Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G

Abecasis, Ana; Deforche, Koen; Snoeck, Joke; Bacheler, Lee T.; McKenna, Paula; Carvalho, Ana Patrícia; Gómes, Perpétua; Camacho, Ricardo Jorge; Vandamme, Anne‐Mieke

doi:10.1097/01.aids.0000188422.95162.b7

Cited by 76 publications

(53 citation statements)

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“…Recent analyses suggest that non-B viruses can develop specific mutations that differ from those identified in subtype B under the same treatment pressure (1,20). For example, in CRF01_AE but not in subtype B viruses, V75M seems to be significantly associated with stavudine treatment (2) and, in subtype C but not in subtype B, V106M is a signature substitution of patients treated with efavirenz (4).…”

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confidence: 99%

Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent

Snoeck

Kantor

Shafer

et al. 2006

Antimicrob Agents Chemother

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The major limitation of drug resistance genotyping for human immunodeficiency virus remains the interpretation of the results. We evaluated the concordance in predicting therapy response between four different interpretation algorithms (Rega 6.3, HIVDB-08/04, ANRS [07/04], and VGI 8.0). Sequences were gathered through a worldwide effort to establish a database of non-B subtype sequences, and demographic and clinical information about the patients was gathered. The most concordant results were found for nonnucleoside reverse transcriptase (RT) inhibitors (93%), followed by protease inhibitors (84%) and nucleoside RT inhibitor (NRTIs) (76%). For therapy-naive patients, for nelfinavir, especially for subtypes C and G, the discordances were driven mainly by the protease (PRO) mutational pattern 82I/V ؉ 63P ؉ 36I/V for subtype C and 82I ؉ 63P ؉ 36I ؉ 20I for subtype G. Subtype F displayed more discordances for ritonavir in untreated patients due to the combined presence of PRO 20R and 10I/V. In therapy-experienced patients, subtype G displayed a lot of discordances for saquinavir and indinavir due to mutational patterns involving PRO 90 M and 82I. Subtype F had more discordance for nelfinavir attributable to the presence of PRO 88S and 82A ؉ 54V. For the NRTIs lamivudine and emtricitabine, CRF01_AE had more discordances than subtype B due to the presence of RT mutational patterns 65R ؉ 115 M and 118I ؉ 215Y, respectively. Overall, the different algorithms agreed well on the level of resistance scored, but some of the discordances could be attributed to specific (subtypedependent) combinations of mutations. It is not yet known whether therapy response is subtype dependent, but the advice given to clinicians based on a genotypic interpretation algorithm differs according to the subtype.Genotyping for the assessment of anti-human immunodeficiency virus (HIV) drug resistance is often used in the management of individual patient therapy. Currently, it is recommended in European as well as American guidelines (17,38). In several retrospective and prospective studies, genotyping proved beneficial in optimizing treatment for individual patients (5,10,16,23,25,31,37).Although genotyping is commonly used, there are still many uncertainties with respect to the value of genotype in the assignment of a new regimen. The current genotypic assays are not always able to report all drug resistance mutations among non-B subtypes (11,18,19,24). Regardless of subtype, genotyping is not sensitive to mutations that are present as a minor variant in the population (22,40). Genotyping results also differ depending on the laboratory where they are performed. Quality control studies indicate that mutations, even present as a pure variant, are often underestimated (32).However, separate from the quality and sensitivity issues, the interpretation of genotypic results is still not standardized.

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Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent

Snoeck

Kantor

Shafer

et al. 2006

Antimicrob Agents Chemother

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“…L89M was observed in two PI-naïve children with no evidence of PIs resistance. This mutation is a naturally occurring polymorphic substitution which may lead to early development of drug resistance in some infected patients (Abecasis et al 2005;Sanches et al 2007). On the other hand, the L89I mutation was reported in two children who were receiving RTVregimen and presented multi-drug viral resistance.…”

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Hiv-1 Drug Resistance Assessment in Pediatric Patients

