HIV-1 transmitted drug resistance in Slovenia and its impact on predicted treatment effectiveness: 2011–2016 update

RESEARCH ARTICLE HIV-1 transmitted drug resistance in Slovenia and its impact on predicted treatment effectiveness: 2011–2016 update Maja M. Lunar1, Snježana Židovec Lepej2, Janez Tomažič3, Tomaž D. Vovko3, Blaž Pečavar3, Gabriele Turel3, Manja Maver3, Mario Poljak1* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia, 2 Dr. Fran Mihaljević University Hospital for Infectious Diseases, Zagreb, Croatia, 3 Department of Infectious Diseases, Ljubljana University Medical Center, Ljubljana, Slovenia * Abstract OPEN ACCESS Citation: Lunar MM, Židovec Lepej S, Tomažič J, Vovko TD, Pečavar B, Turel G, et al. (2018) HIV-1 transmitted drug resistance in Slovenia and its impact on predicted treatment effectiveness: 2011– 2016 update. PLoS ONE 13(4): e0196670. https:// doi.org/10.1371/journal.pone.0196670 Editor: Chiyu Zhang, Institut Pasteur of Shanghai Chinese Academy of Sciences, CHINA Received: February 21, 2018 Accepted: April 17, 2018 Published: April 26, 2018 Copyright: © 2018 Lunar 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. Data Availability Statement: All sequences are available from the GenBank database (accession numbers KF753699-KF753751, KP013639KP013667, KY656612-KY656628, KY656630KY656636, KY656638, KY656640-KY656649, KY656651-KY656667, KY656669-KY656674, MF987697-MF987724). Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. HIV-positive individuals that have a detected transmitted drug resistance (TDR) at baseline have a higher risk of virological failure with antiretroviral therapy (ART). This study offers an update on the prevalence of TDR in Slovenia, looks for onward transmission of TDR, and reassesses the need for baseline drug resistance testing. Blinded questionnaires and partial pol sequences were obtained from 54.5% (168/308) of all of the patients diagnosed with HIV-1 from 2011 to 2016. Subtype B was detected in 82.7% (139/168) of patients, followed by subtype A (8.3%), subtype C (2.4%), and CRF01_AE (1.8%). Surveillance drug resistance mutations (SDRMs) were found in four individuals (2.4%), all of them men who have sex with men (MSM) and infected with subtype B. K103N was detected in two patients and T68D and T215D in one person each, corresponding to a prevalence of 0%, 1.2%, and 1.2% of TDR to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs), respectively. The impact of mutations on drug susceptibility was found to be most pronounced for NNRTIs. No forward spread of TDR within the country was observed; however, phylogenetic analysis revealed several new introductions of HIV into Slovenia in recent years, possibly due to increased risky behavior by MSM. This was indirectly confirmed by a substantial increase in syphilis cases and HIV-1 non-B subtypes during the study period. A drug-resistant HIV variant with good transmission fitness is thus more likely to be imported into Slovenia in the near future, and so TDR should be closely monitored. Introduction Great efforts to provide HIV antiretroviral therapy (ART) to all people living with HIV (PLWH) have been made globally. The World Health Organization (WHO) has promoted this goal under the target of 90-90-90; that is, 90% of PLWH diagnosed, 90% of diagnosed PLWH receiving ART, and 90% of them achieving viral suppression by 2020. By the end of 2016, the PLOS ONE | https://doi.org/10.1371/journal.pone.0196670 April 26, 2018 1 / 14 HIV-1 transmitted drug resistance in Slovenia: 2011-2016 WHO estimated that this goal is yet to be reached, with the current proportions at 70-77-82 [1]. Even though identifying all PLWH and providing them with ART is of outmost importance, this is extremely challenging. On the other hand, a significant impact on the third “90” (i.e., ART effectiveness) can be made by promoting good adherence and thus reducing the risk of emergence of acquired drug resistance coupled with active national and regional monitoring and baseline (pre-treatment) testing of transmitted drug resistance (TDR). A higher risk of virological failure has been observed among PLWH with detected TDR even when only lowlevel resistance was present at baseline [2]. A rising trend of TDR in low- and middle-income countries (LMIC) has been observed because ART has only recently started becoming available there. The prevalence of TDR in LMIC nearly doubled from 2009 to 2013 in comparison to 2004 to 2008. In contrast, a stabilizing trend has been noted in high-income countries [3]. Hofstra et al. (2016) presented data from an international study on monitoring TDR in Europe (the SPREAD program) and found an overall prevalence of 8.3% from 2008 to 2010, confirming the previous observation of TDR stabilizing across Europe. The study concluded that most detected mutations conferred resistance to nucleoside reverse transcriptase inhibitors (NRTIs); however, the predicted impact of TDR mutations was greatest regarding susceptibility to non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimens. The NRTI mutations did not affect the predicted susceptibility of the currently used regimen; however, susceptibility was reduced to inhibitors added to the NRTI backbone—specifically, by mutations conferring resistance to NNRTIs or protease inhibitors (PIs) [4]. High levels of TDR can result from onward transmission of strains carrying TDR mutations within a country, as was shown in a recent study by Paraskevis et al. (2017). A high prevalence of NNRTI resistance was found in HIV-1 subtype A as a result of local Greek transmission networks [5]. A similar finding was observed in Croatia, which borders Slovenia, where a TDR prevalence of an alarming 22% was assessed, primarily due to the onward transmission of T215S revertant mutation [6]. Data from other neighboring countries and regions also showed a higher prevalence of TDR among treatment-naive individuals than the reported European average; specifically, 17% and 12% in Hungary and northern Italy, respectively [7,8]. In contrast, Slovenia, which is a small central European country with a population of 2 million, had a historically low TDR prevalence (i.e., 4.7% TDR among HIV-1 positive individuals diagnosed from 2005 to 2010), which is similar to the rates reported from some Balkan countries; for example, from Bulgaria (5.2%), Serbia (8.8%), and Greece (6.0%) [5,9–11]. This study offers an update on the national prevalence of TDR in the last 6 years in Slovenia (2011–2016), examines whether cases of TDR are due to onward transmission of strains carrying TDR mutations within the country, and r (...truncated)