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HBV Treatments but not by IFN or antiviral drugs Community
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Some studies.

Many Patients with ALTs in the High-Normal Range Have Liver Damage.  

Journal ReviewApril 1, 2010, Vol 7, no 4 by Christine M. KukkaMany Patients with ALTs in the High-Normal Range Have Liver DamageHistorically, researchers have assumed that HBV-infected people who have normal ALT levels have little or no liver damage and do not require treatment. However, recently the “healthy range” of ALT levels has been markedly reduced, and now Australian and Chinese researchers have found that many HBV-infected people with reportedly “normal” ALT levels have significant liver damage.The researchers, writing in the March 2010 issue of the Journal of Viral Hepatitis, compared liver biopsy results, age, viral load, and HBeAg status in 252 patients with normal ALT levels and 270 with elevated ALT levels.They found 38.5% of people with normal ALT levels had healthy livers, 25.4% had significant inflammation and/or fibrosis, and 8.4% had severe liver scarring–cirrhosis. There were significantly higher rates of liver damage in “healthy” patients whose ALT levels were near the high-normal range (40%) than those in the low-normal group (16.6%).Based on their results, researchers recommended biopsies and treatment in patients age 40 or older, especially if their ALT levels were in the normal/high range.
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Subject: Is Response to Hepatitis B Treatment Influenced by HBV Genotype, Liz Highleyman, 3/12/10.

SUMMARY: It remains unclear whether hepatitis B virus (HBV) genotype has an influence on treatment response -- as is the case for hepatitis C virus (HCV) -- due to inconsistencies across studies and failure to account for differences in race/ethnicity, according to a report in the March 2010 Journal of Hepatology.

It is well known that viral genotype has a major impact on response to interferon-based therapy for hepatitis C, but it is unclear whether this is also true for hepatitis B. In addition, the influence of race/ethnicity -- also a major determinant of the efficacy of hepatitis C treatment -- remains poorly defined for hepatitis B.  Sara Raimondi from the European Institute of Oncology in Milan and colleagues performed a literature search on this topic, looking at studies published through April 2009. Recently released clinical practice guidelines and consensus statements point to the importance of HBV genotyping in therapeutic algorithms for the treatment of chronic hepatitis B, they noted as background. However, this recommendation is based on information that usually comes from post hoc analyses of clinical trials that were not originally designed to study associations with HBV genotype. From the available medical literature, the authors selected randomized clinical trials of currently approved anti-HBV drugs that provided information on HBV genotypes and baseline characteristics of study participants, treatment response, and interaction between HBV genotype and type of therapy. "There were several intrinsic features and weaknesses in the majority of clinical trials conducted so far which make it difficult to reach firm conclusions about the role of HBV genotypes in response to antiviral therapy," they stated. Most trials were necessarily multicenter in order to reach a sufficient number of participants to confer sufficient statistical power, the authors noted. However, pooling patients of different racial/ethnic groups "may have revealed false-positive associations between response to antiviral therapy and HBV genotype." For example, if Asian patients respond better to therapy (as appears to be the case for hepatitis C) and tend to have HBV genotype B, it could appear as if genotype B itself is a predictor of good response. Moreover, they continued, "endpoint definitions, especially for the composite ones, varied substantially among studies, leading to lack of homogeneity." Without consistent outcome measures, it is difficult to make comparisons across trials. Finally, they noted, possible interactions between type of therapy (e.g., interferon, direct-acting antiviral agents) and HBV genotype were seldom analyzed. "The present review highlights several caveats regarding current indications proposed by the major clinical practice guidelines and consensus conference statements published thus far and emphasize the need for further long-term studies in the field," the authors concluded.

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; Liver Unit, Department of Medicine, Azienda Ospedaliera Fatebenefratelli e Oftalmico, Milan, Italy; Research Laboratories, Department of Infectious Diseases, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy.
3/12/10
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Subject: New Guidelines Say Viral Load Dictates What Medical Procedures HBV-Infected Health Care Workers Can Perform, 03/07/10, HBV Advocate Journal Review

The National Institutes for Health and the Society for Healthcare Epidemiology of America (SHEA) has issued guidelines regulating what medical procedures that health care workers infected with HBV, HCV and/or HIV can perform. Health care workers are at high risk of contracting these infections, and to date there have been no national guidelines defining which medical procedures these infected workers can perform. Writing in the March 2010 issue of the journal of Infection Control & Hospital Epidemiology, the experts issued the following guidelines for practitioners infected with HBV:

• Those with HBV DNA levels less than 10,000 genome equivalents per millimeter of blood (GE/mL): SHEA recommends no restrictions on their practice, and this includes surgery, as long as the infected healthcare provider has not infected a patient in the past, receives advice from his/her facility’s Expert Review Panel, undergoes follow-up routinely by occupational medicine staff (or an appropriate public health official), and is tested twice a year to monitor viral load. The provider must also be treated by a personal physician with expertise in hepatitis B who is authorized to communicate results to the Expert Review Panel. The infected practitioner must also consult with an expert about optimal infection control procedures and strictly adheres to the recommended procedures, including the routine use of double-gloving for more high-risk procedures and frequent glove changes during procedures, particularly if performing technical tasks known to compromise glove integrity, such as placing sternal wires.

• Those with HBV DNA levels greater than 10,000 GE/mL: SHEA recommends that HBV-infected health care providers who test either positive for HBeAg or negative for HBeAg but who have circulating HBV burdens of greater than or equal to 10,000 GE/mL routinely use double-gloving for all invasive procedures, for all contact with mucous membranes or nonintact skin, and for all instances in patient care for which gloving is recommended, and that they not perform the Category III procedures that are associated with a risk for provider-to-patient HBV transmission despite the use of appropriate infection control procedures. The Category III restricted procedures include general surgery, oral surgery, cardiothoracic surgery, open head and neck surgery involving bones, neurosurgery, open resuscitation efforts, obstetrical or gynecological surgery, orthopedic procedures, plastic surgery, transplantation surgery, trauma surgery, and lengthy open surgical procedures. SHEA also cautioned infected practitioners against interacting with violent or seizure-prone patients who might bite the physician.

SHEA recommends that infected healthcare providers should not be totally prohibited from participating in patient-care activities solely on the basis of their infections, and that each case should be independently considered.
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Subject: Viral Mutations and Genotype B Increase Risk of Liver Failure, 03/07/10, HBV Advocate Journal Review

Researchers compared the HBV for mutations from patients who had chronic hepatitis B against those with chronic hepatitis B who experienced acute liver failure. Neither patient group had signs of cirrhosis. Researchers reported in the January 2010 issue of the Journal of Viral Hepatitis that the 75 patients who developed liver failure, without any pre-existing liver cirrhosis, had a higher incidence of having genotype B than the control group, and they had a higher rate of basal core promoter and precore mutations (BCP/PC) in their HBV. The patients with BCP/PC mutations also had higher rates of HBeAg negativity, higher ALT and lower HBV DNA levels.
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Subject: More Than 26% of Patients with Liver Disease Use Alternative Medicine, 03/07/10, HBV Advocate Journal Review

More Than 26% of Patients with Liver Disease Use Alternative Medicine
U.S. researchers surveyed 1,040 patients with liver disease to determine how many of them used complementary and alternative medicine (CAM), which includes vitamins, supplements, or herbal medicine. Patients were asked about their use of CAM specifically for liver disease and 284 (27.3%) reported current use of at least one of three common CAM therapies. Vitamins or other dietary supplements were the most commonly used, reported by 188 (18.1%) patients, followed by herbal medicine (175 patients, 16.8%) and homeopathy (16 patients, 1.5%). Patients using CAM tended to have higher levels of income and education, and were infected with viral hepatitis or had abused alcohol. “Use of CAM therapies that have the potential to interact with conventional treatments for chronic liver disease was quite common among this population-based sample of patients,” researchers wrote in the February 2010 issue of the Journal of Clinical Gastroenterology. “There is a need for patient and practitioner education and communication regarding CAM use in the context of chronic liver disease.”
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Subject: HBV Genotype C Associated with Higher Rates of Cirrhosis, 03/07/10, HBV Advocate Journal Review

