12% of children had triple-class virological failure after 5 years on ART, and about a fifth had such treatment failure by 8 years on ART. Although these risks are low, and highlight the great success of antiretroviral treatment in children, they raise concerns about the proportion of children starting ART who are likely to maintain viral suppression for life, despite the potential availability of newer drugs from other classes (panel
). The rate of triple-class virological failure was highest in the first 2 years after ART initiation, rising gradually thereafter. After 6 years on ART, the number of children with failure was small and the confidence intervals were wide, but the apparent decline in the rate of triple-class virological failure could also mirror early dropout of children who adhered most poorly to drug regimens, which is in line with our finding that about a quarter of children with triple-class virological failure had never achieved virological suppression. This small group started ART at an earlier age and became triple-class exposed more quickly, raising the issue of adequate dosing in young children and presumably relating to very poor adherence by their caregivers.
Panel. Research in context
Although reports of paediatric cohort studies have described triple-class virological failure among small numbers of children, no large cohort or cohort collaboration has undertaken a formal assessment of the incidence or consequences of triple-class failure and no randomised trials of children with triple-class failure have been done.
Our study shows that the rate of development of triple-class virological failure in children with HIV in Europe is low, which supports the high efficacy of these drugs in children, but the rate is higher than in adults. These children will be receiving antiretroviral therapy for an entire lifetime, and these findings highlight the challenges in attainment of long-term viral suppression. Early identification of non-responders, adherence support, especially for older children and young people aged 13 years or older starting antiretroviral therapy, and simplification of antiretroviral strategies are all needed to attain and sustain virological suppression.
Restriction of the analysis to children starting ART with two NRTIs and either a NNRTI or a boosted protease inhibitor and use of the same definition of treatment failure showed that the overall rate of failure in children was over two-times higher than in adults with heterosexually transmitted HIV in COHERE. This increased rate of triple-class virological failure could be explained by lower virological suppression rates in children than in adults,19
absence of alternative regimens, adherence issues related to taste and formulation, a tendency for switches in regimen for children being delayed because of the need to manage adherence problems before switching treatment and hence switching regimen at high viral loads,24
and social factors, especially those that affect adolescents.
As in the adult analysis,20
adolescents and young adults had the highest risk of triple-class virological failure. Drug adherence is a challenge for children and young people with any chronic disease. For those with HIV infection, there are additional factors, including coming to terms with disclosure of their HIV status, secrecy and guilt among adult family members, and dealing with HIV alongside their own sexual development. Fear of stigma increases their isolation and tendency towards denial, all of which might adversely affect drug adherence. Although there are several studies of adherence to ART in children and young adults with HIV, most are small, heterogeneous—including both caregiver and child adherence measurements—and nearly all have been cross-sectional.25
Murphy and colleagues16
reported a decline in adherence by teenagers over time associated with duration of ART, and Kekitiinwa and colleagues26
described poor responses to ART in newly diagnosed young people aged 10 years or older in the UK and Ireland.
However, when adolescents aged 10–15 years were excluded from the comparison with adults, the HR declined from 2·2 to 1·7, but remained significant. This finding suggests that factors relating to young children, whose drugs are mainly given by caregivers, are also important and need to be considered. Few adherence studies have differentiated child and caregiver adherence or studied changes in adherence longitudinally with age. In addition to adherence, other complexities in treatment of children with HIV include dosing and pharmacokinetics of drugs, and palatability and tolerability of formulations, all of which vary substantially with age.27
All these factors might adversely affect virological response and contribute to poorer responses in children than in adults.
We recorded no association between drug classes used in the initial regimen and triple-class virological failure, supporting the use of regimens containing either NNRTIs or protease inhibitors as first-line ART in accordance with the current guidelines.7–9
Although our study was a non-randomised comparison, the PENPACT-1 trial28
of ART initiation with protease inhibitor versus NNRTI combination ART regimens, in children with HIV-1 infection who have not received ART, showed no significant virological, immunological, or clinical differences between these two randomised arms at 4 years after ART initiation; of note, PENPACT-1 included both boosted and unboosted protease inhibitors, as in the present study. Our results also suggest that the rate of triple-class virological failure was higher in children who had been diagnosed with AIDS before starting ART, compared with those without an AIDS diagnosis at ART initiation, supporting the current recommendations of ART initiation at higher CD4 counts than previously used, and before clinical disease progression.7–9
However, virological failure was not associated with CD4 percentage or viral load at ART initiation, unlike in adults with HIV,20
and could be due in part to low power, but also to the longer time taken to attain a virological set-point after primary infection in children (about 5 years)29
than in adults. No association between virological failure and use of ART for prevention of mother-to-child transmission was seen, although numbers were small.
Virological failure to a drug class does not necessarily mean that no drugs from that class can successfully suppress the virus in the future, especially if no resistance mutations occurred. For children with resistance test data, we found that most children on a NRTI or a NNRTI had resistance mutations, implying loss of future drug options from these classes. By contrast, protease-inhibitor resistance was not seen, which is consistent with results from the linked adult study and a randomised trial in children.30,31
Because boosted protease inhibitors are now the standard of care for children with HIV,7–9
resistance to them is probably unusual in children failing a boosted protease-inhibitor regimen.32
Our results have implications for developing and developed countries. Increasingly, drugs from the original three classes are widely available, and our results provide encouragement that viral load suppression can be achieved and maintained for many years with use of these drugs. In adults, adherence to ART has proved to be at least as high in sub-Saharan Africa as it is in North America, supporting the fact that outcomes reported in developed countries are relevant for developing countries.33
However, regardless of setting, there will be a need for availability of newer drugs if children with HIV infection are to maintain viral suppression for sufficient durations to enable them to live as long as their uninfected peers. If options do become exhausted then it becomes important to understand the immunological and clinical consequences of long-term virological failure on ART in children, as has been studied in adults.34
Such analyses are beyond the scope of this study and, in fact, there have not been large enough numbers of children in the PLATO II project in this situation to allow reliable conclusions to be drawn.
The rate of virological failure of the three original drug classes seen in this study shows the challenge of maintaining lifelong viral suppression in children who start ART much earlier in life than do adults. Further detailed analysis is needed to compare rates of switching to second-line ART and viral suppression on second-line ART between adults and children, and to compare the development of resistance, and to repeat this analysis once further follow-up time has accrued; there is continued need for strategies to promote optimum drug adherence in children, caregivers, and young people to minimise the likelihood of triple-class virological failure, and for development of suitable new drugs and formulations to optimise the treatment of children with treatment failure. Fixed drug combinations and simplification of strategies could be important ways to maintain treatment options while children move through adolescence and reach adulthood.