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Prolonged Persistence of M184V Mutation and Phenotypic Resistance to Lamivudine in Adults with Multi-drug-resistant HIV-1 Infection Interrupting Treatment with Reverse Transcriptase Inhibitors
Roger Paredes*1,2, V Marconi1, R Hoh3, J Martin3, C Petropoulos4, S Deeks3, and D Kuritzkes1
1Brigham and Women's Hosp, Harvard Med Sch, Boston, MA, US; 2Fndn irsiCaixa, Badalona, Spain; 3Univ of California, San Francisco and San Francisco Gen Hosp, US; and 4Monogram Biosci, South San Francisco, CA, US
Background: The lamivudine
(3TC)-associated M184V mutation is associated with reduced replicative capacity
ex vivo. The influence of this
mutation on viral fitness (as defined in absence of drug pressure) has not been
carefully defined in vivo.
Methods: A sensitive allele-specific polymerase chain
reaction (ASPCR) assay was used to estimate the proportion of M184V mutants in
plasma samples from 6 subjects with multi-drug-resistant HIV who interrupted
all reverse transcriptase inhibitors (RTI). Protease inhibitors (PI) were
maintained to prevent emergence of archived wild type HIV. In 5 of 6 subjects,
3TC was one of the RTI interrupted. All subjects were followed for a
minimum of 48 weeks or until study treatment was
modified. Specimens were tested by ASPCR at baseline and at least at 4
week-intervals thereafter. Genotypic and phenotypic resistance data were
obtained before the RTI interruption and at multiple time-points during
follow-up.
Results: The ASPCR had a sensitivity of 0.4% for M184V.
The median HIV-1 RNA levels and CD4+ cell counts at baseline were
3.61 log copies/mL and 313 cells/mm3, respectively. M184V was
detected by ASPCR and standard genotyping at baseline in all 5 subjects
discontinuing 3TC. The proportion of M184V mutants remained approximately 100%
for the first 12 to 16 weeks in all subjects discontinuing 3TC, including 2
subjects who modified therapy at weeks 12 and 16. In 3 subjects remaining off
RTI for >16 weeks, the M184V mutant remained stable until weeks 16, 20, and
28, at which time a rapid decay in M184V was observed, with the levels becoming
undetectable after approximately 8 weeks. Fold-change in IC50
decreased concurrently with loss of M184V. M184V was not measurable at any time
point in the one subject not receiving 3TC at baseline.
Conclusions: In patients with multi-drug-resistant HIV who
receive 3TC- and PI-containing HAART, the M184V mutation and 3TC phenotypic
resistance persist for prolonged periods of time after interrupting all RTI,
and then demonstrate a seemingly biphasic decay. Given the rapid emergence of M184V when 3TC is initiated, the
delayed loss of this mutation in absence of 3TC indicates that the beneficial
impact of M184V on fitness in presence of 3TC is far greater than its negative effect
on viral fitness in absence of 3TC.
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