Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years

Abstract

To provide insight into the dynamics and source of residual viremia in human immunodeficiency virus (HIV) patients successfully treated with antiretroviral therapy, 14 intensely monitored patients treated with indinavir and efavirenz sustaining HIV RNA at <50 copies/ml for >5 years were studied. Abacavir was added to the regimen of eight patients at year 5. After the first 9 months of therapy, HIV RNA levels had reached a plateau ("residual viremia") that persisted for over 5 years. Levels of residual viremia differed among patients and ranged from 3.2 to 23 HIV RNA copies/ml. Baseline HIV DNA was the only significant pretreatment predictor of residual viremia in regression models including baseline HIV RNA, CD4 count, and patient age. In the four of five patients with detectable viremia who added abacavir to their regimen after 5 years, HIV RNA levels declined rapidly. The estimated half-life of infected cells was 6.7 days. Decrease in activated memory cells and a reduction in gamma interferon production to HIV Gag and p24 antigen in ELISpot assays were observed, consistent with a decrease in HIV replication. Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years. Even after years of highly suppressive therapy, HIV RNA levels declined rapidly after the addition of abacavir, suggesting that productive infection contributes to residual ongoing viremia and can be inhibited with therapy intensification.

FIG. 1.

Initial decline of HIV RNA obeys biphasic exponential decay to a nonzero constant. Viral HIV RNA decayed initially with a phase I half-life of 1.2 ± 0.8 days and then with a phase II half-life of 24 ± 16 days. This decay is shown in patient 1 (top) (first-phase half-life, 0.89 [0.41, 1.9] days and second-phase half-life, 23.9 [16.3, 35.7] days) and in patient 9 (bottom) (first-phase half-life, 1.21 [0.59, 2.2] days and second-phase half-life, 30.6 [23.8, 39.5] days). Phase II ended within 6 months of treatment in 13 of 14 patients and within 9 months in the remaining patient.

FIG. 2.

Plateau of plasma HIV RNA. The second-phase RNA decay depicted in Fig. 1 ended in all patients during the first 9 months of treatment. Over the subsequent 4 years of treatment, RNA dynamics in 13 of 14 patients were statistically consistent with a plateau. Levels of residual viremia are shown for patient 1 (top) as 23 copies/ml and for patient 9 (bottom) as 5.9 copies/ml. This low-level virus production is consistent with establishment of a new steady state on antiretroviral therapy.

FIG. 3.

HIV DNA before treatment with indinavir plus efavirenz correlates with residual viremia. Residual HIV RNA was defined as the geometric mean of all measured values after 9 months of therapy. Baseline DNA was the only significant pretreatment predictor of residual viremia in either univariate (R² = 0.51, P = 0.003) or multivariate (P = 0.002) regression including baseline HIV RNA, CD4 counts, and patient age. These correlations remained when HIV DNA was normalized to cell counts, when residual viremia was computed using a maximum likelihood approach with censoring, and when nonparametric statistical methods were used. While the correlation does not define the mechanism connecting HIV DNA and residual RNA, the predictive value of pretreatment DNA levels suggests that long-lived cellular reservoirs of viral DNA activate to kindle HIV RNA production.

FIG. 4.

Effect of abacavir intensification on viremia and cell-associated infectivity. Addition of abacavir resulted in a significant decrease in plasma viremia in four of five patients with sufficient residual viremia to allow a change to be detected. Among these four individuals, only patient 1 (a) retained detectable viremia (>2.5 copies/ml) after intensification. In all others, intensification resulted in suppression of viremia to below this detection threshold (b to d).