The longitudinal assessment of the BAFi pyrimethamine and of the HDACi valproic acid on the HIV reservoir size in HIV patients on antiretroviral therapy.
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The change in HIV reactivation in the reservoir in vivo at treatment initiation
and at the end of treatment measured as the change in cell associated HIV-RNA.
The change in reactivation is compared between the treatment arms.
Secondary outcome
The secondary endpoints are exploratory. 2.1 The change in reservoir size in
vivo at treatment initiation week 0, at the end of treatment week 2, and after
treatment, measured as the number of CD4 T-cells with multiply spliced HIV-RNA
with nested PCR based tat/rev induced limiting dilution assay (TILDA, Procopio
et al. EBiomedicine 2015). The change in reservoir size is compared within and
between the treatment arms. 2.2 The potential synergism or additive effects of
the administration of both drugs will be assessed. 2.3 The change in cell-free
HIV-RNA as measured by routine PCR and single copy assay, cell associated
HIV-RNA, and cell-associated HIV-DNA at week 0, week 2 and week 6 within and
between the treatment arms. 2.4 The change in the level of histone acetylation
and expression of BAF subunits at the RNA and at the protein level at week 0,
week 2 and week 6 within and between the treatment arms. 2.5 The change of the
functionality and phenotype of innate immune cells, HIV specific CD4+ and CD8+
T cells and HIV specific B-cells using proliferation assays, flow cytometry,
cytokine and cytotoxicity analysis at week 0, week 2 and week 6 within and
between the treatment arms. 2.6 Explore and correlate clinical and markers of
the viral reservoir (HIV-DNA, HIV-RNA), immune function and phenotype, and the
level of acetylation/BAF expression with the change in reservoir size (TILDA)
within and between the treatment arms. 2.7 Correlate the latency reversal
activity with pyrimethamine and valproic acid in vitro in cell line based HIV
latency models, in primary CD4 T cells ex vivo, and in vivo with TILDA,
HIV-RNA, HIV-DNA and the level of acetylation/BAF expression. 2.8 Number and
percentage of clinical and biochemical AE according to the latest version of
the Common Toxicity Criteria. 2.9 Number and percentage of patients with HIV-1
RNA level greater than or equal to 20, 50 and 200 c/mL at week 0, week 2 and
week 6 within and between the treatment arms. 2.10 The effect of vaproic acid
on dolutegravir exposure in vivo. 2.11 Assess the pharmacokinetic profile of
pyrimethamine and valproic acid in relation to the primary endpoint
Background summary
The retrovirus HIV integrates as proviral DNA in the genome of our CD4+ T
cells. A subset form a reservoir of latently infected long-lived memory T-cells
with nearly absent HIV-DNA transcription. This persistent latent HIV reservoir
is the major obstacle for a cure. HIV latency is sustained by multiple host
factors that restrict the viral promotor and expression of the viral genome.
Latency reversing agents (LRA) can remove these restrictive components and
mediate HIV latency reversal. LRA monotherapy with histone deacetylase
inhibitors (HDACi), including valproic acid, vorinostat, romidepsin,
panobinostat, reactivates HIV but seems insufficient to eliminate the reservoir
in vivo. Our research group has identified the BAF complex as a repressive
factor that maintains HIV latency (Rafati et al. PLoS Biol 2011). We
investigated the activity of a panel of recently identified small molecule
inhibitors of BAF (BAFi) as a new LRA group and showed that BAFi, including the
clinically approved drug pyrimethamine at tolerable concentrations, are capable
of reversing HIV latency and act synergistic with HDACi in vitro and in CD4+ T
cells obtained from HIV infected patients on suppressive antiretroviral therapy
(Stoszko et al. 2016 EBiomedicine). This offers new opportunities for cure
research. We want to conduct the first study with BAFi and assess the potential
synergism of 2 LRA with different modes of action on the reservoir in HIV
patients.
Study objective
The longitudinal assessment of the BAFi pyrimethamine and of the HDACi valproic
acid on the HIV reservoir size in HIV patients on antiretroviral therapy.
