Introduction For people living with HIV (PLHIV) who are on second-line antiretroviral therapy (ART), attaining viral resuppression is vital to support immune recovery, avoid antiretroviral resistance, and lower HIV-associated morbidity, mortality, and onward transmission. However, evidence on the level of resuppression and its determinants in Ethiopia is limited. Objective To assess the viral resuppression rate and identify predictors among PLHIV on second-line ART at Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. Methods An institution-based retrospective cohort study was conducted at the ART clinic of the University of Gondar Comprehensive Specialized Hospital from November 2021 to May 2022. Patient charts of 385 individuals receiving second-line ART were selected with simple random sampling technique. A validated questionnaire adopted from previous studies was used for data collection from patient records at the ART clinic. Collected data were entered into EpiData version 3.1 and analyzed using Stata version 14. Viral resuppression was defined as a viral load of <1000 copies/mL. In the statistical analysis, variables with a P -value < .20 in the bivariate analysis were included in the multivariable Cox proportional hazards regression model to identify independent predictors of viral resuppression. Results Out of the 385 patient charts initially selected, five charts were excluded because they had incomplete or missing key variables required for the study analysis. Therefore, the final analysis was conducted on 380 complete patient charts. The median age of the study participants was 41.41 years with an interquartile range (35.0-48.0). In the follow-up period, 297 patients (78.16%; 95% CI: 73.90-82.33) achieved viral resuppression. In multivariable Cox proportional hazards regression analysis, the factors significantly associated with viral resuppression were alcohol consumption (adjusted hazard ratio AHR = 1.55; 95% CI: 1.09-2.21), smoking (AHR = 1.49; 95% CI: 1.04-2.13), baseline viral load (AHR = 5.60; 95% CI: 2.07-15.12), good medication adherence (AHR = 1.63; 95% CI: 1.02-2.61), and history of drug substitution (AHR = 1.32; 95% CI: 1.02-1.72). Conclusion and Recommendations This study demonstrated that the viral resuppression rate among people living with HIV receiving second-line ART at Gondar Comprehensive Specialized Hospital remains low. Viral resuppression was significantly associated with alcohol consumption, smoking, medication adherence, prior drug substitution, and baseline viral load. Strengthening adherence support, minimizing unnecessary drug substitutions, and providing targeted follow-up for high-risk patients are critical to improving treatment outcomes.
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