title: Differences in reversion of resistance mutations to wild-type under structured treatment interruption and related increase in replication capacity.
abstract: BACKGROUND
  The CPCRA 064 study examined the effect of structured treatment interruption (STI) of up to 4 months followed by salvage treatment in patients failing therapy with multi-drug resistant HIV. We examined the relationship between the reversion rate of major reverse transcriptase (RT) resistance-associated mutations and change in viral replication capacity (RC). The dataset included 90 patients with RC and genotypic data from virus samples collected at 0 (baseline), 2 and 4 months of STI.
  
  
  RESULTS
  Rapid shift towards wild-type RC was observed during the first 2 months of STI. Median RC increased from 47.5% at baseline to 86.0% at 2 months and to 97.5% at 4 months. Between baseline and 2 months of STI, T215F had the fastest rate of reversion (41%) and the reversion of E44D and T69D was associated with the largest changes in RC. Among the most prevalent RT mutations, M184V had the fastest rate of reversion from baseline to 2 months (40%), and its reversion was associated with the largest increase in RC. Most rates of reversion increased between 2 months and 4 months, but the change in RC was more limited as it was already close to 100%. The highest frequency of concurrent reversion was found for L100I and K103N. Mutagenesis tree models showed that M184V, when present, was overall the first mutation to revert among all the RT mutations reported in the study.
  
  
  CONCLUSIONS
  Longitudinal analysis of combined phenotypic and genotypic data during STI showed a large amount of variability in prevalence and reversion rates to wild-type codons among the RT resistance-associated mutations. The rate of reversion of these mutations may depend on the extent of RC increase as well as the co-occurring reversion of other mutations belonging to the same mutational pathway.
authors.affiliation: Monogram Biosciences, Inc., South San Francisco, California, United States of America. apaquet@monogrambio.com
authors.forename: Agnes C
authors.initials: AC
authors.lastname: Paquet
authors.forename: John
authors.initials: J
authors.lastname: Baxter
authors.forename: Jodi
authors.initials: J
authors.lastname: Weidler
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Jody
authors.initials: J
authors.lastname: Lawrence
authors.forename: Rose
authors.initials: R
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Bates
authors.forename: Eoin
authors.initials: E
authors.lastname: Coakley
authors.forename: Colombe
authors.initials: C
authors.lastname: Chappey
mesh_terms: D018432:Drug Resistance, Multiple / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008137:Longitudinal Studies; D020125:Mutation, Missense; D012194:RNA-Directed DNA Polymerase; D014779:Virus Replication
chemical_list: D012194:RNA-Directed DNA Polymerase