Chinese researchers followed 634 HBsAg-positive patients and compared their HBV strain or genotype with the patients’ incidence of high viral load and cirrhosis. Cirrhosis was only found in the HBeAg-negative patients, and was most common in those with genotype C than in those with genotype B (14.8% vs. 8.0% respectively). In HBeAg-negative patients, high viral load was frequently asso¬ciated with elevated ALT levels, and high ALT levels were more commonly found in those with suspected cirrhosis than those without (19.5% vs. 7.8% respectively). Researchers, writing in the January 2010 issue of the World Journal of Gastroenterology, reported that HBV genotype C, older age, male gender and elevated ALT levels were related to occurrence of cirrhosis.
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Subject: Liver Cancer Is Still a Risk in Patients Who Clear HBsAg, 03/07/10, HBV Advocate Journal Review.

U.S. researchers who followed Alaskan natives infected with hepatitis B over many years, report that liver cancer can still occur in people even after they’ve cleared HBsAg and show no signs of severe liver inflammation and scarring (cirrhosis). To date, many doctors assume that once patients clear HBsAg they are at low risk of liver damage because their immune systems have successfully “fought off” the HBV and reduced the virus to very low levels. Some doctors no longer regularly monitor these patients for liver damage. Researchers in Alaska followed 1,271 Alaska Native persons with chronic HBV for an average of 19.6 years to assess their risk of liver cancer after losing HBsAg. HBsAg loss occurred in 158 persons, many were older and HBsAg loss occurred in men and women equally. HBV strain or genotype played no role in who lost HBsAg. Patients were followed for an average 108.9 months after HBsAg loss. Six patients--two with cirrhosis and four without-- developed liver cancer an average 7.3 years after HBsAg clearance. The incidence of liver cancer in those who cleared HBsAg was much lower than those who remained HBsAg-positive, researchers noted.
Interesting, after loss of HBsAg, HBV DNA continued to be detected in the bloodstream of 28 (18%) of patients even 3.6 years after clearing HBsAg. The researchers recommended that doctors continue to monitor patients who have cleared HBsAg with periodic liver ultrasounds to detect liver cancer in their report published in Hepatology.
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Subject: Significant histopathology in Chinese chronic hepatitis B patients with persistently high-normal ALT, 03/06/10, Journal of Viral Hepatitis, Volume 17 Issue s1, Pages 44 - 50

H. L. Gui 1 , H. Wang 1 , Y. H. Yang 1 , Y. W. Wu 1 , H. J. Zhou 1 , S. M. Guo 1 , L. Y. Lin 1 , L. Wang 1 , W. Cai 1 , R. Chen 1 , Q. Guo 1 , X. Q. Zhou 1 , S. S. Bao 2 and Q. Xie 1

Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China ; and 2 Discipline of Pathology, The Bosch Institute, The School of Medical Sciences, Faculty of Medicine, The University of Sydney, Sydney, Australia

ABSTRACT
Summary. Current guidelines recommend antiviral therapy for chronic hepatitis B (CHB) patients with elevated alanine aminotransferase (ALT) and high viral load. Scant histological data exist for CHB patients with persistently normal ALT (PNALT) because disease progression is thought to be rare. To identify potential predictors of significant histology in the presence of PNALT, we compared the clinical characteristics and histology of Chinese CHB PNALT patients to those in patients with elevated ALT. Percutaneous liver biopsy was performed in 522 CHB patients with Chinese ethnicity who had not had antiviral treatment. Differences in age, ALT, viral load, hepatitis B e antigen (HBeAg) status and liver histology were compared between eligible PNALT (252) and elevated ALT (270) patients. Of the PNALT patients, 38.5% had normal liver histology, 25.4% had significant necroinflammation and/or fibrosis and 8.4% had established cirrhosis. Furthermore, histopathological differences between patients with high–normal ALT (0.5–1.0 × the upper limit of normal (ULN)) and low–normal ALT (≤0.5 × ULN) were evaluated. There was a significantly greater prevalence of histopathology in the high–normal group (40.0%) than in the low–normal group (16.6%) (P < 0.001). Multiple logistic regression identified that significant histopathology findings in PNALT patients correlated with age (P < 0.001) and ALT level (P 40 years and ALT>0.5 × ULN predicting significant histopathology. Our data indicate that liver biopsy is recommended in CHB patients>40 years of age, particularly when their ALT is 0.5–1.0 × ULN. The findings above provide evidence for indication of antiviral therapy in patients with PNALT and significant histopathological change.
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Significance of HBV DNA Levels in Liver Histology of HBeAg and Anti-HBe Positive Patients with Chronic Hepatitis B, 6 May 2004, Man-Fung Yuen MD, Irene Oi-Lin Ng MD, Sheung-Tat Fan MD, He-Jun Yuan PhD, Danny Ka-Ho Wong MSc, John Chi-Hang Yuen BSc, Simon Siu-Man Sum BSc, Annie On-On Chan MD and Ching-Lung Lai MD, Department of Medicine; Department of Pathology; Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Correspondence: Prof. Ching-Lung Lai, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.

OBJECTIVE:  To determine the relationship between hepatitis B virus (HBV) DNA levels and total histologic activity index (HAI), necroinflammation (HAI-NI), and fibrosis (HAI-F) scores.

PATIENTS AND METHODS:  Liver histology and HBV DNA levels were determined in 94 patients with chronic hepatitis B.

RESULTS:  There was no association between HBV DNA levels and liver histology in hepatitis-B-e antigen-positive patients (n = 43). In anti-HBe-positive patients (n = 51), HBV DNA levels correlated positively with HAI-NI (r = 0.31, P = 0.014) and HAI-F (r = 0.33, P = 0.017) scores. Though the majority of anti-HBe-positive patients with HBV DNA levels <105 copies/ml had mild necroinflammation and no fibrosis, 14.3% had established fibrosis. Anti-HBe-positive patients with core promoter mutations had a poorer histology compared to those without. There was no difference in the histology between anti-HBe-positive patients with and without precore mutations. Alanine aminotransferase (ALT) level correlated positively with HAI-NI score. Patients with persistently normal ALT levels had a significantly lower median HAI-NI score compared to patients with either persistently or intermittently elevated ALT levels.

CONCLUSIONS:  In anti-HBe-positive patients, though HBV DNA level <105 copies/ml was associated with better histology, 14.3% patients had established fibrosis. Further studies to define a better cut-off HBV DNA level to differentiate low- and high-risk patients for disease progression are required.
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Decline of Serum HBV DNA and No Change Apportioned by the Same Hepatic Parenchyma Cell Volume from Hepatic Fibrosis Stage 1 to Stage 4 during the Natural History of Chronic Hepatitis B, 2008, Wei-Min Kea, Shi-Bin Xiea, Li-Na Yua, Ting Liua, Jing Laia, Da-Qiu Hea, Xiao-He Lia, Zhi-Liang Gaoa, Ying Keb, Pei-Jia Chenc

aDepartment of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Shipai, Guangzhou, PR China;
bDepartment of Physiology, University of Otago, Dunedin, New Zealand;
cResponse Genetics Inc., Los Angeles, Calif., USA

During the initial phase of chronic hepatitis B virus (HBV) infection, serum HBV DNA levels are high. Contrarily, fibrosis, cirrhosis and hepatocellular carcinoma have been found in patients with lower serum HBV DNA levels. The aim of this study is to clarify HBV DNA level dynamics of serum apportioned by the same hepatic parenchyma cell volume (HPCV) in hepatic fibrosis stages 1-4 during the natural history of chronic hepatitis B. Serum HBV DNA levels were evaluated by real-time polymerase chain reaction. Further, serum HBV DNA levels were apportioned by and compared with the same HPCV in hepatic fibrosis stages 1-4, respectively. Serum HBV DNA levels were 8.91 × 106 ± 4.37 × 101, 8.13 × 106 ± 7.41 × 101, 9.55 × 105 ± 1.02 × 102, and 4.07 × 105 ± 7.24 × 101 copies/ml, respectively; there were differences among hepatic fibrosis stages 1-4 (p  0.203-0.967).Following the progression of hepatic fibrosis from stage 1 to 4, ongoing decline of HPCV is responsible for a declining trend of serum HBV DNA levels.
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HBV-DNA, HBeAg/anti-HBe serological status in hepatitis B chronic individuals from central Italy, 1989, M. Rapicettaa1 et al.

