title: HIV-1 Drug Resistance and Second-Line Treatment in Children Randomized to Switch at Low Versus Higher RNA Thresholds.
abstract: 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.
authors: *Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA; †Seattle Children's Hospital, Seattle, WA; ‡School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; §INSERM, SC10-US019, Paris, France; ‖University College London Hospitals, University College London, London, United Kingdom; ¶Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; #Duke University Medical Center, Durham, NC; and **Imperial College London, London, United Kingdom.
authors: Linda
authors: L
authors: Harrison
authors: Ann
authors: A
authors: Melvin
authors: Susan
authors: S
authors: Fiscus
authors: Yacine
authors: Y
authors: Saidi
authors: Eleni
authors: E
authors: Nastouli
authors: Lynda
authors: L
authors: Harper
authors: Alexandra
authors: A
authors: Compagnucci
authors: Abdel
authors: A
authors: Babiker
authors: Ross
authors: R
authors: McKinney
authors: Diana
authors: D
authors: Gibb
authors: Gareth
authors: G
authors: Tudor-Williams
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007223:Infant; D008297:Male; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral