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GePheRal: Clinical Validation of the Genotypic Diagnosis of Hiv-1 Resistance to Raltegravir by Parallel Analysis of the Genotype and Phenotype Profiles of Resistance

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified February 2013 by Elisabetta Carini, Università Vita-Salute San Raffaele.
Recruitment status was:  Recruiting
Sponsor:
ClinicalTrials.gov Identifier:
NCT01381328
First Posted: June 27, 2011
Last Update Posted: February 11, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
IRCCS San Raffaele
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Elisabetta Carini, Università Vita-Salute San Raffaele
  Purpose
The purpose of this study is to correlate the different patterns of resistance mutations observed in vivo in patients failing RAL treatment with the fold-change resistance determined by the phenotypic assay.

Condition
HIV-1 Infected Patients Fold-change Resistance Resistance Mutations

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: GePheRal: Clinical Validation of the Genotypic Diagnosis of Hiv-1 Resistance to Raltegravir by Parallel Analysis of the Genotype and Phenotype Profiles of Resistance

Resource links provided by NLM:


Further study details as provided by Elisabetta Carini, Università Vita-Salute San Raffaele:

Primary Outcome Measures:
  • - mean value of fold-change resistance determined by the phenotypic assay at baseline [ Time Frame: baseline ]

Secondary Outcome Measures:
  • changes of fold-change resistance determined by the phenotypic assay with respect to baseline. [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation ]
  • genetic changes under continuous drug pressure or drug discontinuation with respect to baseline(dynamics of the reversion of resistance mutations) [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation. ]
  • changes of the replication capacity with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation. ]
  • changes of HIV-RNA with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation ]
  • changes in CD4, CD4%, CD8, CD8% with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation ]

Biospecimen Retention:   Samples Without DNA
whole blood

Estimated Enrollment: 100
Study Start Date: December 2011
Estimated Study Completion Date: September 2013
Estimated Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
RAL Group
HIV-1 infected patients failing to a RALTEGRAVIR-containing regimen

Detailed Description:

The secondary objectives are, as follows:

  • to establish standardised genotypic assay for the HIV-1 pol gene region (region of interest, sensitivity, mutations involved as primary or compensatory changes, role of polymorphism present at baseline).
  • to reach consensus on the algorithm interpretation of in house ex-vivo genotypic evaluations.
  • to assess the genetic changes in RAL-failing patients under continuous drug pressure or drug discontinuation (dynamics of the reversion of resistance mutations).
  • to evaluate in RAL resistant HIV-1 variants the changes in replication capacity (RC) (baseline vs. following-timepoints).
  • to evaluate the immunological and virological trend associated with a raltegravir-regimen failure.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
primary care clinic
Criteria

Inclusion Criteria:

  • Adult (at least 18 years of age) treatment-experienced, HIV-infected subjects of either sex and of any race, failing to a RAL-containing regimen will be enrolled in the study

Exclusion Criteria:

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01381328


Contacts
Contact: Antonella Castagna, MD 0039022643 ext 7934 castagna.antonella@hsr.it
Contact: Elisabetta Carini, Msc 0039022643 ext 7934 carini.elisabetta@hsr.it

Locations
Italy
Department of Infectious Diseases, IRCCS San Raffaele Hospital Recruiting
Milan, Italy, 20127
Contact: Antonella Castagna, MD    0039022643 ext 7934    castagna.antonella@hsr.it   
Contact: Elisabetta Carini, MSc    0039022643 ext 7934    carini.elisabetta@hsr.it   
Principal Investigator: Antonella Castagna, MD         
Principal Investigator: Massimo Clementi, Prof.         
Sponsors and Collaborators
Università Vita-Salute San Raffaele
IRCCS San Raffaele
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Massimo Clementi, Prof. University Vita-Salute San Raffaele Laboratory of Microbiology and Virology
Study Director: Antonella Castagna, MD Department of Infectious Diseases, IRCCS San Raffaele Hospital
  More Information

