Genotypic Tropism Testing In Proviral Dna To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Fundacio Lluita Contra la SIDA
ClinicalTrials.gov Identifier:
NCT01378910
First received: June 17, 2011
Last updated: July 2, 2014
Last verified: July 2014
  Purpose

CCR5 antagonists might be an adequate alternative for HIV-1-infected individuals with suppressed viremia who experience antiretroviral-related toxicity. The assessment of HIV-1 tropism in proviral DNA could be helpful to inform in which of these subjects CCR5 antagonists could be efficacious.


Condition Intervention Phase
HIV
Drug: Unique
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Use Of Genotypic HIV-1 Tropism Testing In Proviral DNA To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia

Resource links provided by NLM:


Further study details as provided by Fundacio Lluita Contra la SIDA:

Primary Outcome Measures:
  • Percentage of patients with viral load under 50 copies/mL [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Percentage of patients without confirmed virological failure. [ Time Frame: Up to week 48 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response.

  • Time to loss of virological response (TLOVR) < 200 copies/mL [ Time Frame: Up to week 48 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response.

  • Time to loss of virological response (TLOVR) < 50 copies/mL [ Time Frame: Up to week 48 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response.

  • Proportion of patients treated with maraviroc with viral load under 50 copies/mL [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response

  • Proportion of patients treated with maraviroc with viral load under 50 copies/mL [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response

  • Proportion of patients treated with maraviroc with viral load under 50 copies/mL [ Time Frame: Week 36 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response

  • Proportion of patients treated with maraviroc with viral load under 50 copies/mL [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response.

  • Time to treatment discontinuation, overall, and due to factors other than loss of virological response [ Time Frame: Up to week 48 ] [ Designated as safety issue: No ]
    To evaluate other aspects related to maintanence of virological response

  • Association between pre-treatment level of X4 viruses detected by deep sequencing at screening and virological response to maraviroc based therapy at week 48. [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    To evaluate changes in HIV tropism

  • Level of X4 viruses by detected by population sequencing. [ Time Frame: Screening (up to 48 weeks) ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • Level of X4 viruses by detected by population sequencing. [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • Level of X4 viruses by detected by population sequencing. [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • Level of X4 viruses by detected by deep sequencing. [ Time Frame: Screening (up to 48 weeks) ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • Level of X4 viruses by detected by deep sequencing. [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • Level of X4 viruses by detected by deep sequencing. [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc.

  • High-resolution assessment of virus diversity and X4 level using deep sequencing [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    High-resolution assessment of virus diversity and X4 level using deep sequencing at week 12 and at the time of virological failure.

  • High-resolution assessment of virus diversity and X4 level using deep sequencing [ Time Frame: In case of virological failure (week 12 up to virological failure) ] [ Designated as safety issue: No ]
    High-resolution assessment of virus diversity and X4 level using deep sequencing at week 12 and at the time of virological failure.

  • Median change of total cholesterol. [ Time Frame: From baseline to week 48. ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of HDL cholesterol. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of LDL cholesterol. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of triglycerides [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of AST serum levels. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: No ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of ALT serum levels. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: No ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of alkaline phosphatase serum levels. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: No ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Median change of total bilirubin serum levels. [ Time Frame: From Baseline to week 48. ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of adverse events [ Time Frame: Week 4 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of adverse events [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of adverse events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of adverse events [ Time Frame: Week 36 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of adverse events [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of grade 3-4 adverse events [ Time Frame: Week 4 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of grade 3-4 adverse events [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of grade 3-4 adverse events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of grade 3-4 adverse events [ Time Frame: Week 36 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Cumulative number of grade 3-4 adverse events [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen

  • Proportion of patients withdrawn from the study and reason for study withdrawal [ Time Frame: Up to week 48 ] [ Designated as safety issue: Yes ]
    To evaluate the tolerability and safety with CCR5 antagonist containing regimen


Enrollment: 74
Study Start Date: June 2011
Study Completion Date: May 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Change of 3rd drug to maraviroc
Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc)
Drug: Unique
Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc)

Detailed Description:

The assessment of HIV-1 tropism is needed before starting treatment with a CCR5-antagonist. Several phenotypic and genotyping tropism tests have been developed in the recent years. Phenotypic assays (i.e. TrofileTM and ES-TrofileTM) have been used.in most clinical trials. Genotypic tropism testing, however, is easier, cheaper and faster than phenotypic methods, and can be performed in a local HIV laboratories.

