A novel pharmacokinetic approach to predict virologic failure in HIV-1-infected paediatric patients

Bouazza, Naïm; Tréluyer, Jean‐Marc; Msellati, Philippe; Perre, Philippe Van de; Diagbouga, Serge; Nacro, Boubacar; Hien, Hervé; Zouré, Emmanuelle; Raffi, François; Ouiminga, Adama; Blanche, Stéphane; Hirt, Déborah; Urien, Saı̈k

doi:10.1097/qad.0b013e32835caad1

Cited by 10 publications

(10 citation statements)

References 25 publications

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“…These models take into account the developmental changes that occur during the first year of life by including weight-and age-related effects on the apparent clearance and volume of distribution parameters. We used the therapeutic pharmacokinetic thresholds previously associated with 3TC or LPV/r virological efficacy in children and adults (7)(8)(9)(10) to evaluate the protocol drug dosages as well as the 2016 WHO dosing guidelines for HIV-infected infants. Regardless of the treatment group, 30 to 40% of LPV C trough or AUC 0 -12 values were below the corresponding therapeutic targets, due in part to missing doses.…”

Section: Discussionmentioning

confidence: 99%

“…We assessed the consistency of the LPV/r and 3TC ANRS 12174 trial weight-based drug dosages by calculating the percentage of (i) trough LPV concentrations above 1 mg/liter and (ii) 3TC AUC 0 -12 values above 4.2 mg · h/liter. These thresholds have been shown to be associated with virological efficacy for LPV/r and 3TC in HIV-infected children and adults (7)(8)(9)(10).…”

Section: Methodsmentioning

confidence: 99%

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Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

Foissac

Blume

Tréluyer

et al. 2017

Antimicrob Agents Chemother

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The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/ liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the ther-

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

Foissac

Blume

Tréluyer

et al. 2017

Antimicrob Agents Chemother

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“…27 Nevirapine has lower potency (protein adjusted IC95 of 196.6 ng/L vs 54.7 ng/L) 32 and shorter half-life than efavirenz, which is the most potent component of NNRTI+2NRTI ART contributing 65% of its total efficacy. 33 A higher contribution to treatment efficacy of the two accompanying NRTIs may have obscured a clear PK efficacy threshold for nevirapine. The above could also explain why virological outcomes were more strongly related to several other factors than nevirapine exposures in children on nevirapine-based ART.…”

Section: Discussionmentioning

confidence: 99%

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

Bienczak

Denti

Cook

et al. 2017

Aids

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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.

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“…In immunology, the PD endpoints are more straight-forward to measure in the target patient groups; HIV infection, which crosses the boundary of infectious diseases and immunology, is a prime example of how PD models can be developed. The integration of these mechanistic PD models with PK has begun in children [172], and applying such methods for studying immune reconstitution following HSCT and transplants indicate a potential approach towards optimising treatment in these patients.…”

Section: Discussionmentioning

confidence: 99%

“…There is still much scope for the development of these models by including realistic pharmacokinetics and this might produce important conclusions about the effects of planned or unplanned treatment interruptions. Recently, a joint PKPD model including mechanistic viral dynamics, CD4 count and the PK of each of three antiretrovirals was published on data from children aged 2 to 15 years using NLME [172]. The authors of this study were able to separate the relative effects of each drug and develop predictive models of virological failure based on individual estimates of drug inhibition scores.…”

Section: Immunologymentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology

Barker

Germovsek²,

Hoare³

et al. 2014

Advanced Drug Delivery Reviews

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Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose–concentration–effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future.

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A novel pharmacokinetic approach to predict virologic failure in HIV-1-infected paediatric patients

Cited by 10 publications

References 25 publications

Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

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

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology

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