Clinical trial NCT01130376: Novel Interventions in HIV-1 Infection
Official title: A Randomised, Open Labelled, Phase I, Safety, Toxicity, and Exploratory Immunogenicity Evaluation of Therapeutic Immunisation +/- IL-2, GM-CSF and Growth Hormone in HIV-1 Infected Subjects Receiving Highly Active Anti-retroviral Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: HIV-1 Infection
Keywords: Immune based therapy
Therapeutic vaccination
cytokine therapy
HIV therapeutic vaccine
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Medical Research Council
First posted: 2010-05-26
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: For several years there has been interest in why some people with HIV-1 progress more slowly to disease and have longer survival without Highly Active Antiretroviral Therapy (HAART) than others. The investigators and others have identified a few HIV positive individuals who can control their viral load for many years without HAART, these rare individuals do not lose their HIV-1-specific cellular immune responses, which are very important for controlling viral load. This group is referred to as long-term non-progressors (LTNP). Unlike LTNP the majority of HIV-1 infected individuals are chronic progressors (CP) who do not make effective HIV-1-specific cellular immune responses, even when on HAART. We propose to use a novel DNA vaccine boosted with immune based therapy (cytokines and hormones) to try to regenerate the missing HIV-1-specific cellular immune responses to make chronically infected HIV-1+ persons more like LTNP.

By injecting this novel DNA vaccine and immune based therapy into the people who are already infected with HIV-1, the immune system may be stimulated to mount a greater immune response not only to the vaccines but also to real HIV-1 particles and HIV-1-infected cells.

Detailed description: This will be a randomised, Phase I, open label comparative study running for 52 weeks (2 screen visits 2 weeks apart followed by 48 weeks of study). 50 patients will be screened in the initial phase of which 30 clade B infected individuals will be randomised into the study, which will consist of 3 arms:

Arm 1 will ascertain vaccine safety and toxicity in the presence of cytokine/hormone therapy.

Arm 2 will identify vaccine safety and toxicity.

Arm 3 will indicate safety and toxicity of cytokine/hormone therapy.

The target patients are chronically HIV-1 clade B infected persons who will have had a nadir CD4 T-cell count of \>200 cells/ul blood before they started ART. The current CD4 T-cell count should be \>400 cells/ul blood. Patients may have received ART for any length of time, but currently should be receiving NNRTI or boosted-PI based HAART, and have a viral load below the level of detection (50 copies/ml plasma). Patients will be bled on two occasions before commencing IBT regimens, in order to establish baselines, and then at regular intervals thereafter (weeks 0,1,2,4,6,8,12,16,24 and 48).

The treatment regimens are consistent with previous findings in animal models which suggest that administration of IL-2 during the antigen-specific T-cell contraction phase of an immune response (between 8 and 15 days post-vaccination) may preserve and lengthen clinically relevant responses. Furthermore studies in man have demonstrated that IL-2 administered before immunisation in ART-treated HIV-1-infected patients does not increase specific lymphoproliferation of T cells.

Recent preliminary studies in HIV-1-infected individuals using tetanus vaccines the investigators have shown that IL-2 administered after immunisation may be more effective at inducing sustained tetanus-specific responses than IL-2 administered before immunisation or together with immunisation. The dosages used in this study are based on those used in previous pilot studies of the administration of IL-2 + GM-CSF and rhGH and at these levels the drugs have been shown to have both positive effect on the immune response and demonstrated clinical benefit whilst being at a level which is safe and well tolerated in HIV-1 positive individuals. The dosage of the vaccine was based on a previous study where a dosage of this level has been shown to induce an immune response although this response was transient. In summary the investigators aim to increase the survival of vaccine responses through the administration of cytokines/hormones and boost memory responses with further rounds of immunisation.

Eligibility criteria: Inclusion Criteria:

* Documented HIV-1 positive result.
* Stable on HAART.
* Two screening viral loads of \<50 cps/ml on 2 consecutive occasions at least one month apart.
* CD4 T cell count of \>400 cells/ul.
* Nadir CD4 T cell count of \>200 cells/ul.
* Over 18 years of age.
* Willing and able to provide informed consent.
* Female subjects must not be pregnant or lactating.
* Subjects must be using adequate double barrier method of contraception as appropriate.

Exclusion Criteria:

* Prior therapeutic vaccination.
* Acute illness within 2 weeks of the start of the study.
* Prior immunomodulatory therapy (e.g. IL-2, rhGH, GCSF, GM-CSF, HU)
* Receiving immunosuppressive medication (e.g. Steroids)
* Participation in other vaccine trials currently
* Patients with diabetes mellitus type 2
* Patients with cardiac abnormalities
* Patients with pre-existing autoimmune disease
* Patients with active neoplasia
* Patients with evidence of any progression or recurrence of an underlying intra-cranial lesion

Primary outcomes:
measure: The primary outcome will be analysis of safety and toxicity data in relation to grade 3 or above laboratory or clinical serious adverse event (SAE) which can be attributed to the treatments given
timeFrame: Weekly
Secondary outcomes:
measure: The secondary immunological outcomes will be percentage change from baseline to study time point in defined cellular immune responses.
timeFrame: weekly
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: St. Stephen's AIDS Trust
Study officials:
affiliation: Imperial College London
name: Nesrina Imami, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herasimtschuk A, Downey J, Nelson M, Moyle G, Mandalia S, Sikut R, Adojaan M, Stanescu I, Gotch F, Imami N. Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection. Vaccine. 2014 Dec 5;32(51):7005-7013. doi: 10.1016/j.vaccine.2014.09.072. Epub 2014 Oct 22.