LRAs United as a Novel Anti-HIV Strategy (LUNA): a Randomized Controlled Trial.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Cell associated HIV-RNA
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 infected patients ≥18 years.
- •World Health Organization (WHO) performance status 0 or
- •Confirmed HIV-1 infection by 4th generation ELISA, Western Blot or PCR.
- •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.
- •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.
- •Current CD4 T-cell count at study entry of ≥200 cells/mm
- •Pre-cART HIV-RNA ≥10.000 copies/mL.
排除标准
- •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.
- •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.
- •Prior exposure to any HDACi, BAFi or other known LRA.
- •Prior exposure to cytotoxic myeloablative chemotherapy for hematological malignancies during cART.
- •Concurrent exposure to strong interacting medication on glucuronidation.
- •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.
- •Inadequate blood counts, renal and hepatic function tests
- •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.
- •Estimated glomerular filtration rate <50 mL/min (CKD-EPI),
- •Alanine aminotransferase or total bilirubin >2.5x upper limit of normal.
- •All laboratory values must be obtained within 42 days prior to the baseline visit.
- •Megaloblastic anemia due to folate deficiency.
- •Pancreatitis in last 6 months, or chronic pancreatitis.
- •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.
- •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.
- •Patients with active substance abuse or registered allergies to the investigational medical products.
- •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.
研究组 & 干预措施
Pyrimethamine
This group receives pyrimethamine for 14 days.
干预措施: Pyrimethamine (Drug)
Valproic acid and Pyrimethamine
This group receives valproic acid and pyrimethamine for 14 days.
干预措施: Valproic Acid (Drug)
Valproic acid and Pyrimethamine
This group receives valproic acid and pyrimethamine for 14 days.
干预措施: Pyrimethamine (Drug)
Valproic acid
This group receives valproic acid (enteric) for 14 days.
干预措施: Valproic Acid (Drug)
结局指标
主要结局
Cell associated HIV-RNA
时间窗: 6 week
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.
次要结局
- Cell associated HIV-RNA(6 week)
- Plasma HIV-RNA(6 week)
- Pharmacokinetics of valproic acid(6 week)
- Immunological functionality(6 week)
- Tat/rev induced limiting dilution assay (TILDA)(6 week)
- Histone deacetylation(6 week)
- In vivo/ex vivo reservoir reactivation correlation(6 week)
- Incidence of Treatment-Emergent Adverse Events(6 week)
- Synergy(6 week)
- Cell associated HIV-DNA(6 week)
- Expression of BAF subunits(6 week)
- Immunological phenotype(6 week)
- Pharmacokinetics of pyrimethamine(6 week)
- Immunological cytotoxicity(6 week)
- Reservoir biomarkers(6 week)
- Pharmacokinetics of dolutegravir(6 week)
研究者
Casper Rokx
MD PhD
Erasmus Medical Center