Hepatitis Ebook

Alternative Hepatitis C Treatments

The therapeutic goals of Natural treatment for Hepatitis C are as follows: Decrease iral load Normalize liver enzyme levels. Enhance/regulate immune system function. Strengthen and promote healthy liver function. Protect the liver, prevent further damage. Virological response; i.e. viral clearance, viral reduction or elimination of the virus. Starve the virus by limiting levels of iron. Optimizing cellular levels of glutathione in the body, making detoxification of the liver possible and enhancing the immune system. Stimulate regeneration of the damaged liver cells. Use of antioxidants to combat the effects of free-radicals generated by the virus. Reduce inflammation. Slow viral replication. Replace all of the inflammation-damaged liver cells. Regulate immune function/prevent auto-immune problems. Cancer preventative measures. Reverse fibrosis to prevent and improve cirrhosis

Alternative Hepatitis C Treatments Overview

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Role Of Liver Transplant In Hepatitis B

Although full consideration of liver transplant for hepatitis B is beyond the scope of this chapter, the availability of liver transplant has the potential to reduce the impact of progressive hepatitis on mortality. Among patients who would otherwise succumb to end-stage cirrhosis or fulminant hepatitis resulting from HBV infection, liver transplant can lead to long-term survival 80 at 1 yr, and 65 at 5 yr, comparable to survival figures for liver transplant in nonviral liver disease. Such excellent outcomes, however, would not be possible without effective antiviral strategies to prevent recurrent infection in the allograft. A number of strategies have been developed to reduce the re-infection rate. At present, the most effective strategy appears to be immunoprophy-laxis with hepatitis B immunoglobulins. In theory, providing patients with high levels of anti-HBs antibodies will neutralize circulating virions and decrease graft re-infection. Despite the high cost of therapy ( 15,000-...

Disease Progression In Chronic Hepatitis

From serial liver biopsies in a population of HCV patients with chronic hepatitis and variable degrees of fibrosis, have demonstrated an average rate of increase in METAVIR fibrosis score of 0.133 U yr (47,54). In the study by Poynard (47), in which risk factors for progression of hepatitis C were studied in 2235 patients, disease progression ranged within a spectrum from rapid to indolent. Only three factors were associated with disease progression age > 40 yr at time of infection, ethanol > 50 g d, and male gender. There was no correlation with viral level or genotype. Some patients rapidly progressed from infection to cirrhosis in less that 10 yr. Others, called slow fibrosers, who often had normal ALT, progressed to cirrhosis only after 30 yr or more of disease. If one assumes linear progression in disease, the annual rate of fibrosis can be calculated for a given patient simply by dividing the METAVIR fibrosis score on liver biopsy (F-METAVIR), by the estimated number of...

Hcv Is Predominantly Transmitted Parenterally

The risk of HCV transmission is far greater in patients who acquire HIV infection through the parenteral, compared to the sexual, route. It is estimated that 50-98 of patients who acquired HIV though intravenous drug use are co-infected with HCV (3). The incidence of HCV infection is also high in HIV-infected hemophiliac patients, who, in the past, were treated with nonviral attenuated-clotting products (60-85 ). Only half of all patients infected with hepatitis C admit to a history of percutaneous exposure sexual transmission is thought to play a role in some of the remaining cases. Despite the fact that a number of studies have addressed this issue, the role of homosexual and heterosexual transmission of HCV is still controversial it is believed to occur, but with low efficiency. Nevertheless, the prevalence of HCV antibodies in HIV-positive homosexual males is 4-8 , which is no different from HIV negative homosexuals (4). However, this is still greatly increased over the Reported...

Hiv Coinfection Accelerates Natural History Of Hcv Disease

Greater than half of immunocompetent, HCV-infected patients develop chronic hepatitis, and about 20 develop cirrhosis after 10-20 yr of infection. Approximately 15 ofpatients with HCV-related cirrhosis will develop hepatocellular carcinoma. Immunosuppression caused by HIV significantly alters the natural history of HCV infection. Hepatic damage resulting from HCV infection is believed to be predominantly caused by direct viral cytotoxicity, with contributions from the host immune response. Cell-mediated immunity, T-helper 1 (TH1) clones that recognize multiple core epitopes of HCV, are important in immune clearance of HCV, through elimination of virally infected hepatocytes (8-10). The decline in CD4 cells associated with progressive HIV infection appears to permit greater HCV replication, with more hepatic spread of HCV, and therefore vast hepatocyte injury. Co-infection with HIV also probably alters the response of immune cells to HCV when CD3+ CD30+ cells are infected with both HIV...

Hepatitis C Infection Limits Ability To Treat

A number of studies have attempted to address the question of whether protease inhibitors and other anti-HIV drugs affect HCV replication, and, conversely, whether HCV effects the development of hepatic damage caused by antiviral agents. HIV protease inhibitors have not been found to inhibit HCV replication (26). Additionally, the control of HIV to less than 400 copies by anti-HIV medications has no effect on the HCV viral load. Instead, initiation of HAART may transiently increase the level of aminotransferases, and even the HCV viral load for the first 3-4 mo of treatment, typically returning to baseline over the ensuing 3-8 mo (27). A number of studies have addressed whether the presence of HCV infection increases the liver toxicity associated with HAART. Many antiretroviral drugs are hepato-toxicity according to data found in the physicians' desk reference, the risk of hepatotoxicity of antiretroviral drugs is between 3 and 12 , depending on the therapeutic agent. Perhaps the...

Presence Of Hiv Does Not Alter Efficacy Of Antihcv Therapy

Given the effect that HIV has on the natural history of HCV disease, infection with HCV should be treated as any other opportunistic disease (33), as has been suggested in the U.S. Public Health Service Infections Disease Society of America 1999 guidelines. Until recently, the only FDA-approved treatment for chronic hepatitis C was a-interferon (IFN-a) monotherapy. A standard dosing regimen of 3 million units, thrice weekly for 6 mo, induces normalization of aminotransferase levels and histological improvement in up to 50 of treated patients. However, of these initial responders, more than one-half relapse within 6 mo after termination of treatment. In all, IFN-a therapy induces a sustained response, with eradication of the virus and stable improvement of liver histology in less than 20 of treated patients. The rate is even lower in patients infected with HCV genotype 1b, who make up the majority of the infected patients in the United States. There are few studies that have reported...

Viral Replication In Hbv And Hcv Coinfection

Mutual suppression of viral replication occurs in hepatitis B and HCV co-infection, with HCV exerting a negative effect on HBV replication. Likewise, HBV exerts a negative effect on HCV replication. Studies investigating the relationship of viral replication markers in co-infected patients have demonstrated that HBV DNA and hepatitis B surface antigen (HBsAg) titers are lower in those individuals with concurrent HCV infection, compared to those with HBV infection alone, implying an interference of HCV on HBV replication. Lower HCV RNA titers have also been noted in patients with concurrent HBV infection, compared to those with HCV infection alone, implying HBV interference with HCV replication (8,53). This phenomena of viral interference involves a complex interplay between the host's immune system and virus-specific replication properties, but the exact mechanism remains unknown.

Effect of HCV on HBV Replication

HCV suppression of HBV replication has been demonstrated in several animal and human studies. In experiments using chimpanzees with chronic HBV infection, inoculation with a non-A, non-B hepatitis agent resulted in an acute elevation of alanine aminostransferase (ALT), and a precipitous decline in HBsAg titers. The loss of HBsAg during the acute phase of non-A, non-B virus super-infection was thought to result from viral interference by the HCV. This may have resulted from an alteration in the mechanisms responsible for virus absorption, penetration, and replication (9). An in vitro study in human hepatoma cell line, HuH-7, has demonstrated the potential role of the HCV core protein in the suppression of HBV gene replication and expression (10). Liaw (11) postulated that liver injury induced by HCV, and its accompanying cell renewal, increases the expression of HBV epitopes on the hepatocyte surface, leading to cytotoxic T-cell clearance of HBV-infected hepatocytes, which may explain...

Effect of HBV on HCV Replication

HBV replication status, as measured by the HBV DNA polymerase (DNA-p) activity, has been shown to affect the HCV RNA titer. This represents reciprocal viral suppression of HCV by HBV, but the mechanism that governs this interaction remains speculative. HCV RNA in serum was detected less frequently in patients with highly replicating HBV (DNA-p > 100 cpm). Higher titers of HCV RNA were measured in those with low-replicating HBV (DNA-p < 100 cpm). HCV RNA titers in co-infected patients with DNA-p < 100 cpm were still lower than those in patients with anti-HCV but without HBsAg (8). In an in vitro co-transfection experiment, wild-type HBV DNA was shown to suppress the secretion of HCV RNA. However, co-transfection of HCV RNA with the HBV DNA silent mutant, (i.e., HBV DNA with eight-nucleotide deletion in the region encoding the X gene) resulted in the release of higher levels of HCV RNA (14).

HCV Usurpation of HBV

HBsAg seroconversion is usually followed by normalization of serum ALT. However, in some patients co-infected with HBV and HCV, elevated ALT and histologic evidence of hepatitis activity persist. There is evidence that active HCV infection is the major cause of persistent hepatitis or ALT elevation after HBsAg clearance in patients co-infected with the HBV (16). HCV may have suppressed or eliminated the HBV, but it then takes over the role of HBV in eliciting continuing chronic inflammation (HCV usurpation of HBV).

Alternating Dominance of HBV and HCV

Alternating appearance of serum HBV DNA and HCV RNA, with concomitant disappearance of the other virus, has been described (11,13a, 17). During the clinical course of patients with dual infection, either HBV or HCV becomes the dominant replicator. This continuous alternating pattern may be responsible for the more unfavorable clinical course of some patients with HBV and HCV co-infection, because of the unrelenting inflammation of the liver. Some authors (18,19) believe that, in co-infected patients, HCV plays the lead role in the maintenance and progression of liver damage, with elimination or suppression of HBV replication. A biphasic pattern of ALT activity was observed in patients with dual infection (20,21), which may represent the sequential alternating expression of HBV and HCV. HCV was thought to be responsible for the second peak of the serum ALT, because it occurred when HBV DNA was undetectable by polymerase chain reaction (PCR), and anti-HBs was detected. Immunoglobulin A...