Viral RNA amplification is difficult in subjects with HIV-1 RNA levels <500-1000 copies/mL. In these cases, the optimal source of genetic material is peripheral blood mononuclear cell (PBMC)-associated proviral DNA. Whereas genotypic tropism testing in proviral DNA is technically feasible, it has not been validated as a tool to predict sustained virological response to CCR5-antagonist therapy in subjects with undetectable viremia.

As of today, maraviroc is the only CCR5-antagonist approved for HIV treatment. It has few drug interactions and a good security profile, particularly in terms of lipid and glucose metabolism. Therefore, it might be an adequate alternative for HIV-1-infected individuals with suppressed viremia who experience antiretroviral-related toxicity or metabolic problems.

This study will evaluate 48-week virological outcomes in aviremic subjects with an R5 virus by proviral genotypic tropism testing who switch the "third drug" of their regimen to maraviroc.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. HIV-1 infected patients.
  2. Age 18 or more.
  3. Antiretroviral treatment containing 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) plus 1 Non-nucleoside reverse-transcriptase inhibitor (NNRTI) or 1 protease inhibitor (PI) or 1 integrase inhibitor (ININ)
  4. Patients receiving stable antiretroviral treatment for at least 6 months.
  5. Viral load under 50 copies/mL in the last 6 months
  6. Patients with CCR5 tropism based in V3 genotyping in proviral DNA using the G2P with a false positive rate of 10% interpretation method.
  7. A change of treatment is needed due to toxicity / tolerability problems with the 3rd drug (PI, NNRTI or ININ), according to investigator criteria.
  8. An antiretroviral regimen containing a CCR5-antagonist is suitable for the patient (physician criteria).
  9. Voluntary written informed consent.

Exclusion Criteria:

  1. Pregnancy or breast-feeding.
  2. Patient previously treated with maraviroc.
  3. Patients with documented resistance to maraviroc or any other drug considered for the new ARV regimen.
  4. Viral failure in the moment of inclusion.
  5. Bad adherence history or anticipated (investigator criteria).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01378910

Locations
Spain
Hospital Xeral de Vigo
Santiago de Compostela, A Coruña, Spain, 15781
Hospital de Elche
Elche, Alicante, Spain, 03203
Hospital Son Espases
Palma de Mallorca, Baleares, Spain, 07011
H. U. Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
H. de Bellvitge
Hospitalet de Llobregat, Barcelona, Spain, 08907
Hospital U. Marqués de Valdecilla
Santander, Cantabria, Spain, 39011
Hospital Sta. Lucía/ H. Sta. Mª del Rosell
Cartagena, Murcia, Spain, 30203
Hospital General de Castellón
Castellón, Valencia, Spain, 12004
Hospital de Cruces
Bilbao, Vizcaya, Spain, 48903
Hospital Gral. U. de Alicante
Alicante, Spain, 03010
Hospital Vall d'Hebron
Barcelona, Spain, 08035
Hospital de Mataró
Barcelona, Spain, 08304
Hospital Virgen de las Nieves
Granada, Spain, 18014
Hospital U. San Cecilio
Granada, Spain, 28012
Hospital Carlos III
Madrid, Spain, 28029
Hospital Ramón y Cajal
Madrid, Spain, 28034
Hospital Clínico San Carlos
Madrid, Spain, 28040
Hospital U. Gregorio Marañón
Madrid, Spain, 28007
Hospital Reina Sofía de Murcia
Murcia, Spain, 30003
Hospital Sant Pau i Santa Tecla
Tarragona, Spain, 43007
Hospital Gral. U. de Valencia
Valencia, Spain, 46014
Hospital La Fe
Valencia, Spain, 46009
Hospital U. Dr. Peset
Valencia, Spain, 46017
Hospital Arnau de Vilanova
Valencia, Spain, 46015
Sponsors and Collaborators
Fundacio Lluita Contra la SIDA
  More Information

No publications provided

Responsible Party: Fundacio Lluita Contra la SIDA
ClinicalTrials.gov Identifier: NCT01378910     History of Changes
Other Study ID Numbers: PROTEST
Study First Received: June 17, 2011
Last Updated: July 2, 2014
Health Authority: Spain: Ministry of Health

Keywords provided by Fundacio Lluita Contra la SIDA:
HIV
TROPISM
PBMC
GENOTYPE
454 SEQUENCING

Additional relevant MeSH terms:
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014