Introduction Failure on second-line antiretroviral therapy (ART) with protease inhibitor (PI) mutations is on the rise. However, there is a paucity of information on the factors associated with this observation in the context of low-income countries. Knowledge of underlying factors is key if we are to minimize the number of PLHIV switched to costly third-line ART. Our study investigated the factors associated with failure on second-line ART with PI mutations. Methods We conducted a matched

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... control analysis of patients' records kept at the Joint Clinical Research Center, starting from January 2008 to May 2018. We matched records of patients who failed the second-line ART with major PI mutations (cases) with records of patients who were virologically suppressed (controls) by a ratio of 1:3. Data analysis was conducted using STATA Version 14, and descriptive statistics comparing cases and controls were generated. Categorical variables were compared with the outcome, failure on second line ART with PI mutations using the Chi-square and Fisher's exact tests where appropriate. Conditional logistic regression for paired data was used to assess the association between the outcome and exposure variables, employing the backward model building procedure was done. Results Of the 340 reviewed patients' records, 53% were women, and 6.2% had previous Tuberculosis treatment. Males (aOR 2.64 CI: 1.0-4.64), type of second-line ART (aOR 3.92 CI: 1.15-13.38), and Tuberculosis treatment while on second-line ART (aOR7.08 CI: 2.35-21.29) highly predicted failure on second-line ART with PI mutations. Conclusion Males and patients concomitantly on Tuberculosis treatment while on second-line ART are at a higher risk of failing on second-line ART with PI mutations. HIV/AIDS response programs should give special attention to this group of people if we are to minimize the need for expensive third-line ART. More extensive explorative studies to ascertain underlying factors are recommended.