Incidence of virological failure and major regimen change of initial combination antiretroviral therapy in the Latin America and the Caribbean: an observational cohort study

Summary

Background

Access to combination antiretroviral therapy (ART) is expanding in Latin America (Mexico, Central America, and South America) and the Caribbean. We assessed the incidence of and factors associated with regimen failure and regimen change of initial ART in this region.

Methods

This observational cohort study included antiretroviral-naive adults starting ART from 2000 to 2014 at sites in seven countries throughout Latin America and the Caribbean. Primary outcomes were time from ART initiation until virological failure, major regimen modification, and a composite endpoint of the first of virological failure or major regimen modification. Cumulative incidence of the primary outcomes was estimated with death considered a competing event.

Findings

14 027 patients starting ART were followed up for a median of 3·9 years (2·0–6·5): 8374 (60%) men, median age 37 years (IQR 30–44), median CD4 count 156 cells per μL (61–253), median plasma HIV RNA 5·0 log₁₀ copies per mL (4·4–5·4), and 3567 (28%) had clinical AIDS. 1719 (12%) patients had virological failure and 1955 (14%) had a major regimen change. Excluding the site in Haiti, which did not regularly measure HIV RNA, cumulative incidence of virological failure was 7·8% (95% CI 7·2–8·5) 1 year after ART initiation, 19·2% (18·2–20·2) at 3 years, and 25·8% (24·6–27·0) at 5 years; cumulative incidence of major regimen change was 5·9% (5·3–6·4) at 1 year, 12·7% (11·9–13·5) at 3 years, and 18·2% (17·2–19·2) at 5 years. Incidence of major regimen change at the site in Haiti was 10·7% (95% CI 9·7–11·6) at 5 years. Virological failure was associated with younger age (adjusted hazard ratio [HR] 2·03, 95% CI 1·68–2·44, for 20 years vs 40 years), infection through injection drug use (vs infection through heterosexual sex; 1·60, 1·02–2·52), and initiation in earlier calendar years (1·28, 1·13–1·46, for 2002 vs 2006), but was not significantly associated with boosted protease inhibitor-based regimens (vs non-nucleoside reverse transcriptase inhibitor; 1·17, 1·00–1·36).

Interpretation

Incidence of virological failure in Latin America and the Caribbean was generally lower than that reported in North America or Europe. Our results suggest the need to design strategies to reduce failure and major regimen change in young patients and those with a history of injection drug use.

Funding

US National Institutes of Health.

Introduction

Combination antiretroviral therapy (ART) has substantially reduced morbidity and mortality in patients living with HIV/AIDS.¹ Improved access has resulted in a sustained increase in the number of people receiving ART in the past 10 years, reaching 12·9 million people at the end of 2013.² Among resource-limited settings, Latin America (Mexico, Central America, and South America) and the Caribbean have the highest rates of ART coverage, achieving more than 70% coverage of those in need in 2012, with 800 000 patients on ART at the end of 2013.³ National HIV programmes in Brazil, Argentina, Colombia, and Venezuela were established early in the epidemic. Individualised prescription of treatment was common, which resulted in high coverage and a very high number of different first-line regimens.

In 2013, WHO updated its guidelines to promote earlier treatment initiation and enhanced monitoring (scaling up and improving access to viral load testing).⁴ In Latin America and the Caribbean, the criteria for ART initiation vary among countries and have changed over time, with some countries now offering early treatment to all HIV-positive adults.5, 6, 7, 8, 9, 10, 11 However, the CD4 threshold for treatment initiation was 350 cells per μL for much of the 2000s. National clinical guidelines recommend measuring CD4 cell count and viral load every 3–6 months in patients starting ART, and then every 3–6 months once viral load suppression has been achieved.7, 9, 10, 11 The number of viral load determinations increased from a median of 1·2 per year in 2010 to 1·8 in 2012 in Latin America and the Caribbean, but with substantial differences between countries.³ In 2011, 77% of adults on ART in this region were receiving first-line regimens and 21% were receiving second-line regimens.

Research in context

Evidence before this study

Access to combination antiretroviral therapy (ART) is expanding in Latin America and the Caribbean. We searched PubMed with the terms (“antiretroviral therapy” OR “antiretroviral treatment”) AND (“virologic failure” OR “treatment failure”) AND (“Latin America” OR “Caribbean”) AND “cohort studies” for papers published up to Aug 26, 2015. There was little information in this region regarding incidence of and factors associated with regimen failure and regimen change.

Added value of this study

This study assessed virological failure and regimen change in 14 027 patients starting ART who were followed up for a median of 3·9 years. Data were collected systematically in a real-world clinic setting, viral load measurements and other key variables were audited at each site by external investigators. Virological failure was associated with younger age, infection through injection drug use, and initiation in earlier calendar years.

Implications of all the available evidence

About a quarter of patients might need to change to a second-line regimen within 5 years. To maximise the benefits of ART, specific support to young individuals and those with a history of drug use should be provided, viral load monitoring should be expanded, and more modern treatment regimens should be adopted.

There is increasing evidence that the immunological and virological responses to treatment in resource-limited settings can equal those in high-income settings.¹² However, switching to second-line regimens is less common in resource-limited settings, probably because of the cost of second-line drugs and low frequency of viral load monitoring.13, 14 Therefore, reliable estimates of the incidence of first-line failure and major regimen change in individuals starting ART could help HIV programmes to estimate the need for second-line drugs. Additionally, the identification of factors associated with ART failure and regimen change could inform the development of preventive interventions aimed at improving durability of the first regimen. In this study, we analysed data from the largest cohort of HIV-positive patients in Latin America and the Caribbean to estimate the cumulative incidence of failure and major change of initial ART and to study potentially relevant demographic and clinical factors.