Abstract
Background: The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments. Methods: We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity ,3, 3?, .6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (,6 months after failure) were identified with multivariable logistic regression. Results: Ninety-nine genotypic resistance tests from PI/r-treated and 129 from NNRTI-treated patients were analyzed. The risk of losing the activity of $1 NRTIs was lower among PI/r- compared to NNRTI-treated individuals ,3, 3?, and .6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p,0.001) and 18.9% vs. 60.9% (p,0.001). The percentages of patients who have lost PI/r activity were 2.9%, 3.6% and 5.4% ,3, 3?, .6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p,0.001). The risk to accumulate an early NRTI mutation was strongly associated with NNRTI-containing cART (adjusted odds ratio: 13.3 (95% CI: 4.1?2.8), p,0.001). Conclusions: The loss of activity of PIs and NRTIs was low among patients treated with PI/r, even after long-lasting exposure to a failing cART. Thus, more options remain for second-line therapy. This finding is potentially of high relevance, in particular for settings with poor or lacking virological monitoring.
?Citation: Scherrer AU, Boni J, Yerly S, Klimkait T, Aubert V, et al. (2012) Long-Lasting Protection of Activity of Nucleoside Reverse Transcriptase Inhibitors and Protease Inhibitors (PIs) by Boosted PI Containing Regimens. Editor: Joseph S. Pagano, The University of North Carolina at Chapel Hill, United States of America Received August 1, 2012; Accepted October 18, 2012; Published November 26, 2012 Copyright: ?2012 Scherrer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported in the framework of the Swiss HIV Cohort Study, by the Swiss National Science Foundation (SNF grant #33CS30-134277). Further support was provided by SNF grant # 3247B0-112594 (to HFG, SY and BL), SNF grant # 324730-130865 and the SHCS projects # 470, 528, 569, 683, the SHCS Research Foundation, the European Community’s Seventh Framework Programme (grant FP7/2007?013), under the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN; grant 223131), and by a further research grant of the Union Bank of Switzerland, in the name of a donor to HFG, and an unrestricted research grant from Tibotec, Switzerland, to HFG and from Gilead, Switzerland, to HFG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: HFG has been an adviser and/or consultant for the following companies: GlaxoSmithKline, Abbott, Novartis, Boehringer Ingelheim, Roche, Tibotec and Bristol-Myers Squibb, and has received unrestricted research and educational grants from Roche, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Tibotec and Merck Sharp & Dohme (all money went to institution). SY has participated in advisory boards of BMS and Tibotec, and has received travel grants from GSK and MSD. TK served as advisor for BMS and Pfizer and has received travel grants from Abbott and Pfizer. EB has been adviser and/or consultant for Gilead, Merck Sharp & Dohme, Janssen, ViiV, and Bristol-Myers Squibb. He also received travel grants from Abbott, Gilead, Merck Sharp & Dohme, Janssen, and ViiV. All others reported no conflict of interest.
Introduction
The emergence of drug resistance is one of the major threats to successful antiretroviral therapy of infection with human immunodeficiency virus-1 (HIV-1) [1]. HIV-1 cannot be eradicated with today’s antiretroviral treatment. The aim of therapy is thus to reduce morbidity and mortality by long-term inhibition of HIV-1 replication. Combination antiretroviral therapy (cART) is highly effective but viruses may start replicating if drug levels are too low(e.g. due to patients poor adherence or drug-drug interaction), concurrent infections or recent vaccinations. In these situations drug resistance mutations can accumulate [2?]. To avoid longlasting episodes of viral replication under cART and to detect a virological failure early, it is recommended to regularly monitor plasma viral load levels [8,9]. However, in resource-limited settings the technical equipment, health care infrastructure and financial capacity are often lacking. Monitoring of cART is therefore often solely based on the measurements of CD4 cell counts. However, monitoring of treatment success by CD4 cell counts results in a significant delay to detecting treatment failure when compared to viral load monitoring and results in a higher burden of mutations [10,11]. The accumulation of drug resistanceassociated mutations reduces the options for subsequent successful second-line treatment dramatically. Therefore, it is important to identify cART combinations that result in long-lasting protection of the antiretroviral activity and to minimize the emergence of drug resistance mutations even if patients need to stay extended periods on a failing therapy [12]. We aimed to study the loss of genotypic activity at different time points after virological failure and the accumulation of mutations. We further sought to identify risk factors for early emergence of mutations and we aimed to describe antiretroviral treatments with a long-lasting protection of the genotypic activity after virological failure. To answer these questions, we used data from the Swiss HIV Cohort (SHCS) and the SHCS drug resistance database and compared sequences from genotypic drug resistance tests that were performed after patients had failed first-line cART.
