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  7th European HIV Drug Resistance Workshop
March 25-27, 2009
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Minority Clusters of K103N Mutation in Antiretroviral-Naive People in B & non-B Subtypes
  7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
Depending on the assay used, 7.5% to 16.5% of people in a German cohort had minority populations of the K103N nonnucleoside resistance mutation before taking any antiretrovirals [1]. The study confirmed earlier reports of covert K103N in untreated people [2,3]. But it turned up no evidence that small pockets of nonnucleoside-resistant virus imperil first-line treatment with efavirenz or nevirapine, though that analysis is small. Perhaps the study's most important finding is the higher prevalence of low-density K103N in people with HIV-1 subtypes other than B, because so many people with non-B virus start treatment with nevirapine or efavirenz.
Robert Ehret and colleagues in Aachen analyzed virus from 160 previously untreated people, 109 of them (68%) infected with HIV-1 subtype B and 51 (32%) infected with other subtypes or circulating recombinant forms (CRFs). Because standard genotyping detects viral subsets that represent about 20% or more of a person's entire viral population, Ehret used an allele-specific PCR assay that uncovers K103N caches making up as little as 0.5% or 0.1%. of a viral population. K103N alone confers resistance to efavirenz and nevirapine, but not to etravirine.
Standard genotyping saw K103N in no viral samples. With a 0.5% cutoff, the supersensitive assay spotted K103N in 12 people (7.5%), 6 of them with subtype B (5.5% of 109 people with subtype B) and 6 with a different type of HIV-1 (11.8% of 51 people with another subtype). With a 0.1% cutoff, the assay saw K103N in 26 people (16.5%), including 15 with subtype B (13.8%) and 11 (21.6%) with another type of HIV-1.
Frequency of low-level K103N in non-B samples varied considerably by subtype or CRF:
• Subtype A (14 samples): 7.1% with 0.5% cutoff, 14.3% with 0.1% cutoff
• Subtype C (3 samples): 0% with either cutoff
• Subtype F (2 samples): 0% with either cutoff
• Subtype G (6 samples): 16.7% with 0.5% cutoff, 33.3% with 0.1% cutoff
• CRF01_AE (9 samples): 22.2% with 0.5% cutoff, 33.3% with 0.1% cutoff
• CRF02_AG (14 samples): 14.3% with 0.5% cutoff, 21.4% with 0.1% cutoff
• 4 other non-B samples: 0% with 0.5% cutoff, 25% with 0.1% cutoff
Four people with pretreatment minority clusters of K103N started a nonnucleoside regimen. Two taking efavirenz and one taking nevirapine had a viral load below 40 copies after 24 weeks. One person taking efavirenz had a viral load of 68,000 copies at 24 weeks, but probably because of poor adherence.
In two studies previously reported by Karen Metzner, who devised the assay used in this study, minority pockets of K103N undetectable by standard sequencing could be detected in 5 of 93 German samples (5.4%) with a 0.01% assay cutoff [2] and in 10 of 211 German samples (4.7%) with a 0.01% cutoff [3]. In a 4-patient study published earlier this year, Metzner found evidence that pretreatment minority populations of M184V/I, the lamivudine mutation, can jeopardize response to a first-line efavirenz or nevirapine regimen containing lamivudine and tenofovir [4].
Ehret and coworkers called for closer study of how often minority nonnucleoside mutations appear in people infected with non-B virus and how those mutations may affect virologic outcome.
1. Braun P, Ehret R, Wiesmann F, Metzner KJ, Knechten H. Prevalence of the K103N mutation at low frequencies in antiretroviral treatment-na´ve patients in Germany 2008. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 71.
2. Metzner KJ, Rauch P, Walter H, et al. Detection of minor populations of drug-resistant HIV-1 in acute seroconverters. AIDS. 2005;19:1819-1825.
3. 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, February 3-6, 2008, Boston. Abstract 879.
4. Metzner KJ, Giulieri SG, Knoepfel SA, et al. Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and -adherent patients. Clin Infect Dis. 2009;48:239-247.