US guidelines recommend genotyping for persons newly diagnosed with HIV infection to identify transmitted drug resistance mutations associated with decreased susceptibility to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. To date, testing for integrase strand transfer inhibitor (INSTI) mutations has not been routinely recommended. We aimed to evaluate the prevalence of transmitted INSTI mutations among persons with primary HIV-1 infection in Seattle, WA, USA.
Methods
Persons with primary HIV-1 infection have enrolled in an observational cohort at the University of Washington Primary Infection Clinic since 1992. We performed a retrospective analysis of plasma specimens collected prospectively from the 82 antiretroviral-naive subjects who were enrolled from 2007–2013, after FDA-approval of the first INSTI. Resistance testing was performed by consensus sequencing.
Results
Specimens for analysis had been obtained a median of 24 (IQR 18–41, range 8–108) days after the estimated date of HIV-1 infection. All subjects were infected with HIV-1 subtype B except for one subject infected with subtype C. Consensus sequencing identified no subjects with major INSTI mutations (T66I, E92Q, G140S, Y143C/H/R, S147G, Q148H/K/R, N155H). Using exact binomial CIs, the upper bound of the 95% CI was 4.4%.
Conclusions
Although our sample size was small, this study does not support the need at this time to evaluate integrase mutations as part of routine consensus sequencing among persons newly diagnosed with HIV-1 infection. However, it is likely that the prevalence of transmitted INSTI mutations may increase with the recent commercial introduction of additional INSTIs and presumably greater INSTI use among persons living with HIV-1.
References
1.
US Department of Health and Human Services.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. (Updated 12 February 2013. Accessed 7 November 2013.) Available from http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.
2.
GrantR.M., HechtF.M., WarmerdamM.Time trends in primary HIV-1 drug resistance among recently infected persons.JAMA2002; 288: 181–188.
3.
LittleS.J., HolteS., RoutyJ.P.Antiretroviral-drug resistance among patients recently infected with HIV.N Engl J Med2002; 347: 385–394.
4.
WheelerW.H., ZiebellR.A., ZabinaH.Prevalence of transmitted drug resistance associated mutations and HIV-1 subtypes in new HIV-1 diagnoses, U.S.-2006.AIDS2010; 24: 1203–1212.
5.
YoungB., FransenS., GreenbergK.S.Transmission of integrase strand-transfer inhibitor multidrug-resistant HIV-1: case report and response to raltegravir-containing antiretroviral therapy.Antivir Ther2011; 16: 253–256.
6.
BoydS.D., MaldarelliF., SeretiI.Transmitted raltegravir resistance in an HIV-1 CRF_AG-infected patient.Antivir Ther2011; 16: 257–261.
7.
SaladiniF., MeiniG., BiancoC.Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naive and pretreated patients.Clin Microbiol Infect2012; 18: E428–E430.
8.
GutiérrezC., Hernandez-NovoaB., Perez-EliasM.J.Prevalence of primary resistance mutations to integrase inhibitors in treatment-naive and -experienced patients infected with B and non-B HIV-1 variants.HIV Clin Trials2013; 14: 10–16.
9.
DescampsD., AssoumouL., ChaixM.L.National sentinel surveillance of transmitted drug resistance in antiretroviral-naive chronically HIV-infected patients in France over a decade: 2001-2011.J Antimicrob Chemother2013; 68: 2626–2631.
10.
MetznerK.J., ScherrerA.U., PreiswerkB.Origin of minority drug-resistant HIV-1 variants in primary HIV-1 infection.J Infect Dis2013; 208: 1102–1112.
11.
YanikE.L., NapravnikS., HurtC.B.Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients.J Acquir Immune Defic Syndr2012; 61: 258–262.
12.
SchackerT.W., HughesJ.P., SheaT., CoombsR.W., CoreyL.Biological and virologic characteristics of primary HIV infection.Ann Intern Med1998; 128: 613–620.
13.
SteklerJ.D., WellmanR., HolteS.Are there benefits to starting antiretroviral therapy during primary HIV infection? Conclusions from the Seattle Primary Infection Cohort vary by control group.Int J STD AIDS2012; 23: 201–206.
14.
SteklerJ.D., EllisG.M., CarlssonJ.Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.PLoS ONE2011; 6: e28952.
15.
SchackerT., CollierA.C., HughesJ., SheaT., CoreyL.Clinical and epidemiologic features of primary HIV infection.Ann Intern Med1996; 125: 257–264.
16.
BullM.E., HeathL.M., McKernan-MullinJ.L.Human immunodeficiency viruses appear compartmentalized to the female genital tract in cross-sectional analyses but genital lineages do not persist over time.J Infect Dis2013; 207: 1206–1215.
17.
BeckI.A., CrowellC., KittoeR.Optimization of the oligonucleotide ligation assay, a rapid and inexpensive test for detection of HIV-1 drug resistance mutations, for non-North American variants.J Acquir Immune Defic Syndr2008; 48: 418–427.
18.
Stanford University HIV Drug Resistance Database.HIVdb Program. Genotypic Resistance Interpretation Algorithm. (Accessed 7 February 2014.) Available from http://hivdb.stanford.edu/pages/algs/HIVdb.html.
19.
Ceccherini-SilbersteinF., MaletI., D'ArrigoR., AntinoriA., MarcelinA.G., PernoC F.Characterization and structural analysis of HIV-1 integrase conservation.AIDS Rev2009; 11: 17–29.
20.
RheeS.Y., LiuT.F., KiuchiM.Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors.Retrovirology2008; 5: 74.
JohnsonJ.A., LiJ.F., WeiX.Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy.PLoS Med2008; 5: e158.
23.
HurtC.B., SebastianJ., HicksC.B., EronJ.J.Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009–2012.Clin Infect Dis2014; 58: 423–431.
