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Covert Mutations in Both Recently and Chronically Infected People
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Standard genotypic resistance testing often overlooked mutations that more sensitive assays spotted in two studies of untreated people with acute, recent, or chronic HIV infection [1,2]. But in the study of people with acute ("primary") infection, two pretreatment resistance mutations did not heighten the risk of virologic failure.
Jeffrey Johnson and Centers for Disease Control (CDC) coworkers used real-time polymerase chain reaction (PCR) assays that see virus representing only 0.4% to 2.0% of a person's viral population [1]. They looked specifically for the L90M mutation in protease and for M41L, K70R, K103N, Y181C, M184V, T215F, and T215Y in reverse transcriptase in 205 people tested in Chicago and Los Angeles from 2003 through 2005. Antibody testing determined that 90 of these people got infected within the past 6 months.
Standard genotyping detected no resistance mutations in virus from any of these people. But the supersensitive PCR test picked up one or more mutations in virus from 33 people (16%). Every mutation Johnson searched for showed up in at least one viral sample at the following frequencies: T215Y in 0.5%, M184V in 1%, Y181C in 1.5%, T215F in 2%, L90M in 3.5%, K103N in 4%, M41L in 4.5%, and K70R in 5%.
One person with recent infection and 3 with chronic infection had covert virus conferring resistance to two antiretroviral classes, with the following mutation sets: L90M plus M184V (in the person with recent infection), L90M plus Y181C, Y181C plus T215F, and L90M plus M41L plus K70R. Mutations hidden from standard tests proved just as common in chronically infected people (19 of 115, 17%) as in recently infected people (15 or 90, 17%), a finding leading Johnson to surmise that a substantial proportion of transmitted resistant virus persists for long periods.
Using a similar ultrasensitive assay that smokes out K103N or M184V representing as little as 0.01% to 0.2% of a person's viral population, Karin Metzner (University of Erlangen-Nuremberg) found one or the other--or both--in 13 of 74 acutely infected people judged to have no resistant virus by standard genotyping [2].
The clinical impact of low-level resistance mutations in these people remains uncertain because neither K103N nor M184V renders virus resistant to protease inhibitors (PIs), and all 9 of the 13 people who began therapy started a ritonavir-boosted PI regimen. All reached and maintained an undetectable viral load for 10 months to 4 years of follow-up. If the clinicians of people with K103N did not know they had that mutation and started an efavirenz regimen, the regimen may well have failed and also caused resistance to the nucleosides taken with efavirenz.
Metzner looked for K103N and M184V in just-infected Zurich residents because transmission of drug-resistant HIV has proved lower in Zurich than in other European locales. Standard genotyping typically spots resistance mutations in 10% of untreated Europeans. And the standard assays saw neither K103N nor M184V in any of these people, who were diagnosed between March 2002 and July 2006. K103N makes HIV highly resistant to efavirenz and nevirapine, and M184V does the same to 3TC and emtricitabine (FTC).
But real-time PCR disclosed K103N in virus from 4 of 74 people (5.4%) at frequencies of 0.18% to 3.76%. And the powerful test saw M184V in virus from 11 of 74 people at frequencies of 0.4% to 8.3%. Two people had both of these mutations, so overall prevalence came to 17.6% (13 of 74 people).
Both Metzner and Johnson probably underestimated prevalence of low-level transmitted resistant virus because they looked only for specific mutations--not for all the mutations that may make virus resistant to HIV.
References
1. Johnson JA, Lipscomb J, J-F Li, et al. Real-time PCR testing allows for sensitive drug
resistance screening and mutation linking in HIV-1. Antiviral Therapy. 2007;12:S153. Abstract 39.
2. Metzner KJ, Rauch P, von Wyl V, et al. Prevalence of minority quasispecies of drug-resistant HIV-1 in patients with primary HIV-1 infection in Zurich in the years 2002-2006. Antiviral Therapy. 2007;12:S47. Abstract 40.
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