MMF for HIV Reservoir Reduction

NCT ID: NCT03262441

Last Updated: 2020-12-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-12
• Study Completion Date: 2019-08-31

Brief Summary

This is an open label, randomized Phase II study to determine whether Mycophenolate mofetil (MMF) given over 22 months meaningfully decreases the size of participants' HIV reservoir.

In addition to primary safety endpoints, the following hypotheses regarding drug efficacy will be tested:

1. MMF will be well tolerated and will not decrease adherence to or antiviral efficacy of ART.

2. Peripheral CD4+ T-cell counts and percentages will not meaningfully decrease during treatment with MMF and ART.

3. There will be no excess risk of opportunistic infections in MMF-treated study participants.

4. MMF therapy will lead to a progressive decrease in reservoir size over 22 months of treatment.

5. MMF therapy will lead to a continual shift in HIV reservoir composition from primarily effector memory CD4+ T cells (TEM) and central memory CD4+ T cells (TCM), to primarily stem cell like memory (TSCM) and naïve (TN) CD4+ T cells.

6. MMF will eliminate detectable measures of the HIV reservoir, including by cell-associated DNA/mRNA and quantitative viral outgrowth.

7. MMF will not decrease the humoral immune response to routine annual influenza vaccination.

Detailed Description

This is an open-label, randomized pilot trial to determine whether MMF given over 22 months meaningfully decreases the size of the HIV reservoir.

At the University of Washington in Seattle, investigators will enroll 5 study participants who have been on ≥2 years of suppressive ART. Study participants will be followed closely for at least 22 months with safety labs and serial measurements of the HIV reservoir (specifically, cell-associated HIV DNA and mRNA (ca-DNA & ca-RNA), quantitative viral outgrowth assay (QVOA), and single copy plasma viral load (scVL)). A "go/no-go" decision will occur after 12 months based on pre-defined thresholds of reduction in the HIV reservoir measured with ca-DNA.

All participants will be offered enrollment in a sub-study in which an anoscopy with rectum biopsies is performed on 3 occasions to assess the reservoir in the gastrointestinal lymphatic tissue (GALT).

Investigators will vaccinate study participants with the annual influenza vaccine and analyze their humoral response to this vaccine approximately one month later with a routine blood draw done in conjunction with a safety labs blood draw.

Investigators hypothesize that low doses of MMF will be well tolerated among healthy HIV-infected study participants who have fully ART-suppressed HIV. Investigators hypothesize that the incidence of opportunistic infections will not exceed that of comparable larger cohorts of HIV-treated patients. Of note, certain opportunistic infections such as herpes zoster or HSV-2 recurrence continue to occur despite suppressive ART, while pneumocystis pneumonia, CMV end organ disease, cryptococcus and many other opportunistic infections are much less common in this context. Therefore, in the event of an infection, Investigators will confer with the data safety management (DSM) panel to discuss whether this event is directly attributable to MMF. Finally, investigators hypothesize that peripheral blood CD4+ and CD8+ T cell counts will remain unchanged throughout MMF therapy, and that HIV replication will remain controlled on ART with addition of MMF.

Investigators hypothesize at least a 0.25-log reduction in cell-associated HIV DNA at one-year intervals in study participants who have a demonstrated anti-proliferative response to MMF treatment. Investigators hypothesize that cell-associated HIV DNA will undergo a shift from predominant residence in TCM and TEM to predominant residence in TN and TSCM. In regards to our sub-study, investigators predict that reservoir depletion will occur with equivalent rates in blood and GALT.

