AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 18, Number 11, 2002, pp. 771–775 © Mary Ann Liebert, Inc. Extent and Importance of Cross-Resistance to Efavirenz after Nevirapine Failure * JOSE L. CASADO, 1 ANA MORENO, 1 KURT HERTOGS, 2 FERNANDO DRONDA, 1 and SANTIAGO MORENO 1 ABSTRACT The objective of this study was to evaluate the activity of efavirenz after the failure of a nevirapine-contain- ing regimen. This prospective study included 47 patients with plasma HIV loads .1000 copies/ml, and who had received nevirapine for at least 16 weeks, included in an efavirenz-based salvage regimen. The main out- come measure was virological response, defined as an HIV RNA level decrease of at least 1 log 10 copies/ml after 24 weeks, according to genotypic and phenotypic resistance to efavirenz. Phenotypic resistance was de- fined as a .10-fold increase in the IC 50 . The median CD4 1 cell count was 236 3 10 6 /liter and the median HIV RNA level was 4.5 log 10 copies/ml. Mutations known to decrease susceptibility to nonnucleoside reverse tran- scriptase inhibitors were observed in 79% of patients, predominantly at residues 181 (49%), 103 (40%), and 106 (19%), but phenotypic resistance to efavirenz was seen in 62% of cases. All the strains with the K103N mutation showed high-level resistance to efavirenz, in contrast with 20% of those carrying exclusively the Y181C mutation. By week 24, 38% of patients had responded and 19% had achieved an undetectable HIV load. Virological failure was observed in patients with phenotypic resistance to efavirenz (67 vs. 11%; rela- tive risk [RR], 4; 95% confidence interval [CI], 1.07–14.89; p 5 0.04), or in presence of the K103N mutation (52 vs. 17%; RR, 1.77; 95% CI, 1.12–2.79; p 5 0.02), and these results remained unchanged after adjusting for HIV load, or by resistance to the accompanying drugs in the salvage regimen. A previous longer period of nevirapine therapy was significantly associated with the emergence of efavirenz resistance (288 vs. 170 days, p , 0.01). We conclude that genotypic and/or phenotypic resistance assays permit the sequential use of non- nucleoside reverse transcriptase inhibitors in the clinical setting. Our data suggest that an early change after nevirapine failure could avoid the emergence of efavirenz resistance. 771 INTRODUCTION N ON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNR- TIs) are structurally diverse but potent inhibitors of HIV- 1, with efficacy at nanomolar to micromolar concentrations. 1 In association with other antiretroviral products, NNRTIs sig- nificantly reduce viral load and increase the CD4 1 cell count, especially in naive patients. 2 The lack of severe side effects, the ease of administration, and their nonoverlappingresistance profile with protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), make this family of drugs an attractive option for naive and pretreated patients. However, NNRTIs interact with a specific pocket site of the HIV-1 re- verse transcriptase (RT), rapidly eliciting resistance due to changes in the amino acids surrounding the NNRTI-binding site. 1 Furthermore, in vitro and in vivo data indicate that cross- resistance is extensive within this class of compounds, because inhibitor binding sites overlap. 3 Because of this fact, current guidelines preclude the sequential use of NNRTIs. 4 However, efavirenz apparently retains activity against some HIV-1 strains selected by other NNRTIs. 5 Studies have shown that some viral strains remain sensitive to efavirenz after lovirideor nevirapinehas failed. 5,6 In a previousstudy we found that up to 30% of the strains that developed resistance after 6 1 Department of Infectious Diseases, Ramón y Cajal Hospital, 28034 Madrid, Spain. 2 Virco, B-2800 Mechelen, Belgium. *Presented, in part, at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 17–21, 2000.