Sequencing paediatric antiretroviral therapy in the context of a public health approach

Abstract

IntroductionAs access to prevention of mother-to-child transmission (PMTCT) efforts has increased, the total number of children being born with HIV has significantly decreased. However, those children who do become infected after PMTCT failure are at particular risk of HIV drug resistance, selected by exposure to maternal or paediatric antiretroviral drugs used before, during or after birth. As a consequence, the response to antiretroviral therapy (ART) in these children may be compromised, particularly when non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used as part of the first-line regimen. We review evidence guiding choices of first- and second-line ART.DiscussionChildren generally respond relatively well to ART. Clinical trials show the superiority of protease inhibitor (PI)- over NNRTI-based treatment in young children, but observational reports of NNRTI-containing regimens are usually favourable as well. This is reassuring as national guidelines often still recommend the use of NNRTI-based treatment for PMTCT-unexposed young children, due to the higher costs of PIs. After failure of NNRTI-based, first-line treatment, the rate of acquired drug resistance is high, but HIV may well be suppressed by PIs in second-line ART. By contrast, there are currently no adequate alternatives in resource-limited settings (RLS) for children failing either first- or second-line, PI-containing regimens.ConclusionsAffordable salvage treatment options for children in RLS are urgently needed.

Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

“…In a secondary analysis using a single VL measurement to define virologic failure, 25% failed. These outcomes are better than the pooled estimates of 60-75% of children achieving viral suppression in the first two years of first-line ART [11], which might reflect the higher potency and the higher "forgiveness of non-adherence" attributed to PIs compared to NNRTIs (mainly used in first-line regimens within LMIC). Moreover, a child's or caregiver's improved motivation to adhere to treatment after failure of first-line treatment might also play a role.…”

“…As a consequence, 56% of children in LMIC still receive a nevirapine-based first-line regimen and switch to PI-based ART in case of failure [7]. Children have higher rates of firstline ART failure compared to adults [8][9][10][11]. The population of HIV-infected adolescents is growing as perinatally infected children now survive until adulthood, and HIV treatment in adolescents is especially challenging [12][13][14].…”

Targeting 90–90–90 – don't leave children and adolescents behind

“…The effects of limited paediatric research range from the inferior and limited HIV and tuberculosis drugs and formulations available for children in all age groups, highlighted in this supplement by Boerma et al . [ 64 ], Cotton et al . [ 24 ], Penazzato et al .…”

“…While paediatric HIV research is not easy for a number of reasons, including the developmental biology of children, decreased number of new paediatric infections, and complex but important regulatory and ethical requirements, it is essential if we are to achieve the 90–90–90 targets. Both clinical and implementation science research is needed to identify more effective and safer ways of treating children, especially newborns [ 24 ], adolescents [ 65 ] and those failing therapy [ 64 ], as well as how best to operationalize and deliver interventions at scale in a range of settings [ 66 ].…”

Next-generation sequencing provides an added value in determining drug resistance and viral tropism in Cameroonian HIV-1 vertically infected children

“…As the footprint of long-term HAART depends largely on the effectiveness of first-line drugs in sustaining viral suppression, establishing adequacy between pediatric HAART and DR-mutations (DRMs) would be clinically relevant. [ 7 , 8 ] In this line, we earlier reported low- and high-HIVDR, respectively, in naïve and HAART-failing children, with successful switch to second-line. [ 9 ] From these observations, we postulated that minority DRMs in HAART-naïve children might grow-up through selective drug-pressure and populate plasma in a short-frame, herein justifying the rapidly emerging DRMs we observed at failure.…”