Clinical And Histologic Presentations Of Hbv And Hcv Coinfection

There are conflicting data on the pathogenic effects of double infection with HBV and HCV, compared to infection with a single virus. Patients with dual infection may have a worse clinical presentation and a more rapidly evolving form of chronic liver disease (8,11,18,23-30). Aminotransferase levels are higher and liver disease more severe, both histo-logically and in the degree of clinical decompensation, in co-infected patients (18,28,30,31). Contrasting views have been reported by others, who found no significant difference in the clinical and histologic presentation of HBV and HCV co-infected patients, compared to those with single infection. Furthermore, they described the liver injury in a majority of co-infected patients as only mild to moderate in severity, similar to those seen in patients infected with either HBV or HCV alone (20,25,32-34).

Risk for HCC in those with Hepatitis C and past HBV Infection

Prior infection with HBV, even in those who have undergone HBsAg seroconversion, has been linked to the development of HCC in the setting of co-infection with HCV (39-41). The risk for hepatocarcinogen-esis increased twofold in those with anti-HBs and anti-HBc, compared to those who were only anti-HCV-positive (42). These patients with inapparent HBV infection were found to have low-level viremia that was detected only with the highly sensitive (PCR) assay (41,43). Therefore, anti-HBs positivity does not exclude the possibility of low-level replication. Moreover, the time to development of HCC from the introduction of a risk factor (i.e., blood transfusion) was shorter in patients with HCV and anti-HBc (without HBsAg) than for those with HCV alone (39). On the other hand, other studies did not find an increased frequency of HCC in anti-HCV-positive patients with antibodies to HBV and only those with apparent chronic hepatitis B infection were found to be at increased risk for HCC...

Outcome Of Liver Transplantation In Hbv And Hcv Coinfection

Although recurrence of HCV after orthotopic liver transplantation (OLT) in patients with HCV mono-infection is common (48), the hepatic damage associated with this is usually mild, and long-term graft survival is not reduced (49). In those co-infected with HBV and HCV, virologic recurrence of HCV is less frequent, but histologic liver injury is thought to be possibly more severe. In one series, only 41 of patients with dual infection (vs 59 of patients with HCV mono-infection) had detectable HCV RNA by PCR in both serum and liver, during post-OLT follow-up. However, there was evidence of ongoing necroinflammatory activity, by histologic in some patients with negative serum HCV RNA (50). It was suggested that HBV may be masking the HCV, and the presence of both viruses led to more injury, and to development of a more severe liver disease. Two patients (5 ) in this study had severe liver damage histologically, and both were co-infected with HBV and HCV (50). Caccamo et al. (51) reported...

Autoimmune Manifestations Of Viral Hepatitis

Chronic viral hepatitis, both type B (3) and type C, has been associated with a spectrum of autoimmune phenomena. McMurray and Elbourne (4) summarized many of the reported autoimmune complications of HCV hepatitis (Table 1). Some of these HCV-related entities, such as membranous glomerulonephritis (GN) (5), cryoglobulinemia, and associated vasculitis (6-9), tend to improve following successful treatment and viral eradication. Among HBV-associated autoimmune phenomena, the HBV-related proteinuria (10) and polyarteritis nodosa (11-16) usually improve, following successful IFN antiviral therapy. Nevertheless, the opposite may also occur Worsening of cryoglobulinemic neuropathy and fatal bleeding secondary to vasculitic gastritis occurred when IFN-a was given to a hepatitis C patient with highly symptomatic cryoglobulinemia (17), in whom steroids had not been tried before IFN. It is not clear whether corticosteroids should be started before, or along with, IFN in the patient with...

Inhibitors of HCV 5 Untranslated Region and Core Gene

2.4.1.1 Ribozymes and Antisense Oligonucleotides. The 5' UTR, which encodes the HCV internal ribosome entry site (IRES), and the core gene encoding the nucleocapsid protein of HCV are highly conserved among HCV isolates, making them attractive targets for ribozyme- and antisense oligonucleotide-based antiviral strategies (301). Ribozyme Pharmaceuticals (RPI) reported their design and synthesis of hammerhead ribozymes targeting various conserved sites in the 5' untranslated region (UTR). These ribozymes significantly reduced HCV 5' UTR-mediated expression in a 5' UTR-luceferase reporter system, as well as inhibited replication of an HCV-poliovirus chimera (302). Moreover, a nuclease resistant ribozyme, tar- getting site 195, was selected for pharmacokinetics and tissue distribution studies after intravenous and subcutaneous administration in mice. The results showed that the ribozyme can be taken up and retained in the liver cells (303). RPI has recently completed their clinical trials...

Treatment Of Chronic Viral Hepatitis In Patients With Preexisting Autoimmune Disorders

The role of IFN therapy in patients with chronic viral hepatitis and a pre-existing autoimmune disorder raises separate issues What is the course of the autoimmune disorders during IFN therapy What is the virologic response to IFN in such patients In addition, does the mere presence of circulating autoantibodies define the existence of an autoimmune disorder, and does the presence of such antibodies affect the response to IFN The following discussion, therefore, focuses on both the role of IFN in the patient with autoantibodies, but without autoim

HBVHCV and Hcvhiv Coinfected Patients

These co-infected patients have been thoroughly discussed in prior chapters in this text. For the HCV-HBV co-infected patient, generally only one virus is active, usually HCV. The active virus dictates treatment. There is increasing evidence of the benefit of treating the HCV, in HIV-infected patients, with IFN. They seem to achieve ALT and virologic responses similar to those in non-HIV-infected patients, and, furthermore, have been shown to result in decreased fibrosis and a decreased incidence of hepatocellular carcinoma. There has been some reluctance to use ribavirin in these patients concomitantly with other nucleoside analogs, such as zidovudine. Initial data, however, suggests that combination therapy can be safely used, with an increased response rate. It has been recommended, however, that further clinical trials need to resolve these concerns, before widespread use (40).

Hcv Infection And Malignancy

The linkage between chronic HCV infection and hepatocellular carcinoma is well established 100 . Recently, an association between HCV infection and non Hodgkin's lymphoma has been reported 25, 101 . Furthermore, we have reported that an association between HCV infection and other extrahepatic malignancies may exist as well 26 . In this paragraph we will review the possible role of HCV infection in hepatic and non hepatic malignancies 26 . 4.1. A. HCV Infection and Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is one of the most common malignancies, especially in Southeast Asia 102 . Studies in the past have demonstrated a close association between HCC and chronic hepatitis B 102 , However, after the discovery of HCV, the incidence of HCC has been shown to be higher in patients with chronic HCV than in those with chronic hepatitis B 104 , Recently, Serfaty et al. 104 reported that the incidence of HCV in patients with hepatitis C cirrhosis is about 3 per year, an incidence...

Approach To Suspected Hepatitis Viral Hepatitis

Most cases of acute hepatitis are caused by infection with one of five viruses hepatitis A. B. C, D, or E. They can produce virtually indistinguishable clinical syndromes, although it is unusual to observe acute hepatitis C. Affected individuals often complain of a prodrome of nonspecific constitutional symptoms, including fever, nausea, fatigue, arthralgias, myalgias, headache, and sometimes pharyngitis and coryza. This is followed by the onset of visible jaundice caused by hyperbilirubinemia, with tenderness and enlargement of the liver, and dark urine caused by bilirubinuria. The clinical course, and prognosis then vary based on the type of virus causing the hepatitis. Hepatitis A and E both are very contagious and transmitted by fecal-oral route, usually by contaminated food or water where sanitation is poor, and in daycare by children. Hepatitis A is found worldwide and is the most common cause of acute viral hepatitis in the United States. Hepatitis E is much less common and is...

Adjustments in Drug Doses in Chronic Viral Hepatitis or Other Chronic Liver Disease

Summary Recommendations for Drug Use and Dose Adjustments in Chronic Viral Hepatitis or other Chronic Liver Diseases In view of such complexities, and in absence of a simple, widely available, well-validated approach for estimating hepatic function, it is currently possible only to offer general guidelines for adjustments of drug doses in chronic viral hepatitis or other chronic liver diseases (Table 4). The need for care, and circumspection in prescribing, increases markedly as the severity of liver disease increases. Although patients with decompensated, end-stage cirrhosis have many symptoms, and often feel miserable, it is unwise to prescribe sedatives or strong analgesics, because of the risk of precipitating or worsening encephalopathy. Close observation and follow-up are mandatory for all such patients, but espe cially whenever new drugs are prescribed. Fortunately, most patients with chronic viral hepatitis are well-compensated (Childs-Turcotte-Pugh score 5-6), and drugs can...

Inhibitors of HCV NS3 Helicase

The helicase activity associated with HCV NS3 protein has also been targeted for potential therapeutic intervention (369). The crystal structure of this enzyme has been determined to provide insights into the mechanism of unwinding (369-372). In addition to unwinding dsRNA, this enzyme also unwinds dsDNA (373). Using a DNA duplex substrate and recombinant HCV NS3 produced in E. coliy Biochem Pharma recently reported an assay system for HCV NS3 helicase activity that might be suitable for high-throughput screening of potential inhibitors (374). Other reported assay systems include an ELISA using a non-radioactive dsRNA substrate (375) and a scintillation proximity assay using radio labeled RNA DNA hetero-duplex as the substrate (376). These assays can be amenable to high-throughput mode. Notwithstanding, there have been only a few HCV helicase inhibitors reported. Viro-Pharma has patented two series of long-chain compounds as low micromolar inhibitors (158 and 159) (see referencesin...

Chronic Hepatitis B Virus Infection

Chronic hepatitis B is a major global public health problem. There are an estimated 350 million chronic HBV virus carriers worldwide. The prevalence rate of chronic hepatitis B is as high as 15-20 in some countries in Asia. Chronic HBV infection may cause advanced liver disease. Once decompensated end-stage liver disease develops, prognosis is poor, with 5-yr survival rates decreasing, from 84 in patients with compensated cirrhosis, to 14 in patients with decompensated disease (7). Moreover, patients with compensated chronic hepatitis B associated with active viral replication are more likely to have progressive disease and a poorer prognosis than patients with inactive replication. Ultimately, many patients with advanced HBV infection become potential candidates for liver transplantation.

