Clinical trial NCT01378910: Genotypic Tropism Testing In Proviral Dna To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia
Official title: Use Of Genotypic HIV-1 Tropism Testing In Proviral DNA To Guide CCR5 Antagonist Treatment In Subjects With Undetectable HIV-1 Viremia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: HIV
TROPISM
PBMC
GENOTYPE
454 SEQUENCING
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Sponsor class: OTHER
First posted: 2011-06-23
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

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 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).

Primary outcomes:
measure: Percentage of patients with viral load under 50 copies/mL
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of patients without confirmed virological failure.
timeFrame: Up to week 48
measure: Time to loss of virological response (TLOVR) < 200 copies/mL
timeFrame: Up to week 48
measure: Time to loss of virological response (TLOVR) < 50 copies/mL
timeFrame: Up to week 48
measure: Proportion of patients treated with maraviroc with viral load under 50 copies/mL
timeFrame: Week 12
measure: Proportion of patients treated with maraviroc with viral load under 50 copies/mL
timeFrame: Week 24
measure: Proportion of patients treated with maraviroc with viral load under 50 copies/mL
timeFrame: Week 36
measure: Proportion of patients treated with maraviroc with viral load under 50 copies/mL
timeFrame: Week 48
measure: Time to treatment discontinuation, overall, and due to factors other than loss of virological response
timeFrame: Up to week 48
measure: Association between pre-treatment level of X4 viruses detected by deep sequencing at screening and virological response to maraviroc based therapy at week 48.
timeFrame: Week 48
measure: Level of X4 viruses by detected by population sequencing.
timeFrame: Screening (up to 48 weeks)
measure: Level of X4 viruses by detected by population sequencing.
timeFrame: Week 12
measure: Level of X4 viruses by detected by population sequencing.
timeFrame: Week 48
measure: Level of X4 viruses by detected by deep sequencing.
timeFrame: Screening (up to 48 weeks)
measure: Level of X4 viruses by detected by deep sequencing.
timeFrame: Week 12
measure: Level of X4 viruses by detected by deep sequencing.
timeFrame: Week 48
measure: High-resolution assessment of virus diversity and X4 level using deep sequencing
timeFrame: Week 12
measure: High-resolution assessment of virus diversity and X4 level using deep sequencing
timeFrame: In case of virological failure (week 12 up to virological failure)
measure: Median change of total cholesterol.
timeFrame: From baseline to week 48.
measure: Median change of HDL cholesterol.
timeFrame: From Baseline to week 48.
measure: Median change of LDL cholesterol.
timeFrame: From Baseline to week 48.
measure: Median change of triglycerides
timeFrame: From Baseline to week 48.
measure: Median change of AST serum levels.
timeFrame: From Baseline to week 48.
measure: Median change of ALT serum levels.
timeFrame: From Baseline to week 48.
measure: Median change of alkaline phosphatase serum levels.
timeFrame: From Baseline to week 48.
measure: Median change of total bilirubin serum levels.
timeFrame: From Baseline to week 48.
measure: Cumulative number of adverse events
timeFrame: Week 4
measure: Cumulative number of adverse events
timeFrame: Week 12
measure: Cumulative number of adverse events
timeFrame: Week 24
measure: Cumulative number of adverse events
timeFrame: Week 36
measure: Cumulative number of adverse events
timeFrame: Week 48
measure: Cumulative number of grade 3-4 adverse events
timeFrame: Week 4
measure: Cumulative number of grade 3-4 adverse events
timeFrame: Week 12
measure: Cumulative number of grade 3-4 adverse events
timeFrame: Week 24
measure: Cumulative number of grade 3-4 adverse events
timeFrame: Week 36
measure: Cumulative number of grade 3-4 adverse events
timeFrame: Week 48
measure: Proportion of patients withdrawn from the study and reason for study withdrawal
timeFrame: Up to week 48
Other outcomes:
Locations:
city: Santiago de Compostela
country: Spain
facility: Hospital Xeral de Vigo
state: A Coruña
city: Elche
country: Spain
facility: Hospital de Elche
state: Alicante
city: Palma de Mallorca
country: Spain
facility: Hospital Son Espases
state: Baleares
city: Badalona
country: Spain
facility: H. U. Germans Trias i Pujol
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: H. de Bellvitge
state: Barcelona
city: Santander
country: Spain
facility: Hospital U. Marqués de Valdecilla
state: Cantabria
city: Castelló De La Plana
country: Spain
facility: Hospital General de Castellón
state: Castelló
city: Cartagena
country: Spain
facility: Hospital Sta. Lucía/ H. Sta. Mª del Rosell
state: Murcia
city: Bilbao
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Alicante
country: Spain
facility: Hospital Gral. U. de Alicante
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital de Mataró
city: Granada
country: Spain
facility: Hospital Virgen de las Nieves
city: Granada
country: Spain
facility: Hospital U. San Cecilio
city: Madrid
country: Spain
facility: Hospital U. Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Carlos III
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Murcia
country: Spain
facility: Hospital Reina Sofía de Murcia
city: Tarragona
country: Spain
facility: Hospital Sant Pau i Santa Tecla
city: Valencia
country: Spain
facility: Hospital La Fe
city: Valencia
country: Spain
facility: Hospital Gral. U. de Valencia
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova
city: Valencia
country: Spain
facility: Hospital U. Dr. Peset
Study officials:
References: