Antiviral Activity Demonstrated in Interim Phase Ib and Consistent with Phase Ia Dose Tolerance, Pharmacokinetics and Immune Response Findings

Depression caused by common treatment for hepatitis C may affect outcome

A lead researcher for a high-stakes trial comparing the world's top-selling drugs for hepatitis C said the study's design could "bias" results in favor of Schering-Plough Corp.'s product.

"Unfortunately life is not perfect and this study is not perfect as well," Dr. John McHutchison, co-lead investigator of the Schering-Plough (SGP.N: Quote, Profile, Research) trial, told Reuters in an interview on Thursday.

Schering-Plough's Peg-Intron and Roche Holding AG's (ROG.VX: Quote, Profile, Research) more popular rival medicine, Pegasys, are both injectible forms of interferon [alfa]. They are used in 48-week treatments with a pill called ribavirin that helps them eradicate the hepatitis C virus, the biggest cause of liver transplants.

McHutchison, a Duke University researcher, said the study's design will probably allow more patients receiving Peg-Intron to stay on stronger doses of ribavirin than those taking Pegasys. "Maintaining the (highest tolerable) dose of ribavirin, regardless of which interferon is used, is very important for controlling the virus, particularly in the early part of treatment," McHutchison said.

Schering-Plough in May launched the 2,880-patient U.S. trial, called IDEAL,  and hopes to unveil results in 2007 that will prove Peg-Intron is superior. Should it triumph, Schering-Plough aims to use the data as a marketing weapon to stem lagging sales of its one-time blockbuster, and help the struggling drug maker regain earnings growth.

Peg-Intron and Schering-Plough's brand of ribavirin had combined third-quarter sales of $184 million, a fraction of the $703 million they boasted in the same quarter of 2002.

McHutchison said Peg-Intron patients will take starting ribavirin doses of 800 milligrams to 1400 milligrams daily, vs 1,000 to 1,200 milligrams for Pegasys patients. But Peg-Intron patients who develop anemia or other side effects from ribavirin will have their daily dose of the pill reduced by 200 milligrams, with subsequent 200-milligram cuts if necessary. By contrast, Pegasys patients with side effects must have their ribavirin cut back to 600 milligrams in one fell swoop.

"The dose reductions for ribavirin are not equivalent in the two arms of the study and could therefore introduce a potential bias" in favor of the Peg-Intron arm of the trial, McHutchison said. McHutchison said he expressed his concerns to Schering-Plough, which in turn relayed them to the U.S. Food and Drug Administration before the trial began.

However, the FDA insisted that instructions on the Pegasys drug label be followed -- any ribavirin reductions must be to 600 milligrams. "The FDA wouldn't allow it (smaller cutbacks), and unfortunately that's the way it stands," McHutchison said. However, McHutchison said most doctors typically reduce ribavirin among Pegasys patients by 200 milligram increments.

Despite the potential ribavirin dose advantage to Peg-Intron patients, McHutchison and Schering-Plough said the study is large enough to demonstrate the true superiority of either medicine.

The new trial began two years after Roche launched Pegasys in the United States and ended Peg-Intron's monopoly for treating the often-fatal disease. An estimated 4 million Americans are believed to be infected by the virus.

Pegasys has leapfrogged Peg-Intron in sales largely due to its greater convenience. All patients receive the same injectible dose, whereas Peg-Intron is given according to body weight. Pegasys and Roche's own brand of ribavirin command a 62 percent share of the U.S. market, according to Verispan LLC, which tracks drug sales for health-care companies.

[For an in-depth analysis of the “IDEAL” trial of Pegasys vs Peg Intron, see HIV and Hepatitis.com article “How Ideal Is the IDEAL Trial?”]  

01/12/05
http://www.hivandhepatitis.com/hep_c/news/2005/011205_b.html

Antiviral Activity Demonstrated in Interim Phase Ib and Consistent with Phase Ia Dose Tolerance, Pharmacokinetics and Immune Response Findings

    WELLESLEY, Mass., Jan. 6 /PRNewswire/ -- Coley Pharmaceutical Group, Inc.
today announced results from the company's Phase Ia study in normal volunteers
and Phase Ib dosing of Hepatitis C patients with Actilon(TM) (CPG10101), the
company's lead antiviral TLR Therapeutic(TM).  Actilon is a first-in-class
Toll-like receptor 9 (TLR9) agonist initially being developed for the
treatment of Hepatitis C.
    The Phase Ia trial of Actilon in forty healthy volunteers demonstrated
that the compound is well tolerated over a wide dose range, and that small
subcutaneous doses induce measurable, dose-related immune responses consistent
with the known pharmacologic mechanisms of this new class of antiviral
activity drugs.  The same range of doses were administrated twice weekly for
four weeks to adults with chronic Hepatitis C virus (HCV) infection who had
relapsed after, or were intolerant of, prior interferon therapy.  One-third of
these patients showed at least a 1.0 log reduction in HCV RNA (range 1.0 to
2.6).
    "Coley staff is very pleased by the consistent and clear results in these
randomized Phase I studies.  The data confirm our expectations regarding
Actilon's TLR9-mediated antiviral activity which was observed over a wide
range of tolerable dose levels," said John Whisnant, M.D., Coley's Senior Vice
President, Drug Development.  "I am also encouraged by the fact that Actilon
demonstrated antiviral activity even among patients with genotype 1 HCV, the
viral genotype which is most difficult to treat.  These results provide us
with important insights on dosing regimens for further development."
    "Actilon showed the predicted two phases of drug activity now
characteristic of TLR9 Therapeutics.  The early phase helps restore innate
immune functions which are commonly dysfunctional in Hepatitis C infected
hosts.  This occurs through TLR9 activation of dendritic cells, leading to
early antiviral cytokine and cellular changes.  Actilon is designed then to
drive long-term adaptive immune response, also through TLR9 and dendritic
cells, to sustain the virus reduction," Dr. Whisnant added.

    Detailed Study Results
    The Phase Ia study, designed to assess the compound's safety, dose
tolerability and immunological activity, randomized forty healthy volunteers
within five sequential dosing cohorts (0.25, 1, 4, 10, or 20 mg).  Two
subcutaneous injections were administered double-blind fourteen days apart and
subjects were evaluated for a total of 29 days.  Researchers observed an
immune system response demonstrating drug-related increases in interferon
alpha (IFN-alpha) levels and other markers indicative of antiviral activity.
Volunteers had no drug-related serious adverse events or dose-limiting
toxicities.  Mild injection site reactions and mild-to-moderate flu-like
symptoms were consistent with the pharmacological mode of action of Actilon.
    The ongoing Phase Ib study is evaluating anti-viral responses among
chronic Hepatitis C patients as well as the safety and tolerability of twice
weekly Actilon over the same dose range (0.25, 1, 4, 10, and 20 mg).  Adult
patients, who had relapsed after or were intolerant of prior IFN-alpha therapy
were randomized to receive Actilon or a placebo two times weekly for four
weeks with monitoring for up to four additional weeks (eight weeks total).  Of
18 patients evaluated to date at the 1, 4, and 10 mg dose levels, six (33
percent) have demonstrated early viral level reduction equal to or better than
1.0 log decrease (or 90 percent) during the four weeks of treatment.  The
viral level reduction observed was consistent with the elevation of IFN-alpha
and other markers associated with an antiviral immune response.  Dose
tolerance and laboratory safety were the same in HCV patients as in normal
volunteers.
    Both the Phase Ia and interim Phase Ib data were presented at national
scientific meetings last fall.  Phase Ia dose tolerance, pharmacokinetic (PK)
and immune response data were presented at the 44th Annual Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in
Washington DC., USA.  Phase Ib data, including antiviral response, were
reported at The American Association of Liver Disease (AASLD) meeting
(November 2004) in a poster entitled "Human Pharmacologic Activity of a New
TLR9 Agonist Antiviral, CPG 10101" in Boston, MA, USA.

    About Actilon
    Actilon is one of Coley's TLR Therapeutic(TM) family of compounds, a new
class of investigational pharmaceutical products which activate and direct the
immune system.  Actilon is designed to act through the toll-like receptor 9
(TLR9) found in dendritic cells and B cells to induce a durable and natural
immune response against the Hepatitis C virus.  The compound is also designed
to not only stimulate the body's own production of anti-viral interferons, but
to also drive both early and sustained virus-specific memory immune responses
to help clear the viral infection.

    About Hepatitis C
    According to the Center for Disease Control (CDC), approximately 200
million people worldwide are infected with the Hepatitis C virus (HCV), a
blood-borne infectious disease of the liver and the leading cause of cirrhosis
and a cause of liver cancer.  An estimated four million people in the United
States carry the Hepatitis C virus, and approximately 85 percent of those
infected with the virus will progress to chronic infection.  Further, 70
percent of those who are infected will develop chronic liver disease, making
HCV the leading cause of liver transplants in the U.S.  Currently, the most
common treatments for Hepatitis C are recombinant forms of interferon alpha
(IFN-alpha) intended to mimic the body's natural immune response in
suppressing the virus.  These therapies may be limited by toxicities and by
viral resistance among some patients.

    About Coley Pharmaceutical Group
    Coley Pharmaceutical is an international biopharmaceutical company,
headquartered in Wellesley, Massachusetts, USA, that discovers and develops
TLR Therapeutics(TM), a new class of drugs that direct the human immune system
to treat cancers, infectious diseases, asthma and allergy.  Coley has
partnered programs with Sanofi-Aventis, Chiron, GlaxoSmithKline and the United
States Government.  For further information please visit
http://www.coleypharma.com.
 

In patients with mild hepatitis C, the usefulness of antiviral therapy is a subject of debate, as a low risk for progression of fibrosis is assumed. Several studies have shown that steatosis (fatty liver) is a strong and independent predictor of the severity as well as the progression of fibrosis in chronic hepatitis C.

The present study assessed the impact of steatosis on the progression of fibrosis between paired liver biopsies in untreated patients with mild hepatitis on index biopsy.

One hundred thirty-five untreated patients (mean age, 38 years; M/F sex ratio, 1.43) with one known risk factor of infection (68 transfusions, 67 injecting drug use) had 2 liver biopsies after a median interval of 61 months (18-158). All had METAVIR score of A1F1 or lower at first liver biopsy.

Unequivocal progression of fibrosis was considered if patients had a fibrosis score of 3 or 4 at the second liver biopsy. The probability of progression of fibrosis was estimated by using the Kaplan-Meier method.

During follow-up, progression of fibrosis occurred in 21 patients (16%) after a median delay of 65 months. Cumulative probabilities of the progression of fibrosis at 4 and 6 years were 5.2% and 19.8%, respectively.

In multivariate analysis, steatosis was the only independent factor predictive of progression of fibrosis. Probability of progression of fibrosis was significantly related to the percentage of hepatocytes with steatosis.

The authors conclude, “Steatosis is a major determinant of the progression of fibrosis in mild hepatitis C, regardless of the genotype. Our results argue for antiviral treatment in the subgroup of patients with mild hepatitis and steatosis.”

01/05/05

Reference
L Fartoux and others. Impact of steatosis on progression of fibrosis in patients with mild hepatitis. Hepatology 41(1): 82-87. January 2005.

