Pilot Opened Trial in HIV-infected Patients Including an Investigational Marketed Product
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ClinicalTrials.gov Identifier: NCT00773708 |
Recruitment Status
:
Completed
First Posted
: October 16, 2008
Last Update Posted
: March 11, 2015
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
HIV Infections | Drug: raltegravir | Phase 4 |
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]).
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 57 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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-) |
Study Start Date : | March 2009 |
Actual Primary Completion Date : | May 2011 |
Actual Study Completion Date : | May 2011 |

Arm | Intervention/treatment |
---|---|
Experimental: 1
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
Other Name: N/P.
|
No Intervention: 2
Continue with the same antiretroviral therapy
|
- CD4 cell count [ Time Frame: From Basal to 48 week (last visit) every 3 months ]
- 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 ]
- 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 ]
- 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 ]
- 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 ]
- Clinical adverse effects and clinical events [ Time Frame: From Basal to 48 week (last visit) every 3 months ]

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Ages Eligible for Study: | 18 Years to 60 Years (Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
-
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)
- 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).
- Good treatment adherence.
- 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.
- 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).
- Voluntary written informed consent.
Exclusion Criteria:
- Pregnancy or fertile women willing to be pregnant.
- Acute infections or uncontrolled chronic infection in the 2 months previous to the inclusion.
- Hepatic toxicity (AST, ALT levels grade +/= 3).

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00773708
Spain | |
H.U. Germans Trias i Pujol | |
Badalona, Barcelona, Spain, 08916 |
Responsible Party: | Sílvia Gel, Eugenia Negredo, Germans Trias i Pujol Hospital |
ClinicalTrials.gov Identifier: | NCT00773708 History of Changes |
Other Study ID Numbers: |
DISCOR-RAL |
First Posted: | October 16, 2008 Key Record Dates |
Last Update Posted: | March 11, 2015 |
Last Verified: | September 2011 |
Keywords provided by Sílvia Gel, 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 |
Additional relevant MeSH terms:
HIV Infections Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Raltegravir Potassium |
Reverse Transcriptase Inhibitors Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents HIV Integrase Inhibitors Integrase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Nucleic Acid Synthesis Inhibitors |