Research Article: Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study

Date Published: January 30, 2018

Publisher: Public Library of Science

Author(s): Ali Judd, Elizabeth Chappell, Anna Turkova, Sophie Le Coeur, Antoni Noguera-Julian, Tessa Goetghebuer, Katja Doerholt, Luisa Galli, Dasja Pajkrt, Laura Marques, Intira J. Collins, Diana M. Gibb, Maria Isabel González Tome, Marisa Navarro, Josiane Warszawski, Christoph Königs, Vana Spoulou, Filipa Prata, Elena Chiappini, Lars Naver, Carlo Giaquinto, Claire Thorne, Magdalena Marczynska, Liubov Okhonskaia, Klara Posfay-Barbe, Pradthana Ounchanum, Pornchai Techakunakorn, Galina Kiseleva, Ruslan Malyuta, Alla Volokha, Luminita Ene, Ruth Goodall, Steven G. Deeks

Abstract: BackgroundPublished estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.Methods and findingsChildren with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4–9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997–2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997–2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9–8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.ConclusionsIn our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.

Partial Text: Studies have reported declining mortality since the introduction of combination antiretroviral therapy (cART) about 20 years ago, both in adults and children [1–3]. For example, in the United Kingdom (UK) and Irish nationwide paediatric cohort, among 1,441 children with median age 9 years at last follow-up, mortality rates declined from 8.2 per 100 person-years before 1996 to 0.6 in 2003–2006 [1]. In an Italian multicentre study, survival of children with perinatal HIV significantly improved between 1996 and 1998, following the introduction of cART [4]. Similarly, in a United States cohort of 3,553 children with median age at enrolment of 6 years and median follow-up of 5 years, mortality rates declined from 7.2 to 0.8 per 100 person-years between 1994 and 2000 and remained relatively stable to the end of 2006 [2]. Mortality rates in adults have shown a similar trend, and life expectancy among those with a CD4 count ≥500 cells/mm3 is now thought to be close to that of the general population [5].

This study was carried out in accordance with the EPPICC Paediatric merger 2014 SOP and the project-specific Concept Sheet (S1 Text). Nineteen cohorts across 17 countries contributed to individual patient data (see S2 Text: “Writing Group members and collaborating cohorts” for list of collaborators). Children were included in this analysis if they had perinatal HIV infection and initiated cART (defined as a ≥3 drug, ≥2 class regimen [excluding unboosted PIs] or ≥3 non-nucleoside reverse transcriptase inhibitor [NNRTI]-only regimen, including abacavir) after 1996 (with no prior antiretroviral therapy [ART] use), aged <18 years. They were at risk from cART initiation until their censor date, defined as the earliest of 21st birthday, last visit in paediatric care, death, or loss to follow-up (as defined by each cohort), with data available until 31 December 2013. Demographic, clinical, laboratory, and treatment-related data from routine clinic visits (typically every 3–6 months) were pooled electronically using a modified HICDEP protocol ( Pooled data were subjected to a battery of consistency checks. Data on all children at participating clinics were included; data are pseudo-anonymised, and therefore individual informed consent was not obtained. All cohorts received approval from local and/or national ethical committees. For example, the UK/Ireland CHIPS cohort had approval from the London Central Research Ethics Committee. Of 3,953 HIV-infected, ART-naïve children in EPPICC at the time of initiating cART, 3,526 (89%) acquired HIV perinatally and were eligible for this analysis; 1,124 (32%) were from the UK or Ireland, 700 (20%) from Thailand, 508 (14%) from Ukraine, and 1,194 (34%) from elsewhere across Europe (Table 1). The median age at cART initiation for the 3,526 participants was 5.2 (IQR 1.4–9.3) years, and the median year of cART initiation was 2006 (2003–2009). Median duration of follow-up was 5.6 (2.9–8.7) years, with 20,574 person-years of follow-up overall (of which 4,531 were of participants aged <5 years, 6,836 aged 5–<10 years, 6,577 aged 10–<15 years, 2,139 aged 15–<18 years, and 512 aged ≥18 years). Our study included more than 3,500 children and young adults with HIV infection followed across 16 Western, Central, and Eastern European countries and Thailand. Median age at cART initiation was 5 years and median follow-up 5 years, with a quarter of participants being followed for ≥9 years. The median year of birth was 2000, with a quarter being born before 1997; thus, many children were born before the introduction of cART, and outcomes in older children who survived reflect the first cohort of patients with perinatal HIV progressing to adult life [13]. Nearly half of all deaths (46%) and 42% of first AIDS-defining events were within 6 months of cART start in our study. We found that multivariable predictors of early death were very young age, residence in Eastern European countries and Thailand, AIDS diagnosis at cART initiation, initiating cART on an NNRTI-based regimen, severe immune suppression for age, and low BMI-for-age z-score at cART initiation. Time-updated (current) severe immune suppression for age and low BMI-for-age z-score were also associated with late death, as was current viral load >400 c/mL.



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