Plasma HIV-1 RNA levels during antiretroviral therapy: how low is low enough?

Antiretroviral therapy prevents human immunodeficiency virus type 1 (HIV-1)– related complications by suppressing viral replication [1]. To forestall virologic rebound and treatment failure, a regimen must reduce the plasma HIV-1 RNA to a threshold below which the virus does not evolve and develop drug resistance. Although this threshold has not been precisely defined, it is probably near the level of quantification for the conventional assays used in the past decade (ie,,50–75 copies/mL), and hence most clinicians have aimed to maintain a viral load that is ‘‘undetectable.’’ This goal can easily be achieved with many modern regimens [2, 3]. Recently, the sensitivity of these assays has improved, resulting in a lower threshold for undetectability. This change has led to a clinical quandary: Should patients who have very low but detectable viremia be considered as having failed therapy? To address this question, Doyle and colleagues performed an analysis of patients on therapy who had viral loads below 50 copies/mL as measured by the Abbott RealTime HIV-1 assay [4]. The lower limit of quantification of this test is 40 copies/mL; below this threshold, the assay detects HIV-1 RNA, but only qualitative results (detectable or nondetectable) are reported. Given the lack of clarity regarding the significance of these low RNA levels, the treating clinician was informed only that the patient’s viral load was below 50 copies/mL, and, hence, the actual results did not affect the clinician’s decision making. Based on their unreported results, patients were retrospectively divided into 3 groups: those with viral load of 40–49 copies/mL, those with a detectable but unquantifiable viral load (RNA), and those with an undetectable viral load (RNA). Of 1247 patients, 19% had an initial viral load of 40–49 copies/mL, 41% had a detectable but nonquantifiable viral load ,40 copies/mL, and 40% had a truly undetectable viral load. Most patients who had viral load between 40–49 copies/mL had only recently achieved virologic suppression (median 0.2 years), whereas those who were RNA and RNA had been suppressed much longer (median 1.3 years and 2.8 years, respectively). Among the subset of patients for whom information was available, those who had a viral load of 40–49 copies/mL were significantly less likely to have perfect adherence, as assessed by pharmacy records, than those in the RNA group. So what were the virologic outcomes over the subsequent 12 months? Compared with those who were RNA, a higher percentage of patients who had a viral load of 40–49 copies/mL had a subsequent viral load above 50 copies/mL (4% vs 34%). This finding is not surprising; patients who had a viral load just ,50 copies/mL might have random variation in RNA levels resulting in intermittent values above this line [5]. When Doyle and colleagues focused on a level of viremia more clearly associated with treatment failure (.400 copies/mL), those who had a viral load of 40–49 copies/mL were still more likely to have virologic rebound (13%) than those whose viral load was below 40 copies/mL (3.8% in the RNA and 1.2% in the RNA group). Based on these results, the authors conclude that ‘‘the goal of [highly active antiretroviral therapy] may need to be revised to a lower cutoff than 50 copies/mL.’’ There are reasons to pause before adopting this recommendation. Even though the investigators performed appropriate analytic adjustments, it is Received 3 November 2011; accepted 8 November 2011; electronically published 11 January 2012. Correspondence: Steven G. Deeks, MD, Positive Health Program, University of California San Francisco, San Francisco General Hospital, San Francisco, CA 94110 (sdeeks@php. ucsf.edu). Clinical Infectious Diseases 2012;54(5):733–5 The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/cir933