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

HIV Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01378910
• Other study ID #: PROTEST
• Status: Completed
• Phase: Phase 4
• Start date: June 2011
• Est. completion date: May 2014

Study information

• Verified date: July 2014
• Source: Fundacio Lluita Contra la SIDA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: May 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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).

Related Conditions & MeSH terms

• HIV
• Viremia

Intervention

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

Locations

Country	Name	City	State
Spain	Hospital Gral. U. de Alicante	Alicante
Spain	H. U. Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital de Mataró	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital de Cruces	Bilbao	Vizcaya
Spain	Hospital Sta. Lucía/ H. Sta. Mª del Rosell	Cartagena	Murcia
Spain	Hospital General de Castellón	Castelló De La Plana	Castelló
Spain	Hospital de Elche	Elche	Alicante
Spain	Hospital U. San Cecilio	Granada
Spain	Hospital Virgen de las Nieves	Granada
Spain	H. de Bellvitge	Hospitalet de Llobregat	Barcelona
Spain	Hospital Carlos III	Madrid
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital U. Gregorio Marañón	Madrid
Spain	Hospital Reina Sofía de Murcia	Murcia
Spain	Hospital Son Espases	Palma de Mallorca	Baleares
Spain	Hospital U. Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Xeral de Vigo	Santiago de Compostela	A Coruña
Spain	Hospital Sant Pau i Santa Tecla	Tarragona
Spain	Hospital Arnau de Vilanova	Valencia
Spain	Hospital Gral. U. de Valencia	Valencia
Spain	Hospital La Fe	Valencia
Spain	Hospital U. Dr. Peset	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Fundacio Lluita Contra la SIDA

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients with viral load under 50 copies/mL		Week 48
Secondary	Percentage of patients without confirmed virological failure.	To evaluate other aspects related to maintanence of virological response.	Up to week 48
Secondary	Time to loss of virological response (TLOVR) < 200 copies/mL	To evaluate other aspects related to maintanence of virological response.	Up to week 48
Secondary	Time to loss of virological response (TLOVR) < 50 copies/mL	To evaluate other aspects related to maintanence of virological response.	Up to week 48
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Median change of total cholesterol.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From baseline to week 48.
Secondary	Median change of HDL cholesterol.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of LDL cholesterol.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of triglycerides	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of AST serum levels.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of ALT serum levels.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of alkaline phosphatase serum levels.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Median change of total bilirubin serum levels.	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	From Baseline to week 48.
Secondary	Cumulative number of adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 4
Secondary	Cumulative number of adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 12
Secondary	Cumulative number of adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 24
Secondary	Cumulative number of adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 36
Secondary	Cumulative number of adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 48
Secondary	Cumulative number of grade 3-4 adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 4
Secondary	Cumulative number of grade 3-4 adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 12
Secondary	Cumulative number of grade 3-4 adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 24
Secondary	Cumulative number of grade 3-4 adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 36
Secondary	Cumulative number of grade 3-4 adverse events	To evaluate the tolerability and safety with CCR5 antagonist containing regimen	Week 48
Secondary	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