http://www.hivandhepatitis.com/hep_c/news/2005/010505_b.html

Medicinal Herbs for HCV (oxymatrin)
	This report contains several recent publications of a clinical studies in patients infected with hepatitis B and/or C and using for treatment a Chinese herb called oxymatrin in the Dec 2004 issue of World Journal of Gastroenterology. Following this full report is a journal article of a systematic review of randomized trials on medicinal herbs published in the American Journal of Gastroenterology in March 2003 prior to the recent Dec article on oxymatrine.   [Preliminary study on therapeutic effect of oxymatrine in treating patients with chronic hepatitis C]   [Article in Chinese] Li J, Li C, Zeng M.Renji Hospital of Shanghai, Second Medical University, Shanghai 200001.   OBJECTIVE: To evaluate the efficacy of oxymatrine in treating chronic hepatitis C and its mechanism. METHODS: Forty-three patient were divided randomly into the treated group (20 cases) and the control group (23 cases). The treated group was given oxymatrine 600 mg per day intramuscularly, and the control group was given the general liver protective agents such as vitamins. The therapeutic course of both groups was 3 months. RESULTS: HCVRNA of 8 in 17 cases (47.1%) of the treated group converted to negative, while in 18 cases of the control group, the negative conversion only took place in 1 patient (5.6%), the negative conversion rate was significantly higher in the treated group than that in the control group (P < 0.05). The normalization rates of serum alanine transaminase (ALT) of the treated group after 1 month and 2 months treatment was higher than that of the control group, but after 3 months treatment, the normalization rates of the two groups were not different significantly. Plasma level of soluble interleukin-2 receptor and serum level of collagen type IV in the treated group were lowered significantly after treatment, but in the control group, there were no significant change, the difference between the two groups was significant (P < 0.01, P < 0.05).   CONCLUSION: Oxymatrine is effective in inhibiting proliferation of HCV, antagonisting liver fibrosis and regulating immune reaction of the host, so it could be a safe, effective drug in treating chronic hepatitis C.   [Oxymatrine in the treatment of chronic hepatitis B for one year: a multicenter random double-blind placebo-controlled trial.]   [Article in Chinese] Lu LG, Zeng MD, Mao YM, Wan MB, Li CZ, Chen CW, Fu QC, Wang JY, She WM. Shanghai Institute of Digestive Diseases, Renji Hospital, Shanghai Second Medical University, Shanghai 200001 China.   OBJECTIVE: To evaluate the efficacy and safety of oxymatrine in the treatment of chronic hepatitis B. METHODS: A multicenter randomized double-blind placebo-controlled trial was conducted. A total of 144 patients with chronic hepatitis B entered the study for 52 weeks; of them 72 received oxymatrine, and 72 received a placebo. Before and after the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reactions were observed. RESULTS: In 144 patients, 14 were dropped and excluded due to inconsistencies in the included standard. Therefore, the efficacy and safety of 130 patients were analyzed. After being treated for 52 weeks, 70.77% of the patients in the study group had a normal ALT level, and in 43.08% and 33.33% their HBV DNA and HBeAg became negative. In the placebo group, 39.68% had normal ALT level, and 12.31% and 3.33% had their HBV DNA and HBeAg become negative. The rates of complete response and partial response in the oxymatrine group were 23.08% and 58.46%, and in the placebo group they were 3.08% and 44.62%. They were significantly higher in the oxymatrine group than in the placebo group. In the oxymatrine treated patients, 12 weeks after its withdrawal, 60.00% had a normal ALT level, 41.54% and 23.33% had both HBV DNA and HBeAg negative. In the placebo group, 31.75% had a normal ALT level, 3.08% and 1.67% had both HBV DNA and HBeAg negative. The rates of complete response and partial response in the oxymatrine group were 21.54% and 47.69%, and in the placebo group they were 0 and 41.54%. They were significantly higher in the study group than in the placebo group. The adverse reaction rates of oxymatrine in the study and the placebo group were 7.69% and 6.15%, respectively, but there was no statistical significant difference between them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.   Oxymatrine therapy for chronic hepatitis B: a randomized double-blind and placebo-controlled multi-center trial.   World J Gastroenterol. 2003 Nov;9(11):2480-3. Lu LG, Zeng MD, Mao YM, Li JQ, Wan MB, Li CZ, Chen CW, Fu QC, Wang JY, She WM, Cai X, Ye J, Zhou XQ, Wang H, Wu SM, Tang MF, Zhu JS, Chen WX, Zhang HQ. Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China.   AIM: To evaluate the efficacy and safety of capsule oxymatrine in the treatment of chronic hepatitis B. METHODS: A randomised double-blind and placebo-controlled multicenter trial was conducted. Injection of oxymatrine was used as positive-control drug. A total of 216 patients with chronic hepatitis B entered the study for 24 weeks, of them 108 received capsule oxymatrine, 36 received injection of oxymatrine, and 72 received placebo. After and before the treatment, clinical symptoms, liver function, serum hepatitis B virus markers, and adverse drug reaction were observed. RESULTS: Among the 216 patients, six were dropped off, and 11 inconsistent with the standard were excluded. Therefore, the efficacy and safety of oxymatrine in patients were analysed. In the capsule treated patients, 76.47% became normal in ALT level, 38.61% and 31.91% became negative both in HBV DNA and in HBeAg. In the injection treated patients, 83.33% became normal in ALT level, 43.33% and 39.29% became negative both in HBV DNA and in HBeAg. In the placebo treated patients, 40.00% became normal in ALT level, 7.46% and 6.45% became negative both in HBV DNA and in HBeAg. The rates of complete response and partial response were 24.51% and 57.84% in the capsule treated patients, and 33.33% and 50.00% in the injection treated patients, and 2.99% and 41.79% in the placebo treated patients, respectively. There was no significance between the two groups of patients, but both were significantly higher than the placebo. The adverse drug reaction rates of the capsule, injection and placebo were 7.77%, 6.67% and 8.82%, respectively. There was no statistically significant difference among them. CONCLUSION: Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B.   Capsule oxymatrine in treatment of hepatic fibrosis due to chronic viral hepatitis: A randomized, double blind, placebo-controlled, multicenter clinical study   World J Gastroenterol 2004 November 15;10(22):3269-3273   Yi-Min Mao (Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Second Medical University, Shanghai 200001, China), Min-De Zeng, Lun-Gen Lu, Mo-Bin Wan, Cheng-Zhong Li, Cheng-Wei Chen, Qing-Chuen Fu, Ji-Yao Wang, Wei-Min She, Xiong Cai, Jun Ye, Xia-Qiu Zhou, Hui Wang, Shan-Ming Wu, Mei-Fang Tang, Jin-Shui Zhu, Wei-Xiong Chen, Hui-Quan Zhang   Abstract   AIM: To evaluate the efficacy and safety of oxymatrine capsule in treatment of hepatic fibrosis in patients with chronic viral hepatitis.   METHODS: It was a randomized, double blind, placebo-controlled, multicenter clinical study. One hundred and forty-four patients were divided into oxymatrine capsule group(group A) and placebo group (group B).The course was 52 wk. Patients were visited once every 12 wk and the last visit was at 12 wk after cessation of the treatment. All patients had liver biopsy before treatment. part of them had a second biopsy at the end of therapy. Clinical symptoms, liver function test, serum markers of hepatic fibrosis were tested. Ultrasound evaluation was performed before, during and at the end of therapy.   RESULTS: One hundred and forty-four patients enrolled in the study. Of them 132 patients completed the study according to the protocol,49 patients had liver biopsy twice (25 patients in group A and 24 in group B). At the end of therapy, significant improvements in hepatic fibrosis and inflammatory activity based on Semi-quantitative scoring system (SSS) were achieved in group A. The total effective rate of the treatment was 48.00%, much higher than that of 4.17% in group B (P<0.05). Significant improvement in serum markers of hepatic fibrosis such as hyaluronic acid (HA) and type III procollagenic peptide (P III P) in group A was seen (P<0.05). The total effective rate of serum markers at the end of therapy in group A was 68.19%, much higher than that of 34.85% in group B (P<0.05). The total effective rate of noninvasive markers at the end of therapy in group A was 66.67%, much higher than that of 30.30% in group B (P<0.05). The rate of adverse events was similar in two groups.   CONCLUSION: Oxymatrine capsule is effective and safe in treatment of hepatic fibrosis due to chronic viral hepatitis.   INTRODUCTION   Hepatic fibrosis is a kind of compensating and healing response in the liver to liver injury induced by a variety of causes and also a common pathological process of many chronic liver diseases characterized by hyperplasia and deposition of fibro-connective tissues. It is essential to block the genesis and progress of hepatic fibrosis[1-5,30,31]. Oxymatrine is a kind of alkaloid extracted from a Chinese herb Sophora alopecuraides L. which has been proved to have antihepatic fibrosis effect[6,7,18-20]. In this paper, we reported the clinical study data of oxymatrine capsule in treatment of hepatic fibrosis in patients with chronic viral hepatitis.   MATERIALS AND METHODS Resarch design This study was a clinical trial characterized by multicentre, randomization, double blinding, and placebo-control. Enrolled patients were randomly assigned into oxymatrine capsule group(group A) or vacant placebo control group (group B), with 72 cases in each group and a treatment course of 52 wk. This study was conformed to the Good Clinical Practice (GCP) of China. The research protocol was discussed and approved by the Ethic Committee of National Clinical Research Base of Drugs in the Institute of Digestive Disease of Renji Hospital. Informed consent was obtained from each patient.   Selection of subjects   Enrolled criteria were age: 18-65 years regardless of sex; positive serum markers of hepatitis B virus (HBV) and hepatitis C virus(HCV) for at least 6 mo before enrollment; abnormal serum value of alanine transaminase (ALT) twice or more within 6 mo before enrollment; liver biopsy examination during 1 mo before enrollment indicating the stage of hepatic fibrosis from 1 to 4 according to National Criteria of Grading and Staging for chronic viral hepatitis amended in 1995 and the scores of stage equal or more than 1 assessed by the semi-quantitative scoring system(SSS) of hepatic fibrosis; total serum bilirubin level less than or equal to 85.5 mmol/L; no history of administrating following drugs: antiviral drugs, immunoregulating drugs and other antifibrotic agents; promising not to receive other systemic antiviral agents, cytotoxic agents, immunoregulators, drugs capable of reducing serum enzyme activity and bilirubin level, and Chinese traditional medicines, etc. Following situations should be excluded: patients with positive laboratory test of HIV; uncompensable liver diseases; suggestive of autoimmune diseases with antinuclear antibody (ANA) titer greater than a 1:160 dilution; bone marrow inhibition; abnormality of serum creatinine with a value 1.5 times greater than normal; concurrence of other associated diseases which might affect the present treatment such as unstable diabetes, renal insufficiency, unstable angina pectoris, alcoholic liver disease, epilepsy, obvious manifestations of neurosis, drug abuser, psychosis, pancreatitis, disability of absorption and malignant disease, and so on; Having taken other drugs in clinical trial within 30 d before the first medication; hypersensitive to oxymatrine capsule; pregnancy and during breast-feeding period; female conceptive patients not adopting any contraceptives.   