LRAs United as a Novel Anti-HIV Strategy.

HIV-1-infection Clinical Trial

— LUNA  

Official title:

LRAs United as a Novel Anti-HIV Strategy (LUNA): a Randomized Controlled Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03525730
• Other study ID #: 2017-002837-48
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 18, 2018
• Est. completion date: October 1, 2020

Study information

• Verified date: April 2021
• Source: Erasmus Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A translational proof of concept study in humans on the primary research question whether novel anti-human immunodeficiency virus (HIV) latency strategies, including a BAF inhibitor and a histone deacetylase inhibitor, result in HIV reservoir reduction in HIV patients on antiretroviral therapy.

Description:

The retrovirus HIV integrates as proviral DNA in the genome of cluster of differentiation (CD)4+ 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) alone, including valproic acid, vorinostat, romidepsin, or panobinostat, reactivate HIV but seems insufficient to eliminate the reservoir in vivo. Our research group has identified the BAF complex as another repressive factor that maintains HIV latency. Pyrimethamine acts as an inhibitor of this BAF complex, is capable of reactivating HIV from latency at clinical tolerable concentrations, and acts synergistic with other LRA classes. This offers new opportunities for cure research. This is the first translational clinical study with BAF inhibitors and it assesses the potential synergism of 2 LRA with different modes of action on the reservoir in HIV patients.

Primary objective:

The longitudinal assessment of the effects of the BAF inhibitor pyrimethamine and of the HDACi valproic acid on the HIV reservoir in HIV patients on antiretroviral therapy.

Study design:

Open label 6 week randomized controlled intervention trial.

Study population:

Participants must be HIV infected, ≥18 years and on antiretroviral therapy with plasma HIV-RNA <50 copies/mL and CD4+ T cell count ≥200 cells/mm3 at enrollment. The HIV-RNA was ≥10.000 copies/mL before antiretroviral therapy initiation.

Intervention:

Participants are randomized to either of 4 arms and receive valproic acid, pyrimethamine, both for 2 weeks, or no intervention. Total study duration is 6 weeks and includes a 2 week treatment period and a 4 week post-treatment period.

Primary endpoint:

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 endpoints:

See below.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: October 1, 2020
• Est. primary completion date: July 25, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. HIV-1 infected patients =18 years.

2. World Health Organization (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 T-cell count at study entry of =200 cells/mm3.

8. Pre-cART HIV-RNA =10.000 copies/mL.

Exclusion Criteria:

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. For hepatitis B: patients should be vaccinated, or on pre-exposure prophylaxis through the use of lamivudine/emtricitabine or tenofovir in their combination ART. Otherwise, standard serological testing should be available within the last 365 days for homosexual HIV positive men. For non-homosexual HIV positive persons, there should be at least one negative hepatitis B test (either by serology or PCR). For homosexual HIV positive men, a negative hepatitis C immunoglobulin G, hepatitis C (HCV) antigen, blot or HCV-RNA PCR should be available within the previous 365 days. For non-homosexual HIV positive persons, there should be at least one negative hepatitis C test (either IgG, blot or PCR) available.

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, antipsychotics, carbapenems, mefloquine, colestyramine, Any documented opportunistic infection related to HIV in the last 90 days.

7. Inadequate blood counts, renal and hepatic function tests

1. 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.

2. Estimated glomerular filtration rate <50 mL/min (CKD-EPI),

3. Alanine aminotransferase or total bilirubin >2.5x upper limit of normal.

4. 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 pre-exposure prophylaxis.

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.

Related Conditions & MeSH terms

• HIV-1-infection

Intervention

Drug:
• Valproic Acid
Valproic acid (enteric) 30mg/kg, divided over 2 doses per day, orally on day 1-14.
• Pyrimethamine
Pyrimethamine 200mg once daily (QD) orally on day 1 and 100mg on day 2-14.

Locations

Country	Name	City	State
Netherlands	Erasmus MC	Rotterdam

Sponsors (1)

