Low-level Q148R in people without integrase inhibitor experience
22 August 2009. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 18 Florida 2009.
Mark Mascolini for natap.org
Minority populations of the Q148R integrase mutation could be found in most integrase-inhibitor-naive people studied by Charlotte Charpentier and colleagues in Paris. [1]
The study yielded two other interesting findings:
- Low-level Q148R did not affect response to raltegravir in a large majority of people who started that integrase inhibitor.
- Experience with other antiretrovirals had no apparent impact on prevalence of low-frequency Q148R.
Charpentier and coworkers used allele-specific PCR that can detect Q148R representing only 0.10% of a persons viral population. Q148R may make HIV resistant to raltegravir or elvitegravir. [2, 3]
The investigators probed viral samples from two groups–40 people with heavy antiretroviral experience but without integrase inhibitor experience, and 51 people who never took any antiretrovirals. The supersensitive PCR assay proved successful in 74 of the 91 viral samples (82%). Most of the samples that could not be amplified were HIV-1 subtypes other than B. Charpentier also used a highly sensitive K103N assay to probe for minority populations of this nonnucleoside mutation in 47 of the antiretroviral-naive people.
Among 32 antiretroviral-experienced people whose viral sequences could be amplified, 26 (81%) had detectable Q148R at a median frequency of 0.40% (range 0.15% to 0.92%). Among 42 antiretroviral-naive people, allele-specific PCR spotted minority clusters of Q148R in 36 (86%), a proportion close to that in the antiretroviral-experienced group. Q148R turned up at a median frequency of 0.46% (range 0.13% to 1.98%) in the untreated people.
Allele-specific PCR uncovered low-frequency K103N in 12 of 47 antiretroviral-naive people (26%). Thus minority Q148R variants were significantly more common in both groups of integrase inhibitor-naive people than minority K103N variants were in naive people (P < 0.0001).
Of 26 people with detectable but low-frequency Q148R who started a raltegravir salvage regimen, 24 (92%) responded with a viral load below 40 copies. Twenty of these 24 responders reached an undetectable load within 12 weeks of starting raltegravir, while the other 4 attained undetectable viremia between week 18 and week 36.
In the 2 people whose raltegravir regimen failed, the resistance pathway began with Q148R, which emerged as a majority population within 3 months of starting the integrase inhibitor. Everyone without low-frequency Q148R before raltegravir-based salvage responded to their regimen.
Charpentier and colleagues suggested that the high prevalence of minority Q148R variants found in antiretroviral-experienced patients is not the consequence of a history of long-term reverse transcriptase inhibitor-containing therapies, since similar data are found in antiretroviral-naive patients.
References:
- Charpentier C, Piketty C, Tisserand P, et al. Assessment of prevalence of minority Q148R variants in antiretroviral (ARV)-experienced patients and in ARV-naive patients. XVIII International Drug Resistance Workshop. 9-13 June 2009, Fort Myers, Florida. Abstract 117.
- Waters J, Margot N, Hluhanich R, et al. Evolution of resistance to the HIV integrase inhibitor (INI) elvitegravir can involve genotypic switching among primary INI resistance patterns. XVIII International Drug Resistance Workshop. 9-13 June 2009, Fort Myers, Florida. Abstract 116.
- Johnson VA, Brun-Vezinet F, Clote B et al. Update of the drug resistance mutations in HIV-1: spring 2008. Top HIV Med. 2008;16:62-68.