Risk factors for first-line antiretroviral therapy regimen modification in adults with HIV across treatment eras: a global scoping review of 86 studies in 1.9 million participants

Background Antiretroviral regimen modification (ARM) is a critical event in the clinical management of people living with HIV (PLHIV). This scoping review maps the available evidence and identifies gaps in the literature regarding the risk factors driving first-line ARM. Methods The review followed the Arksey and O'Malley framework (updated by Levac) and adhered to the PRISMA-ScR guidelines. A systematic search of electronic databases (PubMed, Scopus, Cochrane, CINAHL, Web of Science, and Africa Index Medicus) was conducted for studies up to June 2026, alongside forward and backward citation tracking. Observational studies published in English that used multivariable analysis to evaluate risk factors for adult first-line ARM were included. Methodological quality was appraised using the Newcastle-Ottawa Scale (NOS). Results A total of 86 highly heterogeneous studies published between 2001 and 2025 were included, representing a cumulative sample size of 1,984,424 participants from 59 countries and territories. The majority of the studies (N = 44) were conducted in the WHO African Region. Outcome definitions varied: 30 studies evaluated component drug substitutions, 22 evaluated switching to second-line regimens, and 34 combined both approaches. Where reported, the cumulative proportion of participants who underwent first-line ARM ranged from 2.9% to 83% (median = 25%), across widely varying treatment eras, follow-up durations and outcome definitions. Low baseline CD4 count (41 studies), AZT/d4T-based regimens, advanced clinical stage (16 studies), and elevated viral load (15 studies) were the most consistently reported risk factors. Only seven studies examined dolutegravir- or integrase inhibitor-based first-line regimens, six of which found them protective against ARM, but none was from sub-Saharan Africa. Other reported risk factors include socio-demographic (age, sex), clinical (baseline regimen, viral load, BMI, coinfections, and adverse events), behavioral (substance use and adherence), and system-level factors (clinic location/type), though evidence on system-level factors was limited and inconsistent. Conclusion First-line ARM is influenced by a complex interplay of socio-demographic variations, clinical and biological vulnerabilities, behavioral adherence patterns, and health system infrastructures. Tailoring retention strategies to these distinct multi-level risk factors may enhance the longevity of first-line regimens, and contemporary evidence from dolutegravir-based programmes is needed.