BACKGROUND:
In patients successfully treated with potent antiretroviral therapy, HIV RNA
levels establish a steady state (residual viraemia) after 6–9 months of
therapy that persists for years and reflects low-level viral replication. We
evaluated the predictors of residual viraemia among 100 treatment-naive
patients randomized to tenofovir (TDF)+lamivudine (3TC)+ efavirenz (EFV)
(TDF arm) or stavudine (d4T)+3TC+ EFV (d4T arm) in Gilead study 903.
METHODS:
A cohort of 100 sequentially enrolled patients with <50 copies/ml of HIV RNA
from week 48 to 72 and available baseline PBMCs were selected from study 903
for analysis. Residual viraemia was determined by measuring HIV RNA levels
at weeks48, 64 and 72 using a modification (limit of detection 2.5 HIV RNA
copies/ml) of the Roche Amplicor assay. HIV DNA was measured from stored
baseline PBMCs using the Roche Monitor assay. The outcome variable of
undetectable residual viraemia was defined as allthree measures of HIV RNA
below 2.5 copies/ml. Predictors of residual viraemia were examined in
univariate and multivariate logistic regression analyses.
RESULTS:
Baseline mean HIV RNA levels (4.8 ±0.6 log10 copies/ml), HIV DNA levels (1.9
±0.5 log10 copies/µg cellular DNA) and CD4 cell counts (320 cells/ml) were
similar among patients in the TDF arm (n=55) and d4T arm (n=45)
of this cohort. Residual viraemia between 2.5 and 50 copies/ml was
detectable in 29/55 (53%) in the TDF arm and 32/45 (71%) in the d4T arm. In
the stepwise logistic regression model, there were three independent
predictors of residual viraemia – higher baseline HIV RNA (P=0.02),
higher baseline HIV DNA (P=0.05) and treatment assignment (P=0.05).
HIV RNA ‘blips’ above 50 copies/ml after 72 weeks, but not change in CD4
cell count from week 48 to 96, were associated with detectable levels of
residual viraemia. CONCLUSIONS: Lower baseline proviral HIV DNA levels and
randomization to the TDF arm were associated with lower levels of residual
viraemia, independent of baseline HIV RNA levels. In this exploratory
analysis, lower levels of residual viraemia in the TDF arm suggests greater
antiviral potency of this regimen as compared to the d4T regimen. Higher
proviral HIV DNA at baseline may either directly contribute to residual
viraemia through subsequent activation of the latent reservoir, or
alternatively, the proviral HIV DNA level may be a surrogate for host
factors that sustain residual HIV infection during therapy.