Study design
Open label 6 week randomized controlled intervention trial.
Intervention
Group 1 receives valproic acid (Depakine enteric) 30mg/kg, divided over 2 doses
per day, orally on day 1-14.
Group 2 receives pyrimethamine 200mg QD orally on day 1 and 100mg on day 2-14.
Group 3 receives valproic acid (Depakine enteric) 30mg/kg, divided over 2 doses
per day, orally on day 1-14 in combination with pyrimethamine 200mg QD orally
on day 1 and 100mg on day 2-14.
Group 4 receives no intervention.
Study burden and risks
There is no direct benefit for the patient to participate. Potential beneficial
observed effects would have an impact on future research in the HIV cure field.
This study can only be done in HIV infected patients and is therefore related
to this group only. The total study time for a patient is 6 weeks in which
patients have 10 study related visits: 1 pre-treatment screening, 5 during
treatment, and 4 post-treatment. Only with additional consent, 1 additional
phlebotomy will be done at least 6 months after the visit at day 42. The risks
are associated with the study procedures and the administered compounds. The
study procedures are blood sampling by phlebotomy. Patients are informed on the
sampling methods and will have sufficient time for consideration prior to
inclusion. The team ensures that participants have understood the potential
risks.
Phlebotomy is a safe well-defined procedure with a negligible low complication
rate. The total amount of blood volume is 738mL over 6 weeks at 10 time-points.
This is comparable to the maximum of blood donations in the same period (max of
2 of 500mL per donation, drawn in one setting of one hour). The maximum amount
will be 174mL, which happens at 2 occasions. Patients are selected on adequate
hemoglobin levels and ferritin levels are monitored. Only with additional
consent, 1 extra blood donation of 100mL will be done at least 6 months after
the day 42 visit.
Both pyrimethamine as BAFi and valproic acid as HDACi are FDA/EMA approved for
clinical use for other medical conditions in patients. Their safety profiles
are therefore well characterized. Pyrimethamine is an inhibitor of
dihydrofolate reductase, resulting in a blockade of folic acid metabolism.
Pyrimethamine and valproic acid are used in their approved dosages and for a
shorter duration (2 weeks) than usual in the treatment of toxoplasmosis or
epilepsy in HIV patients. The pyrimethamine concentration at which we observed
effects on the HIV reservoir is well within the therapeuric range in humans
with approved dosing.(Jacobson. AAC 1996; Klinker. AAC/Infection 1996; McLeod.
AAC 1992; Schmidt. Eur J Pediatr 2006). For valproic acid, the effects on HIV
are also observed at therapeutic dosing.(Ylisastigui et al. 2004 AIDS 1101-1108)
The study drugs have no known or predicted interaction on each other or with
current approved recommended first line antiretroviral drugs for HIV. Valproic
acid and pyrimethamine have a risk of side effects, intolerability and allergy.
The main side effects of valproic acid are gastro-intestinal, skin,
psychological, central nervous system, and bone marrow depression. Patients
with significant cytopenias at baseline cannot participate. The main side
effects of pyrimethamine are bone marrow depression and electrolyte
disturbances. Due to its working mechanism, patients on pyrimethamine will
receive prophylactic folinic acid suppletion.
Exclusion criteria are used to prevent drug exposure in certain patient
categories. Women in the reproductive age cannot participate. Male patients
must consent to condom use. Participation is stopped if any AIDS defining
illness classified as CDC C occurs. Patients with strong glucuronidation
interacting comedication cannot participate because valproic acid is
metabolized by this pathway. To minimize the risk associated with participation
in this trial, biochemical and clinical safety is frequently monitored, and
expert consultants in the field of clinical pharmacology and hematology are
involved.
