Triple Immune Regimen for HIV
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
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
Trial Summary
What is the purpose of this trial?The purpose of this study is to evaluate the safety, tolerability, and efficacy of therapeutic vaccination with chimpanzee adenovirus ChAdOx1- and poxvirus modified vaccinia Ankara (MVA)-vectored conserved mosaic T-cell vaccines in a sequential regimen with the toll-like receptor 7 (TLR7) agonist vesatolimod (VES) and two broadly neutralizing antibodies (bNAbs) compared to placebo, to induce HIV-1 control during analytic treatment interruption (ATI).
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.
What data supports the effectiveness of the Triple Immune Regimen for HIV treatment?
The research on enfuvirtide, a drug used in combination with other antiretrovirals, shows that it can significantly increase CD4+ cell counts and reduce HIV RNA levels, suggesting potential benefits for immune system improvement in HIV patients.
12345Is vesatolimod safe for humans?
Vesatolimod has been tested in humans and is generally considered safe, as it was evaluated in a Phase Ib study for people living with HIV-1, showing immune activation without significant safety concerns.
678910What makes the Triple Immune Regimen for HIV unique compared to other HIV treatments?
The Triple Immune Regimen for HIV is unique because it combines multiple components, including ChAdOx1 and MVA vectors, which are designed to stimulate the immune system in a novel way, potentially offering a different mechanism of action compared to traditional antiretroviral therapies that primarily target viral replication.
411121314Eligibility Criteria
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
I have taken a pregnancy test within the last 48 hours and it was negative.
I have completed a leukapheresis or LVBD procedure.
I have been on HIV treatment with specific drugs for at least 6 weeks.
My weight is between 50 kg and 115 kg.
Exclusion Criteria
I have had inflammatory diseases affecting my nervous system.
I have previously received treatment with a latency-reversing agent.
I have a history of bleeding disorders or I'm on long-term blood thinners.
I do not have serious skin conditions like severe rashes or eczema.
I have had a serious infection due to a weak immune system.
I have or recently had cancer that is not related to HIV.
I have a history of heart disease related to artery blockage.
My liver disease is in an advanced stage.
I have received a simian adenovirus-vectored vaccine before.
I have severe allergies or reactions to certain medications.
I haven't been hospitalized or needed serious treatment in the last 3 months.
I have received monoclonal antibody therapy, not for COVID.
I have had cancer linked to HIV.
I have HIV that is resistant to drugs in at least two classes.
I have or might have an active or untreated TB infection.
I have an autoimmune disease and am on continuous immunosuppressants.
Participant Groups
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.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Arm A: Active ChAdOx1 and MVA/HIVconsvX vaccines, vesatolimod and bnAbsExperimental Treatment7 Interventions
Group II: Arm B: Placebos for vaccines, vesatolimod and bnAbsPlacebo Group1 Intervention
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Northwestern University CRSChicago, IL
Ohio State University CRSColumbus, OH
University of California, San Diego AntiViral Research Center CRSSan Diego, CA
Washington University Therapeutics CRSSaint Louis, MO
More Trial Locations
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Who is running the clinical trial?
National Institute of Allergy and Infectious Diseases (NIAID)Lead Sponsor
Gilead SciencesIndustry Sponsor
University of OxfordCollaborator
References
Immunologic benefits of enfuvirtide in patients enrolled in a drug assistance program. [2018]Randomized clinical trials have demonstrated that enfuvirtide plus an optimized background regimen can cause a significant increase in CD4+ cell counts and a reduction in HIV RNA levels.
