Free Standard AU & NZ Shipping For All Book Orders Over $80!
Register      Login
Sexual Health Sexual Health Society
Publishing on sexual health from the widest perspective
Shopping Cart: ( empty )
You are here: Home > Journals > SH > SH03012
REVIEW
Contents Vol 1(2)

Virological significance, prevalence and genetic basis of hypersusceptibility to nonnucleoside reverse transcriptase inhibitors

Gilda Tachedjian A B C E and Anne Mijch D
+ Author Affiliations
- Author Affiliations

A Molecular Interactions Group, Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, Vic. 3001, Australia.

B Department of Microbiology, Monash University, Clayton, Vic. 3800, Australia.

C Department of Medicine, Monash University, Prahran, Vic. 3181, Australia.

D Victorian HIV Service, Department of Infectious Diseases and Microbiology, Alfred Hospital, Prahran, Vic. 3181, Australia.

E Author for correspondence; email: gildat@burnet.edu.au

Sexual Health 1(2) 81-89 https://doi.org/10.1071/SH03012
Submitted: 15 October 2003  Accepted: 5 April 2004   Published: 24 June 2004

Abstract

Nonnucleoside reverse transcriptase inhibitors (NNRTI) are used to treat HIV-infected individuals in combination with nucleoside analogues (NRTI) and protease inhibitors. Long-term treatment with antiretroviral agents results in the emergence of strains with decreased susceptibility (resistance) to the drugs and is one of the major factors in loss of drug efficacy. Conversely, there have been recent reports of HIV strains with increased susceptibility (hypersusceptibility) to NNRTIs. These isolates emerge in patients on long-term antiretroviral therapy particularly in individuals receiving NRTIs. The prevalence of NNRTI hypersusceptibility ranges between 17.5 and 50% in NRTI-treatment experienced compared to 10% in NRTI-naïve patients. There is an inverse correlation between NNRTI hypersusceptibility and phenotypic NRTI resistance and a direct correlation between the number of NRTI resistance mutations present in the HIV reverse transcriptase. Re-sensitisation of phenotypic NNRTI resistance has been reported by NRTI mutations and is not likely to be detected using genotypic resistance assays. Recent studies demonstrate that NNRTI hypersusceptible virus at baseline is likely to predict better virological outcomes in patients on NNRTI-based salvage regimens compared to patients with NNRTI susceptible virus. These studies have implications for the sequence of antiretroviral drug use where patients may benefit from NRTI therapy before the introduction of NNRTIs, however more studies are needed to examine this treatment rationale.


References


[1] Furman PA,  Fyfe JA,  St Clair MH,  Weinhold K,  Rideout JL,  Freeman GA, et al. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 1986; 83(21): 8333–7.
| PubMed |

[2] De Clercq E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 1998; 38(3): 153–79.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[3] Pillay D,  Taylor S,  Richman DD. Incidence and impact of resistance against approved antiretroviral drugs. Rev Med Virol 2000; 10(4): 231–53.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[4] Shafer RW,  Kantor R,  Gonzales MJ. The genetic basis of HIV-1 resistance to reverse transcriptase and protease inhibitors. AIDS Rev 2000; 2 211–28.


[5] Shulman N,  Zolopa AR,  Passaro D,  Shafer RW,  Huang W,  Katzenstein D, et al. Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy. AIDS 2001; 15(9): 1125–32.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[6] Whitcomb JM,  Huang W,  Limoli K,  Paxinos E,  Wrin T,  Skowron G, et al. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates. AIDS 2002; 16(15): F41–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[7] Haubrich RH,  Kemper CA,  Hellmann NS,  Keiser PH,  Witt MD,  Forthal DN, et al. The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis. AIDS 2002; 16(15): F33–40.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[8] Hammer SM,  Vaida F,  Bennett KK,  Holohan MK,  Sheiner L,  Eron JJ, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 2002; 288(2): 169–80.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[9] Katzenstein DA,  Bosch RJ,  Hellmann N,  Wang N,  Bacheler L,  Albrecht MA. Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs. AIDS 2003; 17(6): 821–30.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[10] 10 Mellors J , Vaida F , Bennett K , Hellmann NS , DeGruttola V , Hammer SM . Efavirenz hypersusceptibility improve virologic response to multidrug salvage regimens in ACTG 398 (abstract 45). In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections; 2002; Seattle: Alexandria, VA: Foundation for Retrovirology and Human Health; 2002. p. 69.

