Rapid Changes in Human Immunodeficiency Virus Type 1 RNA Load and Appearance of Drug-Resistant Virus Populations in Persons Treated with Lamivudine (3TC)

Schuurman, Rob; Nijhuis, Monique; Leeuwen, Remko van; Schipper, P; Jong, Dorien de; Collis, Phil; Danner, Sven A.; Mulder, John E.; Loveday, Clive; Christopherson, Cindy; Kwok, Shirley; Sninsky, John J.; Boucher, Charles A.

doi:10.1093/infdis/171.6.1411

Cited by 480 publications

(351 citation statements)

References 21 publications

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“…Mutations in the YMDD motif of the HBV polymerase gene, potentially associated with diminished response to lamivudine, [6][7][8][9] were detected as described. 5,10 During the course of the study, we used an operational definition of virological breakthrough (HBV DNA Ͼ10 pg/mL on 2 successive determinations, after at least 2 previous values had been undetectable) to identify patients for whom YMDD-mutant HBV evaluation would be appropriate.…”

Section: Methodsmentioning

confidence: 99%

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Dienstag¹,

Schiff²,

Mitchell³

et al. 1999

Hepatology

188

128

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In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and Chronic hepatitis B virus (HBV) infection occurs in approximately 5% of the world' s population and is among the top 10 causes of death. Although interferon alfa has been approved as therapy for chronic hepatitis B, such treatment is suboptimal, yielding clinical benefit in a minority of patients. Lamivudine is an oral dideoxynucleoside that inhibits reverse transcription by causing chain termination of nascent viral DNA in human immunodeficiency virus (HIV) and HBV infection. 1 As reported previously, phase-II dose-ranging trials in North American and western European patients with chronic hepatitis B included daily doses of 5 to 600 mg administered for 1 to 6 months. 2-4 Therapy was well tolerated, doses of 100 mg or more suppressed serum HBV DNA levels consistently during therapy, and no significant advantage was identified for doses above 100 mg. 3,4 A sustained response posttreatment, however, defined as the loss of hepatitis B e antigen (HBeAg) and failure of HBV DNA to reappear after discontinuation of therapy, occurred in only 4% to 12% of patients in these dose-ranging studies. In a recently completed placebo-controlled phase-III trial involving 358 Chinese patients, Lai et al. 5 reported that 12 months of lamivudine therapy at a dose of 100 mg/d was associated with histological improvement in 67% of patients and HBeAg seroconversion in 16%, which is significantly better than response rates observed in concurrent placebo controls. This study in Asian patients, however, did not address treatmentstopping criteria; regardless of HBeAg status at the end of 12 months of therapy, all patients were enrolled in a continuingtreatment follow-up study. 5 In the present study, we wished to determine whether prolonged lamivudine therapy in Western patients would be safe and tolerable and result in loss of HBeAg and HBeAg seroconversion in a higher proportion of patients compared with the shorter dosing regimens studied previously. We also sought to determine whether lamivudine therapy could be withdrawn after HBeAg loss or HBeAg seroconversion. Therefore, we undertook an extended-treatment trial in previously Abbreviations: HBV, hepatitis...

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Section: Methodsmentioning

confidence: 99%

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Dienstag¹,

Schiff²,

Mitchell³

et al. 1999

Hepatology

188

128

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“…For example, mutations at codons 41, 67, 70, 210, 215, and 219 of reverse transcriptase (RT) typically confer resistance to zidovudine (ZDV) (6,12,13,27). Similarly, mutation M184V in RT has been shown to be specifically associated with high-level (Ն50-fold) phenotypic resistance to lamivudine (3TC) (1,22,28). No "specific" mutation(s) associated with moderate levels of phenotypic resistance (4-to Ͻ50-fold) to 3TC has been described before.…”

