Combination antiretroviral therapy (cART) disrupts the fatal course of infection but does not eradicate the HIV reservoir. Previously we have shown that 4 weeks treatment with the TLR9 agonist lefitolimod (MGN1703, Mologen AG) adjunctive to cART functions as both a latency reversing agent and as activator of cytotoxic NK cells. In this 2nd part of the trial, we assessed safety and evaluated if extended administration of lefitolimod could enhance the HIV-specific T cell responses, decrease the latent reservoir and prolong time to rebound.
This was a phase Ib/IIa, open label, investigator-initiated clinical trial (NCT02443935). We included 13 HIV-infected individuals on cART. Lefitolimod (60 mg s.c.) was administered twice weekly for 24 weeks while participants remained on cART. Safety was assessed at each visit. After the 24-week dosing period, most participants initiated an analytical treatment interruption (ATI) until viral rebound occurred (two consecutive plasma HIV RNA >5000 c/mL). Blood samples were collected at baseline, after 12 and 24 weeks and at time of rebound. HIV-specific immunity was assessed by CD8+ T cell intracellular cytokine stain (ICS) for IFN-γ, TNF-α and IL-2. Total HIV DNA was measured by ddPCR. Plasma HIV RNA was measured by Cobas Taqman assay.
Lefitolimod was safe and well tolerated. ICS revealed a significant (p=0.0068) cohort-wide increase in IFN-γ response in HIV-specific CD8+ T Effector Memory (TEM) and Terminally Differentiated (TTD) cells from baseline to after 24 weeks treatment. On a cohort level, HIV DNA did not change significantly during the treatment period. During the ATI, one individual who initiated cART during chronic infection (pre-cART HIV RNA >100,000 c/mL and nadir CD4 of 29 cells/µL) demonstrated plasma HIV RNA levels below limits of detection (20 c/mL) for >21 weeks. Notably, this person had the highest percentage of polyfunctional HIV-specific CD8+ TEM (IFN-γ+, TNF-α+ and IL-2+) which further increased 3-fold from baseline to end of treatment, indicating that polyfunctional HIV-specific CD8+ T cells might have contributed to the observed virological control. Time to rebound for the remaining 8 individuals participating in the ATI was comparable to historical data.
In conclusion, 24 week adjunctive TLR9 agonist therapy was safe, enhanced HIV-specific T cell responses and might increase time to rebound in some individuals with strong polyfunctional HIV-specific CD8+ TEM responses.