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AASLD 2013: Aspirin and Cenicriviroc May Help Reduce Liver Fibrosis

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Hepatitis C patients who took low-dose aspirin after liver transplantation experienced slower fibrosis progression, researchers reported at the AASLD Liver Meeting this month in Washington, DC. Two other studies showed that cenicriviroc -- a drug being developed for HIV treatment that blocks both CCR5 and CCR2 cell surface receptors -- had anti-inflammatory and anti-fibrotic activity in mice and rats.

Aspirin Post-transplant

Hepatitis C is a leading indication for liver transplantation in the U.S. and Europe. Hepatitis C virus (HCV) almost always recurs after transplantation, which can lead to aggressive fibrosis, cirrhosis, and loss of the new liver.

Chronic HCV infection triggers liver inflammation and damage to hepatocytes (primary liver cells). Fibrosis happens when hepatic stellate cells (support cells) in the liver produce collagen and other scar tissue material in an attempt to repair itself.

Armelle Poujol-Robert from Hôpital Saint Antoinein Paris and colleagues conducted a study to evaluate fibrosis progression in liver transplant recipients with recurrent HCV who received daily low-dose aspirin.

Thrombosis, or clotting in small blood vessels in the liver, contributes to fibrosis, and anti-coagulant and anti-platelet therapies have been shown to reduce fibrous tissue build-up in animal models, the researchers noted as background.

This retrospective study looked at nearly 200 hepatitis C patients who received liver transplants at 4 French centers between 2000 and 2010. More than 80% were men and the mean age was 52 years. About 45% had cirrhosis without hepatocellular carcinoma and 36% had moderate or greater histological activity (Metavir A2 or higher) between 6 and 18 months post-transplant, reflecting liver inflammation. People with hepatitis B or HIV coinfected were excluded. Follow-up was stopped if antiviral treatment was started.

There were 109 patients who received 75 to 100 mg daily aspirin, while 79 did not. There were no significant differences between the 2 groups with regard to donor age or sex, graft cold ischemia time, episodes of acute rejection, post-transplant diabetes, or type of immunosuppressive therapy.

Results

  • Fibrosis progression was slower in the aspirin group compared with the no-aspirin group.
  • Mean duration of progression to moderate or worse fibrosis (Metavir F2 or higher) was 4.6 vs 3.1 years, respectively.
  • In a univariate analysis, factors significantly associated with higher risk of fibrosis progression included older donor age, male donor sex, moderate or greater histological activity, and number of corticosteroid bolus doses received.
  • Aspirin use and older recipient age were protective against fibrosis progression.
  • HCV genotype, preservation injury, cold ischemia time, and post-transplant diabetes were not associated either way with fibrosis progression.
  • In a multivariate analysis, older donor age (hazard ratio [HR] 1.17 per 10 years), moderate to severe histological activity (HR 2.09), and number of corticosteroid boluses (HR 1.37) remained significantly associated with rapid fibrosis progression.
  • Aspirin (HR 0.65, or 35% risk reduction) was the only factor associated with slower fibrosis progression.
  • After adjustment for immunosuppressive therapy, aspirin remained significantly associated with reduced fibrosis progression (HR 0.59, or 41% risk reduction).

"Aspirin at low doses reduces liver fibrosis progression" in patients with HCV recurrence following liver transplantation, the researchers concluded.

"Aspirin may interfere with fibrosis progression through its anti-thrombotic and/or anti-inflammatory properties," they suggested. "Aspirin could represent a new clinical approach in the development of anti-fibrotic therapies" for transplant patients and people with other liver disorders without specific treatments.

Anti-fibrosis Activity of Cenicriviroc

A pair of studies presented at the conference looked at the effect of cenicriviroc (formerly TBR-652), a dual CCR5/CCR2 antagonist, on liver fibrosis in mice and rats. Cenicriviroc blocks the CCR5 co-receptor that HIV uses to enter cells, and it has shown promising efficacy as antiretroviral therapy in a Phase 2 trial. It also blocks CCR2, a receptor that plays a role in inflammatory response. CCR2 and CCR5 are present on monocytes, macrophages, and hepatic stellate cells.

