Ugandan children in the PROMOTE (Prevention of Malaria and HIV disease in Tororo) paediatrics trial were randomised to receive ritonavir-boosted lopinavir (LPV/r)-based ART vs NNRTI-based.
Recently published data (also presented last year at CROI 2012) showed children receiving LPV/r experienced a lower incidence of malaria compared to those receiving NNRTI-based ART.1-3
At CROI 2013, Theodore Ruel showed results from a planned non-inferiority analysis of virologic efficacy and a comparison of immunologic outcomes between the two ART regimens in a late breaker oral presentation.4
ART-naive and eligible, or virologically suppressed (<400 copies/mL) children ages 2 months to <6 years were enrolled in this open-label randomised trial from October 2009 to October 2011.They received either LPV/r- or NNRTI-based ART with nevirapine (<3 years) or efavirenz (>3 years) with 2 NRTI (3TC/AZT, or d4T if the child was anaemic). Children who had been exposed to nevirapine perinatally and were less than 2 years old were excluded form the trial.
The primary endpoint was viral load <400 copies/mL at 48 weeks. A pre-specified non-inferiority margin of -11% for LPV/r in per-protocol analysis was used. The mean change in CD4 count and CD4 percentage since enrollment, and the proportion of children experiencing grade 3/4 adverse events were also compared by arm.
The trial randomised 185 children to LPV/r-based (n = 92) or NNRTI-based (n = 93) ART. Children were a median age at enrollment of 3.1 years, about half were girls and 70% were ART naive. Children who were ART naive at baseline had CD4 counts of about 570 cells/mm3, CD4 percentage of 16% and viral load 5.4 log copies/mL. In children who were already receiving ART, these values were, approximately 1100 cells/mm3, 30% and all had undetectable viral loads. Characteristics were similar across both arms.
A total of 163 children had available viral load results at 48 weeks; (67/84) 80% in the LPV/r-arm were suppressed vs (60/79) 76% in the NNRTI-arm, a difference of 4% (95% CI 17 to -9). This excluded the pre-specified non-inferiority margin of -11%.
Differences in the proportion of children with viral suppression between the treatment groups were not significant when they were stratified by ART naive or experienced. Time to suppression between the groups was also similar, as was increase in CD4 count and percentage.
Similar numbers of children experienced grade 3/4 adverse events in the LPV/r (n=91) and NNRTI (n=92) arms. The majority of events were neutropenia: 23% vs 16% in the LPV/r and NNRTI arms respectively. Small proportions of children also experienced anaemia, thrombocytopenia, elevated ATT and Stevens Johnson syndrome -- the later occurred in a child receiving nevirapine and led to the only antiretroviral substitution in the study. There were 4 deaths (1 LPV/r vs 3 NNRTI), none considered to be associated with the study medication.
Dr Ruel remarked that as there was also a reduction in malaria incidence associated with LPV/r use in this cohort, the results suggest that wider use of LPV/r to treat HIV positive African children in similar settings could be considered.
In a related oral presentation, Norah Mwebaza showed results from a study in PROMOTE children (with negative controls) to evaluate the pharmacokinetics/pharmacodynamics (PK/PD) of artemether-lumefantrine (AL) -- the most widely used first-line regimen for malaria -- co-administered with different ART regimens.5
Children treated for uncomplicated malaria with a 3-day regimen of AL were enrolled. The children were HIV negative children receiving AL alone or HIV positive children receiving AL plus stable LPV/r, nevirapine or efavirenz containing ART.
This study used extensive PK sampling: exposure was estimated to 21 days (AUC) with 42 days follow-up. Artemether (AR), its active metabolite dihydroartemisinin (DHA), and the long-acting partner drug, lumefantrine (LR) were assessed by LC/MS/MS.
As in the main study, children receiving efavirenz were slightly older than those receiving the other two antiretrovirals (and negative controls).
PK data for 85 children (27 receiving AL alone, 29 LPV/r, 13 efavirenz and 16 nevirapine) showed reduced exposure of artemether and DHA with efavirenz compared to negative controls: AUC 0-8hr (hr*ng/mL) ratio 0.36, p=0.002 and Cmax (ng/mL) ratio 0.35, p=0.004. Artemether but not DHA exposure was reduced with nevirapine, AUC0-8hr ratio 0.28, p=0.0004 and Cmax ratio 0.22, p=0.0002. Co-administration with LPV/r did not result in significant differences to exposure from the controls.
Furthermore, LPV/r increased lumefantine concentrations by 2-3 fold whereas efavirenz reduced this by half; nevirapine had no significant effect.
When the investigators compared the risk of re-infection at 28-days between the three ART regimens, preliminary findings revealed LPV/r to be associated with a 90% reduction in risk of recurrent parasitaemia compared to efavirenz as reference, HR 0.1 (95% CI, 0.01-0.82), p=0.03. Low lumefantrine exposure was also associated with parasitological failure.
These data are compelling, for settings with high malaria risk and add to the evidence in favour of starting treatment with a boosted PI, particularly for infants and young children.
Nevertheless, the logistical problems and cost of the current formulation of LPV/r remain. As well as the question of what to do for second line, which was raised after the presentation by Charles Gilks, who described an NNRTI plus two NRTI second line after PI-based regimen failure as "brittle".
Unless stated otherwise, references are to the Programme and Abstracts for the 20th Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2013, Atlanta.
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