Plasma Lopinavir Concentrations Predict Virological Failure in a Cohort of South African Children Initiating a Protease-Inhibitor-Based Regimen

Moholisa, Retsilisitsoe R.; Schomaker, Michael; Kuhn, Louise; Meredith, Sandra; Wiesner, Lubbe; Coovadia, Ashraf; Strehlau, Renate; Martens, Leigh; Abrams, Elaine J.; Maartens, Gary; McIlleron, Helen

doi:10.3851/imp2749

Cited by 13 publications

(12 citation statements)

References 20 publications

(26 reference statements)

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“…In keeping with our analysis of the pre-randomization phase of the same study 17 , higher LPV concentrations are associated with sustained viral suppression. Our data suggests that children with LPV concentrations >1 mg/L have a reduction in the risk of viremia of about 40%, compared to children with LPV <1 mg/L.…”

Section: Discussionsupporting

confidence: 71%

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children

Moholisa

Schomaker

Kuhn

et al. 2016

Pediatric Infectious Disease Journal

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Background Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long term viral suppression have not been adequately defined in children. Aim We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy. Methods After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to remain on a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post-randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL) Results At randomization, the median (IQR) age, CD4+ T-Lymphocyte percentage, weight-for-age and weight-for-height z-scores were 19 (16–24) months, 29 (23–37) %, −0.6(−1.3 to 0.2) and −3.2 (−4.1 to −2.1) respectively. The proportion of children with viral load 51–400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1mg/L vs ≥1mg/L (adjusted hazard ratio 0.62 [95% CI, 0.40–0.94]) and for children with viral loads 51–400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia. Conclusion Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1mg/L of lopinavir to ensure sustained viral suppression.

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Section: Discussionsupporting

confidence: 71%

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children

Moholisa

Schomaker

Kuhn

et al. 2016

Pediatric Infectious Disease Journal

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“…The effect of lopinavir on eryptosis was accompanied by enhanced hemolysis. The concentrations required for the effect are well in the range of plasma concentrations determined in patients under lopinavir treatment [61]. The observed eryptosis and hemolysis may thus well explain the anemia following lopinavir treatment [14].…”

Section: Discussionmentioning

confidence: 52%

Enhanced Eryptosis Following Exposure to Lopinavir

Bissinger

Waibel

Bouguerra

et al. 2015

Cell Physiol Biochem

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Background/Aims: The protease inhibitor lopinavir, used for the treatment of HIV infections, triggers suicidal death or apoptosis of nucleated cells. Side effects of lopinavir include anemia, which could in theory result from stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and by phospholipid scrambling of the cell membrane leading to phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), and ceramide. The present study explored, whether lopinavir induces eryptosis. Methods: Flow cytometry was employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, reduced glutathione (GSH) from mercury orange fluorescence and ceramide abundance utilizing labelled specific antibodies. Hemolysis was estimated from haemoglobin concentration of the supernatant. Results: A 48 hours exposure of human erythrocytes to lopinavir significantly increased the percentage of annexin-V-binding cells (≥ 10 µg/ml), significantly decreased forward scatter (≥15 µg/ml), significantly increased hemolysis (≥ 15 µg/ml), significantly increased Fluo3-fluorescence (20 µg/ml), and significantly increased DCFDA fluorescence (20 µg/ml) but did not significantly modify ceramide abundance. The effect of lopinavir on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca²⁺. Conclusion: Lopinavir treatment of erythrocytes from healthy volunteers is followed by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of ROS formation and Ca²⁺ entry.

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“…They observed that with LPV concentrations <1.0 mg/L, the hazard ratio for having HIV RNA >400 copies/mL was 2.3 times higher when compared to LPV concentrations ≥1.0 mg/L [9]. In our study, we found that the odds of having HIV RNA >1000 copies/mL among those with plasma LPV concentrations <1.0 mg/L was 6.47 times when compared to those with plasma LPV concentrations ≥1.0 mg/L.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Drug Monitoring of Lopinavir in HIV-Infected Children on Second-Line Antiretroviral Therapy in Asia

Aurpibul

Teerananchai

Prasitsuebsai

et al. 2016

Therapeutic Drug Monitoring

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Background Failure rates of second-line boosted protease inhibitor antiretroviral therapy regimens in children rise over time. Therapeutic drug monitoring (TDM) can contribute to assessments of adherence. The authors assessed the performance characteristics of the US DHHS-recommended lopinavir (LPV) concentration of 1.0 mg/L for predicting virologic failure (VF) and intermediate-to-high level LPV resistance in Asian children. Materials and Methods LPV concentration, HIV RNA level, and adherence data from study participants in Indonesia, Thailand, and Vietnam receiving second-line LPV-based ART and followed for ≥24 weeks were analyzed. Results A total of 223 children at a median age of 10.4 (interquartile range, IQR 7.9–13.4) years were enrolled, 61% were male. Their mean CD4 was 842±438 cells/mm3, and the median LPV duration was 2.5 (IQR 1.3–4.2) years. Five out of 84 (6%) and 18 out of 139 (13%) children had LPV trough and random concentrations <1.0 mg/L at study week 24. Using either of these trough or random LPV concentrations, a cutoff at 1.0 mg/L gave an area under the receiver operating characteristics (AROC) curve of 0.69 in predicting VF with sensitivity of 44% (95% CI 23–66) and specificity of 94% (95% CI 89–97). Seven of 21 with VF and resistance results available had ≥1 major protease inhibitor mutation. Multivariate logistic regression found LPV concentrations <1.0 mg/L (OR 6.47; 95% CI 2.15–19.50, P = 0.001) and CD4 ≤20% (OR 2.83; 95% CI 1.01–7.89, P = 0.05) were independently associated with HIV RNA >1000 copies/mL. No factors predicted major LPV resistance mutations. Conclusions The authors support that the DHHS target LPV concentration of <1.0 mg/L is predictive of virologic failure (VF), but not of the presence of major LPV mutations.

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Plasma Lopinavir Concentrations Predict Virological Failure in a Cohort of South African Children Initiating a Protease-Inhibitor-Based Regimen

Cited by 13 publications

References 20 publications

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children

Enhanced Eryptosis Following Exposure to Lopinavir

Therapeutic Drug Monitoring of Lopinavir in HIV-Infected Children on Second-Line Antiretroviral Therapy in Asia

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