Treatment procedures and drugs   After completion of selection and assessment, qualified subjects were allocated into group A or B randomly. The patients in group A took 300 mg oxymatrine capsules orally 3 times a day, and 2 tablets of complex vitamins B and C at the same time for 52 wk. The patients in group B took 3 tablets of vacant capsules instead of oxymatrine capsules and complex vitamins B and C at the same frequency as described above for 52 wk. All patients received follow-up once every 12 wk during treatment and were followed up at out-patient department 12 wk after treatment. Oxymatrine capsule, vacant placebo capsule, complex vitamins B and C tablets were manufactured and provided by Ningxia Pharmaceutic Institute and Shanghai Green Valley Ecological Engineering Co.LTD.   Observation of indexes and assessment Clinical manifestations Clinical symptoms and signs were divided into grades from 0 to 3 according to the symptomatic grading criteria , evaluated at each follow-up visit, and examined 24 and 52 wk after treatment and 12 wk after drug withdrawal.   Analysis of blood and urine routines and related liver function indexes   These indexes were evaluated at each follow-up visit and examined 52 wk after treatment and 12 wk after drug withdrawal.   Analysis of serum markers of hepatic fibrosis   Tests of serum hyaluronic acid (HA), laminin (LN), type III procollagenic peptide (p III p), type IV collagen-7S (IV-7S) were fulfilled by Military Clinical Immunologic Research Centre of Changzheng Hospital, Second Military Medical University. The above markers were evaluated before treatment, 24 and 52 wk after treatment,12 wk after drug withdrawal respectively, and examined 24 and 52 wk after treatment,12 wk after drug withdrawal, respectively.   Imaging examination (type B ultrasound)   The detection included 5 indexes: maximal oblique radius of right liver lobe, main trunk diameter of portal vein and its blood flow parameters per minute; width of spleen at the hilus and the diameter of spleenic vein. Ultrasound examination was performed on fixed machines and by fixed operators and the data were recorded and input in computers which were read by experts. All the indexes were evaluated before treatment and 52 wk after therapy, examined 52 wk after drug withdrawal.   Histopathological detection   Histopathological specimens were independently observed and assessed based on National Criteria of Grading and Staging for chronic viral hepatitis amended in 1995 and SSS by 3 pathologists from Department of Pathology, Medical College, Fudan University. The observed results were checked by another 3 pathologists who did not anticipate in the study by Kappa test. The reciprocal consistence among the above pathologists was satisfactory. The observed results in all patients were evaluated before therapy and part of them were evaluated 52 wk after therapy. All data were examined 52 wk after therapy.   During treatment and after therapy was terminated, the following events were recorded: combined medication, adverse reactions and the compliance of patients.   Assessment of therapeutic effects Indexes of histopathology The curative effect was evaluated based on SSS. Distinctly effective: the scores of hepatic fibrosis based on SSS from liver biopsy decreased at least 6 scores compared with that before treatment. Effective: the above scores decreased at least 2 scores. Ineffective: the effect did not meet the effective criteria.   Assessment of indexes of noninvasive tests   These indexes were evaluated comprehensively in terms of clinical manifestations, serum liver fibrotic markers and ultrasound detection data. Distinctly effective: any two values among serum liver fibrotic indexes decreased by at least 80% compared with that before treatment, at least the main trunk diameter of portal vein and splenic width returned to normal after treatment, clinical symptoms and signs disappeared or their total scores decreased by at least 75% compared with that before treatment. Effective: any two values among serum liver fibrotic indexes decreased by at least 40% compared with that before treatment, the main trunk diameter of portal vein and splenic width reduced after treatment, clinical symptoms and signs disappeared basically or their total scores decreased by at least 25% compared with that before treatment. Ineffective: the effect did not meet the effective criteria.   Assessment of safety   Any abnormal clinical manifestations and laboratory tests occurred during treatment were recorded and divided into 4 grades according to the criteria published by WHO and the Ministry of Public Health of China in 1994.   Statistical analysis   Statistical analyses were performed by professor Su BH and He QB from Department of Statistics, Shanghai Second Medical University, and SAS 6.12 software kit was used.   RESULTS   Selected patients   A total of 144 patients satisfied the selection criteria. Of them,12 cases withdrew or were excluded during treatment, 132 cases fulfilled the treatment course according to the required protocol(66 cases in group A and 66 cases in group B). Before treatment, the following general data between two groups were similar (P>0.05, respectively): sex, age, drinking history, duration of hepatitis, duration of abnormality of liver function and a more than 2-fold normal elevation of serum ALT, etc. Each qualified patient received liver biopsy before treatment. A total of 49 cases had a second liver biopsy (25 cases in group A and 24 cases in group B).   Analysis of observed indexes   Clinical symptoms and signs Clinical manifestations in group A were obviously improved 52 wk after therapy (P<0.05), except for epistaxis (P = 1.0000). Heptomegaly was also improved significantly after therapy (P = 0.0313), symptoms of gum bleeding and epistaxis were not improved obviously in group B (P>0.05). Signs of hepatomegaly, splenomegaly and liver palm were significantly improved in group B (P<0.05), improvement of anorexia in group A was greater than that in group B (P = 0.0263).   Liver function   Indexes of liver function in group A were significantly improved 52 wk after treatment (P<0.05) except for serum gamma glutamino transpeptidase (GGT) and TB (P>0.05). In group B, indexes such as serum ALT, AST, TB and alkaline phosphatase (ALP) had no obvious difference before and after therapy (P>0.05). Compared with group B, the improvement of ALT and AST in group A was much greater (P = 0.0007 and 0.0025). Fifty-two wk after therapy, the normalization rate of ALT in group A was 70.77%, much higher than 39.68% in group B (P = 0.0003). In groups A and B, 14 out of 46 cases (30.43%) and 12 out of 25 cases (48.00%) had their serum ALT levels returned to normal 52 wk after treatment ,and their serum ALT levels became abnormal again after drug withdrawal.   Liver histologic examination   Evaluation of hepatic fibrosis based on SSS: In group A, the scores of hepatic fibrosis after therapy were 4.72±5.63, much smaller than 6.76±6.67 before therapy (P = 0.0001), while the scores in group B after therapy increased significantly (P = 0.0009). There was an obvious difference between two groups (P = 0) (Table 1). Evaluation of histolgic inflammatory activity based on SSS: In group A, the scores of histologic activity decreased from 46.08±3.84 before treatment to 4.00±2.97 after therapy (P = 0.0002), while the scores in group B after therapy did not decrease obviously (P = 0.2344). There was an obvious difference between two groups (P = 0008) (Table 2).   Evaluation of serum markers of hepatic fibrosis   In group A, serum levels of HA, LN, p III p and IV-7S decreased significantly 24 and 52 wk after treatment (P<0.05). In group B, serum levels of LN, p III p and IV-7S also decreased obviously after treatment(P<0.05). However, degrees of improvement in HA and p III p between two groups were distinctly different (P<0.05). In group A, except for LN (P = 0.1493), the other 3 liver fibrotic markers increased significantly 12 wk after drug withdrawal compared with that 52 wk after treatment (P<0.05). In group B, except for HA (P = 0.4212), the other markers also increased obviously 12 wk after drug withdrawal compared with that 52 wk after treatment(P<0.05). The increase of HA in group A was more than that in group B (P = 0.0002) and the increase of IV-7S in group B was more than that in group A (P = 0.0048).   Imaging examination   After treatment, the average values of main trunk diameters of portal vein and splenic width in group A obviously decreased (P<0.05). However, in group B, the above two parameters and the parameters of blood flow volume per minute of portal vein and diameters of splenic vein all increased significantly compared with those before therapy (P<0.05). The changes in main trunk diameters of portal vein and splenic width between two groups were statistically significant (P<0.05).   Analysis of therapeutic effect Assessment of histopathology based on SSS After treatment, the rates of distinct effectiveness and effectiveness in group A were both 24.00%, and the total effective rate was 48.00%. In group B, none achieved distinct effectiveness and the effective rate was only 4.17%; Comparison of the rates of distinct effectiveness and effectiveness between two groups had a significant difference (P = 0.004) (Table 3).   Assessment of serum markers of hepatic fibrosis   The total effective rate of group A 24 and 52 wk after therapy was 57.43% and 68.19%, more than 24.24% and 34.85% of group B (P = 0.0002 and 0.0004, respectively). Twelve weeks after treatment, the total effective rate of group A was 50.00%, more than 15.16% of group B (P =0.00).   Assessment of noninvasive indexes of hepatic fibrosis   After treatment, the rates of distinct effectiveness and effectiveness in group A were respectively 3.03% and 63.64%, and the total effective rate was 66.67%. In group B, the rates of distinct effectiveness and effectiveness were respectively 0% and 30.30%, and the total effective rate was 30.30%. The comparison of the above statistics between two groups had a significant difference (P = 0.0001) (Table 4).   