BACKGROUND: One of the critical clinical decisions made in antiretroviral therapy (ART) is when to switch from an initial regimen to another due to treatment failure. This complex process requires consideration of multiple factors including: (1) what type of monitoring (e.g. clinical, immunologic, virologic) is available to guide switching; (2) establishing criteria for treatment failure (e.g. viral load >10,000 copies/mL); (3) integrating data from different types of monitoring; (4) making a decision; and, if possible, (5) follow-up and monitoring to determine patient outcomes. The initial step in this model of deciding when to switch is determining what type of monitoring for guiding when to switch is available and appropriate. This review seeks to find and summarize evidence on optimal monitoring strategies for guiding when to switch first-line regimens due to treatment failure among adults and adolescents living with HIV in low-resource settings. This review was one of a series of reviews prepared in 2009 at the request of the World Health Organization to inform the development of new guidelines on ART for adults and adolescents. OBJECTIVES: To assess optimal monitoring strategies for guiding when to switch antiretroviral therapy regimens for first-line treatment failure among adults and adolescents living with HIV in low-resource settings. SEARCH STRATEGY: We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status. In July 2009, we search the following electronic journal and trial databases: MEDLINE, EMBASE, CENTRAL. We also searched conference databases using NLM Gateway (for HIV/AIDS conference abstracts before 2005), abstract databases from the Conferences on Retroviruses and Opportunistic Infections, International AIDS Conferences, and International AIDS Society Conferences on HIV Pathogenesis, Treatment, and Prevention from 2005 to 2009, and the trials registers ClinicalTrials.gov, Current Controlled Trials, and Pan-African Clinical Trials Registry. We contacted researchers and relevant organizations and checked reference lists for all included studies. SELECTION CRITERIA: We selected studies which evaluated a monitoring intervention/strategy that helps guide when to switch ART. Study types included randomized controlled trials and observational studies (cohort and case-control) which included comparators. DATA COLLECTION AND ANALYSIS: One author performed an initial screening. Two authors performed a detailed screening. Two authors independently assessed study eligibility, extracted data, and graded methodological quality. Differences were resolved by a third reviewer. Heterogeneity was assessed, and meta-analyses were performed where appropriate. MAIN RESULTS: Two randomized trials were identified which were in abstract form only. Two cohort studies (both published) with comparators were identified. Of the evidence available, three comparisons were studied: clinical versus immunologic and clinical monitoring; clinical versus virologic, immunologic, and clinical monitoring; and immunologic and clinical monitoring versus virologic, immunologic, and clinical monitoring. Clinical vs. Immunologic and Clinical Monitoring: Based upon two randomized trials, clinical monitoring alone results in increased mortality (low-quality evidence), increased AIDS-defining illnesses and mortality as a composite endpoint (moderate), no difference in serious adverse events (low), increased numbers of unnecessary switches (low), and no difference in switches to second-line (low) compared to immunological and clinical monitoring. Clinical vs. Virologic, Immunologic, and Clinical Monitoring: Based upon a single randomized trial, clinical monitoring alone results in a trend toward increased mortality (low), increased AIDS-defining illnesses and mortality as a composite endpoint (low), increased unnecessary switches (low), no difference in virologic treatment failures (low), and a trend toward increased switches to second-line (low) compared to virologic, immunologic, and clinical monitoring. Immunologic and Clinical vs. Virologic, Immunologic, and Clinical Monitoring: Based upon a single randomized trial, immunologic and clinical monitoring results in no difference in mortality (low), no difference in AIDS-defining illnesses and mortality as a composite endpoint (low), no difference in unnecessary switches (very low), no difference in virologic treatment failures (low), and no difference in switches to second-line (low) compared to virologic, immunologic, and clinical monitoring. Observational studies appear to demonstrate that programs with virologic, immunologic, and clinical monitoring switch therapy more frequently (very low), earlier (very low), and at higher CD4 counts (very low) compared with programs that have immunologic and clinical monitoring alone. AUTHORS' CONCLUSIONS: A limited number of studies were available to address this topic, and, of the two randomized trials identified, both were in abstract form only. Observational studies also were limited in number and were of lesser quality. Although the quality of the evidence varied from the randomized trials, ranging from very low to moderate, there appeared to be substantial benefits for key outcomes (e.g. mortality, AIDS-defining illness and mortality as a composite endpoint, and unnecessary switches) favoring both immunologic and clinical monitoring or virologic, immunologic, and clinical monitoring versus clinical monitoring alone. Very low-quality evidence from observational studies suggested that virologic, immunologic, and clinical monitoring led to more frequent switching, earlier switching, and switching at higher CD4 counts compared with immunologic and clinical monitoring. Further information on the studies currently reported in abstract form will provide insight. Ongoing studies addressing this topic likely will provide information to further clarify optimal monitoring strategies for guiding when to switch first-line therapy. Additionally, studies looking at different virologic monitoring frequencies and/or virologic monitoring at different times after ART initiation (e.g. after 2-3 years) would be informative. Finally, cost-analysis studies will lend further insights into the applicability of these findings to low-resource settings.