Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

NRTI-Resistance Mutations and Response to New NRTI-Containing Regimens

Three fundamental types of correlations form the basis of drug resistance knowledge: (i) Correlations between genotypic data with the treatments of persons from whom sequenced HIV-1 isolates have been obtained (genotype-treatment); (ii) Correlations between genotype and in vitro drug susceptibility (genotype-phenotype); and (iii) Correlations between genotype and the clinical response to a new treatment regimen (genotype-outcome). The following table summarizes the results of published studies linking RT genotype and the clinical response to a new NRTI-containing regimen.

Nearly all publications on genotype and clinical outcome have described only the results of their analyses. None have published their underlying data, in part, because until now there had been no resource for making such data publicly available. As this database has now been modified to represent such data we have written to the authors of those studies that are most relevant today to request such data.
Pre-HAART Studies of the Effect of TAMs on d4T and ddI
ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWkEffect of Baseline Mutations on Response
Japour (1995)AZTAZT or ddINone18852215Y/F was associated with increased risk of disease progression but this did not reach statistical significance in a model that also included CD4, syncytium inducing phenotype, AIDS diagnosis, and treatment assignment. M41L + T215Y/F were associated with an increased risk of disease progression regardless of treatment assignment.
Yerly (1996)AZTddINone12112T215Y/F was associated with a poorer CD4 count response to ddI monotherapy.
Shulman (2001)AZTd4TNone318The presence of any TAMs except K70R alone interfered with a virologic response defined as a 0.3 log RNA decrease.
Izopet (1999)AZT + ddCd4T/ddINone2024The 13 pts with TAMs (11/13 had 215Y ± 41L ± 210W) had significantly less RNA suppression (-0.5 and -0.1 logs) at W12 and W24 compared with the 7 pts lacking TAMs (-1.6 and -2.0 logs).
Montaner (2000)AZT ± ddI or ddC or 3TCd4T/3TCNone484In a multivariate model, T215Y/F and to a lesser extent M184Vwere associated with a marked decrease of having a 0.5 log RNA decrease.
Calvez (2002)AZT ± ddI or ddCd4T/3TCNone2624RNA decrease was 0.3 logs among the 20 pts with 215FY compared with 1.3 logs in the 6 pts without this mutation.
Effect of TAMs on Initial HAART
ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWkEffect of Baseline Mutations on Response
Kuritzkes (2000)AZTAZT/3TC + RTVNone4024-4832/40 pts had >=1 TAM including 18 with T215Y/F. 26/40 pts had RNA<100 at week 24 or 48. No association between response and specific mutations was demonstrated.
Gulick (1997)AZTAZT/3TC + IDVNone312426/31 pts had unamplifiable virus at week 24 despite the fact that ~80% had TAMs at baseline.
Descamps, Joly (2002)AZT ± (ddI, ddC)AZT/3TC + IDV d4T/3TC + IDVNone15524>=2 TAMs were present in 123/155 patients. Virologic failure (RNA > 5000) occurred in 7/24 classified as AZT-susceptible and in 26/131 classified as AZT-resistant by the ANRS algorithm (p=NS). The proportion of patients with virologic failure did not differ between the AZT- and d4T-containing arms
Abacavir (ABC)
ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWkEffect of Baseline Mutations on Response
Lanier (2004)>=2 NRTIs, (rare PI, NNRTI)Addition of ABCNone1664Meta-analysis of 5 intensification studies. Data on concomitant NNRTIs and PIs are not available. Median baseline RNA was 3.9 logs. 151/166 pts had >=1 NRTI mutation (usually TAMs and 184V). RNA decrease with (i) 184V alone >= 0.74 logs; (ii) 1 TAM >= 0.56 logs; (iii) 184V + 1 TAM >= 0.95 logs; (iv) 2-3 TAMs or 2 TAMs+184V >= ~0.35 logs; (v) 184V + 3 TAMs >= 0.18 logs; (vi) 4 TAMs >= 0.36 logs.
Katlama (2000)>=2 NRTIs, (rare PI, NNRTI)Addition of ABCNone9216-48This study includes a subset of patients in the above analysis. M184V did not preclude an antiviral response. At week 16, 16/25 with 184V had RNA <=400 or RNA decrease of >=1 log.
Brun-Vezinet (2003)NRTI, PI, NNRTIABC as part of a new HAART regimenOB17512RNA decrease was -0.2 logs, -0.7 logs, and -1.6 logs in persons containing 5-6, 4, or <4 mutations at the following positions: 41, 67, 210, 215, 74, and 184.
Tenofovir (TDF)
ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWkEffect of Baseline Mutations on Response
Miller (2004)NRTI, PI, NNRTIAddition of TDFNone22224-48Among pts receiving TDF, there was a mean 0.6 log RNA decrease at week 24 by ITT.
Pts with 215Y/F alone had a 0.7 log RNA decrease. Pts with 41L+210W+215Y had a 0.2 log RNA decrease. Mutations at positions 67, 70, and 219 did not appear to affect response. K65R was present at baseline in 6 pts and was associated with lack of response. M184V was associated with a modest but significant improved response particularly in the absence of TAMs.
Masquelier (2004)NRTI, PI, NNRTITDF as part of a new HAART regimenOB16112Observational study. The strongest association with RNA decrease was the set of the 7 mutations: 41L, 44D, 67N, 69D/N/S, 74V, 210W, and 215Y/F: (i) <3 mutations >= median RNA reduction of -1.3 logs; (ii) 3-5 mutations >= median RNA reduction of 0.8 logs; (iii) >=6 mutations >= median increase of 0.1 logs.
65R and 69ins were not included because although they cause phenotypic resistance, there were insufficient pts with these mutations.
Barrios (2003)NRTI, PI, NNRTITDF as part of a new HAART regimenOB15324Observational study. The presence of 41L, 210W, and 215Y were inversely associated with RNA response.
Didanosine (ddI)
ReferencePrevious NRTIFollow-up NRTIOther RxNo.PtsWkEffect of Baseline Mutations on Response
Molina (2005)NRTI, PI, NNRTIAddition of ddINone1094Median overall response was 0.6 log RNA decrease. 184V alone >= 0.8 log RNA decrease. Pts with 0-1 TAMs >= 0.8-1.0 log RNA decrease (n=40); 2 TAMs >= 0.7 log RNA decrease (n=10); 3 TAMs >= 0.5 log RNA decrease (n=25); 4 TAMs >= 0.2 log RNA decrease (n=21). Median log RNA decrease in the presence of L74V (n=9) was 0.1 logs.
Frank (2004)0, 1, and 2 NRTIsddIHydroxy-urea13424Hydroxyurea + ddI led to a greater RNA decrease than ddI alone at week 8 (~1.8 vs 0.8 logs). The combination was associated with a sustained response ~1.2-1.6 logs at week 24. At week 8, there was a greater reduction in RNA in the NRTI-naïve group (1.7 vs 1.2 logs) but there was little difference in response between those with M184V (1.2 logs in 18 3TC-experienced patients with M184V vs 1.4 logs in 61 3TC-naïve patients).
Sproat (2005)NRTI, PI, NNRTIddI as part of a new HAART regimenOB281Apr-48Observational study. Overall RNA decrease was 1.2, 1.0, 0.8, and 0.8 at weeks 4, 12, 24, and 48. There was no significant difference in RNA response between the 105 pts with and the 176 pts without 184V.
Winters (2003)NRTINRTI changeNFV, EFV, NFV/EFV10416-48In pts with isolates containing 184V, substitution of ddI for 3TC was associated with a decreased risk of virologic failure (confirmed RNA >2000)
De Luca (2007)NRTI (including ddI in 76%) +/- NNRTI +/- PIddI as part of a new HAART regimenOB48512M41L, E44D/A/G, T69D/S/N/A, L210W, T215Y or T215 revertants, and L228H/R were associated with a reduced RNA decrease. D123E/N/G/S was associated with improved virological response. The following weighted score was derived: (M41L x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y revertants + L228H/R - D123E/N/G/S. Relative to those with a score <=0, those with a score of 1 to 3 had a 0.34 decreased log RNA response and those with a score >=4 had a 0.68 decreased RNA log response.

