Comparison of a Rule-Based Algorithm with a Phenotype-Based Algorithm for the Interpretation of HIV Genotypes in Guiding Salvage Regimens in HIV-Infected Patients by a Randomized Clinical Trial: The Mutations and Salvage Study

Gianotti, Nicola; Mondino, Vincenzo; Rossi, María Cristina; Chiesa, Elisabetta; Mezzaroma, Ivano; Ladisa, Nicoletta; Guaraldi, Giovanni; Torti, Carlo; Tarquini, Pierluigi; Castelli, P.; Carlo, Aldo Di; Boeri, Enzo; Keulen, Wilco; Kenna, Paula Mc; Lazzarin, Adriano

doi:10.1086/503568

Cited by 11 publications

(8 citation statements)

References 12 publications

(21 reference statements)

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“…This was a retrospective study. The patients had participated in the Mutations and Salvage (MUSA) study [Gianotti et al, 2006], in which only selected centers participated in sample collection. Human PBMCs from HIV1-positive individuals were cryopreserved.…”

Section: Samplesmentioning

confidence: 99%

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Expression levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapy

Turriziani

Gianotti

Falasca

et al. 2008

Journal of Medical Virology

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The aim of the study was to evaluate the mRNA expression of four relevant ABC-transporter genes [MDR1 (P-glycoprotein; Pgp), MRP1, MRP4, and MRP5] in HIV-positive individuals failing treatment and analyze the association between the levels of their expression and viral load, CD4 cell count, and therapeutic history. Ninety-eight HIV-positive samples and 20 samples from healthy donors were analyzed, retrospectively. Peripheral blood mononuclear cells (PBMCs) from HIV1-positive individuals were collected at the time of virological failure. Expression of mRNA of Pgp, MRP1, MRP4, and MRP5 in PBMCs was evaluated by real-time PCR. A high inter-individual variability was observed in both HIV-positive individuals and healthy donors but the expression levels of all mRNA analyzed were significantly higher in the HIV-infected group (P < 0.05). A weak but significant inverse correlation was observed between CD4 cell counts and expression levels of MRP4 and MRP5. Comparison of mRNA expression between individuals with different therapeutic histories showed that expression of MRP4 and MRP5 genes in patients who were both protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced was significantly higher than in patients who were PI experienced but NNRTI-naïve. In conclusion, the mRNA expression of Pgp, MRP1, MRP4, and MRP5 varies among HIV-infected patients and healthy donors but is significantly higher in HIV-positive patients than in donors. The expression of MRP4 and MRP5 seems to correlate with CD4 cell counts. The same protein seems to be overexpressed in patients receiving NNRTIs.

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Section: Samplesmentioning

confidence: 99%

“…In order to evaluate whether different therapeutic histories were associated with different mRNA transporter expression levels, samples were divided into three groups on the basis of their treatment history [Gianotti et al, 2006].…”

Section: Expression Of Abc-transporters and Therapeutic Historymentioning

confidence: 99%

Expression levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapy

Turriziani

Gianotti

Falasca

et al. 2008

Journal of Medical Virology

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“…Paired plasma and whole blood samples were collected from the first 80 patients participating in the Italian multicentric Mutations and Salvage (MuSa) Study [Gianotti et al, 2006]. The MuSa study was a randomized clinical trial which enrolled HIV-infected patients during virological failure at their first or second HAART regimen; the study compared a rule-based and a phenotypic-based algorithm for the interpretation of HIV genotypes to guide salvage regimens.…”

Section: Patientsmentioning

confidence: 99%

Antiretroviral genotypic resistance in plasma RNA and whole blood DNA in HIV‐1 infected patients failing HAART

Saracino

Gianotti

Marangi

et al. 2008

Journal of Medical Virology

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The extent to which HIV-1 proviral DNA mutations cause clinically relevant antiretroviral resistance is still controversial. Paired plasma HIV-1 RNA and whole blood DNA were compared in patients failing HAART to investigate if the additional knowledge of archived mutations could improve the selection of potentially active drugs. Seventy-three HIV-1-infected patients with first/second HAART failure were studied before starting a new regimen based on RNA genotyping. Follow-up data after a 12-week therapy were available. DNA genotyping was retrospectively performed on stored whole blood samples and mutational profiles were compared to those from RNA. The mean number of IAS pol mutations was significantly higher in RNA (4.45 +/- 2.76) than in DNA (2.88 +/- 2.47) (P < 0.001). DNA genotyping provided a 6% increase in detection of resistance-associated mutations. Among 64/73 patients showing discordant DNA/RNA profiles, 54 (84%) also differed for predicted active drugs. 16/73 (22%) patients had >or=1 mutation revealed by DNA genotyping alone, probably affecting therapy success in 2/16. However, neither RNA/DNA discordance nor detection of isolated DNA mutations were statistically associated with outcome. In conclusion, plasma RNA remains the elective choice for HIV genotyping in patients with therapy failure, even if the detection of proviral resistance-associated mutations, not simultaneously found in RNA, is a frequent event. Therefore, in some cases DNA plus RNA genotyping might assist in choosing more accurately subsequent antiretroviral regimens.

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“…Most studies have found a therapeutic advantage in terms of likelihood of viral suppression and mean virologic RNA reduction for resistance-test-guided treatments when compared to treatments based only on clinical judgment (DeGruttola et al, 2000;Durant et al, 1999;Gianotti et al, 2006;Ormaasen et al, 2004;Tural et al, 2002). Consequently, most international guidelines recommend resistance to assist the selection of therapeutic regimens following pharmacologic viral failure (DDHS, 2006Vandamme et al, 2004).…”

Section: Clinical Value Of Hiv Drug Resistance Testingmentioning

confidence: 99%

“…Common limitations for all resistance tests are inability to detect virus archived in viral reservoirs, insensitivity to viral quasispecies that represent less than 20% of the total viral mixture, and the requirement of a minimum viral load (500-1000 plasma HIV RNA copies/milliliters) for the test to be performed. Current methods appear to have similar performance at detecting antiretroviral resistance (Ferrer et al, 2003;Gianotti et al, 2006;Mazzotta et al, 2003;Saracino et al, 2004), but GART is more sensitive for minority populations than PART. Consequently, GART can detect sentinel mutations (e.g., M184V) before changes in phenotypic resistance become evident.…”

Section: Clinical Value Of Hiv Drug Resistance Testingmentioning

confidence: 99%

Antimicrobial Resistance and Implications for the Twenty-First Century

2008

Emerging Infectious Diseases of the 21st Century

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Comparison of a Rule-Based Algorithm with a Phenotype-Based Algorithm for the Interpretation of HIV Genotypes in Guiding Salvage Regimens in HIV-Infected Patients by a Randomized Clinical Trial: The Mutations and Salvage Study

Abstract: Both the virtual phenotype and rule-based interpretation methods of HIV genotyping can guide the selection of effective antiretroviral drugs for a salvage regimen.

Cited by 11 publications

References 12 publications

Expression levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapy

Expression levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapy

Antiretroviral genotypic resistance in plasma RNA and whole blood DNA in HIV‐1 infected patients failing HAART

Antimicrobial Resistance and Implications for the Twenty-First Century

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