SUMMARY:  A population of 488 HBsAg carrier individuals, from central Italy, classified on the basis of biochemical, clinical and histological parameters, was analysed for the presence of HBV-DNA in serum and its relationship with HBeAg/anti-HBe markers. The prevalence of HBV-DNA was 32•8% in chronic patients with biopsy-proven liver disease, and 20 and 4•3% respectively in asymptomatic carriers with and without altered ALT levels. The values in chronic patients were correlated with the histological activity.  Concordance of HBV-DNA presence and HBeAg positivity was observed in only 61•4% of cases. However HBV-DNA prevalence in sera of anti-HBe positive individuals was very low in asymptomatic carriers with normal ALT levels (2•5%). Higher values were observed in anti-HBe positive chronic patients (15•8%) and in carriers occasionally found with changes in ALT without any other clinical sign of illness (16•7%). These data would indicate that HBV-DNA is the serological marker which is most closely related to liver disease.
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The role of serial measurement of serum HBV DNA levels in patients with chronic HBeAg(−) hepatitis B infection: Association with liver disease progression. A prospective cohort study, Volume 49, Issue 6, Pages 884-891 (December 2008)

George Zacharakis12Corresponding Author Informationemail address, John Koskinas2, Stamatia Kotsiou3, Fevronia Tzara1, Nikolaos Vafeiadis1, Menelaos Papoutselis1, Eustratios Maltezos3, Eleftherios Sivridis4, Kostantinos Papoutselis1

Background/Aims
To evaluate the fluctuating course of serum HBV-DNA levels during the natural history of chronic HBV infection in the general population of North-Eastern Greece, in association with liver disease progression.

Methods
Two hundred and sixty-three adults with chronic HBV, median 34 years of age, were randomly selected and prospectively followed-up for a maximum period of 12 years. Viral markers, liver biochemistry and physical examination were performed every 6 months, and liver biopsy/abdominal ultrasound every 2–4 years.

Results
At entry, 195/263 (76%) were HBeAg (−)/anti-HBe (+) inactive carriers: (a) almost all 195 individuals with undetectable or HBV-DNA levels 2000IU/ml.

At entry, 48/263 (18%) patients were chronic HBeAg(−); (a) 1/3 patients had intermittently HBV-DNA <2000IU/ml for at least one occasion and were misclassified as inactive carriers (b) 22/48 (46%) had moderate/severe histology at entry and 5/48 (10%) showed liver disease progression during follow-up. Logistic regression analysis was used to derive OR (95%CI) for factors associated with liver disease progression.

Conclusions
Close monitoring of serum HBV-DNA levels is useful in the management of chronic HBeAg(−) patients, as associated with liver disease progression.
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High Viral Load and Hepatitis B Virus Subgenotype Ce Are Associated With Increased Risk of Hepatocellular Carcinoma, Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 177-182

Henry Lik-Yuen Chan, Chi-Hang Tse, Frankie Mo, Jane Koh, Vincent Wai-Sun Wong, Grace Lai-Hung Wong, Stephen Lam Chan, Winnie Yeo, Joseph Jao-Yiu Sung, Tony Shu-Kam Mok

From the Department of Medicine and Therapeutics, Institute of Digestive Disease; and the Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong

Corresponding author: Tony S.-K. Mok, MD, Department of Clinical Oncology, Sir YK Pao Center for Cancer, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong; e-mail: ***@**** or ***@****

Purpose We aimed to investigate the impact of hepatitis B virus (HBV) DNA and HBV genotypes/subgenotypes on the risk of hepatocellular carcinoma (HCC).

Patients and Methods A prospective cohort of patients infected with chronic HBV in a surveillance program for HCC since 1997 was studied. Ultrasound and alpha-fetoprotein evaluation were regularly performed to detect HCC. Risk factors for HCC and the relationship between HBV DNA and HBV genotypes were determined.

Results Among 1,006 patients with a median follow-up of 7.7 years, 86 patients (8.5%) developed HCC. With reference to the low HBV DNA stratum (log HBV DNA ≤ 4.5 copies/mL), the hazard ratio for HCC of the intermediate HBV DNA stratum (log HBV DNA > 4.5 to 6.5 copies/mL) was 1.62 (95% CI, 1.05 to 2.48; P = .027) and that of the high HBV DNA stratum (log HBV DNA > 6.5 copies/mL) was 2.73 (95% CI, 1.76 to 4.25; P < .001). Among patients with genotyping results, 330 patients had HBV genotype B and 439 patients had HBV genotype C (94 subgenotype Ce and 345 subgenotype Cs). With reference to HBV genotype B, HBV subgenotype Ce has the highest risk of HCC (hazard ratio = 2.75; 95% CI, 1.66 to 4.56; P < .0001) and HBV subgenotype Cs has intermediate risk (hazard ratio = 1.70; 95% CI, 1.09 to 2.64; P = .020). On multivariate analysis, HBV DNA, HBV genotypes, liver cirrhosis, male sex, older age, and lower serum albumin were independent risk factors of HCC.

Conclusion High HBV DNA level and HBV genotype C, particularly subgenotype Ce, increased the risk of HCC in chronic hepatitis B.
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Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level, JAMA. 2006 Jan 4;295(1):65-73.

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group.

Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan. ***@****
Abstract

CONTEXT: Serum hepatitis B virus (HBV) DNA level is a marker of viral replication and efficacy of antiviral treatment in individuals with chronic hepatitis B. OBJECTIVE: To evaluate the relationship between serum HBV DNA level and risk of hepatocellular carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 3653 participants (aged 30-65 years), who were seropositive for the hepatitis B surface antigen and seronegative for antibodies against the hepatitis C virus, recruited to a community-based cancer screening program in Taiwan between 1991 and 1992. MAIN OUTCOME MEASURE: Incidence of hepatocellular carcinoma during follow-up examination and by data linkage with the national cancer registry and the death certification systems. RESULTS: There were 164 incident cases of hepatocellular carcinoma and 346 deaths during a mean follow-up of 11.4 years and 41,779 person-years of follow-up. The incidence of hepatocellular carcinoma increased with serum HBV DNA level at study entry in a dose-response relationship ranging from 108 per 100,000 person-years for an HBV DNA level of less than 300 copies/mL to 1152 per 100,000 person-years for an HBV DNA level of 1 million copies/mL or greater. The corresponding cumulative incidence rates of hepatocellular carcinoma were 1.3% and 14.9%, respectively. The biological gradient of hepatocellular carcinoma by serum HBV DNA levels remained significant (P or =10,000 copies/mL) is a strong risk predictor of hepatocellular carcinoma independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis.
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HBV DNA & ALT Predict HCC in HBV+, Jules Levin, DDW, Washington DC, May 19-24, 2007

"...These results indicate that ongoing viral replication leads to biochemical abnormalities and eventual liver damage. This would suggest that viral load at a single point in time (in CHB subjects aged 30-65) captures the eventual risk of ALT elevation as well as that of future HCC risk..."

