Triple Immune Regimen for HIV

Recruiting at 15 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Integrase inhibitors, NRTIs

Must not be taking: Immunomodulatory medications

Disqualifiers: Pregnancy, Autoimmune disease, Anaphylaxis, others

Compensation: Varies

Number of Visits: 1

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to managing HIV by using vaccines and antibodies to control the virus without continuous medication. It combines three treatments: two vaccines, a medicine that activates the immune system, and special antibodies that can neutralize the virus. The goal is to determine if this combination can safely and effectively control HIV. Individuals who have been on a stable HIV treatment plan for over a year and have no history of stopping their medication might be suitable candidates for this trial. As a Phase 1/Phase 2 trial, it offers a unique opportunity to explore how well this innovative treatment manages HIV.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on a specific HIV treatment regimen before joining. You cannot use complementary or alternative medicines within 14 days before starting the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the components of the triple immune regimen being tested have promising safety records from previous studies. The ChAdOx1 and MVA vaccines were well-tolerated, with participants generally not experiencing severe side effects.

Broadly neutralizing antibodies (bNAbs), such as GS-2872, also demonstrated good tolerability. Studies reported no serious adverse reactions, indicating safety for use.

Vesatolimod, a toll-like receptor 7 (TLR7) agonist, has undergone testing in several studies. It was generally well-tolerated, though some participants experienced mild flu-like symptoms, particularly at higher doses. These symptoms were usually mild and manageable.

Overall, these treatments have been tested for safety in various studies and appear well-tolerated, with no major safety concerns reported. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple immune regimen for HIV because it combines innovative vaccines and antibodies to enhance the body's immune response against the virus. Unlike the standard antiretroviral therapy, which targets the virus directly, this approach uses ChAdOx1 and MVA/HIVconsv vaccines to stimulate T-cells, potentially providing a more robust immune defense. Additionally, vesatolimod, a toll-like receptor 7 (TLR7) agonist, is included to further boost immune activation, aiming for a functional cure by reducing the viral reservoir. This combination has the potential to transform HIV treatment from lifelong medication to a more sustainable and manageable approach.

What evidence suggests that this trial's treatments could be effective for HIV?

This trial will compare two approaches for managing HIV. Arm A will receive active ChAdOx1 and MVA-vectored HIV vaccines, vesatolimod, and broadly neutralizing antibodies (bNAbs). Research has shown that the ChAdOx1 and MVA-vectored HIV vaccines trigger promising immune responses. These vaccines target specific parts of the HIV virus, potentially helping the immune system recognize and combat it more effectively. Studies suggest that using these vaccines together enhances their effectiveness.

For bNAbs, research indicates they can target and neutralize different HIV strains, adding another defense layer. Vesatolimod, a TLR7 agonist, has been linked to longer virus control periods when treatment is paused, suggesting it might help manage HIV without constant medication.

Arm B will receive placebos for the vaccines, vesatolimod, and bNAbs. These treatments aim to strengthen the body's ability to handle HIV by attacking the virus in various ways. However, ongoing studies are essential to fully understand their effectiveness and safety when used together. ^{3 6 7 8 9}

Who Is on the Research Team?

Sharon Riddler, MD, MPH

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

Adults who started ART for acute HIV within 28 days of diagnosis, have been on consistent treatment without breaks longer than 14 days, and have maintained an undetectable viral load for at least a year. They must weigh between 50-115 kg, have a CD4 count ≥500 cells/mm3, and agree to use two forms of contraception if applicable.

Inclusion Criteria

You must provide laboratory results taken within the past two months.

I have my HLA typing results available.

I have taken a pregnancy test within the last 48 hours and it was negative.

Exclusion Criteria

You have received an experimental vaccine or HIV-1 vaccine within the past 6 months.

You have known allergies or sensitivities to any of the ingredients used in the study treatments.

You have experienced a severe allergic reaction called anaphylaxis, which includes symptoms like hives, trouble breathing, or swelling.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Study Intervention and ART

Participants receive the study intervention including ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod, and bnAbs while continuing ART

67 weeks

Analytic Treatment Interruption

Participants undergo a treatment interruption to evaluate HIV-1 control

up to 24 weeks

ART Restart

Participants who experience virologic rebound resume ART

24 weeks

Continuation of ATI

Participants who do not meet ART restart criteria continue the treatment interruption

up to 24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ChAdOx1.HIVconsv62
• ChAdOx1.tHIVconsv1
• GS-2872
• GS-5423
• MVA.tHIVconsv3
• MVA.tHIVconsv4
• Placebo
• Vesatolimod (VES)

Trial Overview The trial is testing the effectiveness of therapeutic vaccines using ChAdV and MVA vectors along with TLR7 agonist vesatolimod (VES) and bNAbs versus placebo in controlling HIV during treatment interruption. Participants will be monitored to see how well their bodies control HIV without regular medication.

How Is the Trial Designed?