Adverse effects   In group A, there were 5 patients who suffered from adverse drug reactions and the incidence was 6.94%. The adverse drug reactions mainly included nausea, rash, chest discomfort, fever, epigastric comfort, diarrhea and poor taste, and most of them were mild or moderate. None of the patients withdrew because of adverse drug reactions. In group B, adverse effects occurred in 7 patients and the incidence was 9.72%. The manifestations were similar to those in group A and 1 patient withdrew because of weakness, anorexia, epigastric discomfort after taking drugs.   DISCUSSION   Hepatic fibrosis, a precuror of cirrhosis, is a consequence of sever liver damage that occurred in many patients with chronic liver disease, and involves the abnormal accumulation of extracellular matrix[3,4,11,12]. Liver fibrosis represents a major worldwide healthcare burden. Current therapy is limited to removing the causal agent. This approach has been successful in some diseases, particularly in haemochromatosis and chronic viral hepatitis[9,10,17,28]. However, for many patients treatment was not possible, while other patients presenting to medical attention were at an advanced stage of fibrosis[8,9]. There is therefore a great need for novel therapies for liver fibrosis. Tremendous insights into the understanding of hepatic fibrosis have taken place over the past ten years. Foremost among these is the recognition that hepatic stellate cells (formerly known as lipocytes, Ito cells, or fat-storing cells) play a central role based on their ability to undergo activation following liver injury of any cause[11,15,16,29]. Hepatic stellate cells have been recognised to be responsible for most of the excess extracellular matrix observed in chronic liver fibrosis. The detailed understanding of hepatic stellate cell biology has allowed the rational design of novel antifibrotic therapies[29]. Effective therapy for hepatic fibrogenesis would probably also be multifactorial, based on the basic mechanisms underlying the fibrogenic process[13,14,21-23].   At present, it is considered that treatment of hepatic fibrosis and antihepatic fibrosis are two different concepts and antifibrotic drugs should act on various parts of the genesis and development of hepatic fibrosis. Firstly, as for etiological treatment, oxymatrine could effectively treat chronic viral hepatitis and promote the serum markers of hepatitis B virus (HBV) and hepatitis C virus(HCV) in chronic hepatitis B and C to convert to negative and reduce serum level of ALT[6,7]. Secondly, oxymatrine could inhibit the proliferation of hepatic stellate cells (HSC) at the concentrations of 0.5-16 mg/mL in vitro. In addition, oxygen stress and lipid peroxidation are important mechanisms responsible for hepatic injury and hepatic stellate cell activation. Therefore, inhibition of lipid peroxidation is an essential strategy of antihepatic fibrosis[12-16]. By establishing D-galactosamine-induced rat liver fibrosis model, we observed the effect of oxymatrine on serum and tissue biochemical indexes, content of liver hydroxyline, expression of TGFb1 mRNA and changes of tissue pathology, the results showed oxymatrine had prophylactic and therapeutic effects on D-galactosamine induced rat liver fibrosis. This was partly by protecting hepatocytes and suppressing fibrosis accumulation through anti-lipoperoxidation[10]. In present study, We found that the scores of hepatic fibrosis after therapy in group A were 4.72±5.63, much smaller than 6.76±6.67 before therapy, and the scores in group B after therapy increased significantly. There was an obvious difference between two groups. The scores of histological inflammatory activity in group A decreased from 46.08±3.84 before treatment to 4.00±2.97 after therapy, and the scores in group B after therapy did not decrease obviously. There was an obvious difference between two groups both in improvement of histopathology and in improvement of noninvasive indexes such as clinical manifestations, serum markers of hepatic fibrosis[24-27]. Associated indexes of liver function and imaging detection indicated that oxymatrine was an ideal drug of antihepatic fibrosis. It is valuable to pay more attentions to the basic and clinical research of oxymatrine in order to explore the accurate mechanisms of its effect on antihepatic fibrosis.   REFERENCES http://www.natap.org/ Medicinal Herbs for Hepatitis C Virus Infection: A Cochrane Hepatobiliary Systematic Review of Randomized Trials   American Journal of Gastroenterology Volume 98 Issue 3 Page 538 - March 2003   Jianping LiuM.D., Ph.D. a, b * , Eric ManheimerPh.D. c , Kiichiro TsutaniM.D. d , Christian GluudDr. Med. Sci. a   Objective The aim of this study was to assess beneficial and harmful effects of medicinal herbs for hepatitis C virus (HCV) infection.   Methods The databases of the Cochrane Collaboration, MEDLINE, EMBASE, and BIOSIS were searched combined with manual searches of five Chinese and one Japanese journals. We included randomized trials comparing medicinal herbs with placebo, no intervention, nonspecific treatment, other herbs, or interferon and/or ribavirin. Trials of herbs with or without other drug(s) were included. Methodological quality of the trials was evaluated by randomization, double blinding, and the Jadad scale.   Results Thirteen randomized trials (n = 818) evaluated 14 medicinal herbs. Four trials had adequate methodology. Compared with placebo, none of the herbs showed effects on HCV RNA or liver enzyme, except for silybin, which showed a significant reduction of serum AST and gamma-glutamyltranspeptidase levels in one trial. Oxymatrine showed effects on clearance of HCV RNA (relative risk = 9.20, 95% CI = 1.26-67.35) compared with vitamins. The herbal mixture Bing Gan Tang plus interferon-alpha showed better effects on clearance of HCV RNA (relative risk = 2.54, 95% CI = 1.43-4.49) and on normalization of serum ALT (relative risk = 2.54, 95% CI = 1.43-4.49) than interferon-alpha alone. The herbal mixture Yi Zhu decoction showed better effects on clearance of HCV RNA and normalization of ALT compared with glycyrrhizin plus ribavirin. Yi Er Gan Tang showed effects on normalizing serum ALT compared with silymarin plus glucurolactone. The herbs were associated with adverse events.   Conclusions There is no firm evidence supporting medicinal herbs for HCV infection, and further randomized trials are justified.   INTRODUCTION   Hepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV) (1). Currently, an estimated 170 million persons worldwide are chronically infected with HCV (2). HCV infection may be self-limited (viral clearance) or persistent (3-5). Viral clearance occurs in about 15% of persons with HCV-specific antibodies (anti-HCV) when HCV RNA is undetectable in multiple tests (4-6). About 85% patients develop persistent HCV infection (7), and liver cirrhosis develops in about 20% patients with chronic hepatitis C within 20 yr (8, 9). Once cirrhosis is established, one fourth of them will ultimately suffer from liver cancer or liver failure (9, 10). However, other studies suggest that chronic HCV infection may have a much better prognosis (11-14).   Presently, the most effective therapy for chronic hepatitis C is interferon (IFN)-alpha plus ribavirin (13, 14). Both of them demonstrated a significant effect on virological and histological responses. However, we do not yet know whether the effects on these surrogate outcome measures can be turned into patient-relevant outcomes such as quality of life and decreased mortality. Furthermore, IFN and ribavirin are connected with a plethora of adverse events and are costly. Therefore, new medications and approaches to treatment are needed. Complementary therapies are being used increasingly (15, 16). The number of randomized trials of complementary treatments has doubled every 5 yr, and The Cochrane Library now includes nearly 50 systematic reviews of complementary medicine interventions (16). Many people turn to this therapy when conventional medicine fails, or they believe strongly in the effectiveness of complementary medicine.   Clinical trials have shown that some medicinal herbs might have therapeutic potential for chronic hepatitis C (17-22), or alleviating adverse effects of conventional therapy such as depression (23). On the other hand, there are reports about liver toxicity and other adverse events from some herbal products (24-26). Accordingly, the efficacy and safety of treating HCV infection using medicinal herbs should be evaluated systematically.   Materials and methods   This study is based on a previously published protocol for a Cochrane systematic review (27).   Searching   Eligible trials were identified through electronic searches (February, 2002) of the Controlled Trials Registers of the Cochrane Hepatobiliary Group, the Cochrane Complementary Medicine Field, The Cochrane Library, MEDLINE, EMBASE, BIOSIS, Chinese biomedical databases, and Japanese databases. Five Chinese journals, one Japanese journal, conference proceedings, and the references of identified trials were handsearched.   Selection   Inclusion criteria were randomized clinical trials comparing medicinal herbs with placebo, no intervention, nonspecific treatments, such as vitamins, other medicinal herbs, or IFN (no limitation regarding IFN type or regimen), and/or ribavirin. Trials on medicinal herbs plus IFN and/or ribavirin versus IFN and/or ribavirin alone were also included. Cointerventions were allowed as long as both arms of the randomized allocation received the same intervention(s). There were no limits on blinding, publication status, language, age, gender, or ethnic origin of patients with acute or chronic HCV infection. The main outcomes were virological response (loss of detectable HCV RNA) at the end of treatment and at maximal follow-up after completion of the treatment, liver fibrosis, cirrhosis, cancer, and liver-related mortality (28). Secondary outcomes were biochemical response (normalization of serum transaminases), improvement of histological activity index (29), quality of life, cost, and adverse events (30). Trials on patients coinfected with HIV were excluded. Two reviewers independently selected the trials.   Validity assessment   Methodological quality was assessed by the adequacy of generation of the allocation sequence, allocation concealment, double blinding (31-33), and the Jadad scale (32-34).   Data extraction   Data were extracted independently by two reviewers and validated by a third party. The following data were extracted: primary author, study design, mean age, gender and ethnicity of patients, numbers of patients randomized and lost during follow-up, inclusion and exclusion criteria, dosage and duration of intervention, outcome measures, and adverse events. The missing data were sought by correspondence with the principle investigator.   Data synthesis   Dichotomous data were presented as relative risk and continuous outcomes as weighted mean difference (WMD), both with 95% CIs. For dichotomous outcomes, patients with incomplete or missing data were included in sensitivity analysis by counting them as treatment failures to explore the possible effect of loss to follow-up on the findings ("worst-case" scenario). Meta-analysis was performed in Review Manager 4.1 (The Cochrane Collaboration, Oxford, England, 2000) within comparisons of the same medicinal herb versus the same controls. The random effects model was used when there was heterogeneity ( p< 0.1) among trials. If a sufficient number of trials were identified, we planned to perform sensitivity analyses according to their methodological quality. Potential biases were investigated according to Egger et al. (35).   