Prevalence of Mutations Associated with Reduced Antiretroviral Drug Susceptibility among Human Immunodeficiency Virus Type 1 Seroconverters in the United States, 1993–1998

Weinstock, Hillard; Respess, Richard; Heneine, Walid; Petropoulos, Christos J.; Hellmann, Nicholas S.; Luo, Chi‐Cheng; Pau, Chou‐Pong; Woods, Toni C.; Gwinn, Marta; Kaplan, Jonathan E.

doi:10.1086/315686

Cited by 67 publications

(40 citation statements)

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“…However, our overall TDR data mirror the mutation rates reported in other studies within the United States (Castor et al, 2012;Huaman et al, 2011;Hurt et al, 2009;Little et al, 1999;Little et al, 2002;MacVeigh et al, 2013;Readhead et al, 2012;Ross et al, 2007;Truong et al, 2011;Weinstock et al, 2000;Weinstock et al, 2004;Wheeler et al, 2010;Yanik et al, 2012;Youmans et al, 2011).…”

Section: Discussionsupporting

confidence: 88%

“…In addition, our rate of 15% NNRTI mutations contributing to NNRTI resistance was higher than what was typically reported for this drug class (Castor et al, 2012;Huaman et al, 2011;Hurt et al, 2009;Little et al, 2002;MacVeigh et al, 2013;Readhead et al, 2012;Ross et al, 2007;Taniguchi et al, 2012;Truong et al, 2011;Weinstock et al, 2000;Weinstock et al, 2004;Wheeler et al, 2010;Yanik et al, 2012;Youmans et al, 2011). The increase in TDR was primarily due to NNRTI mutations and occurred during the 4-year study period in a trend similar to other studies in the United States (Grant et al, 2002;Ross et al, 2008;Shet et al, 2006;Simon et al, 2002).…”

Section: Discussionsupporting

confidence: 75%

“…We observed low rates of individual major Pr mutations, all below 1%; our overall rate of 2% major Pr mutations is slightly less than many other studies in the United States (Castor et al, 2012;Huaman et al, 2011;Hurt et al, 2009;Little et al, 2002;MacVeigh et al, 2013;Readhead et al, 2012;Ross et al, 2007;Taniguchi et al, 2012;Truong et al, 2011;Weinstock et al, 2000;Weinstock et al, 2004;Wheeler et al, 2010;Yanik et al, 2012;Youmans et al, 2011). Although in the minority, persons with dual and triple class ARV resistance mutations were seen in 2% (8 patients) and 0.7% (3 patients), respectively.…”

Section: Discussioncontrasting

confidence: 61%

“…Based on United States Department of Health and Human Services (DHHS) guidelines, genotypic antiretroviral resistance testing (GART) was initially given CIII and DIII recommendations in 2000 for acutely-infected and chronically-infected treatment-naïve patients, (DHHS, 2007). For ARV treatment naïve individuals in the U.S., TDR mutation rates have ranged from about 5% to as high as 25% (Castor et al, 2012;Huaman et al, 2011;Hurt et al, 2009;Little et al, 1999;Little et al, 2002;MacVeigh et al, 2013;Readhead et al, 2012;Ross et al, 2007;Taniguchi et al, 2012;Truong et al, 2011;Weinstock et al, 2000;Weinstock et al, 2004;Wheeler et al, 2010;Yanik et al, 2012;Youmans et al, 2011). TDR has several important implications.…”

Section: Introductionmentioning

confidence: 99%

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Human immunodeficiency virus (HIV) in Washington, D.C.: Prevalence of antiretroviral resistance in treatment nave patients from 2007 to 2010

Swierzbinski¹,

Kan²,

Parenti³

2015

J. AIDS HIV Res.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 75%

Section: Discussioncontrasting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

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Human immunodeficiency virus (HIV) in Washington, D.C.: Prevalence of antiretroviral resistance in treatment nave patients from 2007 to 2010

Swierzbinski¹,

Kan²,

Parenti³

2015

J. AIDS HIV Res.

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“…Patients who are infected with drug-resistant HIV-1 and initiate antiretroviral therapy show poorer treatment responses than patients who are infected with wild-type (WT) viruses (17,24). A number of studies have shown that the prevalence of viruses with drug resistance mutations in acutely or recently infected persons varies between 10 and 20% (1,3,17,23,24,(34)(35)(36).…”

mentioning

confidence: 99%

Transmitted Human Immunodeficiency Virus Type 1 Carrying the D67N or K219Q/E Mutation Evolves Rapidly to Zidovudine Resistance In Vitro and Shows a High Replicative Fitness in the Presence of Zidovudine

