Les thérapeutiques antirétrovirales : entre nouveauté et expérience

Transcription

1 Les thérapeutiques antirétrovirales : entre nouveauté et expérience Les nouveaux ARV, un réel besoin virologique Aix en Provence, 2018 JC Tardy, Lyon

2 New antiretroviral agent use affects prevalence of HIV drug resistance in clinical carepopulations T.Davy-Mendez et al ; AIDS in press Patients who initiated ART in the last decade have consistently low resistance prevalence estimates Meanwhile, non-adherent patients failing therapy may continue to develop resistance in spite of novel regimens HIV drug resistance in low-income and middle-income countries R.L Hamers et al ; Lancet 2018 After 15 years of global scale-up of antiretroviral therapy (ART), rising prevalence of HIV drug resistance in many LMICs poses a growing threat to the HIV response, with the potential to drive an increase in mortality, HIV incidence, and costs

3 Emergence of Integrase Resistance Mutations During Initial Therapy Containing Dolutegravir J.A Fulcher et al ; CID 2018 Our report is a reminder that, despite a high barrier to resistance, no agent as initial therapy for HIV-1 is impervious to resistance First reported case of integrase (R263K, G163R) and reverse transcriptase (M184V) -transmitted drug resistance from a drug-naive patient failing Triumeq S.Cochrane et al ; AIDS 2018 If BL integrase resistance is not reviewed prior to starting therapy, there is a risk New Resistance Mutations to Nucleoside Reverse Transcriptase Inhibitors at Codon 184 of HIV-1 Reverse Transcriptase (M184L and M184T) L. Pouga et al ; Chem.Biol.Drug.Des in press Antiretroviral resistance selected at failure in HIV infected patients treated by triple and dual therapies V.Calvez EACS 2017 Failure on dual regimen is globally associated with higher resistance selection Epidemiological study of Doravirine associated resistance mutations in HIV-1-infected treatmentnaïve patients from two large databases in France and Italy A.G Marcelin et al ; 15th European Meeting on HIV & Hepatitis / , significant in K103N/S (1.8% vs 3 %) and in G190A/E/S (0.3% vs 0.8%)

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7 ❶ ❷ ❶ ❷ EFdA (MK-8591) Doravirine (MK-1439)

8 Future of nonnucleoside reverse transcriptase inhibitors N.Sluis-Cremer ; PNAS 2018 All NNRTIs bind to the same pocket in HIV-1 RT, and the genetic barrier to NNRTI resistance is low nearly all of the resistance mutations are located within or adjacent to the NNRTI-binding pocket there is a high level of cross-resistance. Transmitted NNRTI resistance is also becoming a major issue Consensus 100 L 101 K 103 K 106 V 138 E 181 Y 188 Y 190 G 230 M NVP I EP NS AM CIV LCH ASE L EFV I EP NS AM CIV LCH ASE L ETR I EP AGKQ CIV L ASE L RPV I EP AGKQ CIV L ASE L HIV db version (last updated on )

9 Methyl-triazolone Pyridone core Aryl ether The nitrogen atoms in the methyl-triazolone ring interact with the backbone, but not with the side chain, of K103 via two hydrogen bonds As a result, the impact of the K103N substitution on the interactions between the residue and DOR is minimal, as the interactions between N103 and the DOR triazole ring remain intact M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

10 Methyl-triazolone Pyridone core Aryl ether Y181 does not play an important role in the binding of DOR to RT, given the long distance between the cyanochlorophenol group of DOR and Y181 M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

11 Methyl-triazolone Pyridone core Aryl ether Y181 does not play an important role in the binding of DOR to RT, given the long distance between the cyanochlorophenol group of DOR and Y181 The cyanochlorophenol moiety forms π-π stacking with Y188, and the Y188L substitution eliminates the π π interactions and creates a clash with DOR M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

12 Methyl-triazolone Pyridone core Aryl ether The side chain of V106 is close to the central ring of DOR, with a distance of 3.5 Å based on the X-ray structure. It appears that the isopropyl group on the Val side chain makes van der Waals interactions with DOR in the NNRTI binding pocket. Replacement of the isopropyl group with a methyl group (V106A) weakens the interactions between RT and DOR M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

13 Methyl-triazolone Pyridone core Aryl ether Interestingly, substitutions at position V106 were often found to be associated with substitution at F227. Although the F227 residue has a limited interactions with the triazole ring of DOR, it is in close proximity to V106. Substitution at position 227 may, in turn, alter the interactions between the residue at 227 and V106A, causing conformation changes of the latter, which may further reduce the interactions between the V106A mutant and DOR, causing significant resistance to DOR M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

14 Y188L; V106A; M230L; L100I+K103N; K103N+P225H K103N; Y181C/I; K101P; E138K M-T Lai et al ; AAC 2014 M.Feng et al ; AAC 2015

15 Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial J.M Molina et al ; Lancet HIV 2018 Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus 1 Infection: Week 48 Results of the DRIVE-AHEAD Trial C.Orkin et al ; CID 2018 Non-compliance at week 24 V106I, H221Y, and F227C Y188L; Y318Y/F; V106I, F227C; V106V/I, H221H/Y, F227C; F227C; V106A, P225H, Y318Y/F; V106M/T, F227C/R In Phase 3 trials : 7 of 747 participants (0.9%) developed resistance to DOR