Effectiveness and Safety Analysis of PIs/r Based Dual Therapy in Treatment-Naïve, HIV/AIDS Patients: A Network Meta Analysis of Randomized Controlled Trials. [2022]Background: Dual anti-retroviral therapy is the main proven valuable intervention type for treating naïve HIV/AIDS. Currently, no high-quality evidence is available regarding the best dual schemes. Objectives: The aim of this study is to evaluate the effectiveness and safety of PIs/r-based dual therapy in treatment-naïve HIV/AIDS patients by using network meta-analysis. Methods: Randomized controlled trials of PIs/r-based dual therapy in treatment-naïve HIV/AIDS were searched based on Embase, PubMed and Cochrane library database from January 2006 to June 2021. Taking viral suppression rate, CD4+T cell count changes from baseline as the primary indicator and adverse events rate as secondary indicator, the network meta-analysis was performed on Review Manager and STATA software. Heterogeneity was assessed by the Q statistic and I2. We registered our protocol in Prospero with ID CRD42021275466. Results: Among 15 randomized controlled trials (3,497 patients and 7 PIs/r-based dual therapy) were reviewed in this study. According to the forest map, DRV/r + INSTIs was more effective compared to triple therapy (TT) in viral suppression [OR 0.82, 95% CI (0.61-1.11)], in CD4+T cell count changes from baseline [MD 1.9, 95% CI (0.7, 3.1), I 2 86%], in adverse events [OR 0.98, 95% CI (0.68-1.39)]. Furthermore, SUCRA ranking analysis indicated that DRV/r + INSTIs was superior to TT in viral suppression (DRV/r + INSTIs 75.5% > TT 41.2%) and in immune construction (DRV/r + INSTIs 67% > TT 42%). In addition, DRV/r + INSTIs was similar to TT in adverse events (DRV/r + INSTIs 54.9% ≈ TT 54.7%). Conclusion: DRV/r + INSTIs was obviously superior to TT in viral suppression and immune reconstruction, and was not higher than TT in adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021275466.
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). [2020]Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens.
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. [2013]We have individually treated ten AIDS patients whose CD4 numbers were inferior to 200/mm3, with the five following HIV1 virostatics: a) azido-deoxythymidine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), which affect the same viral target, retrotranscriptase, b) acriflavine (ACF) and methyl-hydroxy-ellipticine (MHE) which we have discovered to be strong virostatics in vivo, in mice, against Friend's virus, and in man, against AZT resistant HIV1. We have shown that their combinations with AZT, hitting three viral targets, reduces in mice, the blood Friend's virus load below detectable level. Due to the short doubling time of HIV1, AIDS therapy must be continuous, and to allow the best tolerance, the five virostatic combinations were applied in short, three-week sequences, each differing as much as possible from the former and from the following one, due to drug rotation [1]. Among the ten patients, a) three received the two-drug combinations for 15 to 30 months, followed by the three-drug combinations, b) three received the three-drug combinations from the beginning, c) four received the four-drug combinations also from the beginning, two having less than 10 CD4/mm3 at initiation of treatment, and two having more than 100. The tolerance was remarkable: the only side-effect being macrocytosis. The application of the two-drug combination sequences maintained stable CD4 levels in two subjects whose viral load (the evaluation of which had became available) was, at the end of this period, of 4,486 and 39,238 RNA copies. The third subject who had received, an intensive UV irradiation for a psoriasis, presented an irreversible decrease in his CD4 count and a high viral load (1,352,495 RNA copies/mL) at the end of the two-drug period. Fifteen to 25 months after the shift to the three-drug combinations, the viral load decreased, from 39,328 to 13,291 in one of the non-UV irradiated subjects, and from 1,352,495 to 314,387 in the irradiated one. No subject had an increase in CD4 number. In the three patients having initially received the three-drug combinations, a very strong decrease of viral load was registered after periods of observation varying from 77 to 40 months, while the CD4 counts increased moderately in two subjects, and noticeably in the third (from 126 to 266). Out of the four subjects initially treated with four-drug combinations, the two with less than 10 CD4/mm3 had a moderate decrease in viral load in about three months, and the CD4 increased from 9 to 34/mm3 in one. But the two subjects, because of opportunistic infections and psychological reasons, abandoned their treatments. In the two subjects who had more than 100 CD4/mm2 at initiation of the four-drug combination treatment, the viral load decreased to undetectable levels after four months: but their CD4 counts, after some oscillations, had very moderately increased at the end of the observation period (respectively, from 200 to 222, and from 129 to 134). In practice, these results suggest the interest of conducting phase II or III studies of AIDS treatment protocols, starting with the four-drug combination model, and attempting to maintain the effect with the three-drug combination one. As for theoretical considerations, one must underline the contrast between the remarkable reduction of the viral load and the usually moderate increase of the CD4 counts. The study but not the trial has been interrupted, due to the unavailability of three antiproteases, saquinavir, ritonavir and indinavir, which are now introduced in the same type of combinations, one by one, in replacement of one of the studied agents as shown in figure 1. The effect of increasing the total number of virostatics from five to eight will be published in the second part of this article series.
