Dual Resistance to Zidovudine and Lamivudine in Patients Treated with Zidovudine‐Lamivudine Combination Therapy: Association with Therapy Failure

Miller, Veronica; Phillips, Andrew; Rottmann, Carsten; Staszewski, Schlomo; Pauwels, Rudi; Hertogs, Kurt; Béthune, Marie‐Pierre de; Kemp, Sharon D.; Bloor, Stuart; Harrigan, P. Richard; Larder, Brendan A.

doi:10.1086/515304

Cited by 82 publications

(54 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Resistance to this combination requires more complex patterns of mutations than is required when either drug is used in monotherapy (39). An important aspect of 3TC-plus-AZT combination therapy is the frequent development of the M184V mutation despite the suppressive effect that it has on common AZT resistance mutations (26,37,39,42). In contrast, another mutation that causes phenotypic suppression of AZT resistance, Y181C (27), emerges with nevirapine monotherapy (45,47) but not in the presence of the combination of AZT plus nevirapine (47).…”

mentioning

confidence: 99%

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Murry¹,

Higgins²,

Matthews³

et al. 2003

J Virol

View full text Add to dashboard Cite

The methionine-to-valine mutation in codon 184 (M184V) in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) confers resistance to (؊)-2-deoxy-3-thiacytidine (3TC; lamivudine) and increased sensitivity to 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir). We have used the SIV model to evaluate the effect of the M184V mutation on the emergence of resistance to the combination of 3TC plus PMPA. A site-directed mutant of SIVmac239 containing M184V (SIVmac239-184V) was used to select for resistance to both 3TC and PMPA by serial passage in the presence of increasing concentrations of both drugs. Under these selection conditions, the M184V mutation reverted in the majority of the selections. Variants resistant to both drugs were found to have the lysine-to-arginine mutation at codon 65 (K65R), which has previously been associated with resistance to PMPA in both SIV and HIV. Similarly, in rhesus macaques infected with SIVmac239-184V for 46 weeks and treated daily with The rapid emergence of drug-resistant mutants of human immunodeficiency virus (HIV) has proven to be a major obstacle in antiviral therapy for AIDS (7,32,36,63). Even highly active antiretroviral therapy has been limited by the emergence of multidrug-resistant HIV (32,46,61). This has led to efforts to identify drug combinations in which resistance to one drug results in a mutant virus that suppresses normal resistance to a second drug or in a mutant virus that is hypersensitive to other drugs (2,27,28,35,52).One mutation that results in phenotypic changes in HIV type 1 (HIV-1) that are useful in certain drug combinations is the methionine-to-valine mutation in codon 184 (M184V) of reverse transcriptase (RT). This mutation arises rapidly in therapy with the oxathiolane nucleosides, (Ϫ)-2Ј-deoxy-3Ј-thiacytidine (3TC; lamivudine) and (Ϫ)-2Ј-deoxy-5-fluoro-3Ј-thiacytidine [(Ϫ)-FTC], and results in high-level (Ͼ100-fold) resistance to these drugs (49,55). This is often preceded by emergence of a methionine-to-isoleucine mutation in codon 184 (M184I), which is quickly replaced by M184V (22, 50). This M184V mutation is located in the highly conserved YMDD motif of RT, which is directly involved in binding the incoming nucleotide during reverse transcription (19,20,24,53). It results in decreased processivity (1,3,21,23,51) and increased fidelity (11,41,62) of the DNA polymerase activity of RT in biochemical assays. However, the increase in fidelity was less than twofold in an M13 phage-based assay that scored the overall mutation rate after transfection of RT products into bacteria (9). M184V mutants of HIV-1 also have reduced replication rates in certain cell lines (1, 35, 51), and they have a broad array of changes in susceptibility to nucleoside analogs (15,28,35,54,55,64).A major effect of the M184V mutation is to suppress phenotypic resistance to 3Ј-azido-3Ј-deoxythymidine (AZT; zidovudine) when M184V is present along with mutations that normally confer resistance to AZT (28,55). Clinical...

