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

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:

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Raltegravir Raltegravir potassium

U.S. FDA Resources

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

Primary Outcome Measures:

- mean value of fold-change resistance determined by the phenotypic assay at baseline [ Time Frame: baseline ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]
changes of the replication capacity with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation. ] [ Designated as safety issue: No ]
changes of HIV-RNA with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation ] [ Designated as safety issue: No ]
changes in CD4, CD4%, CD8, CD8% with respect to baseline [ Time Frame: 24 and 48 hours, W1, W2, W3 and W4 upon discontinuation ] [ Designated as safety issue: No ]

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

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
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:

none

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: 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

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.

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.

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. 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. 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. 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. 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. 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.
Study First Received:	June 23, 2011
Last Updated:	February 8, 2013
Health Authority:	Italy: Ethics Committee

Keywords provided by Università Vita-Salute San Raffaele:

HIV-1 infected patients
RALTEGRAVIR regimen
genotypic evaluations
phenotypic evaluations

ClinicalTrials.gov processed this record on May 16, 2013