Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy

Abstract

Residual viremia can be detected in most HIV-1-infected patients on antiretroviral therapy despite suppression of plasma RNA to <50 copies per ml, but the source and duration of this viremia is currently unknown. Therefore, we analyzed longitudinal plasma samples from 40 patients enrolled in the Abbott M97-720 trial at baseline (pretherapy) and weeks 60 to 384 by using an HIV-1 RNA assay with single-copy sensitivity. All patients were on therapy (lopinavir/ritonavir, stavudine, and lamivudine) with plasma HIV RNA <50 copies per ml by week 96 of the study and thereafter. Single-copy assay results revealed that 77% of the patient samples had detectable low-level viremia (>/=1 copy per ml), and all patients had at least one sample with detectable viremia. A nonlinear mixed effects model revealed a biphasic decline in plasma RNA levels occurring over weeks 60 to 384: an initial phase of decay with a half-life of 39 weeks and a subsequent phase with no perceptible decay. The level of pretherapy viremia extrapolated for each phase of decay was significantly correlated with total baseline viremia for each patient (R(2) = 0.27, P = 0.001 and R(2) = 0.19, P < 0.005, respectively), supporting a biological link between the extent of overall baseline viral infection and the infection of long-lived reservoirs. These data suggest that low-level persistent viremia appears to arise from at least two cell compartments, one in which viral production decays over time and a second in which viral production remains stable for at least 7 years.

Fig. 1.

Sample selection and number of patients in the M97-720 trial included for analysis with the single-copy assay.

Fig. 2.

Decline in persistent viremia over 7 years of treatment. (A) Initial two-phase decline in viremia after the initiation of treatment for the 720 patients included in this study, as assayed by Amplicor. (B) Individual HIV-1 RNA values determined by SCA starting at week 60 (open symbols indicate negative assay values plotted at the limit of quantification). Thick black line, fitted biphasic decay model; thin gray lines, decay rates corresponding to the compartments and half-lives shown.

Fig. 3.

Individual data from six typical patients. Plasma HIV-1 RNA values (triangles) and empirical Bayes estimates of fitted individual biphasic decay curves are plotted.

Fig. 4.

Correlation between baseline plasma HIV-1 RNA and subject-specific estimates of baseline HIV-1 RNA from each compartment. Empirical Bayes estimates of individual-patient baseline HIV-1 RNA arising from compartment 3 (A) and compartment 4 (B) were computed and found to be significantly correlated with total baseline plasma viremia.

Fig. 5.

Comparison of phase 3 decay in two different studies. Analysis of longitudinal samples from 157 patients enrolled in the M97-720 (red diamonds) and M98-863 (black triangles) studies who consistently had viral RNA levels of <50 copies per ml. A statistically significant decline in HIV-1 RNA, representing a third phase of decay, was consistent between the studies (black line, M97-720; red line, M98-863). Only values obtained between 60 and 120 weeks are shown for the M97-720 study. Levels of virus above the limit of detection are shown by filled symbols, and levels below this limit are shown by open symbols plotted at the assay limit.