Group I: Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbs Experimental Treatment 7 Interventions

Group II: Arm B: Placebos for vaccines, vesatolimod and bnAbs Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Gilead Sciences

Industry Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

University of Oxford

Collaborator

Trials

1,113

Recruited

21,220,000+

Published Research Related to This Trial

HIV-1 can develop significant resistance to the drug lamivudine (3TC) within just two months of therapy, specifically through a mutation (Met184-->Val) in the reverse transcriptase gene, leading to a 1800- to 5500-fold decrease in sensitivity to the drug.

While patients initially experienced a decrease in viral load and an increase in CD4 counts during 3TC therapy, these improvements were temporary and correlated with the emergence of the resistance mutation, indicating that 3TC may only provide short-term benefits in advanced HIV-1 infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine. Kavlick, MF., Shirasaka, T., Kojima, E., et al.[2019]

In a review of 15 randomized controlled trials involving 3,497 patients, the combination of DRV/r and INSTIs was found to be more effective than triple therapy in achieving viral suppression and improving CD4+ T cell counts.

The safety profile of DRV/r + INSTIs was comparable to that of triple therapy, indicating that this dual therapy is not only effective but also safe for treatment-naïve HIV/AIDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety Analysis of PIs/r Based Dual Therapy in Treatment-Naïve, HIV/AIDS Patients: A Network Meta Analysis of Randomized Controlled Trials. Hui, L., Xiaoxu, H., Yuqi, W., et al.[2022]

In a study involving 63 HIV-1-positive individuals, maraviroc, a CCR5 antagonist, demonstrated significant efficacy by reducing viral load by more than 1.6 log(10) copies/ml after 10 days of treatment.

The maximum reduction in viral load was observed between 10 to 15 days, supporting the idea that targeting CCR5 can be an effective strategy for HIV treatment in patients without CXCR4-using virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. Fätkenheuer, G., Pozniak, AL., Johnson, MA., et al.[2018]

Enfuvirtide, when used with an optimized background regimen, is particularly effective for HIV-1 patients who meet specific criteria, such as having a CD4+ count above 100/mm3 and a viral load below 100,000 copies/ml, leading to an 80% chance of achieving a viral load below 400 copies/ml after 24 weeks.

Patients treated with enfuvirtide also report improvements in health-related quality of life compared to those receiving only optimized therapy, highlighting its benefits beyond viral suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic indications, antiretroviral treatment optimization and quality of life of patients taking enfuvirtide]. Raffi, F.[2018]

In a study involving three randomized clinical trials with patients receiving either double or triple combination therapy for up to 52 weeks, there was no unique immunological benefit in CD4 cell count from triple therapy that included HIV protease inhibitors (PIs) compared to dual therapy.

The results showed that changes in CD4 cell counts were not significantly different between patients on triple therapy and those on double therapy, indicating that the effectiveness of treatment in increasing CD4 counts is not dependent on the type of therapy used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly active antiretroviral therapy including protease inhibitors does not confer a unique CD4 cell benefit. The AVANTI and INCAS Study Groups. [2004]

In a Phase Ib study involving 48 adults living with HIV-1, vesatolimod was found to be well tolerated at doses ranging from 1 to 12 mg, with no serious adverse events reported.

While there were no significant changes in plasma HIV-1 RNA levels compared to placebo, immune stimulation was observed at doses above 4 mg, indicating potential for future combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1. Riddler, SA., Para, M., Benson, CA., et al.[2021]

In a study of 187 HIV-infected patients over an average of 19.4 months, enfuvirtide treatment led to a significant mean increase of approximately 102 CD4+ cells/mm³, regardless of the patients' initial CD4+ cell counts.

Patients starting enfuvirtide with CD4+ counts below 100 cells/mm³ did not reach the same CD4+ levels as those starting with higher counts, suggesting that initiating treatment at higher CD4+ levels may provide better immunologic benefits, even if complete viral suppression is not achieved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunologic benefits of enfuvirtide in patients enrolled in a drug assistance program. Saberi, P., Caswell, NH., Gruta, CI., et al.[2018]

In a study involving ten AIDS patients with CD4 counts below 200/mm3, various combinations of five different HIV virostatics were used, showing that these combinations could effectively reduce viral loads, with some patients experiencing significant decreases over time.

The treatment was generally well-tolerated, with macrocytosis as the only notable side effect, and while viral loads decreased significantly, the increase in CD4 counts was moderate, suggesting the need for further studies to optimize treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AIDS therapy with two, three or four agent combinations, applied in short sequences, differing from each other by drug rotation. I. First of two parts: a phase I trial equivalent, concerning five virostatics: AZT, ddI, ddC, acriflavine and an ellipticine analogue. Mathé, G., Pontiggia, P., Orbach-Arbouys, S., et al.[2013]

In a study of 104 HIV-infected individuals with prior lamivudine (3TC) treatment, those who switched to a didanosine (ddI)-containing regimen had a lower risk of virologic failure compared to those who continued with 3TC.