Simonetti¹,

Lima²,

Schatzmayr³

et al. 2009

VR&R

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Twenty-one vertically HIV-1 infected children were assessed for drug resistance genotyping. Eighteen children presented at least one mutation conferring resistance to the nucleoside reverse transcriptase inhibitors, and seven children presented resistance to the non-nucleoside inhibitors. Among them, two children in whom the therapy had been discontinued two to three years before testing presented K101E, K103N, and G190A mutations conferring resistance to all the non-nucleoside drugs available for treatment. Protease gene mutations conferring resistance to at least two to up to twelve drugs were reported in 12 children. Studies in HIV-infected children have a particular meaning, and with antiretroviral therapy becoming more widely available, surveillance of viral resistance regional levels is relevant for treatment guidelines, supporting the rational use of antiretroviral drugs by treatment programs. Additional larger studies are still required to give more information on HIV-1 drug resistance in pediatric patients.

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“…Several studies have revealed novel mutations or differences in the prevalence of known mutations in non-B subtypes (1,3). Others have demonstrated the impact of the genetic background on subtype dependencies in drug susceptibility and resistance development (2, 6, 7).…”

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Novel Recombinant Virus Assay for Measuring Susceptibility of Human Immunodeficiency Virus Type 1 Group M Subtypes To Clinically Approved Drugs

et al. 2009

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, and CRF12-13) and displaying a viral load range of 200 to >500,000 RNA copies/ml was 97%. The drug susceptibility measurements, based on discrimination between infected and noninfected cells on a single-cell level by flow cytometry, were reproducible, with coefficients of variation for resistance ranging from 7% to 31%, and were consistent with scientific literature in terms of magnitude and specificity.Despite continued improvements in treatment of human immunodeficiency virus type 1 (HIV-1)-infected patients, therapy failure still occurs, often leading to drug resistance development, which necessitates a change in regimen. At this moment, clinicians have at their disposal 22 drugs, targeting the viral protease (PR), the reverse transcriptase (RT), the integrase (IN), the transmembrane glycoprotein (gp41), or the interaction between the surface glycoprotein (gp120) and the cellular coreceptor CCR5. The choice of which drugs to include in the next regimen is based upon the likelihood of the drugs being active against the mutant virus present in the patient with incomplete suppression of replication (11).Currently, genotypic drug resistance testing is used more frequently within the clinical setting of patient follow-up due to practical reasons, such as a shorter turnaround time, easier implementation within laboratories, and lower cost, but also due to the fact that no clinical trial has yet provided sufficient evidence for supporting phenotypic over genotypic drug resistance testing. Nevertheless, the interpretation of genotypic drug resistance testing can be very complex, which makes phenotypic drug resistance testing in certain settings very useful and even necessary (48).Increasing numbers of drug resistance mutations have been identified within gag, pol, and env, reflecting the genetic flexibility of HIV-1. These mutations can directly boost the ability of the virus to specifically replicate in the presence of the drug (major mutations) or indirectly aid the virus by increasing its replication capacity in general, whether in the presence or absence of the drug (minor or compensatory mutations). In general, the major mutations are found at the drug binding sites within the targeted protein (or the viral protein that interacts with the cellular target), whereas the others can be found at distinct sites within the target protein or even other proteins. In this respect, PR inhibitor (PI) mutations have been observed not only within the PR but also at several sites within its Gag substrate (13,28).The use of genotypic data to determine if certain drugs are still active against patient-derived virus is further complicated by the presence of natural polymorphisms in non-B strains and by baseline subtype-dependent combinations of mutations that occur during treatment, leading to discordances between different interpretation algorithms (43,51). Several studies have revealed novel mutations or differences in the prevalence of known mutations in non-B subtypes (1, 3). Others have demonstrated the impact of the genet...

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Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G

Abstract: The results of the present study show that M89I/V is associated with PI experience in subtypes C, F and G but not in subtype B. M89I/V should be considered a secondary PI mutation with an important effect on nelfinavir susceptibility in the presence of L90M.

Cited by 76 publications

References 17 publications

Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent

Discordances between Interpretation Algorithms for Genotypic Resistance to Protease and Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Are Subtype Dependent

Hiv-1 Drug Resistance Assessment in Pediatric Patients

Novel Recombinant Virus Assay for Measuring Susceptibility of Human Immunodeficiency Virus Type 1 Group M Subtypes To Clinically Approved Drugs

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