Virologic and Immunologic Outcomes of HIV-Infected Ugandan Children Randomized to Lopinavir/Ritonavir or Nonnucleoside Reverse Transcriptase Inhibitor Therapy

Abstract

Background In the PROMOTE-pediatrics trial, HIV-infected Ugandan children randomized to receive lopinavir-ritonavir (LPV/r)-based antiretroviral therapy (ART) experienced a lower incidence of malaria compared to children receiving non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based-ART. Here we present the results of the non-inferiority (NI) analysis of virologic efficacy and comparison of immunologic outcomes. Methods ART-naïve or -experienced (HIV RNA < 400 copies/ml) children ages 2 months to 6 years received either LPV/r or NNRTI-based-ART. The proportion of children with virologic suppression (HIV RNA <400copies/ml) at 48 weeks was compared using a pre-specified NI margin of −11% in per-protocol analysis. Time to virologic failure by 96 weeks, change in CD4 counts and percentages, and incidence of adverse event rates were also compared. Results Of 185 children enrolled, 91 initiated LPV/r and 92 initiated NNRTI-based ART. At baseline, the median age was 3.1 years (range: 0.4 to 5.9) and 131 (71%) were ART-naïve. The proportion of children with virologic suppression at 48 weeks was 80% (67/84) in the LPV/r-arm vs. 76% (59/78) in the NNRTI-arm, a difference of 4% (95%CI: −9% to +17%). Time to virologic failure, CD4 changes, and the incidence of DAIDS grade III/IV adverse events were similar between arms. Conclusions LPV/r-based ART was not associated with worse virologic efficacy, immunologic efficacy, or adverse event rates compared to NNRTI-based ART. Considering these results and the reduction in malaria incidence associated with LPV/r previously reported for this trial, wider use of LPV/r to treat HIV-infected African children in similar malaria endemic settings could be considered.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

“…An underpowered subanalysis by individual drug in children younger than 3 years of age found no difference in virological outcome between children on NVP‐ and LPV/r‐containing ART regimens (G. Tudor‐Williams, unpublished results). In agreement with PENPACT‐1, the Prevention of Malaria and HIV Disease in Tororo, Uganda (PROMOTE) study, a small open‐label RCT in Uganda of children aged 0.4–5.9 (median 3.1) years not exposed to NVP, showed comparable results at 48 weeks in terms of virological suppression, CD4 gain and severe adverse events for NNRTI‐ and LPV/r‐containing ART regimens 71.…”

“…The results of the ARROW trial in children have also shown clinical monitoring to be a safe and effective alternative to laboratory monitoring, in resource‐poor settings 71. This supports a recommendation that monitoring of CD4 count and laboratory tests for drug toxicity can safely be performed less frequently than every 3 months when a child is clinically well, has had VL < 50 copies/ml for over 1 year and is not severely immunosuppressed.…”

“…Starting with ABC and 3TC also has the advantage of preserving (and even increasing) susceptibility to ZDV for future options in cases of virological failure, whereas starting on ZDV may lead to accumulation of thymidine analogue‐associated mutations (TAMs) affecting subsequent susceptibility to ABC 84, 85. Both ABC and 3TC can be given once daily to children over 3 months old, which is supported by PK data in PENTA 13 and PENTA 15, and virological outcomes in ARROW 71, 86, 87, 88. 3TC and ABC both have palatable liquid formulations, and scored breakable tablets have recently become available.…”

“…However, in view of the above‐mentioned evidence and the fragility of NVP at high VLs, we recommend that NVP should be accompanied by three NRTIs, as an induction‐maintenance strategy, in infants and young children with VL > 100 000 copies/ml or signs of CNS involvement, including neurodevelopmental delay (Table 4). Earlier viral suppression and greater early CD4 responses with the use of four‐drug induction with a triple NRTI backbone 42, 71 may have potential benefits in terms of reduced viral reservoirs and reduced risk of CNS compartmentalization. Early detection of treatment failure should be picked up by regular monitoring of viral response in the first few months following treatment initiation.…”

“…The ARROW study showed that children on a three‐NRTI maintenance regimen with 3TC, ABC and ZDV had inferior virological outcomes at week 144 and more ZDV‐related neutropenia, but no difference in disease progression or immunological outcomes when compared to NNRTI plus 3TC and ABC 71. Based on these data, triple‐NRTI regimens are not recommended except in special circumstances when significant drug interactions or toxicity risks prevent the use of NNRTI‐ or PI‐containing ART (e.g.…”