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Edoxaban lowers coagulation but not inflammation in people on ART
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Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2019, Seattle
From Jules: this is the 2nd anti-inflammation drug presentation showing benefit plus Jak inhibitor study which I reported already.
Mark Mascolini
Edoxaban, which inhibits a blood coagulation factor called FX or Factor 10, reduced coagulation marker levels in HIV-positive people taking effective antiretroviral therapy (ART), but it did not ease inflammation marker levels [1]. US researchers who conducted this trial suggested the significant anticoagulant activity of edoxaban may help lower risk of serious non-AIDS events or death.
The FX inhibitors edoxaban (Savaysa) and rivaroxaban (Xarelto) are prescribed to prevent or treat deep vein thrombosis and pulmonary embolism. Because edoxaban has fewer interactions with antiretrovirals, researchers from the University of Minnesota and other centers picked it to assess anticoagulant and antiinflammatory activity in people with HIV. Plentiful evidence links ongoing inflammation and coagulation to end-organ disease in HIV-positive individuals taking suppressive ART.
This pilot trial enrolled 44 antiretroviral-treated people with a viral load below 200 copies for at least 2 years and levels of D-dimer, a coagulation marker, above 100 ng/mL [2]. Researchers randomized half of participants to add edoxaban (30 mg daily) to their ART for 4 months and half to add placebo. After an interim 4 months without edoxaban or placebo, the edoxaban group switched to placebo and vice versa.
Among all study participants median age stood at 51, 91% were men, and 70% were white. Median CD4 count measured 675 and everyone had a viral load below 200 copies. A median 11 years had passed since this group began antiretroviral therapy.
Sixteen of 20 randomized people in one group and 17 of 20 in the other completed all study visits. A significantly higher number of people had grade 1 or 2 bleeding or bruising while taking edoxaban than while taking placebo (33 versus 17, P = 0.03) and the total adverse event rate was marginally higher during edoxaban therapy (43 versus 27, P = 0.06). Researchers recorded 1 serious adverse event during edoxaban treatment and 1 during the placebo period.
Compared with placebo, edoxaban did not significantly reduce markers of inflammation or monocyte activation (IL-6, TNF-RI, IL-1beta, sCD163, sCD14). But treatment with the FX inhibitor did significantly lower coagulation activity as measured by D-dimer (42% lower than placebo) and thrombin-antithrombin (26% lower than placebo).
The researchers noted that participants had low IL-6 levels when entering the trial, indicating they had only modest inflammation when starting edoxaban. The investigators believe epidemiologic data suggest that "even in the absence of an effect on IL-6, the 40% decline in D-dimer levels would predict about a 25% reduction in risk for serious non-AIDS events or death." The investigators called for further research to explore mechanisms of HIV-associated coagulopathy, "some of which are likely distinct from drivers of systemic inflammation."
References
1. Baker JV, Wolfson J, Peterson T, et al. Factor X inhibition reduces coagulation but not inflammation in persons with HIV. Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2019. Seattle. Abstract 36.
2. ClinicalTrials.gov. Targeted Anticoagulation Therapy to Reduce Inflammation and Cellular Activation in Long-term HIV Disease (TACTICAL-HIV). ClinicalTrials.gov identifier NCT02339415. https://clinicaltrials.gov/ct2/show/NCT02339415
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