Home Go to http://www.treatHIV.com
Mutation and Drug Data HomeBoardAboutContact
 

Perspectives and OpinionsMutation and Drug DataAsk the ExpertsTest InfoFrom the PodiumDaily Resistance NewsBest of SiteArchive
Nevirapine select another drug
nonnucleoside reverse transcriptase inhibitor

DRUG RESISTANCE SUMMARY
Prepared by Brian Conway, M.D.

Name of drug:
spaceNevirapine (NVP), Viramune

Mechanism of action:
spaceNon-nucleoside reverse transcriptase inhibitor (NNRTI)
 
Phenotypic resistance: Isolates carrying single resistance mutations (K103N, V106A, Y181C, Y188C) have a 200-fold or greater increase in IC50 to nevirapine compared to wild-type isolates. The combination of K103N with either L100I, V108I or P225H leads to even greater increases in IC50 values.
Cross-resistance: Isolates carrying the V106A or Y188C mutations may remain susceptible to other NNRTIs (delavirdine, efavirenz). Isolates carrying the Y181C mutation are resistant to delavirdine but susceptible to efavirenz. Although it is generally accepted that isolates carrying the K103N mutation are resistant to all NNRTIs, recent in vitro data suggest that some delavirdine-resistant viruses with this mutation may remain susceptible to efavirenz in vitro. Although this may also apply to nevirapine-resistant isolates carrying the same mutation, the observations must be confirmed before its clinical significance can be determined.
Emergence of resistance in vivo: This occurs rapidly in subjects receiving nevirapine therapy in the absence of maximal virologic suppression. Most commonly, this is accompanied by the emergence of the K103N or Y181C mutation.
Clinical correlates of resistance: If therapy is continued in the presence of drug resistance, a rapid rebound in plasma viral load is observed, followed by a progressive decrease in CD4 cell counts.
Other comments: Based on the pattern of emergence of resistance mutations in vivo, a high degree of cross-resistance can be expected between delavirdine and nevirapine. This is not necessarily true of efavirenz if the K103N mutation is not present. Further, although the addition of the Y181C mutation in an AZT resistance background was shown to restore AZT susceptibility in vitro, the clinical correlation of this observation remains uncertain.
Additional drug information:
Viramune (nevirapine) prescribing information is available at: http://www.bidocs.com/renetnt:/Prescribing+Information/PIs/Viramune/Viramune.pdf



Bibliography
  1. Bartlett J. Severe Liver Toxicity in Patients Receiving Two Nucleoside Analogues and a Non-Nucleoside Reverse Treanscriptase Inhibitor. 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 19.

  2. Byrnes VW; Sardana VV; Schleif WA; Condra JH; Waterbury JA; Wolfgang JA; Long WJ; Schneider CL; Schlabach AJ; Wolanski BS; et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother. 1993;37:1576-1579.

  3. Casado JL, Arrizabalaga J, Antela A, et al. Long-Term Efficacy and Tolerance of Switching the Protease Inhibitor for Non- Nucleoside Reverse Transcriptase Inhibitors: A 52- Week, Multicenter, Prospective Study. 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 673.

  4. Deeks SG, Parkin N, Petropoulos CJ, Grant RM, Volberding PA, Whitcomb J, Tian H, Wrin T, Limoli K, Drews B, Warmerdam M, Hellmann NS. Correlation of baseline phenotypic drug susceptibility with 16 week virologic response in a pilot combination therapy study in HIV-infected patients who failed indinavir therapy. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 53.

  5. Delaugerre C, Wirden M, Simon A, et al. Resistance Profile and Cross-Resistance to HIV-1 among 104 Patients Failing a Non-Nucleoside Reverse Transcriptase Inhibitor- Containing Regimen. 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 449.

  6. Desire N, Amiel C, Schneider V, Delphin N, E Dam, Clavel F, Nicolas JC, Rozenbaum W. An HIV-1 isolate with the mutation G190E and an insertion between codons 100-105 of reverse transcriptase: phenotypic resistance implications. Antiviral Ther 2002; 7:S35.

  7. Gunthard HF; Wong JK; Ignacio CC; Guatelli JC; Riggs NL; Havlir DV; Richman DD. Nucleoside RT-inhibitor and NNRTI combination therapy drives evolution of HIV-1 pol resulting in increased evolutionary distances. J Virol. 1998;72:2422-2428.

  8. Haubrich R, Hellmann N, Keiser P, Kemper C, Witt M, Forthal D, Leedom J, Leibowitz M, Richman D. The clinical relevance of non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility: a prospective cohort analysis. XIV International AIDS Conference. 7-12 July 2002, Barcelona, Spain. Abstract ThOrB1388.

  9. Havlir DV; Richman DD; Gamst A; Eastman S. Nevirapine-resistant human immunodeficiency virus: kinetics of replication and estimated prevalence in untreated patients. J Virol. 1996;70:7894-7899.

  10. 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;36:2664-2669.

  11. Launay O, Gerard L, Morand-Joubert L, et al. Comparative Antiviral Activity and Toxicity of Nevirapine (NVP) versus Lamivudine (3TC) in Combination with Stavudine (d4T) and Indinavir (IDV) for the Treatment of HIV-1-Infected Patients. 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 326.

  12. Leigh Brown AJ, D'Aquila RT, Johnson VA, Kuritzkes DR, Richman DD. Baseline sequence clusters predict response to combination therapy in ACTG 241. Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 50.

  13. Najera I; Lopez-Galindez C; Najera R; Perucho M.Peinado MA; Rojas JM; Olivares I; Richman DD. Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses. 1994;10:1479-1488.

  14. Podzamczer D, Ferrer E, Consiglio E, et al. A Randomized, Open, Multicenter Trial Comparing Combivir plus Nelfinavir or Nevirapine in HIV-Infected Naive Patients (The Combine Study). 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 327.

  15. Richman DD; et al; Pauletti D; Barringer K.Cheeseman S; Sullivan J; Spector SA; Ignacio C; Looney D, Corbeil J; Havlir D. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994;68:1660-1666.

  16. Stammers DK, Ren J, Nichols CE, Chamberlain PP, Weaver KL, Short SA, Stuart DI. Crystal structures of HIV-1 reverse transcriptase mutated at codons 100, 106 and 108 show nevirapine resistance is mediated via perturbation of interactions with Tyr181 or Tyr188. Antiviral Ther 2002; 7:S23.

  17. Wathen L, Freimuth W, Sharp T, Ruzicka K. Delavirdine resistant clinical isolates remained susceptible to PNU142721 and DMP266. 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 111.

(click titles to view abstracts)

Go to Mutation Matrices: PI, NRTI, NNRTI
  Vertibrae
Copyright © 1997–2003, Vertibrae, Inc. and HIVresistanceWeb. All rights reserved.  |  Privacy Policy
RegisterLogin