[11] Kohlstaedt LA,  Wang J,  Friedman JM,  Rice PA,  Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992; 256(5065): 1783–90.
| PubMed |

[12] Spence RA,  Kati WM,  Anderson KS,  Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 1995; 267(5200): 988–93.
| PubMed |

[13] Rittinger K,  Divita G,  Goody RS. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 1995; 92(17): 8046–9.
| PubMed |

[14] Ding J,  Das K,  Tantillo C,  Zhang W,  Clark AD,  Jessen S, et al. Structure of HIV-1 reverse transcriptase in a complex with the non- nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution. Structure 1995; 3(4): 365–79.
| PubMed |

[15] Esnouf R,  Ren J,  Ross C,  Jones Y,  Stammers D,  Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non- nucleoside inhibitors. Nat Struct Biol 1995; 2(4): 303–8.
| PubMed |

[16] Tachedjian G,  Orlova M,  Sarafianos SG,  Arnold E,  Goff SP. Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase. Proc Natl Acad Sci USA 2001; 98(13): 7188–93.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[17] Tachedjian G,  Goff SP. The effect of NNRTIs on HIV reverse transcriptase dimerization. Curr Opin Investig Drugs 2003; 4(8): 966–73.
| PubMed |

[18] Baba M,  Tanaka H,  De Clercq E,  Pauwels R,  Balzarini J,  Schols D, et al. Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. Biochem Biophys Res Commun 1989; 165(3): 1375–81.
| PubMed |

[19] Pauwels R,  Andries K,  Desmyter J,  Schols D,  Kukla MJ,  Breslin HJ, et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 1990; 343(6257): 470–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[20] Deeks SG. International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr 2001; 26 S25–33.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[21] Moyle G. The emerging roles of non-nucleoside reverse transcriptase inhibitors in antiretroviral therapy. Drugs 2001; 61(1): 19–26.
| PubMed |

[22] Staszewski S,  Morales-Ramirez J,  Tashima KT,  Rachlis A,  Skiest D,  Stanford J, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999; 341(25): 1865–73.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[23] Montaner JS,  Reiss P,  Cooper D,  Vella S,  Harris M,  Conway B, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands Can Aust Study. J. Am. Med. Assoc. 1998; 279(12): 930–7.
| Crossref | GoogleScholarGoogle Scholar |

[24] van Leeuwen R,  Katlama C,  Murphy RL,  Squires K,  Gatell J,  Horban A, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17(7): 987–99.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[25] Anon. An open-label randomized trial to evaluate different therapeutic strategies of combination therapy in HIV-1 infection: design, rationale, and methods of the initio trial. Control Clin Trials 2001; 22(2): 160–75.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[26] Kuritzkes DR,  Bassett RL,  Johnson VA,  Marschner IC,  Eron JJ,  Sommadossi JP, et al. Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370. AIDS 2000; 14(11): 1553–61.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[27] Albrecht MA,  Bosch RJ,  Hammer SM,  Liou SH,  Kessler H,  Para MF, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 2001; 345(6): 398–407.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[28] Harris M,  Montaner JS. Clinical uses of non-nucleoside reverse transcriptase inhibitors. Rev Med Virol 2000; 10(4): 217–29.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[29] Merluzzi VJ,  Hargrave KD,  Labadia M,  Grozinger K,  Skoog M,  Wu JC, et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor Science 1990; 250(4986): 1411–3.
| PubMed |

