Background: Antiretroviral therapy (ART), notably lopinavir and nevirapine substantially
reduces Human immune-deficiency virus (HIV) associated morbidity and mortality in HIVinfected children. Low concentrations of nevirapine and lopinavir have been linked to inferior
virological outcomes; it is recommended that lopinavir and nevirapine concentrations are
maintained above 1 mg/L and 3 mg/L, respectively, in order to maintain viral suppression.
Adherence to both lopinavir and nevirapine ART, respectively has long known to be a crucial
contributor to HIV treatment success. Lopinavir and nevirapine pharmacokinetics
demonstrate considerable inter-individual variability, which may affect treatment outcomes.
At least part of this variability may be explained by host genetic factors. Associations between
human genetic variants and exposure to lopinavir and nevirapine are incompletely
understood, and have not been studied in a South African paediatric population. Data in this
thesis were from a clinical trial conducted at Rahima Moosa Mother and Child Hospital in
Johannesburg to assess whether NVP can be re-used (Post-randomization Phase) among 323
children exposed to NVP for PMTCT if they are first suppressed on ritonavir-boosted lopinavir
based regimen (Pre-randomization Phase). This thesis assessed the relationship between
serial clinic visits lopinavir (Pre-and-Post-randomization) and nevirapine (Postrandomization) concentrations and/or percentage adherence(Pre-and-Post-randomization)
and virological outcomes in children. Moreover, population pharmacokinetics models were
used to characterise lopinavir and nevirapine parameters. From the final models parameters
were derived and were used to assess the relationship between lopinavir and nevirapine
pharmacokinetics and genetic polymorphism relevant to both drugs
Methods: Cox proportional hazard regression modelling for multiple failure events was used
to estimate the crude and adjusted hazard effect of lopinavir (Pre-and Post-randomization)
and nevirapine(Post-randomization) concentrations and/or percent adherence(Pre-and
Post-randomization) of viral load>400 copies/mL (Pre-randomization) and >50 copies/mL
(Post-randomization), respectively. The population means and variances of lopinavir and
nevirapine pharmacokinetic parameters at steady state were estimated using non-linear
mixed-effects regression. The final models of lopinavir and nevirapine were used to derive
individual clearances (CL/F), minimum concentrations (Cmin) and area under the
concentration time curves (AUC). The associations between model-derived pharmacokinetic parameters and genotypes in selected genes relevant to lopinavir or nevirapine were
explored.
Results: In 237 children pre-randomization with viral loads and lopinavir concentrations, the
crude and adjusted Cox models revealed significant associations between virologic failure
(viral load>400 copies/mL) and both lopinavir plasma concentrations (<1/mg/L) and pretreatment height-for-age z-scores but not percent adherence. In 99 children postrandomization, lopinavir concentrations >1 mg/L reduced the risk of viremia (viral load >50
copies/mL) with about 40%, compared to children with LPV <1 mg/L. No association was
found with percent adherence in this group. In 95 children on nevirapine post-randomization,
nevirapine concentrations were not significantly associated with increased hazard of viremia
(viral load >50 copies/mL). Similarly, there was no significant association with percent
adherence in this group. Lopinavir and nevirapine pharmacokinetics were both separately
best described with a one compartment models with absorption lag time and transit
compartment absorption models, respectively. There was an age driven effect on lopinavir
and nevirapine relative bioavailability, respectively. After adjusting for multiple testing, there
was no significant association between lopinavir CL/F, Cmin and AUC and genetic
polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1. CYP2B6 516G→T and CYP2B6
983T→C were associated with NVP CL/F. CYP2B6 983T→C was associated with NVP Cmin and
AUC. Additionally, polymorphisms in the ABCB1 and CYP3A5 were independently associated
with NVP CL/F, Cmin and AUC.
Conclusions: Lopinavir concentrations <1mg/L were associated with the increased hazard of
viremia (viral load >400 copies/mL or >50 copies/mL). The results suggest that lopinavir
plasma concentration monitoring at a routine clinic visit may be a useful tool in identifying
sub-therapeutic antiretroviral concentrations in children, and this could be used as a guide to
therapeutic drug monitoring in children. There was no statistically significant association
between polymorphisms in the ABCB1, CYP3A4, CYP3A5 and SLCO1B1 and lopinavir
pharmacokinetics. Polymorphisms in the ABCB1, CYP2B6 CYP3A4 and CYP3A5 predicted
nevirapine pharmacokinetics.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/30123 |
| Date | 15 May 2019 |
| Creators | Moholisa, Retsilisitsoe R |
| Contributors | McIlleron, Helen, Maartens, Gary, Sinxadi, Phumla |
| Publisher | Faculty of Health Sciences, Department of Medicine |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
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