Identification of trials   Our initial searches identified 110 references, 90 from the electronic searches and 20 from the handsearches. After reading titles and abstracts, 59 of these articles were excluded. A total of 51 references published in three languages (Chinese, English, and Japanese) were retrieved for further assessment. Of these, 37 were excluded, and the reasons for exclusion were listed under "characteristics of excluded studies" (36). One abstract was excluded because of duplication of an included trial (37). The remaining 13 randomized trials reported random allocation of patients (n = 818) with mainly chronic hepatitis C to medicinal herbs versus placebo in four trials, nonspecific drug (vitamin) in one trial, IFN in five trials, other herbal medicines in two trials, and herb plus ribavirin in one trial (Table 1). All patients were adults (mean age 38 yr), and the proportion of men was 69%. The average size per trial was 69 patients (range 20-192). Four trials confirmed the diagnosis by liver biopsy (38-41). Ten trials included patients with chronic hepatitis C (85%), one in patients with acute and chronic hepatitis C (42), and another two in undefined patients with hepatitis C (43, 44). Nine trials were tested in Chinese patients and one each in Australians, Italians, Americans, and Europeans.   Fourteen medicinal herbs were tested in the trials, without one tested twice (Table 1). The median duration of treatment was 17 wk (1-24 wk). No trial reported mortality, liver cirrhosis or cancer, quality of life, or cost. The reported outcomes were viral and biochemical responses, liver histology, symptoms, and adverse effects.   Of 13 included trials, one trial had adequate generation of allocation sequence, two trials had adequate allocation concealment, and four trials had adequate double blinding. Four trials reported the numbers of patients withdrawn and the reasons (38, 40, 45, 46). The four double-blind trials obtained high Jadad scores (>=3) (38-40, 45), and nine obtained low scores (<=2) (41-44, 46-50). No trial reported sample size estimation or stated that intention-to-treat analysis was used.   End-of-treatment responses   Compared with placebo, herbal medicine CH-100 and glycyrrhizin showed no significant effect on clearance of serum HCV RNA or normalization of serum ALT level (38, 40). Complete Thymic Formula showed no significant effect on clearance of HCV RNA and on serum AST level compared with placebo (45). Compared with placebo, silybin showed a significant effect on reducing serum AST level (WMD = -24.60 U/L, 95% CI = -34.28 to -14.92 U/L) and serum gamma-glutamyltranspeptidase level (WMD = -18.40 U/L, 95% CI = -23.78 to -13.02 U/L) after treatment for 7 days, but no significant effect on serum ALT or bilirubin level (39). Compared with vitamins, herbal extract oxymatrine showed a significant effect on clearance of HCV RNA (46), but no significant effect on normalizing ALT level (Table 2). Compared with IFN-alpha, the herbal compound Bing Gan Ling had no significant difference on the clearance of HCV RNA and normalization of ALT level at the end of a 3-month treatment (41). Another herbal compound, Bing Gan Ning granule, showed no significant difference on the clearance of HCV RNA and on ALT normalization compared with IFN-alpha (42). The herbal compound Bing Gan Tang plus IFN-alpha showed a significant effect on the clearance of HCV RNA and ALT normalization compared with IFN-alpha alone (43). Compared with IFN alone, the combinations of herbal compound Bing Gan capsules with IFN and Gansu capsules with IFN showed no significantly better effect on clearance of HCV RNA and ALT normalization (44, 50).
	Compared with glycyrrhizin plus ribavirin, Yi Zhu decoction showed significant effects on clearance of HCV RNA and ALT normalization at the end of a 3-month treatment (49). Compared with silymarin plus glucolactone, the herbal compound Yi Er Gan Tang showed a significant effect on ALT normalization (48). Compared with no intervention, the herbal compounds Qinggan granule and Bushen granule showed no significant effect on reducing AST, ALP, and gamma-glutamyltranspeptidase levels (47).   One trial evaluated histological outcome through liver biopsy using inflammatory grade and fibrotic stage indexes (47). A semiquantitative score (Chevallier's system) (51) showed that the score of liver fibrosis decreased significantly (WMD = -3.51, 95% CI = -6.97 to -0.05, p = 0.05) using the herbal compound Qinggan compared with no intervention; however, there was no significant difference between Bushen and no intervention. For the score of inflammatory grade, Qinggan or Bushen showed no significant effect.   Sustained responses and clinical effects   Sustained responses could not be assessed because of inadequate reporting in seven trials with follow-up. The outcome of symptoms could not be assessed because of inadequate reporting in the trials. Adverse events were reported in seven trials (38-41, 44-46). Four patients experienced adverse events during herbal therapy with CH-100, in which one patient developed palpitation, two had diarrhea, and one had abdominal discomfort (38). Cold or "flu-like" symptoms, rash, itching, diarrhea, and nausea were observed in patients treated with glycyrrhizin (40). One patient developed severe thrombocytopenia during the fifth month of therapy with Complete Thymic Formula (45).   The limited number of trials prevented us from doing meaningful sensitivity analyses or funnel plot analysis.   Discussion   This systematic review demonstrates that there is insufficient evidence for treating HCV infection with any of the examined medicinal herbs because of the small number of randomized trials conducted, the paucity of patients having entered these trials, and the low methodological quality of the trials.   The majority of the 13 trials included had low methodological quality. They provided very limited description of generation of the allocation sequence, allocation concealment, and only four were double blinded. Methodologically less rigorous trials showed larger treatment effects than those conducted with better rigor (31-33). No large randomized clinical trials were identified. They examined different herbal medicines in different formulations (tablet, capsule, injection, or decoction). Therefore, it is not possible to infer anything on the applicability of these herbs in different populations. Ideally, we should evaluate well-defined herbal constituents, dosage, duration, and control intervention in two or more independently conducted randomized trials when evaluating the efficacy of medicinal herbs. We were limited in this respect by the small number of identified trials. When dealing with efficacy and adverse events of medical herbs, one should apply the same rigorous criteria in the evaluation of interventions as internationally required for pharmaceutical products (52). Many factors may affect the impact of herbs, including species, geographical origin, harvest season, preparation, storage, and extraction procedures, as well as dosage and duration of therapy (53, 54). In clinical trials on herbs, it is, therefore, important to mention specific botanical identification of a plant material, its geographical source, and the condition under which the plant substances are obtained. When the plant preparation is described in a monograph of a national or international Pharmacopoeia, all the quality control requirements should be fulfilled (55). If a monograph concerning the plant preparations does not exist, the manufacturer should write a protocol dealing with the above quality control requirements (53).   In four trials obtaining high Jadad scores, only one small, short-term trial suggests that silybin (a milk thistle preparation) may have a liver-protecting effect (39). One should be aware that this beneficial effect came from a trial with only 20 patients treated for 1 wk and without any follow-up. A recent health technology assessment on milk thistle products for liver disease patients concluded that there is not substantial evidence supporting these herbal products (56). In nine low-score trials, oxymatrine seemed to be better than vitamins in clearance of HCV RNA; Yi Er Gan Tang seemed to be better than silymarin plus glucurolactone in normalizing ALT. Yi Zhu decoction seemed to be better than glycyrrhizin plus ribavirin in clearing HCV RNA and normalizing ALT. Neither glycyrrhizin nor ribavirin have demonstrated significant beneficial effects for chronic hepatitis C (14). Bing Gan Tang plus IFN may have positive effects on clearance of HCV RNA and on ALT normalization compared with IFN alone. The potential benefit of these herbs in chronic hepatitis C could justify further trials. Herbs with a potential benefit can be tested against placebo in chronic hepatitis C patients who do not respond to IFN and ribavirin treatment or who have contraindications to the standard treatment or in combination with these interventions (13). However, some of the herbs led to the occurrence of adverse events. Safety monitoring of medicinal herbs in hepatitis C is important through adequate recording and reporting of adverse events in clinical trials.   It is likely that certain medicinal herbs contain substances that may interact with viral load and/or prevent further liver injury. It is a difficult question, however, to point to which trials we need to conduct in the future. The field of medicinal herbs is more difficult than the traditional development of pharmaceutical interventions. First, we are dealing with a vast plethora of substances that have been brought to us from ancient times. Second, even focusing on one single medicinal herb raises the problems of its components and how they work in consort. Third, despite the fact that we may not have a plausible biological reason for using some of the herbs, the use of these herbs is widespread in the East as well as in the West (53). To find medicinal herbs that work and to prevent patients from taking herbs that have no efficacy or may cause detrimental effects, we need to conduct randomized trials, which can reveal the true benefits and harms these herbs may cause.   In future trials, it is necessary to have a much better description of the medicinal herbs being tested, e.g., plant species, geographical origin, harvest season, preparation procedures, and quality control. In patients with HCV infection, it is necessary to have information on clinical and/or histological stage of liver disease, the presence or absence of cirrhosis, the genotype of HCV, and other well-proven prognostic indicators when assessing the efficacy of medicinal herbs. Rigorously designed, randomized, multicenter clinical trials are required to evaluate medicinal herbs with potential efficacy for hepatitis C, and such trials should be reported following the guidelines of the CONSORT Statement (www.consort-statement.org).   REFERENCES

