HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy

Abstract

Background: Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined.

Methods: Blood mononuclear cells obtained during 7-12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR.

Results: Thirty participants were studied. HIV-1 DNA decreased significantly from years 0-1 and 1-4 of ART with median decay slopes of -0.86 (interquartile range, -1.05, -0.59) and -0.11 (-0.17, -0.06) log10(copies/10(6) CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4-7 (-0.02 [-0.06, 0.02]; P = .09) or after year 7 of ART (-0.006 [-0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/10(6) CD4+ T-cells; range: 7-2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1-4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up.

Conclusions: Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1-4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. NCT00001137.

Keywords: HIV-1 persistence; antiretroviral therapy; HIV-1 DNA decay; immune activation.

Figure 1.

Longitudinal measures of CD4+ T-cell count, total human immunodeficiency virus type 1 (HIV-1) DNA, and 2-LTR circle detection. A, CD4+ T-cell count over time for all participant pre-antiretroviral therapy (ART) and at years 1, 4, 7, and 10. B, Total HIV-1 DNA levels per million peripheral blood mononuclear cells (black circle) and per million CD4+ T-cells (red square) over time for all participants pre-ART at years 1, 4, 7 and 10. C, Participant-specific decay patterns of total HIV-1 DNA per million CD4+ T-cells. D, The proportion of participants with positive (detectable) 2-LTR circles over time pre-ART and at years 1, 4, 7, and 10. Abbreviations: CI, confidence interval; LTR, long terminal repeat; PBMC, peripheral blood mononuclear cells.

Figure 2.

Longitudinal plots for a subset of representative participants (6 of 30) of total human immunodeficiency virus type 1 (HIV-1) DNA levels (black circle, per million peripheral blood mononuclear cells; red square, per million CD4+ T-cells), 2-LTR circles positivity (+/−), and HIV RNA levels over time (black diamond, copies/milliliter detected; open symbol, undetected values; gray line, limit of quantification). Longitudinal plots of the remaining 24 patients are displayed in Supplementary Figure 1. Abbreviations: ART, antiretroviral therapy; ID, participant identification; LTR, long terminal repeat; PBMC, peripheral blood mononuclear cells; SCA, single-copy HIV-1 RNA assay.

Figure 3.

A, Correlation between pre-antiretroviral therapy (ART) plasma human immunodeficiency virus type 1 (HIV-1) RNA (log₁₀copies/mL) and total HIV-1 DNA decline pre-ART to year 1 [log₁₀(copies/10⁶ CD4+ T-cells) slope/year]. B, Correlation between pre-ART total HIV-1 DNA and total HIV-1 DNA at years 4, 7, and 10 on ART. C, Correlation between pre-ART total HIV-1 DNA and pre-ART CD4+ T-cell count. D, Correlation between pre-ART CD4+ T-cell count and total HIV-1 DNA slope/year from pre-ART to year 1 on ART.