One in eight European children with HIV experienced failure of three drug classes within five years

One in eight children and adolescents receiving HIV treatment at major HIV clinics in Europe experienced failure of three classes of antiretroviral drugs after five years of treatment, highlighting the need for formulations of new antiretroviral drugs to be developed that are suitable for children, European researchers report in The Lancet.

Triple-class failure implies that a child has experienced the failure of at least two antiretroviral regimens, one containing a non-nucleoside reverse transcriptase inhibitor combined with a nucleoside analogue, and one containing a protease inhibitor combined with a nucleoside analogue. It also implies a degree of cross-resistance to other drugs in the same class.

Children were twice as likely as adults with HIV in Europe to experience failure of their first antiretroviral regimen.

The PLATO II investigators for the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) reported a retrospective cohort study of 1007 children, among whom over one-third (33%) had started a third drug class after a median of 4.2 years (of which 105 (44% or 10% overall) were on a failing regimen).

About 25% of those who developed triple-class virological failure had never achieved viral suppression (a viral load measurement under 500 copies/ml).

The longer the children were on ART the greater the risk of triple-class virological failure: after five years the risk was 12% (95% CI: 9.4-14.6).

Approximately 2 million children are living with HIV, the majority infected through perinatal transmission. An estimated 700 children die every day because of AIDS-related causes. Without treatment an estimated 50% will die before they reach the age of two.

Antiretroviral therapy has dramatically improved the prognosis for HIV-infected children. Children have responded well to protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Guidelines now recommend starting treatment as soon as possible after HIV diagnosis.

Results from adults treated, in both resource-poor and resource-rich settings, with all three classes of antiretrovirals (PIs, NNRTIs and nucleoside reverse transcriptase inhibitors (NRTIs) suggest that long-term viral suppression is possible and virological failure happens slowly. It is unclear whether the same is true for children who will need to maintain viral suppression the longest.

The major challenge in treating children is to minimise virological failure and the development of drug resistance so that children will continue to have treatment options throughout adolescence and adulthood.

Alexandra Calmy and Nathan Ford from Médecins Sans Frontières in an accompanying Comment stress the potential difficulties for children, notably in resource-poor settings where 90% of HIV-infected children live: limited availability of current and effective treatment regimens, unclear strategies for the best drug sequencing as well as difficulties in maintaining good adherence from infancy to adulthood, all of which may contribute to drug resistance and virological failure.

The authors looked at the rate and predictors of triple-class virological failure to the three original drug classes in children.

From 1998 to 2008, in COHERE, the rate of triple-class failure was analysed in children under 16 years of age infected perinatally who started antiretroviral therapy with three or more drugs. 1007 children from 14 COHERE cohorts were identified with over 90% from the UK and Ireland, Spain, Holland and France.

Incidence of triple-class virological failure increased over time, reaching close to 20% after eight years. The authors note that the rate of triple-class failure was steepest in the first two years after having started ART, after which it continued to rise, but more gradually.

Older age (10-15) when starting ART was associated with an increased risk of failure.

Calmy and Ford suggest these findings be understood in context. Close to a quarter of the children had started ART in 2000 when less effective regimens were in use and standardised treatment guidelines lacking.

However, Calmy and Ford note the findings give cause for concern.

The overall virological failure rate is comparatively low. Nonetheless when the analysis is limited to children exposed to boosted PIs the cumulative proportion of failure is twice that of adults in the same cohort collaboration, 8.2% (95% CI: 5.1-11.2) compared to 4.2% (95% CI:  3.8-4.6) HR 2.2 (95% CI: 1.6-3.0, p<0.0001).

This raises the critical issue of treatment durability. Calmy and Ford add that no matter what the age the goal is to achieve and maintain sustained virological suppression. The fact that a significant number of children experiencing virological failure had never achieved virological suppression is disturbing, they add.

Reasons include: the complexities around adherence, particularly in very young children who depend on caregivers; very limited and often poorly adapted treatment options.

In young children and adolescents the authors note overlapping social issues: stigma, secrecy and guilt, disclosure as well as sexual development all contribute to poor adherence. Few studies, they add, have looked at these issues.

While they welcome the World Health Organization’s (WHO) efforts to issue user-friendly dosing tablets, Calmy and Ford express concern “that paediatric antiretrovirals are not currently a part of WHO’s work on priority medicines for maternal and child health.”

Calmy and Ford stress the urgency of developing new fixed-drug formulations for children. The absence of clinical data on the use of specific drugs in children hinders the process.

Calling upon researchers and drug developers to “prioritise the pursuit of paediatric indications for antiretroviral drugs” they note, “…children [notably in resource-poor settings] receive a lower standard of care than do adults.”

They conclude “The fact that the Drugs for Neglected Diseases Initiative…has recently included paediatric HIV/AIDS in its portfolio is telling: paediatric HIV/AIDS is a neglected disease.”