In Table 1: HBV DNA >1 million was associated with the highest risk for medium & high ALT levels (3 to 4 times higher compared to HBV DNA 100,000 to 1 million).

In Table 4: HBV DNA >1 million copies/ml increased HCC risk, associated with Hazard Ratio of 8.6 (3.7-20.1) (p <.0001) compared to HBV DNA <300 c/ml (undetectable). HBV DNA 100,000 to 1 million associated with Hazard Ratio of 7.3 (3.3-16.4) (p <.0001). HBV DNA 10,000 to 100,000 associated with Hazard Ratio of 2.8 (1.2-6.6) (p 0.0173). HBV DNA 300-10,000 associated with Hazard Ratio of 1.6 (0.7-3.9) (p 0.2675).

"Changes in Serum Alanine Aminotransferase (ALT) Level Using A Trajectory Model and Risk of Hepatocellular Carcinoma (HCC) in Chronic Hepatitis B (CHB): THE R.E.V. E. A. L.- HBV Study"

Summary
Describing ALT Trajectories over time
- Four classes of serum ALT trajectories were identified by the model
- The majority of the study subjects were in Class II and had serum ALT between 15 and 45 U/L at study entry and remained there throughout follow-up

Baseline factors associated with serum ALT change over time
- Males were more likely than females to be in the trajectory Classes II-IV compared to Class I
- Age did not appear to be associated with changes in serum ALT over time
- Alcohol consumption and HBeAg status were associated with serum ALT changes
- The baseline HBV DNAwas strongly associated with serum ALT trajectory across a biological gradient

Serum ALT change and incidence/risk of progressing to HCC
- The incidence of HCC increased with serum ALT trajectory class
(reference subjects with Class I trajectory)
- In the Cox model, change in serum ALT as measured by the serum ALT trajectory class was a strong predictor of HCC risk
- Increasing HBV DNA level at baseline was the strongest risk predictor of HCC progression even after adjusting for changes in serum ALT over time

Author Conclusions
Through our modelling, four distinct serum ALT trajectory classes were identified, and change in serum ALT level was an independent predictor of HCC risk

Serum HBV DNA at baseline was strongly associated with the serum ALT changes over time

After adjusting for the change in serum ALT over time, baseline HBV DNA remained a strong independent predictor of progressing to HCC in this cohort, and the HCC risk increased across a biological gradient

These results indicate that ongoing viral replication leads to biochemical abnormalities and eventual liver damage

This would suggest that viral load at a single point in time (in CHB subjects aged 30-65) captures the eventual risk of ALT elevation as well as that of future HCC risk

Abstract
Background and Aims: Serum ALT is a marker of hepatocyte damage in CHB. Our aims were to:
1) evaluate the relationship between ALT changes over time and HCC risk;
2) examine the baseline factors associated with ALT changes over time.

Methods: A subgroup of the R.E.V. E. A. L.- HBV cohort of HBsAg-seropositive and anti-HCVseronegative participants, with ≥5 ALT measurements, was used in the analyses. The outcome was new HCC cases. We defined low, medium, and high ALT as <20 U/L, ≥20 U/L but <45 U/L, and ≥45 U/L, respectively. Asemi-parametric group-based modelling was used to determine major classes of ALT trajectories. Associations between baseline risk factors and the ALT trajectories were examined using polytomous logistic regression. Cox proportional hazards modelling was used to analyze the associations between the ALT trajectory classes and HCC risk.

Results: A total of 1712 subjects with 61 new HCC cases contributed 21,225 person-years of follow-up.

Four ALT trajectory classes were identified:
Class I, persistently low (n = 551);
Class II, low-to-medium (n = 808);
Class III, high-to-medium (n = 99);
Class IV, medium-to-high (n = 254).

Of the baseline risk factors, gender, age, HBeAg status, serum HBV DNA levels, and alcohol consumption were significantly associated with the ALT trajectory.

With Class I subjects as the reference group, the adjusted hazard ratio [HRadj (95% CI)] of developing HCC was 4.0 (1.2-13.4) for Class II subjects; 4.6 (1.1-18.9) for Class III subjects; and 7.4 (2.1-25.9) for Class IV subjects after adjustment for gender, age, HBeAg status, HBV DNA levels, cigarette smoking, and alcohol consumption.
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With HBV DNA <300 copies/mL as reference, the HRadj ( 95% CI) of developing HCC associated with baseline HBV DNA level was 1.8 (0.5-7.4) for HBV DNA 300 to <104 copies/mL (10,000); 4.0 (1.1-14.8) for HBV DNA ≥ 104 to <105 copies/mL (100,000); 7.1 (2-25.6) for HBV DNA ≥ 105 to <106 (1 million); and 9.6 (2.5-36.2) for HBV DNA ≥ 106 copies/mL.

Conclusions: Serum ALT changes over time are a strong independent predictor of HCC. Baseline HBV DNA was a significant predictor of the ALT trajectory over time and remained an important risk factor for HCC development after adjusting for the ALT trajectories.

Introduction
The risk of disease progression in CHB is linked to several viral, biochemical, and immunologic markers

In our published analyses,1,2 baseline serum ALT was not statistically significant as an independent predictor of liver cirrhosis and HCC. Those analyses were limited by not accounting for changes in serum ALT over time

Serum ALT level is known to correlate with the level of hepatocyte damage in a variety of liver diseases, as well as with eventual mortality in the general population3

The primary objectives of these analyses were:
- Describe the latent trajectory classes of serum ALT changes over time in the R.E.V.E.A.L-HBV study cohort
- Examine the baseline factors associated with serum ALT changes over time
- Evaluate the relationship between serum ALT changes over time and risk of progressing to HCC adjusted for other variables including baseline serum HBV DNA level

Study Design
As previously described, the R.E.V.E.A.L.-HBV study is a population-based prospective cohort study with a mean follow-up of 11 years

A subgroup of this study cohort contributed to these analyses

Of the 3,653 anti-HCV-negative, HBsAg-positive subjects with adequate serum sample for HBV DNA testing, 3,054 had follow-up serum ALT levels beyond the baseline measurement. These subjects were enrolled in these analyses

There were 132 incident cases of HCC in this subpopulation.

Analyses:
- HBV DNA of cohort entry serum samples by PCR (Roche Diagnostics Co., Indianapolis, IN)
- HBsAg and HBeAg by radioimmunoassay (Abbott Laboratories, North Chicago, IL)
- Anti-HCV antibody by 2nd generation ELISA kits (Abbott Laboratories, North Chicago, IL)
- ALT by serum chemistry autoanalyser (Model 736, Hitachi Co., Tokyo, Japan) using commercial reagents (bioMérieux, Marcy l'Etoile, France)

Study Population/Methods
- Complete description of the case ascertainment for the HCC has been described1
- Semiparametric group-based modelling was used to determine major classes of serum ALT trajectories (Objective 1)
- The group-based trajectory model was designed to identify clusters of individuals following similar progressions of repeated measurements over time4 - Model selection was based on the Bayesian Information Criterion (BIC) as a measure of goodness-of-fit5
- According to the graphical summary of the group-based trajectory model, we defined low, medium, and high ALT as <15 U/L, ≥15 U/L but 45 U/L, respectively (Note: the ALT cut point was adjusted between the abstract and the final analyses, explaining the difference in cut points.)
- Associations between baseline risk factors and the serum ALT trajectories were examined using polytomous logistic regression (Objective 2)
- Cox proportional hazards modelling was used to analyze the association between the serum ALT trajectory classes and progression to HCC
- The statistical software SAS (SAS Institute Inc., Cary, NC) was used to obtain the corresponding estimates and figures
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Do HBV-DNA levels affect liver histology in patients with chronic hepatitis B?, 2008, Yetkin M.A., Bulut C., Kinikli S., Ustün H., Yücel M., Karakoc E., Tulek N., Demiröz A.P.