Hepatitis B Immune Globulin Prophylaxis for HBV ReInfection

A major breakthrough was reported in 1993, when the European Concerted Action on Viral Hepatitis Study showed that patients who received prophylactic hepatitis B immunoglobulin (HBIg) perioperatively, and long-term, after liver transplantation, had a lower incidence of recurrent HBV and improved survival rate (13). This study showed that patients with evidence of active viral replication before liver transplantation, i.e., detectable serum HBeAg and or HBV DNA, were at an increased risk for recurrent HBV infection (Table 1). On the other hand, patients without active viral replication, transplanted for fulminant hepatitis rather than cirrhosis, or co-infected with HDV, had a lower incidence of HBV recurrence. Several studies from the United States later confirmed that the administration of high-dose intravenous HBIg, after liver transplantation, reduces the incidence of recurrence to 20-30 or less (14-17). The finding that some patients without recurrence of HBsAg, the routine test...

Chronic Hcv Infection

CHC with end-stage liver disease is the leading indication for liver transplantation in the United States (1,43). The World Health Organization estimates that 120 million people worldwide are infected with HCV, and that 20 of these will develop cirrhosis. Most cases of hepatocellular carcinoma not associated with HBV are caused by HCV. In the United States, 1.8 of the population, or 4 million Americans, have been infected with HCV, and about 8000 die each year from this infection. Approximately 25 of all liver transplantations in the United States are performed for end-stage liver disease secondary to HCV infection, and this percentage will increase, based on the large number of patients with CHC on the waiting list. Liver transplantation is the best treatment for decompensated cirrhosis caused by HCV infection, but HCV re-infection poses important clinical problems that may appear either early or late after liver transplantation (44,45).

Spontaneous HBsAg Seroconversion in CoInfection with HCV

In co-infected patients, HBsAg appearance may be delayed, its level lower, and the duration of hepatitis B surface antigenemia shorter than in non-co-infected patients (20). Spontaneous HBsAg seroconversion is higher in HBV and HCV co-infection. In one series (22), the actuarial cumulative probability of spontaneous serum HBsAg seroconversion, at 5 and 10 yr, was 9.1 and 17.6 in HBV and HCV co-infected patients, respectively, compared to 1.2 and 5.6 in patients with chronic hepatitis B with no evidence of super-infection with HCV. Using Cox multivariate regression analysis, older age (i.e., > 35 yr old) and HCV super-infection were the only independent factors related to a significantly higher HBsAg clearance rate. Co-infection with HDV had no additive suppres-sive effect.

Liver Transplantation for HCV

Like hepatitis B, the natural history of HCV infection in liver transplantation recipients is often accelerated, and the spectrum of recurrent disease ranges from asymptomatic mild hepatitis to severe chronic hepatitis and cirrhosis. Re-infection with HCV after liver transplantation is virtually universal, occurring in more than 95 of cases (44-46). Acute lobular hepatitis is seen in up to 75 of the patients, at a median of 4 mo after liver transplantation. Fortunately, approx 85 of patients with recurrent HCV generally do well, with only mild manifestations of re-infection, but an unpredictable 15 of patients have a more severe course, with rapidly recurrent disease and progression to cirrhosis. The most sensitive method of detecting HCV infection after liver transplantation is measurement of HCV RNA. A common problem facing transplant physicians and pathologists is the differentiation of recur rent HCV infection from acute allograft rejection. Since the majority of patients with...

Risk Factors for Recurrent HCV in Transplant Recipients

The underlying cause for recurrence of HCV infection with progressive liver disease is probably multifactorial and largely undefined (47-67). However, certain characteristics associated with the virus, the recipient, and the type of immunosuppressive therapy have been identified as possibly influencing the course of posttransplant HCV infection, and warrant further investigation (Table 2). HCV genotype 1b has been associated with progression of liver injury after liver transplantation, in some (44,47,48), but not all, trials (49). Some European studies have suggested that HCV genotype 1b is associated with more severe recurrent HCV, but this association has not been confirmed by more recent studies in the United States (49). Additional risk factors for recurrent HCV include age and absence of pretransplant co-infection with HBV (47). Pretransplant serum HCV RNA level is associated with more rapid disease progression and lower survival (50,53). The results of trials that studied early...

Treatment of Recurrent HCV

Unfortunately, in contrast to the success in preventing HBV re-infection after liver transplantation, there is as yet no effective antiviral treatment to prevent HCV re-infection. Recurrent HCV may be accelerated in immunosupressed liver transplantation recipients, progressing to cirrhosis in 8-16 of patients within 5 yr, in some reports (44). The rapid rate of progression to liver failure has been observed in a subset of HCV-infected transplant recipients who develop a cholestatic pattern of liver injury (42,56,57). Cholestatic hepatitis is an infrequent cause of jaundice in HCV-infected liver transplantation patients, and should be a diagnosis of exclusion (68). Cholestatic hepatitis C ranges in severity, and does not always signal impending graft failure. The natural history of cholestatic hepatitis C differs dramatically from that of cholestatic hepatitis B, which has been shown to lead to death or need for retransplantation within several weeks (9). There are numerous emerging...

Inhibitors of NS5B RNADependent RNA Polymerase The HCV NS5B protein which encodes RNAdependent RNA polymer

Ase (RdRp) activity, involves in the synthesis of complementary (-)-RNA using the genome as the template and the subsequent synthesis of genomic RNA using this (-)-RNA. In addition to its important role in the viral RNA replication, the NS5B amino acid sequence is highly conserved among different HCV strains, this protein has been considered as an attractive target for antiviral therapy (377, 380). Biochemical and kinetic characterizations and the crystal structure of this enzyme have been reported (380-383). Gliotoxin (160), a known poliovirus 3D RdRp inhibitor, inhibited HCV NS5B RdRp in a dose-dependent manner (381) however, broad-spectrum antiviral agent ribavirin (in triphosphate form) did not show any effect (380). In a recent review article, there were several patented diketoacids (161a-d) cited as low nanomolar inhibitors (377). 2.4.4 VX-497. Although ribavirin may inhibit viral replication through multiple mechanisms of action, the major event is thought to be a depletion of...

Blood and Blood ProductAssociated Hepatitis

In the early 1970s, blood-donor screening for (hepatitis B surface antigen HBsAg ) was introduced. Subsequently, in 1986, after considerable discussion, surrogate testing for non-A, non-B hepatitis was implemented, by screening for the presence of antibody to the hepatitis B core antigen, and by identifying donors with elevated levels of serum alanine aminotransferase. These hepatitis-screening techniques, together with changes in blood-donor selection criteria, resulted in a major decline in the frequency of posttransfusion HBV and HCV infection. The introduction of successive generations of anti-HCV screening of blood donors, beginning a decade ago, dramatically reduced the risk of transfusion-associated HCV infection. The estimated risk of HBV and HCV infection by transfusion, based on studies of repeat blood donors (3), is about 1 65,000 U transfused for the former, and 1 100,000 U transfused for the latter. Currently, transfusion-associated HBV or HCV infection is either the...

Sexual Transmission of HBV and HCV

Both HBV and HCV may be spread by sexual contact, although the efficiency of sexual transmission is thought to be much lower for HCV. Primary care physicians should routinely inquire about high-risk sexual practices, such as failure to use condoms, multiple sex partners, and a past history or the presence of sexually transmitted diseases. If answered Table 1 Strategies for Reducing Transfusion-associated Bloodborne Hepatitis Virus Infection in the affirmative, advice is appropriate about changing behavior and the use of condoms to protect their partners and themselves. Vaccination against HBV should be undertaken in those susceptibles engaged in high-risk sex, and, if the individual is a male homosexual, vaccination against HAV is also reasonable. HBV vaccine should also be offered to as many of the sexual contacts of individuals found to be HBsAg-posi-tive as logistically possible. Potential strategies for reducing sexual transmission are listed in Table 2. Long-term and monogamous...

Maternal Neonatal Transmission of HBV and HCV

Other than identification of the HBV-infected mother and immunization of her newborn infant, realistic methods for reducing the risk of maternal-neonatal transmission of the bloodborne hepatitis viruses are unknown. Breastfeeding has not been definitively implicated in transmission of HBV or HCV to the infant, even in HIV-positive women with high hepatitis virus titers (5). For the nonpregnant HBV- or HCV-infected woman considering beginning a family or enlarging an established one, effective preconception antiviral treatment, leading to clearance of the responsible virus, would seem likely to eliminate or reduce the risk of transmission to the infant. Strategies for Reducing Sexual Transmission of Bloodborne Hepatitis Viruses

Needlestick Injury and Mucosal Exposure to HBV and HCV in Health Care Workers

The risk of needlestick injury leading to bloodborne hepatitis virus infections in health care personnel has been studied for many years. Prevention efforts directed at health care workers have focused on the development of safer injection devices, the use of personal protective equipment, continuing education about the handling and disposal of used equipment, acceptance of the principles of universal precautions, and the prompt reporting of critical exposures. Infected patients with either HBV or HCV require education about the potential infectivity of their blood and body fluids, and the risks of sharing razor blades, tooth brushes, and other personal hygiene equipment. Blood spills in the house should be cleaned by the responsible patient, or, if undertaken by another member of the household, protective rubber or latex gloves should be worn. The risk of hepatitis virus transmission, resulting from tattooing, body-piercing, acupuncture, electrolysis, manicures, pedicures, and the...

