Hepatitis B virus (HBV) infection remains a significant global health problem. Approximately 5% of the global population is infected with HBV—that is, 400 million HBV carriers worldwide. It is estimated that 1.4 million people in the United States have chronic hepatitis B, with 46,000 documented new hepatitis B viral infections in 2006 . Chronic hepatitis B is responsible for 1 million deaths per year globally. It is a major cause of cirrhosis, fulminant hepatitis, and hepatocellular carcinoma (HCC) worldwide [2,3]. Cirrhosis develops in approximately 20% of chronically infected patients, subsequently leading to hepatic insufficiency and portal hypertension .
Treatment of chronic hepatitis B is aimed at viral suppression to reduce hepatic damage and improve overall survival rate. There are 7 drugs currently approved by the Food and Drug Administration (FDA) for treatment of hepatitis B. They include interferon-alpha (IFN-α), pegylated interferon-alpha (PEG-IFN-α), three nucleoside analogues (entecavir, lamivudine, and telbivudine), and two nucleotide analogues (adefovir and tenofovir). Since clevudine has been withdrawn, no new drugs are currently in early developmental stages focusing on the treatment of chronic hepatitis B, however, emtricitabine is in phase III trials. Nevertheless, effective and individualized treatment of hepatitis B is necessary. Resistance is a major pitfall of oral nucleoside/nucleotide therapy, however, and treatment must be tailored to specific genetic and resistance profiles. New drugs are needed as resistance will continue to affect the way infected patients are treated. Drug-resistant strains will be a significant clinical issue, and new drug development is crucial.
CHRONIC HEPATITIS B
A confirmed hepatitis B surface antigen (HBsAg)-positive result indicates active HBV infection, either acute or chronic; chronic infection is confirmed by the absence of IgM antibody to hepatitis B core antigen (anti-HBc), and by the persistence of HBsAg or HBV deoxyribonucleic acid (DNA) for at least 6 months. All HBsAg-positive persons should be considered infectious . There are three phases of chronic HBV infection: immunotolerant, immunoactive, and inactive phase. The majority of individuals with chronic HBV acquired the virus through vertical transmission. The immunotolerant phase occurs primarily after perinatal infection where alanine aminotransferase (ALT) levels are normal, hepatitis B e antigen (HBeAg) is positive, and HBV DNA levels are elevated usually >20,000 IU/mL. The immunoactive phase has elevated ALT levels and elevated HBV DNA levels of at least 2000 IU/mL or greater, and liver inflammation is usually present with or without liver fibrosis. Patients may either be HBeAg positive or negative. The inactive phase shows normal ALT, HBV DNA <2000 IU/mL, HBeAg negative, and anti-HBe positive . The ultimate goal of treatment is eradication of the infectious agent. Treatment of HBV should be based on HBV DNA levels, ALT, presence of HBeAg, liver histology, familial history of HCC, resistance profile, and/or presence of basal core promotor/precore mutations.
GOAL OF HEPATITIS B VIRUS THERAPY
The goal of therapy in patients with chronic hepatitis B is rapid viral suppression and long-lasting maintenance of undetectable levels of serum HBV DNA. Nucleoside/ nucleotide analogues are generally well tolerated and have become the mainstay treatment of chronic HBV infection, resulting in rapid viral suppression, improvement in Child-Pugh scores in patients with cirrhosis, and improved overall survival. The major drawback of nucleoside/ nucleotide analogue treatment is the considerable risk of developing antiviral resistance .
Drugs approved for treatment
There are 7 drugs approved by the FDA for treatment of hepatitis B (listed earlier). At present, the preferred first-line treatment choices are entecavir, PEG-IFN-α, and tenofovir because of their superior efficacy, tolerability, superior potency, and favorable resistance profiles in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B over comparable drugs in pivotal clinical trials .
Drugs no longer in development
Famciclovir, clevudine, Val-d-cytosine, valtorcitabine, alamifovir, and pradefovir are drugs that showed potential antiviral activity against hepatitis B and are no longer used for HBV treatment.
