{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T01:45:28Z","timestamp":1766627128440},"reference-count":34,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2015,6,1]],"date-time":"2015-06-01T00:00:00Z","timestamp":1433116800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The most common pattern of emergent resistance in the phase III clinical trials of coformulated elvitegravir (EVG)-cobicistat (COBI)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF) was the EVG resistance substitution E92Q in integrase (IN) with the FTC resistance substitution M184V in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R. In this study, the effect of these IN and RT substitutions alone and in combination in the same genome on susceptibility to antiretroviral inhibitors and viral replication fitness was characterized. Single resistance substitutions (E92Q in IN [IN-E92Q], M184V in RT [RT-M184V], and K65R in RT [RT-K65R]) specifically affected susceptibility to the corresponding inhibitor classes, with no cross-class resistance observed. The IN-E92Q mutant displayed reduced susceptibility to EVG (50-fold), which was not impacted by the addition of RT-M184V or RT-K65R\/M184V. Viruses containing RT-M184V had high-level resistance to FTC (&gt;1,000-fold) that was not affected by the addition of IN-E92Q or RT-K65R. During pairwise growth competitions, each substitution contributed to decreased viral fitness, with the RT-K65R\/M184V + IN-E92Q triple mutant being the least fit in the absence of drug. In the presence of drug concentrations approaching physiologic levels, however, drug resistance offset the replication defects, resulting in single mutants outcompeting the wild type with one drug present, and double and triple mutants outcompeting single mutants with two drugs present. Taken together, these results suggest that the reduced replication fitness and phenotypic resistance associated with RT and IN resistance substitutions are independent and additive. In the presence of multiple drugs, viral growth is favored for viruses with multiple substitutions, despite the presence of fitness defects.<\/jats:p>","DOI":"10.1128\/aac.00040-15","type":"journal-article","created":{"date-parts":[[2015,4,1]],"date-time":"2015-04-01T09:41:41Z","timestamp":1427881301000},"page":"3441-3449","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Reduced Viral Fitness and Lack of Cross-Class Resistance with Integrase Strand Transfer Inhibitor and Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations"],"prefix":"10.1128","volume":"59","author":[{"given":"Kristen N.","family":"Andreatta","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derrick D.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Miller","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten L.","family":"White","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, California, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012","author":"British HIV Association","year":"2013","unstructured":"British HIV Association. 2013. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. British HIV Association, London, United Kingdom. http:\/\/www.bhiva.org\/TreatmentofHIV1_2012.aspx."},{"key":"e_1_3_2_3_2","volume-title":"European AIDS Clinical Society guidelines, version 7.0","author":"Lundgren JD","year":"2013","unstructured":"Lundgren JD, Clumeck N, Rockstroh J, Ryom L. October 2013. European AIDS Clinical Society guidelines, version 7.0. European AIDS Clinical Society, Brussels, Belgium."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.7961"},{"key":"e_1_3_2_5_2","volume-title":"Addendum to U.S. Department of Health and Human Services (DHHS) guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents","author":"U.S. Department of Health and Human Services","year":"2013","unstructured":"U.S. Department of Health and Human Services. 30 October 2013. Recommendation on integrase inhibitor use in antiretroviral treatment-naive HIV-infected individuals from the HHS panel on antiretroviral guidelines for adults and adolescents. In Addendum to U.S. Department of Health and Human Services (DHHS) guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Revised 12 February 2013. Panel on Antiretroviral Guidelines for Adults and Adolescents, a Working Group of the Office of AIDS Research Advisory Council, U.S. Department of Health and Human Services, Washington, DC. http:\/\/aidsinfo.nih.gov\/guidelines."},{"key":"e_1_3_2_6_2","volume-title":"HIV\/AIDS programme: consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, Kuala Lumpur, Malaysia","author":"World Health Organization","year":"2013","unstructured":"World Health Organization. 2013. HIV\/AIDS programme: consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, Kuala Lumpur, Malaysia .World Health Organization, Geneva, Switzerland. http:\/\/www.who.int\/hiv\/pub\/guidelines\/arv2013\/download\/en\/."},{"key":"e_1_3_2_7_2","first-page":"87","article-title":"Resistance to protease inhibitors","volume":"7","author":"Kuritzkes DR","year":"2002","unstructured":"Kuritzkes DR. 2002. Resistance to protease inhibitors. 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