Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in Spain

Puig, Teresa; Pérez‐Olmeda, Mayte; Rubio, Amalia; Ruiz, Lı́dia; Briones, Carlos; Franco, José M.; Gómez-Cano, M; Stuyver, Lieven; Zamora, Laura; Alvarez, Camilo; Leal, M; Clotet, Bonaventura; Soriano, Vincent

doi:10.1097/00002030-200004140-00012

Cited by 54 publications

(16 citation statements)

References 17 publications

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“…Nearly 80% of samples from treatment-experienced patients showed resistant genotypes at the pol gene, a rate similar to that reported in previous studies conducted with subjects whose antiretroviral treatment failed (6,7,15 Extensive polymorphisms were observed in the gag region throughout the p7, p1, and p6 proteins. However only four point mutations localized immediately upstream of the pol gene, in the cleavage sites, were more frequently found among treatment-experienced subjects ( Table 1).…”

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confidence: 86%

Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients

et al. 2003

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Resistance to antiretroviral agents often results from mutations within the human immunodeficiency virus (HIV) pol gene. Moreover, insertions within the p6 gag-pol region have recently been found to be involved with resistance to nucleoside analogs. Overall, we found that 21% of 156 specimens collected from HIV-infected individuals (17.6% from 74 drug-naive patients and 24.4% from 82 pretreated patients) harbored these insertions. Insertions around the KQE (Lys-Gln-Glu) motif were found in 12.2% of the pretreated patients but in none of the drug-naive subjects (P ‫؍‬ 0.002). In contrast, insertions around the PTAP (Prol-Thre-Ala-Prol) motif were seen at similar rates (ϳ15%) among drug-naive and pretreated patients, which supports the idea that they may be natural polymorphisms.

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confidence: 86%

Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients

et al. 2003

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“…However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).…”

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confidence: 99%

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Resch¹,

Parkin

Watkins

et al. 2005

J Virol

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We examined the population dynamics of human immunodeficiency virus type 1 pro variants during the evolution of resistance to the protease inhibitor ritonavir (RTV) in vivo. pro variants were followed in subjects who had added RTV to their previously failed reverse transcriptase inhibitor therapy using a heteroduplex tracking assay designed to detect common resistance-associated mutations. In most cases the initial variant appeared rapidly within 2 to 3 months followed by one or more subsequent population turnovers. Some of the subsequent transitions between variants were rapid, and some were prolonged with the coexistence of multiple variants. In several cases variants without resistance mutations persisted despite the emergence of new variants with an increasing number of resistance-associated mutations. Based on the rate of turnover of pro variants in the RTV-treated subjects we estimated that the mean fitness of newly emerging variants was increased 1.2-fold (range, 1.02 to 1.8) relative to their predecessors. A subset of pro genes was introduced into infectious molecular clones. The corresponding viruses displayed impaired replication capacity and reduced susceptibility to RTV. A subset of these clones also showed increased susceptibility to two nonnucleoside reverse transcriptase inhibitors and the protease inhibitor saquinavir. Finally, a significant correlation between the reduced replication capacity and reduced processing at the gag NC-p1 processing site was noted. Our results reveal a complexity of patterns in the evolution of resistance to a protease inhibitor. In addition, these results suggest that selection for resistance to one protease inhibitor can have pleiotropic effects that can affect fitness and susceptibility to other drugs.Protease inhibitors (PIs) potently inhibit human immunodeficiency virus type 1 (HIV-1) replication, and their initial introduction into combination antiretroviral therapy was associated with a significant decrease of HIV-1-associated mortality and morbidity (41, 45). However, in clinical practice, virologic failure of protease inhibitor-containing therapy occurs in a significant fraction of the treated population (19,22,42,46,52,70). Virologic failure of protease inhibitor treatment is often due to the selection of HIV-1 strains with mutations in the pro gene, which encodes the viral protease (PR), and in specific protease cleavage sites encoded in the gag gene that collectively confer reduced drug susceptibility to the harboring strain (11,12,28,36,43,47,72).The resistance mutations are hypothesized to be largely preexisting, generated by the highly error-prone and rapid replication of HIV-1 in large virus populations (5, 10, 57). However, in PI-naïve subjects, some critical resistance mutations cannot be detected or can only be detected at very low levels, suggesting that these mutations may confer a selective disadvantage relative to wild-type HIV-1 strains (3,18,25,32,34,63). Indeed, it has been shown that the catalytic efficiency of protease is reduced by PI resis...

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“…Cross-sectional drug resistance surveys have been performed in Spain over the last four years (4,5,11,12). The results of these studies have shown that the rate of genotypic resistance is above 70% for nucleoside analogues (NA) and 27% for protease inhibitors (PI) for subjects previously exposed to antiretroviral drugs.…”

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confidence: 99%

Rate of Virological Treatment Failure and Frequencies of Drug Resistance Genotypes among Human Immunodeficiency Virus-Positive Subjects on Antiretroviral Therapy in Spain

et al. 2002

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The knowledge of which drug-resistant human immunodeficiency virus (HIV) genotypes are the most prevalent in a community may be helpful for designing the best salvage regimens. A total of 540 individuals on antiretroviral therapy attending 18 different outclinics in Spain were examined in a cross-sectional study conducted during June 2000. The overall rate of virologic failure (>50 HIV RNA copies/ml) was 54%. Among the subjects showing treatment failure, 79% harbored resistant HIV genotypes, 77% showed resistance to nucleoside analogues, 53% showed resistance to protease inhibitors, and 42% showed resistance to nonnucleoside reverse transcriptase inhibitors. Overall, 78.5% of individuals harbored HIV strains which showed resistance to two or more drug classes. Moreover, nucleotide substitutions causing broad cross-resistance among compounds within each drug family were quite common. These findings suggest that drug resistance mutations are very prevalent among subjects who have experienced several treatment failures. Therefore, facilitating the arrival of compounds belonging to new drug classes should be considered a priority.

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Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in Spain

Cited by 54 publications

References 17 publications

Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients

Changes in the Human Immunodeficiency Virus p7-p1-p6 gag Gene in Drug-Naive and Pretreated Patients

Evolution of Human Immunodeficiency Virus Type 1 Protease Genotypes and Phenotypes In Vivo under Selective Pressure of the Protease Inhibitor Ritonavir

Rate of Virological Treatment Failure and Frequencies of Drug Resistance Genotypes among Human Immunodeficiency Virus-Positive Subjects on Antiretroviral Therapy in Spain

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