Cut-offs suggested for predicting efavirenz failure with low-level K103N
Mark Mascolini for natap.org
Studies of virologic outcome in people who begin a nonnucleoside with low-frequency K103N mutations yielded conflicting results. [1-3]
A new analysis of low-level K103N in people starting efavirenz in a trial comparing tenofovir/emtricitabine (TDF/FTC) with zidovudine/lamivudine (AZT/3TC) suggested that more than 2000 copies/mL of K103N before efavirenz or K103N making up more than 2% of the viral population independently boosts the odds of virologic failure. 
Evguenia Svarovskaia and Gilead Sciences colleagues analyzed the impact of K103N on virologic response in 509 people enrolled in GS-01-934. The original primary efficacy analysis excluded 22 people (4%) in whom standard genotyping detected a nonnucleoside mutation before treatment began. Of the remaining 487 study participants, 48 (10%) with resistance data available endured virologic failure through week 144, including 19 taking TDF/FTC and 29 taking AZT/3TC.
The Gilead team reanalysed these 487 pretreatment viral samples with an allele-specific PCR assay that detects K103N representing as little as 0.5% of a persons viral population. Almost all of those samples 476 of 485 (98%) yielded allele-specific PCR results. Sixteen of those 476 (3%) had detectable K103N missed by standard sequencing. Thus, the percentage of all study participants with a NNRTI mutation before treatment rose to 7.5% (38 of 509 samples).
Among the 16 people with low-level K103N, efavirenz failed in 6 (37.5%), including 5 taking AZT/3TC and 1 taking TDF/FTC. Pretreatment K103N correlated strongly with virologic failure in the 5 people taking AZT/3TC with efavirenz (p=0.005). In these 16 people with low-frequency K103N, the percentage of K103N detected by the ultrasensitive assay and K103N copy count were higher in the 6 with virologic failure (0.8% to 15%, 1254 to 16,071 copies/mL) than in the 10 virologic successes (0.6% to 3.2%, 51 to 5535 copies/mL). Five of 6 people with more than 2000 copies/mL of K103N had a virologic failure, compared with 1 of 10 people without virologic failure, a significant difference (p=0.008). Efavirenz plus TDF/FTC failed in 1 person with a K103N load under the 2000 mark (1254 copies/mL), but this person began treatment with a CD4 count of only 20.
Multivariate statistical analysis that considered predictors as categorical variables determined that a K103N copy number at or above 2000 copies/mL hoisted the risk of virologic failure nearly 50 times (odds ratio [OR] 47.4, 95% confidence interval [CI] 5.2 to 429.2, p=0.0006). In the same analysis, randomization to TDF/FTV versus AZT/3TC, pretreatment viral load above 100,000 copies, and pretreatment CD4 count above 199 did not independently predict failure. In a similar analysis, K103N making up more than 2% of a persons viral population upped the failure risk 25 times (OR 25.5, 95% CI 4.6 to 142.1, p=0.0002).
Svarovskaia and coworkers suggested their findings point to a pretreatment K103N threshold that predicts virologic failure with efavirenz. However, that conclusion rests on a sample of only 16 people. The investigators point out that only 6 of 476 study participants with allele-specific PCR results (1.3%) had a pretreatment K103N population above 2000 copies/mL.
- Metzner KJ, Walter H, Rauch P, et al. The prevalence of drug-resistant virus as a minority quasispecies before initiating art is not associated with therapy failure in persons initiating therapy with Truvada plus PI/r or NNRTI. 15th Conference on Retroviruses and Opportunistic Infections. 3-6 February 2008, Boston. Abstract 879.
- Garcia-Diaz A, Johnson JA, Fox ZV, et al. Low-frequency mutations strengthen the impact of transmitted drug resistance on virological responses to first-line efavirenz or nevirapine based antiretroviral therapy. 7th European HIV Drug Resistance Workshop. 25-27 March 2009, Stockholm. Abstract 113.
- Braun P, Ehret R, Wiesmann F, Metzner KJ, Knechten H. Prevalence of the K103N mutation at low frequencies in antiretroviral treatment-naive patients in Germany 2008. 7th European HIV Drug Resistance Workshop. 25-27 March 2009, Stockholm. Abstract 71.
- Goodman DD, Margo NA, McColl DJ, et al. Pre-existing low-levels of the K103N HIV-1 RT mutation above a threshold is associated with virological failure in treatment-naive patients undergoing EFV-containing antiretroviral treatment. XVIII International Drug Resistance Workshop. 9-13 June 2009, Fort Myers, Florida. Abstract 41.