HIVNCT01346878
Antiretroviral Resistance Detection by Ultrasensitive Pyrosequencing of the HIV-1 Genome and Virological Response to Antiretroviral Rescue Treatment
An observational study of HIV, run by Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia at 4 sites in Spain.
Trial summary
This study aims to analyze the association between the baseline detection of resistance mutations through Ultra deep Sequencing (UDS) and the virological outcome of salvage antiretroviral therapy, in comparison with conventional genotypic resistance tests. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV
- How many people
- 143 participants
- Where
- 4 sitesSpain
- Study dates
- Jul 2010to Apr 2012
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: * PI GROUP: prior virologic failure of a Highly active antiretroviral therapy (HAART) regimen including a Protease inhibitor (PI) (ritonavir boosted or not), and a second consecutive start HAART regimen including a PI boosted with ritonavir + 2 Nucleoside Reverse Transcriptase Inhibitor (NRTI). The 6 months prior to the start of the second HAART regimen, are considered as a baseline. * NNRTI GROUP: Virologic failure after a HAART regimen that includes 1 Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and 2 NRTIs, and beginning, consecutive or not, a rescue HAART regimen with etravirine, in combination with any other drug. The 6 months before starting rescue HAART regimen with etravirine, are considered as a baseline. * II GROUP: Virologic failure to any prior HAART and initiation of rescue HAART including raltegravir, in combination with any other drug. The 6 months before starting rescue HAART with raltegravir are considered as a baseline.
Who may be able to join
- Adults over 18 years old, HIV +, distributed in one of the following 3 treatment groups:
- PI GROUP: prior virologic failure of a HAART regimen including a PI (ritonavir boosted or not), and a second consecutive start HAART regimen including a PI boosted with ritonavir + 2 NRTIs. The 6 months prior to the start of the second HAART regimen, are considered as a baseline.
- NNRTI GROUP: Virologic failure after a HAART regimen that includes 1 NNRTI and 2 NRTIs, and beginning, consecutive or not, a rescue HAART regimen with etravirine, in combination with any other drug. The 6 months before starting rescue HAART regimen with etravirine, are considered as a baseline.
- II GROUP: Virologic failure to any prior HAART and initiation of rescue HAART including raltegravir, in combination with any other drug. The 6 months before starting rescue HAART with raltegravir are considered as a baseline.
- Sample of 1 mL of plasma available for pyrosequencing before starting rescue HAART.
- Viral load of HIV-1 > 5,000 copies / mL at the time of obtaining the plasma sample.
Show all 10Show fewer
- Any CD4 + count.
- Availability of clinical follow-up, viral load of HIV-1 and quarterly CD4 counts to at least 48 weeks after initiation of rescue HAART.
- Good adherence to therapy.
- The investigation period is in any event before the start of the study.
Who cannot join
- HIV-2 infection or HIV-1 subtype non-B.
- Poor adherence to therapy.
- Lack of adequate clinical and laboratory follow up.
- Non-compliance of the patient to participate in the study.
Trial locations and contacts
4 sites in 1 country.
Spain4 sites
Laboratorio de Retrovirología irsiCaixa
Badalona, Barcelona, 08916
Hospital Universitario San Cecilio
Granada, Granada, 28012
Hospital 12 de Octubre
Madrid, Madrid, 08041
Mútua de Terrassa
Terrassa, Barcelona, 08227
About this study
This study aims to analyze the association between the baseline detection of resistance mutations through Ultra deep Sequencing (UDS) and the virological outcome of salvage antiretroviral therapy, in comparison with conventional genotypic resistance tests. Based on the data generated in this study, new resistance interpretation tools and algorithms will be developed to improve the prediction of antiretroviral therapy outcomes. The final aim of the study is to improve the clinical care of HIV-1-infected patients through the incorporation of improved new antiretroviral resistances tests in the clinical practice.
Read the detailed description
Antiretroviral resistance testing is an essential tool for the clinical management of Human Immunodeficiency Virus (HIV-1)-infected persons and HIV surveillance in the community. In the absence of appropriate treatment, HIV-1 infection leads toward the collapse of the immune system and death of most HIV-1-infected persons. Adequate antiretroviral treatment usually reverses this process. Nevertheless, HIV-1 easily develops treatment resistance through the accumulation of mutations in its genome. This causes treatment failure, and the requirement of increasingly complex, toxic and expensive treatments. Resistant viruses can be transmitted to other persons. More than 10 % of HIV-1-positive persons in Spain become infected with viruses that are already resistant to at least one antiretroviral drug. Antiretroviral treatment regimens designed on the basis of drug resistance information are more efficacious, effective and efficient.
In spite of their clinical relevance, however, conventional resistance tests are insensitive and underestimate antiretroviral resistance. By means of new ultrasensitive resistance tests it is possible to detect resistant viruses in minority populations that remain undetected by conventional genotypic tests. Ultrasensitive resistance tests thus double or triple the number of patients in whom antiretroviral resistance is detected. It is important to emphasize that detection of minority resistant mutants in antiretroviral naïve patients increases more than triples the risk of virological failure. The clinical impact of detecting minority resistant variants in treatment-experienced patients with therapeutic failure remains unknown.
