A phase IIa randomized, placebo controlled, double blinded study to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy.

The human immunodeficiency virus (HIV) is a single-stranded positive-sense RNA
virus belonging to the lentivirus genus. It mainly infects human dendritic
cells (DCs), macrophages and CD4+T cells where it integrates into the host
genome after reverse transcription to double-stranded DNA. In the absence of
antiretroviral therapy, infection progresses to acquired immunodeficiency
syndrome (AIDS) as defined by progressive depletion of CD4+ T cells. Patients
with advanced HIV infection have a CD4+ T-cell count below 50/mm3 and their
median survival is between 12 to 18 months in the absence of antiretroviral
therapy.
The HIV pandemic has caused as much as 35 million deaths worldwide. As of
December 2013, 35 million people were estimated to be infected with HIV, from
which 23.5 million were living in Sub-Saharan regions.
Current therapy for HIV infection is based on combined anti-retroviral
treatment (cART). HIV infected patients, which are currently treated with cART
show a stabilized condition with no clinical progression. However, cART has to
be maintained for life, since it is not able to eradicate the infection by
itself. This represents very high costs for administrations together with
difficulties for treatment adherence and widespread distribution, mainly in
developing countries, but also in the developed world. Therefore, there is a
clear unmet need regarding cost-effective and viable treatments for
HIV-infected patients. Therapeutic vaccination has emerged as an attractive
strategy aiming at achieving a *functional cure*, a situation in which the
immune system is able to control viral replication without the need for cART.
In this regard, several antigenic molecules, administration routes and
strategies have been employed, so far with limited success. The most promising
results to date were obtained by Garcia et al. (partner of the consortium
iHIVARNA). In this clinical trial, HIV-infected patients were administered
autologous dendritic cells pulsed with HIV viral particles, a strategy known as
*ex vivo modification of DCs*. The results of this clinical trial indicate that
DC-based vaccines offer a promising strategy for therapeutic vaccination.
DC-based vaccines rely on the ability of DCs to uptake and present antigens to
CD4+ and CD8+ T cells, eliciting an immune response that should ultimately
control viral replication by lysing infected cells. In fact, in a small
percentage of individuals who are known to efficiently suppress viral
replication in the absence of cART (known as *elite controllers*), control of
viral replication has been associated with effective CD8+T cell responses.
Although results obtained by Garcia et al. demonstrated a reduction of 90-95%
of pVL in HIV-infected patients, *functional cure* (a 100% reduction of pVL)
was not achieved. In addition, the use of ex vivo modification of DCs is a
technical challenge for widespread use and a very costly strategy.
For that reason, iHIVARNA-01, which is the current product under development,
is based on the so-called *in vivo modification of DCs*, in which the product
is directly administered to the patient without the need to modify DCs ex-vivo.
The intended indication for iHIVARNA-01 is the therapeutic vaccination of
HIV-infected patients. iHIVARNA-01 is a biological product that consists of
naked mRNA to be administered through the intranodal route.
The product is a combination of mRNA sequences that fulfil two main objectives:
1) providing effective HIV antigens for specific T cell activation that will
lead to protective immunity (HIVACAT mRNA sequence) and 2) providing adequate
stimuli required for the activation of antigen presenting cells (APCs) (DCs)
and co-activation of specific T cells (TriMix mRNA sequences).

To evaluate the safety and immunogenicity of iHIVARNA-01 as a new therapeutic
vaccine in HIV infected patients.

Phase IIa, multicentre double-blind placebo controlled intervention study. Each
patient will be followed for 30 weeks. The study duration will be 38 weeks from
inclusion of the first patient.

One group (n=40) receives the HIVACAT TriMix (300 microgram TriMix + 900
microgram HIVACAT-T) vaccine intranodally on three occasions with a two-week
interval. One control group (n=15) receives TriMix only (300 microgram TriMix)
and one group (n=15) receives saline intranodally on three occasions with a
two-week interval. Two weeks after the last vaccination cART treatment will be
interrupted. If plasma virus is detectable, cART will be re-initiated twelve
weeks after treatment interruption. cART can always be re-initiated for medical
reasons, as judged by the clinical investigator.

Participation to the trial will consist of 15 visits to the hospital for a
estimated total of 11 hours for vaccinations and exams, during a 30-week
period. During these visits blood will be drawn for various assays. A total of
926ml blood will be taken over a 30-week period.
Before inclusion a physical screening will be performed. The patient will be
asked to fill in a diary card to record local and systemic adverse events
during one week after vaccination.
Discomfort can be experienced as a result of intranodal vaccination including:
local injection site reactions: pain, itching, redness/discoloration or
fluid/blood filled blisters at the injection site. Hard swelling in skin
surface at or close to site. General/ systemic reactions may include:
temperature raise, chills/rigors, malaise, tiredness muscle aches, headache,
nausea or vomiting.

As a result of treatment interruption a viral rebound syndrome may be
experienced, with symptoms similar to those of acute HIV infection. Symptoms
may include fever, fatigue, pharyngitis, lymphadenopathy, rash and/or weight
loss.