, the National Center for Tuberculosis and Leprosy Control (CENAT), and the Cambodia Anti-Tuberculosis Association (CATA), we will conduct a pragmatic cluster randomized controlled trial comparing 1) the ACF with the seed-and-recruit model; 2) ACF targeting household and neighborhood contacts; 3) ACF targeting the older population using mobile screening units; and 4) passive case finding (PCF) approach. The primary outcome will be the case notification rate in the intervention and control districts during the study period. We will also determine additionality, comparing the yield in each arm with its respective historical baseline and the cumulative yield over the implementation period. The secondary outcomes include the number needed to screen to detect one TB case, cost-effectiveness (direct and indirect costs per TB case notified), and the treatment outcome of all people with TB in this study. The project will be carried out over two years in eight operational districts (province name in parenthesis) - Koh Soutin (Kampong Cham), Stong (Kampong Thom), Kanchreach (Prey Veng), Choeung Prey (Kampong Cham), Dambae (Thbong Khmum), Boribo (Kampong Chhnang), Ponhea Leu (Kandal), and Phnom Srouch (Kampong Speu) - in Cambodia. The selection was also based on the number of health centers to increase comparability and generalizability of study findings. This study will randomize currently underserved operational districts (without active intervention at least in the past six months from the implementation date) to receive the interventions (ACF) and PCF as the control. The results from this proposal will enable a nationwide scale-up of an effective intervention that is contextualized and complies with the principles set by the national TB program to find undiagnosed cases and control TB in Cambodia. Also, this project will complement existing ACF programs in Cambodia by expanding ACF to other operational districts that are currently not served by the Global Fund, its implementing partners, and other organizations. Findings from this trial could also potentially inform active case finding strategies in other countries with a high TB burden.

Tuberculosis (TB) is a leading infectious cause of morbidity and mortality worldwide, accounting for 10 million new cases and 1.6 million deaths in 2017. The disease burden is disproportionately concentrated in low- and middle-income countries with over 95% of TB deaths contributed by these regions. In 2016, the number of new TB cases was estimated at 10 million, and nearly 40% remained undiagnosed. Limited access to health care, high treatment cost, and social stigma of TB contributed to delayed detection and poor treatment uptake. Other risk factors such as poor living conditions and overcrowding further perpetuated the transmission of TB, which, in turn, leads to social and economic insecurity. Cambodia is one of the countries with the world's highest burden of TB, with an estimated incidence of active TB of 326 (95% CI: 224-447) per 100,000 population in 2017. Through the years, TB control programs in Cambodia has achieved significant milestones made possible by committed partners and focused efforts at the grassroots, national, and international level. In 2016, the TB incidence was approximately half of that in the year 2000, and a similar decline was observed in the TB mortality rate. Furthermore, the country has made notable progress in the fight against TB by achieving a treatment success rate of 94%, one of the highest among the 30 high TB burden countries.

However, the successes are impeded by a significant proportion of undiagnosed cases. Globally, it is estimated that 36% of the TB cases were undiagnosed in 2017, and a similar proportion is observed in Cambodia. Traditionally, TB cases are captured and passively notified when people with TB present themselves to a health facility. In recent years, a more proactive strategy to increase TB case notification, namely active case finding (ACF) has gained traction and is reported to be effective. Alongside passive case finding (PCF), the ACF strategy has been adopted by countries affected by the epidemic, including Cambodia, to reach people with TB effectively. Nevertheless, despite increased efforts to improve case detection, TB case finding remains a great challenge due to limited resources, geographical barriers, and social stigma. The current approaches rely solely on skilled healthcare workers and community health volunteers to find TB cases. Its utility and sustainability, in the long run, have yet to be substantially demonstrated.

Empirically, a snowball approach (seed-and-recruit mechanism) has been widely accepted to reach concealed populations such as populations who are at-risk for HIV in many countries, including Cambodia, due to its practical feasibility. A community-based peer-led strategy as such has been an inherent component in HIV responses worldwide, and successes have been reported. However, little is known about the feasibility and effectiveness of ACF with the snowball model in improving TB case notification. However, given the comparable hard-to-reach nature of HIV and TB populations, it is a concept worth exploring. In partnership with KHANA, the National Center for Tuberculosis and Leprosy Control (CENAT), and the Cambodia Anti-Tuberculosis Association (CATA), this project seeks to examine the effectiveness of different ACF strategies in increasing TB case notification in the community and its impact on treatment outcome. This project is congruent with the global plan to end TB. and the Global Fund's strategy 2017-2022 by informing sustainable and evidence-based solutions for TB control in Cambodia.

We will conduct a cluster randomized controlled trial with four arms comparing ACF with the seed-and-recruit model, other ACF approaches, and PCF approach in eight operational districts in Cambodia. The project will be carried out over two years. ACF with the seed-and-recruit model by KHANA, ACF targeting household and neighborhood contacts by CENAT, ACF targeting the older population using mobile screening units by CATA will be implemented in the intervention arms and PCF will be implemented in the control arm. These case finding strategies have been piloted in Cambodia, and they are endorsed by the national TB program in Cambodia. This study will randomize currently underserved operational districts (without active intervention, at least in the past six months from the implementation date). The interventions will be carried out as per the protocol devised by the partner organizations, respectively.

This study aims to 1) evaluate the effectiveness of an ACF strategy using a seed-and-recruit model for increasing TB case notification (case notification rate, additionality, comparing the yield in each arm with its respective historical baseline and the cumulative yield over the implementation period) in Cambodia, 2) establish the effect of ACF strategies on TB treatment outcomes, 3) evaluate number needed to screen to detect one TB case and the cost-effectiveness (costs per TB case notified) of different ACF strategies.

Inclusion Criteria:

Presumptive TB cases will be referred to the health centers for TB screening and diagnosis in the intervention arms and self-presented to the health centers in the control arm. We will include the aggregated number of cases diagnosed and notified from all arms regardless of age. In this project, an individual is defined as a presumptive TB case if he/she exhibits any of the following symptoms19:

1. Pulmonary TB (PTB): A cough more than two weeks and at least one general symptom
2. Extra-pulmonary TB (EPTB): Presence of symptoms, depending on the location of TB, (e.g., cervical lymph node, swollen backbone, swollen articulation, etc.) and at least one general symptom
3. General symptoms: Fever, night sweat for more than two weeks or unintentional weight loss (>5% reduction in usual body weight over the last 6 to 12 months)20

People newly diagnosed with TB age 18 and above* from the selected health centers. We will only include all people with TB aged 18 years or over with TB (all-forms) for the baseline and follow-up survey.

Exclusion Criteria:

• We will exclude those who refused to participate.

IPD will be made available upon request due to ethics restriction.

Project coordinators and residents in the selected operational districts will not be masked to the intervention. However, all case finding activities will be done without reference to the intervention group. The data analysts will be masked to intervention allocation and will only analyse de-identified data.