Recently developed techniques of parallel emulsion sequencing of thousands of amplicon clones (Ultra deep Sequencing (UDS), Roche Diagnostics/454 Life Sciences) increase the sensibility to detect polymorphisms and mutations in highly variable genomes such as in HIV-1 in several orders of magnitude. In addition, this technique allows stablishing genetic linkage of such mutations and polymorphisms in thousands of HIV-1 clonal sequences for every patient and point of follow-up. This generates an unprecedented opportunity to characterize the nature of HIV-1 variability and the physiopathology of antiretroviral resistance in depth. Ultrasensitive resistance tests hold the promise of improving the clinical management of HIV-1 seropositive patients, avoiding unnecessary toxicities, improving epidemiological estimations of antiretroviral resistance, improving the knowledge of the pathogenesis of HIV-1 infection and antiretroviral resistance, and improving the cost-efficiency of HIV-related pharmaceutical cost.
This study aims to analyze the association between the baseline detection of resistance mutations through UDS and the virological outcome of salvage antiretroviral therapy, in comparison with conventional genotypic resistance tests. Based on the data generated in this study, new resistance interpretation tools and algorithms will be developed to improve the prediction of antiretroviral therapy outcomes. The final aim of the study is to improve the clinical care of HIV-1-infected patients through the incorporation of improved new antiretroviral resistances tests in the clinical practice.
- Conditions
- HIV
- Keywords
- Ultra deep sequencing, Virological failure, Salvage antiretroviral therapy
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to virological failure
Measured: One year
Secondary outcomes (6)
Proportion of patients with VL <50 and <200 copies
Measured: week 12 and 48
Absolute decrease of viral load
Measured: week 24 and 48
Area under curve of viral load
Measured: week 24 and 48
CD4 increase
Measured: week 24 and 48
Comparison of virological failure rate associated with baseline genotypic resistance detection by conventional sequencing and ultrasensitive pyrosequencing of the HIV-1 genome.
Measured: One year
Cost-benefit analysis of minority mutant detection by ultrasensitive pyrosequencing.
Measured: Week 48
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2011 (estimated)
- Study startJul 2010
- Primary completionApr 2012
- Study completionApr 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 143 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01346878
- Sponsor's protocol ID
- PRIUS-2
- Status last verified
- Oct 2012
- First submitted
- 18 Apr 2011
- Last updated
- 25 Oct 2012
- Results posted
- No
- Data monitoring committee
- No
Publications
Pou C, Noguera-Julian M, Perez-Alvarez S, Garcia F, Delgado R, Dalmau D, Alvarez-Tejado M, Gonzalez D, Sayada C, Chueca N, Pulido F, Ibanez L, Rodriguez C, Casadella M, Santos JR, Ruiz L, Clotet B, Paredes R. Improved prediction of salvage antiretroviral therapy outcomes using ultrasensitive HIV-1 drug resistance testing. Clin Infect Dis. 2014 Aug 15;59(4):578-88. doi: 10.1093/cid/ciu287. Epub 2014 May 29.
PubMed 24879788
Study at a glance
From the registry record, last updated by the sponsor on 25 Oct 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Antiretroviral Resistance Detection by Ultrasensitive Pyrosequencing of the HIV-1 Genome and Virological Response to Antiretroviral Rescue Treatment
- ClinicalTrials.gov ID
- NCT01346878
- Acronym / sponsor ID
- PRIUS-2
- Conditions
- HIV
- Keywords
- Ultra deep sequencing, Virological failure, Salvage antiretroviral therapy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 143 participants (actual)
- Lead sponsor
- Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la CienciaUniversity, hospital or other
- Study start
- Jul 2010
- Primary completion
- Apr 2012 (actual)
- Study completion
- Apr 2012 (actual)
- First posted
- 3 May 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study aims to analyze the association between the baseline detection of resistance mutations through Ultra deep Sequencing (UDS) and the virological outcome of salvage antiretroviral therapy, in comparison with conventional genotypic resistance tests. Based on the data generated in this study, new resistance interpretation tools and algorithms will be developed to improve the prediction of antiretroviral therapy outcomes. The final aim of the study is to improve the clinical care of HIV-1-infected patients through the incorporation of improved new antiretroviral resistances tests in the clinical practice.
Detailed description
Antiretroviral resistance testing is an essential tool for the clinical management of Human Immunodeficiency Virus (HIV-1)-infected persons and HIV surveillance in the community. In the absence of appropriate treatment, HIV-1 infection leads toward the collapse of the immune system and death of most HIV-1-infected persons. Adequate antiretroviral treatment usually reverses this process. Nevertheless, HIV-1 easily develops treatment resistance through the accumulation of mutations in its genome. This causes treatment failure, and the requirement of increasingly complex, toxic and expensive treatments. Resistant viruses can be transmitted to other persons. More than 10 % of HIV-1-positive persons in Spain become infected with viruses that are already resistant to at least one antiretroviral drug. Antiretroviral treatment regimens designed on the basis of drug resistance information are more efficacious, effective and efficient.
