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Session 121 Poster Abstracts
Impact of Drug Resistance on Virologic Response and Clinical Outcomes
Friday, 1:30 - 3:30 pm
Hall A


708    
Thymidine Analog Mutation Profiles: Factors Associated with Acquiring Specific Profiles and Their Effect on Virologic Response to Therapy
Alessandro Cozzi-Lepri*1, L Ruiz3,4, C Loveday2, A Phillips1, B Clotet4,7, P Reiss5, J Lundgren6, and EuroSIDA Study Group
1Royal Free and Univ Coll Med Sch, London, UK; 2Intl Clin Virology Ctr, Great Missenden Bucks, UK; 3Univ Autónoma de Barcelona, Spain; 4Hosp Germans Trias i Pujol, Barcelona, Spain; 5Academic Med Ctr, Univ of Amsterdam, The Netherlands; 6Copenhagen HIV Prgm, Hvidovre Hosp, Denmark; and 7irsiCaixa Fndn, Badalona, Spain

Background:  Different profiles of thymidine analog mutations (TAM) seem to exist.

Methods:  The analysis focused on 724 patients in the EuroSIDA cohort with a genotypic test carrying ≥ 1 TAM. Of these, 254 (35.1%) patients subsequently started therapy. Trugene HIV Genotyping Kit was used to sequence RT. Patients carrying a pattern containing 41L, 210W, and 215Y were classified as profile TAM1 and those carrying 67N, 70R, and 219Q as TAM2. Factors associated with TAM1/TAM2 were identified using multivariable logistic regression; the month 6 viral load change was compared using a linear regression accounting for censored data.

Results:  We classified 425 (58.7%) patients as harboring TAM1, and 171 (23.6%) TAM2. The 2 profiles are shown in the table according to the total number of TAM. Mutations 44A/D, 118I, and 74V were more likely to be found in patients carrying TAM1 profiles (19.3%, 30.1%, and 3.1%) than in those with TAM2 (0.6%, p = 0.0001, 13.5% p = 0.0001 and 0.0%, p = 0.02). Longer exposure to zidovudine (ZDV) monotherapy was the only factor associated with detecting a TAM2 instead of TAM1 (adjusted OR = 1.26 per year longer 95% CI 1.14 to 1.39). In the presence of TAM2, the viral load decrease in patients starting stavudine (d4T) was 1.18 log10 copies/mL (95% CI 0.44 to 1.92) higher than that observed in those starting ZDV (p = 0.02).

 

Number of TAM

TAM1

TAM2

 

1              n = 115

41L                                   5.9%

210W                               0.7%    

215Y                               10.1%

67N                                 2.3%

70R                                21.1% 

219Q                               2.3% 

 

2              n = 173

210W+215Y                    4.5%

41L+215Y                       25.4%

41L+210W                       1.7%

67N+70R                        15.2%

70R+219Q                        4.1%

67N+219Q                       3.5%

3              n = 170

41L+210W+215Y           27.3%

67N+70R+219Q              31.6%

 

4              n = 138

 

41L+67N+210W+215Y   24.5%

67N+70R+215Y+219Q     6.4%

41L+67N+70R+219Q       13.5%

Total        n = 596

                                   425 (100.0%)

                                    171 (100.0%)

 

Conclusions:  Some RT mutations (e.g., 44A/D, 118I, 74V) seem to cluster with a TAM1 profile. The TAM2 profile seems to be mainly driven by longer exposure to ZDV. In the presence of TAM2 profiles, d4T-regimens appear to be more potent virologically than ZDV-regimens. This observation needs to be confirmed in randomised studies.

Keywords: thymidine analogue mutations; profiles; virological response