Immunoprophylaxis Of Hepatitis B

Hepatitis B virus (HBV) infection is the most common vaccine-preventable liver disease in the world. Over 300 million are chronically infected, and as many as 1 million deaths are attributed to the sequelae of this infection annually. The extraordinary protective efficacy of HBV vaccines, combined with their ability to provide prolonged protection in most individuals, strongly suggests that, despite concerns about the emergence of mutant HBV strains, universal use of the vaccines will eventually markedly reduce, if not eliminate, this infection. Although routine infant immunization against HBV has been adopted in many nations,

Prevention of HAV Superinfection in Chronic Hepatitis B and CHC

HAV super-infection of individuals with chronic hepatitis B virus and chronic hepatitis C virus infection may exacerbate the liver disease, and, in some instances, may lead to acute liver failure (19,20). This concept has not been accepted by all workers in the field (21), but the recommendation that HAV-susceptible patients with chronic liver disease should be targeted for vaccination with one of the inactivated, whole HAV vaccines seems reasonable, and has become standard practice in many hep-atology centers. HAV vaccination of patients who have received liver transplants is also reasonable. Information about the immunogenicity of HAV vaccines in patients with chronic liver disease remains limited, but, in general, the immune response to the vaccines appear to be adequate in those with mild to moderately severe disease. In one study, the immune response to inactivated HAV vaccine among Chinese HBV-carrier children appeared to be reduced, compared to that in noncarrier children, but...

Immunoprophylaxis Of Hepatitis C

Neither passive immunization with conventional or HCV hyperimmune globulin preparations nor active immunization with an HCV vaccine are currently recommended or available. Immunity to HCV infection is thought to be weak, and neutralizing, protective antibodies can be detected in only a small proportion of infected individuals, and seem to be isolate-specific. One consequence of this limited response is that superinfection by another HCV genotype may be identified in some patients chronically infected with one HCV genotype (30). The high frequency of mutations, in that portion of the viral genome encoding the HCV envelope proteins, may be responsible for the escape of the virus from antibody-mediated clearance. Early studies (31) suggested that primary infection with HCV did not induce protective immunity in the chimpanzee model of infection. However, there is evidence (32) that the immune response of chimpanzees to HCV may not be analogous to that seen in infected patients.

Hyperimmune AntiHCV Immunoglobulin

In a study (40) utilizing the chimpanzee model of HCV infection, the plasma of a patient with CHC was shown to contain antibodies to HCV, capable of neutralizing the virus in vitro. Challenge of animals with this inoculum did not produce infection, indicating that the virus had been neutralized. In addition to supporting the existence of neutralizing antibodies in HCV infection, that study also indicated that cell-based immunity was not essential for HCV neutralization in vitro. Neutralizing antibodies to HCV are thought to inhibit the replicative cycle of HCV (41). Unfortunately, HCV-neutralizing antibody are isolate-specific, and may change as a consequence of the emergence of escape HCV mutants. Utilizing a synthetic peptide derived from HVR I as the inducing antigen, a HCV hyperimmune serum has been developed (42). When mixed with HCV in vitro, this material appeared to neutralize the virus, since, when the mixture was inoculated into chimpanzees, infection was prevented. HCV...

Candidates for HCV Vaccine

Appropriate candidates for a HCV vaccine may include newly identified injection drug users or intranasal cocaine users, renal failure patients at risk for hemodialysis, patients with blood-clotting disorders, and other recipients of multiple blood products, the sex partners of HCV-infected individuals, and possibly sex workers. Patients with other chronic liver diseases would be targeted, as well. Although the prevalence of infection appears to be low in health care personnel, those regularly exposed to blood and body fluids might be considered for immunization. If early administration, e.g., shortly after birth, of a HCV vaccine to the neonates of infected women could protect the neonates, then identification pre-delivery of pregnant HCV-infected women would become critically important. Because vaccine delivery to injection drug users early in their careers remains problematic, it seems likely that a targeted approach to high-risk individuals is likely to fail. If this concept is...

Alcohol and Chronic Viral Hepatitis

The most common form of nonalcohol-induced liver disease seen in patients with alcoholism is CHC (7). In patients with CHC, chronic alcoholism has been shown to cause more severe and rapidly progressive liver disease. This can lead more frequently to cirrhosis of the liver and hepatocellular carcinoma. Alcohol intake in excess of 10 g d has been associated with increased serum hepatitis C viral RNA and amino-transferase levels (7). The mechanisms of these increases are poorly understood, but, as mentioned, Fe may enhance viral replication and or reduce immune-dependent viral killing. The histological picture in hepatitis C patients with chronic alcohol abuse is usually indistinguishable from that in CHC patients who do not use EtOH. In alcoholic patients, compared with nonalcoholic patients, IFN therapy has been shown to be less effective, even after a period of abstinence. Alcohol intake should be restricted to 10 g d or less in patients with CHC. If cirrhosis is present, or IFN...

Effects of Current Therapy of Chronic Viral Hepatitis on Drug Metabolism

Interplay of factors that influence allergic or idiosyncratic responses to drugs or toxins in patients with viral hepatitis. Fig. 4. Interplay of factors that influence allergic or idiosyncratic responses to drugs or toxins in patients with viral hepatitis. Drugs of Special Importance in Patients with Chronic Viral Hepatitis Drugs Used in Therapy of Tuberculosis. Antimycobacterial drugs (INH, rifampin, pyrazinamide) are well-known for their propensity to cause elevations of serum aminotransferases and idiosyncratic liver injury, particularly in older women. A recent study from Hong Kong (40), in patients given antituberculous drugs, reported that the incidence of worsening serum aminotransferases was significantly greater in patients treated with these drugs who also had chronic hepatitis B (15 43, 35 ) than in those without (26 276, 9 ). Highly Active Antiretroviral Therapies (HAART). Many of the nucleoside analogs, protease inhibitors, and other newer drugs used for therapy...

Hepatitis Caused by Injecting Illicit Drugs and Intranasal Cocaine

The sharing of needles, syringes, and other equipment for the injection of illicit drugs is responsible for a substantial proportion of both HBV and HCV infections. Prevention efforts may be instituted by primary care physicians through routine inquiry about the use of injection illicit drugs by their patients. Advice to discontinue drug use, discussion of substance abuse treatment, and, where available, participation in needle-exchange programs may be effective. If the latter are not available, education concerning appropriate sterilization techniques may be implemented. Unfortunately, because percutaneous transmission through shared injection equipment is highly efficient for both HBV and HCV, these approaches are likely to be effective only if instituted very early after drug use begins (1). Current evidence suggests that needle-exchange programs reduce the risk of HIV infection, but their role in the control of HCV is more enigmatic. Higher concentrations of HCV and a higher...

Inhibitors of HCV NS3 Protease

TheNS3-dependent cleavage sites of the polyprotein have a consensus feature with cleavage occurring after cysteine (at the three intermolecular cleavage sites) or threonine (at NS3-4A intramolecular cleavage site) (Table 10.3). Other conserved features are an acid residue in the P, position (aspartic acid or glutamic acid), a small residue (serine or alanine) in Pr, and a hydrophobic residue in the P4- position (332). Crystal structural studies have shown that the active site of the HCV enzyme is extended, shallow, with very little surface feature, and solvent exposed, requiring multiple weak interactions for binding of substrates and inhibitors. Moreover, NS3 4A is an induced-fit enzyme, requiring both the cofactor and the substrate to acquire its bioactive conformation (333). These characteristics pose significant challenge for the design of inhibitors. This challenge is demonstrated by the fact that common protease inhibitors, including serine...

Fulminant Hepatitis

In a recent survey of FHF in the United States, no cases could be attributed to hepatitis C (18). Likewise, in the two series from Europe of acute exposure to anti-D immunoglobulin (19,20), there were no cases of fulminant hepatitis caused by hepatitis C. In contrast, reports from Asia indicate that hepatitis C may account for as many as one-half of their cases of FHF resulting from non-A, non-B causes (21,22). One study from California (23) of Hispanic patients of low socioeconomic status, indicated that 60 had seropositivity for hepatitis C. Farci et al. (24) described a case of a 68-yr-old man who died of fulminant posttransfusion hepatitis (PTH). Serial performance of clinical, virologic, and histologic tests firmly established hepatitis C as the etiology. The latter authors reviewed their past experience with PTH and concluded that this was the sole patient who developed fulminant hepatitis. Thus, although it can be a consequence of acute hepatitis C, it must be a rare event,...

HCV tropism

Oncogenic potential of the chronic HCV infection. (SS Sjogren's syndrome, MC mixed cryoglobulinemia, CH chronic hepatitis cirrhosis). Figure 1. Oncogenic potential of the chronic HCV infection. (SS Sjogren's syndrome, MC mixed cryoglobulinemia, CH chronic hepatitis cirrhosis).

Hepatitis C Virus

The HCV genome is a 9.5-kilobase, single-stranded, positive-sense RNA molecule, containing a single open reading frame that encodes for a polyprotein of 3010-3033 amino acids. This polyprotein undergoes matura-tional processing in the cytoplasm or in the endoplasmic reticulum (ER) of the infected cell to produce at least 10 mature proteins (C, El, E2, P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). In addition, an unusual feature of the HCV viral genome is the presence of two long and highly ordered untranslated regions at both 5' and 3' ends. All of these viral functions are potential target for therapeutic intervention nevertheless, recent advances in anti-HCV drug development have largely focused on the 5' untranslated region, the core, and the NS3 protein.

HBV and HCV Latency

The mutual suppression of viral replication in HBV and HCV co-infection may lead to the development of both HBV and HCV latency. In one study, co-infected patients with active HCV infection lost their HBsAg, and had undetectable serum HBV DNA. However, histologic evaluation of tumorous and nontumorous liver tissues from these patients revealed the presence of HBV DNA (HBV latency). Likewise, some patients with dual infection who had active HBV replication had undetectable serum HCV RNA, and yet were found to have HCV RNA in liver biopsy specimens (HCV latency) (15).

Hepatitis A

The hepatitis A virus (HAV) is an RNA picornavirus that is enterically transmitted. Affected adults usually develop mild-to-moderate generalized symptoms, such as malaise, anorexia, and nausea. Peak aminotransferase (AT) (alanine AT, aspartate AT) levels range from 500 to 5000 U L. Patients experience complete clinical and biochemical recovery within 3-6 mo. Perinatal transmission of HAV, although rare, has been associated with blood or fecal contact during delivery (1). Pregnancy does not appear to affect the natural course of the infection. Similarly, hepatitis A is not thought to affect the course of pregnancy, although the authors reported (2) two patients who experienced third trimester premature delivery during the course of severe hepatitis A. The treatment of HAV infection in affected children is supportive. Prevention of infection transmission is achieved by immunization of women in endemic areas with inactivated HAV vaccine or by postexposure use of immunoglobulin.