In spite of their clinical relevance, however, conventional resistance tests are insensitive and underestimate antiretroviral resistance. By means of new ultrasensitive resistance tests it is possible to detect resistant viruses in minority populations that remain undetected by conventional genotypic tests. Ultrasensitive resistance tests thus double or triple the number of patients in whom antiretroviral resistance is detected. It is important to emphasize that detection of minority resistant mutants in antiretroviral naïve patients increases more than triples the risk of virological failure. The clinical impact of detecting minority resistant variants in treatment-experienced patients with therapeutic failure remains unknown.
Recently developed techniques of parallel emulsion sequencing of thousands of amplicon clones (Ultra deep Sequencing (UDS), Roche Diagnostics/454 Life Sciences) increase the sensibility to detect polymorphisms and mutations in highly variable genomes such as in HIV-1 in several orders of magnitude. In addition, this technique allows stablishing genetic linkage of such mutations and polymorphisms in thousands of HIV-1 clonal sequences for every patient and point of follow-up. This generates an unprecedented opportunity to characterize the nature of HIV-1 variability and the physiopathology of antiretroviral resistance in depth. Ultrasensitive resistance tests hold the promise of improving the clinical management of HIV-1 seropositive patients, avoiding unnecessary toxicities, improving epidemiological estimations of antiretroviral resistance, improving the knowledge of the pathogenesis of HIV-1 infection and antiretroviral resistance, and improving the cost-efficiency of HIV-related pharmaceutical cost.
This study aims to analyze the association between the baseline detection of resistance mutations through UDS and the virological outcome of salvage antiretroviral therapy, in comparison with conventional genotypic resistance tests. Based on the data generated in this study, new resistance interpretation tools and algorithms will be developed to improve the prediction of antiretroviral therapy outcomes. The final aim of the study is to improve the clinical care of HIV-1-infected patients through the incorporation of improved new antiretroviral resistances tests in the clinical practice.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- * PI GROUP: prior virologic failure of a Highly active antiretroviral therapy (HAART) regimen including a Protease inhibitor (PI) (ritonavir boosted or not), and a second consecutive start HAART regimen including a PI boosted with ritonavir + 2 Nucleoside Reverse Transcriptase Inhibitor (NRTI). The 6 months prior to the start of the second HAART regimen, are considered as a baseline. * NNRTI GROUP: Virologic failure after a HAART regimen that includes 1 Non Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and 2 NRTIs, and beginning, consecutive or not, a rescue HAART regimen with etravirine, in combination with any other drug. The 6 months before starting rescue HAART regimen with etravirine, are considered as a baseline. * II GROUP: Virologic failure to any prior HAART and initiation of rescue HAART including raltegravir, in combination with any other drug. The 6 months before starting rescue HAART with raltegravir are considered as a baseline.
Key inclusion criteria (10 listed)
- Adults over 18 years old, HIV +, distributed in one of the following 3 treatment groups:
- Sample of 1 mL of plasma available for pyrosequencing before starting rescue HAART.
- Viral load of HIV-1 > 5,000 copies / mL at the time of obtaining the plasma sample.
- Any CD4 + count.
- Availability of clinical follow-up, viral load of HIV-1 and quarterly CD4 counts to at least 48 weeks after initiation of rescue HAART.
Key exclusion criteria (4 listed)
- HIV-2 infection or HIV-1 subtype non-B.
- Poor adherence to therapy.
- Lack of adequate clinical and laboratory follow up.
- Non-compliance of the patient to participate in the study.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Time to virological failure
Time frame: One year
6 secondary outcomes
Proportion of patients with VL <50 and <200 copies
Time frame: week 12 and 48
Absolute decrease of viral load
Time frame: week 24 and 48
Area under curve of viral load
Time frame: week 24 and 48
CD4 increase
Time frame: week 24 and 48
Comparison of virological failure rate associated with baseline genotypic resistance detection by conventional sequencing and ultrasensitive pyrosequencing of the HIV-1 genome.
Time frame: One year
Cost-benefit analysis of minority mutant detection by ultrasensitive pyrosequencing.
Time frame: Week 48
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Oct 2012.
- Derived from this study: PubMed 24879788Pou C, Noguera-Julian M, Perez-Alvarez S, Garcia F, Delgado R, Dalmau D, Alvarez-Tejado M, Gonzalez D, Sayada C, Chueca N, Pulido F, Ibanez L, Rodriguez C, Casadella M, Santos JR, Ruiz L, Clotet B, Paredes R. Improved prediction of salvage antiretroviral therapy outcomes using ultrasensitive HIV-1 drug resistance testing. Clin Infect Dis. 2014 Aug 15;59(4):578-88. doi: 10.1093/cid/ciu287. Epub 2014 May 29.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV, run by Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia at 4 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Oct 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to virological failure (time frame: One year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01346878, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Oct 2012.