Global temporal changes in the proportion of children with advanced disease at the start of combination antiretroviral therapy in an era of changing criteria for treatment initiation

Abstract

Introduction: The CD4 cell count and percent at initiation of combination antiretroviral therapy (cART) are measures of advanced HIV disease and thus are important indicators of programme performance for children living with HIV. In particular, World Health Organization (WHO) 2017 guidelines on advanced HIV disease noted that >80% of children aged <5 years started cART with WHO Stage 3 or 4 disease or severe immune suppression. We compared temporal trends in CD4 measures at cART start in children from low-, middle- and high-income countries, and examined the effect of WHO treatment initiation guidelines on reducing the proportion of children initiating cART with advanced disease.

Methods: We included children aged <16 years from the International Epidemiology Databases to Evaluate acquired immunodeficiency syndrome (AIDS) (IeDEA) Collaboration (Caribbean, Central and South America, Asia-Pacific, and West, Central, East and Southern Africa), the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE), the North American Pediatric HIV/AIDS Cohort Study (PHACS) and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 219C study. Severe immunodeficiency was defined using WHO guidelines. We used generalized weighted additive mixed effect models to analyse temporal trends in CD4 measurements and piecewise regression to examine the impact of 2006 and 2010 WHO cART initiation guidelines.

Results: We included 52,153 children from fourteen low-, eight lower middle-, five upper middle- and five high-income countries. From 2004 to 2013, the estimated percentage of children starting cART with severe immunodeficiency declined from 70% to 42% (low-income), 67% to 64% (lower middle-income) and 61% to 43% (upper middle-income countries). In high-income countries, severe immunodeficiency at cART initiation declined from 45% (1996) to 14% (2012). There were annual decreases in the percentage of children with severe immunodeficiency at cART initiation after the WHO guidelines revisions in 2006 (low-, lower middle- and upper middle-income countries) and 2010 (all countries).

Conclusions: By 2013, less than half of children initiating cART had severe immunodeficiency worldwide. WHO treatment initiation guidelines have contributed to reducing the proportion of children and adolescents starting cART with advanced disease. However, considerable global inequity remains, in 2013, >40% of children in low- and middle-income countries started cART with severe immunodeficiency compared to <20% in high-income countries.

Keywords: Asia; CD4 cell count; Caribbean; Central and South America; Europe; North America; WHO guidelines; advanced HIV disease; antiretroviral therapy; sub-Saharan Africa.

Figure 1

Map of countries contributing patients to the collaborative analysis

Figure 2

Severe immunodeficiency at the start of cART by age, sex and country income groups (colours) Severe immunodeficiency was defined according to WHO as CD4% <25% (age <12 months), <20% (12 to 35 months), <15% (36 to 59 months) and CD4 count <200 cells/μL or CD4% <15% (≥5 years). Results from generalized additive mixed effects models based on 52,153 children after imputation of missing data. 95% CIs are shown as shaded areas. Vertical lines indicate the changes in WHO guidelines on when to start cART. Age groups are shown along the right edge. Note that no data available for the analysis for 2003 in LMIC and after 2012 for HIC; hence, the periods shown on the graph differ slightly by country income group. cART, combination antiretroviral therapy; WHO, World Health Organization; LMIC, lower middle‐income country; HIC, high‐income country.

Figure 3

Median CD4 cell count in children aged 5 years or older and median CD4% in children below 5 years of age at the start of cART by age, sex and income group (colours) Results from generalized additive mixed effects models based on 52,153 children after imputation of missing data. 95% CIs are shown as shaded areas. Vertical lines indicate the changes in WHO guidelines on when to start cART. Age groups are shown along the right edge. cART, combination antiretroviral therapy; WHO, World Health Organization.