Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients

Background: Doravirine is a novel HIV-1 NNRTI recently shown to be non-inferior to both darunavir/ritonavir and efavirenz in combination therapy with two NRTIs in treatment-naive patients. Doravirine has an in vitro resistance profile that is distinct from other NNRTIs and retains activity against viruses containing the most frequently transmitted NNRTI mutations. Objectives: The aim of this study was to examine the prevalence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients in Europe. Methods: From 2010 to 2016, 9764 treatment-naive patients were tested for NNRTI antiretroviral drug resistance by bulk sequencing in Greece, Italy and France. We studied the prevalence of doravirine resistance-associated mutations previously identified in vitro: V106A/M, V108I, Y188L, V190S, H221Y, F227C/L/V, M230I/L, L234I, P236L, Y318F and K103N/Y181C. Results: Among 9764 sequences, 53.0% and 47.0% of patients had B and non-B subtypes, respectively. Overall, the presence of at least one doravirine resistance-associated mutation (n " 137; 1.4%) or the K103N/Y181C mutations (n " 5; 0.05%) was very rare. The most prevalent mutations were V108I (n " 62; 0.6%), Y188L (n " 18; 0.2%), H221Y (n " 18; 0.2%) and Y318F (n " 23; 0.2%). The frequency of doravirine resistance-associated mutations was similar between B and non-B subtypes. In comparison, the prevalence of rilpivirine, etravirine, nevirapine and efavirenz resistance was higher whatever algorithm was used (ANRS: 8.5%, 8.1%, 8.3% and 3.9%, respectively; Stanford: 9.9%, 10.0%, 7.5% and 9.4%, respectively). Conclusions: The prevalence of doravirine resistance-associated mutations is very low in antiretroviral-naive patients. These results are very reassuring for doravirine use in naive patients.