ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia

Frank Maldarelli, Sarah Palmer, Martin S King, Ann Wiegand, Michael A Polis, JoAnn Mican, Joseph A Kovacs, Richard T Davey, Diane Rock-Kress, Robin Dewar, Shuying Liu, Julia A Metcalf, Catherine Rehm, Scott C Brun, George J Hanna, Dale J Kempf, John M Coffin, John W Mellors, Frank Maldarelli, Sarah Palmer, Martin S King, Ann Wiegand, Michael A Polis, JoAnn Mican, Joseph A Kovacs, Richard T Davey, Diane Rock-Kress, Robin Dewar, Shuying Liu, Julia A Metcalf, Catherine Rehm, Scott C Brun, George J Hanna, Dale J Kempf, John M Coffin, John W Mellors

Abstract

Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50-75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that >80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy.

Conflict of interest statement

Competing interests. MSK, SCB, GJH, and DJK are employees of Abbott Laboratories. JWM is a member of the Abbott Scientific Advisory Committee for HIV and hepatitis C virus therapeutics.

Figures

Figure 1. Decline and Stable Persistence of…
Figure 1. Decline and Stable Persistence of Plasma HIV-1 RNA in Patients Suppressed on Antiretroviral Therapy
Plasma from patients initiating antiretroviral therapy with stavudine + lamivudine + efavirenz (patients A and B) or stavudine + lamivudine + indinavir + nevirapine (patient C) was assayed by bDNA (diamonds) and SCA (squares). Levels of virus above the limit of detection for each assay are shown by filled symbols; levels below this limit are shown by hollow symbols plotted at the assay limit.
Figure 2. Distribution of Plasma HIV-1 RNA…
Figure 2. Distribution of Plasma HIV-1 RNA Levels in Patients with Persistently Suppressed Viremia (HIV-1 RNA
Week 60 viral RNA levels for M98–863 patients on LPV/r- (blue) or NFV-containing (red) regimens were determined by SCA. The percentile of patients in each group with a given RNA level is presented. SCA determinations for patients on NNRTI- containing regimens (n = 28) for >1 y are included (green). The inset shows the mean and median log10 RNA levels for each group.
Figure 3. Correlation between Pretherapy and On-Therapy…
Figure 3. Correlation between Pretherapy and On-Therapy Viral RNA Levels
Pretherapy and week 60 SCA values were determined for 130 patients from both the NFV and LPV/r arms in M98–863. Correlation coefficients for patients taking LPV/r and NFV regimens were similar.
Figure 4. HIV-1 RNA Levels Over 50…
Figure 4. HIV-1 RNA Levels Over 50 wk of Suppressive Antiretroviral Therapy
Plasma samples from patients in both arms of the M98–863 trial with viremia suppressed to

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