Evidence of Stavudine-Related Phenotypic Resistance Among Zidovudine-Pretreated HIV-1–Infected Subjects Receiving a Therapeutic Regimen of Stavudine Plus Lamivudine

Milazzo, Laura; Rusconi, Stefano; Testa, Letizia; S, La Seta-Catamancio; Galazzi, Morena; Kurtagic, Semir; Citterio, Paola; Gianotto, Marcio; Grassini, Anna; Adorni, Fulvio; D'Arminio-Monforte, Antonella; Galli, Massimo; Moroni, Mauro

doi:10.1097/00042560-199909010-00013

Cited by 9 publications

(4 citation statements)

References 13 publications

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“…Reversal of ZDV resistance has been observed in 40–60% of patients with M184V HIV [73], and phenotypic ZDV susceptibility has been observed to be restored both in vitro and in vivo . One in vitro study indicated that phenotypic resistance associated with ZDV mutations increased with the loss of M184V [74], and a further study of ZDV pretreated patients, randomized to receive either ZDV or d4T plus 3TC, found a decrease in ZDV IC 50 parallel to the emergence of M184V [75].…”

Section: Mechanisms That May Contribute To Residual 3tc Activity In Tmentioning

confidence: 99%

The impact of the M184V substitution in HIV‐1 reverse transcriptase on treatment response

et al. 2002

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The M184V mutation in the HIV-1 reverse transcriptase gene is primarily associated with rapid, high-level lamivudine (3TC) resistance. It has also been observed to arise under selective pressure by abacavir, to which it confers low-level resistance. Although the development of viral drug resistance remains a major concern in antiretroviral therapy, it is known that some immunological and clinical benefit can still be derived from highly active antiretroviral therapy (HAART) regimens despite resistance-associated virological failure. This residual benefit on a failing regimen is commonly attributed to the preservation of fitness-reducing protease inhibitor (PI) resistance mutations under continued drug pressure. However, fitness-reducing nucleoside reverse transcriptase inhibitor (NRTI) mutations may also contribute to the effect. M184V is both common in the treated population and fitness-reducing. A number of studies, both of dual nucleoside therapy and HAART, have noted a residual treatment effect for 3TC despite the assumed or observed presence of M184V and high-level phenotypic resistance. The speed and consistency with which this mutation is selected by 3TC under suboptimal viral suppression therefore makes M184V a particularly interesting model for further clinical studies on the association of drug resistance with ongoing treatment benefit. While fitness considerations are likely to be a major contributor to the clinical observations noted, there are a number of other potential mechanisms that may contribute to a continuing response to 3TC in the presence of M184V. These include the delay and reversal of zidovudine (ZDV) resistance, hypersensitization to other NRTIs, reduced reverse transcriptase (RT) processivity and a possible reduction in RT pyrophosphorolysis. The full impact of M184V on therapeutic prospects will require further elucidation; ideally, the risk/benefit of preserving this substitution would be investigated in randomized trials. However, existing data suggest that the presence of this mutation may preserve some benefit in spite of the loss of 3TC susceptibility which, with further study, may prove valuable.

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Section: Mechanisms That May Contribute To Residual 3tc Activity In Tmentioning

confidence: 99%

The impact of the M184V substitution in HIV‐1 reverse transcriptase on treatment response

et al. 2002

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“…The emergence of mutants resistant to d4T and ddI is a rare event, mainly described during monotherapy or prolonged virological therapy failure (5,12,14). Nonetheless, patients heavily pretreated with two NRTIs could have diminished virologic response to d4T-containing regimens (11).…”

Section: Discussionmentioning

confidence: 99%

Discordance between Genotypic and Phenotypic Drug Resistance Profiles in Human Immunodeficiency Virus Type 1 Strains Isolated from Peripheral Blood Mononuclear Cells

et al. 2002

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The aim of the study was to analyze the relationship between genotypic and phenotypic drug resistance profiles of human immunodeficiency virus type 1 (HIV-1) strains isolated from patients during doubleanalogue nucleoside therapy. A drug-resistant HIV strain was isolated from 20 out of 25 patients, with 16 (64%) subjects carrying a virus with multiple drug resistance mutations. The most frequent resistance mutations were M184V (18 isolates) and M41L (7 isolates). Discordance between the genotypic and phenotypic profile for at least one drug was detected in 16 out of 25 strains. Particularly, eight isolates had a discordant genotypicphenotypic resistance pattern for two drugs and one isolate had such a pattern for three drugs. A genotypic resistance pattern with a phenotypic sensitivity profile was detected in six isolates (four resistant to zidovudine and two resistant to lamivudine). On the other hand for several strains a genotypic pattern of sensitivity pattern to abacavir (10 strains), didanosine (7 strains), stavudine (3 strains), zidovudine (2 strains), and lamivudine (1 strain) with a phenotypic resistance profile was detected. After a follow-up period of 8 months, an impairment of virological and immunological parameters was detected only in subjects with an HIV-1 isolate with a phenotypic resistance profile in despite of the genotypic results. Predicting resistance phenotype from genotypic data has important limitations. Despite the low number of patients and the short follow-up period, this study suggests that during failing therapy with analogue nucleosides, a phenotypic analysis could be performed in spite of an HIV genotypic sensitivity pattern.Mutations in the human immunodeficiency virus (HIV) reverse transcriptase (RT) and protease genes are associated with reduced sensitivity to antiretroviral drugs (9, 15). Recently, two studies (3, 7) provided evidence that antiretroviral therapy adapted to genotypic resistance mutations gave moreeffective results than therapy adapted to treatment history in patients who failed combination regimens.Genotype-and phenotype-based assays are fundamentally different but yield complementary information. Phenotypic tests measure virus drug susceptibility, resulting from known or unknown resistance-related mutations and their interactions. Genotypic tests detect mutations in the viral genome that may be associated with decreased drug susceptibility.In previous studies, during primary HIV infection, in antiretroviral-naïve patients, discordance between genotypic and phenotypic drug resistance analyses has been described (4, 13). However, the clinical relevance of a large number of mutations has not been established. Moreover, the level of phenotypic resistance predictive of therapy failure is not known and is probably dependent on the drug or antiviral combinations used. Both phenotypic and genotypic resistance assays should be interpreted with an understanding of all issues surrounding the efficacy of antiretroviral medications such as pharmacokinetics and adherence, ...

