Effect of CCR5 Inhibition by Maraviroc on HIV-1 Infected Subjects Who Require Allogeneic Hematopoietic Cell Transplant for Any Indication and Its Observed Effect on Graft Versus Host Disease and HIV-1 Persistence
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Time to hematopoietic cell and immune recovery
研究概览
简要总结
The goal of this proposal is to determine the effect of maraviroc when it has been a part of the antiretroviral (ART) regimen given immediately after allogeneic hematopoietic cell transplant (allo-HCT) for HIV-1 infected participants who have a hematopoietic malignancy or other underlying disorder requiring an allogeneic transplant. Maraviroc has been given in practice to alleviate symptoms of graft vs. host disease (GvHD). Given its mechanism of action, it may also have an effect on the reservoir size of HIV-1 in infected patients. This study will inform potential future studies, evaluating the effect of this approach on the incidence and severity of GvHD, and determining its effect on HIV-1 reservoir.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Supportive Care
- 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 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL.
- •Receipt of allo-HCT for any indication at least 100 days prior to study entry.
- •Receipt of maraviroc for at least 30 days starting at date of transplant. Longer receipt of maraviroc is acceptable. Documentation of HIV-1 tropism for CCR5 should be obtained if available, but it is not necessary that the participant have prior CCR5-tropic.
- •At least 18 years of age.
- •HIV-1 RNA that is <50 copies/mL using a FDA-approved assay performed by any laboratory that has a CLIA certification or its equivalent within 45 days prior to study entry.
- •For females of reproductive potential (i.e., women who have not been post-menopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy), negative urine pregnancy test (with a sensitivity of 15-25 mIU/mL) within 48 hours prior to screening and entry.
- •Negative HBsAg result obtained within 6 months prior to study entry, or documentation of HBV immunity by positive HBV sAb at any time
- •The following laboratory values obtained within 45 days prior to enrollment:
- •CD4+ T cell count >250 cells/ mm^3
- •Absolute neutrophil count (ANC) ≥1000 cells/mm^3
- •Hemoglobin ≥10.0 g/dL for men and ≥9.0 g/dL for women
- •Platelet count ≥ 50,000/mm3
- •Ability and willingness of participant or legal representative to provide informed consent.
- •Additional Inclusion Criteria for Step 2 of Study:
- •HIV-1 latent reservoir undetectable by co-culture and DNA
- •No confirmed detectable HIV-1 RNA > 1000 cells/mm3 since discontinuation of maraviroc
- •Prior HIV-1 genotype results that confirm that there are active agents available in at least three classes of ART drugs (NRTI, NNRTI, PI or integrase).
- •Willing to stop ART
- •Willing to undergo high volume blood draw (125 cc) at Week 16
- •Willing to restart ART if HIV-1 viremia returns
- •Provide informed consent for Step 2
排除标准
- •Ongoing AIDS-related opportunistic infection (including oral thrush).
- •Pregnant and/or breastfeeding.
研究组 & 干预措施
Maraviroc after allo-HCT
- Step 1: participants who have received at least 30 days of maraviroc immediately post allo-HCT can be enrolled. Blood will be drawn at 2 time points at least 2 weeks apart, but within 4 weeks, and assessed for HIV-1 reservoir using both DNA assays and cell-associated reactivation by infectivity after stimulation. If any biopsies post allo-HCT are performed as part of standard of care and available, these will also be assessed for HIV-1
- Step 2: If HIV-1 reservoir is undetecable, antiretrovirals (ART) will be stopped in a structured treatment interruption (STI). HIV-1 VLs and CD4+ T-cells check weekly. Week 16, participants will have a large volume blood draw if remain suppressed. If confirmed return of viremia, ART will be reinitiated and he/she will be followed until HIV VL is <50 copies/ml. If he/she remains suppressed at Week 16 and repeat assays confirm no detectable HIV-1, HIV-1 VLs and CD4+ T-cell counts will be checked monthly until Week 52, and then quarterly until Year 5
干预措施: For Step 2: Structured treatment interruption (Other)
Maraviroc after allo-HCT
- Step 1: participants who have received at least 30 days of maraviroc immediately post allo-HCT can be enrolled. Blood will be drawn at 2 time points at least 2 weeks apart, but within 4 weeks, and assessed for HIV-1 reservoir using both DNA assays and cell-associated reactivation by infectivity after stimulation. If any biopsies post allo-HCT are performed as part of standard of care and available, these will also be assessed for HIV-1
- Step 2: If HIV-1 reservoir is undetecable, antiretrovirals (ART) will be stopped in a structured treatment interruption (STI). HIV-1 VLs and CD4+ T-cells check weekly. Week 16, participants will have a large volume blood draw if remain suppressed. If confirmed return of viremia, ART will be reinitiated and he/she will be followed until HIV VL is <50 copies/ml. If he/she remains suppressed at Week 16 and repeat assays confirm no detectable HIV-1, HIV-1 VLs and CD4+ T-cell counts will be checked monthly until Week 52, and then quarterly until Year 5
干预措施: Peripheral blood draw (Procedure)
结局指标
主要结局
Time to hematopoietic cell and immune recovery
时间窗: Up to 100 days after transplant
-In general, the mean time of engraftment of the donor cells is approximately 90 to 100 days post-transplant and this can be monitored by measuring the percent chimerism of donor cells.
Number of participants who experience chimerism
时间窗: At the time of screening
-Chimerism is measured by ≥ 98% of blood cells donor derived
Survival of participants
时间窗: 5 years after transplant
-Number of participants who are alive 5 years after transplant
Event free survival
时间窗: 5 years after transplant
-Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events
HIV-1 proviral DNA levels in peripheral blood
时间窗: Up to week 16 after transplant
* Obtained from peripheral blood * Used to determine if participant can proceed to Step 2
Presence and severity of GvHD
时间窗: Through 5 years after transplant
-GvHD will be measured using the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: IV. Response Criteria Working Group Report
HIV-1 reactivation in stimulated assay
时间窗: Up to week 16 after transplant
* Obtained from peripheral blood * Used to determine if participant can proceed to Step 2
Survival of participants
时间窗: 100 days after transplant
-Number of participants who are alive 100 days after transplant
Survival of participants
时间窗: Week 26 after transplant
-Number of participants who are alive 26 weeks after transplant
Survival of participants
时间窗: Week 52 after transplant
-Number of participants who are alive 52 weeks after transplant
Event free survival
时间窗: 100 days after transplant
-Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events
Event free survival
时间窗: Week 26 after transplant
-Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events
Event free survival
时间窗: Week 52 after transplant
-Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events
次要结局
- Number of participants who achieve a state of functional cure(Through 5 years after transplant)
- Number of participants who achieve a state of sterilizing cure(Through 5 years after transplant)
- Number of participants who have plasma viral load <50 copies/ml(Through 5 years after transplant)
- Number of participants who have gut immune reconstitution(Through 5 years after transplant)
- Number of participants who have existence of replication competent HIV-1 reservoirs in peripheral blood, gut and other tissue compartments(Through 5 years after transplant)