PROJECT SUMMARY/ABSTRACT The purpose of this project is to optimize a smoking cessation program for PWH in South Africa by evaluating the efficacy, implementation, and cost-effectiveness of evidence-based smoking cessation interventions with demonstrated success in other low-resource settings. South Africa is home to 7.5 million people with HIV (PWH), nearly 20% of the global burden. South Africa also has one of the highest annual tuberculosis (TB) incidences globally (520/100,000) and an increasing burden of cardiovascular disease and chronic obstructive pulmonary disease (COPD). Smoking is a risk factor for TB, the leading cause of death among PWH. Further, PWH are at high risk for other smoking-related diseases, including cardiovascular disease and pulmonary comorbidities in addition to TB. In South Africa, tobacco smoking is prolific; we have found 52% of men and 13% of women with HIV to be current smokers. South African policy supports screening for smoking and smoking cessation efforts for PWH; these are included in the South African National antiretroviral therapy (ART) guidelines, the South African STG-EML, and the South African clinical practice guidelines. Currently, screening for smoking in primary care settings is low and delivery of smoking cessation interventions even lower. Effective strategies to support smoking cessation among PWH are necessary to reduce the burden of HIV- and smoking-associated comorbidities. We have found that social and interpersonal stressors and difficulty managing cravings are barriers to cessation among PWH who smoke in South Africa. Interventions developed for low-resourced settings often address these proximal predictors and mediators of cessation, and can be easily adapted for South Africa, provided they result in meaningful smoking abstinence rates and are feasible to implement. We will evaluate four evidence-based smoking cessation interventions that address these identified challenges: (1) intensive behavioral counseling, (2) peer counseling, (3) combination nicotine replacement therapy, and (4) varenicline. Intervention development is guided by the Multiphase Optimization Treatment Strategy (MOST), a framework for developing, optimizing, and evaluating interventions with consideration of time and financial resources, as well as feasibility of implementation and cost. During this optimization phase of MOST, our first aim will evaluate the main and interaction effects of these interventions among PWH. The second aim will characterize implementation determinants of delivery of these smoking cessation interventions using the Reach, Effectiveness, Adoptions, Implementation, Maintenance (RE-AIM) framework to inform scale-up and sustainability. The third aim will compare the costs, cost-effectiveness, and budget impact of smoking cessation interventions implemented as a routine program. Results will inform the development of a smoking cessation treatment package optimized for PWH engaged in the South Afric...