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HIV has remained a public health problem in Nigeria. The purpose of this cross-sectional study was to examine the effect of social support and HIV-related stigma on depression in people living with HIV/AIDS (PLWHA) and to examine the moderating effect of sociodemographic factors, Quality of Life (QOL), and time since HIV diagnosis on this relationship. This study was based on the social cognitive theory. Data were collected from 98 PLWHA attending the antiretroviral clinic of Federal Medical Center, Umuahia, Nigeria. Regression analyses were used to examine the relationships between the variables. Some 24.5% of the study participants were depressed. Significant relationships identified included negative relationships between depression and social support, positive relationships between depression and negative self-image, and a combination of poor social support and HIV-related stigma having synergic effects in predicting depression. Sociodemographic variables, quality of life, and time since HIV diagnosis did not have a moderating effect on the relationship between social support, HIV-related stigma, and depression in PLWHA. There is a need to improve social support and reduce HIV-related stigma in PLWHA in order to improve their mental health. These findings can help in bringing about positive social change by informing the development of public health initiatives aimed at improving the mental health of PLWHA.