290 
Low-level Viremia Decays over 7+ Years to a Residual Level Correlated with Baseline HIV-1 RNA
Martin King*1, S Palmer2, A Wiegand2, F Maldarelli2, B Bernstein1, D Kempf1, G Hanna1, J Mellors3, and J Coffin2
1Abbott Labs, Abbott Park, IL, US; 2HIV Drug Resistance Prgm, NCI, NIH, Frederick, MD, US; and 3Univ of Pittsburgh, PA, US
Background: Initial treatment
of HIV-1 infection results in biphasic viral decay, representing rapid
clearance (half-life of 1 to 2 days) of virus from productively infected cells
and more gradual clearance (half-life of 2 to 3 weeks) from longer-lived cells.
The dynamics of subsequent phases of decline have not been well-described.
Methods: We analyzed
longitudinal plasma samples, using an HIV-1 RNA assay with single-copy
sensitivity, from 157 subjects in 2 studies who consistently had <50 copies
of RNA/mL by conventional assays: Study
720 (lopinavir/ritonavir [LPV/r] plus stavudine [d4T] and lamivudine [3TC]; 306
samples from 40 subjects from weeks 60 to 360) and Study 863 (LPV/r or nelfinavir [NFV], plus d4T/3TC; 370 samples from 117
subjects from weeks 60 to 110). The assay detection limit was typically 0.4 to 0.7 copies/mL with the
sample volumes available. Using nonlinear mixed effects models, we
fitted bi-exponential models to assess HIV-1 RNA decay from week 60 through 7
years of treatment.
Results: We observed a
statistically significant decline in HIV-1 RNA, representing a third phase of
decay, that was consistent between studies, with half-lives of 77 weeks (95%
CI: 46 to 236) for Study 720 and 69 weeks (95% CI: 38 to 408) for Study 863 (p = 0.87 for the difference between
studies). The decline appeared to level off after the third phase, implying a
fourth phase with no decay. Empirical Bayes estimates of subject-specific
residual viremia were correlated with baseline viremia (Study 720: R2
= 0.24, p = 0.001; Study 863: R2
= 0.11, p <0.001). Results
were comparable if Study 720 was analyzed alone.
Conclusions: We observed a
non-linear decline in plasma HIV-1 RNA <50 copies/mL
beginning 1 year after initiation of suppressive therapy, suggesting additional
phases of viral dynamics. The third-phase half-life of 16 to 18 months was
observed in both studies. No decay during a fourth phase was discernable, and
residual viremia was correlated with baseline. Low-level persistent viremia
appears to arise from at least 2 cell compartments, one with a half-life
comparable to that previously described for latently infected CD4+ T
cells (6 to 44 months), and one or more with a half-life longer than the 7-year
treatment period.
|
