Journal
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
Volume 70, Issue 1, Pages 42-53Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAI.0000000000000671
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Funding
- Paediatric European Network for Treatment of AIDS (PENTA) Foundation
- Agence Nationale de Recherche sur le Sida et les hepatites virales (ANRS)
- Pediatric AIDS Clinical Trials Group (PACTG)
- International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT)
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Institute of Mental Health (NIMH)
- 7th framework programme under the Eurocoord grant [260694]
- 6th framework [LSHP-CT-2006-018865]
- 5th framework programme [QLK2-CT-2000-00150]
- PENTA Foundation
- MRC
- Istituto Superiore di Sanita-Progetto Terapia Antivirale
- ANRS
- NICHD
- MRC [MC_UU_12023/16, MC_UU_12023/26, MC_U122886352] Funding Source: UKRI
- Medical Research Council [MC_UU_12023/26, MC_UU_12023/16, MC_U122886352, MC_UU_12023/23] Funding Source: researchfish
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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 x 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 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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