Eric Lefebvreand colleagues studied the effect of cenicriviroc in a mouse model of non-alcoholic steatohepatitis (NASH), which is characterized by fat accumulation in the liver, fibrosis, and chronic inflammation, including macrophage activation. Like chronic hepatitis C, NASH can lead to cirrhosis or liver cancer as the liver attempts to repair itself.

Prior studies have suggested that CCR2 and its main ligand or binding partner, monocyte chemotactic protein-1 (MCP-1), contribute to macrophage recruitment in the liver. In HIV studies, levels of MCP-1 increased in people taking cenicriviroc, indicating that it effectively blocks CCR2. 

The researchers induced NASH in mice by administering streptozotocin, which causes insulin resistance, followed by a high fat diet. Mice then received placebo, low-dose (20 mg/kg/day), or high-dose (100 mg/kg/day) cenicriviroc orally for 3 weeks.

MCP-1 levels increased in cenicriviroc-treated mice, as previously observed in humans. Cenicriviroc had no effect on body weight, blood glucose, or liver triglyceride levels. However, mean alanine aminotransferase (ALT) levels -- an indicator of liver inflammation -- were significantly lower in both cenicriviroc dose groups compared with the placebo group. Levels of collagen type 1 messenger RNA also decreased by around 30% in the cenicriviroc-treated mice, as did percentage of liver area affected by fibrosis and histological activity score, primarily due to reduced inflammation.

These data suggest that cenicriviroc "has anti-fibrotic and anti-inflammatory activity in a mouse model of NASH, warranting further investigation," the researchers concluded. "These findings provide further evidence that disrupting the CCR2/monocyte chemotactic protein-1 axis may be a novel treatment approach for NASH."

In a related study, researchers studied the activity of cenicriviroc in rats that had liver fibrosis or cirrhosis induced by administration of thioacetamide, a hepatotoxic agent. Rats received placebo or 30 or 100 mg/kg/day cenicriviroc either concurrently with thioacetamide (early intervention), during weeks 4-8 (emerging fibrosis), or after completion of thioacetamide administration (established cirrhosis).

When started concurrently with thioacetamide, both low and high doses of cenicriviroc significantly reduced fibrosis by about 10%. Collagen type 1

protein levels and alfa-smooth muscle actin levels both decreased. Cenicriviroc led to reduced pressure in the portal vein and decreased aspartate aminotransferase (AST) levels. Expression of genes associated with fibrosis did not change, however.

When cenicriviroc was started during emerging fibrosis, a significant anti-fibrotic effect was observed in the low-dose cenicriviroc group, but not in the high-dose group. Significant decreases in collagen deposition in liver tissue and collagen type 1 protein levels were also observed in the low-dose mice. But when treatment was delayed until after cirrhosis was present, cenicriviroc had no significant effect on fibrogenic gene expression or fibrosis.

Based on these findings, the investigators concluded, "cenicriviroc is a potent anti-fibrotic agent in non-cirrhotic hepatic fibrosis due to thioacetamide. The drug was effective in early intervention and in emerging fibrosis, but not when cirrhosis was already established."

11/27/13

References

A Poujol-Robert, P Boëlle, F Conti, et al. Aspiring reduces liver fibrosis progression in hepatitis C recurrence after liver transplantation. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 62.

E Lefebvre, T Hashiguchi, H Jenkins, et al. Anti-fibrotic and anti-inflammatory activity of the dual CCR2 and CCR5 antagonist cenicriviroc in a mouse model of NASH. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract 30.

SL Friedman, F Hong, H Chou, et al. Significant  anti-fibrotic activity of cenicriviroc, a dual CCR2/CCR5 antagonist in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, November 1-5, 2013. Abstract LB-7.