Objectives: In hepatitis B patient hepatitis B virus DNA (HBV-DNA) in serum is correlated with the progression of the liver disease. In this study we aimed to determine the relationship between hepatitis B virus (HBV-DNA) levels and clinical and histological findings in patients with chronic hepatitis B.

Metods: A total number of 216 patients with chronic hepatitis B (CHB) (112 inactive carriers, 44 HBeAg positive CHB and 72 HBeAg negative CHB patients) who were admitted to our clinic between 1999 to 2005 were included into the study. CHB was diagnosed on patients who were HBsAg positive for more than six months and had HBV DNA levels greater than 105 copy/mL and whose alanin transferase (ALT) levels were elevated persistently or intermittently. Inactive HbsAg carrier state was accepted as presence of HBsAg for more than six months, having HBV DNA level less than 104 copy/mL and persistently normal ALT levels. Serum HBV-DNA levels and the other parameters relevant to liver function were determined in all patient. Liver biopsy was performed on 116 patients with CHB patients.

Result: The HBeAg positive CHB patients were significantly younger than the HBeAg negative group and inactive carriers (p = 0.000). The mean HBV-DNA levels were 2×103copy/ml, 3×108 copy/ml and 9×108 copy/ml in inactive carriers, HBeAg negative CHB patients and HBeAg positive CHB patients respectively. HBeAg positive CHB group had significantly higher HBV DNA levels than HbeAg negative CHB patients and inactive carriers (p = 0.003). The HBeAg negative group had more severe inflammation and fibrosis scores compared to the HBeAg positive groups (p = 0.037 and p = 0.001). There was not any correlation between HBV-DNA levels and necro-inflammation and fibrosis scores of neither HBeAg negative CHB patients or HBeAg positive CHB patiens. Alanine aminotransferase and aspartate aminotransferase levels correlated positively with HBV-DNA levels in HBeAg negative CHB patients. Similar correlation was not observed in HBeAg positive CHB patients.

Conclusion: Although HBV DNA levels were higher in CHB patients when compared with inactive carrieres, no correlation between serum HBV DNA level and fibrosis of liver was detected in CHB patients.
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Traditional Chinese Medicine May Perform Better than Interferon or Lamivudine for Chronic Hepatitis B, 04/16/10,

SUMMARY: Various traditional Chinese medicine (TCM) formulations were found to work as well as or better than the pharmaceutical drugs interferon and lamivudine for people with chronic hepatitis B, according to a joint U.S./Chinese review of clinical trials published in the February 2010 issue of Hepatology. While many of these studies were considered to be of poor quality according to Western drug testing standards, the review authors concluded that some TCM remedies appear effective and warrant further study.

By Liz Highleyman
Chronic hepatitis B is major global health problem, but its impact is especially great in Asia. In China, it is estimated that approximately 120,000,000 people have chronic HBV infection. For centuries, the disease has been treated with traditional medicines.

Lingyi Zhang, Herbert Bonkovsky, and colleagues performed a meta-analysis of clinical trials of TCM formulations for treatment of chronic hepatitis B reported in China from 1998 through 2008.

An ancient book called the Yellow Emperor's Internal Classic indicates that TCM remedies have been used to treat chronic liver disease in China at least since 475 BCE, the authors noted as background. Today, TCM is still used extensively for the treatment of chronic hepatitis B in China, with some 80% of patients relying on Chinese remedies. While interferon alpha and lamivudine (Epivir-HBV) are often available, newer nucleoside/nucleotide analog drugs such as adefovir (Hepsera), entecavir (Baraclude), and tenofovir (Viread) are "prohibitively expensive" and not widely used, they noted.

Thousands of different herbs have been used in TCM formulations for liver disease, including astragalus (Huang Qi), bupleurum (Chai Hu), licorice root (Gan Cao), red sage (Dan Shen), rhubarb (Da Huang), and schisandra (Wu Wei Zi). "These TCM formulations are based on the collective wisdom of Chinese clinicians and practitioners, coupled with centuries of accumulated experience working with these herbs," the researchers wrote.

The review authors searched electronic databases (China National Knowledge Infrastructure and PubMed) to identify studies that either compared TCM formulations versus interferon (alpha-1b, alpha-2a, or alpha-2b, at least 3 million units administered 3 times per week for at least 3 months) or lamivudine (at least 100 mg administered once-daily for at least 30 consecutive days), or that added Chinese remedies to interferon or lamivudine to see if the combination worked better than the Western drugs alone. They also looked at which specific Chinese herbs are used most often.

The initial search included both randomized controlled trials (RCTs) -- the "gold standard" for Western drug testing -- and other types of studies that reported objective outcome measures such as serum alanine aminotransferase (ALT) normalization, HBV DNA viral load clearance, or hepatitis B "e" antigen (HBeAg) loss.

A total of 643 reports were selected for inclusion (596 in Chinese, 47 in English). Of these, 487 were clinical trials (356 RCT and 131 non-RCT), 80 were pre-clinical experimental studies, and 76 were summaries of non-randomized clinical experience.

Out of these studies, the researchers identified 53 RCTs that reported random allocation of patients with chronic hepatitis B to treatment with TCM formulations; these trials met the inclusion criteria and were used in the meta-analysis. The studies used a variety of TCM formulations, with an average of 9 ingredients, but approximately 50%-60% of the herbs overlapped across different formulations.

Overall, the quality of studies was judged to be "poor"; 16 (27%) of the 53 RCTs had Jadad scores (a standard algorithm for assessing trials) of 3, while the rest (73%) had scores of 2. None of the reports described methods used for randomization or whether they were double-blind, single-blind, or unblinded.

Among the 53 selected RCTs, 16 (1918 total participants) compared responses in patients receiving TCM formulations alone versus interferon, 6 RCTs (723 total participants) compared TCM alone versus lamivudine,18 trials (1738 total participants) compared TCM plus interferon versus interferon alone, and another 14 trials (1548 total participants) compared TCM plus lamivudine versus lamivudine alone

Results

A total of 203 different herbs were included in 230 TCM formulations for the treatment of chronic hepatitis B.

TCM formulations alone had a significantly greater beneficial effect than interferon for ALT normalization (odds ratio [OR] 2.42, or 2.4-fold greater; P = 0.0003).

Chinese formulations and interferon had a statistically similar likelihood of reducing HBeAg (OR 1.60; P = 0.07).

TCM and interferon also performed similarly with regard to HBV viral load clearance (OR 1.31; P = 0.20).

TCM formulations were significantly more effective than lamivudine for normalizing ALT (OR 1.96, or nearly twice as effective; P = 0.01).

TCM and lamivudine showed no significant difference in likelihood of reducing HBeAg (OR 1.57; P = 0.36).

Again, TCM and lamivudine were about equally likely to produce HBV DNA clearance (OR 1.20; P = 0.59).

When used in combination, TCM plus interferon enhanced antiviral activity and liver function improvement compared with interferon alone:

ALT normalization: OR 3.07, or about 3-fold greater benefit (P < 0.00001);

HBeAg reduction: OR 2.17, or about twice the benefit (P < 0.00001);

HBV DNA clearance: OR 2.05, again about twice the benefit (P < 0.00001).


TCM formulations plus lamivudine were also significantly more effective than lamivudine alone:

ALT normalization: OR 3.40 (P < 0.00001).

