We demonstrated that patient-related factors (e.g. use of traditional/herbal medicine, depression, family/social support) but not necessarily provider-related factors, health system factors or treatment related factors contribute to poor adherence on second-line ART. Based on our findings, there is a need for on-going counselling and education of patients on second-line ART. Strategies to support patients, improved adherence evaluation and intensified monitoring need to be considered and evaluated in order to reduce the risk of virologic failure. Competing priorities and life circumstances can play a role in adherence and suppression, and should be taken into consideration when thinking through strategies or interventions to address these.