Hepatitis E

The HEV is an RNA virus that is enterically transmitted. It is widely distributed in the developing world, but rare in the United States. The clinical presentation of acute HEV hepatitis during pregnancy is that of liver failure, with high AT levels and increased prothrombin time. Acute HEV infection during the third trimester of pregnancy may result in up to 20 mortality caused by fulminant liver failure (3). It is believed that the fulminant course of HEV during pregnancy may result from some pregnancy-induced abnormality, perhaps some partial immunodeficiency, that alters the usually benign course of the infection in nonpregnant individuals. HEV infection has also been associated with reported cases of intrauterine deaths, but it is not clear whether this is related to maternal factors or direct fetal effects. Maternal-fetal transmission of HEV, resulting in neonatal symptomatic hepatitis, has been reported (4). There

Hepatitis B

The hepatitis B virus (HBV) is a DNA virus belonging to the hepadnavirus family. The viral nucleocapsid (core) is comprised of double-stranded circular DNA and the hepatitis B core antigen. The hepatitis B e antigen (HBeAg) is a derivative of hepatitis B core antigen. The surface antigen (HBsAg) comprises the outer shell of the virus. HBV affects humans and chimpanzees. Interferon is not used in pregnancy to treat chronic hepatitis B virus infection. Lamivudine (LAM), a nucleoside analog useful in the treatment of hepatitis B, has been used in pregnancy for the treatment of HIV infection. Concentrations of LAM in maternal serum, amniotic fluid, and neonatal serum are similar, probably because of free transplacental diffusion of the drug. LAM has also been found in breast milk (6). Adverse pregnancy outcomes, such as frequent prematurity or biliary malformations caused by use of LAM have been reported (7). Based on those reports, the use of LAM for treatment of HBV infection in...

Hepatitis C

Most individuals infected with the hepatitis C virus become long-term carriers. Chronic infection with hepatitis C virus affects an estimated 170 million individuals worldwide. Up to one-third of these will progress to cirrhosis with its attendant complications including hepatocellular carcinoma, over a period of 30-40 years. In the western world hepatitis C infection arises mainly from intravenous drug abuse. Treatment with interferon alfa leads to suppression of circulating hepatitis C viral RNA and improvement in hepatic inflammation in about 40 , but at least half relapse on cessation of treatment. Combination of interferon alfa with ribavirin greatly enhances the response, achieving sustained remission in up to 70 age, duration of infection and viral genotype are among the factors that determine the response. Interferon alfa is cleared rapidly, mainly by the kidney (ta 2 4 h), and must be given by s.c. injection three times per week. Increasing the molecular weight of the drug by...

Hepatitis D

Hepatitis D virus (HDV) is a defective RNA virus that requires the presence of HBsAg for replication. Consequently, HDV infection occurs only in HBV-affected individuals. The predominant mode of viral transmission is parenteral, and cases of vertical transmission are uncommon. Prevention of vertical transmission is achieved by preventing maternal HBV infection with vaccination, or clearing the presence of HBV virus with interferon or LAM.

Robert M Smith BS and George Y Wu MD PhD

Introduction Hepatitis B Virus Hepatitis C Virus Despite fundamental differences in genome structure, hepatitis B (HBV) and C (HCV) viruses use many of the same strategies to achieve high-level replication and persistence of infection in hepatocytes. The limited genome size of these viruses necessitates an efficient use of host-cell machinery to carry out viral gene expression. This strong dependence on virus-host interactions restricts HBV- and HCV-cell tropism to the hepatocytes of higher primates and precludes their reliable and reproducible propagation in cell culture. Recent studies have begun to overcome this experimental limitation, so as to permit a more complete understanding of the molecular basis for viral replication, and the concomitant induction or evasion of the host antiviral immune response. Some of the important molecular biological properties of these viruses, as well as how they are reflected in the clinical manifestations of viral infection, are presented below....

Robert L Carithers Jr MD

Prevalence of Hepatitis B and Hepatitis C There are striking epidemiological and clinical parallels between hepatitis B and hepatitis C virus infections . Each virus can be transmitted by bloodborne routes, such as transfusions or injection drug use. Acute infections often are asymptomatic, but can result in persistent viremia and chronic liver injury. Finally, chronic infection with either virus may cause minimal symptoms for decades, but ultimately can progress to cirrhosis and hepatocellular carcinoma (HCC). There also are distinctive differences between hepatitis B and hepatitis C. The risk of developing chronic hepatitis B is closely correlated with the patient's age at the time of infection. Most infants and children exposed to hepatitis B develop chronic infection, but adults typically have self-limited infection. By contrast, the risk of developing chronic hepatitis C (CHC) is high, irrespective of the age at which initial infection occurs. There also are marked differences in...

Future Considerations

Since Blumberg's discovery of the Australia antigen, progress in understanding HBV and the natural hepatitis B has been substantial. Effective and safe vaccination is now available to prevent new infections, and, for those infected, increasingly effective antiviral thers are available. Both of these interventions have already affected the natural history of hepatitis B. Future success in the struggle against hepatitis B infection will depend on universal application of vaccination programs, and the development of more effective multidrug combination thers aimed at multiple targets within the virion. With such advances, global eradication of hepatitis B within several decades is a realistic goal.

Prevalence Risk Factors And Incidence Prevalence

Current estimates of the prevalence of hepatitis C in the United States are based on data from the third study of the National Center for Health Statistics (NHANES III), Centers for Disease Control and Prevention (CDC) (2). Serum samples from 21,241 persons, age > 6 yr, who participated in the study between 1988 and 1994, were analyzed for both antibody to hepatitis C and HCV RNA. The results indicate that the prevalence of seropositivity to hepatitis C virus antibody in the general population of the United States is 1.8 , representing approx 3,900,000 citizens. 74 of patients positive for hepatitis C virus antibody were also positive for HCV RNA, indicating that 2,700,000 U.S. citizens are currently chronically infected with hepatitis C. The number of patients with CHC dwarfs the number infected with either HBV ( 1.25 million) or HIV ( 0.9 million).

Chronic Infection And Sequelae

Most patients with CHC cannot recall a previous illness consistent with acute hepatitis, and only one-third experience clinical jaundice or symptoms (25). For this reason, patient recall of past events is not likely to yield a clear picture of the spectrum of acute hepatitis C. Accurate assessment of the natural history of acute hepatitis C can only be gained by studying a population of patients with a known time-point of exposure to the virus, such as occurs with acquisition of hepatitis C by transfusion or by widespread use of a contaminated blood product. The prolonged time-course of disease progression after acute hepatitis C was suggested by two older studies. Kiyosawa (26) studied 231 patients with transfusion-related hepatitis C. 96 had chronic hepatitis without cirrhosis, 81 had cirrhosis, and 54 had HCC. The time of acquisition of infection was presumed to be the time of transfusion. Using Clinical Outcomes After Infection with HCV A. Rates of progression to cirrhosis and HCC...

Risk Factors For Disease Progression

Patients with abnormal ALT are at greatest risk of disease progression, and most of the information regarding evolution of fibrosis in patients with hepatitis C is obtained in patients with biopsy evidence of active chronic hepatitis and abnormal ALT. Because disease progression is so highly variable, it is likely that a number of factors affect disease progression (Table 3). These risk factors are categorized as primarily host, viral, or extraneous.

Rate of Progression to Cirrhosis

HBV co-infection in chronic hepatitis C has been associated with a higher prevalence of cirrhosis, as well as an accelerated evolution to cirrhosis (8,23,30,53). A similar observation was noted in those with occult HBV co-infection (25). Patients with hepatitis C infection, who were HBV DNA-positive, had worse Knodell scores, attributed to more severe piecemeal necrosis and fibrosis, compared to those who were HBV DNAnegative (15,23). This implies that the persistence of HBV replication plays an important role in disease progression. On the contrary, Colombari et al. (33) and Liaw et al. (34) reported that the prevalence and time to development of cirrhosis in co-infected patients were not different from those who were infected with only a single virus. Furthermore, the effect of dual infection with HBV and HCV on the long-term outcome of the disease was thought to be insignificant.

Outcomes of Surgical Resection of HCC

Surgical resection of HCC in co-infected patients was associated with only a slight increase in postoperative morbidity and mortality, compared to those with either infection alone (44). The incidence of liver failure, ascites, and infection was higher in co-infected patients, although the differences were not statistically significant. The long-term survival rate after resection was lower in those with dual infection, but this was not statistically significant. Recurrence rate after surgery, however, was significantly lower in those with HBV and HCV co-infection, compared to the HBV mono-infected patients with HCC, but was significantly higher, compared to those with HCV-related HCC. It is evident from available data that concurrent HCV, and active or past HBV infection, increases the risk for the development of HCC, and the overall prognosis of these patients may be worse, compared to those with either infection alone.

Response Of Patients With Dual Infection To Ifn Therapy

Approximately 30-45 of patients with chronic HCV respond to IFN therapy by clearance of serum HCV RNA and normalization of transaminases, and half of these may achieve a sustained response. In patients with chronic hepatitis B, a higher dose of IFN is used, and this leads to hepatitis B-sensitive antigen seroconversion and loss of HBV DNA, in about 30-40 of cases. The efficacy of IFN, in chronic HCV patients co-infected by HBV, has been poor (31,45,46). Using the standard treatment regimen for hepatitis C, of 3 million units of recombinant IFN-a-2a 3 x weekly for 12 mo, less than one-third of patients had normalization of their transaminases, and all of them relapsed after withdrawal of therapy (45). The ALT elevation during relapse was associated with an isolated HBV viremia, and not with HCV or combined HBV and HCV vire-mia. Treatment of co-infected patients with the standard dose used for chronic hepatitis C may be inadequate. Apparently, this approach favored HBV replication and...