In conclusion: only HIV patients who can understand the pros and cons of
participation will be included. The main uncertainty is in the use of both
pyrimethamine and valproic acid. However, experience exists with valproic acid
pyrimethamine in HIV patients with epilepsy or toxoplasmosis. and in this study
we use similar dosages of pyrimethamine and valproic acid but for a
significantly shorter time. Two specific safety measures will account for these
uncertainties: study visits are frequent during the 6 week study period and
will include AE monitoring. Furthermore, a contingency plan including
predefined safety criteria has been made with rules to interrupt the trial if
unexpected toxicity occurs. The remaining risk is low and acceptable; we use
approved drugs for other indications at approved dosage for a shorter time than
its approved indication. Most AE can be anticipated on, and a safety plan has
been installed for unexpected AE. As patients continue their cART during the
study, they can immediately resume their routine care after study end. The
outcome of the study could be that an effect or that no effect is observed.
This does not affect study continuation. Both positive and negative outcomes
are relevant observations for future HIV reservoir research. As the potential
risks are minimal with the used drugs which are also used for a shorter
duration than usual and the risks with these compounds are well characterised,
and as the visits can be planned with the patient (i.e. earlier or later on the
study-days according to patients' own schedules), the procedures are well
characterised and safe, and the potential outcome of the study can have a major
impact, we believe that this justifies participation.
Wytemaweg 80
Rotterdam 3015CE
NL
Wytemaweg 80
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
1. HIV-1 infected patients *18 years.
2. WHO performance status 0 or 1.
3. Confirmed HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
4. Wild type HIV infection or polymorphisms associated with at highest
low-level resistance to any class of ART according to Stanford HIV drug
resistance database. Transmitted mutations and acquired mutations due to
virological failure associated with resistance of at highest low-level
resistance are allowed.
5. On cART.
6. Current plasma HIV-RNA <50 copies/mL for at least 365 days and measured on
at least 2 occasions of which at least 1 must be obtained within 365 and 90
days prior to study entry.
7. Current CD4 count at study entry of *200 cells/mm3.
8. Pre-cART HIV-RNA *10.000 copies/mL.
Exclusion criteria
1. 1. Previous virological failure, defined as either acquired resistance
mutations (>low level resistance) on cART or HIV-RNA >1000 copies/mL on two
consecutive measurements during cART.
2. Uncontrolled hepatitis B or C co-infection.
3. Prior exposure to any HDACi, BAFi or other known LRA.
4. Prior exposure to cytotoxic myeloablative chemotherapy for hematological
malignancies during cART.
5. Concurrent exposure to strong interacting medication on glucuronidation.
6. Exposure within 90 days prior to study entry to immunomodulators, cytokines,
systemic antifungals, dexamethasone, vitamin K antagonists, anti-epileptics,
antipsychotica, carbapenems, mefloquine, colestyramine, Any documented
opportunistic infection related to HIV in the last 90 days.
7. Inadequate blood counts, renal and hepatic function tests
a. Haemoglobin <6.5 mmol/L (males) or <6.0 mmol/L (females), leucocytes <2.5
x109/L, absolute neutrophil count <1000 cells/mm3, thrombocytes <100 x109/L,
international standardized ratio >1.6, activated partial thromboplastin time
>40 seconds.
b. Estimated glomerular filtration rate <50 mL/min (CKD-EPI),
c. ALAT or total bilirubin >2.5x upper limit of normal.
d. All laboratory values must be obtained within 42 days prior to the baseline
visit.
8. Megaloblastic anemia due to folate deficiency.
9. Pancreatitis in last 6 months, or chronic pancreatitis.
10. Active malignancy during the past year with the exception of basal
carcinoma of the skin, stage 0 cervical carcinoma, Kaposi Sarcoma treated with
cART alone, or other indolent malignancies.
11. Females in the reproductive age cannot participate. Males cannot
participate if they refuse to abstain from sex or condom use in serodiscordant
sexual contact during the study, except if their sexual partner(s) use PREP.
12. Patients with active substance abuse or registered allergies to the
investigational medical products.
13. Last, any other condition (familial, psychological, sociological,
geographical) which in the investigator*s opinion poses an unacceptable risk or
would hamper compliance with the study protocol and follow up schedule, will
prohibit participation.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002837-48-NL |
| CCMO | NL62552.078.17 |