Table 1 Overview of ‘kick’ studies in humans completed to date
From: Landscape review of current HIV ‘kick and kill’ cure research - some kicking, not enough killing
Study | Drug Studied | Patient Eligibility | No. Pts | Study Design | Tx Dose and Duration | Length of Study | Key findings |
|---|---|---|---|---|---|---|---|
Agents targeting cellular transcription factors | |||||||
Lehrmann 2005 | Valproic Acid (HDACi) | Viral RNA < 50cp/mL for at least 2 years | 4 | Proof-of-concept | 500-750 mg bid for 3 months | 18 weeks | 68%–83% reduction in resting infected CD4 T-cells in 3 of 4 patients |
Sagot-Lerolle et al. 2008 | Valproic Acid (HDACi) | Viral RNA < 50cp/mL for at least 2 year | 24 | Retrospective matched cohort study (pilot) | Not reported (retrospective) | 2 years | No difference in viral DNA quantified in PBMCs |
Archin 2010 | Valproic Acid (HDACi) | Viral RNA < 50cp/mL for at least 6 months; healthy CD4 T-cells >300/μL | 12 | Single arm phase 1 trial | 1000 mg qd (Depakote ER) | 16 weeks | No sustained depletion of resting CD4+ T-cell infection observed |
Routy et al. 2012 | Valproic Acid (HDACi) | Viral RNA < 50cp/mL for at least 1 year; healthy CD4 T-cells >200/μL | 56 | Multicenter randomized cross-over trial | Up to 500 mg bid (as per tolerance) | 16 weeks (× 2) | No reduction in CD4 T-cells with replication-competent HIV |
Elliot et al. 2014 | Vorinostat (HDACi) | Not reported Baseline CD4 T-cell count range from 371 to 1136 | 20 | Proof-of-concept single arm | 400 mg bid for 14 days | 12 weeks | Cell-associated unspliced RNA Increased by 7.4 fold at 14 days |
Archin et al. 2013 | Vorinostat (HDACi) | Viral RNA < 50cp/mL for at least 6 months; healthy CD4 T-cells >300/μL | 11 | Proof-of-concept single arm | 200 mg initially 400 mg after 2–3 and 4–5 weeks | 5 weeks | RNA expr. in resting CD4+ T-cells increased 4.8 fold (1.5–10) |
Rasmussen et al. 2014 | Panobinostat (HDACi) | Viral RNA < 50cp/mL for at least 2 years; healthy CD4 T-cells >500/μL | 15 | Phase 1/2 | 20 mg three times/week for 8 weeks | 32 weeks | Cell-associated RNA Increased during treatment by 3.5 fold |
Soegaard 2015 | Romidepsin | Viral RNA < 50cp/mL for at least 2 years; healthy CD4 T-cells >500/μL | 6 | Proof-of-concept phase II | One 4 h 50 mg infusion per week for 3 weeks | 70 days after last infusion | Plasma RNA increased to detectable levels in 5/6 patients |
Katlama 2016 | IL-7 agonist Raltegravir Maraviroc | Viral RNA < 200cp/mL last 3 years, <50cp/mL last 6 months, CD4 T-cells >350/μL | 29 | Randomized trial | 8 weeks of RAL + MAR intensification, then 3 x weekly 30mcg/kg of IL-7 | 28 weeks | Data safety monitoring board stopped trial at 28 weeks due to concerns of >1500 CD4+ T-cell counts |
Levy Y 2012 | IL-7 recombinant | Viral RNA < 50cp/mL for at least 6 months; healthy CD4 T-cells: 100–400/μL | 32 | Randomized trial | weekly 10, 20, or 30mcg/kg for 3 weeks | 52 weeks | IL-7 well tolerated up to 20mcg/kg. Brisk increase in CD4 count. |
Sereti 2009 | IL-7 recombinant | Viral RNA < 50cp/mL (grp 1) Viral RNA < 50,000cp/mL (grp 2) for at least 12 months; healthy CD4 T-cells > 100/μL | 25 | Randomized double blind | Single dose of 3, 10, 30, 60 or 100μg/kg | 8 weeks | 30μg/kg max tolerable dose. Significant increase in transient HIV-RNA in 6 patients. Increase in central memory phenotype T-cells |
Vibholm 2017 | TLR-9 agonist (MGN1703) | Viral RNA < 50cp/mL for at least 12 months; healthy CD4 T-cells >350/μL | 15 | Phase 1/2a Single arm | 60 mg MGN1703 subcutaneously twice weekly for 4 weeks | 4 weeks (80 days follow-up) | Pronounced activation of plasmacytoid dendritic cells. Significant increase in proportions of activated cytotoxic NK cells and CD8+ T cells |
Epigenetic modulation agents | |||||||
Elliott et al. 2015 | Disulfram | Viral RNA < 50cp/mL for at least 3 years; healthy CD4 T-cells >350/μL | 30 | Non-randomized prospective dose-escalation | Three days of 500 mg, 1000 mg, or 2000 mg | 30 days | Approximately 2-fold increase in cell-associated RNA |
Spivak et al. 2014 | Disulfram | Viral RNA < 50cp/mL for min 1 year; healthy CD4 T-cells >500/mcg for min 24 weeks | 16 | Pilot single arm | 500 mg/day for 14 days | 84 days | Well-tolerated, but latent reservoir did not change in size |
Gutiérrez et al. 2016 | Bryostatin-1 | Viral RNA < 50cp/mL for at least 2 years; healthy CD4 T-cells >350/μL | 12 | Double-blind randomized phase I trial | Placebo 10mcg/mm2 20mcg/mm2 | 672 days | No detectable difference in cell-associated unspliced RNA |