Lamivudine Epivirtmhbv 3tc

This is the first orally administered antiviral agent approved for the treatment of chronic hepatitis B virus infection. It is the (-) enantiomer of 2'-3' didexoy-3'-thiacytidine. It is phosphorylated in vivo to the active triphosphate (3' thiacytidine triphosphate 3TC-TP ), which competes with deoxycytidine triphosphate for DNA synthesis. Incorporation of 3TC-TP into newly synthesized DNA results in premature chain termination during reverse transcription of the first HBV DNA strand. It has similar effect on the synthesis of the second HBV DNA strand. LAM, by decreasing the viral load, may have an added effect of reversing T-cell hyporesponsiveness to HBV antigens in patients with chronic hepatitis B virus infection (27).

Other Nucleoside Analogs

This is the oral prodrug of penciclovir. It is a deoxyguanosine analog, and, in its triphosphate state (PCV-TP), competes with dGTP for incorporation into viral DNA. PCV-TP also competes with deoxyguanosine triphosphate (dGTP) for the priming of reverse transcription during the synthesis of the first strand of HBV DNA. Clinical studies showed that famciclovir is less potent, compared with LAM, with 1 vs 2-3 log decrease in serum HBV DNA levels. A study of 417 chronic hepatitis B patients (50) found that famciclovir, at 500 mg tid for 1 yr, resulted in a low rate of HBeAg seroconversion 9 vs 3 among controls. The same study demonstrated that famciclovir, administered as a single daily dose (1.5 g), was less effective. Resistance to famciclovir has been reported. The most common mutation involves a substitution from leucine to methionine at position 528 (L528M) (51). Thus, these mutants may have crossresis-tance with LAM (52). In view of the low efficacy of famciclovir, and the need for...

S andpreS HBV Vaccines

The basis for peptide vaccine therapy in chronic hepatitis B is to stimulate immune response to HBV. Pre-S Ags have been shown to be more immunogenic than the S antigen (HBsAg), and may stimulate both Tand B-cell response. In one study (62), 170 patients were randomized to receive GenHevac (preS2 S antigen-containing vaccine), Recombivax (S antigen-containing vaccine) or no treatment. Most patients were subsequently treated with IFN-a after completion of the vaccine schedule. The data, available only in 40 patients, showed that clearance of HBV DNA and HBeAg were seen in 5 17 patients vaccinated with GenHevac. Significant decrease in HBV DNA level was seen in 2 10 patients vaccinated with Recombivax. HBV DNA clearance was seen in 1 13 controls. Because of the design of the study, which included IFN- a treatment after the end of vaccination schedule, and the high dropout rate, it is not possible to ascertain the efficacy and durability of the response to the vaccines per se....

DNAbased HBV Vaccines

Experimental DNA vaccines stimulate both T- and B-cell immune responses to HBV, and may be more effective in the treatment of chronic hepatitis B than peptide vaccines (63). Trials conducted on transgenic mice that express the HBV surface gene showed that vaccination with plasmid DNA resulted in decreased production of HBsAg. The results of pilot clinical trials are eagerly awaited. Cytotoxic T-cells play an important role in the clearance of intracellular virus. A vaccine incorporating a cytotoxic T-lymphocyte epitope, derived from hepatitis B core protein, was evaluated in a pilot clinical study (64). Although the vaccine induced a cytotoxic T-lymphocyte response in some patients, it was not sufficient to achieve virus clearance. In addition, this vaccine appeared to be less effective in patients who are in the immune-tolerant phase of HBV infection.

Treatment Strategies In The New Millennium

Current FDA-approved therapy are effective in achieving HBeAg clearance in 20-30 and HBeAg seroconversion in 15-20 of treated patients. IFN-a has the advantages of a finite duration of treatment, and no reports of drug-resistant mutants. However, side effects are common, and may be debilitating. LAM, on the other hand, has minimal side effects, but the emergence of resistant mutants, and the need for long-term treatment, limit the widespread use of LAM. Whether IFN-a or LAM should be used as the primary therapy is a decision that should be made jointly by the physician and patient, after careful discussions of the pros and cons of the two therapy (Table 7). Current recommendations for management of patients with chronic hepatitis B are summarized in Table 8.

Who to Consider for Treatment

All patients with HCV-induced liver disease should be considered for treatment with IFN and ribavirin. A liver biopsy provides considerable information for patient management, and is highly desirable. Serum liver aminotransferases, symptoms, physical findings, and HCV RNA level do not correlate closely with histologic activity, and cannot be used as surrogates for liver biopsy (25,26). Liver biopsy confirms the cause of liver disease, and documents the degree of inflammation activity and fibrosis. The latter, specifically the presence or absence of cirrhosis, is essential in counseling the patient regarding long-term prognosis, and establishing a management plan to monitor for hepatic decompensation and development of hepatocellular carcinoma. Liver biopsy also provides a sense of the urgency of treatment and an estimation of the likelihood of response to treatment. The National Institutes of Health Consensus Development Conference on Hepatitis C (27), and the more recent European...

Combination Therapy with IFN Plus Ribavirin

Ribarivin is an orally active synthetic guanosine analog that has recently been approved for use in combination with IFN for the treatment of chronic hepatitis C. Ribavirin has in vitro activity against several DNA and RNA viruses, including the flaviviridae such as HCV (36,37). The mechanism of action of HCV infection, particularly the mechanism(s) that account for the increased efficacy of IFN, when it is used in combination, is not clear (38,39). Ribavirin appears to increase the antiviral effects of IFN in the infected cell, since it results in a longer suppression of replication after the dose (40,41). Ribavirin may augment virus-specific CTL, as well as nonspecific immune response, by inhibiting interleukin-4, an inhibitor of CTL activity, while preserving interleukin-2 and IFN-y activity (42,43). Finally, anecdotal observations of flu-like side effects that were more severe with combination therapy, than with IFN alone, suggests that ribavirin may somehow increase the end-organ...

Safety and Tolerance of Combination Therapy

Most clinical trials have shown that the addition of ribavirin to the treatment regimen of chronic hepatitis does not increase clinically perceived side effects of treatment (33,45,50). However, many patients complain of more intense flu-like side effects when receiving combination treatment. Discontinuation of treatment is more common in those receiving both drugs than with IFN alone (9 vs 5 ). The most common reason for dose reduction or interruption is anemia and resulting fatigue (33,45,50).

Issues in Assessing Treatment Response

The development of accurate molecular assays for assessing HCV genotype and level of viremia has resulted in significant progress in the clinical assessment of the treatment responses in patients with HCV infection. HCV RNA testing can be either qualitative (present or not) or quantitative. The former are typically PCR-based methods the latter are performed with either a PCR-based or signal-amplification method. Qualitative measurement of HCV RNA by PCR confirms active infection. It is a useful diagnostic tool in clinical situations in which the presence of infection requires documentation, e.g., during the early weeks of acute infection, in immunosuppressed patients in whom antibodies to HCV may be undetectable (83), and in the anti-HCV-positive patient with persistently normal ALT values. Documentation of viremia by either method is important prior to consideration of therapy. Quantitative HCV RNA methods are helpful in monitoring the response to treatment. Failure of the HCV RNA...

Prospects For New Treatment Options

Current therapy for hepatitis C infection is believed to be based mostly on the ability of IFNs to directly inhibit intracellular HCV replication and prevent infection in uninfected hepatocytes. However, the exact mechanism of action, by which IFN and ribavirin exert their action remains unclear. On average, the currently available therapy regimens for CHC infection appears capable of eradicating HCV in up to 40 of treated patients. However, the majority of patients treated do not achieve an initial response, or never respond to these therapy regimens. The current treatments available for HCV are far from ideal, and new cost-effective, safe, and well-tolerated agents are needed. There are several other potential avenues open to the development of new antiviral treatment strategies for HCV infection. Virus could be neutralized outside of the hepatocyte, by neutralizing antibodies (93) or receptor inhibition, thereby preventing viral binding, uptake, and uncoating. Intracellular...

Positive Autoantibodies but Without Symptoms of Autoimmune Disorders

The presence of serum autoantibodies is essential for the diagnosis of an autoimmune disorder, but no one marker is pathognomonic for a certain autoimmune condition. In addition, many healthy persons carry silent autoantibodies, and they remain asymptomatic throughout their lives. These autoantibodies may represent a subclinical autoimmune dysregulation state, which may become manifest when a trigger, such as HCV or IFN, affects the subject. The presence of these autoantibodies ultimately does not compromise the host's immunologic response to pathogens, compared to the general population, and the literature suggests that these individuals have an acceptable response to IFN therapy. Nevertheless, these patients appear to be at a higher risk for the development of autoimmune complications during IFN therapy. The report by Okanoue et al. (28), which followed 677 patients with chronic hepatitis C virus during therapy, found that autoimmune side effects were more frequent among those...

Educating The Patient

The patient must be included in the development of the therapeutic plan. All patients should be educated regarding the transmission of viral hepatitis, the natural history of the disease, the treatment, and the potential side effects of treatment. Each patient has a unique medical history

Patients with Psychosocial Issues

Patients with significant psychosocial issues are not suitable for treatment until resolution of these issues. The importance of obtaining a thorough social history can never be underscored enough, to identify problems or demands at home or at work, which would make treatment not only challenging but invariably worsen the issue at hand. This emphasizes the importance of the timing of treatment. The psychosocially challenged patient is unlikely to be able to complete a successful course of treatment, and it is rarely so urgent that treatment could not be delayed until a later time, when the patient's problem has been stabilized or resolved. Successfully completing a course of therapy is much more likely to occur for the HBV- or HCV-infected patient who does not have any concurrent psychosocial issues.

Children Elderly Patient

The elderly patient with CHC may be a challenge for treatment. The primary question to answer before treating the elderly patient is whether the HCV infection is going to impact longevity or quality of life. Knowing the approximate time of infection, and the severity of liver disease on liver biopsy, may suggest that treatment is unnecessary in the patient with advanced age. In addition, the elderly patient may have other co-morbidities that make treatment of the CHC inappropriate. However, the decision to treat the elderly HCV-infected patient should be individualized, and not be denied because of age.