http://www.natap.org/

HCV Persistence: Cure Is Still A Four Letter Word  
 

By Jordan J. Feld  and T. Jake Liang

Hepatology, January 2005
Liver Disease Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD

The last decade has seen major improvements in antiviral therapy for chronic HCV infection. The initial aims were to normalize liver enzyme levels and to clear HCV viremia at the end of treatment (ETR).

However, it soon became apparent that many patients quickly relapsed following a complete course of therapy. This led to the development of the concept of sustained virological response (SVR), defined as the absence of HCV viremia 6 months after the end of treatment.

With current combination therapy with pegylated interferon and ribavirin, 56% of patients may achieve an SVR. Numerous long-term follow-up studies have shown that SVR appears to be a durable clinical endpoint.] Less than 4% of patients will relapse by 6 years following SVR, and in addition to viral clearance, liver biochemistry remains persistently normal and liver histology has been shown to improve in many patients.

These observations have led some to cautiously consider the possibility that SVR may actually represent cure.

Pham et al. recently reminded us that the word CURE must not be used prematurely (1). Using highly sensitive reverse transcription-polymerase chain reaction (RT-PCR)-nucleic acid hybridization assays, they looked for the presence of residual HCV RNA in individuals up to 5 years after apparent spontaneous or treatment-induced viral clearance.

In addition to sera, peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells were examined because of known HCV lymphotropism. In all 16 patients studied, residual HCV RNA was detected.

Importantly, after mitogen stimulation they were able to document the presence of negative-strand HCV RNA in 9 of (75%) 12 PBMC samples. Because HCV negative-strand RNA is a replicative intermediate in the viral life cycle, its presence is generally accepted as evidence of ongoing HCV replication.

In this issue of Hepatology (January 2005), Radkowski et al. (2) confirm and expand upon the important finding of HCV persistence. Using similar methods to those employed by Pham's group, they looked for the presence of HCV RNA in serum and PBMCs from patients who were persistently HCV RNA negative by conventional assays after spontaneous or treatment-induced recovery.

In addition, they examined liver tissue from biopsies performed 3 to 8 years after antiviral therapy. Of 17 patients studied, HCV RNA was found in at least one compartment in all but two patients. Negative-strand HCV RNA, suggestive of ongoing viral replication, was detected in lymphocytes from 2 patients and in macrophages from 4 other patients but not in any of the liver tissue examined. Sequencing of detected RNA allowed for genotype determination, which correlated with pretreatment genotype in all but one patient.

This suggests that the HCV RNA detected was residual virus rather than the result of re-infection.

The findings of these two studies are certainly intriguing and will potentially have important implications for our future understanding and management of HCV infection. Both studies confirm the presence of HCV RNA long after apparent resolution of infection; however, it is unclear what the significance may be of such low levels of virus.

We have been here before. These observations are reminiscent of the data regarding occult hepatitis B infection. Numerous studies have documented low levels of hepatitis B virus (HBV) DNA in both liver and extra-hepatic compartments in patients negative for all serologic markers of HBV infection as well as in patients with isolated anti-hepatitis B core antibody.

Occult HBV has been found in patients with apparently resolved infection (clearance of hepatitis B surface antigen and presence of anti-HBs), patients with no known history of HBV, patients with hepatocellular carcinoma, and patients with HCV infection. The prevalence of occult HBV varies greatly but is very high in certain populations; however, the clinical significance remains uncertain.

