Although cART effectively suppresses HIV replication, it cannot eradicate the virus, which persists in reservoirs resistant to therapy. Therefore, cART must be taken for life, increasing the risk of non-adherence and of the selection and transmission of drug-resistant viral variants. New therapeutic interventions are therefore necessary to improve cART effectiveness and, possibly, eradicate the infection. Studies conducted by CNAIDS indicate that Tat is an optimal target for vaccine strategies aimed at controlling HIV replication, its propagation in tissues, and the establishment and maintenance of viral reservoirs.
The persistence of HIV infection under effective cART causes inflammation and activation of the immune system, which leads to premature-aging and to the onset of tumors and diseases typical of the elderly. In addition, a substantial proportion of patients, particularly in developing countries but also in Italy, starts late cART (T cells CD4+ <200/µl) and can respond poorly to therapy, resulting in an increased risk of progression and of co-morbidities, as compared to the general population. The consequences are the reduced quality of life of infected patients and high costs for the National Health System (NHS). New therapeutic interventions are therefore necessary to improve the effectiveness of cART (ART intensification), and, possibly, eradicate the infection. Studies conducted by CNAIDS indicate that Tat represents an optimal target for both preventive and therapeutic vaccine strategies aimed at controlling HIV replication, its propagation in tissues and the establishment and maintenance of viral reservoirs. In particular, observational studies conducted in Italy and South Africa indicate that the presence of natural anti-Tat antibodies is associated with a slower progression towards AIDS and a more effective response to therapy.
In the effort to develop new therapeutic vaccine strategies, CNAIDS has conducted, over the years, 5 Tat-based vaccine trials in Italy and South Africa (for a total of 426 volunteers), funded by the European Commission, the Italian Ministry of Health, and the Ministry of Foreign Affairs.
These studies have demonstrated the Tat-vaccine safety, immunogenicity and capability of intensifying cART effects, normalizing the immune system, and reducing immunoactivation and viral reservoirs, even in patients poorly responding to therapy. Very recent studies also demonstrated the long-term effects of Tat vaccination, culminating in a drastic reduction of virus reservoirs (90% mean reduction in blood) after 8 years from Tat vaccination, with a rate that is 4 to 7 times faster as compared to similar cohorts of cART-treated patients. Moreover, in vaccinated volunteers the reduction of latent virus reservoirs was associated with an increase in CD4+ T cells and the CD4+/CD8+ T-cell ratio. These features are also found in those rare patients called "post-treatment controllers", who spontaneously control the reactivation of viral replication after therapy interruption. This suggests that Tat-vaccinated patients might control the virus without taking drugs for periods of time whose duration should be evaluated in dedicated trials, which are currently being planned to verify this hypothesis.
CNAIDS is now actively seeking funds to conduct the following clinical trials:
- Phase 2 trial to assess whether Tat immunization in cART-treated patients allows prolonged treatment interruption in the absence of viral replication. This study, which will be conducted in volunteers vaccinated as part of the ISS T-002 and/or ISS T-003 trials, could lead to a reduction of cART cumulative-toxicity and open new perspectives for a functional cure and eradication strategies.
- Phase 3 trial for the registration of the use of Tat therapeutic vaccine in HIV+ adult subjects (>18 aa). The trial is aimed at confirming Tat vaccine efficacy in intensifying the immunological reconstitution promoted by cART on a larger number of volunteers, in support of its registration for the use in patients poorly responding to therapy (CD4+ T cells ≤500/µl).
- Phase 2/3 study to evaluate Tat vaccine safety, immunogenicity and efficacy in intensifying cART in patients at the first diagnosis of HIV infection, in accordance with the new international guidelines that recommend to start cART at diagnosis (Test & Treat), regardless of the immunological status of the patient. The study will be conducted in South Africa and is aimed at confirming Tat vaccine effectiveness in improving CD4+ T lymphocyte-recovery and reducing plasma viremia.
- Phase 1/2 trial of Tat therapeutic vaccine in HIV+ adolescents (12-17 aa) and children (6-11 aa), in preparation for the conduct of phase 3 trials for vaccine registration also in the pediatric population. The trial will be conducted in South Africa and is aimed at assessing the safety and effective dose of the Tat vaccine in these age groups.