CIRBA

Immune recovery in an African population
HIV+ undergoing antiretroviral therapy:
Identification of patients candidates for a vaccine project at Abidjan (Ivory Coast).

(by Luc Montagnier, Vittorio Colizzi, Henry Chenal)

Introduction

The availability of effective antiviral combined therapy has dramatically modified the natural history of the HIV infection in industrilized countries. The reduction of HIV viral load determined by the HAART allows a partial recovery of immune functions with an increased control on the onset of opportunistic infections. However, in a fraction of patients the antiretroviral therapy is ineffective for the appearance of drug-resistant viral variations or for the scarce adherence to complexes therapeutic regimens. Almost 80-90% of HIV+ patients undergoing HAART show, following a known viral kinetics, undetectable HIV RNA plasma levels. Nevertheless, the temporary suspension of HAART also determines an immediate viral rebound and all clinical and biological data on the effect of antiretroviral therapy on the immune system (and generally on the natural history of HIV infection) are related to studies performed predominantly on Caucasian patients within national and international trials.

Actually, scarce data on the impact of antiretroviral therapy in Africans with HIV infection are available. In this context, the dramatic socio-economic scenario of the African epidemic doesn't allow to develop a therapeutic approach able to affect efficacy on the devastating course of HIV infection in Africa. Interestingly, recent data are emerging on the possibility to prevent the vertical transmission of HIV through simplified and relatively unexpensive therapeutic treatments. However, the elevated costs of management of an effective antiretroviral therapy in these countries, where the pro-capite sanitary budget is derisive, deny the possibility to control HIV and therefore to improve the sanitary infrastructures to control the diffusion of the epidemic.

In the next few years, effective anti-HIV vaccines will be developed by industries and then used by most of the seropositive patients. However, preliminary to the introduction of therapeutic anti-HIV vaccines, are the informations that we still need on the recovery of the immune system by the antiretroviral thrapies, mainly considering the viral genotypes and the biological background of the african populations. The main aim of this Project is to collect informations on the immune system recovery in the course of the antiretroviral therapies in the Abidjan population. A more extensive and complete form of this Project is in preparation by Dr. Giulia Cappelli (International Centre for AIDS & other emergent infections, Rome) and will be submitted to the evaluation of the National Ethical Committee of Ivory Coast and to UNAIDS.


Objectives

The specific objectives of the present Project are the following:
to study the modifications of the functional parameters of the immune system following the introduction of the HAART in a group of African patients from Ivory Coast. Specifically, these aims will be to monitore the phenotypical markers and functional characteristic of the immune reconstitution and the dynamics of viral kinetics in a naive population to antiretroviral therapy (with a peculiar viral heterogeneity presumably for the absence of pharmacological selective pressure).
to evaluate the adherence to therapeutic regimens and the incidence of side effects to HAART (lipodistrophy, metabolic disorders) in an African population.
to identify a group of patients undergone to HAART like candidates to a novel model of vaccine therapy.


Patients and Methods

• 50 asymptomatic patients HIV+ will be selected: 25 male and 25 female (naive to antiretroviral therapy). The start of antiretroviral therapy will be evaluated according to most recent recommendations of the International AIDS Society-USA Panel and therefore it will be started in patients with HIVRNA> 30.000 copies/mL independently from the number of lymphocytes CD4+, and lymphocytes CD4+ <350/cmm, independently from the plasma viremia.

• The following antiretroviral therapeutic regimens will be used: two NRTI (inhibitor of rereverse trascriptase) and a NNRTI (not nucleosidic inhibitor of the reverse trascriptase). The introduction of a therapeutic program that provided the direct and daily administration of antiretroviral therapy (DOT: Direct Observed Therapy) could represent a strategy to limit scarce adherence of the patients to the therapy, recognized as one of the principal causes of therapeutic failure. Before to start HAART, the patient will be correctly informed on the goals of therapy, on the role of HAART on the immune system, on the importance of adherence to the therapeutic regimens and on the possible occurence of side effects. Such informative phase will have the objective to explain to treated patient that he play an integral role in the project and be aware of the impact of therapy on his habits and life style. Monthly, hemato-biochemical analysis will be performed to assess the toxicity of HAART.

