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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Use Of Genotypic HIV-1 Tropism Testing In Proviral DNA To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia

Conditions
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HIV

Intervention / Treatment
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* Drug: Unique


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected patients. Age 18 or more. 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) Patients receiving stable antiretroviral treatment for at least 6 months. Viral load under 50 copies/mL in the last 6 months Patients with CCR5 tropism based in V3 genotyping in proviral DNA using the G2P with a false positive rate of 10% interpretation method. A change of treatment is needed due to toxicity / tolerability problems with the 3rd drug (PI, NNRTI or ININ), according to investigator criteria. An antiretroviral regimen containing a CCR5-antagonist is suitable for the patient (physician criteria). Voluntary written informed consent. Exclusion Criteria: Pregnancy or breast-feeding. Patient previously treated with maraviroc. Patients with documented resistance to maraviroc or any other drug considered for the new ARV regimen. Viral failure in the moment of inclusion. Bad adherence history or anticipated (investigator criteria).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Change of 3rd drug to maraviroc<br>Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc) | Drug: Unique<br>* Change of PI, NNRTI or integrase inhibitor to CCR5 antagonist (maraviroc)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with viral load under 50 copies/mL |  | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients without confirmed virological failure. | To evaluate other aspects related to maintanence of virological response. | Up to week 48 | 
| Time to loss of virological response (TLOVR) < 200 copies/mL | To evaluate other aspects related to maintanence of virological response. | Up to week 48 | 
| Time to loss of virological response (TLOVR) < 50 copies/mL | To evaluate other aspects related to maintanence of virological response. | Up to week 48 | 
| Proportion of patients treated with maraviroc with viral load under 50 copies/mL | To evaluate other aspects related to maintanence of virological response | Week 12 | 
| Proportion of patients treated with maraviroc with viral load under 50 copies/mL | To evaluate other aspects related to maintanence of virological response | Week 24 | 
| Proportion of patients treated with maraviroc with viral load under 50 copies/mL | To evaluate other aspects related to maintanence of virological response | Week 36 | 
| Proportion of patients treated with maraviroc with viral load under 50 copies/mL | To evaluate other aspects related to maintanence of virological response. | Week 48 | 
| Time to treatment discontinuation, overall, and due to factors other than loss of virological response | To evaluate other aspects related to maintanence of virological response | Up to week 48 | 
| Association between pre-treatment level of X4 viruses detected by deep sequencing at screening and virological response to maraviroc based therapy at week 48. | To evaluate changes in HIV tropism | Week 48 | 
| Level of X4 viruses by detected by population sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Screening (up to 48 weeks) | 
| Level of X4 viruses by detected by population sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Week 12 | 
| Level of X4 viruses by detected by population sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Week 48 | 
| Level of X4 viruses by detected by deep sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Screening (up to 48 weeks) | 
| Level of X4 viruses by detected by deep sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Week 12 | 
| Level of X4 viruses by detected by deep sequencing. | Evolution of viral tropism in PBMC-associated DNA by population and deep sequencing between screening and week 48 in subjects treated with maraviroc. | Week 48 | 
| High-resolution assessment of virus diversity and X4 level using deep sequencing | High-resolution assessment of virus diversity and X4 level using deep sequencing at week 12 and at the time of virological failure. | Week 12 | 
| High-resolution assessment of virus diversity and X4 level using deep sequencing | High-resolution assessment of virus diversity and X4 level using deep sequencing at week 12 and at the time of virological failure. | In case of virological failure (week 12 up to virological failure) | 
| Median change of total cholesterol. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From baseline to week 48. | 
| Median change of HDL cholesterol. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of LDL cholesterol. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of triglycerides | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of AST serum levels. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of ALT serum levels. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of alkaline phosphatase serum levels. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Median change of total bilirubin serum levels. | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | From Baseline to week 48. | 
| Cumulative number of adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 4 | 
| Cumulative number of adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 12 | 
| Cumulative number of adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 24 | 
| Cumulative number of adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 36 | 
| Cumulative number of adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 48 | 
| Cumulative number of grade 3-4 adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 4 | 
| Cumulative number of grade 3-4 adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 12 | 
| Cumulative number of grade 3-4 adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 24 | 
| Cumulative number of grade 3-4 adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 36 | 
| Cumulative number of grade 3-4 adverse events | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Week 48 | 
| Proportion of patients withdrawn from the study and reason for study withdrawal | To evaluate the tolerability and safety with CCR5 antagonist containing regimen | Up to week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, TROPISM, PBMC, GENOTYPE, 454 SEQUENCING