Garcı́a-Lerma¹,

MacInnes²,

Bennett³

et al. 2004

J Virol

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Drug-naive patients infected with drug-resistant human immunodeficiency virus type 1 (HIV-1) who initiate antiretroviral therapy show a shorter time to virologic failure than patients infected with wild-type (WT) viruses. Resistance-related HIV genotypes not commonly seen in treated patients, which likely result from reversion or loss of primary resistance mutations, have also been recognized in drug-naive persons. Little work has been done to characterize the patterns of mutations in these viruses and the frequency of occurrence, their association with phenotypic resistance, and their effect on fitness and evolution of resistance. Through the analysis of resistance mutations in 1082 newly diagnosed antiretroviral-naive persons from the United States, we found that 35 of 48 (72.9%) persons infected with HIV-1 containing thymidine analog mutations (TAMs) had viruses that lacked a primary mutation (T215Y/F, K70R, or Q151M). Of these viruses, 9 (25.7%) had only secondary TAMs (D67N, K219Q, M41L, or F77L), and all were found to be sensitive to zidovudine (AZT) and other drugs. To assess the impact of secondary TAMs on the evolution of AZT resistance, we generated recombinant viruses from cloned plasma-derived reverse transcriptase sequences. Two viruses had D67N, three had D67N and K219Q/E, and three were WT. Four site-directed mutants with D67N, K219Q, K219E, and D67N/K219Q were also made in HIV-1 HXB2 . In vitro selection of AZT resistance showed that viruses with D67N and/or K219Q/E acquired AZT resistance mutations more rapidly than WT viruses (36 days compared to 54 days; P ‫؍‬ 0.003). To investigate the factors associated with the rapid selection of AZT mutations in these viruses, we evaluated fitness differences among HXB2 WT and HXB2 D67N or HXB2 D67N/K219Q in the presence of AZT. Both HXB2 D67N/K219Q and HXB2 D67N were more fit than HXB2 WT in the presence of either low or high AZT concentrations, likely reflecting low-level resistance to AZT that is not detectable by phenotypic testing. In the absence of AZT, the fitness cost conferred by D67N or K219Q was modest. Our results demonstrate that viruses with unique patterns of TAMs, including D67N and/or K219Q/E, are commonly found among newly diagnosed persons and illustrate the expanding diversity of revertant viruses in this population. The modest fitness cost conferred by D67N and K219Q supports persistence of these mutants in the untreated population and highlights the potential for secondary transmission. The faster evolution of these mutants toward AZT resistance is consistent with the higher viral fitness in the presence of AZT and shows that these viruses are phenotypically different from WT HIV-1. Our study emphasizes the need for clinical studies to better define the impact of these mutants on treatment responses and evolution of resistance.

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Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection

et al. 2000

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Baseline genotype resistance analysis was carried out in 48 adults with primary HIV-1 infection between 1995 and 1998 before starting early combination therapy. Seventeen percent (8/48) of the isolates displayed key mutations conferring resistance to reverse transcriptase (RT) inhibitors such as amino acid substitutions 215Y/F (5/48,10%), 70R (3/48, 6%), 184V (2%). Two percent (1/48) had a major mutation associated with resistance to protease inhibitors (D30N). Other mutations at positions 10, 15, 20, 33, 36, 46, 63, 71, 77, 82, 93 of the protease gene were frequent (73%). Among the 46 patients who were given antiretroviral combination therapy and who responded durably to treatment after 6 and 12 months, there was no significant difference between those harboring RT mutant strains (Group I) and those with wild-type isolates (Group II). No significant difference was found at months 6 and 12 between the two groups in terms of CD4+ cell counts. These findings suggest that the presence of drug-resistant strains at the time of primary HIV-1 infection does not necessarily predict drug failure. Other factors, such as adherence to treatment, tolerance and pharmacokinetics parameters are probably major determinants of virological response in patients with early therapeutic intervention.

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Prevalence of Mutations Associated with Reduced Antiretroviral Drug Susceptibility among Human Immunodeficiency Virus Type 1 Seroconverters in the United States, 1993–1998

Cited by 67 publications

References 14 publications

Human immunodeficiency virus (HIV) in Washington, D.C.: Prevalence of antiretroviral resistance in treatment nave patients from 2007 to 2010

Human immunodeficiency virus (HIV) in Washington, D.C.: Prevalence of antiretroviral resistance in treatment nave patients from 2007 to 2010

Transmitted Human Immunodeficiency Virus Type 1 Carrying the D67N or K219Q/E Mutation Evolves Rapidly to Zidovudine Resistance In Vitro and Shows a High Replicative Fitness in the Presence of Zidovudine

Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection

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