HBeAg reduction: OR 2.54 (P < 0.00001);

HBV DNA clearance: OR 3.20 (P < 0.00001);


In a similar analysis of the 16 RCTs of higher technical quality (Jadad scores of 3), the pattern of the results were similar.

Among 20 RCTs that included information about adverse events, no serious adverse side effects of TCM formulations were reported.
Based on these findings, the review authors concluded, "Some TCMs seem effective as alternative remedies for patients with chronic hepatitis B, suggesting that further study of TCMs in the treatment of chronic hepatitis B is warranted, both in preclinical models of HBV infection and in higher quality RCTs worldwide."

"Our meta-analysis suggests that in patients with chronic hepatitis B, (1) TCMs have a similar curative effect as interferon/lamivudine on antiviral activity as evidenced by the loss of serum HBeAg and HBV DNA; (2) TCMs have a better effect on normalization of serum ALT; and (3) TCMs enhance interferon and lamivudine antiviral activity and improvement of liver function," they elaborated in their discussion.

"It is noteworthy that there were no reported serious adverse events associated with the combinations of TCM studied," they added. "As used in China, these formulations seem to be very well tolerated, although many reports did not include data on adverse effects of therapy."

Liver-Biliary-Pancreatic Center and the Liver, Digestive Diseases, and Metabolism Laboratory, NC; McColl-Lockwood Laboratory, Carolinas Medical Center, Charlotte, NC; Institute of Clinical Medical Science, China-Japan Friendship Hospital, Beijing, China; Department of Biology, University of North Carolina at Charlotte, Charlotte, NC; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; Departments of Medicine and Molecular, Microbial & Structural Biology, University of Connecticut Health Center, Farmington, CT.
4/6/10
Reference
L Zhang, G Wang, W Hou, and others. Contemporary clinical research of traditional Chinese medicines for chronic hepatitis B in China: An analytical review. Hepatology 51(2): 690-698 (Free full text). February 2010.
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Nucleos(t)ide Analogues Only Induce Temporary Hepatitis B e Antigen Seroconversion in Most Patients with Chronic Hepatitis B, Gastroenterology. 2010 Apr 7. [Epub ahead of print] ,Reijnders JG, Perquin MJ, Zhang N, Hansen BE, Janssen HL.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Abstract
BACKGROUND & AIMS:: Inconsistencies in results and guideline recommendations regarding the durability of nucleos(t)ide analogue-induced hepatitis B e antigen (HBeAg) seroconversion require clarification. We studied the long-term durability of nucleos(t)ide analogue-induced HBeAg seroconversion in patients with chronic hepatitis B virus (HBV) infection. METHODS:: We performed a single-center cohort study of 132 HBeAg-positive patients that had received nucleos(t)ide analogue therapy. RESULTS:: During a median treatment duration of 26 months (16-43 months), HBeAg seroconversion occurred in 46 of 132 subjects (35%). Forty-two subjects (91%) had follow-up after HBeAg seroconversion. During a median follow-up of 59 months (28-103 months) after HBeAg seroconversion, 13 of 42 patients (31%) demonstrated a durable remission (defined as HBeAg negative and HBV DNA < 10,000 copies/mL). Overall, 33 of 42 subjects (79%) continued therapy after HBeAg seroconversion; of these, 22 (67%) demonstrated serological and/ or virological recurrence. Nine of 42 subjects (21%) discontinued therapy after HBeAg seroconversion and at least 6 months of consolidation therapy. Only 2 patients demonstrated a durable response in the absence of therapy. Disease recurrence in patients that continued therapy after HBeAg seroconversion was preceded by the development of resistance (80% of these patients); resistance only occurred in subjects given lamivudine monotherapy. In contrast, recurrence after treatment discontinuation or non-compliance was observed in all patients given nucleos(t)ide analogues. CONCLUSIONS:: Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection. Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary.
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Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides, Emmet B Keeffe and Jean-François Rossignol, 2009,

Abstract
Nitazoxanide, the first thiazolide, was originally developed for the treatment of Cryptosporidium parvum. More recently, antiviral activity of nitazoxanide against hepatitis B virus (HBV) and hepatitis C virus was recognized in in vitro systems. These basic studies led to phase II clinical trials that demonstrated the safety and efficacy of nitazoxanide in combination with peginterferon, with or without ribavirin, in the treatment of chronic hepatitis C genotype 4. The sustained virologic response rate was 79% and 80% in two studies, which was higher than the response rate of 50% with the standard of care with peginterferon plus ribavirin. In very preliminary studies of patients with chronic hepatitis B, nitazoxanide suppressed serum HBV DNA and led to loss of hepatitis B e antigen in the majority of patients and hepatitis B surface antigen in approximately a quarter of patients. Randomized controlled studies of naive and nonresponder patients with chronic hepatitis C genotype 1 are underway, new second generation and controlled release thiazolides are being developed, and future studies of patients with chronic hepatitis B are planned.

INTRODUCTION
Nitazoxanide (Alinia®, Romark Laboratories, L.C., Tampa, Fl, USA), the first thiazolide, was licensed in the USA for the treatment of Cryptosporidium parvum and Giardia lamblia in immunocompetent adults and children in 2002[1]. A number of emerging basic and clinical studies support an additional role of nitazoxanide in the treatment of chronic hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) infection. This brief review summarizes current data from emerging phase II studies related to this new potential use of nitazoxanide combined with peginterferon and ribavirin for the treatment of chronic hepatitis C and very preliminary experiences with nitazoxanide for the treatment of chronic hepatitis B.

ANTIVIRAL MECHANISM OF ACTION OF NITAZOXANIDE
The antiviral mechanism of action of nitazoxanide is different from the mechanism of action in protozoa and anaerobic bacteria via direct inhibition against the pyruvate-ferrodoxin oxidorectase reaction[1], and appears in recent studies to involve activation of the protein kinase activated by double-stranded RNA (PKR), an interferon-induced mediator of the cellular antiviral response[2]. The activation of PKR results in phosphorylation of its substrate, eukaryotic initiation factor 2 alpha (eIF2α). Nitazoxanide, thus, represents a new class of small molecules that modulate host antiviral pathways. By targeting a host function, the barrier to development of antiviral resistance is significantly higher than for drugs directly targeting a viral function.

IN VITRO ACTIVITY OF NITAZOXANIDE AGAINST HBV AND HCV
After nitazoxanide was serendipitously suspected as active against viral hepatitis in patients with acquired immune deficiency syndrome (AIDS) treated with nitazoxanide for Cryptosporidium, the antiviral activities of nitazoxanide and its metabolite, tizoxanide, were confirmed in standard antiviral assays in vitro[3,4]. Both nitazoxanide and tizoxanide are potent inhibitors of HBV, and in combination with other antiviral agents such as lamivudine or adefovir, show synergistic effects. Nitazoxanide and tizoxanide are also effective against HBV-resistant mutants to lamivudine and adefovir. Additionally, both nitazoxanide and tizoxanide are potent inhibitors of HCV in genotype 1a- and 1b-derived replicon cells and genotype 2a cell culture models, and synergistic effects are observed when tizoxanide is combined with interferon[3]. Three days of pretreatment of the HCV replicon model with nitazoxanide sensitizes the virus to the effects of subsequent treatment with interferon, providing support to the clinical studies underway using a nitazoxanide lead-in phase prior to combination therapy.

LACK OF DIRECT ANTIVIRAL RESISTANCE TO NITAZOXANIDE
Studies were carried out in HCV replicons exposed to increasing concentrations of nitazoxanide or tizoxanide over 24 wk in an attempt to produce resistance to nitazoxanide and tizoxanide[5]. This serial passage did not reduce the susceptibility of HCV replicons to interferon, ribavirin, or 2′-C-methyl-cytidine, indicating that nitazoxanide and tizoxanide do not induce resistance to these agents.

