Paediatric European Network for Treatment of AIDS (PENTA) Guidelines for Treatment of Paediatric HIV-1 Infection 2015

Optimizing Health in Preparation for Adult Life

A Bamford; A Turkova; H Lyall; C Foster; N Klein; D Bastiaans; D Burger; S Bernadi; K Butler; E Chiappini; P Clayden; M Della Negra; V Giacomet; C Giaquinto; D Gibb; L Galli; M Hainaut; M Koros; L Marques; E Nastouli; T Niehues; A Noguera-Julian; P Rojo; C Rudin; HJ Scherpbier; G Tudor-Williams; SB Welch

Disclosures

HIV Medicine. 2018;19(1):e1-e42. 

In This Article

Abstract and Introduction

Abstract

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Introduction

  • These guidelines apply to children with HIV-1 infection in Europe.

  • Thresholds for starting antiretroviral therapy (ART) have changed as continuing improvements in treatment mean that the objectives of ART should increasingly be optimizing health status for a full and productive adult life rather than just survival.

  • New drugs have been incorporated into the guideline as first- and second-line options.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines have been updated from those of 2009,[1] and make recommendations based on a shift in aims of treatment away from minimization of short-term morbidity and mortality towards optimizing immune status and general health for a full and productive adult life. This mirrors the general trend in global treatment guidelines that now include higher CD4 thresholds for ART initiation and an increased number of clinical indications in both adults and children.[2–6]

The aim is to provide a practical guide to treatment rather than a comprehensive review of all the evidence on ART in children. More detailed information for resource-rich and resource-poor settings is available from recently updated US[4] and World Health Organization (WHO)[6] paediatric guidelines. Special considerations for children in resource-limited settings where background rates of concomitant infections and malnutrition are much higher are not considered here, and the reader is referred to WHO guidelines. Differences from the WHO and US Department of Health and Human Services (DHHS) guidelines will be referred to where relevant in the document and are summarized in Table 1.

Licensing of newer drugs in children and the availability of more appropriate formulations have allowed inclusion of a larger number of drug options at different ages. These drugs, with limited data on long-term toxicity, are included with the caveat that clinicians should be vigilant for signs of adverse effects and fully counsel children and families regarding what is known and unknown about long-term use of newer drugs.

Much of the new paediatric data (published since 2009) that have been used to inform the 2015 PENTA guidelines have come from non-European settings and therefore must be considered with caution when applied to European cohorts. As with previous versions of the guidelines, there remains a paucity of data from randomized controlled trials (RCTs) on which to base European paediatric ART guidelines. Therefore, we continue to rely on cohort studies, extrapolation from adult data, and expert opinion. Wherever possible, children should be entered into clinical trials.

The guidelines have been developed using a similar method to that used for the adult European AIDS Clinical Society (EACS) guidelines.[3,7] A panel of experts reviewed the published literature and formulated the main recommendations. The full PENTA Steering Committee then reviewed and refined the recommendations until consensus was reached. This approach has recently been criticized by some. Latest WHO and British HIV Association (BHIVA) guidelines have now moved to using the structured Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.[7] It is the opinion of PENTA that the paucity of RCT evidence means that the GRADE system would not provide sufficient additional benefit to the guidelines' development to justify its use and therefore the writing group has elected to continue using the less formalized system described above.

PENTA guidelines seek to optimize treatment for children in Europe. However, particularly during adolescence, care may need to be individualized. This document should not be seen as a standard for litigation as individualization of case management and departure from this guidance may be necessary and indicated.

Significant changes since the 2009 guidelines include:

  • decreased frequency of laboratory monitoring in clinically stable children both on and off ART;

  • consideration of ART initiation in all children aged 1–3 years in order to minimize the risks of disease progression or death;

  • consideration of ART initiation at higher CD4 thresholds in children > 5 years of age in order to optimize potential for immune reconstitution;

  • additional clinical indications for ART initiation at all ages;

  • addition of newer protease and integrase inhibitors to first-line preferred and alternative third agent options, respectively;

  • update on specific guidance in the context of hepatitis B and C virus and tuberculosis (TB) coinfection in light of new ART options at younger ages;

  • a summary of new drugs [including new fixed dose combinations (FDCs)] that can be considered for second- and third-line options and of the 'pipeline' of new drugs likely to become available;

  • an emphasis on the needs of older children and adolescents as they approach transition to adult care;

  • an updated drug dosing table including all currently recommended licensed antiretroviral drugs for children.

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