Drug resistance mutations and outcome of second-line treatment in patients with ®rst-line protease inhibitor failure on nel®navir-containing HAART BT Rùge, TL Katzenstein, HL Nielsen and J Gerstoft Department of Infectious Diseases, Rigshospitalet, University Hospital of Copenhagen, Denmark Objectives To determine resistance mutations emerging in HIV-1-infected patients experiencing their ®rst proteaseinhibitor(PI)-failureonnel®navir-containinghighlyactiveantiretroviraltherapy(HAART), andtoassessvirologicalresponsetorescueregimens. Methods PlasmaHIV-1RNAfrom24patientsfailingnel®navir-containingHAARTwassequenced.Failurewas de®nedastwoconsecutivemeasurementsofviralload > 400HIV-1RNAcopies/mL.Patientswith previousfailureonotherPIswereexcluded.Dataonresponsetosecond-linetreatmentwasextracted from patient ®les. Results Atfailureprimaryproteasemutationswerefoundin14patients(58%).TenpatientshadD30N(38%), ®vepatientshadL90M(19%),twopatientshadV82A/F(8%)andtwopatientshadM46I/L(8%).Two patientshadbothD30NandL90M.Pronouncedincreasesofsecondaryproteasemutationswereseen atcodon88(D:33%),codon36(D:30%)andcodon71(D:17%).OfeightpatientswithN88D,seven alsoharbouredD30N(P < 0.01).Polymorphismsatcodon63weredetectedatbaselineinallpatients whodevelopedprimaryresistancemutationsatfailure(P < 0.01).Onrescueregimens,78%achieved viralloadsbelowlimitofdetection(BLD).Thepresenceofprimaryproteasemutationswasnot associatedwithahigherriskoffailureonsecond-linetreatment. Conclusion In patients failing nel®navir-containing HAART, D30N was detected frequently and L90M occasionally. A pronounced accumulation of the secondary protease mutations N88D, M36I, and A71V/Twasfound,andD30NwasstronglyassociatedwithN88D.Ahighproportionofpatients becameundetectableonsecond-linetreatmentandthepresenceofprimaryresistancemutationsdid notnegativelyaffecttheoutcomeofrescueregimens. Keywords: D30N, HIV, N88D, nel®navir, resistance mutation Received: 3 May 2002, accepted 18 September 2002 Introduction Theef®cacyofhighlyactiveantiretroviraltherapy(HAART) inHIV-1-infectedpatientshasbeenhamperedbytheemer- gence of drug resistance [1±4]. Mutations occur randomly during periods of insuf®cient suppression of viral replica- tionandresistancemutationsthatconferreplicativeadvan- tage in the presence of drugs will be selected. In order to attain full viral suppression, patients are commonly treated with one or two nucleoside reverse transcriptase inhibitors (NRTI) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or one or two protease in- hibitors (PI) [5]. In spite of the combined action of several drugs,manypatientsfailtoachievesustainedandcomplete suppression of viral replication, most probably due to poor adherence, pharmacological factors and/or emergence of drug resistance [6,7]. The resistance mutations developing during ongoing viral replication can be either drug speci®c or may hamper the effect of an entire drug class [8±11]. The need for knowledge of the impact of single resistance 38 Correspondence:DrBirgitTRùge,DepartmentofInfectDiseases, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel:  4535457726;fax:  4535456648; e-mail: roege@rh.dk ORIGINAL RESEARCH ß 2003 British HIV Association HIV Medicine (2003), 4, 38±47