Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets

Abstract

Background Nevirapine is the only non-nucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimisation. Methods We analysed data from 322 African children (aged 0.3–13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load (VL)>100 copies/mL and transaminase increases >grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment(ART)-naïve children. Results Pre-ART VL, adherence, and nevirapine Cmin were associated with VL non-suppression (hazard-ratio [HR]=2.08 [95% CI: 1.50–2.90, p<0.001] for 10-fold higher pre-ART VL, HR=0.78 [95% CI: 0.68–0.90, p<0.001] for 10% improvement in adherence and HR=0.94 [95% CI: 0.90–0.99, p=0.014] for a 1mg/L increase in nevirapine Cmin). There were additional effects of pre-ART CD4% and clinical site. The risk of virological non-suppression decreased with increasing nevirapine Cmin and there was no clear Cmin threshold predictive of virological non-suppression. Transient transaminase elevations >grade 1 were associated with high Cmin (>12.4 mg/L), HR=5.18 (95%CI 1.95–13.80, p<0.001). Conclusions Treatment initiation at lower pre-ART VL and higher pre-ART CD4%, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.

Non‐nucleoside reverse transcriptase inhibitor levels among HIV‐exposed uninfected infants at the time of HIV PCR testing – findings from a tertiary healthcare facility in Pretoria, South Africa

“…Detectable NVP levels at birth can be accounted for by workflow practices whereby NVP is routinely administered by nursing staff in labour ward immediately after delivery but infant blood is usually taken at a later time‐point by medical staff during routine working hours. Regarding the minimum effective concentration of NVP predictive of virological suppression among infants, it is important to note that it has not been possible to define a meaningful cut‐off ‐ possibly due to the combined effect of NRTI exposure as well as other variables including pre‐treatment viral load . Furthermore, it is unclear what effect, if any, simultaneous exposure to EFV and NVP have on NNRTI dose‐response.…”

“…An EFV plasma mid‐dosing and trough concentration target of 1000 to 4000 ng/mL is usually cited, with levels of >4000 ng/mL being associated with increased risk of side‐effects . These data are, however, derived from adult clinical monitoring studies with data from children suggesting that an increased risk of viral replication occurs at a much lower trough level of <650 ng/mL . Regarding NVP, target trough levels required for prophylaxis are lower than those proposed for treatment.…”

Determinants of nonsuppression of HIV viral load among children receiving antiretroviral therapy in the Simiyu region: a cross-sectional study

“…Additionally, poor adherence increases the risk of developing drug resistance and the occurrence of opportunistic infections; thus, the virus replicates more frequently and faster. Bitwale et al showed that poor ART adherence in Tanzania was associated with virological treatment failure [ 40 ]. Similarly, another study in Tanzania showed that poor ART adherence was associated with childhood treatment failure [ 41 ].…”

State‐of‐the‐Art Review of HIV‐TB Coinfection in Special Populations

“…52 Coadministered rifampin predictably lowers nevirapine levels, and in children, reduced trough concentrations of nevirapine are associated with an increase in virologic failure, although a trough plasma concentration threshold has not been clearly established. 53 Even so, in children receiving nevirapine-based ART, rifampin-based TB treatment did not seem to alter clinical or immunological outcomes significantly. 54 Some experts advocate increasing the nevirapine dose by 50%, although this has not been explicitly studied.…”

“…Even given this, however, most children (>88%) receiving NNRTI‐based ART and concurrent TB therapy do sustain virologic suppression, so coadministration of rifampin and efavirenz without dose adjustment is likely acceptable . Coadministered rifampin predictably lowers nevirapine levels, and in children, reduced trough concentrations of nevirapine are associated with an increase in virologic failure, although a trough plasma concentration threshold has not been clearly established . Even so, in children receiving nevirapine‐based ART, rifampin‐based TB treatment did not seem to alter clinical or immunological outcomes significantly .…”