16 ddn dn All approved anti-hiv NRTIs lack a 3 -hydroxyl moiety and, thus, act as chain terminators following their incorporation into the nascent DNA chain The absence of a 3 -OH imparts detrimental properties to these inhibitors, including reduced intracellular phosphorylation to the active triphosphate form and reduced RT binding affinity H.Ohrui ; The Chemical Record 2006

17 ddn These EdN analogs, unlike the existing approved nucleoside reverse transcriptase inhibitors, possess a 3 -OH in their sugar moiety; however, they cause viral DNA chain termination, resulting in RT inhibition E.I Kodama et al ; AAC 2001 dn 4 -ethynyl-2-fluoro-2 - deoxyadenosine (EFdA; MK-8591)

18 Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4 -ethynyl-2-fluoro-2 -deoxyadenosine (EFdA) using pre-steady-state kinetics Y.Muftuoglu et al ; Ant.Res The striking discrimination by pol γ in contrast with the preference of EFdA over datp by RT indicates EFdA is a very promising RT inhibitor EFdA can likely be used in the clinical setting to treat HIV patients with low doses and minimal mitochondrial-based toxicity C.A Stoddart et al ; AAC 2015

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20 E.Michailidis et al ; JBC 2009 EFdA is the first inhibitor of RT to be identified as an NRTTI

21 4-Ethynyl-2-fluoro-2-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms E.Michailidis et al ; JBC 2014

22 Structural basis of HIV inhibition by translocationdefective RT inhibitor 4 -ethynyl-2- fluoro-2 - deoxyadenosine (EFdA) Z.L Salie et al ; JBC 2016 Finally, regarding 2-F, provides exceptional resistance to adenosine deaminasecatalyzed degradation in cells What makes MK 8591 particularly interesting is its long intracellular half-life ( 150 hours)

23 Emerging reverse transcriptase inhibitors for HIV-1 infection M.A Ray et al ; Exp.Opin.Emerg.Drug Other formulations of MK-8591 may be administered parenterally. In animal studies, a single parenteral dose of MK produced persistent target drug levels and accumulated in target sites, including lymph nodes and vaginal and rectal tissues MK-8591 also prevented simian-human immunodeficieny virus (SHIV) infection when used as in PrEP macaques Investigational Antiretroviral Drugs: What is Coming Down the Pipeline R.Gulick; IAS USA Topics in Antiviral Medicine April 2018 EFdA is a novel antiretroviral with activity against both wild-type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention S.E Barrett et al ; AAC 2018 In summary, MK 8591 can revamp the treatment administration timing for HIVinfected patients, as well as have a possible role for HIV prevention. This drug can tackle many of the problems currently encountered when treating HIV patients on HAART, ranging from poor adherence to the development of drug-resistant virus

24 Structural basis of HIV inhibition by translocationdefective RT inhibitor 4 -ethynyl-2- fluoro-2 - deoxyadenosine (EFdA) Z.L Salie et al ; JBC 2016 Finally, regarding 2-F, provides exceptional resistance to adenosine deaminasecatalyzed degradation in cells The 3 -OH of EFdA contributes to its rapid and facile activation by the deoxycytidine kinase What makes MK 8591 particularly interesting is its long intracellular half-life ( 150 hours)

25 Structural basis of HIV inhibition by translocationdefective RT inhibitor 4 -ethynyl-2- fluoro-2 - deoxyadenosine (EFdA) Z.L Salie et al ; JBC 2016 The 4 -E of EFdA- TP is bound at a preformed hydrophobic pocket defined by conserved residues A114, Y115, F160, and M184, and the aliphatic part of D185 The 3 -OH of EFdA contributes to its rapid and facile activation by the deoxycytidine kinase Finally, regarding 2-F, provides exceptional resistance to adenosine deaminasecatalyzed degradation in cells What makes MK 8591 particularly interesting is its long intracellular half-life ( 150 hours)

26 The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase Y.Takamatsu et al ; Cell.Chem.Biol This activity was due to the strong van der Waals interactions with critical amino acid residues A114, Y115, F160, and M184 present in the hydrophobic pocket of HIV-1 reverse transcriptase F160 is one of the most critical amino acids for HIV-1 RT activity, and thus the virus does not select F160 as a drugresistant substitution. This strong vdw interaction was not reduced or lost even in the presence of drug-resistant mutations, such as M184V.

27 M184I/V substitutions and E138K/M184I/V double substitutions in HIV reverse transcriptase do not significantly affect the antiviral activity of EFdA M.Oliveira et al ; JAC 2017 Hypersusceptibility mechanism of Tenofovir-resistant HIV to EFdA E.Michailidis et al ; Retrovirology 2013 K65R RT a significant decrease in the excision efficiency of EFdA-MP from the 3 primer terminus appears to be the primary cause of increased susceptibility to the inhibitor Understanding the Resistance Profile of the HIV-1 NNRTI Doravirine in Combination With the Novel NRTTI MK-8591 D.J Hazuda et al ; Abs.THPEBO68 IAS 2018 DOR-associated clinical mutants containing F227C, alone or in combination with other substitutions, are hypersusceptible to the NRTTI, MK-8591