mentioning

confidence: 99%

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

Hertogs¹,

Bloor²,

Vroey³

et al. 2000

Antimicrob Agents Chemother

108

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We describe a new human immunodeficiency virus type 1 (HIV-1) mutational pattern associated with phenotypic resistance to lamivudine (3TC) in the absence of the characteristic replacement of methionine by valine at position 184 (M184V) of reverse transcriptase. Combined genotypic and phenotypic analyses of clinical isolates revealed the presence of moderate levels of phenotypic resistance (between 4-and 50-fold) to 3TC in a subset of isolates that did not harbor the M184V mutation. Mutational cluster analysis and comparison with the phenotypic data revealed a significant correlation between moderate phenotypic 3TC resistance and an increased incidence of replacement of glutamic acid by aspartic acid or alanine and of valine by isoleucine at residues 44 and 118 of reverse transcriptase, respectively. This occurred predominantly in those isolates harboring zidovudine resistance-associated mutations (41L, 215Y). The requirement of the combination of mutations 41L and 215Y with mutations 44D and 44A and/or 118I for phenotypic 3TC resistance was confirmed by site-directed mutagenesis experiments. These data support the assumption that HIV-1 may have access to several different genetic pathways to escape drug pressure or that the increase in the frequency of particular mutations may affect susceptibility to drugs that have never been part of a particular regimen.The emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is almost always observed during the course of treatment of patients with antiretroviral drugs (3, 10, 14-16, 18, 21, 27 Strategies, abstr. 19, p. 15, 1998). The mutational profile of the resistant viruses generally is characteristic for the particular drug(s) taken. For example, mutations at codons 41, 67, 70, 210, 215, and 219 of reverse transcriptase (RT) typically confer resistance to zidovudine (ZDV) (6,12,13,27). Similarly, mutation M184V in RT has been shown to be specifically associated with high-level (Ն50-fold) phenotypic resistance to lamivudine (3TC) (1,22,28). No "specific" mutation(s) associated with moderate levels of phenotypic resistance (4-to Ͻ50-fold) to 3TC has been described before. Those mutations that confer moderate (4-to Ͻ50-fold) levels of phenotypic resistance to 3TC reported previously always appeared in the context of a constellation of mutations that confer resistance to multiple nucleoside analogues or as a cross-resistance phenomenon that appears with the emergence of resistance to another nucleoside analogue. This has been the case for the nucleoside multidrug resistance complex of mutations Q151M, F77L, F116Y, A62V, and V75I, although the increase in the level of phenotypic resistance to 3TC in viruses that harbor those mutations is slight (9,20,24,25). In the case of the insertion mutations near position 69 of RT, a notable increase in the frequency of 3TC resistance has been reported together with an increased frequency of phenotypic resistance to other nucleosides (2, 17, 29). The K65R mutation appears infrequently during the course of tr...

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“…The replication fitness deficit conferred by the M184V mutation in reverse transcriptase, which causes highlevel resistance to the cytosine analogs lamivudine and emtricitabine, has been the subject of extensive study (reviewed in reference 132). M184V occurs frequently in viral isolates from patients failing lamivudine or emtricitabine therapy (63,153). M184V has a fitness similar to that of the wild type in most T-cell lines where nucleotide concentrations are high (10) but reduced fitness in primary cells that have limited nucleotide pools, such as PBMCs and macrophages (3,10,129).…”

Section: Mutations Conferring Resistance To Reversementioning

confidence: 99%

“…Early observations of viral load rebound during lamivudine monotherapy and lamivudine-containing regimens demonstrated that plasma HIV-1 RNA concentrations remained lower than pretherapy levels despite the uniform presence of M184V in plasma viruses (132,153). However, other studies have shown that lamivudine does exert some antiretroviral effect on the M184V mutant, suggesting that the incomplete viral rebounds that occur may represent residual antiviral activity rather than selection for a mutant with reduced fitness (139).…”

Section: Mutations Conferring Resistance To Reversementioning

confidence: 99%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

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SUMMARY The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

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Rapid Changes in Human Immunodeficiency Virus Type 1 RNA Load and Appearance of Drug-Resistant Virus Populations in Persons Treated with Lamivudine (3TC)

Cited by 480 publications

References 21 publications

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

A Novel Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutational Pattern Confers Phenotypic Lamivudine Resistance in the Absence of Mutation 184V

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

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