[30] Dueweke TJ,  Poppe SM,  Romero DL,  Swaney SM,  So AG,  Downey KM, et al. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 1993; 37(5): 1127–31.
| PubMed |

[31] Young SD,  Britcher SF,  Tran LO,  Payne LS,  Lumma WC,  Lyle TA, et al. L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995; 39(12): 2602–5.
| PubMed |

[32] Richman DD,  Havlir D,  Corbeil J,  Looney D,  Ignacio C,  Spector SA, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994; 68(3): 1660–6.
| PubMed |

[33] Campiani G,  Ramunno A,  Maga G,  Nacci V,  Fattorusso C,  Catalanotti B, et al. Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives. Curr Pharm Des 2002; 8(8): 615–57.
| PubMed |

[34] Shulman NS,  Zolopa AR,  Passaro DJ,  Murlidharan U,  Israelski DM,  Brosgart CL, et al. Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response. J Acquir Immune Defic Syndr 2000; 23(3): 221–6.
| PubMed |

[35] Briones C,  Soriano V,  Dona C,  Barreiro P,  Gonzalez-Lahoz J. Can early failure with nevirapine be rescued with efavirenz? J Acquir Immune Defic Syndr 2000; 24(1): 76–8.
| PubMed |

[36] D'Aquila RT,  Schapiro JM,  Brun-Vezinet F,  Clotet B,  Conway B,  Demeter LM, et al. Drug Resistance Mutations in HIV-1. Top HIV Med 2002; 10(5): 21–5.
| PubMed |

[37] Tantillo C,  Ding J,  Jacobo-Molina A,  Nanni RG,  Boyer PL,  Hughes SH, et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J Mol Biol 1994; 243(3): 369–87.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[38] Hsiou Y,  Das K,  Ding J,  Clark AD,  Kleim JP,  Rosner M, et al. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol 1998; 284(2): 313–23.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[39] Hsiou Y,  Ding J,  Das K,  Clark AD,  Boyer PL,  Lewi P, et al. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol 2001; 309(2): 437–45.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[40] Sarafianos SG,  Das K,  Clark AD,  Ding J,  Boyer PL,  Hughes SH, et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci USA 1999; 96(18): 10027–32.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[41] Arion D,  Kaushik N,  McCormick S,  Borkow G,  Parniak MA. Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry 1998; 37(45): 15908–17.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[42] Meyer PR,  Matsuura SE,  Mian AM,  So AG,  Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 1999; 4(1): 35–43.
| PubMed |

[43] Larder BA,  Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989; 246(4934): 1155–8.
| PubMed |

[44] Kellam P,  Boucher CA,  Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci USA 1992; 89(5): 1934–8.
| PubMed |

[45] Hooker DJ,  Tachedjian G,  Solomon AE,  Gurusinghe AD,  Land S,  Birch C, et al. An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3′-azido-3′-deoxythymidine. J Virol 1996; 70(11): 8010–8.
| PubMed |

[46] Whitcomb JM,  Parkin NT,  Chappey C,  Hellmann NS,  Petropoulos CJ. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003; 188(7): 992–1000.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[47] Shirasaka T,  Kavlick MF,  Ueno T,  Gao WY,  Kojima E,  Alcaide ML, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci USA 1995; 92(6): 2398–402.
| PubMed |

[48] Larder BA,  Bloor S,  Kemp SD,  Hertogs K,  Desmet RL,  Miller V, et al. A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance. Antimicrob Agents Chemother 1999; 43(8): 1961–7.
| PubMed |

[49] de Jong JJ,  Goudsmit J,  Lukashov VV,  Hillebrand ME,  Baan E,  Huismans R, et al. Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs. AIDS 1999; 13(1): 75–80.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[50] Winters MA,  Coolley KL,  Girard YA,  Levee DJ,  Hamdan H,  Shafer RW, et al. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest 1998; 102(10): 1769–75.
| PubMed |

