In our study, virological response in infants starting ART before 12 months of age showed improvement with calendar year of ART initiation, and virological and immunological responses were better in those starting with 4-drug NNRTI-based regimens compared with 3-drug NNRTI-based and boosted PI regimens, which were similar. The rate of switching to second-line ART was low, and almost 65% of children remained on first-line ART without treatment interruption after five years.
Our study has several limitations. We were unable to assess the influence of unmeasured confounders, and there is a risk of attrition and selection bias, particularly for data acquired from non-birth cohorts. Clinicians’ preference in first-line treatment choice, influenced by patient presentation and adherence patterns, cannot be ruled out. However, there was no evidence of differences across countries (data not shown), nor by clinical stage at presentation. Data on HIV resistance mutations were not available for most children, and thus the impact of resistance could not be assessed.
Our findings demonstrate that across Europe, virological responses have improved over calendar time in infants starting ART early in life. Possible explanations include better regimen efficacy, better dosing and improved management resulting in better caregiver adherence. Of note, in the CHER trial, the proportion of children on lopinavir/ritonavir with viral load <400c/mL at 12 months was similar to that observed here for 2004-2008 (77%).5, 27
Firm evidence of better virological response to boosted PI-based versus NNRTI-based regimens is lacking in our study, after controlling for potential confounders. This is in agreement with the PENPACT-1 trial,16
but in contrast to the short-term IMPAACT 1060 trial findings.17
However, power to detect small differences was low in our study as relatively few infants started boosted PI-based ART. African children in IMPAACT 1060 started ART according to clinical and immunological criteria and were more severely immuno-suppressed (median CD4% 15% overall, versus 29% in our study), and were assessed for a different study endpoint after only 24 weeks. PENPACT-1 included few infants and, like our study, included some started on early ART when asymptomatic with high CD4 values; duration of follow-up in both PENPACT-1 and our study was considerably longer than in IMPAACT 1060.
Of interest, use of 4-drug NNRTI-based regimens resulted in improved virological and immunological responses compared with other regimens. Given high viral loads in infancy and potential advantages of a PI-sparing regimen in terms of tolerability, adherence, lack of interaction with other drugs, preservation of effective second-line options, and cost, an NNRTI-based 4- to 3-drug induction-maintenance strategy could be valuable in infants not exposed to single-dose nevirapine for pMTCT. However, as infants initiating 4-drug regimens in our study were mainly from UK/Ireland, potential biases in indication for treatment cannot be excluded; the results of the ARROW trial, which is evaluating this strategy, are awaited in 2012.
Immunological recovery was better in those initiating therapy with a lower CD4 Z-score at baseline, confirming good thymic activity in young children20, 28
and a possible “ceiling effect” of CD4 response in infants, as noted elsewhere15
. In addition, the negative association with exposure to maternal ART prima facie
suggests the possibility, supported by previous findings, that infants acquiring HIV despite prophylactic maternal ART may have a worse prognosis and potentially suboptimal immunological response to treatment.29, 30
. However, exposure to maternal ART was varied in our study, with infants being exposed to many different regimens, and we had insufficient data to fully evaluate this association.
Five years after starting ART, two-thirds of infants in our study were still on their first-line regimen without interruption, and a fifth had switched to second-line. Children starting ART on 4-drug NNRTI-based or boosted PI regimens switched to second-line ART more slowly, in line with evidence that these regimens maybe more durable, and result in a more sustained virological response and/or a higher genetic barrier to drug resistance.31, 32
Despite treatment interruption not being currently recommended in international paediatric guidelines, a quarter of infants interrupted treatment during follow-up. Sixty-two per cent of interruptions occurred with detectable viral load, likely reflecting challenges encountered with tolerability, acceptability and adherence, which may be exacerbated in young children, with unclear impact on subsequent treatment response. Five-year results of the CHER trial comparing outcomes in infants randomised to planned interruption at 12 or 24 months of age after early ART versus deferred ART are awaited later this year. In our study, children remained on first-line therapy longer than adults,33
even following the occurrence of viral load rebound. This is likely due to a more conservative approach to the clinical management of young children, especially in earlier years, and limited treatment options.
In conclusion, our findings suggest that outside trial settings, an effective treatment response can now be achieved in infants who start ART early in life, with the majority remaining on first-line ART after five years. However issues around choice of first-line ART including potential treatment sequencing, feasibility and cost, require careful consideration. Our findings are in line with evidence in the PENPACT-1 trial, suggesting similar responses to initial 3-drug NNRTI-based and PI-based regimens, but in addition, suggest that a 4-drug NNRTI-based initial regimen maybe superior. However, this approach needs further evidence from ongoing randomised trials, as do strategies of 4- to 3-drug NNRTI induction-maintenance and treatment interruption following early ART in infancy.