Combinatorial Therapy to Induce an HIV Remission

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

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).

Study Overview

• Status: Completed
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: Combination Intervention

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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General Hospital, University of California San Francisco

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade 3 or Greater Adverse Event Count	Number of participants who experience a new grade 3 or greater adverse event	Week 0 through 102
Proportion of Participants Achieving Post-treatment Control	This will be defined as: 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; Participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control	Week 34 through 86

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Any Grade 2, 3 or 4 Adverse Event Through Week 62	Occurrence of any unsolicited adverse events for 28 days after administration of each study agent	Week 0 through 62
Any Serious Adverse Events, Medically Attended Adverse Event, and Potentially Immune-mediated Medical Condition	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	Week 0 through 86
Magnitude of T Cell Responses	We measured the magnitude of the CD8+ T cells to gag conserved elements (CE) 2 weeks after MVA boost (Week 22). We measured new or boosted pre-existing interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses. The magnitude was determined based on intracellular cytokine staining (ICS) by measuring the frequency of interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses after 6 hour stimulation with peptide pools matching the CE immunogen.	Week 22
Breadth of T Cell Responses	We measured the breadth of the vaccine-induced T cell response after DNA/MVA vaccination (two weeks after the MVA boost; Week 22). We defined breadth based on the number of conserved epitope (CE) pools with a positive CD8+ T cell responses, as defined by measuring the frequency of interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses after 6 hour stimulation with peptide pools matching the CE immunogen (using intracellular cytokine staining, ICS). Seven smaller CE pools were tested on each sample. Positive responses were determined based on a magnitude of IFNg+ cells greater than 0.001% of CD8+ T cells after peptide stimulation and after subtraction of background responses.	Week 22
Intact Provirus DNA Levels	The HIV-1 DNA reservoir was estimated using digital droplet PCR (Intact Proviral DNA Assay; IPDA). The frequency of intact proviruses (per million CD4+ T cells) was estimated at baseline and prior to the antiretroviral treatment interruption (Week 34). The change from baseline to Week 34 was calculated. A decrease (negative number) is a better outcome. The units are intact genomes/million CD4+ T cells.	Baseline to pre-interruption (week 34)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); amfAR, The Foundation for AIDS Research; International AIDS Vaccine Initiative; Rockefeller University; Ichor Medical Systems Incorporated; GeoVax, Inc.; Mologen AG

Publications and helpful links

General Publications

• Peluso MJ, Sandel DA, Deitchman AN, Kim SJ, Dalhuisen T, Tummala HP, Tiburcio R, Zemelko L, Borgo GM, Singh SS, Schwartz K, Deswal M, Williams MC, Hoh R, Shimoda M, Narpala S, Serebryannyy L, Khalili M, Vendrame E, SenGupta D, Whitmore LS, Tisoncik-Go J, Gale M Jr, Koup RA, Mullins JI, Felber BK, Pavlakis GN, Reeves JD, Petropoulos CJ, Glidden DV, Spitzer MH, Gama L, Caskey M, Nussenzweig MC, Chew KW, Henrich TJ, Yukl SA, Cohn LB, Deeks SG, Rutishauser RL. Correlates of HIV-1 control after combination immunotherapy. Nature. 2026 Feb;650(8100):187-195. doi: 10.1038/s41586-025-09929-5. Epub 2025 Dec 1.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Actual): January 29, 2024
• Study Completion (Actual): June 12, 2025

Study Registration Dates

• First Submitted: April 18, 2020
• First Submitted That Met QC Criteria: April 21, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): August 28, 2026
• Last Update Submitted That Met QC Criteria: August 6, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: 18-26957; UM1AI164560 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No