{"id":4416,"date":"2009-08-22T12:59:50","date_gmt":"2009-08-22T11:59:50","guid":{"rendered":"http:\/\/moomango.co.uk\/htb\/?p=4416"},"modified":"2013-08-16T13:20:01","modified_gmt":"2013-08-16T13:20:01","slug":"cut-offs-suggested-for-predicting-efavirenz-failure-with-low-level-k103n","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/4416","title":{"rendered":"Cut-offs suggested for predicting efavirenz failure with low-level K103N"},"content":{"rendered":"

Mark Mascolini for natap.org<\/strong><\/p>\n

Studies of virologic outcome in people who begin a nonnucleoside with low-frequency K103N mutations yielded conflicting results.<\/strong> [1-3]<\/p>\n

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 \u0096 or K103N making up more than 2% of the viral population \u0096 independently boosts the odds of virologic failure. [4]<\/p>\n

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.<\/p>\n

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 person\u0092s viral population. Almost all of those samples \u0096 476 of 485 (98%) \u0096 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).<\/p>\n

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.<\/p>\n

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 person\u0092s viral population upped the failure risk 25 times (OR 25.5, 95% CI 4.6 to 142.1, p=0.0002).<\/p>\n

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.<\/p>\n

References:<\/p>\n

    \n
  1. 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.<\/li>\n
  2. 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.<\/li>\n
  3. 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.<\/li>\n
  4. 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.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    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 …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,36],"tags":[115],"class_list":["post-4416","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-drug-resistance","tag-ihdrw-18th-2009"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/4416","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=4416"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/4416\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=4416"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=4416"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=4416"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}