Abbreviations

  • Pts: patients
  • W: week
  • M: month
  • NA: not available
  • DRM: drug-resistance mutation
  • OB: optimized background
  • PI: protease inhibitor
  • NRTI: nucleoside RT inhibitor
  • NNRTI: non-nucleoside RT inhibitor
  • Rx: regimen
  • TAMs: thymidine analogue mutations
  • 3TC: lamivudine
  • ABC: abacavir
  • DRV: darunavir
  • d4T: stavudine
  • ddI: didanosine
  • EFV: efavirenz
  • IDV: indinavir
  • NFV: nelfinavir
  • RTV: ritonavir
  • TDF: tenofovir
References
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  • Brun-Vezinet F., Descamps D., Ruffault A., Masquelier B., Calvez V., Peytavin G., Telles F., Morand-Joubert L., Meynard J.L., Vray M., Costagliola D. Clinically relevant interpretation of genotype for resistance to abacavir. AIDS. 2003 Aug 15;17(12):1795-802.
  • Calvez V., Costagliola D., Descamps D., Yvon A., Collin G., Cecile A., Delaugerre C., Damond F., Marcelin A.G., Matheron S., Simon A., Valantin M.A., Katlama C., Brun-Vezinet F. Impact of stavudine phenotype and thymidine analogues mutations on viral response to stavudine plus lamivudine in ALTIS 2 ANRS trial. Antivir Ther. 2002 Sep;7(3):211-8.
  • De Luca A., Giambenedetto S.D., Trotta M.P., Colafigli M., Prosperi M., Ruiz L., Baxter J., Clevenbergh P., Cauda R., Perno C.F., Antinori A. Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine. J Infect Dis. 2007 Dec 1;196(11):1645-53.
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  • Katlama C., Clotet B., Plettenberg A., Jost J., Arasteh K., Bernasconi E., Jeantils V., Cutrell A., Stone C., Ait-Khaled M., Purdon S. The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team. AIDS. 2000 May 5;14(7):781-9.
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  • Lanier E.R., Ait-Khaled M., Scott J., Stone C., Melby T., Sturge G., St Clair M., Steel H., Hetherington S., Pearce G., Spreen W., Lafon S. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir Ther. 2004 Feb;9(1):37-45.
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  • Miller M.D., Margot N., Lu B., Zhong L., Chen S.S., Cheng A., Wulfsohn M. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis. 2004 Mar 1;189(5):837-46.
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  • Sproat M., Pozniak A.L., Peeters M., Winters B., Hoetelmans R., Graham N.M., Gazzard B.G. The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine. Antivir Ther. 2005;10(2):357-61.
  • Winters M.A., Bosch R.J., Albrecht M.A., Katzenstein D.A. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients. J Infect Dis. 2003 Aug 15;188(4):537-40.
  • Yerly S., Denereaz N., Mermillod B., Hirschel B., Perrin L. Predictive value of codon 215 reverse transcriptase mutation on the efficacy of didanosine in HIV-infected, zidovudine-experienced patients. Antivir Ther. 1996 Aug;1(3):167-71.