Pretreatment Evaluation And Education

In the era of managed care, patient-physician contact tends to be brief, and, in many cases, complex decisions about treatment are made after only one or two visits to the physician. In the authors' practice, at the initial consultation, the patient is counseled about risk factors for the transmission of hepatitis C to family and friends. The second visit to the physician is usually for a percutaneous liver biopsy, and it is at the third visit that the major discussion about treatment takes place. Prior to that visit, the authors utilize available educational tools, such as patient information brochures and booklets, and videos about hepatitis C and its therapy, to give the patient some base-line understanding of the disease and its therapy. In addition, specific websites are recommended, such as those of the American Liver Foundation, that the patient can access for research into their disease. Unfortunately, since there is so much misinformation on the Web, recommending appropriate...

Monitoring Of Therapy

The patient with hepatitis C requires frequent visits while on IFN and ribavirin therapy, mainly for monitoring for side effects, and to aid in compliance with therapy. In the first 8 wk of therapy, monitoring for hemolysis, and helping the patient cope with the early side effects, is most important. After 12 wk, the major reason for monitoring is to ensure compliance, and to rule out neuropsychiatry problems. The authors recommend a visit at wk 2 and 4, then every 4 wk, while a patient is on therapy. In addition to a history and questioning about side effects, complete blood count (CBC), ALT, and pregnancy test are obtained at every visit, and every 12 wk, a TSH is performed. Monitoring is also necessary once therapy has stopped, and the authors recommend a visit a wk 4, 12, and 24 posttreatment. Late-onset depression and suicides have been reported in patients who have completed treatment. The authors also continue to monitor pregnancy tests and TSH for 24 wk posttreatment. The...

Licorice Glycyrrhizin

One trial (20), which evaluated a glycyrrhizin-based compound against other herbs, included 193 hepatitis C patients, followed prospectively for 2-16 yr for evidence of progression to cirrhosis or the development of hepatocellular carcinoma. Although glycyrrhizin appeared to slow the histological progression of the disease, both groups appeared to progress to carcinoma more frequently than in similar patients treated with IFN. Side effects attributed to glycyrrhizin included hypokalemia in 11 and hypertension (HT) in 3.6 . In a single randomized control study of iv glycyrrhizin vs placebo, among 58 IFN nonresponders or patients unlikely to respond (cirrhotic patients with genotype 1), the herb resulted in lower ALT, with no effect on HCV RNA levels (21). The adverse effects of glycyrrhizin in humans are well-characterized. Glycyrrhizin inhibits 11- -hydroxysteroid hydrogenase in the kidney, inhibiting the conversion of cortisol to cortisone. This results in a...

Thymosin Thymic Gland Extract

Sedative Acute hepatitis Antiseptic Centrilobular necrosis, chronic hepatitis Sleep, pain relief Acute hepatitis, cholestatic hepatitis Weight reduction Acute hepatitis, chronic hepatitis extracts for the treatment of chronic hepatitis B found that aminotransferase levels improved more quickly, and that the virus was cleared more often, among those on therapy, compared to placebo a third trial (24) showed no improvement in efficacy, compared to IFN therapy. When used alone in the treatment of hepatitis C, thymosin appears to be ineffective (25-27). However, in one trial (28), patients treated with thymosin a 1, in combination with IFN, cleared HCV RNA more often, compared to patients receiving IFN alone or patients treated with placebo (37 vs 16 vs 3 , respectively). However, sustained virologic response rates were not shown to be different in this trial (28).

Major Types Of Injury Resulting From Drugs And Toxins

Lesions indistinguishable from viral hepatitis some agents give rise usually to hepatocellular reactions others to cholestatic. Fat is rare granulomas, eosinophils common. The number of drugs that fall into the predictable category is small, partly because the usual doses of drugs result in plasma and tissue concentrations of the drugs or their metabolites, which are well below toxicity levels for most patients. However, attempts at keeping drug levels safe can fail for several reasons, including advanced age, genetically altered metabolism, interactions with other drugs, or underlying liver disease (e.g., chronic viral hepatitis). These conditions may interfere with normal drug clearance, resulting over a period of time in toxic concentrations. Such alterations are called pharmacokinetic changes (1). The presence of underlying liver diseases, such as chronic viral hepatitis, may predispose patients to greater dose-dependent toxicity, unless drug dosage is adjusted downward. This is...

EtOH and Increased Damage Caused by Iron Overload

Excessive iron (Fe) in the body is toxic to many cells. High Fe levels per se (as in hemochromatosis) can cause cirrhosis, liver failure, and hepatocellular carcinoma (13,14). There is also growing evidence that only mildly increased, or even normal, amounts of Fe can cause or enhance hepatic injury in the presence of alcohol. Evidence is now accumulating that Fe can also potentiate hepatotoxicity caused by other etiologies, such as chronic viral hepatitis (13). In addition, Fe overload may facilitate or exacerbate microbial infections, and suppress the ability of the host's immune system to overcome such infections. Abnormalities in serum parameters of Fe status (ferritin, transferrin saturation) are common in patients with chronic viral hepatitis, probably because of the release of Fe from injured hepatocytes. The increased, metabolically active Fe, in turn, may increase the severity of chronic viral hepatitis and the degree of hepatocyte damage (13). Some of the proposed mechanisms...

Dosedependent Hepatotoxicity

Chronic Viral Hepatitis Is not Unique Among Liver Diseases Few studies of drug metabolism or population-based surveys ofhepato-toxicity have been carried out in patients with chronic viral hepatitis. There is no recognized unique aspect of chronic viral hepatitis known to be a predisposing cause of increased drug- or toxin-dependent hepatotoxicity. CYP, Cytochrome P-450 GSH, reduced glutathione NASH, nonalcoholic steato-hepatitis NSAIDs, nonsteroidal anti-inflammatory drugs. CYP, Cytochrome P-450 GSH, reduced glutathione NASH, nonalcoholic steato-hepatitis NSAIDs, nonsteroidal anti-inflammatory drugs. Thus, for the present, one should assume that patients with chronic viral hepatitis will respond to drugs and toxins like other patients with chronic liver disease of similar severity, regardless of cause. natural products continues to grow steadily, it is remarkable that dose-dependent hepatotoxicity is reported so rarely. The reasons for this are not entirely clear. Perhaps many...

Idiosyncratic Unpredictable Hepatotoxicity

As for dose-dependent hepatotoxicity, in all likelihood, a complex interplay of host and environmental factors influences the development and evolution of allergic or idiosyncratic hepatitis (Fig. 4). Fig. 3. Interplay of factors that influence dose-dependent hepatotoxicity in patients with viral hepatitis. Fig. 3. Interplay of factors that influence dose-dependent hepatotoxicity in patients with viral hepatitis.

Chronic Viral Coinfection

Patients with HBV and hepatitis D virus (HDV) co-infection demonstrate more rapid progression to cirrhosis, compared to patients with isolated HBV infection (4). However, after liver transplantation, the outcome is favorable in patients who are co-infected prior to liver transplantation, in part because HDV downregulates HBV replication. Patients who are co-infected with HBV and HDV usually develop HDV infection of the liver allograft early posttransplant, without markers of HBV infection (4). The course of isolated HDV infection after liver transplantation is indolent, and usually results in spontaneous resolution, except when HBV recurs. Between 10 and 20 of patients with chronic hepatitis B have detectable anti-HCV (4,5). Alternatively, 2-10 of patients with anti-HCV demonstrate markers of HBV infection. Co-infection with HBV and HCV results in more severe liver disease, compared to patients with isolated HBV or HCV infection. Posttransplant, HCV suppresses HBV, and thereby...

Liver Transplantation for HBV

The long-term outcome after liver transplantation for chronic HBV infection with cirrhosis is excellent, but this has not always been the case in fact, in the early 1990s, patients with chronic hepatitis B were generally regarded as poor candidates for liver transplantation. The initial experience with liver transplantation for hepatitis B was associated with a disappointing 50 survival after 3 yrs of follow-up (9). The reason for this relatively poor survival was that HBV re-infection with detectable hepatitis B surface antigen (HBsAg) occurred in 80 of patients, usually within the first year. In many instances, recurrent HBV infection had an aggressive course, with rapid progression to cirrhosis and death. Histologically, a pattern of fibrosing cholestatic hepatitis was recognized as an unusual, but rapidly progressive, and usually fatal, form of liver disease associated with HBV re-infection that occurred in some recipients after liver transplantation (10,11). High levels of...

LAM Prophylaxis for HBV ReInfection

HBIg prophylaxis is expensive, poorly tolerated in some patients, periodically unavailable, and associated with HBV recurrence rates of 20 (13,23). Lamivudine has been investigated as a prophylactic therapy option for HBV re-infection. In various open-label studies of patients with advanced chronic hepatitis B undergoing liver transplan

Treatment of Recurrent HBV Infection Posttransplant with LAM

Finally, the role of retransplantation for recurrent HBV infection has been evaluated. In the past, the management of patients with severe recurrent hepatitis B with retransplantation was poor (41). A more recent study (42) showed that retransplantation, using high-dose, long-term HBIg treatment, can also result in good long-term success.

Patient Selection

The initial selection of patients for therapy is an important determinant of the outcome of treatment. In a typical cohort of patients diagnosed with hepatitis C, approx one-third of patients are not candidates of therapy. Typically, in this third of patients are included those who are still actively using intravenous (iv) drugs, patients who are abusing alcohol, patients with concomitant serious medical illnesses, patients with advanced liver disease, and patients who decline therapy. In this latter group, both patient and physician bias can influence the choice of therapy. Patients may decline therapy because they believe it is not effective, or because they are worried about the side effects profile of treatment. Physicians are often influenced by their perception of the patient's individual commitment to a long course of treatment, and are frequently worried about the effect of therapy on the patient's quality of life. Recently, the authors evaluated 175 consecutive patients...

