BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is critical to the end TB strategy. There is limited evidence on its long-term protective effect among people living with HIV (PLWH) receiving antiretroviral therapy (ART) in high-burden programmatic settings. METHODS: This observational cohort study included PLWH who initiated a single TPT course from March 2017 to September 2018 at 14 ART centres in Andhra Pradesh, India (TB prevalence: 274/100,000). We followed PLWH for 6 years and censored person-time at TB diagnosis, loss to follow-up, or death. We calculated TB incidence rates (IR) and mortality rates (MR) per 100 person-years (PY) stratified by TPT completion and effective ART (viral load<1000 copies/ml). Cox-proportional hazards models estimated adjusted hazard ratios (aHR) with 95% confidence limits (95% CL) for TB and mortality. FINDINGS: We followed 4,706 PLWH for 23,414 PY. TB was diagnosed in 135 PLWH (2.9%)-122 among 4,454 PLWH who completed TPT (IR: 0.55/100PY, 95% CL: 0.46-0.66), and 13 among 252 PLWH who did not (IR: 1.06/100PY, 95% CL: 0.56-1.81). There were 553 all-cause deaths (11.8%)-MR: 2.2/100PY (95% CL: 2.0-2.4) among those who completed TPT compared to 13.5/100PY (95% CL: 11.1-16.3) among those who did not. TPT, combined with effective ART, was associated with an 87% reduction in TB (aHR: 0.13; 95% CL: 0.05-0.37) and a 94% reduction in all-cause mortality (aHR: 0.06; 95% CL: 0.04-0.10). CONCLUSION: A single TPT course combined with effective ART conferred durable protection against TB and significantly reduced mortality among PLWH in a high-burden TB setting.

BACKGROUND: The advanced disease management (ADM) package, which aims to reduce morbidity and mortality in people with Advanced HIV disease (AHD, WHO stage III/IV and/or CD4 count < 200 cells/mm(3) or age < 5 years), is not fully implemented in India. We assessed the feasibility of implementing the full WHO ADM package as part of routine HIV care under the programmatic setting in antiretroviral therapy centers of Mumbai. METHODS: We implemented the ADM package (screening, treatment, and prophylaxis for major opportunistic infections, rapid ART initiation, and ART adherence support) in 17 ART centers from October 2020 to December 2021. Treatment naïve and experienced persons with AHD, including children, were enrolled. We assessed the feasibility through coverage of ADM package components and reported the proportion of rapid ART initiation (≤ 7 days), cotrimoxazole prophylaxis, TB preventive treatment (TPT) for those eligible [(excluded active TB disease (n = 280) and those completed TPT prior to enrolment (n = 1,186)], TB-LAM screening (excluded current TB disease), and cryptococcal antigen (CrAg) assay (excluded children < 10 years of age). We used a point of care test for TB (LAM) and cryptococcus (CrAg) screening. We followed the prospective cohort for one year (through 31 July 2022) to document outcomes for survival and lost to follow- up (LTFU). RESULTS: We identified 4,334 PLHIV with AHD and provided the full ADM package to 64% (2,779/4,334); 297 did not receive ADM (146 died, 151 LTFU), and 1,258 received routine standard of care (587 had TB, 366 were at decentralized sites, and 305 LAM/CrAg kits were not available) with existing ART center staff. Nearly 78% (385/494) of treatment naïve were rapidly initiated on ART. Nearly 82% (1,129/1,383) and 99% (2,751/2,779) received TPT and cotrimoxazole prophylaxis, respectively. Of the eligible, 99% (2,508/2,524) and 98% (2,715/2,758) were screened for TB and cryptococcal infection, respectively. At the end of 12 months, 88% (2,458/2,779) were alive, 8% (210/2,779) died, and 4% (111/2,779) were LTFU. Mean survival time was significantly (p < 0.001) higher among treatment experienced people; 11.6 months (95% CI: 11.5,11.7) compared to treatment naïve people 10.8 months (95% CI: 10.5,11.0). CONCLUSION: With careful anticipatory planning, stakeholder engagement, and training, implementing the full ADM package is feasible in a routine program setting with existing human resources. Additional intensive case management may be necessary for the reduction of mortality among treatment naïve PLHIV.

