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Pilot Opened Trial in HIV-Infected Patients Including an Investigational Marketed Product
This study is currently recruiting participants.
Verified by Germans Trias i Pujol Hospital, May 2009
First Received: October 14, 2008   Last Updated: May 14, 2009   History of Changes
Sponsored by: Germans Trias i Pujol Hospital
Information provided by: Germans Trias i Pujol Hospital
ClinicalTrials.gov Identifier: NCT00773708
  Purpose

This study aims to provide new knowledge about the pathogenesis of HIV infection, specifically, the role that immune activation and apoptotic activity play in immune recovery, and in particular, in the paradoxical immunologic response of some patients on antiretroviral therapy despite achievement of sustained and complete viral suppression. In this regard, the investigators will prospectively evaluate the impact of intensification with Raltegravir in those "discordants" patients with high index of immune activation, measured as the percentage of CD8+HLADR+CD38+ cells. This will provide relevant information on the effectiveness of this drug in guided intensification regimens.


Condition Intervention Phase
HIV Infections
Drug: raltegravir
Drug: 1 P inhibitor + 2 nucleoside reverse transcriptase inhibitor or 1 non-nucleoside reverse transcriptase inhibitor + 2 nucleoside reverse transcriptase inhibitor
Phase IV

Study Type: Interventional
Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title: Pilot Study to Assess the Role of Immune Activation and Apoptosis as a Marker for Treatment Intensification With Raltegravir in Hiv-Infected Patients on Antiretroviral Therapy With Long-Term Viral Suppression and Unfavourable Immunologic Response (Discordant Patients: v+i-)

Resource links provided by NLM:


Further study details as provided by Germans Trias i Pujol Hospital:

Primary Outcome Measures:
  • CD4 cell count [ Time Frame: From Basal to 48 week (last visit) every 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Epidemiologic variables: Age, sex, time of HIV diagnosis/duration of HIV infection, duration of antiretroviral treatment with HAART, duration of treatment with a PI, HIV infection status/CDC disease stage. Epidemiologic, virologic, and immunologic data [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Virologic and immunologic variables: Time/duration of viral suppression, nadir CD4+ count, change in CD4+ count (absolute and percentage) since initiation of antiretroviral therapy, since initiation of HAART, and since achieving and undetectable viral [ Time Frame: From Basal to 48 week (last visit) every 3 months ] [ Designated as safety issue: No ]
  • Apoptotic variables: Cell death in CD4 and CD8 cells, defined as the percentage of cells which present a weak DIOC measurement (DIOC low) after 1 or 4 days of culture. [ Time Frame: From Basal to 48 week (last visit) every 3 months ] [ Designated as safety issue: No ]
  • The toxicity parameters will be evaluated: Hematology: Hematocrit, red blood cell count, hemoglobin, MCV, lymphocyte, platelet count, quick Index. • Biochemistry: glucose, total cholesterol, HDL and LDL cholesterol, triglycerides, urea, creatinine, A [ Time Frame: From Basal to 48 week (last visit) every 3 months ] [ Designated as safety issue: Yes ]
  • Clinical adverse effects and clinical events [ Time Frame: From Basal to 48 week (last visit) every 3 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 57
Study Start Date: March 2009
Estimated Study Completion Date: October 2010
Estimated Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental
intensify their triple-drug therapy with Raltegravir (RAL)
Drug: raltegravir
intensify their therapy with Raltegravir(RAL):1 Protease inhibitor plus 2 nucleoside reverse transcriptase inhibitor plus RAL or 1 non-nucleoside reverse transcriptase inhibitor plus 2 nucleoside reverse transcriptase inhibitor plus RAL
2: No Intervention
Continue with the same antiretroviral therapy
Drug: 1 P inhibitor + 2 nucleoside reverse transcriptase inhibitor or 1 non-nucleoside reverse transcriptase inhibitor + 2 nucleoside reverse transcriptase inhibitor

1 PI (lopinavir/ritonavir, atazanavir/ritonavir, fosamprenavir/ritonavir, tipranavir/ritonavir, darunavir/ritonavir) + 1 NNRTI (nevirapine or efavirenz)

Continue with the same antiretroviral therapy


Detailed Description:

One of the many adverse consequences of the human immunodeficiency virus (HIV) infection is the increase in the rate of lymphocyte cell death (Badley AD, Blood. 2000; 96:2951-64). Increased lymphocyte death is associated with the level of activation of the immune system (Gougeon ML. Nat Rev Immunol. 2003: 3:392-404), along with the disregulation of the cytokine network and a plethora of cytotoxic effects induced by HIV proteins (Badley AD, Blood. 2000; 96:2951-64). Hence, cell death can be observed in vivo not only in CD4+ cells, which are the main target of HIV, but also in CD8 T cells. Current knowledge suggest that immune activation and different mechanisms of cell death play a determinant role in T-lymphocyte (CD4+) loss during HIV infection and recovery after HAART (Bofill M et al AIDS. 1996 :827-34). Highly active antiretroviral treatment (HAART) induces a decline in the level of immune activation and lymphocyte apoptosis in HIV-infected patients as a result of a reduction in viral replication (Kolber MA, et al, Clin Immunol. 2007 [Epub ahead of print]). This reduction contributes to the recovery of immune system associated with antiretroviral therapy. In addition to this effect, which is induced through the reduction in viral load, antiretroviral therapy has been implicated in the regulation of apoptosis in different cell types, inhibiting or activating the process and influencing treatment efficacy and toxicity (Petit F, et al.Trends Pharmacol Sci.