TREATMENT OF CHRONIC HEPATITIS C
Completed studies
Romark made the decision to initially focus on the potential treatment of chronic hepatitis C with nitazoxanide. Three phase II studies of nitazoxanide for the treatment of chronic hepatitis C have been completed and communicated in publications or presentations at national and international meetings[6–8]. The first study was a randomized, double-blind, placebo-controlled study of the treatment of chronic hepatitis C with nitazoxanide 500 mg twice daily in 50 adult patients with chronic hepatitis C infected with genotype 4[6]. Seven of 23 patients (30%) had a virologic end-of-treatment response (ETR) with undetectable virus, and a sustained virologic response (SVR) with undetectable virus 24 wk after the completion of treatment was observed in 4 of 23 patients (17%). All responders had low serum HCV RNA levels less than 400 000 IU/mL. This study was the first use of nitazoxanide in patients with chronic hepatitis C and for a longer time period than for its use for cryptosporidiosis and giardiasis, and the drug was well tolerated with the same number of mild gastrointestinal adverse events in the treated and placebo groups.
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A second randomized, double-blind, placebo-controlled study (STEALTH C-1) evaluated the effects of nitazoxanide plus peginterferon alfa-2a (dual regimen) or nitazoxanide plus peginterferon alfa-2a and ribavirin (triple regimen) versus the standard of care (SOC) with peginterferon alfa-2a and ribavirin in 96 treatment-naive patients with chronic hepatitis C infected with genotype 4[7]. Nitazoxanide 500 mg twice daily was administered over a 12-wk lead-in followed by an additional 36 wk in combination with peginterferon alfa-2a 180 μg weekly with or without ribavirin 1000-1200 mg daily. The SOC group received the same doses of peginterferon alfa-2a and ribavirin for 48 wk. A rapid virologic response (RVR; undetectable serum HCV RNA after 4 wk of combination therapy) occurred in 38%, 54%, and 64% of patients receiving the SOC, dual regimen and triple regimen, respectively (P = 0.048, SOC vs triple regimen). A complete early virologic response (cEVR; undetectable serum HCV RNA at week 12 of combination therapy) occurred in 70, 68 and 86% of the SOC, dual regimen and triple regimen, respectively. The SVR rates at 24 wk post-treatment were 50%, 61% and 79%, respectively, demonstrating a 29% difference between the SOC and the triple regimen with nitazoxanide (P = 0.023).
A third open label study was carried out in 44 patients; 40 were infected with genotype 4, and 3 were infected with genotype 1, and 1 infected with genotype 2[8]. This study evaluated a shorter 4-wk lead-in phase with nitazoxanide 500 mg twice daily followed by 36 wk of treatment with a combination of nitazoxanide with peginterferon alfa-2a 180 μg weekly without ribavirin, and the results were compared with the historical results from the STEALTH C-1 study. The RVR, cEVR, and SVR rates were 59%, 82% and 80%, respectively, and the SVR rate of 80% in this study was significantly higher than the historical SVR rate of 50% in the SOC group (P = 0.006). The 3 patients infected with genotype 1 and the single patient infected with genotype 2 all had an SVR. The SVR rate of 80% raises the possibility using nitazoxanide in place of ribavirin, which requires further study.
In both this study and the STEALTH C-1 study, the administration of nitazoxanide in combination with peginterferon, with or without ribavirin, was associated with a low relapse rates (3 of 38 in the current study; and 3 of 20 patients receiving dual therapy and 1 of 23 patients receiving triple therapy, compared with 10 of 30 patients in the SOC arm in the STEALTH C-1 study). These low relapse rates, with or without ribavirin, suggest the possibility that nitazoxanide might play a similar role as ribavirin in reducing the relapse rate and be a possible substitute for ribavirin in combination with peginterferon for the treatment of chronic hepatitis C.
The results of these preliminary studies in Egypt in patients predominantly infected with genotype 4 were met with considerable interest in the hepatology community; but, studies conducted in the United States and the response to nitazoxanide in combination with the SOC in patients with genotype 1 were recognized as the next steps required to confirm these initial interesting findings.
Ongoing studies
A phase II randomized, double-blind, placebo-controlled study with of nitazoxanide or placebo monotherapy (2:1 randomization) over a 4-wk lead-in phase followed by nitazoxanide or placebo in combination with peginterferon alfa-2a plus ribavirin is currently underway in 112 naive patients infected with genotype 1 at 13 USA study sites. The preliminary results of the early virologic responses will be communicated in early 2009.
A second phase II, randomized, double-blind, placebo controlled study of nitazoxanide with peginterferon and ribavirin is being conducted in 10 USA sites in 64 patients who are prior nonresponders to peginterferon and ribavirin. Preliminary results from this study will also be communicated in 2009

CONTROLLED RELEASE TABLET
Studies have recently been initiated to study the pharmacokinetics, viral kinetics, and tolerability of a controlled release tablet of nitazoxanide in adult healthy volunteers as well as a phase II study in patients with chronic hepatitis C[9]. The new nitazoxanide controlled release tablet contains 675 mg of the drug, and kinetics has been evaluated using either 675 mg or 1350 mg twice daily for 7 d in a phase I study. The pharmacokinetics profile is substantially improved compared to the standard tablet, with higher blood levels and an increased area under the curve of approximately 70%.
In a subsequent randomized, controlled trial, 40 treatment-naive patients with chronic hepatitis C genotype 4 have been allocated to receive either 675 mg or 1350 mg or placebo twice daily for 4 wk followed by the same regimen plus the addition of peginterferon alfa-2a 180 μg weekly and ribavirin 1000 or 1200 mg daily based on body weight. An early interim analysis has shown that the mean reduction in serum HCV RNA from baseline to week 8 (after 4 wk of combination therapy) were 5.45, 5.25, and 2.75 in the high-dose, low-dose and placebo groups, respectively[9]. Nitazoxanide was well tolerated without gastrointestinal toxicity.
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TREATMENT OF CHRONIC HEPATITIS B
Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one year course of therapy[10]. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg[11]. These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase II study is being planned for 2009.
SECOND GENERATION THIAZOLIDES
Newer thiazolide analogs have been identified with higher specific activity against HBV and HCV. The objective of this search for alternative thiazolides is to identify compounds that do not have antiparasitic or antibacterial activity via direct inhibition against the pyruvate-ferredoxin oxidoreductase reaction and increased antiviral activity. There are several lead compounds that have undergone preliminary study in experimental replicon models and have the potential to move into clinical trial.

CONCLUSION
Nitazoxanide shows significant activity against HBV and HCV, both in cell culture models as well as in patients with chronic hepatitis B and C. The HCV antiviral mechanism of action has been elucidated to involve up-regulation of PKR and eIF2α phosphorylation, which enhances natural cellular antiviral mechanisms without induction of antiviral resistance. Second generation molecules in controlled release formulations are in development. Interim results of the American phase II trial involving treatment of naive and nonresponder patients with chronic hepatitis C infected with genotype 1 will be reported in early 2009. The thiazolides have a very favorable toxicity profile with a very low incidence of mild gastrointestinal side effects.
There are many future potential uses of nitazoxanide in treatment regimens for chronic hepatitis C. Nitazoxanide might allow reduction in the duration of a standard peginterferon-based regimen, as the results in the phase II studies of patients with genotype 4 were achieved with 36 wk of combination therapy versus the usual 48 wk used in the current SOC. Further studies using even shorter duration of combination therapy, i.e. 24 wk, are warranted. It is also possible that the interferon-like mechanism of action of nitazoxanide will allow use of a reduced dose of peginterferon in combination treatment regimens. The findings of high SVR rates with nitazoxanide in combination with peginterferon without ribavirin require confirmation, but raise the possibility that nitazoxanide might be used in the place of ribavirin and avoid the substantial hematologic and other side effects of this drug. Finally, nitazoxanide might be used with a reduced dose of peginterferon or even without peginterferon in combination with a protease inhibitor and/or polymerase inhibitor as part of an all-oral cocktail for treatment of chronic hepatitis C, avoiding the need for injectable interferon with all of its side effects.
Footnotes
Peer reviewer: Dr. Vicente Carreño, Fundacion Estudio Hepatitis Virales, C/ Guzman el Bueno 72, Semisotano, Madrid 28015, Spain
S- Editor Tian L L- Editor Negro F E- Editor Lin YP

