Zinc combination therapy shows slight trend toward survival benefit in alcoholic hepatitis

SAN FRANCISCO — Combination therapy with Kineret, Trental and zinc sulfate showed only a slight trend toward 90-day improved survival in patients with alcoholic hepatitis but otherwise showed little benefit, according to data presented at The Liver Meeting 2018.

Gyongyi Szabo, MD, of the University of Massachusetts Medical School, and colleagues, aimed to target inflammation with anakinra (Kineret, Sobi) 100 mg subcutaneously for 14 days, protect from cellular injury using oral Trental (pentoxifylline, Pentoxil) at 400 mg three times daily for 28 days, and manage gut leakiness with zinc at 220 mg daily for 6 months. Patients in the control arm received treatment with methylprednisolone 32 mg daily orally for 28 days.

“Our hypothesis was that targeting key pathogenic factors will improve survival in alcoholic hepatitis,” Szabo said. “The pathogenic role of IL-1 in alcoholic hepatitis has recently received attention.”

Szabo suggested that biomarkers associated with challenges in treating alcoholic hepatitis include endotoxin, TNF-alfa, plasma 16S, and cytokeratin 18 M65. She outlined the pathogenic role of IL-1 in this patient population, suggesting that it upregulates other cytokines, sensitizes hepatocytes to cell death, impairs hepatocyte regeneration and stimulates fibrosis.

The final data set included 53 patients in the combination therapy arm, and 50 controls. Six-month mortality served as the primary outcome measure, while 30- and 90-day mortality and changes in MELD score at 30, 90 and 180 days served as secondary endpoints.

“There were no differences in baseline demographics between treatment groups in relation to age, race, gender, ethnicity, or family history of alcoholic liver disease,” Szabo said

At 30 days, the survival rates were 83.4% for the combination group vs. 81.2% for controls (HR = 0.91). At 90 days, the rates were 69.7% for combination group and 55.8% for controls (HR = 0.69; P = .28). By 180 days, the rates were 66.7% for the combination group and 52.8% for controls (HR = 0.69).

Looking at MELD score, patients with a score of 20 to 25 experienced significantly improved survival compared with patients who scored 26 or greater (P = .002). However, the difference in survival between combination therapy and treatment with methylprednisolone was not significant regardless of MELD score.

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Compliance rates were 96.1% for the IL-1 injections and just shy of 90% for the oral therapies in the combination.

There were 63 serious adverse events among patients in the combination therapy arm and 64 serious events in the methylprednisolone group. Infections occurred more frequently in patients treated with methylprednisolone, 26.4% vs. 42%.

Acute kidney injury rates were also comparable between the two arms.

“A combination of anakinra, pentoxifylline and zinc provides comparable survival at 30 days with a trend towards improved survival at 90 and 180 days compared to standard therapy with methylprednisolone in patients with severe alcoholic hepatitis,” Szabo concluded. “Initial MELD score is an important predictor of survival at 30, 90 and 180 days.

Future studies should consider 90-day survival endpoints and include patients with high MELD scores.” – by Rob Volansky

Reference:

Szabo G, et al. Abstract LB-1. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.

Disclosure: Szabo reports being a scientific consultant for Allergan, Arrow Diagnostics, Carlos Foundation, GLG, Glympse Bio, Quest Diagnostic, Salix, Terra Firma, and Tobira; and receiving grants or research support from Allergan, Genfit, Gilead, Intercept, Novartis, Shire, SignaBlok, and Verlyx.

Editor's note: Changes were made to the article to better reflect the data presented.