show abstract

mentioning

confidence: 99%

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Murry¹,

Higgins²,

Matthews³

et al. 2003

J Virol

View full text Add to dashboard Cite

show abstract

“…Numerous retrospective studies have evaluated the clinical utility of both genotypic and phenotypic drug resistance testing (3,4,9,13,14,16,17,22), while prospective studies on clinical utility are more limited (1, . Prospective studies generally support an improved response to therapy in groups treated with access to antiretroviral drug resistance information.…”

mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Drug Resistance Testing: a Comparison of Three Sequence-Based Methods

Erali¹,

Page²,

Reimer

et al. 2001

J Clin Microbiol

View full text Add to dashboard Cite

The use of genotypic assays for determining drug resistance in human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients is increasing. These tests lack standardization and validation. The aim of this study was to evaluate several tests used for the determination of HIV-1 drug resistance. Two genotypic tests, the Visible Genetics TruGene HIV-1 Genotyping Kit and the Applied Biosystems HIV Genotyping System, were compared using 22 clinical samples. Genotyping results were also obtained from an independent reference laboratory. The Visible Genetics and Applied Biosystems genotyping tests identified similar mutations when differences in the drug databases and reference strains were taken into account, and 19 of 21 samples were equivalent. The concordance between the two assays was 99% (249 of 252 mutation sites). Mutations identified by the reference laboratory varied the most among those identified by the three genotypic tests, possibly because of differences in the databases. The concordance of the reference laboratory results with the results of the other two assays was 80%

show abstract

“…The introduction of potent antiretroviral therapy has had a major impact on the morbidity and mortality associated with HIV disease (15), but the efficacy of combination therapy is impaired if strains resistant to the component drugs are present (14). Recent studies of the prevalence of reduced susceptibility to antiretrovirals among patients with primary HIV infection have addressed the question in patients infected since combination therapy became the standard of care (21,26).…”

mentioning

confidence: 99%

Reduced Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) from Patients with Primary HIV Infection to Nonnucleoside Reverse Transcriptase Inhibitors Is Associated with Variation at Novel Amino Acid Sites

Brown

Precious

Whitcomb³

et al. 2000

J Virol

View full text Add to dashboard Cite

Recently, significant numbers of individuals with primary human immunodeficiency virus (HIV) infectionhave been found to harbor viral strains with reduced susceptibility to antiretroviral drugs. In one study, HIV from 16% of such antiretroviral-naive individuals was shown to have a susceptibility to nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) between 2.5-and 10-fold lower than that of a wild-type control. Mutations in the RT domain that had previously been associated with antiretroviral resistance were not shared by these strains. We have analyzed by logistic regression 46 variable amino acid sites in RT for their effect on susceptibility and have identified two novel sites influencing susceptibility to NNRTIs: amino acids 135 and 283 in RT. Eight different combinations of amino acids at these sites were observed among these patients. These combinations showed a 14-fold range in mean susceptibility to both nevirapine and delavirdine. In vitro mutagenesis of the control strain combined with a phenotypic assay confirmed the significance of amino acid variation at these sites for susceptibility to NNRTIs.

show abstract

Dual Resistance to Zidovudine and Lamivudine in Patients Treated with Zidovudine‐Lamivudine Combination Therapy: Association with Therapy Failure

Cited by 82 publications

References 37 publications

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Reversion of the M184V Mutation in Simian Immunodeficiency Virus Reverse Transcriptase Is Selected by Tenofovir, Even in the Presence of Lamivudine

Human Immunodeficiency Virus Type 1 Drug Resistance Testing: a Comparison of Three Sequence-Based Methods

Reduced Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) from Patients with Primary HIV Infection to Nonnucleoside Reverse Transcriptase Inhibitors Is Associated with Variation at Novel Amino Acid Sites

Contact Info

Product

Resources

About