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Are Single Transmitted Mutants the Tip of a Resistance Iceberg?
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
"This 10,458-patient study calculated that people with resistance to one or more antiretrovirals had a 2.5 times higher risk of virologic failure, a result that could suggest detected mutations did represent the tip of the iceberg in some of these individuals."
Detection of a single resistance mutation in an untreated person may not be the "tip of an iceberg" representing broader mutation patterns, according to results of a deep-sequencing study of 10 gay men in the Netherlands [1]. The findings suggest that single mutations in antiretroviral-naive people--called singletons--may not signal an array of other transmitted mutants undetectable by standard genotyping, an array that imperils response to first-line antiretrovirals. But the study also found that singletons may at least occasionally signal transmission of a potentially more dangerous mutation set.
A widely accepted hypothesis holds that detection of a singleton in an untreated person represents transmission of virus with a more extensive resistance profile. While a newly infected person remains untreated, many additional transmitted mutations may fade to undetectable levels, leaving a single detectable mutation behind. But those undetectable mutations may re-emerge if treatment begins with antiretrovirals vulnerable to those mutants.
To analyze the import of singletons in untreated people, Marieke Pingen and colleagues in Rotterdam and Utrecht retrospectively used 454 "deep" sequencing to scrutinize virus in 10 men diagnosed with HIV and harboring apparent singleton mutations before they started therapy. Between 1 and 49 weeks had elapsed since HIV diagnosis and the start of antiretroviral therapy, so the frequency of mutations transmitted with a still-detectable single mutant could have dropped to undetectable levels. But 454 "deep" sequencing should be able to detect many or most of such hidden mutations.
Standard sequencing detected M41L, T69N, M184V, K219Q, and T215L in 1 man each, T215E in 2 men, and T215S in 3. (Position 69 insertions are associated with resistance to all nucleosides.) All men had a pretreatment viral load above 100,000 copies and began an appropriate antiretroviral regimen including a nonnucleoside or a boosted protease inhibitor plus tenofovir and emtricitabine. The researchers followed their response over a median of 69 weeks (range 14 to 218).
"Deep" sequencing of pretreatment viral samples did not spot any additional major reverse transcriptase or protease mutations in 9 of the 10 men. But in the man with a single T69N change detected by standard sequencing, the supersensitive technique uncovered a T69A/D/N mixture and a minority population of K103N, the mutation that compromises treatment with efavirenz or nevirapine. Because standard sequencing missed the K103N, this man started a regimen including efavirenz. To complicate matters, he reported poor adherence to his regimen, which failed after about a half-year.
"At this stage of the epidemic," the investigators concluded, "variants with a single mutation may represent the circulation of stable, true singletons" in most people. The researchers called for further studies "to determine the implication of singletons (especially atypical variants) at baseline for the choice of initial therapy."
Another study (reviewed separately by NATAP) found that transmitted resistance can predict virologic failure if first-line therapy is not planned to counter resistant virus [2]. This 10,458-patient study calculated that people with resistance to one or more antiretrovirals had a 2.5 times higher risk of virologic failure, a result that could suggest detected mutations did represent the tip of the iceberg in some of these individuals.
References
1. Pingen M, van der Ende ME, Wensing AMJ, et al. Single transmitted drug resistance mutations: not always an indicator of transmission of more extensive resistance profiles. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 28.
2. Wittkop L on behalf of the EuroCoord-CHAIN project team. Impact of transmitted drug resistance on virological response to initial combination antiretroviral therapy. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 98.
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