Time to first-line ART failure andtime to second-line ART switch in the IeDEA pediatric cohort

Abstract

As of 2015, globally 1.8 million children were living with HIV, the vast majority of whom resided in low- and middle-income countries (LMIC).1 Of these children (ages 0–14), 49% were accessing treatment, ranging from 20% in West and Central Africa to >95% in Europe and North America.1,2 The effectiveness of combination antiretroviral therapy (ART) in children is undisputed, with 12-month viral suppression rates ranging from 49–83.3%.3–10However, there are limited data from LMIC concerning the long-term durability of first-line ART regimens. Because children in LMIC HIV treatment programs tend to start treatment at older ages with significant immune compromise, and are often monitored in the absence of virologic data, estimates of first-line ART durability taken from high-income settings may not be generalizable to these programs.11, 9,12 Though targeted viral load (VL) testing is currently recommended to confirm suspected failure many public-sector programs still rely on clinical and immunologic criteria to detect therapeutic failure, and are likely to continue to do so in full or in part because of issues with access to equipment, reagents or availability of consistent specimen transport to reference laboratories.13 Within this context it is important to understand the cumulative incidence of failure and the time to transition to second-line ARTThe cumulative incidence of switch to second-line ART in children has been assessed in both clinical trials and cohort studies. However, studies vary with regard to the initial ART regimen, monitoring strategy and definitions for the switch to a second regimen. The proportion switched to second-line after five years on treatment in the EPPICC Cohort and the PENPACT Trial were 35% and 29%, respectively.4,6 In Asia, the proportions of switch to second-line have been reported at 22% and 17.6% in cohorts with median on ART observation periods of 4.5 years and 4.9 years, respectively.14,15 However, much lower rates of switch have been reported from sub-Saharan Africa, with one observational cohort from South Africa reporting a three-year estimated probability of switch of only 6.2%, and the ARROW trial reporting switch rates at approximately 2 years on ART of 5%–6%.10,16 With the exception of the ARROW Trial, which identified failure based on clinical or immunologic criteria, the above studies predominately or exclusively utilized VL criteria for failure. As the positive predictive value of the WHO’s immunologic criteria for failure has been estimated to range from 20.0 to 54.9% in children, there is a high likelihood that first- line failure is significantly under-diagnosed in studies and programs utilizing CD4 monitoring in the absence of VL.17 Of note, while the South African cohort only had a 6.2% cumulative incidence of switch, the cumulative incidence of virologic failure was 19.3%, thus suggesting that even in the face of virologic failure there may be issues with transitioning antiretroviral regimens.16 In light of the complex environment in which HIV-infected children in LMIC are being assessed for failure and transitioned to second-line regimens, the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium sought to explore the time to and factors associated with ART failure as well as change to second-line in children initiating ART between 2–14 years of age.