Anti-HCV and Anti-fibrotic Effects of Drugs Used for Other Indications  

By Liz Highleyman

The current standard therapy for chronic hepatitis C -- pegylated interferon alpha plus ribavirin -- does not produce a cure in about half of all patients. In addition, better treatments are needed for individuals with HCV who have already developed significant liver fibrosis or cirrhosis.

Several research teams at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston (November 2-6, 2007) presented data from studies looking at drugs usually used for other indications -- such as managing high cholesterol or high blood pressure -- in the treatment of hepatitis C and the management of liver disease.

Bezafibrate (Abstract 291)

Previous studies have shown that lipoproteins play a role in HCV infection of cells. Further, a recent study from Japan indicated that some statin drugs, used to lower blood cholesterol, demonstrated activity against HCV in the test tube..

At the AASLD meeting, German researchers presented data from a laboratory study of bezafibrate, a member of a different class of cholesterol-lowering drugs known as fibrates. Bezafibrate alters lipid metabolism by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which modulates the expression of key genes involved in lipid transport, fatty acid and lipoprotein metabolism in the liver, and inflammation.

The investigators assessed the efficacy and safety of bezafibrate monotherapy in 34 patients with advanced chronic hepatitis C who did not achieve sustained response to previous combination therapy with pegylated interferon plus ribavirin. All but one had hard-to-treat HCV genotype 1, about half (n=18) had advanced fibrosis, and 16 had compensated cirrhosis. All participants received open-label oral bezafibrate 400 mg/day.

Clinical, biochemical, and virological data were evaluated over an average treatment duration of 12 months (range 2-49 months).

Results

• 3 patients dropped out of the study complaining of vertigo (dizziness) or palpitations within the first days of treatment.

• Among the remaining 31 patients, no major adverse events were reported.

• During treatment, all patients experienced a significant improvement in alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) levels.

• In 3 patients, liver enzyme levels normalized completely.

• The mean ALT level fell from 108 to 80 IU/L (P < 0.025).

• The mean GGT level decreased from 171 to 107 IU/L (P < 0.001).

• However, the mean aspartate aminotransferase (AST) level did not change significantly, falling from 91 IU/L at baseline to 88 IU/L at the end of the observation period.

• Overall, there was no significant effect on HCV viral load (mean HCV RNA 5.8 log₁₀ IU/mL at baseline vs 5.9 5.8 log₁₀ IU/mL at the end of observation).

• Only 1 patient experienced an HCV viral load decline of 1 log₁₀ after 11 months of treatment.

Based on these findings, the researchers concluded, “This observational study provides evidence that bezafibrate is effective for patients with chronic hepatitis C by reducing significantly ALT and GGT levels and could be therefore a therapeutic option, especially for those, in whom peg-interferon combination treatment was previously unsuccessful.”

Angiotensin-blocking Agents (Abstract 1047)

Evidence from prior studies has implicated the blood protein angiotensin II as a factor implicated in liver fibrogenesis. Angiotensin II appears to induce oxidative stress, promote liver inflammation, and stimulate collagen gene expression. Thus, suggest that angiotensin-blocking agents may help lessen fibrosis.

Researchers at AASLD reported data from retrospective chart review of histological data from 234 chronic hepatitis C patients with hypertension (high blood pressure) treated at Massachusetts General Hospital between 2001 and 2006.

Patients in Group 1 (n=143) received angiotensin-blocking agents -- either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blocking agents -- while those in Group 2 (n=91) received other types of drugs to treat hypertension (including beta-adrenergic blocking agents, calcium antagonists, alpha-adrenergic blocking agents, and diuretics).

The 2 groups were similar with respect to age, sex, HCV genotype, baseline HCV RNA level, and estimated duration of HCV infection; however, Group 1 included 3 times as many diabetic patients (30% vs 11%).

The analysis found that there was a significant difference in Ishak fibrosis scores: 3.20 in Group 1 vs 3.73 in Group 2 (P = 0.04). A subgroup analysis of the non-diabetic patients demonstrated an even more significant difference: 3.07 in Group 1 vs 3.69 in Group 2 (P = 0.023).

The researchers concluded that, “The administration of angiotensin-blocking agents in patients with HCV infection and hypertension was associated with histological evidence of decreased fibrosis. In patients without diabetes, this difference was even more pronounced.”

They added that, “These data provide support for prospective evaluation of ACE inhibitors or [angiotensin II receptor blocking agents] as possible hepatic fibrosis inhibitors in patients with HCV.”

Another group investigated the effect of a specific angiotensin II receptor blocking agent, losartan (Cozaar), on liver fibrogenesis in hepatitis C patients who did not respond to antiviral therapy.

In this study, 14 patients with chronic hepatitis C and significant liver fibrosis (stage F2-F4) received oral losartan 50 mg/day for 18 months. Two paired liver biopsies were performed before and after treatment. The degree of fibrosis and inflammation was evaluated by histological analysis according to the METAVIR scoring system. Collagen content and the amount of myofibroblasts and inflammatory cells in biopsy samples were also estimated. Liver fibrogenesis was assessed by quantifying expression of key genes encoding extracellular matrix proteins, fibrogenic mediators, inflammatory cytokines, pro-oxidant proteins, and components of the renin-angiotensin system.

