NNRTI-Resistance Mutations and Response to New NNRTI-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 NNRTI-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.
|Reference||Previous NNRTI||Follow-up NNRTI||Other Rx||No.Pts||Wk||Effect of Baseline Mutations on Response|
|100% >= 1 NNRTI
||Factors associated with virological response to ETR
||OBT (RAL included 64%, T20 icluded in 16%, DRV/r included in 79%)
||243 ||8 ||The authors examined the 17 mutations identified by Vingerhoets J et al (2010). Y181C, V179I, V106I, Y188L, and E138A were associated with a decreased VR. K103N was with an increased VR. Insufficient were availabe for the following mutations: Y181I/V, K101P, M230L, G190S, K103H, and V179D/T.
DUET-1 and 2
48-week, randomized, double-blind, placebo-controlled, multicenter phase III trial
|93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotype
||ETR in treatmen-experienced HIV-1 patients
||17 baseline mutation were associated with a decreased VR. The ETR-weighted genotypic score which emerged from this analysis was: Y181I/V(3.0), K101P, L100I, Y181C, M230L (2.5), E138A, V106I, G190S, V179F (1.5), and V90I, V179D, K101E, K101H, A98G, V179T, G190A (1.0).
Phase II, multinational, randomized, open label
|100% had received >=1 NNRTI. Around 70% >= 1 NNRTI mutation
||ETR vs PI in NNRTI failure and PI naive ||2 NRTIs
12W-Stop DSMB by lower VR in interim analysis in the TMC-125 group
|Patients with Y181C but not K103N had a a decreased VR.|
|Madruga_(2007), Katlama_(2007), Lazzarin_(2007) DUET ||93% had received >= 1 NNRTI. All had >=1 NNRTI resistance mutation at screening or from a historical genotype||ETR vs placebo||DRV/RTV + OB||406||24||13 baseline mutations were associated with a decreased response to ETR: V90I, A98G, L100I, K101EP, V106I, V179DF, Y181CIV, G190AS. When 3 or more of these mutations were present, the response to ETR was no different from placebo.|
DUET follow-up study
|Additional 3 baseline mutations were identified as associated with a decreased VR (defined by RNA <50 copies/ml) at W24: K101H, E138A and V179T. 77% of patients with none of these 16 (13 from the study above + 3 new ones), 61% patients with one of these 16, 56% with two and 38% with >=3 were associated with a decreased VR.|
||AZT/3TC vs AZT/3TC/ABC
||This was a case cohort study of the influence of pre-existing NNRTI-resistance mutations on the response to first-line therapy. K103N was the most commonly occurring pre-existing NNRTI-resistance mutation. In the AZT/3TC/EFV arm, baseline NNRTI resistance was detected in 13/97 (13%) of subjects with VF versus in 0/72 (0%) of those without VF (p=0.001).|
Octane Trial 1e
|Single-dose nevirapine administered > 6 months prior to baseline
|| NVP vs LPV/r
||12 and 24
||33/239 (14%) women had baseline NNRTI resistance mutations (K103N, G190A, Y181C/I, V108I). In women with NVP resistance at baseline, 11/15 (73%) in the NVP group versus 1/18 (6%) in the LPV/r group reached the primary endpoint of virological failure or death (p=0.006). In women without NVP resistance, 20/105 (19%) receiving NVP vs 9/101 (9%) receiving LPV/r reached the primary endpoint (p=0.04)|
- Katlama C., Campbell T., Clotet B., Johnson M., Lazzarin A., Arasteh K., Towner W., Trottier B., Peeters M., Vingerhoets J., De Smedt G., Baeten B., Beets G., Sinha R., Woodfall B.
DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients
Abstract presented at 4th IAS Conference, July 22-25, 2007, Sydney, Australia.
- Kuritzkes DR, Lalama CM, Ribaudo HJ, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis. 2008;197:867-870.
- Lazzarin A., Campbell T., Clotet B., Johnson M., Katlama C., Moll A., Towner W., Trottier B., Peeters M., Vingerhoets J., de Smedt G., Baeten B., Beets G., Sinha R., Woodfall B.
Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial.
Lancet. 2007 Jul 7;370(9581):39-48.
- Lockman S, Hughes MD, McIntyre J, et al. Antiretroviral therapies in women after single-dose nevirapine exposure. N Engl J Med. 2010;363:1499-1509.
- Madruga J.V., Cahn P., Grinsztejn B., Haubrich R., Lalezari J., Mills A., Pialoux G., Wilkin T., Peeters M., Vingerhoets J., de Smedt G., Leopold L., Trefiglio R., Woodfall B.
Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial.
Lancet. 2007 Jul 7;370(9581):29-38.
- Vingerhoets J., Peeters M., Azijn H., Tambuyzer L., Hoogstoel A., Nijs S., de Bethune M-P., Picchio G.
An update of the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data [abstract 24].
Antiviral Therapy. 2008; 13 Suppl 3:A26.