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Background Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. Methods HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. Results In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. Conclusions Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic. [ABSTRACT FROM AUTHOR]

Objectives: We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance.Methods: We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms.Results: NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients.Conclusions: The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype-phenotype studies are necessary to elucidate the role of V106I in doravirine resistance. [ABSTRACT FROM AUTHOR]

Objectives: Doravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients.Methods: Doravirine-associated resistance mutations identified in vitro or in vivo were studied in a set of 9199 HIV-1 RT sequences from HIV-1 antiretroviral-experienced patients, including 381 NNRTI-failing patients in France and Italy between 2012 and 2017. The following mutations were considered as resistance mutations: V106A/M, V108I, Y188L, G190S, F227C/L/V, M230I/L, L234I, P236L, K103N + Y181C, K103N + P225H and K103N + L100I.Results: The frequencies of doravirine-associated resistance mutations (total dataset versus NNRTI-failing patients) were: V106A/M, 0.8% versus 2.6%; V108I, 3.3% versus 9.2%; Y188L, 1.2% versus 2.6%; G190S, 0.3% versus 2.1%; F227C/L/V, 0.5% versus 1.8%; M230I/L, 2.8% versus 0%; L234I, 0.1% versus 0.5%; K103N + Y181C, 3.9% versus 3.9%; K103N + P225H, 2.9% versus 4.7%; and K103N + L100I, 1.7% versus 3.9%, with a significantly higher proportion of these mutations in the NNRTI-failing group (P < 0.05), except for M230I/L and K103N + Y181C. The overall prevalence of sequences with at least one doravirine-associated resistance mutation was 12.2% and 34.9% in the total dataset and NNRTI-failing patients (P < 0.001), respectively. In comparison, the prevalence of the common NNRTI mutations V90I, K101E/P, K103N/S, E138A/G/K/Q/R/S, Y181C/I/V and G190A/E/S/Q were higher (8.9%, 7.9%, 28.6%, 12.6%, 14.2% and 8.9%, respectively).Conclusions: These results suggest that doravirine resistance in antiretroviral-experienced patients generally and specifically among NNRTI-failing patients is lower than resistance to other NNRTIs currently used, confirming its distinguishing resistance pattern. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: To describe the prevalence of transmitted drug resistance (TDR) among 84 children newly diagnosed with HIV in France in 2006-17.Methods: HIV-1 resistance-associated mutations (RAMs) were characterized using both the 2009 Stanford list of mutations and the 2017 French National Agency for AIDS Research (ANRS) algorithm. A genotypic susceptibility score (GSS) was estimated for each first-line recommended ART combination.Results: Patients were mainly infected through mother-to-child transmission (MTCT) (73/84; 86.9%), but only 18 children (24.7% of vertically infected patients) were previously exposed to antiretroviral prophylaxis from MTCT. Non-B variants were identified in 90.5% (76/84) of patients. The frequency of TDR was 8.3% (7/84) using the 2009 Stanford list and 16.7% (14/84) using both the Stanford list and the 2017 ANRS algorithm. The prevalence of PI-, NRTI-, efavirenz/nevirapine-, etravirine/rilpivirine- and doravirine-associated RAMs was 0%, 3.6%, 6.0%, 11.9% and 2.4%, respectively. Single-, dual- and triple-class resistance was present in 15.5%, 1.2% and 0% of cases, respectively. Additionally, 3/60 (5%) strains had integrase inhibitor (INI)-related RAMs (an isolated E157Q mutation, which could mostly affect the susceptibility to raltegravir/elvitegravir rather than that to dolutegravir). Among the 18 children exposed to MTCT prophylaxis, RAMs were identified in only 1 case (5.6%). The proportion of fully active combinations (GSS = 3) was ≥97.6%, ≥94.1%, ≥92.9% and ≥89.3% for PI-, INI-, efavirenz/nevirapine- and rilpivirine-based regimens, respectively.Conclusions: The proportion of NRTI- and NNRTI-related TDR in children is lower in France than in low- and middle-income countries. However, we suggest favouring PI- or dolutegravir- over NNRTI-based combinations to treat newly diagnosed HIV-infected children, even in the absence of previous exposure to antiretroviral prophylaxis of MTCT. [ABSTRACT FROM AUTHOR]