Barriers to paediatric switching to second-line ART
Authors: Stephen J Kerr, Thanyawee Puthanakit
Journal: The Lancet HIV (2019)

In the past decade, impressive scale-up in antiretroviral therapy (ART) has occurred, but access to timely viral load monitoring has lagged behind. In The Lancet HIV, The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration1The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort CollaborationIncidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaboration.Lancet HIV. 2019; 6: e105-e115Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar report on the incidence of switching to second-line ART regimens, globally and by geographical region among children infected with HIV who initiated non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based or protease inhibitor-based combination ART between 1993 and 2015. During this period, the availability of ART and paediatric formulations and guidelines for initiation of ART and monitoring of children changed substantially. The incidence of switching varied substantially by geographical region. The global cumulative incidence of switching to second-line ART 3 years after initiation of ART was 3·1% (95% CI 3·0–3·2), with the highest estimated cumulative incidence of switching in the USA (26·1%, 20·0–32·7) and the lowest estimate in sub-Saharan Africa (not including South Africa and Botswana; 1·5%, 1·4–1·6). As expected, in sub-Saharan Africa (excluding South Africa and Botswana), which is the region with the highest burden of HIV and lowest resources for laboratory monitoring and treatment options included in the study, the incidence of switching to second-line ART was low when the monitoring strategy depended on targeted viral load monitoring, routine monitoring of CD4 (measured as CD4% or CD4 cell count), or clinical observations alone. The CIPHER study focused on switching to second-line ART rather than the incidence of first-line treatment failure, but studies2Wools-Kaloustian K Marete I Ayaya S et al.Time to first-line ART failure and time to second-line ART switch in the IeDEA pediatric cohort.J Acquir Immune Defic Syndr. 2018; 78: 221-230Crossref PubMed Scopus (14) Google Scholar have shown that the incidence of first-line treatment failure among children, even in settings with routine viral load monitoring, exceed the incidence of children who switch to second-line regimens. This observation suggests that even when failure of first-line treatment has been identified, paediatric providers might not be able to switch patients to second-line regimens in settings where only protease inhibitor-based or NNRTI-based ART are available because of a need to preserve their restricted future treatment options. Consequently, children could be left on failing regimens for longer than adults would be in the same position, putting them at risk of further accumulation of resistance mutations to backbone regimens while their health declines. Other barriers can delay switching to a different regimen. First, as already noted, the treatment monitoring strategy can restrict the ability to detect first-line failure. Point-of-care HIV viral-load tests are available and financial donors and national programmes should integrate these tests into existing ART programmes.3Dorward J Drain PK Garrett N Point-of-care viral load testing and differentiated HIV care.Lancet HIV. 2018; 5: e8-e9Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Second, ritonavir-boosted lopinavir is the mainstay of second-line paediatric protease inhibitor-based regimens, but available formulations are not palatable for children. Most children in the CIPHER study were on NNRTI-based regimens, which are highly susceptible to mutations if adherence is poor. Raltegravir is approved for infants from birth and dolutegravir has been approved for children with a bodyweight of 30 kg or heavier.4HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIVGuidelines for the use of antiretroviral agents in pediatric HIV infection. AIDSinfo.http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdfDate accessed: November 6, 2018Google Scholar These integrase inhibitors have a high genetic barrier to resistance, but they are not readily available in resource-limited settings, and donors should be negotiating with pharmaceutical companies to provide low cost forms of paediatric doses. Third, children who take antiretroviral drugs are dependent on caregivers to administer their medicine. Family and caregiver treatment literacy needs to be strengthened before a switch to a second-line regimen is made. Of 93 351 children included in the CIPHER cohort, most initiated ART at or after age 3 years, an age after which many children with perinatally acquired HIV would have died without ART, reflecting failures and delays in scale-up of early diagnostic testing among infants. 43·1% of children in the CIPHER cohort had clinical AIDS at ART initiation and, among the 50 892 children for whom immunodeficiency at ART initiation could be calcualated, 37 962 (74·6%) had advanced or severe immunodeficiency at initiation. Consequences of delayed ART initiation include delays in neurodevelopment, malnutrition, and stunting.5Jesson J Koumakpai S Diagne NR et al.Effect of age at antiretroviral therapy initiation on catch-up growth within the first 24 months among HIV-infected children in the IeDEA west African pediatric cohort.Pediatr Infect Dis J. 2015; 34: e159-e168Crossref PubMed Scopus (32) Google Scholar, 6Puthanakit T Ananworanich J Vonthanak S et al.Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study.Pediatr Infect Dis J. 2013; 32: 501-508Crossref PubMed Scopus (115) Google Scholar The 19·6% loss to follow-up after a median of 26 months is another crucial indicator of the vulnerability of these patients because in settings where linkage to a death registry is possible loss to follow-up is a strong predictor of mortality.7Teeraananchai S Kerr SJ Puthanakit T et al.Attrition and mortality of children receiving antiretroviral treatment through the universal coverage health program in Thailand.J Pediatr. 2017; 188: 210-216Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar The size of the CIPHER cohort shows the success of scale-up of ART in the past decade. In the future, improved treatment monitoring and drug availability should narrow the gap between treatment failure and switching to second-line ART. The ultimate goal is to see improvements in the quality of life of children living with HIV and life expectancy similar to the general population in resource-limited settings, as has been achieved in adults living with HIV in Thailand.8Teeraananchai S Chaivooth S Kerr SJ et al.Life expectancy after initiation of combination antiretroviral therapy in Thailand.Antivir Ther. 2017; 22: 393-402Crossref PubMed Scopus (19) Google Scholar This online publication has been corrected. The corrected version first appeared at thelancet.com/hiv on January 28, 2020 This online publication has been corrected. The corrected version first appeared at thelancet.com/hiv on January 28, 2020 We declare no competing interests. Incidence of switching to second-line antiretroviral therapy and associated factors in children with HIV: an international cohort collaborationOur global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations. Full-Text PDF Open AccessCorrection to Lancet HIV 2019; 6: e71–72Kerr SJ, Puthanakit T. Barriers to paediatric switching to second-line ART. Lancet HIV 2019; 6: e71–72—this Comment has been made Open Access. This correction was made on Jan 28, 2020. Full-Text PDF Open Access