Virological and Immunological Outcomes of Combined Therapeutic Interventions and Dendritic Cell Therapy in People With HIV

Abstract

Background: Except for hematopoietic cell transplantation, therapeutic-driven HIV-1 curative approaches have been unsuccessful. Here, we describe a 2-step randomized clinical trial designed to evaluate the safety and impact of individual and combinatorial therapeutic strategies on changes in peripheral and gut mucosal HIV reservoirs, immune activation and function in people with HIV with chronic disease and high CD4 T-cell nadirs.

Methods: Thirty participants were enrolled and randomized equally into 6 study arms based on treatments with either standard antiretroviral therapy (ART) alone or a combination of candidate anti-HIV reservoir strategies that included ART intensification, auranofin (an apoptotic-inducer antirheumatic drug), nicotinamide (vitamin B3), and a personalized dendritic cell therapy.

Results: After an analytical treatment interruption post intervention, all eligible participants rebounded within 14 weeks, except for 1 participant with rebound detected at 84 weeks and 2 participants receiving all combined therapies maintained viral loads below 1000 copies/mL through the study period. These posttreatment controllers all received nicotinamide containing regimens and exhibited immune cellular epigenetic age reversal.

Conclusions: This proof-of-concept clinical trial demonstrates the safety of multiple interventions with distinct antireservoir activities in people with HIV and argues for continued investigation of both single and combinatorial interventions towards posttherapy HIV control.

Keywords: CCR5; antiretroviral therapy (ART); cure; immunotherapy; nicotinamide.

Figure 1.

Participant flow diagram and trial design. Flow diagram of participant inclusion and randomization (A). SPARC-7 trial design and analysis (B). ART, antiretroviral treatment; ATI, analytical treatment interruption. Screening commenced on 24 August 2015, and the last study follow-up visit for the 48-week intervention period occurred on 28 August 2017. Personalized DC therapy for participants in arms E and F commenced on 14 August 2017, and the last participant received DC therapy on 8 December 2017. Subsequently, study participants were maintained on the same ART regimen they received before study initiation, with follow-up visits every 3 months.

Figure 2.

Changes in T-cell counts and viral load during the interventional period. Change in absolute CD4 (A) and CD8 (B) T-cell counts, CD4/CD8 ratio (C), and plasma HIV-1 RNA viral load (D) is shown according to the intervention groups.

Figure 3.

Cell-associated HIV RNA and DNA assessments in peripheral and rectal cells during interventional period and post-DC therapy. Cell-associated (CA) RNA (A) and total DNA (B) in PBMCs and in rectal tissue (C). CA-RNA and total DNA in PBMC time point differences per group were evaluated by repeated measures 1-way ANOVA with Geisser-Greenhouse correction and Tukey test for multiple comparisons. Total HIV DNA in rectal tissue differences were evaluated by paired t-test.

Figure 4.

Viral loads during ATI. Individual plasma HIV-1 RNA levels are shown and coded by intervention arm (A). Viral load set point pre- and posttherapy values were based on the latest documented viral load measurement across the interventions (B). Viral load set point differences per group were evaluated by paired t-test (2-sided) following Log transformation.