• The following functional aspects of the immune system will be evaluated:

1 - Lymphocyte immunophenotyping, with particular references to CD4/CD8 lymphocytes and to Natural Killer T cells (with gd or a24 T cell receptors);

2 - Analysis of T cell reactivity in terms of proliferative responses to mitogens and recall microbial (mycobacterial and toxoplasma) antigens, production of citochine/chemochine and:or induction of apoptosis;

3 - Cytotoxic T lymphocyte activity agaisnt viral (HIV) peptides able to bind MHC african population.

The immunological study will be performed at baseline (at the start of antiretroviral therapy) and subsequently every 4 months up to the 12° month of therapy.

• Plasma HIV RNA level and the number of latently infected cells will be determined. The copies of HIV-RNA will be quantified using the Amplicor HIV-1 Monitor (Roche Molecular Systems USA). The determination of the number of HIV-DNA in the PBMCs will be analyzed with competitive PCR.

• mycobacterial gene expression will be evaluated in patients coinfected with HIV and M. tuberculosis, with the aim to evaluate the selective pressure of the recovered anti-mycobacterial immune response during HAART therapy.


Expected results

A study on effective antiretroviral therapy in naive patients as Africans, can allow the identification of a valid model to understand the immune recovery following HAART. In particular, the individualization of functional markers of immunoreconstitution after HAART associated to undetectability of plasma HIV RNA can represent a further approach to the long term control of HIV infection. The analysis of natural immunity and the mycobaterial gene expression will allow to identifie and characterize HIV+ patients higly responsive to HAART treatment and susceptible to undergone a program of HIV vaccine therapy.

Ethical aspects

The patients that will initiate antiretroviral therapy, will have guaranteed the prosecution sine die of HAART.
The project will be submitted to the evaluation of the National Ethical Committee of Ivory Coast.
An UNAIDS international board will appraise periodically the results of the study.

CIRBA and Collaborating groups:

The project will be performed at the Centre Integré de Recherches Biocliniques d'Abidjan (CIRBA, Abdjan), an internationally accretited center of clinical and immune-virologic research for the study of HIV infection in Ivory Coast. The peculiarity of the Center of is to share in the same structure the clinical aspects of HIV infection and the aspects of virologic and immunologic research. In such sense, tight collaboration between the medical staff and the personnel of research is favored. Currently, in the Clinical Center, risen in 1998, 400 patients HIV+ of which around the half with antiretroviral therapy are followed. The Center of research and advanced diagnostic includes at least 4 laboratories for a total surface of around 500 mqs. The Center is composed of 3 laboratories of molecular biology and a laboratory of sierology and immunological diagnostic for the study of lymphocytes markers. The laboratories are equipped with: 3 equipment for PCR, 2 laminar flow hood, a flow cytometer FACSCALIBUR (Becton Dickinson), an automatic instrument for biochemical routine analysis (AUTOLAB) and hematologic counter (COULTER ACS). Moreover, a virologic P3 laboratory equipped with 1 laminar flow hood and another for virologic culture is available. The Center is also equipped with a room for multifunctional meetings (seminars and scientific library).
Currently, the CIRBA research group, located at Adbjan, is composed of a laboratory technician, a fellowship in molecular biology and 3 biologists (Responsible of the Laboratory of search Dr G Dahourou). The clinical staff of CIRBA is composed of a medical director expert in AIDS, a pediatrician and a dermatologist (Clinical Manager of the Center Dr H Chenal)

UNESCO is actively supporting this project by the following three distinct structures:

• UNESCO Venice Office (director: Prof. P. Lasserre) with administrative duty;
• World Foundation for AIDS Research and Prevention (President Prof. Luc Montagnier, Secretary general Dr. P. Vagliani) with scientific and management duties;
• International Centre for AIDS and Emergine & Re-emerging Infections (director: Prof. V. Colizzi) with operative research duty in Rome and Abidjan.

The collaboration of the National Institute for Infectious Diseases "L. Spallanzani" to this african Project will be actively encouraged by UNESCO through the UNESCO National Commission.

Duration of the Project: 3 years. However, antiretroviral treatment will be continued after the end of the trial according to the medical requirement.

Cost of the Project.

This Project has been financed for a 3 year period by the UNESCO Venice Office for 300,000 USD (including: purchase of antiretroviral drugs, personnel and laboratory testing).

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