OBJECTIVES: To describe the implementation of screening for cryptococcal antigenaemia by point-of-care (POC) serum cryptococcal antigen (CrAg) lateral flow assay, measure the prevalence and factors associated with serum cryptococcal antigenaemia in the routine programmatic setting. DESIGN: Cross-sectional study. SETTING: Seventeen publicly funded antiretroviral therapy (ART) centres in Mumbai, India. PARTICIPANTS: Serum CrAg screening was offered to all adolescents (>10 years of age) and adults with advanced HIV disease (AHD) (CD4 <200 cells/mm(3) or with WHO clinical stage III/IV) regardless of symptoms of cryptococcal meningitis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to describe the implementation of serum CrAg screening and secondary outcome was to measure the prevalence of serum cryptococcal antigenaemia and its risk factors. RESULTS: A total of 2715 patients with AHD were tested for serum CrAg by POC assay. Of these, 25 (0.9%) had a CrAg positive result. Among CrAg-positive patients, only one had symptoms. Serum CrAg positivity was 3.6% (6/169) and 1.6% (6/520) among those presenting with CD4 <100 cells/mm(3) in the treatment naïve and treatment experienced group, respectively. On multivariable analysis, CD4 count <100 cells/mm(3) (OR: 2.3, 95% CI 1.01 to 5.3; p=0.05) and people living with HIV who were treatment naïve (OR: 2.5, 95% CI 1.04 to 6.0; p=0.04) were significantly associated with a positive serum CrAg result. Lumbar puncture was obtained in 20/25 patients within 4 days (range: 1-4 days) of positive serum CrAg result and one person was confirmed to have meningitis. All serum CrAg-positive patients who had a negative cerebrospinal fluid CrAg were offered pre-emptive therapy. CONCLUSIONS: Implementation of a POC CrAg assay was possible with existing ART centre staff. Initiation of pre-emptive therapy and management of cryptococcal antigenaemia are operationally feasible at ART centres. The Indian National AIDS Control Programme may consider reflexive CrAg screening of all AHD patients with CD4 <100 cells/mm(3).

Since September 2015, the World Health Organization has recommended antiretroviral therapy (ART) for all persons with human immunodeficiency virus (HIV) infection, regardless of clinical stage or CD4 count (1). This Treat All policy was based on evidence that ART initiation early in HIV infection as opposed to waiting for the CD4 count to decline to certain levels (e.g., <500 cells/mm(3), per previous guidelines), was associated with reduced morbidity, mortality, and HIV transmission (2-4). Further, approximately half of persons enrolled in non-ART care that included monitoring for HIV disease progression (i.e., in pre-ART care) were lost to follow-up before becoming ART-eligible (5). India, the country with the third largest number of persons with HIV infection in the world (2.1 million), adopted the Treat All policy on April 28, 2017. This report describes implementation of Treat All during May 2017-June 2018, by India's National AIDS Control Organization (NACO) and partners, by facilitating ART initiation among persons previously in pre-ART care at 46 ART centers supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR)* in six districts in the states of Maharashtra and Andhra Pradesh. Partners supported these 46 ART centers in identifying and attempting to contact persons who were enrolled in pre-ART care during January 2014-April 2017, and educating those reached about Treat All. ART center-based records were used to monitor implementation indicators, including ART initiation. A total of 9,898 (39.6%) of 25,007 persons previously enrolled in pre-ART care initiated ART; among these 9,898 persons, 6,315 (63.8%) initiated ART after being reached during May 2017-June 2018, including 1,635 (16.5%) who had been lost to follow-up before ART initiation. NACO scaled up efforts nationwide to build ART centers' capacity to implement Treat All. Active tracking and tracing of persons with HIV infection enrolled in care but not on ART, combined with education about the benefits of early HIV treatment, can facilitate ART initiation.