Publications:
Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell. 1991 Dec 20;67(6):1211-21.
Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov. 2005 Mar;4(3):236-48. Review.
Anker M, Corales RB. Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection. Expert Opin Investig Drugs. 2008 Jan;17(1):97-103. Review.
Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-9.
Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Teppler H, Nguyen BY; BENCHMRK Study Teams. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008 Jul 24;359(4):355-65. doi: 10.1056/NEJMoa0708978.
Canducci F, Sampaolo M, Marinozzi MC, Boeri E, Spagnuolo V, Galli A, Castagna A, Lazzarin A, Clementi M, Gianotti N. Dynamic patterns of human immunodeficiency virus type 1 integrase gene evolution in patients failing raltegravir-based salvage therapies. AIDS. 2009 Feb 20;23(4):455-60. doi: 10.1097/QAD.0b013e328323da60.
Nakahara K, Wakasa-Morimoto C, Kobayashi M, Miki S, Noshi T, Seki T, Kanamori-Koyama M, Kawauchi S, Suyama A, Fujishita T, Yoshinaga T, Garvey EP, Johns BA, Foster SA, Underwood MR, Sato A, Fujiwara T. Secondary mutations in viruses resistant to HIV-1 integrase inhibitors that restore viral infectivity and replication kinetics. Antiviral Res. 2009 Feb;81(2):141-6. doi: 10.1016/j.antiviral.2008.10.007. Epub 2008 Nov 21.
Kobayashi M, Nakahara K, Seki T, Miki S, Kawauchi S, Suyama A, Wakasa-Morimoto C, Kodama M, Endoh T, Oosugi E, Matsushita Y, Murai H, Fujishita T, Yoshinaga T, Garvey E, Foster S, Underwood M, Johns B, Sato A, Fujiwara T. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antiviral Res. 2008 Nov;80(2):213-22. doi: 10.1016/j.antiviral.2008.06.012. Epub 2008 Jul 14.
Ceccherini-Silberstein F, Malet I, D'Arrigo R, Antinori A, Marcelin AG, Perno CF. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev. 2009 Jan-Mar;11(1):17-29. Review.
Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF, Katlama C, Calvez V, Marcelin AG. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother. 2008 Apr;52(4):1351-8. doi: 10.1128/AAC.01228-07. Epub 2008 Jan 28.
Menzo S, Monachetti A, Balotta C, Corvasce S, Rusconi S, Paolucci S, Baldanti F, Bagnarelli P, Clementi M. Processivity and drug-dependence of HIV-1 protease: determinants of viral fitness in variants resistant to protease inhibitors. AIDS. 2003 Mar 28;17(5):663-71.
Sichtig N, Sierra S, Kaiser R, Däumer M, Reuter S, Schülter E, Altmann A, Fätkenheuer G, Dittmer U, Pfister H, Esser S. Evolution of raltegravir resistance during therapy. J Antimicrob Chemother. 2009 Jul;64(1):25-32. doi: 10.1093/jac/dkp153. Epub 2009 May 14.
Malet I, Delelis O, Soulie C, Wirden M, Tchertanov L, Mottaz P, Peytavin G, Katlama C, Mouscadet JF, Calvez V, Marcelin AG. Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients. J Antimicrob Chemother. 2009 Apr;63(4):795-804. doi: 10.1093/jac/dkp014. Epub 2009 Feb 16.

Responsible Party: Elisabetta Carini, Professor Massimo Clementi, Università Vita-Salute San Raffaele
ClinicalTrials.gov Identifier: NCT01381328     History of Changes
Other Study ID Numbers: Gepheral
Merck Sharp & Dohme Corp. ( Other Identifier: Merck Sharp & Dohme Corp. )
First Submitted: June 23, 2011
First Posted: June 27, 2011
Last Update Posted: February 11, 2013
Last Verified: February 2013

Keywords provided by Elisabetta Carini, Università Vita-Salute San Raffaele:
HIV-1 infected patients
RALTEGRAVIR regimen
genotypic evaluations
phenotypic evaluations

Additional relevant MeSH terms:
Raltegravir Potassium
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action


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