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

Overview

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.

Full Title of Study: “Use Of Genotypic HIV-1 Tropism Testing In Proviral DNA To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Basic Science
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2014

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.

Interventions

  • Drug: Unique
    • Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc)

Arms, Groups and Cohorts

  • Experimental: Change of 3rd drug to maraviroc
    • Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc)

Clinical Trial Outcome Measures

Primary Measures

  • Percentage of patients with viral load under 50 copies/mL
    • Time Frame: Week 48

Secondary Measures

  • Percentage of patients without confirmed virological failure.
    • Time Frame: Up to week 48
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • To evaluate changes in HIV tropism
  • Level of X4 viruses by detected by population sequencing.
    • Time Frame: Screening (up to 48 weeks)
    • 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
    • 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
    • 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)
    • 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
    • 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
    • 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
    • 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)
    • 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.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Median change of HDL cholesterol.
    • Time Frame: From Baseline to week 48.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Median change of LDL cholesterol.
    • Time Frame: From Baseline to week 48.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Median change of triglycerides
    • Time Frame: From Baseline to week 48.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Median change of AST serum levels.
    • Time Frame: From Baseline to week 48.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Median change of ALT serum levels.
    • Time Frame: From Baseline to week 48.
    • 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.
    • 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.
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of adverse events
    • Time Frame: Week 4
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of adverse events
    • Time Frame: Week 12
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of adverse events
    • Time Frame: Week 24
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of adverse events
    • Time Frame: Week 36
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of adverse events
    • Time Frame: Week 48
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of grade 3-4 adverse events
    • Time Frame: Week 4
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of grade 3-4 adverse events
    • Time Frame: Week 12
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of grade 3-4 adverse events
    • Time Frame: Week 24
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of grade 3-4 adverse events
    • Time Frame: Week 36
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen
  • Cumulative number of grade 3-4 adverse events
    • Time Frame: Week 48
    • 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
    • To evaluate the tolerability and safety with CCR5 antagonist containing regimen

Participating in This Clinical Trial

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).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Fundacio Lluita Contra la SIDA
  • Provider of Information About this Clinical Study
    • Sponsor

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