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“…The P157S mutation, originally observed in a drug-resistant isolate of feline immunodeficiency virus, confers resistance to (Ϫ)-␤-2Ј,3Ј-dideoxy-3Ј-thiacytidine (lamivudine [3TC]) in both feline immunodeficiency virus and HIV-1 (61, 62). Mutation P157S or P157A is occasionally observed in RT sequences from patients receiving nucleoside analog therapy (15,43,46,52).Additional evidence for the role of motif B in substrate selectivity comes from biochemical studies of HIV-1 RT mutants. Specific substitutions at position Q151 affect nucleotide insertion fidelity, discrimination against rNTPs, and the incorporation of nucleotide analogs (10,23,28,33,54,74).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Hypersusceptibility to Substrate Analogs Conferred by Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Smith

Anderson

Preston

2006

J Virol

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Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) contains four structural motifs (A, B, C, and D) that are conserved in polymerases from diverse organisms. Motif B interacts with the incoming nucleotide, the template strand, and key active-site residues from other motifs, suggesting that motif B is an important determinant of substrate specificity. To examine the functional role of this region, we performed "random scanning mutagenesis" of 11 motif B residues and screened replication-competent mutants for altered substrate analog sensitivity in culture. Single amino acid replacements throughout the targeted region conferred resistance to lamivudine and/or hypersusceptibility to zidovudine (AZT). Substitutions at residue Q151 increased the sensitivity of HIV-1 to multiple nucleoside analogs, and a subset of these Q151 variants was also hypersusceptible to the pyrophosphate analog phosphonoformic acid (PFA). Other AZT-hypersusceptible mutants were resistant to PFA and are therefore phenotypically similar to PFA-resistant variants selected in vitro and in infected patients. Collectively, these data show that specific amino acid replacements in motif B confer broad-spectrum hypersusceptibility to substrate analog inhibitors. Our results suggest that motif B influences RT-deoxynucleoside triphosphate interactions at multiple steps in the catalytic cycle of polymerization.Conversion of viral RNA to double-stranded DNA by reverse transcriptase (RT) is a defining step in the retroviral life cycle (8) and a key target of therapy for human immunodeficiency virus type 1 (HIV-1) infection (17). The 66-kilodalton subunit of HIV-1 RT contains four motifs (A, B, C, and D) that are similarly arranged in all known structures of replicative DNA and RNA polymerases (21). Three additional structural elements, motifs E and F and premotif A, are also conserved among RTs and viral RNA-dependent RNA polymerases (4,21,45,76). Together, motifs A, B, C, and F and premotif A form a closely packed protein framework that positions the templating nucleotide, the primer terminus, and incoming deoxynucleoside triphosphate (dNTP) at the RT active site (Fig. 1A). Amino acid substitutions within this conserved core can affect dNTP insertion fidelity, susceptibility to nucleoside analogs, and/or discrimination against ribonucleoside triphosphates (rNTPs) during DNA synthesis (40,49,64,72). Thus, these motifs influence the stringency and specificity of substrate incorporation by RT.Motif B is of particular interest because of its central position in the RT core structure (Fig. 1) (12, 24). Motif B contacts the template strand, the incoming dNTP, and each of the other motifs in the core structure (premotif A and motifs A, C, and F) (Fig. 1A), including residues within these other motifs that are known to affect dNTP substrate recognition (Fig. 1B) (12, 24). The importance of motif B in substrate selection is evident from studies of HIV-1 mutants resistant to nucleoside analogs (49, 72). Two amino acid substitutions in motif B a...

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Evidence of Stavudine-Related Phenotypic Resistance Among Zidovudine-Pretreated HIV-1–Infected Subjects Receiving a Therapeutic Regimen of Stavudine Plus Lamivudine

Cited by 9 publications

References 13 publications

The impact of the M184V substitution in HIV‐1 reverse transcriptase on treatment response

The impact of the M184V substitution in HIV‐1 reverse transcriptase on treatment response

Discordance between Genotypic and Phenotypic Drug Resistance Profiles in Human Immunodeficiency Virus Type 1 Strains Isolated from Peripheral Blood Mononuclear Cells

Hypersusceptibility to Substrate Analogs Conferred by Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

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