[Therapeutic indications, antiretroviral treatment optimization and quality of life of patients taking enfuvirtide]. [2018]In combination with other antiretroviral drugs, enfuvirtide is indicated in the treatment of HIV-1 patients, exposed or with failure to previous therapy with at least one of each of the three antiretroviral drugs classes (nucleoside inhibitors, non nucleoside inhibitors and protease inhibitors) or intolerant to these therapies. Genotypic resistance tests are helpful to evaluate acquired resistance to individual drugs, to select the remaining active drugs and to eliminate from the background regimen those with characterized resistance. In patients receiving enfuvirtide plus an optimized background regimen, the best results are reported in those with a baseline CD4+ count above 100/mm3, a plasma viral load below 100000 copies/ml, having been previously treated with less than 10 antiretroviral drugs and having at least 2 active drugs in their background regimen. Patients combining these 4 criteria have an 80% chance to have a plasma viral load below 400 copies/ml after a 24 weeks course of therapy. In terms of Quality of Life, studies demonstrated that patients treated with enfuvirtide have improvement in many measures of health-related quality of life, comparatively to those receiving the optimized therapy alone.
Activation of HIV-specific CD8+ T-cells from HIV+ donors by vesatolimod. [2021]Label="BACKGROUND">Vesatolimod (VES; GS-9620) is a Toll-like receptor 7 (TLR7) agonist that directly activates human plasmacytoid dendritic cells (pDCs) and B lymphocytes resulting in direct and indirect production of cytokines and immune activation. VES is being evaluated in HIV-1-infected people as part of an HIV remission strategy. Here we investigated the potential of VES to trigger indirect activation of HIV-specific CD8+ T-cells using immune cell cultures derived from HIV+ donors.
The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy. [2022]Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1-infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.
Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus-1. [2021]Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1.
Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1. [2018]We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.
Lopinavir/ritonavir vs. indinavir/ritonavir in antiretroviral naive HIV-infected patients: immunovirological outcome and side effects. [2013]We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.
Highly active antiretroviral therapy including protease inhibitors does not confer a unique CD4 cell benefit. The AVANTI and INCAS Study Groups. [2004]To determine if triple combination therapy, particularly including HIV protease inhibitors (PI), confers an unique immunological benefit that is independent of reductions of plasma viral load (pVL).
Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine. [2019]We attempted to determine whether HIV-1 developed resistance to (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection during therapy with 3TC. Genotypic analysis of HIV-1 strains isolated from 6 patients receiving 3TC revealed that as early as 2 months of therapy, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met184-->Val) in the reverse transcriptase-coding region of the pol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with Ile by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution were profoundly less susceptible to 3TC (1800- to 5500-fold decreased sensitivity) as compared to pretherapy virus strains. These strains were also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14-fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient. Our data suggest that reversal of such beneficial changes is associated with the Met184-->Val substitution of the pol gene of HIV-1. The data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection, but only transiently.
Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients. [2022]Virologic outcome among 104 lamivudine (3TC)-experienced individuals infected with human immunodeficiency virus type 1 who switched to a didanosine (ddI)-containing triple- or quadruple-drug regimen was compared with those who continued receiving a 3TC-containing regimen. A significantly increased independent risk of virologic failure was associated with continuing a 3TC-containing regimen. In addition, most patients for whom the ddI-containing regimen failed lost the M184V/I mutation. These results show that ddI continues to provide activity against viruses with the M184V/I mutation and suggest that the presence of the M184V/I mutation should not preclude the use of ddI in nucleoside-experienced patients.
Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir. [2022]Simplified antiretroviral regimens have been developed with the aim of improving treatment adherence and quality of life of HIV-infected patients. The single-class triple-nucleoside reverse transcriptase inhibitor combination has contributed to the improvement of the management of HIV infection, especially in patients with adherence problems and special groups of the patient population. Such a regimen remains an alternative option because of lower virological efficacy compared with the preferred multiclass antiretroviral regimens. However, recently, a nucleoside reverse transcriptase inhibitor abacavir/lamivudine/zidovudine plus tenofovir has been investigated in both antiretroviral-naive patients and in heavily pre-treated patients, as well in the setting of simplification/switching strategies. This experimental combination could be a safe and attractive option that offers the advantages of limited toxicity, few drug interactions and the use of future treatment options with new drugs, especially for patients in later stages of infection.