HBV Vaccines and Regimens

Plasma-derived vaccines comprise about 80 of worldwide HBV vaccine production, but are no longer available in the United States. Recombinant HBV vaccines were approved for use in the United States in 1986 and 1989. The two commercially available vaccines are produced by cloning the gene encoding the HBsAg, through use of a plas-mid vector inserted into common baker's yeast. The yeast-derived HBsAg particles induce immunity by stimulating the endogenous production of neutralizing antibody to HBsAg (anti-HBs). Seroprotection is thought to be achieved when anti-HBs levels are 10 mlU mL or higher. Antibody to the hepatitis B core antigen (anti-HBc) is not induced by the recombinant HBV vaccines. Rarely, transiently positive tests for HBsAg in serum may be found within 24 h following vaccine administration. The HBV vaccines are highly immunogenic, and are conventionally given in a three-dose schedule utilizing a deltoid injection site, or, in infants, the anterolateral muscle of the thigh....

Vaccination Strategies

And hepatitis B immunoglobulins of the neonates of those women found to be HBsAg-positive. Other infants, children, and adolescents through 18 yr of age, and high-risk groups are also candidates for HBV vaccine. Patients with chronic liver disease, e.g., chronic hepatitis C (CHC), are also candidates for the HBV vaccine, if serologic markers of HBV infection are absent, since super-infection by HBV may result in increased morbidity and high case-fatality rates. Limited data (9) indicate that vaccine responsiveness may decline with advancing disease, and that patients with cirrhosis awaiting transplantation are among the least responsive. Hence, early immunization, after the diagnosis of chronic liver disease, seems appropriate. Although, in a recently reported European study (10), patients with CHC were less responsive to a non-U.S.-approved recombinant vaccine than were healthy controls, conflicting data (11) have been

Future Problems in HBV Immunoprophylaxis

The emergence of transmissable HBV escape mutants, which may lead to chronic infection, is a major concern, since these have been reported from many parts of the world, albeit in low frequency. They appear to be responsible for instances of breakthrough infections in immunized infants, but also have been reported in liver transplant patients who have been treated with hepatitis B immunoglobulins. The most common mutations found to date affect the common a determinant of HBsAg, and result in less binding of HBsAg to anti-HBs. Thus, the mutant HBV evades the protective ability of anti-HBs (25). The mutant HBV virus

Mechanisms of Protection

The immunodominant epitopes of HCV are likely to be localized to the structural, rather than the nonstructural proteins, of the virus. The HCV envelope glycoproteins (GP), designated E1 and E2, are the putative sites of the immunodominant epitope. Antibodies to the envelope proteins are present in low titer in most HCV-infected individuals. At the N-terminal portion of E2, a hypervariable region I (HVR I) is present, and may play a key role in the emergence of HCV variants that escape immune recognition by neutralizing antibody activity. Antibodies to HVR I may have neutralizing ability, since they have been shown to block the attachment of HCV to human fibroblasts in tissue culture (33). Despite these observations, it remains uncertain whether HVR I is the principal target of the neutralizing immune response to HCV. In studies of HCV infection in both chimpanzees and human beings, antibodies to E2 could not be correlated with self-limited infection (34). In fact, persistence of these...

Passive Immunization with Immunoglobulin

Passive immunization, with conventionally prepared immunoglobulin, was studied prior to the availability of serological tests for antibodies to HCV, and prior to the characterization of HCV as an RNA virus. Attempts to reduce the risk of transfusion-associated non-A, non-B hepatitis (now known to have been mostly HCV infection) were undertaken in the hope that neutralizing antibodies might be present in immunoglobulin preparations in sufficient concentrations to reduce the severity or completely abort infection in the recipients. Prospective, randomized clinical trials of conventional immunoglobulin in the United States and in Spain (35- 38), provided conflicting results. Because HCV infection rates could not be accurately determined at that time, and measurement of neutralizing antibodies was impossible, the studies are difficult to interpret. Nonetheless, prophylactic of transfusion-associated hepatitis C with immunoglobulin has not been recommended, and the extraordinary...

Chronic Infection With Normal Alt Carrier

Patients with hepatitis C, who have a persistently normal ALT, represent a unique subgroup of patients. One early study indicated that 26 of patients with positive hepatitis C virus antibody had normal ALT (36). But, as noted previously, this is likely an underestimate of the true proportion of patients with positive hepatitis C virus antibody who are ALT-normal. In the two studies of women who acquired hepatitis C after administration of anti-D immunoglobulin, nearly two-thirds of those who were antibody-positive had normal ALT (19,20). Approximately one-half were positive for HCV RNA, and one-half were negative for HCV RNA. Women are more likely than men to have normal ALT, but normal ALT is not related to viral load, genotype, or degree of quasispe-cies. Other factors, such as human lymphocyte antigen (HLA) type, cellmediated immune response, hepatic iron (Fe) concentration, and obesity may be important. Long-term follow-up, with repeat testing of HCV RNA, is required to determine...

Risk for Development of HCC

Dual infection with HBV and HCV may accelerate the progression of chronic liver disease to cirrhosis and HCC (35-38). In one study of patients with HCC, the presence of both anti-HCV and HBsAg was found in 12 of cases (38). 45 did not have HBsAg, but integrated HBV DNA was detected in the tumor tissue. The relative risk of developing HCC was highest in those with HBsAg and anti-HCV positivity (RR 40.05), compared to those who are positive for only anti-HCV (RR 27.12) or HBsAg (RR 13.96), and those who were negative for both markers (RR 1.00). In a multivariate analysis of cirrhotic patients, male gender, older age, alcohol abuse, and dual positivity for HBsAg and anti-HCV were determined to be independent risk factors for the development of HCC. Benvegnu et al. (35) suggested that HBV might act as the initiating factor, by altering the arrangement of the hepatocyte genome, and that HCV is the promoting factor, by virtue of its contribution to continuing liver injury and regeneration.

Initial Evaluation History and Physical Examination

A detailed history and physical examination on the initial patient-physician encounter, will provide the most important early information leading to the therapeutic plan, and ultimately aid in managing the potential side effects of treatment. Taking a detailed history from the patient with chronic viral hepatitis will provide the approximate time and source of infection in many cases, symptoms of liver disease, if present, and disease co-factors, such as alcoholism and drug addiction. Furthermore, significant co-morbidities, such as uncontrolled depression or heart disease, which would be contraindications to treatment, will also be identified by the initial patient history (see Table 1).

Patients Not Suitable for Treatment Developing the Therapeutic Plan

Alcohol Abuse Treatment Algorithms

There are many patients infected with HBV or HCV, who, at the time of initial evaluation, are not considered suitable for treatment. These patients include the alcoholic who is actively drinking, the active drug user,the patient with a significant psychiatric history, and those patients with significant psychosocial issues. These patients should have a well-formulated plan centered on those factors. The HCV-infected alcoholic patient is at increased risk for the development of cirrhosis (28). In addition, the response rate to treatment has been shown to be significantly lower in these patients (29,30). Cessation of drinking, and treating the alcoholic, should be the first line of therapy. Abstinence for at least 6 mo is necessary, prior to considering further treatment. In fact, alcohol use should be condemned for all HCV-infected patients. One of the few positive outcomes of the HCV epidemic has been the cessation of drinking in many HCV-infected patients, including alcoholics. The...

EtOH and Increased Acetaminophen Toxicity

Acetaminophen is well-absorbed from the gastrointestinal tract, and is uniformly distributed throughout most body fluids. Conjugation occurs in the liver, mostly with glucuronic acid, and, to a smaller extent, with phosphoadenosine phospho-sulfate (PAPS) (Table 1 Fig. 2). 80 is excreted in the urine after hepatic conjugation. Hepatotoxicity caused by overdose results from the formation of a highly reactive intermediary metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine, produced by the action of cytochromes P450, especially CYP 2E1 and CYP 1A1 2. As described above, chronic heavy EtOH induces CYP2E1, thus increasing formation of acetaminophen's toxic metabolite. Heavy EtOH use also depletes GSH. Then, too, persons who drink heavily often eat poorly, and this may cause further depletion of GSH. Thus, the combination of large amounts of EtOH and acetaminophen, as well as chronic EtOH consumption and acetaminophen, should be avoided in all patients, particularly those with chronic...

EtOH and Increased Methotrexate Toxicity

Methotrexate (MTX) may induce liver damage. The pathogenesis of hepatotoxicity with MTX is poorly understood. Some patients may develop fibrosis or cirrhosis, following long-term treatment with MTX. However, several studies, with serial liver biopsies during continued treatment, have shown that MTX-induced liver cirrhosis is not of an aggressive nature. Alcohol has been cited as a major contributing factor to development of cirrhosis in patients treated chronically with MTX (10,11). There is a strong association with previous or concurrent heavy EtOH intake and host susceptibility to injury by MTX (12). Pre-existing hepatic injury, as may be seen with chronic viral hepatitis, may also contribute to injury with MTX (12). Whenever chronic MTX use is contemplated, discontinuation of alcohol use should be recommended. In addition, careful patient screening and selection are advisable. Patients should be screened, at baseline, for potential risk factors for liver disease, including chronic...

David G Forcione MD Raymond T Chung MD and Jules L Dienstag MD

Chronic Hepatitis B Virus Infection of Hepatitis Injury on Outcome of Hepatitis B Extrahepatic Manifestations in Chronic Hepatitis B Virus Infection Prognosis and Survival in Chronic Hepatitis B HCC and Chronic Hepatitis B Virus Infection Infection with HBV Mutants Vaccination in HBV Infection Antiviral Therapy for Chronic Hepatitis B Virus Infection Role of Liver Transplant in Hepatitis B Hepatitis B virus (HBV) infects over 350 million persons, and represents one of the world's leading public health problems. Although viral hepatitis has been known to mankind since the days of Hippocrates, it has only been in the last half century that the complex interactions between HBV and its human host have been unraveled. Understanding of the natural history of HBV infection has evolved significantly since Blumberg's discovery of the Australia antigen (hepatitis B surface antigen HBsAg ) in 1965. This landmark finding has been followed by a research explosion that has produced new insights...