Antiretroviral Resistance Detection by Ultrasensitive Pyrosequencing of the HIV-1 Genome and Virological Response to Antiretroviral Rescue Treatment
Condition: HIV
Study type: Observational

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. 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.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
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.
      
Biospecimen description: 
      Plasma samples
    
Keywords: Ultra deep sequencing; Virological failure; Salvage antiretroviral therapy