Maraviroc on HIV-1 Infected Subjects Who Require Allogeneic Hematopoietic Cell Transplant

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV-1-infection

Intervention / Treatment
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* Other: For Step 2: Structured treatment interruption
* Procedure: Peripheral blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Step 1) 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 Exclusion Criteria: Ongoing AIDS-related opportunistic infection (including oral thrush). Pregnant and/or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc after allo-HCT<br>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 | Other: For Step 2: Structured treatment interruption<br>* -Accepted tool in the evaluation of immunological interventions, gene therapy, or therapeutic vaccines for the treatment of HIV infection<br>* Other names: STI;Procedure: Peripheral blood draw<br>* -Screening, entry for Step 1, Step 1 visit 2, entry for Step 2, weekly, week 16, monthly through week 52, week 52, quarterly through year 5, year 5, and viral relapse<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-1 proviral DNA levels in peripheral blood | Obtained from peripheral blood Used to determine if participant can proceed to Step 2 | Up to week 16 after transplant | 
| HIV-1 reactivation in stimulated assay | Obtained from peripheral blood Used to determine if participant can proceed to Step 2 | Up to week 16 after transplant | 
| Presence and severity of GvHD | -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 | Through 5 years after transplant | 
| Time to hematopoietic cell and immune recovery | -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. | Up to 100 days after transplant | 
| Number of participants who experience chimerism | -Chimerism is measured by ≥ 98% of blood cells donor derived | At the time of screening | 
| Survival of participants | -Number of participants who are alive 100 days after transplant | 100 days after transplant | 
| Survival of participants | -Number of participants who are alive 26 weeks after transplant | Week 26 after transplant | 
| Survival of participants | -Number of participants who are alive 52 weeks after transplant | Week 52 after transplant | 
| Survival of participants | -Number of participants who are alive 5 years after transplant | 5 years after transplant | 
| Event free survival | -Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events | 100 days after transplant | 
| Event free survival | -Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events | Week 26 after transplant | 
| Event free survival | -Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events | Week 52 after transplant | 
| Event free survival | -Defined as survival where the cancer does not recur, the graft takes, and there are no life-threatening events | 5 years after transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who achieve a state of functional cure | -Functional Cure: Following the discontinuation of all HIV-1 related treatment interventions, including HAART, a participant will be considered to have achieved an HIV-1 functional cure if for at least 5 years they: maintain an undetectable plasma viral load, using standard clinical assays, have achieved full CD4+ lymphocyte recovery with normal levels of T cell activation and proliferation, and normal levels of immunoglobulins with no disease progression. It is anticipated that participants who have achieved a functional cure will continue to have detectable HIV-1 DNA in peripheral blood cells and/or tissues. | Through 5 years after transplant | 
| Number of participants who achieve a state of sterilizing cure | -Sterilizing cure: same definition of functional cure but no detectable replication-competent virus in peripheral blood and minimal (near limits of detection) HIV-1 DNA in peripheral blood and or tissue | Through 5 years after transplant | 
| Number of participants who have plasma viral load <50 copies/ml | -Obtained from peripheral blood | 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 | -Obtained from peripheral blood | Through 5 years after transplant | 
| Number of participants who have gut immune reconstitution | -Will consist of tissue immunohistochemistry to analyze CD4 T cells when feasible, and for plasma markers of gut microbial translocation namely lipopolysaccharide (LPS) and soluble CD14 (sCD14) a marker of monocyte activation attributed to LPS effects | Through 5 years after transplant |