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Low-Level K103N in Primary Infection
Can Reappear After Suppressive Therapy
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
HIV Resistance Wksp: Cutoffs Suggested for Predicting Efavirenz Failure With Low-Level K103N - written by Mark Mascolini - (06/15/09)
HIV Resistance Wksp: Most Low-Level Pretreatment Mutations Did Not Affect Outcome in PI Trial CASTLE Study of Boosted PIs Reyataz and Kaletra - written by Mark Mascolini - (06/15/09)
Low-frequency K103N mutant virus, which confers resistance to efavirenz and nevirapine, disappeared after treatment of primary infection with a lopinavir-based regimen, then reappeared during a planned treatment interruption in 2 of 4 patients, according to results from the Zurich Primary HIV Infection (ZPHI) study [1]. Low-level M184V detected before treatment did not reappear during the planned treatment interruption.
Earlier work by ZPHI investigators found that virus from 15 of 93 people with primary HIV infection (16%) harbored trace levels of K103N and M184V mutants that could not be detected by standard genotyping. Karen Metzner and colleagues used allele-specific PCR to search for these mutations after suspension of treatment for primary infection in 6 people who had them before therapy and in 5 who did not.
All patients were infected with subtype B HIV-1 between April 2003 and September 2005, and all started lopinavir/ritonavir plus zidovudine and lamivudine during primary infection. Treatment continued for 8 to 27 months, and everyone reached a viral load below 40 copies for at least 6 months during that time. Then everyone suspended treatment for 8 to 27 months and Metzner searched for the minority resistant variants with assays that detect K103N representing about 0.01% of a person's viral population and M184V representing about 0.2% of the population.
Comparing the 6 people with low-frequency pretreatment mutations and the 5 without them, Metzner found no significant differences in viral load after treatment interruption (4.5 versus 4.3 log copies/mL), number of viral samples analyzed, time from treatment interruption to the first sample, or duration of follow-up during the treatment interruption.
In 2 of 4 people with low-frequency K103N before treatment, low levels of that mutation reappeared after treatment stopped. One of the 2 had K103N in 1 of 4 plasma samples during the treatment interruption, and the other had K103N in 5 of 9 plasma samples. In all samples, K103N represented less than 1% of the viral population. K103N could not be detected, even at low levels, in the 2 people who had M184V before treatment or in the 5 who had no evidence of resistance mutations before therapy.
Of the 2 people with low-frequency M184V before treatment, that mutation did not re-emerge after therapy stopped.
Studies to determine whether minority mutant virus affects later response to therapy have yielded differing results [2-6]. A study at this workshop linked efavirenz failure to low-level K103N above a K103N threshold of 2000 copies/mL [7].
References
1. Metzner KJ, von Wyl V, Leemann C, et al. Reappearance and persistence of minority quasispecies of K103N-harboring HIV-1 present prior to ART in patients with primary HIV-1 infection after treatment interruption. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 103.
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, 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.
4. 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.
5. 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. March 25-27, 2009. Stockholm. Abstract 113.
6. 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. March 25-27, 2009. Stockholm. Abstract 71.
7. 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. International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 41 (http://www.natap.org/2009/ResisWksp/ResisWksp_08.htm).
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