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Non-nucleoside reverse transcriptase inhibitors

 Mutations associated with resistanceMutations associated with « possible resistance »
EFV
 L100I
 K101E
 K103H/N/S/T [1]
 V106M [2]
 E138K [12, 13]
 Y181C/I
 Y188C/L
 G190A/C/E/Q/S/T/V
 P225H
 M230L
 
NVP
 A98S (for HIV-1 subtype C only) [3]
 L100I
 K101E
 K103H/N/S/T [1]
 V106A/M [2]
 Y181C/I
 Y188C/H/L
 G190A/C/E/Q/S/T/V
 M230L
 E138K [13]
ETR At least 3 among: V90I, A98G, L100I, K101E/H/I/P/R, V106I, V179D/F/I/L/M/T, G190A/S, M230L [4, 7, 8, 9, 10, 11]
 E138K [12, 13]
 Y181C/I/V [5, 6]
 H221Y [12,16]
2 mutations among: V90I, A98G, L100I, K101E/H/I/P/R, V106I, V179D/F/I/L/M/T, G190A/S, M230L [4, 7, 8, 9, 10, 11]
 E138A/G/Q/R/S [5, 6, 7, 8]
RPV  K101E/P [9, 13]
 E138A/G/K/Q/R/S [12, 13, 14]
 V179L [9]
 Y181C/I/V [13]
 Y188L [9]
 F227C [9]
 H221Y [13]
 M230I/L/V [9]
 L100I + K103N/S [9, 15]
 L100I + K103R + V179D [15]
 A98G [22]
DOR  V106A/M [17, 18, 19, 20, 21]
 Y188L
 G190E/S [21]
 M230L
 L100I + K103N [17, 19]
 K103N + Y181C
 K103N + P225H
 F227C [21]
  At least 4 among: A98G, L100I, K101E, V106I, E138K, Y181C/V, G190A or H221Y [23]
At least 2 among: A98G, L100I, K101E, V106I, E138K, Y181C/V, G190A or H221Y [23]
 

EFV: efavirenz, NVP: nevirapine, ETR: etravirine, RPV : rilpivirine, DOR : doravirine.

For DNA provirus, impact of stop codons and G->A mutations on ARV resistance is unknown.

1/ Harrigan PR, Mo T, Wynhoven B, Hirsch J, Brumme Z, McKenna P, Pattery T, Vingerhoets J, Bacheler LT. Rare mutations at codon 103 of HIV-1 reverse transcriptase can confer resistance to non-nucleoside reverse transcriptase inhibitors. AIDS. 2005 Mar 24;19(6):549-54.

2/ Brenner B et al. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS. 2003 Jan 3;17(1):F1-5.

3/ Deshpande A et al. Resistance mutations in subtype C HIV type 1 isolates from Indian patients of Mumbai receiving NRTIs plus NNRTIs and experiencing a treatment failure: resistance to AR. AIDS Res Hum Retroviruses 2007; 23 : 335-40

4/ Vingerhoets J et al. Impact of baseline NNRTI mutations on the virological response to TMC125 in the Phase III clinical trials DUET-1 and DUET-2. XVI International HIV drug resistance workshop : basic principles and clinical implications, 12-16 June 2007, Barbados, West Indies, abstract 32

5/ Marcelin AG et al. Factors associated with virological response to etravirine in nonnucleoside reverse transcriptase inhibitor-experienced HIV-1-infected patients. Antimicrob Agents Chemother. 2010 Jan;54(1):72-7.

6/ Vingerhoets J et al. Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS. 2010 Feb 20;24(4):503-14.

7/ Vingerhoets J et al. Impact od transmitted drug resistance (TDR) on virological response to initial combination antiretroviral therapy (cART). Antiviral Therapy 2010; 15 Suppl 2: A125 (abstract 99).

8/ El A et al. In vitro selection of novel etravirine-associated resistance mutations in B and non-B HIV-1 subtypes. Antiviral Therapy 2010; 15 Suppl 2: A134 (abstract 108).

9/ Azijn H et al. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother. 2010 Feb;54(2):718-27.

10/ Marcelin AG et al. Mutations selected in patients displaying treatment failure under an etravirine-containing regimen. Antiviral Therapy 2011; 10.3851/IMP1886.

11/ Maïga AI et al. Resistance-associated mutations to etravirine (TMC-125) in antiretroviral-naïve patients infected with non-B HIV-1 subtypes. Antimicrob Agents Chemother. 2010 Feb;54(2):728-33.

12/ Asahchop EL et al. Characterization of the E138K resistance mutation in HIV-1 reverse transcriptase conferring susceptibility to etravirine in B and non-B HIV-1 subtypes. Antimicrob Agents Chemother. 2011 Feb;55(2):600-7.

13/ Eron J et al. Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE. 50th ICAAC 2010 (abstract H-1810).

14/ Haddad M et al. Impact of HIV-1 reverse transcriptase E138 mutations selected on rilpivirine drug susceptibility. Antiviral Therapy 2011; 16 Suppl 1: A18 (abstract 10).

15/ Haddad M et al. Combinations of HIV-1 reverse transcriptase mutations L100I+K103N/S and L100I+K103R+V179D reduce susceptibility to rilpivirine. 53rd ICAAC 2013 (abstract H-677).

16/ Melikian et al. Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. J Antimicrob Chemother. 2014 Jan;69(1):12-20.

17/ Lai MT et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58(3):1652-63.

18/ Feng M, et al. In vitro resistance selection with doravirine (MK-1439), a novel nonnucleoside reverse transcriptase inhibitor with distinct mutation development pathways. Antimicrob Agents Chemother. 2015 Jan;59(1):590-8.

19/ Feng M, et al. Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2241-7.

20/ Smith SJ, et al. Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants. J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):485-91.

21/ Lai MT et al. Characterization of Doravirine-Selected Resistance Patterns from Participants in Treatment-Naïve Phase 3 Clinical Trials. Abstract THPDB0101. 22nd International AIDS Conference, Amsterdam, the Netherlands, 23-27 July 2018.

22/ Raymond S et al. Impact of Human Immunodeficiency Virus Type 1 Minority Variants on the Virus Response to a Rilpivirine-Based First-line Regimen.
Clin Infect Dis. 2018 May 2;66(10):1588-1594.

23/ Saladini F et al. In vitro analysis of doravirine activity on HIV-1 clones harboring multiple NNRTI resistance mutations. Abstract PS5/6, EACS 2019, Basel, Switzerland, Nov 6-9, 2019