Publications

1

Jan, 2015

HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds

 

Authors: Harrison L, Melvin A, Fiscus S, et al; PENPACT-1 (PENTA 9PACTG 390) Study Team.

Published in: J Acquir Immune Defic Syndr. 2015;70(1):42-53

Background The PENPACT-1 trial compared virologic thresholds to determine when to switch to second-line antiretroviral therapy (ART). Using PENPACT-1 data, we aimed to describe HIV-1 drug resistance accumulation on first-line ART by virologic threshold.

Methods PENPACT-1 had a 2 × 2 factorial design, randomizing HIV-infected children to start protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and switch at a 1000 copies/mL versus 30,000 copies/mL threshold. Switch criteria were not achieving the threshold by week 24, confirmed rebound above the threshold thereafter, or Center for Disease Control and Prevention stage C event. Resistance tests were performed on samples ≥1000 copies/mL before switch, resuppression, and at 4-years/trial end.

Results Sixty-seven children started PI-based ART and were randomized to switch at 1000 copies/mL (PI-1000), 64 PIs and 30,000 copies/mL (PI-30,000), 67 NNRTIs and 1000 copies/mL (NNRTI-1000), and 65 NNRTI and 30,000 copies/mL (NNRTI-30,000). Ninety-four (36%) children reached the 1000 copies/mL switch criteria during 5-year follow-up. In 30,000 copies/mL threshold arms, median time from 1000 to 30,000 copies/mL switch criteria was 58 (PI) versus 80 (NNRTI) weeks (P = 0.81). In NNRTI-30,000, more nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations accumulated than other groups. NNRTI mutations were selected before switching at 1000 copies/mL (23% NNRTI-1000, 27% NNRTI-30,000). Sixty-two children started abacavir + lamivudine, 166 lamivudine + zidovudine or stavudine, and 35 other NRTIs. The abacavir + lamivudine group acquired fewest NRTI mutations. Of 60 switched to second-line, 79% PI-1000, 63% PI-30,000, 64% NNRTI-1000, and 100% NNRTI-30,000 were <400 copies/mL 24 weeks later.

Conclusions Children on first-line NNRTI-based ART who were randomized to switch at a higher virologic threshold developed the most resistance, yet resuppressed on second-line. An abacavir + lamivudine NRTI combination seemed protective against development of NRTI resistance.

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1

Jan, 2015

Atazanavir exposure is effective during pregnancy regardless of tenofovir use

 

Authors: Colbers A, Hawkins D, HidalgoTenorio C, et al.

Published in: Antivir Ther. 2015; 20(1):57-64

Background We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.

Methods This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.

Results 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.

Conclusions Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effectiveconcentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis

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