Conditions

Human Immunodeficiency Virus I Infection

Keywords

HIV; Antiretroviral treatment; Mycophenolate mofetil; Cure; Latency; Reservoir; CD4 T cell; Anti-proliferation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mycophenolate mofetil

Mycophenolate Mofetil 500mg Tablets once per day for one week as a lead in to limit drug-related side effects. Provided they are tolerating the drug at lower dose, they will then initiate Mycophenolate Mofetil 500mg Tablets twice daily orally for 22 months

Group Type: EXPERIMENTAL

Mycophenolate Mofetil 500Mg Tab

Intervention Type: DRUG

500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months

Interventions

Mycophenolate Mofetil 500Mg Tab

500 mg once daily for one week. If tolerating the drug, then initiate twice daily for 22 months

Intervention Type: DRUG

Other Intervention Names

Mycophenolate Mofetil Tablets USP Roxane Laboratories

Eligibility Criteria

Inclusion Criteria

1. Confirmed HIV infection, by two different positive antibody tests and/or detectable plasma HIV RNA on two different dates

2. ≥18 and ≤65 years of age

3. Continuous ART during the last two years, with current ART preferably including an integrase inhibitor

4. HIV RNA <40 copies / mL on four occasions during continuous ART of ≥ 2 years with no more than one blip of <1000 HIV RNA copies / mL

5. CD4+ T cell count > 350/mm3 within the past 365 days

6. Karnofsky score ≥80

7. Plan to reside in area 2 years

8. Consents to study

9. Tolerability of MMF during one week dose escalation lead-in phase of 500 mg once daily

10. Demonstrated anti-proliferative effect of MMF 500 mg twice daily

Exclusion Criteria

1. Active malignancy including skin cancer, myelodysplastic syndrome, or myeloproliferative disease within 24 weeks prior to study entry

2. Prior organ or bone marrow transplantation

3. Diagnosed autoimmune disease

4. Medical need for ongoing treatment with an immunosuppressive drug

5. Diagnosis of AIDS (defined as any AIDS-defining opportunistic infection or cancer, or a history of blood CD4+ T cell count < 200/µL)

6. Active opportunistic infection

7. Using disallowed medications (see 4.3)

8. Vomiting or diarrhea which prohibits consistent use of study drugs

9. Pregnant, intention to become pregnant, or breastfeeding

10. Woman of child bearing age who are NOT using two forms of birth control OR practicing complete abstinence

11. Excessive ingestion of ethanol, determined by an AUDIT score of >8

12. Substance abuse

13. History of medical non-compliance

14. Quantiferon TB positive

15. The following laboratory values (< 30 days before enrollment):

• Hemoglobin < 8.5 mg/dL
• Absolute neutrophil count < 1000 cells/mm3
• ALT > 2 x upper limit of normal
• Platelet count < 100,000/uL
• Creatinine clearance < 60 mL/min

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Washington

OTHER

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Joshua Schiffer

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joshua T Schiffer, MD MSc

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Center

Florian Hladik, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

2 West Clinic at Harborview Medical Center

Seattle, Washington, United States

Countries

United States

References

Reeves DB, Duke ER, Hughes SM, Prlic M, Hladik F, Schiffer JT. Anti-proliferative therapy for HIV cure: a compound interest approach. Sci Rep. 2017 Jun 21;7(1):4011. doi: 10.1038/s41598-017-04160-3.

Reference Type: BACKGROUND

PMID: 28638104 (View on PubMed)

Schiffer JT, Levy C, Hughes SM, Pandey U, Padullo M, Jerome KR, Zhu H, Puckett K, Helgeson E, Harrington RD, Hladik F. Stable HIV Reservoir Despite Prolonged Low-Dose Mycophenolate to Limit CD4+ T-cell Proliferation. Open Forum Infect Dis. 2022 Nov 19;9(12):ofac620. doi: 10.1093/ofid/ofac620. eCollection 2022 Dec.

Reference Type: DERIVED

PMID: 36519118 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

STUDY00002182

Identifier Type: OTHER

Identifier Source: secondary_id

109614-62-RGRL

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

ACTU-2100

Identifier Type: OTHER

Identifier Source: secondary_id

8589

Identifier Type: -

Identifier Source: org_study_id