Background
Programmed death (PD-1) is expressed on activated and exhausted T-cells and elevated expression persists on antiretroviral therapy (ART). PD-1 blockade can reverse HIV latency and increase HIV specific T-cell response in people with HIV and cancer. We investigated the effects of a single low dose of anti-PD1 (Nivolumab) as a potential strategy to reduce adverse events and still enhance HIV-specific T-cell function.
Methods
NIVO-LD is a two-part phase 1/2 trial in PWH on ART receiving a single low dose of Nivolumab (0.1, 0.3 or 1 mg/kg, n=6 for each dose). Fine needle aspirates aspirates (FNA) of a groin lymph node were collected before and 2 weeks after the infusion and regular blood sampling was performed over 24 weeks. The second part compares Nivolumab to placebo during ART interruption. We assessed safety, PD-1 receptor occupancy in blood and tissue by flow cytometry and quantified cell associated total HIV DNA by PCR.
Results
26 PWH were enrolled (Median 49 yrs, 88% male), with 8 screened out (5 positive anti-nuclear antibodies, 2 positive Glutamic Acid Decarboxylase, 1 elevated liver function). For 18 participants dosed there was one possible immune related adverse event (hepatitis) at 4 weeks post-Nivolumab (ALT 135 [Grade 2] and AST 181 [Grade 3] units/L) which resolved Other related events were: mild groin bruising/pain (n=16) post FNA in all cohorts and mild fatigue (n=9) in the 0.3-1 mg/kg cohorts which resolved. One unrelated serious adverse event (appendicitis) occurred and two unrelated increases in liver transaminases occurred 12 weeks post Nivolumab after significant alcohol intake which resolved with ceasing alcohol.
Median PD-1 occupancy in CD4+ / CD8+ T-cells in lymph node 2 weeks after 0.1, 0.3 and 1 mg/kg Nivolumab was 62%/62% [n=6], 91%/94% [n=4], and, 81%/84% respectively. Median PD-1 occupancy in blood was similar to lymph node at 2-weeks with increasing duration of occupancy with increasing dose (Figure). Compared to baseline, there was no statistically significant change in HIV DNA after 2- and 17-weeks of Nivolumab for all doses (n=6 [0.1 and 0.3 mg/kg], n=4 [1 mg/kg]; p=0.31).
Conclusions
A single low dose of Nivolumab at 0.1, 0.3 or 1 mg/kg was well tolerated. PD-1 receptor occupancy was similar in blood and lymph node was prolonged following1mg/kg. The second randomised part of the trial will progress with a single 1mg/kg dose.
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