Lead Sponsor	Collaborator
Erasmus Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cell associated HIV-RNA	The change in cell associated HIV-RNA between treatment initiation (week 0) and at the end of study (week 6). The change wil be compared between the study arms.	6 week
Secondary	Tat/rev induced limiting dilution assay (TILDA)	The change in TILDA between the groups between week 2 and week 0, between week 6 and week 2, and between week 6 and week 0 The change will be compared between the study arms.	6 week
Secondary	Synergy	Potential synergism or additive effects of the administration of both drugs will be assessed by performing separate models including either both treatments or separate and subsequently investigating which model best predicts the outcome. the Bliss independence method to assess synergism will be performed. The combination therapy is considered synergistic if the difference and its 95% normal confidence interval (CI) were >0.	6 week
Secondary	Cell associated HIV-RNA	The change in cell associated HIV-RNA between and within the groups between week 2 and week 0, between week 6 and week 2, and between week 6 and week 0.	6 week
Secondary	Cell associated HIV-DNA	The change in cell associated HIV-DNA between and within the groups between week 2 and week 0, between week 6 and week 2, and between week 6 and week 0.	6 week
Secondary	Plasma HIV-RNA	The change in plasma HIV-RNA between and within the groups between week 2 and week 0, between week 6 and week 2, and between week 6 and week 0.	6 week
Secondary	Histone deacetylation	The change in the level of histone acetylation between and within the groups between week 0 and week 2, and between week 2 and week 6.	6 week
Secondary	Expression of BAF subunits	The change in the level of expression between and within the groups between week 0 and week 2, and between week 2 and week 6.	6 week
Secondary	Immunological functionality	The change of the functionality of innate immune cells, HIV specific CD4+ and CD8+ T cells and HIV specific B-cells between and within the groups between week 0 and week 2, and between week 2 and week 6.	6 week
Secondary	Immunological cytotoxicity	The change of the cytotoxicity of innate immune cells, HIV specific CD4+ and CD8+ T cells and HIV specific B-cells between and within the groups between week 0 and week 2, and between week 2 and week 6.	6 week
Secondary	Immunological phenotype	The change of the phenotype of innate immune cells, HIV specific CD4+ and CD8+ T cells and HIV specific B-cells between and within the groups between week 0 and week 2, and between week 2 and week 6.	6 week
Secondary	Reservoir biomarkers	The correlations between clinical markers, markers of the viral reservoir (HIV-DNA, HIV-RNA), frequency and functionality of immune cells, cytokines, and level of acetylation/BAF expression with the change in reservoir (cell asociated-HIVRNA and TILDA) within and between the treatment arms	6 week
Secondary	In vivo/ex vivo reservoir reactivation correlation	The correlation between ex vivo/in vitro (primary CD4 T cells, and cell line based) LRA efficacy, assessed using the size of the reservoir as measured by TILDA, HIV-DNA, HIV-RNA and level of acetylation/BAF expression after stimulation by pyrimethamine, valproic acid or both, and this will be correlated to these observed reservoir measurements outcomes in vivo at week 2 and week 6.	6 week
Secondary	Incidence of Treatment-Emergent Adverse Events	The clinical and biochemical adverse events will be assessed by the Common Toxicity Criteria.	6 week
Secondary	Plasma HIV-RNA	The proportion of subjects with plasma HIV-RNA >=20, >=50, >=200 at weeks 0, weeks 2 and week 6.	6 week
Secondary	Pharmacokinetics of dolutegravir	Plasma concentrations Cmax dolutegravir will be measured using validated methods in patients receiving these medications. The pharmacokinetic profiles of the dolutegravir will be assessed in relation to the primary endpoint and use of valproic acid.	6 week
Secondary	Pharmacokinetics of dolutegravir	Plasma concentrations Ctrough dolutegravir will be measured using validated methods in patients receiving these medications. The pharmacokinetic profiles of the dolutegravir will be assessed in relation to the primary endpoint and use of valproic acid.	6 week
Secondary	Pharmacokinetics of valproic acid	Plasma concentrations Ctrough of valproic acid will be measured using validated methods in patients receiving these medications. The total and free (nonprotein-bound) plasma concentrations of valproic acid will be measured. The pharmacokinetic profiles of the investigational medical products will be assessed in relation to the primary endpoint.	6 week
Secondary	Pharmacokinetics of valproic acid	Plasma concentrations Cmax of valproic acid will be measured using validated methods in patients receiving these medications. The total and free (nonprotein-bound) plasma concentrations of valproic acid will be measured. The pharmacokinetic profiles of the investigational medical products will be assessed in relation to the primary endpoint.	6 week
Secondary	Pharmacokinetics of pyrimethamine	Plasma concentrations Cmax of pyrimethamine will be measured using validated methods in patients receiving this medication. The pharmacokinetic profiles of the investigational medical products will be assessed in relation to the primary endpoint.	6 week
Secondary	Pharmacokinetics of pyrimethamine	Plasma concentrations Ctrough of pyrimethamine will be measured using validated methods in patients receiving this medication. The pharmacokinetic profiles of the investigational medical products will be assessed in relation to the primary endpoint.	6 week