Impact of Raltegravir on HIV-1 cDNA Slope Following Antiretroviral Therapy (ART) Initiation

The recruitment status of this study is unknown because the information has not been verified recently.
Verified November 2009 by Goethe University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
University Hospital Heidelberg
Information provided by:
Goethe University
ClinicalTrials.gov Identifier:
NCT01168167
First received: July 21, 2010
Last updated: July 22, 2010
Last verified: November 2009
  Purpose

Recent clinical trials of combination antiretroviral therapy (cART) containing the first approved integrase inhibitor (i.e. raltegravir) have demonstrated a more rapid decay of HIV-1 RNA in plasma, compared to conventional potent antiretroviral combinations. This was observed especially during the early phase (up to week 12) following initiation of cART.

To explain this, two mechanistic hypotheses have been developed:

  1. - Macrophage reservoir death hypothesis. A major source of virus production during the second phase decay are believed to be long-lived infected cells with continuous virus production - e.g. macrophages. An accumulation of unintegrated, episomal HIV-1 cDNAs can promote apoptosis (Li et al. Embo J. 2001;20: 3272). In case of HIV superinfection of such a productively infected cell, an INI-based cART may induce apoptosis and thus contribute to a decrease in HIV RNA load during second phase decay. However, no study has thus far addressed the consequences of INI treatment on HIV-1 cDNA species on any cell population in vivo.
  2. - Resting CD4 T-cell reservoir integration block hypothesis. Resting CD4 T-cells may represent a substantial reservoir for HIV replication during the second phase decay as well. A special characteristic of these cells is that HIV-1 cDNA is typically localized to the nucleus in a not-integrated form (Chun et al., PNAS 1997;94:13193). These resting cells likely integrate HIV-DNA upon activation and then contribute to HIV viremia and viral spread. Conceptually, integration could be prevented by RGV, but not by RTI or PI. An accumulation of circular episomal HIV-1 cDNA species may also be a consequence of RGV treatment in this cell type.

Patient disposition:

To explore raltegravir-induced shifts in HIV-1 cDNA species in vivo, this non-interventional clinical observation investigates the dynamics of the three major HIV-1 cDNA species (total HIV-1 cDNA, HIV-1 integrants in the host cell genome, episomal HIV-1 2-LTR circles) over a period of 4 months in two groups of patients starting off cART from a single study center. Patients who begin cART in regular clinical routine with 2N(t)RTI plus either (n=10 patients) raltegravir or (n=10 patients) a boosted protease inhibitor/ alternatively an NNRTI will be offered to participate in this observation. Only patients are offered to participate in this trial if no other antiretroviral drugs than the above mentioned and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of >5,000 copies/mL and CD4-cell count of >200/µL within 12 weeks before cART initiation.

Preliminary analyses of PBMCs from HIV-infected patients indicate that all three major HIV-1 cDNA species can be quantified by real-time PCR under these baseline conditions.


Condition
HIV-1

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Comparing the Dynamics of Different HIV-1 cDNA Species in CD4-positive T-cells and HIV-1 RNA in Plasma of Infected Individuals After Initiation of Antiretroviral Therapy With or Without Raltegravir

Resource links provided by NLM:


Further study details as provided by Goethe University:

Primary Outcome Measures:
  • Dynamical measurement of HIV-1 DNA-species extracted from whole blood-PBMCs [ Time Frame: one year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • CD4 cell counts [ Time Frame: one year ] [ Designated as safety issue: No ]
  • plasma-HIV-1 RNA [ Time Frame: one year ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
Study Start Date: June 2010
Estimated Study Completion Date: April 2011
Estimated Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts
raltegravir-based cART
Patients who begin cART in regular clinical routine with 2N(t)RTI plus raltegravir (n=10 patients) will be offered to participate in this observation arm, but only if no other antiretroviral drugs and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of >5,000 copies/mL and CD4-cell count of >200/µL within 12 weeks before cART initiation.
standard of care-cART
Patients who begin cART in regular clinical routine with 2N(t)RTI plus either a boosted protease inhibitor or efavirenz (n=10 patients) at standard doses will be offered to participate in this observation arm. They will be offered to participate in this trial only if no other antiretroviral drugs and no concomitant drugs with relevant impact on antiretroviral's pharmacokinetics are administered. At time of study inclusion, patients should be characterised by a HIV-1 RNA load of >5,000 copies/mL and CD4-cell count of >200/µL within 12 weeks before cART initiation.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Patients who begin cART in regular clinical routine with 2N(t)RTI plus either (n=10 patients) raltegravir or (n=10 patients) a boosted protease inhibitor/ alternatively an NNRTI as third substance will be offered to participate in this non-interventional study. Observation time is a period of 4 months after cART initiation.

Criteria

Inclusion Criteria:

  • Initiation of antiretroviral therapy, consisting of 2 nucleoside/ nucleotide reverse transcriptase inhibitors at physician's disposition plus a third substance, i.e. either raltegravir (n=10 patients) or a standard third substance (efavirenz or boosted protease inhibitor)
  • Men or women with a documented HIV-1 infection, treated at the study center
  • age at least 18 years old
  • physical examination and vital signs, according to the treating physician do not give any hint for a active AIDS-defining illness or other serious disease
  • patients are naive to cART or in therapy interruption for at least 3 months
  • last available HIV-1 RNA was >5,000 copies/mL within 3 months prior to cART initiation
  • last available CD4-cell count showed at least 200 cells/µL within 3 months prior to cART initiation
  • according to German-Austrian antiretroviral treatment recommendations, there is a given therapy indication

Exclusion Criteria:

  • cART with other than the above mentioned drugs
  • administration of concomitant drugs with relevant impact on antiretroviral's pharmacokinetics
  • documented problems with patient visit- or medication-adherence
  • any condition or disease requiring a medication that may interact relevantly with cART
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01168167

Contacts
Contact: Christoph Stephan, M.D. +49 69 6301 ext 7680 c.stephan@em.uni-frankfurt.de
Contact: Kathleen Mantzsch, study coordinator +49 69 6301 ext 6140 studien@hivcenter.de

Locations
Germany
Johann Wolfgang Goethe-University Hospital Recruiting
Frankfurt, Hessen, Germany, 65520
Contact: Christoph Stephan, M.D.    +49 69 6301 ext 7680    c.stephan@em.uni-frankfurt.de   
Contact: Kathleen Mantzsch, study coordinator    +49 69 6301 ext 6140    studien@hivcenter.de   
Principal Investigator: Christoph Stephan, M.D.         
Sub-Investigator: Markus Bickel, M.D.         
Sub-Investigator: Pavlo Khaykin, M.D.         
Sub-Investigator: Annette Haberl, M.D.         
Sub-Investigator: Gabriele Nisius, M.D.         
Sub-Investigator: Nils von Hentig, M.D.         
Sponsors and Collaborators
Goethe University
University Hospital Heidelberg
  More Information

No publications provided

Responsible Party: Christoph Stephan, M.D. = Principal Investigator, Johann Wolfgang Goethe-University Hospital Frankfurt
ClinicalTrials.gov Identifier: NCT01168167     History of Changes
Other Study ID Numbers: JWG-HIVCENTER-Hopp1
Study First Received: July 21, 2010
Last Updated: July 22, 2010
Health Authority: Germany: Ethics Commission

Keywords provided by Goethe University:
Antiretroviral Therapy, Highly Active
MK 0518
HIV-1 DNA species
viral slope
Ribonucleic Acid
DNA, Complementary

ClinicalTrials.gov processed this record on July 28, 2014