(See the Major Article by Santoro et al on pages 1156–64, and the Editorial Commentary by Richman on pages 1174–5.)

Background. Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50–999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predic-tive of future virologic outcomes in patients beginning ART. Methods. Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. Results. Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or non-nucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95 % confidence interval, 1.2- to 3.7-fold) than those without resistance (P =.007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P <.001). Acquisition of additional resis