Influence of a 3-month Letermovir Treatment on Gut Inflammation in ART-treated HIV-infected Persons in an Open Labelled Controlled Randomized Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Gut Inflammation
研究概览
简要总结
This is a multi-centre, open-label, randomized, controlled clinical trial to assess the influence of letermovir on gut translocation marker LPS in blood in ART-treated cytomegalovirus (CMV)-seropositive adult people living with HIV (PLWH). The study will explore the influence of letermovir treatment on gut damage, with no intention for label change. Participants (n=60) should have a cluster of differentiation 4 cells (CD4) count greater than 400 cells/µl and a negative viral load. Forty (40) participants will be randomized to receive letermovir (PREVYMIS® 480 mg or 2x240mg orally) in addition to their usual ART, and 20 participants will receive standard of care alone (ART only) for 14 weeks. Study visits will include screening, 2 baselines, followed by follow-up visits at 2 and 4 weeks and at 14 weeks after starting treatment and 12 weeks after end of letermovir treatment to assess a carry-over effect.
In an optional sub-study, colonoscopies and colon biopsies will be performed before and after letermovir treatment or standard of care alone to assess gut mucosa inflammation.
详细描述
INTRODUCTION, BACKGROUND, AND STUDY RATIONALE
Cytomegalovirus (CMV) seropositivity is frequent in the general population and even more so in persons living with HIV (PLWH). In the general population, high anti-CMV immunoglobulins G (IgG)-titer has been associated with earlier mortality, cluster of differentiation 8 (CD8) T-cell expansion, low CD4/CD8 ratio and increased cluster of differentiation cells (CD57) senescence marker expression on T cells. Such elevated IgG titer may be linked to transient CMV replication. The investigators have shown that gut permeability is correlated with anti-CMV IgG titers in PLWH on antiretroviral therapy (ART). Increased gut permeability is associated with microbial translocation and systemic inflammation, and correlates with frequency of non-infectious/non-AIDS comorbidities such as cardiovascular diseases, neurocognitive disorders and cancer. Moreover, gut permeability has been linked with reduced response to commercialized vaccines . The investigators recently demonstrated that, in HIV elite controllers, a rare subgroup of PLWH who can control HIV replication in absence of ART, CMV coinfection and anti-CMV IgG levels were associated with CD4 count decay. As HIV replication is well controlled with ART, our findings suggest that CMV co-infection is a driving factor behind increased gut permeability and inflammation in PLWH, contributing to immune exhaustion and senescence.
Hunt et al. have shown that administration of valganciclovir, an anti-CMV medication, in ART-treated PLWH for 4 weeks was associated with a decrease in immune activation markers compared to the control group. However, long-term use of valganciclovir is not convenient due to its toxicity and its activity is not specific to CMV. Furthermore, its influence on gut permeability has not been assessed.
A novel anti-CMV agent with an excellent safety profile, letermovir, was approved in 2017 for anti-CMV prophylaxis in allogeneic hematopoietic cell transplant recipients. In these patients, a drastic reduction of both low-grade replication and CMV infections, combined with an improved immune reconstitution after the graft was reported. In vitro, in intestinal tissues reconstituted from primary cells, letermovir anti-CMV treatment could prevent CMV-induced epithelial disruption.
Potential Risks and Benefits to Human Participants
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants will be eligible for the study if they meet the following criteria:
- •Male or female adults ≥18 years of age.
- •Documented HIV-1 infection by Western Blot, Enzyme Immuno Assay (EIA) or viral load assay.
- •CMV seropositive (as per clinical lab test).
- •On ART for at least 3 years, and stable ART regimen (same prescription) for at least 3 months.
- •Undetectable viral load < 50 copies/ml for the past 3 years. Viral blips in the past 3 years, below 200 copies/ml, are allowed if preceded and followed by a HIV viremia below 50 copies/ml.
- •CD4 count >400 cells/µL of blood
- •Able to communicate adequately in either French or English.