Results

• Oral losartan was associated with a decrease in inflammatory activity in 8 patients (57%) and a decrease in fibrosis stage in 7 patients (50%).

• Losartan was also associated with significant reductions in the expression of key genes involved in liver fibrogenesis, ranging from 23% to 40%.

• Patients with reduced inflammatory activity exhibited down-regulation of procollagen-alpha-1(I), TIMP-1, and inflammatory cytokines, as well as a significant decrease in the CD43-positive area.

• Patients with improved fibrosis showed a reduction in collagen content and the amount of myofibroblasts, compared to those with without fibrosis improvement.

• Losartan was well tolerated overall, and did not affect kidney function.

• Losartan was not associated with a reduction in HCV viral load or liver function tests.

The investigators concluded that, “Oral losartan for 18 months decreases the expression of genes involved in liver fibrogenesis and reduces the inflammatory activity in patients with chronic hepatitis C.”

Another group of researchers presented data from an animal study of one of the statin drugs, atorvastatin (Lipitor). Here, rats were infused with either saline or angiotensin II for 4 weeks, and received either atorvastatin 40 mg/kg/day or placebo. Degree of liver inflammation, oxidative stress, and expression of genes involved in the hepatic wound healing response -- which involves increased production of fibrous tissue -- were assessed.

Infusion of angiotensin II into normal rats resulted in liver inflammation, as indicated by an increased necroinflammatory score and infiltration of CD43-positive cells; it also caused thickening of hepatic vessels. However, these effects were markedly reduced by the administration of atorvastatin. Atorvastatin also prevented oxidative stress, attenuated production of tumor necrosis factor alpha and interleukin-6, and reduced procollagen-alpha-1(I) and TGF-beta-1 gene expression caused by angiotensin II.

Next, they studied the effects of angiotensin II and atorvastatin on cultured hepatic stellate cells, the liver cells that produce the extracellular matrix proteins responsible for fibrosis. Angiotensin II stimulated stellate cell proliferation, pro-inflammatory action, and increased expression of procollagen-alpha-1(I), all of which were reduced in the presence of atorvastatin.

The researchers concluded that, “Atorvastatin attenuates the inflammatory and fibrogenic effects of angiotensin II in the liver. Therefore, statins could have beneficial effects in conditions characterized by hepatic inflammation and fibrogenesis.”

Celecoxib (Celebrex) is a selective COX-2 inhibitor non-steroidal anti-inflammatory drug used to treat painful conditions such as rheumatoid arthritis. A South Korean research team had previously shown that celecoxib has an anti-proliferative and pro-apoptotic (promoting programmed cell death) effect on human hepatic stellate cells.

In a study reported at the AASLD meeting, the same researchers investigated the mechanism underlying the pro-apoptotic effect of celecoxib in a human hepatic stellate cell line in the laboratory, and evaluated the drug’s anti-fibrotic effect in rats with chemically induced liver fibrosis or bile duct ligation.

In the cell culture study, celecoxib induced hepatic stellate cell apoptosis. This was significantly attenuated in cells infected with adenoviruses expressing Akt, but not GFP.

In the rats with chemically induced liver fibrosis, but not those with bile duct ligation, celecoxib administration was associated with decreased ALT, AST, and alkaline phosphatase levels. Celecoxib also decreased hepatic extracellular matrix deposition in rats with both types of liver damage. Further, celecoxib-treated rats showed significantly decreased expression of COX-2, alpha-SMA, TGF-beta-1, and collagen-alpha-1(I) compared with untreated rats.

Celecoxib “shows anti-fibrogenic effects” in rats with both bile duct ligation and chemically induced fibrosis, “suggesting celecoxib as a potential anti-fibrotic agent for hepatic fibrosis,” the investigators concluded. “Celecoxib-induced inhibition of Akt activation in hepatic stellate cells at least partially contributes to the anti-fibrotic effect of celecoxib.”

Together, these studies suggest that various medictaions most often prescribed for other conditions -- including angiotensin-blocking agents, statins, and COX-2 inhibitors -- may play a role in reducing fibrosis progression in people with chronic hepatitis C. None of these studies, however, demonstrated a direct effect of these drugs on HCV replication.

12/04/07

References

V Weich, B Schlosser, J Halangk, and others. Bezafibrate treatment for chronic hepatitis C after failure of previous combination therapy with Interferon and Ribavirin. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA, November 2-6, 2007. Abstract 291.

N Shah, H Zheng, J Misdraji, and others. Beneficial Effect of Angiotensin-Blocking Agents on Liver Fibrosis in Patients with Hepatitis C. AASLD 2007. Abstract 1047.

J Colmenero, R Bataller, P Sancho-Bru,and others. Losartan Reduces The Expression Of Profibrogenic Genes And Inflammation In Patients With Chronic Hepatitis C. AASLD 2007. Abstract 1078.

LN Ramalho, M Moreno, P Sancho-Bru, and others. Atorvastatin attenuates Angiotensin-II induced inflammatory and fibrogenic actions in the liver. AASLD 2007. Abstract 1079.

Y Paik, K Lee, S Kang, and others. Celecoxib shows anti-fibrotic effect in hepatic fibrosis models in rat and induces apoptosis of hepatic stellate cells through inhibition of Akt activation. AASLD 2007. Abstract 1081.