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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Unique

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.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: June 17, 2011
• First Submitted That Met QC Criteria: June 22, 2011
• First Posted (Estimate): June 23, 2011

Study Record Updates

• Last Update Posted (Actual): November 14, 2019
• Last Update Submitted That Met QC Criteria: November 11, 2019
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: HIV; PBMC; TROPISM; GENOTYPE; 454 SEQUENCING
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Viremia
• Other Study ID Numbers: PROTEST