The ddI regimen remained effective against HIV strains with the M184V/I mutation, indicating that this mutation should not prevent the use of ddI in patients with prior nucleoside experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients. Winters, MA., Bosch, RJ., Albrecht, MA., et al.[2022]

In a study of 89 very immunosuppressed HIV-1-infected patients, an efavirenz-based regimen showed similar effectiveness in increasing CD4 cell counts after 48 weeks compared to two ritonavir-boosted protease inhibitor regimens.

All three treatment regimens achieved comparable rates of viral suppression and had similar safety profiles, with no reported deaths, indicating that efavirenz can be a viable option for very advanced HIV-1 infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Reconstitution in Severely Immunosuppressed Antiretroviral-Naive HIV-1-Infected Patients Starting Efavirenz, Lopinavir-Ritonavir, or Atazanavir-Ritonavir Plus Tenofovir/Emtricitabine: Final 48-Week Results (The Advanz-3 Trial). Miro, JM., Manzardo, C., Ferrer, E., et al.[2020]

Simplified antiretroviral regimens, particularly the combination of abacavir/lamivudine/zidovudine plus tenofovir, have been developed to improve adherence and quality of life for HIV-infected patients, especially those with adherence issues.

This regimen shows promise as a safe alternative with limited toxicity and fewer drug interactions, making it suitable for both antiretroviral-naive and heavily pre-treated patients, while still allowing for future treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir. Mastroianni, CM., d'Ettorre, G., Vullo, V.[2022]

Vesatolimod (VES) effectively activates CD8+ T-cells in HIV-positive individuals, with a significant increase in activation observed in all 31 donors studied, reaching up to 88%.

Among the donors, 20 out of 31 showed a concentration-dependent increase in HIV-specific CD8+ T-cell activation, indicating VES's potential role in enhancing immune responses as part of an HIV remission strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of HIV-specific CD8+ T-cells from HIV+ donors by vesatolimod. Ram, RR., Duatschek, P., Margot, N., et al.[2021]

In a phase 1b clinical trial involving 25 HIV-1-infected participants, the TLR7 agonist vesatolimod showed promise by inducing immune cell activation and reducing intact proviral DNA, which is linked to a modest increase in the time to viral rebound after stopping antiretroviral therapy (ART).

The study suggests that vesatolimod may enhance immune responses through increased dendritic cell and natural killer cell activity, indicating its potential as part of combination therapies for long-term HIV control, although larger studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy. SenGupta, D., Brinson, C., DeJesus, E., et al.[2022]

In a study of 107 antiretroviral naïve HIV-1 patients, those treated with LPV/r achieved and maintained undetectable HIV-RNA levels more effectively than those on IDV/r, with a significantly lower probability of virological success for IDV/r (risk ratio of 0.46).

Patients on IDV/r experienced greater increases in total cholesterol and had a much higher risk of treatment discontinuation due to toxicity, with 21 out of 52 patients stopping IDV/r compared to only 3 out of 55 on LPV/r.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects. Bongiovanni, M., Bini, T., Chiesa, E., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10384973/

Adenovirus Transcriptome in Human Cells Infected with ... In the present work, we examined RNA transcriptomes of two candidate HIV-1 vaccines, ChAdOx1.tHIVconsv1 (C1) and ChAdOx1.HIVconsv62 (C62), using ...

2. thelancet.com thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00209-X/fulltext

Safety and immunogenicity of the ChAdOx1–MVA-vectored ... Progress towards an effective HIV-1 vaccine has been slow and full of obstacles. However, the systematic development of vaccine components for ...

3. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/09/NCT05604209/SAP_002.pdf

IGHID 12107 - A Phase I Study to Evaluate the Safety and ... This statistical analysis plan (SAP) details the statistical procedures that address the study objectives specified in Protocol version 3.0 ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2666524724003094

Safety and broad immunogenicity of HIVconsvX conserved ... Data on the safety and immunogenicity of the HIVconsvX vaccines from trials involving people living with HIV-1 will be available in the near future. Results ...

5. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/453936

Evaluation of Safety, Immunogenicity and Efficacy of a Triple ... The purpose of this study is to evaluate the safety, tolerability, and efficacy of therapeutic vaccination with chimpanzee adenovirus ChAdOx1- and poxvirus ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S266652472400209X

Safety and immunogenicity of the ChAdOx1–MVA-vectored ... We developed a T-cell immunogen-based bivalent mosaic vaccine, HIVconsvX, delivered by vaccine vectors ChAdOx1 and modified vaccinia Ankara.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05604209?tab=results

Safety and Immunogenicity of HIV-1 Vaccines C62-M4 or ... ChAdOx1.tHIVconsv1 (C1) and ChAdOx1.HIVconsv62 (C62) vaccines administered at Day 0, followed by MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) vaccines ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39612921/

Safety and immunogenicity of the ChAdOx1-MVA-vectored ... Low-dose C1 was safe and well tolerated in group 1, and all three vaccine components were well tolerated in volunteer group 2. There were no serious adverse ...

9. thelancet.com thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00309-4/fulltext

Safety and broad immunogenicity of HIVconsvX conserved ... Data on the safety and immunogenicity of the HIVconsvX vaccines from trials involving people living with HIV-1 will be available in the near ...