Marked sex differences in all-cause mortality on antiretroviral therapy in low-and middle-income countries: A systematic review and meta-analysis

Introduction: While women and girls are disproportionately at risk of HIV acquisition, particularly in low- and middle-income countries (LMIC), globally men and women comprise similar proportions of people living with HIV who are eligible for antiretroviral therapy. However, men represent only approximately 41% of those receiving antiretroviral therapy globally. There has been limited study of men's outcomes in treatment programmes, despite data suggesting that men living with HIV and engaged in treatment programmes have higher mortality rates. This systematic review (SR) and meta-analysis (MA) aims to assess differential all-cause mortality between men and women living with HIV and on antiretroviral therapy in LMIC. Methods: A SR was conducted through searching PubMed, Ovid Global Health and EMBASE for peer-reviewed, published observational studies reporting differential outcomes by sex of adults (≥15 years) living with HIV, in treatment programmes and on antiretroviral medications in LMIC. For studies reporting hazard ratios (HRs) of mortality by sex, quality assessment using Newcastle-Ottawa Scale (cohort studies) and an MA using a random-effects model (Stata 14.0) were conducted. Results: A total of 11,889 records were screened, and 6726 full-text articles were assessed for eligibility. There were 31 included studies in the final MA reporting 42 HRs, with a total sample size of 86,233 men and 117,719 women, and total time on antiretroviral therapy of 1555 months. The pooled hazard ratio (pHR) showed a 46% increased hazard of death for men while on antiretroviral treatment (1.35-1.59). Increased hazard was significant across geographic regions (sub-Saharan Africa: pHR 1.41 (1.28-1.56); Asia: 1.77 (1.42-2.21)) and persisted over time on treatment (≤12 months: 1.42 (1.21-1.67); 13-35 months: 1.48 (1.23-1.78); 36-59 months: 1.50 (1.18-1.91); 61 to 108 months: 1.49 (1.29-1.71)). Conclusions: Men living with HIV have consistently and significantly greater hazards of all-cause mortality compared with women while on antiretroviral therapy in LMIC. This effect persists over time on treatment. The clinical and population-level prevention benefits of antiretroviral therapy will only be realized if programmes can improve male engagement, diagnosis, earlier initiation of therapy, clinical outcomes and can support long-term adherence and retention.