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We assessed resistance prevalence and patterns at second\u2010line VF, stratified by PI (atazanavir\/ritonavir or lopinavir\/ritonavir), and examined correlations of resistance and treatment strategies with VF at 6\u201318 months post\u2010genotype. Analyses employed inverse probability weighting, adjusting for calendar year, age, gender, ART duration, PI at genotyping and class\u2010specific resistance, and considered guidelines\u2010supported versus unsupported strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 187 participants (median age 41 years, 54% female, 41% on atazanavir\/ritonavir, 59% on lopinavir\/ritonavir\u2010based ART), 91% had any resistance (NRTI 79%, NNRTI 80%, major PI 37%, dual\u2010class 36%, triple\u2010class 37%). Predicted resistance to third\u2010line options was 67% for etravirine or rilpivirine and 10% for darunavir\/ritonavir. Despite higher resistance detected on atazanavir\/ritonavir versus lopinavir\/ritonavir, predicted darunavir\/ritonavir resistance was similar. At median 9 months post\u2010genotype, 95% of 173 participants with available data were on a guidelines\u2010supported regimen (55% second\u2010line; 45% third\u2010line, 86% dolutegravir\u2010based), of whom 28% had post\u2010genotype VF. Of the 5% not on guidelines\u2010supported regimens, 71% had post\u2010genotype VF. Adjusted odds of VF were higher for guidelines\u2010unsupported versus supported regimens (OR = 4.52; 95% CI 1.02\u221226.24), and odds of VF were 97% lower for those on third\u2010line versus second\u2010line (OR = 0.07; 95% CI 0.02\u22120.20).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We found high levels of drug resistance and early VF following PI\u2010based second\u2010line failure in Kenya. Treatment guidelines compliance and switches to third\u2010line, even within guidelines recommendations, improved early viral outcomes. Findings highlight the vulnerability of PLWH with advanced ART experience and resistance profiles, and the importance of following guidelines and improving access to third\u2010line and drug resistance testing, particularly in the new ART era.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.26523","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T04:44:42Z","timestamp":1749530682000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HIV drug resistance, early treatment outcomes and impact of guidelines compliance after protease inhibitor\u2010based second\u2010line failure in a dedicated resistance clinic in western Kenya: a retrospective cohort study"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3156-1065","authenticated-orcid":false,"given":"John M.","family":"Humphrey","sequence":"first","affiliation":[{"name":"Department of Medicine Indiana 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(AMPATH)  Eldoret Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bilal","family":"Jawed","sequence":"additional","affiliation":[{"name":"Department of Medicine Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Kemboi","sequence":"additional","affiliation":[{"name":"Academic Model Providing Access to Healthcare (AMPATH)  Eldoret Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Ngetich","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Moi Teaching and Referral Hospital  Eldoret Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Goodrich","sequence":"additional","affiliation":[{"name":"Department of Medicine Indiana University School of Medicine  Indianapolis Indiana 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