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Few Integrase Inhibitor (INI) Mutations in INI-Naive People
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 29, 2007
Mark Mascolini
Two studies of integrase inhibitor (INI) resistance mutations in people who never took the new drugs found low-level pretreatment mutation rates. But a few INI mutations proved substantially more or less frequent depending on antiretroviral experience, according to a report from Italy, France, and Spain [1].
Research so far has cataloged dozens of mutations in HIV integrase that dampen viral susceptibility to these drugs. To find out how many of these mutations appear in INI-naive people, Francesca Ceccherini-Silberstein (University of Rome Tor Vergata) and colleagues evaluated viral samples from 134 antiretroviral-naive people and from 115 taking a failing regimen, all of them infected with HIV-1 subtype B.
The integrase protein sequence bore 0 or 1 mutation in 178 of 286 viral samples (62% conservation) from naive individuals and in 178 of 286 samples (67% conservation) from experienced patients. In contrast, HIV-1 protease is 69% conserved and reverse transcriptase 73% conserved in people with no antiretroviral experience. In antiretroviral-naive people 22% of samples had 2 to 6 INI mutations, 7% had 7 to 14, 6.5% had 15 to 33, and 3% had 34 or more. In people with antiretroviral experience, rates were 17% with 2 to 6 mutations, 8% with 7 to 14, 5% with 15 to 33, and 3% with 34 or more. None of the rate differences between naive and experienced people reached statistical significance.
Eleven mutations linked to high-level INI resistance in cell studies (T66I, F121Y, A128T, E138K, G140S, Q146K, Q148K, V151I, S153Y, N155S, V249I) appeared in none of the viral isolates analyzed. Nine other mutations did appear, six of them (I72V, T125AV, M154I, V165I, V201I, S230N) in both treated an untreated people.
The M154I and V165I mutations both occurred in 6% of untreated people but in 43.5% (P < 0.0001) and 17.4% (P = 0.004) of people with antiretroviral experience. On the other hand, I72V, L74I, and T125V turned up more in untreated people than in those who had tried antiretrovirals (P < 0.05). L74M, which causes high-level resistance to INIs, appeared in isolates from 2 individuals (1.5%).
Researchers from Madrid's Carlos III Hospital confirmed low rates of INI-linked mutations in 104 viral isolates from INI-naive people, 29 of them (27.9%) with subtype B and the rest with non-B subtypes or recombinant forms [2]. They detected the V151I mutation in 3% of subtype B samples and 3.8% of non-B isolates. K156N, a substitution that increases susceptibility to the Merck integrase inhibitor raltegravir (MK-0518), turned up in 12.3% of subtype Bs and 11.5% of URF_BF isolates. V72I, which heightens resistance to INIs when it appears with F121Y, T125K, and V151I, occurred in 83 viral samples (59.3%).
Analysis of 1512 multiple-subtype sequences in the Los Alamos Database detected several mutations at low rates: T125K in 0.07%, V151I in 0.3%, T97A in 1.9%, K156N in 1.8%, H51Y in 0.13%, S147G in 0.13%, and E 157Q in 0.5%.
Note from Jules Levin: what matters is the response by patients not necessarily in vitro mutations in ART-naive patients.
References
1. Malet I, Fabeni L, de Mendoza C, et al. Specific mutations associated with in-vitro resistance to HIV-1 integrase inhibitors are present in untreated and NRTI/NNRTI/PI-treated HIVinfected patients. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 52.
2. Cuevas M, Perez-Alvarez L, Sierra M, et al. Low frequency of natural resistance associated mutations to integrase inhibitors in HIV-1 infected patients. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 51.
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