References
1. Anderson VR, Curran MP. Nitazoxanide: a review of its use in the treatment of gastrointestinal infections. Drugs. 2007;67:1947–1967. [PubMed]
2. Elazar M, Liu M, McKenna S, Liu P, Gehrig EA, Elfert A, Puglisi J, Rossignol JF, Glenn JS. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR phosphorylation [abstract]. Hepatology. 2008;48:1151A.
3. Korba BE, Montero AB, Farrar K, Gaye K, Mukerjee S, Ayers MS, Rossignol JF. Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antiviral Res. 2008;77:56–63. [PubMed]
4. Schaninger T, Hong J, Luo GG. Nitazoxanide inhibits hepatitis C virus replication in vitro [abstract]. Hepatology. 2008;48:756A.
5. Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS. Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069–4071. [PubMed]
6. Rossignol JF, Kabil SM, El-Gohary Y, Elfert A, Keeffe EB. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Aliment Pharmacol Ther. 2008;28:574–580. [PubMed]
7. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009;136:856–862. [PubMed]
8. Rossignol JF, Elfert A, Keeffe EB. Evaluation of a 4 week lead-in phase with nitazoxanide (NTZ) prior to peginterferon (PegIFN) plus NTZ for treatment of chronic hepatitis C: final report [abstract]. Hepatology. 2008;48:344A–345A. [PubMed]
9. Keeffe EB, Rossignol JF, Elfert A, Abdelatif S, Cavens L, Phong TLT. Controlled release tablet improves pharmacokinetics, viral kinetics and tolerability of nitazoxanide for treatment of chronic hepatitis C [abstract]. Hepatol Int. 2009;3:49.
10. Rossignol JF, Keeffe EB. Thiazolides: a new class of drugs for the treatment of chronic hepatitis B and C. Future Microbiol. 2008;3:539–545. [PubMed]
11. Kolozsi WZ, El-Gohary Y, Keeffe EB, Rossignol JF. Treatment of chronic hepatitis B (CHB) with nitazoxanide (NTZ) alone or NTZ plus adefovir (ADV) for two years with loss of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg): report of two cases [abstract]. Am J Gastroenterol. 2008;103:S150–S151.
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Author: [email protected]
Date: 2010-05-23 06:04 -700
To: hbv_research
Subject: Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B
J Viral Hepat. 2010 May 17. [Epub ahead of print]

Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B.

Akbar SM, Furukawa S, Horiike N, Abe M, Hiasa Y, Onji M.

Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan.


Abstract

Summary. The immune modulator capacity of antigen-pulsed dendritic cells (DC) has been documented in patients with cancers and in animal models of chronic viral infections. Cancer antigen-pulsed DC are now used for treating patients with cancer. But viral antigen-pulsed DC are not used in chronic viral-infected patients because safety of antigen-pulsed DC has not been evaluated in these patients. DC were isolated from human peripheral blood mononuclear cells by culturing with human-grade granulocyte-macrophage colony stimulating factor and interleukin-4. Human blood DC were cultured with hepatitis B surface antigen (HBsAg) for 8 h to prepare HBsAg-pulsed DC. After immunogenicity assessment of HBsAg-pulsed DC in vitro, five million HBsAg-pulsed DC were administered intradermally to five patients with chronic hepatitis B (CHB) 1-3 times. HBsAg-pulsed DC were immunogenic in nature because they produced significantly higher levels of interleukin-12 and interferon-gamma compared to unpulsed DC (P < 0.05). Also, HBsAg-pulsed DC induced proliferation of HBsAg-specific T lymphocytes in vitro. CHB patients injected with HBsAg-pulsed DC did not exhibit generalized inflammation, exacerbation of liver damage, abnormal kidney function, or features of autoimmunity. Administration of HBsAg-pulsed DC induced anti-HBs in two patients and HBsAg-specific cellular immunity in 1 patient. This is the first study about preparation of antigen-pulsed DC using human consumable materials for treating patients with CHB. Because HBsAg-pulsed DC were safe for all patients with CHB and had immune modulation capacity in some patients, phase I and phase II clinical trials with antigen-pulsed DC in CHB and other chronic infections are warranted.

PMID: 20487261 [PubMed - as supplied by publisher]
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QUANTITATIVE HBSAG: A NEW SPECIFIC MARKER FOR THE DIAGNOSIS OF HBSAG INACTIVE CARRIAGE

M. Martinot-Peignoux1*, R. Moucari1,2, L. Leclere1, A.-C. Cardoso3, R. Carvalho4, N. Boyer4, M.P. Ripault4, T. Asselah1,4, P. Marcellin1,2
1INSERM U 773-CRB3, Université Paris VII, 2Service Hépatology, Hopital Beaujon, 3Service Hépatology, Université Partis VII, 4Service Hépatology, Université Paris VII, Clichy, France. *michelle.***@****

Background/aim: According to the EASL guidelines, a minimal follow-up of one year, with a 3-monthly monitoring of serum alanine aminotransferase and HBV DNA levels is needed to distinguish true inactive hepatitis B virus (HBV) carriers from patients with active HBeAg-negative chronic hepatitis B (CHB). The aim of this study was to evaluate the role of hepatitis B surface antigen (HBsAg) as a new quantitative marker for the diagnosis of HBV inactive carriage.
Methods: 127 patients followed for a median period of 6 years (0.5 to 18), 102 inactive-carriers (n=102) and 25 HBeAg-negative CHB patients, were evaluated. Serum HBsAg was quantified using the Elecsys HBsAg II assay. Samples were tested at 1:400 dilution. If result revealed cut off index (c.o.i.) of > 1, then the final result is c.o.i. 400. If c.o.i. < 1, then the sample is retested undiluted and final result is result of retest (c.o.i.). If c.o.i. ≥ 1000, then the sample is retested at 1:8000 dilution and final result is c.o.i. 8000. HBsAg was estimated using a conversion factor of 1 c.o.i. = 0.055 IU/mL.
Results: At baseline serum HBV DNA was < 5 log10 copies/mL in all patients, but was significantly lower in true inactive-carriers compared to patients with HBeAg-negative CHB (3.0±1.2 vs. 4.3±1.2 log10 copies/mL, p=0.001).
At baseline, serum HBsAg was significantly lower in true inactive-carriers compared to patients with HBeAg-negative CHB (3.2±0.9 vs. 3.6±0.5 log10 IU/mL, p=0.006).
At baseline, 25 patients had a serum HBsAg  500 IU/mL, 25 out of them had HBeAg-negative CHB (NPV 25%). Serum HBV DNA and serum HBsAg showed a significant correlation in inactive-carriers only (Spearman Rho=0.407, p< 0.001). HBsAg sero-conversion was observed in 9% inactive-carriers and 8% HBeAg-negative CHB.
Conclusion: Quantitative serum HBsAg is a new specific marker for the diagnosis of HBV inactive carriage. A low serum HBsAg (< 500 IU/mL) allows the diagnosis of inactive carriage with 100% specificity at baseline without additional monitoring. New guidelines should include quantitative HBsAg in the virological tools for HBV management.
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