Although the initial report documented more advanced liver disease in patients with HCV and evidence of occult HBV than in those with HCV alone, subsequent studies have not confirmed this finding. Similarly, with isolated occult HBV the jury is still out. While Chan et al. found that one third of patients with cryptogenic cirrhosis had occult HBV in Hong Kong, Komori et al. showed that patients with persistent low-level HBV viremia after clearance of HBsAg actually had improved histology.

Clearly, the significance of occult HBV still needs some clarification. What about HCV? Although the data from Radkowski et al. confirm the presence of HCV many years after apparent disease resolution, the clinical significance of this finding remains unclear.

The observation of negative-strand HCV RNA in hepatocytes strongly suggests that they have not simply identified HCV remnants from past infection. This appears to be replicating virus and therefore has potentially important clinical and public health implications. Patients with persistent hepatic HCV RNA had no histological improvement, whereas all of the other patients had reduced fibrosis and inflammatory scores.

While intriguing, more data are clearly needed before conclusions on clinical outcome can be made. In 2004, Castillo et al. described occult hepatitis C infection in 57 of 100 patients with persistently abnormal liver enzymes but no markers of HCV infection by commercial assays. They documented HCV RNA in hepatocytes as well as in PBMCs using highly sensitive RT-PCR and in situ hybridization.

Negative-strand HCV RNA was also found in 48 patients (84.2%). Histologic analysis showed that patients with occult HCV infection were more likely to have both necroinflammatory activity and fibrosis on liver biopsy; however, the majority (65%) had only mild nonspecific changes or isolated steatosis. These provocative findings await confirmation.

The clinical significance of low levels of HCV RNA in patients with apparently resolved infection is even less clear. The largest study looking at long-term duration of SVR showed that in 80 patients with up to 7.5 years of follow-up, 96% remained HCV RNA negative, 93% had persistently normal alanine aminotransferase, and 94% had clear histological improvement.

McHutchison et al. found that only 7 of 170 sustained responders of the large treatment trials of interferon and ribavirin had detectable intrahepatic HCV RNA 24 weeks after treatment. Of those, only 2 (1.2% of all sustained responders) had a serological relapse up to 3.5 years later. It is likely that using the sensitive techniques of Radkowski et al.,  HCV RNA would have been detected in a significant proportion of these cohorts; the implication being that despite low-level viral persistence, clinical improvement is still the most common outcome. Whether the presence, quantity, and location of replicating virus has any impact on clinical outcome remains to be seen.

Other clinical issues of HCV persistence will also need clarification. HCV significantly increases the risk of the development of hepatocellular carcinoma, and to date, although it is commonly felt that successful HCV treatment reduces the risk of hepatocellular carcinoma, there are few data to support this contention.

Even very low levels of circulating HCV may have an important effect on hepatocarcinogenesis in patients with cirrhosis. This certainly appears to be the case with occult HBV infection.  Low levels of circulating virus may also account for the finding that many patients have persistent HCV-specific CD4⁺ and CD8⁺ T-cell populations many years after SVR or natural viral clearance. Low levels of antigen may be the necessary stimulus to maintain these cell populations. Unlike HBV, HCV reactivation after immunosuppression has not been reported, but it is possible that such a scenario will only become evident as more and more patients successfully treated for HCV are followed longer.

Occult HCV persistence may account for the report of recurrent HCV infection after liver transplantation in a small number of patients treated successfully with antiviral therapy prior to the transplantation.  Understanding the mechanisms by which the virus persists at low levels for extended periods of time may also be important. Although the complete mechanisms of occult HBV (HBsAg negative) are not yet entirely clear, the presence of covalently closed circular HBV DNA in an episomal form in the nuclei of hepatocytes accounts partially for HBV's ability to persist in the face of immunological surveillance and viral suppression. HCV is not known to have a similar latent stage in its replication cycle.

However, HCV has been found in numerous nonhepatic compartments, some of which are immunologically privileged (e.g., central nervous system), and this may account for the low-level persistence after apparently successful antiviral therapy. It has been proposed that HCV compartmentalization may occur, in which HCV confined to a given "compartment" may not be capable of "infecting" other compartments. Such a theory could explain the finding of HCV virions in PBMCs but not in liver in many of the patients studied.

Perhaps even more important than the clinical consequences of persistent HCV are the public health implications. If patients with no markers of HCV infection still carry infectious virions, they are a potential source of HCV spread in the community. This may be significant for blood donation and organ transplantation programs, as patients may well be missed by current screening strategies.

However patients carrying such a low level of virus may not be infectious at all, as we have learned that the risk of transmission of low-level or occult HBV is minimal. To help clarify this issue, examination of high-risk cohorts with no standard markers of HCV infection will be very important, as will the demonstration that this is in fact infectious virus.

Radkowski et al. (2) have certainly opened our eyes with their provocative findings. The significance of occult HCV persistence remains to be seen, and future work in this area is anxiously anticipated.

For now, we will have to watch our tongues before using the word cure.

01/03/05

Citations

1. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virology 2004; 78: 5867-5874.

2. Radkowski M, Gallegos-Orozco JF, Jablonska J, Colby TV, Walewska-Zielecka B, Kubicka, J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. HEPATOLOGY 2005; 41: 106-114

Reference

J Feld and T J Liang. HCV persistence: Cure is still a four letter word (editorial). Hepatology 41(1): 23-25. January 2005.   January 2005.

Link to Index to All Hepatitis

http://www.hivandhepatitis.com/hep_c/news/2005/010305_b.html

Public release date: 14-Jan-2005
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Contact: Kathi Baker
kobaker@emory.edu
404-727-9371
Emory University Health Sciences Center
 

Depression caused by common treatment for hepatitis C may affect outcome

ATLANTA–An article appearing in the January 2005 issue of Brain, Behavior and Immunity suggests that developing depression while on interferon-alpha plus ribavirin may impact how well the medications work.

In a study conducted in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine, Charles L. Raison, MD, Andrew Miller, MD, and colleagues, observed that patients who develop depressive symptoms during interferon-alpha plus ribavirin therapy were significantly less likely to have cleared the hepatitis C virus from their blood following six months of treatment.

"Hepatitis C infection affects three to five million Americans, and is the leading cause of liver transplantation," said Dr. Raison. "With advances in treatment, 40-50 percent of patients can be cleared of the virus. Unfortunately, however, the current treatment for hepatitis C – interferon-alpha plus ribavirin – produces a high rate of psychiatric side effects that have long been recognized as impediments to successful antiviral therapy. In the past we primarily worried that depression interfered with quality of life, or would cause patients to stop taking the medicine. These new data suggest that even if patients stay on treatment, they are less likely to have a good outcome if they develop depression."

The study examined 103 participants who received pegylated interferon-alpha-2b plus ribavirin (PEG IFN/ribavirin). All participants were psychiatrically evaluated prior to initiation of the medication and at 4, 8, 12 and 24 weeks of PEG IFN/ribavirin treatment.

Only 34% of the patients who had a significant increase in depression cleared the hepatitis C virus from their blood at 24 weeks, as compared to 59%-69% of patients with milder increases in depression. The effect of depression on viral clearance persisted even after adjusting for factors known to affect treatment outcome, such as viral genotype, or whether medications had to be reduced.

"The findings of this study provide preliminary evidence that baseline mood state should be assessed in patients prior to commencing treatment," said Dr. Raison. "Significant deviations from this state may increase the likelihood of treatment failure. Moreover, these findings provide further support that the development of depression can have a negative impact on health outcomes in medically ill subjects."

Researchers from the Rollins School of Public Health, Emory University and the Department of Medicine, Gasteroenterology and Hepatology, Weill Medical College of Cornell University were also involved in the study. The study was supported by grants from the National Institute of Mental Health, Schering–Plough, and the Centers for Disease Control and Prevention.