[51] Larder BA. 3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 1992; 36(12): 2664–9.
| PubMed |

[52] Byrnes VW,  Emini EA,  Schleif WA,  Condra JH,  Schneider CL,  Long WJ, et al. Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reserve transcriptase inhibitors. Antimicrob Agents Chemother 1994; 38(6): 1404–7.
| PubMed |

[53] Tachedjian G,  Mellors J,  Bazmi H,  Birch C,  Mills J. Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet. J Virol 1996; 70(10): 7171–81.
| PubMed |

[54] Hirsch MS,  Brun-Vezinet F,  Clotet B,  Conway B,  Kuritzkes DR,  D'Aquila RT, et al. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1: 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis 2003; 37(1): 113–28.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[55] Petropoulos CJ,  Parkin NT,  Limoli KL,  Lie YS,  Wrin T,  Huang W, et al. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000; 44(4): 920–8.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[56] Hellmann N,  Johnson P,  Petropoulos C. Laboratory atVR. Validation of the performance characteristics of a novel, rapid phenotypic drug susceptibility assay, PhenoSense HIV. Antivir Ther 1999; 4 34.


[57] Parkin NT,  Hellmann NS,  Whitcomb JM,  Kiss L,  Chappey C,  Petropoulos CJ. Natural variation of drug susceptibility in wild-type human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48(2): 437–43.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[58] Clevenbergh P,  Cua E,  Dam E,  Durant J,  Schmit JC,  Boulme R, et al. Prevalence of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations and polymorphisms in NNRTI-naive HIV-infected patients. HIV Clin Trials 2002; 3(1): 36–44.
| PubMed |

[59] Moreno S,  Casado JL,  Perez-Elias MJ,  Dronda F,  Antela A,  Moreno A, et al. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1. AIDS 2003; 17(9): 1413–4.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[60] Sturmer M,  Staszewski S,  Doerr HW,  Larder B,  Bloor S,  Hertogs K. Correlation of phenotypic zidovudine resistance with mutational patterns in the reverse transcriptase of human immunodeficiency virus type 1: interpretation of established mutations and characterization of new polymorphisms at codons 208, 211, and 214. Antimicrob Agents Chemother 2003; 47(1): 54–61.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[61] Harrigan PR,  Montaner JS,  Wegner SA,  Verbiest W,  Miller V,  Wood R, et al. World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing. AIDS 2001; 15(13): 1671–7.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[62] Bacheler L,  Jeffrey S,  Hanna G,  D'Aquila R,  Wallace L,  Logue K, et al. Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol 2001; 75(11): 4999–5008.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[63] Jacobo-Molina A,  Ding J,  Nanni RG,  Clark AD,  Lu X,  Tantillo C, et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci USA 1993; 90(13): 6320–4.
| PubMed |

[64] Rodgers DW,  Gamblin SJ,  Harris BA,  Ray S,  Culp JS,  Hellmig B, et al. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1995; 92(4): 1222–6.
| PubMed |

[65] Huang H,  Chopra R,  Verdine GL,  Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 1998; 282(5394): 1669–75.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[66] Tachedjian G,  Aronson HE,  Goff SP. Analysis of mutations and suppressors affecting interactions between the subunits of the HIV type 1 reverse transcriptase. Proc Natl Acad Sci USA 2000; 97(12): 6334–9.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[67] Van Laethem K,  Witvrouw M,  Pannecouque C,  Van Remoortel B,  Schmit JC,  Esnouf R, et al. Mutations in the non-nucleoside binding-pocket interfere with the multi-nucleoside resistance phenotype. AIDS 2001; 15(5): 553–61.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

[68] Ren J,  Esnouf RM,  Hopkins AL,  Jones EY,  Kirby I,  Keeling J, et al. 3′-Azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes. Proc Natl Acad Sci USA 1998; 95(16): 9518–23.
| Crossref | GoogleScholarGoogle Scholar | PubMed |