- •Able to understand and willing to provide written informed consent prior to screening.
- •Women of childbearing potential must have a negative serum pregnancy test.
- •Women of childbearing potential must agree to use one of the following approved methods of birth control while in the study and until 2 weeks after completion of the study:
- •Complete abstinence from penile-vaginal intercourse from the screening period until 2 weeks after study completion.
- •Double barrier method (acceptable barrier methods include diaphragm, coil, contraceptive foam, sponge with spermicide, or condom).
- •Oral, injectable or implant contraceptives, started at least 30 days before screening, plus one barrier method.
- •Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion) plus one barrier method.
- •Male partner sterilization confirmed prior to the female participant's entry into the study; this male is the sole partner for that participant.
- •Another method approved by the Investigator with published data showing that the expected failure rate is <1% per year preferably with one barrier method.
- •Any contraception method must be used consistently, in accordance with the approved product label, and for the duration of the study until two weeks after study completion.
- •Women of non-child-bearing potential as defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy.
- •Sexually active men with a female partner of childbearing potential must agree to one of the following methods of birth control:
- •The use of at least one barrier method of contraception (e.g. condom) with a female partner using a second approved method of contraception (IUD, hormonal contraceptive pill, diaphragm, spermicide, etc.) during the study and until two weeks after study completion.
- •Have had a successful vasectomy. Be confirmed sterile.
排除标准
- •Patients who are hypersensitive to letermovir or to any ingredient in the formulation of PREVYMIS®, including any non-medicinal ingredient, or component of the container.
- •Current AIDS-related event or serious health condition including systemic infections in the last 3 months.
- •Severe systemic diseases (e.g. uncontrolled hypertension, chronic renal failure), or active uncontrolled infections including Coronavirus disease 19 (COVID-19) (as tested by PCR).
- •Co-infection with active Hepatitis B or C Virus. Current use or have used in the past 3 months: immune-modulatory agents, prophylactic antibiotics, proton pump inhibitors, Metformin or Morphine as these drugs modulate inflammation and/or gut microbiota composition.
- •Current use of any drug with known drug-on-drug interaction with letermovir, as described in the PREVYMIS® (letermovir tablets) Product Monograph, including pimozide, ergot alkaloids, cyclosporine concomitantly administered with lovastatin, rosuvastatin, simvastatin or bosentan. For patients not using cyclosporine, dose of statins will be reduced by 50% for the duration of the study as a precaution, which is not expected to increase cardiovascular risk. Regarding HIV medication, exclusionary agents include darunavir, efavirenz, etravirine and nevirapine.
- •Recent changes in dietary habits, intermittent fasting, chronic constipation or laxative use as these can affect gut microbiota.
- •Psychiatric or cognitive disturbance or any illness that could preclude compliance with the study.
- •Current participation in an experimental therapy study or receipt of experimental therapy within the last 6 months.
- •Women who are planning to become or who are pregnant, or breast-feeding. A score of higher than 8 on a Full AUDIT questionnaire at the screening visit, suggesting an alcohol abuse problem.
- •Patients with moderate hepatic impairment combined with moderate or severe renal impairment (CrCl less than 50 mL/min)
研究组 & 干预措施
Letermovir
40 patients with CMV infection will be treated with Letermovir
干预措施: Letermovir (Drug)
结局指标
主要结局
Gut Inflammation
时间窗: 28 weeks
To assess the influence of CMV replication inhibition with letermovir on gut translocation markers (LPS) in blood of PLWH.
次要结局
- Gut permeability(28 weeks)
- Inflammation markers(28 weeks)
- Anti-CMV immune response(28 weeks)
- CMV DNA detection in gut(28 weeks)
研究者
Jean-Pierre Routy
Clinical Director of the Chronic Viral Illness Service Division of Hematology and Chronic Viral Illness Service Louis Lowenstein Chair in Hematology & Oncology Professor of Medicine, McGill University
McGill University Health Centre/Research Institute of the McGill University Health Centre