Direct and indirect factors associated with health-related quality of life among PLHIV on second-line antiretroviral therapy at Dessie and Woldia Comprehensive Specialized Hospitals in Ethiopia: application of structural equation modelling

People living with HIV have a longer lifespan and a lower mortality rate due to advancements in antiretroviral therapy. However, the clinical signs of HIV and psychological difficulties continue to impair their health-related quality of life. Therefore, this study aimed to assess health-related quality of life and examine the direct and indirect factors influencing it among people living with HIV on second-line antiretroviral therapy in Dessie and Woldia Comprehensive Specialized Hospitals Northeast Ethiopia. An institutionally based cross-sectional study was conducted in Dessie and Woldia Comprehensive Specialized Hospitals in Northeast Ethiopia from January 13 to April 13, 2025, with 825 people living with HIV on second-line antiretroviral therapy selected through simple random sampling. Data were collected through face-to-face interviews, document reviews, and analyzed with STATA version 17. Quality of life was measured with the WHOQOL-HIV BREF, and depression with the PHQ-9. Structural equation modeling was employed to assess the direct and indirect effects of variables on quality of life. Statistical significance was declared at P < 0.05, and effect sizes are reported with 95% CIs. The findings were presented through text, tables, and graphs. The mean quality of life score was 48.7 (95% CI: (47.44, 49.96)). Internalized stigma had a direct [β ̂ = −0.59, (95% CI: -0.80, -0.381)] and indirect [β ̂ = −0.16, (95% CI: -0.249, -0.077)] negative effect on overall quality of life. The absence of opportunistic infection had a direct [β ̂ = 0.14, (95% CI: 0.028–0.248)] positive effect on overall quality of life. Depression had a direct [β ̂ = −0.54, (95% CI: -0.734, -0.339)] negative effect on the physical domain quality of life. Social support had a direct [β ̂ = 0.20, (95% CI: 0.046, 0.337)] positive effect on the social domain quality of life. Moreover, patients with nonworkable functional status had a 0.18 lower physical domain quality of life score [β ̂ = −0.18, (95% CI: -0.358, -0.008)]. Health-related quality of life for individuals living with HIV receiving second-line antiretroviral therapy was found to be significantly impacted psychosocial and clinical variables. It was predicted by opportunistic infections, social support, depression, internalized and perceived stigma, and functional status. Therefore, regular mental health screenings and interventions should be strengthened and integrated into HIV care programs at healthcare facilities.