Zidovudine Resistance Reverse Transcriptase Mutations during Didanosine Monotherapy

Shafer, Robert W.; Winters, Mark A.; Jellinger, Robert M.; Merigan, Thomas C.

doi:10.1093/infdis/174.2.448

Cited by 11 publications

(3 citation statements)

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“…It has been shown that patients receiving combination AZT-ddI therapy rarely develop ddI resistance mutations but do develop AZT resistance mutations (15,23). While surreptitious use of AZT during this study is unlikely for one patient (24), it cannot be ruled out for the other four patients whose viruses developed AZT resistance mutations. In contrast, evidence that some AZT resistance mutations may confer partial resistance to ddI does exist (2,19).…”

Section: Discussionmentioning

confidence: 75%

Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years

Winters

Shafer

Jellinger

et al. 1997

Antimicrob Agents Chemother

132

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The genetic mechanisms of human immunodeficiency virus type 1 (HIV-1) resistance to dideoxyinosine (ddI) in vivo have been described based on data from primary HIV-1 isolates. To better define the spectrum of HIV-1 reverse transcriptase (RT) changes occurring during ddI therapy, we determined the genotype and ddI susceptibility of the RT gene of HIV RNA isolated from the plasma of 23 patients who had received 1 to 2 years (mean, 87 +/- 16 weeks) of ddI monotherapy. Population-based sequencing of plasma virus showed that 12 of 23 (52%) patients developed known ddI resistance mutations: L74V (7 patients), K65R (2 patients), L74V with M184V (3 patients), and L74V with K65R (1 patient). Five patients developed one or more known zidovudine resistance mutations (at codons 41, 67, 70, 215, and/or 219) during the study. Other amino acid substitutions were found, but only S68G and L210W occurred in more than one patient. Studies of sensitivity to ddI were performed on population-based recombinant-virus stocks generated by homologous recombination between a plasmid containing an HXB2 clone with the RT gene deleted and RT-PCR products of the RT genes from patients' plasma RNA. The sequences of the virus stocks produced by this procedure were typically identical to the sequence of the input PCR product from plasma RNA. Both an MT-2 cell-based culture assay and a cell-free virion-associated RT inhibition assay showed that viruses possessing an L74V and/or M184V mutation or a K65R mutation had reduced sensitivity to ddI. Viruses without these specific mutations had no change in sensitivity to ddI. The results presented here show that the spectrum of RT mutations in a population of patients on ddI monotherapy is more complex than previously described. The development of multiple mutational patterns, including those that confer resistance to other nucleoside analogs, highlights the complexity of using the currently available nucleoside analogs for antiretroviral therapy.

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Section: Discussionmentioning

confidence: 75%

Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years

Winters

Shafer

Jellinger

et al. 1997

Antimicrob Agents Chemother

132

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show abstract

“…Mutations from this group are most frequently selected for after the failure of drug combinations that include thymidine analogues, such as zidovudine and stavudine, but they can promote resistance to almost all nucleoside and nucleotide analogues, including tenofovir. [38][39][40][41] These mutations occur gradually, and their order of emergence can vary. 10,42 Thymidine analogue mutations promote resistance by fostering ATP-or pyrophosphate-mediated removal of nucleoside analogues from the 3' end of the terminated DNA strand (Fig.…”

Section: Removal Of the Analogue From The Terminated Dna Chainmentioning

confidence: 99%

HIV Drug Resistance

2004

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he use of combinations of antiretroviral drugs has proven remarkably effective in controlling the progression of human immunodeficiency virus (HIV) disease and prolonging survival, 1 but these benefits can be compromised by the development of drug resistance. 2,3 Resistance is the consequence of mutations that emerge in the viral proteins targeted by antiretroviral agents. In the United States, as many as 50 percent of patients receiving antiretroviral therapy are infected with viruses that express resistance to at least one of the available antiretroviral drugs. 4 Consequently, the transmission of drug-resistant strains is also a growing concern. 5-7 Because drug-resistant HIV often exhibits resistance to several classes of antiretroviral drugs 8 and because cross-resistance between drugs within a class is frequent, 9-12 the emergence of resistance always complicates further efforts to control viral replication. This review focuses on the mechanisms underlying the selection of drug-resistant HIV and on the consequences of viral resistance with respect to the evolution of HIV infection. The drugs currently used to treat HIV type 1 (HIV-1) infection (Table 1) belong to four distinct classes: nucleoside and nucleotide analogues, which act as DNA-chain terminators and inhibit reverse transcription of the viral RNA genome into DNA, a crucial event occurring at an early stage of the viral life cycle; nonnucleoside reverse-transcriptase inhibitors, which bind and inhibit reverse transcriptase, the viral enzyme that conducts reverse transcription; protease inhibitors, which target the viral protease, the enzyme required for the cleavage of precursor proteins (gag and gag-pol), permitting the final assembly of the inner core of viral particles; and entry inhibitors, which block the penetration of HIV virions into their target cells. Combinations of antiretroviral drugs are now used for the treatment of HIV infection-so-called highly active antiretroviral therapy (HAART). Current HAART regimens generally comprise three antiretroviral drugs, usually two nucleoside analogues and either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor. 13 The use of agents from different classes is instrumental in controlling the development of resistance, but whereas some drug combinations have been shown to be antagonistic, there is no evidence that any combinations of currently available drugs are strongly synergistic in vitro. induced resistance Two concepts are important to an understanding of the development of drug resistance. First, HIV infection is characterized by high levels of virus production and turnover. In most untreated patients, the total number of productively infected cells in the lymphoid tissue has been estimated to be approximately 10 7 to 10 8 cells. 14 During the chronic phase of HIV infection, this number is relatively stable, reflecting the balance between t principles of drug therapy for hiv development of resistance

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“…Tais mutações são freqüentemente selecionadas após a falência de combinações a drogas que incluem análogos da timidina, como AZT e D4T. Porém, promovem resistência à maioria dos análogos nucleosídeos e nucleotídeos, inclusive o TDF (Coakley et al 2000;Larder et al 1989;Picard et al 2001;Shafer et al 1996). O aparecimento dessas mutações é gradual e a ordem em que elas surgem pode variar (Boucher et al 1992;Richman 1990).…”

Section: Resistência Aos Anti-retrovirais Nrtisunclassified

Avaliação da resistência do HIV-1 às drogas anti-retrovirais em 150 pacientes em interrupção terapêutica por mais de seis meses

Kalmar¹

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Zidovudine Resistance Reverse Transcriptase Mutations during Didanosine Monotherapy

Cited by 11 publications

References 0 publications

Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years

Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years

HIV Drug Resistance

Avaliação da resistência do HIV-1 às drogas anti-retrovirais em 150 pacientes em interrupção terapêutica por mais de seis meses

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