Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092

Abstract

Background: Severe acute malnutrition (SAM) may alter the pharmacokinetics (PK), efficacy, and safety of antiretroviral therapy. The phase IV study, IMPAACT P1092, compared PK, safety, and tolerability of zidovudine (ZDV), lamivudine (3TC), and lopinavir/ritonavir (LPV/r) in children with and without SAM. Materials and methods: Children living with HIV 6 to <36 months of age with or without World Health Organization (WHO)-defined SAM received ZDV, 3TC, and LPV/r syrup for 48 weeks according to WHO weight band dosing. Intensive PK sampling was performed at weeks 1, 12, and 24. Plasma drug concentrations were measured using liquid chromatography tandem mass spectrometry. Steady-state mean area under the curve (AUC 0–12h ) and clearance (CL/F) for each drug were compared. Grade ≥3 adverse events were compared between cohorts. Results: Fifty-two children were enrolled across 5 sites in Africa with 44% (23/52) female, median age 19 months (Q1, Q3: 13, 25). Twenty-five children had SAM with entry median weight-for-height Z-score (WHZ) −3.4 (IQR −4.0, −3.0) and 27 non-SAM had median WHZ −1.0 (IQR −1.8, −0.1). No significant differences in mean AUC 0–12h or CL/F were observed ( P ≥ 0.09) except for lower 3TC AUC 0–12h (GMR, 0.60; 95% CI, 0.4–1.0; P = 0.047) at week 12, higher ZDV AUC 0–12h (GMR, 1.52; 1.2–2.0; P = 0.003) at week 24 in the SAM cohort compared with non-SAM cohort. Treatment-related grade ≥3 events did not differ significantly between cohorts (24.0% vs. 25.9%). Conclusion: PK and safety findings for ZDV, 3TC, and LPV/r support current WHO weight band dosing of syrup formulations in children with SAM.

Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV

“…Our study cohort also had comparatively lower median WAZ. Poor nutritional status can be associated with low exposure and higher variability of lopinavir in infants and children because of reduced bioavailability [15][16][17] ; however, we found no association between the pharmacokinetic parameters of lopinavir and nutritional status. Importantly, in our study, lopinavir pre-dose concentrations without TB treatment were lower compared with those in other studies that achieved pre-dose concentrations ≥1 mg/L in 87%-100% of children, 7,10,14,18 suggesting that factors other than TB treatment contributed to the reduced exposures in our study.…”

“…LPV/r was administered in combination with 2 NRTIs (abacavir or zidovudine with lamivudine). Children received rifampicin 15 mg/kg [10][11][12][13][14][15][16][17][18][19][20] co-formulated with isoniazid 10 mg/kg, [7][8][9][10][11][12][13][14][15] administered as dispersible fixed-dose combination tablets of rifampicin and isoniazid 75/50 mg using World Health Organization (WHO) recommended weight bands for the continuation phase of TB treatment. 13 Dosing was switched to WHO-recommended 12-hourly LPV/r 2 weeks after stopping rifampicin-based TB treatment.…”

Lopinavir-menthol co-crystals for enhanced dissolution rate and intestinal absorption

“…Lopinavir is also used as a prophylactic treatment for pregnant HIV-mothers to protect their neonates [ 5 , 6 ]. Lopinavir has been shown to be safe for HIV-infected children with severe acute malnutrition [ 7 ]. Lopinavir exhibited an inhibition of growth of some fungal cells and has potential effect as a therapy for fungal infections [ 8 , 9 ].…”

Micronutrients and Nutritional Status among Children living with HIV with and without Severe Acute Malnutrition: IMPAACT P1092

“…This is a secondary analysis in the IMPAACT P1092 study, a Phase IV, multicenter, open label, nonrandomized study conducted at ve sites in four countries (Malawi, Tanzania, Uganda, and Zimbabwe) between October 2015 and September 2017. Details of the main study methods and results from the primary analyses of the pharmacokinetics and safety of zidovudine, lamivudine and lopinavir/ritonavir in children with SAM have been previously published (19). Brie y, nutritional status of CLHIV aged six to < 36 months at screening was classi ed using WHO criteria as SAM (WHZ <-3 or mid-upper arm circumference (MUAC) < 115mm) or non-SAM (WHZ >-2) (7).…”