2005. 26:258-64). Interestingly, it is not always true that antiretroviral therapy and viral suppression are associated with progressive immune recovery. Approximately 30% of patients present a paradoxical response to treatment, achieving progressive increases in immunity (measured by CD4+ count) despite failing to achieve viral suppression, or, vice versa, patients who maintain or reduce CD4+ cell count despite achieving viral suppression. Indeed, it is well known that higher CD8 activation is associated with fewer treatment-mediated CD4 gain. Each 10% increase in activated CD8+HLADR+CD38+ mean 90 fewer CD4 cell gained (Hunt PW et al J Infect Dis. 2003. 187:1534-43). The failure of recover CD4 T cells may rely on a incomplete viral suppression than could be responsible for increased immune activation and lymphocyte death. Recently, it has been pointed out that intensification strategies may be useful in reducing activation and improving CD4 T cell recovery (Kolber MA, et al, Clin Immunol. 2007 [Epub ahead of print]).

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient having a diagnosis of HIV infection, on continuously HAART for at least 2 years, including:

    • 2 NRTI/NtRTIs (except ddI+TDF), plus
    • 1 PI/ritonavir (lopinavir/ritonavir, atazanavir/ritonavir, fosamprenavir/ritonavir, tipranavir/ritonavir, darunavir/ritonavir) or 1 NNRTI (nevirapine or efavirenz)
  2. Undetectable plasma HIV-1 RNA (VL < 50 copies/mL) during the last 2 years prior to screening (with at least 4 determinations of viral load during this time period).
  3. Good treatment adherence.
  4. No presence of other factors which could contribute to CD4+ declines, such as treatment with chemotherapy, treatment with interferon/ribavirin, a ddI+TDF-containing regimen, etc, at least 12 months prior to screening.
  5. Patient classified as "discordant" who showed high level of CD8+HLADR+CD38+ and cell death values at the screening (see reference values in the definition section in page 9: 4.2. AIMS).
  6. Voluntary written informed consent.

Exclusion Criteria:

  1. Pregnancy or fertile women willing to be pregnant.
  2. Acute infections or uncontrolled chronic infection in the 2 months previous to the inclusion.
  3. Hepatic toxicity (AST, ALT levels grade +/= 3).
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00773708

Locations
Spain, Barcelona
H.U. Germans Trias i Pujol Recruiting
Badalona, Barcelona, Spain, 08916
Contact: Negredo Eugenia, MD,PhD     93 497 88 87     enegredo@flsida.org    
Principal Investigator: Negredo Eugenia, MD,PhD            
Sponsors and Collaborators
Germans Trias i Pujol Hospital
  More Information

No publications provided

Responsible Party: Lluita Sida Foundation ( Lluita Sida Foundation )
Study ID Numbers: DISCOR-RAL
Study First Received: October 14, 2008
Last Updated: May 14, 2009
ClinicalTrials.gov Identifier: NCT00773708     History of Changes
Health Authority: Spain: Ministry of Health

Keywords provided by Germans Trias i Pujol Hospital:
HIV infection
Discordant patient
CD4 recovery
intensification antiretroviral therapy
raltegravir
HIV-1 infected patient classified as "discordant" who showed high level of CD8+HLADR+CD38+ and cell death values at the screening

Study placed in the following topic categories:
Anti-Infective Agents
Efavirenz
Death
Sexually Transmitted Diseases, Viral
Acquired Immunodeficiency Syndrome
Atazanavir
Antiviral Agents
Immunologic Deficiency Syndromes
Darunavir
Protease Inhibitors
Tipranavir
Reverse Transcriptase Inhibitors
Virus Diseases
Nevirapine
Anti-Retroviral Agents
Fosamprenavir
Lopinavir
HIV Infections
Ritonavir
Sexually Transmitted Diseases
Retroviridae Infections

Additional relevant MeSH terms:
Anti-Infective Agents
RNA Virus Infections
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Molecular Mechanisms of Pharmacological Action
Immune System Diseases
Acquired Immunodeficiency Syndrome
Enzyme Inhibitors
Infection
Antiviral Agents
Pharmacologic Actions
Immunologic Deficiency Syndromes
Reverse Transcriptase Inhibitors
Virus Diseases
Anti-Retroviral Agents
HIV Infections
Therapeutic Uses
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 11, 2009