Combinatorial Therapy to Induce an HIV Remission

• ClinicalTrials.gov Identifier: NCT04357821
• Recruitment Status: Active, not recruiting
• First Posted: April 22, 2020
• Last Update Posted: May 10, 2023
• Sponsor: University of California, San Francisco
• Collaborators: amfAR, The Foundation for AIDS Research; International AIDS Vaccine Initiative; Ichor Medical Systems Incorporated; National Institute of Allergy and Infectious Diseases (NIAID); Rockefeller University; Mologen AG; GeoVax, Inc.
• Information provided by (Responsible Party): Steven Deeks, University of California, San Francisco

Study Description

Brief Summary:

Combination approaches will almost certainly be required to generate durable control of HIV in the absence of antiretroviral therapy (a "remission"). In this study, 20 individuals will receive a combination regimen administered during ART and then undergo an analytic treatment interruption (ATI).

Condition or disease	Intervention/treatment	Phase
HIV/AIDS	Drug: Combination Intervention	Phase 1; Phase 2

Detailed Description:

The investigators will perform a single arm study of twenty individuals with HIV infection on effective ART. All participants will receive a combination regimen administered during ART and then undergo an analytic treatment interruption. Our strategy has five stages

1. IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4
2. IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12
3. MVA/HIV62B (MVA62B) boost at Week 20
4. single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses)
5. ATI with single dose of VRC07 and 10-1074 at Week 34

Follow-up off ART will occur through at least Week 46 (expected) and on or off ART (depending on outcome) through Week 86.

Should this approach work, viral load would be expected to rebound in all individuals a few weeks after the bNAb levels decrease to sub-therapeutic levels. This acute rebound would be followed by a new lower viral load set-point and perhaps a long-term remission.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combinatorial Therapy With a Therapeutic Conserved Element DNA Vaccine, MVA Vaccine Boost, TLR9 Agonist and Broadly Neutralizing Antibodies: a Proof-of-concept Study Aimed at Inducing an HIV Remission
• Actual Study Start Date: August 1, 2020
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Combination intervention arm; All volunteers will receive the combination intervention outlined above.

Drug: Combination Intervention; IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4; IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12; MVA/HIV62B (MVA62B) boost at Week 20; single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses); ATI with single dose of VRC07 and 10-1074 at Week 34

Outcome Measures

Primary Outcome Measures :

1. Proportion of participants who experience a new grade 3 or greater adverse event [ Time Frame: Week 0 through 86 ]
2. Proportion of participants achieving post-treatment control. [ Time Frame: Week 34 through 86 ]

   This will be defined as:

   1. Participants who fail to show any consistent rebound above 400 copies RNA/mL between Week 12 of the ATI (when bNAb levels wane) and Week 36 of the ATI
   2. Participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control

Secondary Outcome Measures :

1. Occurrence of any unsolicited adverse events for 28 days after administration of each study agent [ Time Frame: Week 0 through 62 ]
2. Occurrence of any serious adverse events, medically attended adverse event, and potentially immune-mediated medical condition from the time of administration of the first study injection through 12 months after administration of the final study injection [ Time Frame: Week 0 through 86 ]
3. Occurrence of two consecutive measurements HIV RNA >200 copies/mL using conventional assays [ Time Frame: Week 34 to 86 ]
4. Resumptions of antiretroviral therapy after treatment interruption and the events that trigger them [ Time Frame: Week 34 to 86 ]
5. Frequency of confirmed declines (two consecutive measurements) in CD4+ T cell counts (> 50%) [ Time Frame: Week 34 to 86 ]
6. Frequency of confirmed declines (two consecutive measurements) to below 350 cells/mm3 [ Time Frame: Week 34 to 86 ]
7. Proportion experiencing any clinically defined episode of acute retroviral syndrome [ Time Frame: Week 34 to 86 ]
8. Magnitude of T cell responses [ Time Frame: Week 14 ]
9. Breadth of T cell responses [ Time Frame: Week 14 ]
   The proportion of participants with at least one additional epitope response at week 14 (2 weeks after last vaccination) compared to their baseline response

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 67 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria

1. Willing and able to provide written informed consent.
2. Age ≤67 years at the time of enrollment for those who started treatment during early infection and <65 years for those who started treatment during chronic infection.
3. Documented HIV-1 infection.
4. On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days within the last 1 year, and on a stable regimen that does not include an non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks, without plans to modify ART during the study period.
5. Screening plasma HIV RNA levels below the level of quantification on all available determinations in past 24 months.
6. Screening CD4+ T-cell count ≥ 500 cells/mm3.

Key Exclusion Criteria

1. Subjects receiving a non-nucleoside reverse transcriptase inhibitor
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
3. High-level resistance to both 10-1074 and VRC-07 as defined using the PhenoSense Neutralizing Antibody Assay (Monogram Biosciences).
4. Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers.
5. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months.
6. CD4+ T cell nadir <350 cells/mm3 during the chronic phase of infection (beginning 6 months following the estimated infection date and confirmed on repeat testing).
7. Active hepatitis B (HBV) infection defined as positive HBV surface antigen test.

9. Active hepatitis C (HCV) infection. 10. Presence of significant abnormalities on electrocardiogram. 11. History of potential immune-mediated medical conditions. Individuals with isolated Raynaud's phenomenon or localized disease requiring topical therapy alone will not be excluded.

Contacts and Locations

Locations

United States, California

Zuckerberg San Francisco General Hospital, University of California San Francisco

San Francisco, California, United States, 94110

Sponsors and Collaborators

University of California, San Francisco

amfAR, The Foundation for AIDS Research

International AIDS Vaccine Initiative

Ichor Medical Systems Incorporated

National Institute of Allergy and Infectious Diseases (NIAID)

Rockefeller University

Mologen AG

GeoVax, Inc.

More Information

• Responsible Party: Steven Deeks, Professor in Residence, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT04357821
• Other Study ID Numbers: 18-26957
• First Posted: April 22, 2020
• Last Update Posted: May 10, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome; HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases