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
| Reference | Previous NRTI | Follow-up NRTI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Japour (1995) | AZT | AZT or ddI | None | 188 | 52 | 215Y/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) | AZT | ddI | None | 121 | 12 | T215Y/F was associated with a poorer CD4 count response to ddI monotherapy. |
| Shulman (2001) | AZT | d4T | None | 31 | 8 | The presence of any TAMs except K70R alone interfered with a virologic response defined as a 0.3 log RNA decrease. |
| Izopet (1999) | AZT + ddC | d4T/ddI | None | 20 | 24 | The 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 3TC | d4T/3TC | None | 48 | 4 | In 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 ddC | d4T/3TC | None | 26 | 24 | RNA 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
| Reference | Previous NRTI | Follow-up NRTI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Kuritzkes (2000) | AZT | AZT/3TC + RTV | None | 40 | 24-48 | 32/40 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) | AZT | AZT/3TC + IDV | None | 31 | 24 | 26/31 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 + IDV | None | 155 | 24 | >=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 |
| Reference | Previous NRTI | Follow-up NRTI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Lanier (2004) | >=2 NRTIs, (rare PI, NNRTI) | Addition of ABC | None | 166 | 4 | Meta-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 ABC | None | 92 | 16-48 | This 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, NNRTI | ABC as part of a new HAART regimen | OB | 175 | 12 | RNA 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. |
| Reference | Previous NRTI | Follow-up NRTI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Miller (2004) | NRTI, PI, NNRTI | Addition of TDF | None | 222 | 24-48 | Among 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, NNRTI | TDF as part of a new HAART regimen | OB | 161 | 12 | Observational 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, NNRTI | TDF as part of a new HAART regimen | OB | 153 | 24 | Observational study. The presence of 41L, 210W, and 215Y were inversely associated with RNA response. |
| Reference | Previous NRTI | Follow-up NRTI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Molina (2005) | NRTI, PI, NNRTI | Addition of ddI | None | 109 | 4 | Median 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 NRTIs | ddI | Hydroxy-urea | 134 | 24 | Hydroxyurea + 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, NNRTI | ddI as part of a new HAART regimen | OB | 281 | Apr-48 | Observational 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) | NRTI | NRTI change | NFV, EFV, NFV/EFV | 104 | 16-48 | In 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 +/- PI | ddI as part of a new HAART regimen | OB | 485 | 12 | M41L, 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. |
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