Abstract: Rilpivirine is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) that was approved for use in the United States in May 2011. Because it has been coformulated with emtricitabine and tenofovir as a once daily tablet (Complera; Gilead Sciences, Inc., Foster City, California, USA) that retains activity against HIV in the presence of a K103N mutation, it has quickly become a popular choice for both treatment-naive and treatment-experienced HIV-infected patients. We recently encountered an antiretroviral-naive HIV-infected patient with rilpivirine virologic failure 1 month after being started on antiretroviral therapy. The patient had a CD4 cell count of 15 cells/μl and HIV-1 RNA level of 269 000 copies/ml. Baseline HIV genotype reported no resistance to any class of antiretroviral agents, although an isolated E138A mutation was listed. Of note, rilpivirine was not listed as one of the available NNRTIs on the genotype report. The patient was started on emtricitabine/tenofovir/efavirenz but was switched after 1 week to emtricitabine/rilpivirine/tenofovir due to severe side effects. After 5 weeks of therapy only a 0.3 log reduction in HIV RNA level was achieved. On further investigation, the baseline isolated E138A NNRTI mutation was noted and, after discussion with the virology laboratory that had performed the genotype, it was realized that rilpivirine resistance had been predicted prior to initiation of therapy. The patient's therapy was switched to a protease inhibitor-based regimen and she has since then had an appropriate virologic response. Given the lack of data on the incidence of E138 mutations in antiretroviral-naive patients, we decided to investigate the incidence of baseline rilpivirine resistance-associated mutations (RAM)s due to E138A/G/K/Q mutations in treatment-naive HIV-infected patients seen in our institutions. We reviewed baseline genotypic resistance profiles on 422 antiretroviral-naive HIV-infected patients at the George Washington University Medical Center and Veterans Affairs Medical Center, both in Washington, DC, between 2007 and 2010. Eight patients (1.9%) had baseline E138 mutations detected, three in 2008, two in 2009 and three in 2010. Of these, six were E138A mutations, one was an E138G mutation and one was an E138K mutation. Interestingly, in seven of these cases (88%) the E138 mutation was the only mutation identified. Physicians need to be aware of the presence of isolated baseline E138 mutations and the implication for resistance to rilpivirine. Review of 7295 resistance tests recorded since 1995 in the Frankfurt Resistance Database showed a 0.4% incidence of the E138K mutation, although many of these resistance tests were from treatment-experienced patients [1]. The ECHO (efficacy comparison in treatment-naive HIV-infected subjects of TMC278 and efavirenz) and THRIVE (TMC278 against HIV, in a once-daily regimen versus efavirenz) trials of rilpivirine excluded individuals with baseline E138A/G/K/Q/R mutations, and therefore the baseline prevalence of these mutations is unknown. In these phase 3 studies, 10% of rilpivirine-treated patients experienced virologic failure, of whom, the majority (71%) had developed rilpivirine RAMs [2]. The most common RAM that emerged was the E138K mutation that was seen in 45% of rilpivirine failures. The E138K mutation was frequently associated with a M184I mutation, which has been shown to further reduce the phenotypic susceptibility to rilpivirine [3]. Although not initially identified as a clinically significant RAM, the E138A mutation has also been associated with reductions in susceptibility for rilpivirine similar to the E138G/K/Q mutations [4], and this mutation has been included as one of the 15 rilpivirine RAMs in the 2011 update of the IAS-USA HIV drug resistance mutations reference [5]. Although E138A/G/K/Q/R mutations are listed as major rilpivirine RAMs, E138A/G/K/Q mutations are also listed as minor etravirine RAMs. Ideally, this patient should never have been switched from emtricitabine/tenofovir/efavirenz to emtricitabine/rilpivirine/tenofovir because the E138A mutation has been listed as a major RAM in the latest update of the IAS-USA HIV drug resistance mutations reference since November 2011. However, as this case illustrates, busy infectious disease practitioners can be lulled into a false sense of security by only looking at the interpretation of a patient's genotype and not also reviewing the mutations listed. This case highlights the importance of knowing that there is a low level of baseline resistance to the second generation NNRTIs and of reviewing the individual resistance mutations on genotype reports as well as the interpretation provided by the laboratory. Acknowledgements Conflicts of interest There are no conflicts of interest.