Clevudine is a pyrimidine nucleoside analogue, previously in phase III clinical trials in the United States and approved for treatment in Korea. The FDA and data safety monitoring board voluntarily terminated the clinical development of clevudine for the treatment of chronic hepatitis B in April 2009 after several reports of myotoxicity. Seven Korean patients complained of progressive muscle weakness occurring after at least 8 months on clevudine therapy with marked elevation in creatinine kinase levels. Muscle biopsies confirmed drug toxicity showing myonecrosis associated with numerous ragged red fibers and predominant type II fiber atrophy supporting the diagnosis of mitochondrial myopathy . Seok et al concluded that long-term therapy with clevudine can cause depletion of mitochondrial DNA and lead to myopathy characterized by mitochondrial dysfunction and myonecrosis. After discontinuation of clevudine, patients experienced normalization of biochemical markers of myositis and slowly recovered motor strength, suggesting that these adverse effects are reversible with drug withdrawal . Further clinical development of clevudine, both domestic and abroad, was voluntarily terminated after report of mitochondrial toxicity.
New therapeutic strategies
Emtricitabine, a nucleoside analogue structurally similar to lamivudine with potent activity against HBV and human immunodeficiency virus (HIV), is currently in phase III clinical trials . This trial randomized 248 treatment-naïve patients into blinded groups, the first group received emtricitabine and the second received placebo. At 48 weeks the treatment group receiving emtricitabine had significant histologic improvement in 62% of their patients and 54% had complete viral suppression; with 79% of the DNA-negative group also HBeAg negative. Loss of detectable HBV DNA also occurred significantly more often with emtricitabine (54 vs 2%). Emtricitabine had similar seroconversion rates when compared to lamivudine and adefovir trials collectively ranging from 12 to 17%. Emtricitabine’s resistance profile is similar to lamivudine. Studies of emtricitabine as monotherapy for treatment of HBV are limited; future studies are in progress to evaluate its use in combination therapy .
Nitazoxanide (Alinia), first licensed for treatment of Cryptosporidium parvum and Giardia lamblia, has been used in very preliminary studies for the treatment of chronic hepatitis B. Nitazoxanide appears to involve activation of protein kinase initiated by double-stranded ribonucleic acid (RNA), an interferon-induced mediator of the cellular antiviral response . Nitazoxanide may alter cellular processes required for virus protein production and maturation and/or assembly . Nitazoxanide monotherapy has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a 1-year course of therapy . Nitazoxanide at a dose of 500 mg twice daily resulted in a decrease in serum HBV DNA in all of the 4 HBeAg-positive patients, loss of HBeAg in 3 patients, and loss of HBsAg in 1 patient . Nitazoxanide 500 mg twice daily suppressed serum HBV DNA and led to loss of HBeAg in the majority of patients and HBsAg in approximately one-quarter of patients . In vitro studies show synergistic interactions with nitazonaxide combined with either lamivudine or adefovir when used to treat 2.2.15 cells . Nitazoxanide is an inhibitor of HBV and in combination with other antiviral agents may have the potential to increase loss of HBsAg, which is the ultimate end point of therapy. A formal phase II study is planned for 2009 .
SMALL INHIBITORY RIBONUCLEIC ACID
The use of small inhibitory RNA (siRNA) molecules has not been studied in humans, but in vitro and animal studies show promise of inhibiting HBV expression and replication. SiRNA molecules reduced woodchuck hepatitis virus (WHV) replication and led to an upregulation of IFN-stimulated genes . SiRNA can enhance antiviral immune responses through specific cellular signaling pathways. WHV-specific siRNA, called siWHx, was used to knockdown WHV gene expression and replication in primary murine hepatocytes from WHV transgenic mice. This study found that siWHx decreased hepatocyte WHV transcripts by more then 50% and led to myxovirus-resistance protein A (MxA) upregulation by an estimated 30-fold . Future studies are needed to determine if the effect of siRNAs is able to facilitate immunotherapy and lead to enhanced antiviral activity in vivo.
SIMVASTATIN AND SYNERGISTIC INTERACTIONS WITH ORAL NUCLEOSIDES/NUCLEOTIDES
In vitro studies show that the combination of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins)—specifically simvastatin—with nucleoside/nucleotide analogues displays synergistic activity against HBV replication. Bader and colleagues presented in vitro data at the European Association for the Study of the Liver (EASL) annual meeting reporting the activity of simvastatin and lamivudine; simvastatin and adefovir; and simvastatin plus tenofovir. Using the cell line Hep 2.2.15 to produce HBV virions, combination drugs were tested showing that simvastatin displayed moderate synergistic interactions with lamivudine and tenofovir and additive interactions with adefovir against HBV replication . These combinations have not been tested in vivo and only suggest a potential role for HBV antiviral effect. More studies will need to take place before combination therapy is officially recommended.
The goal of antiviral medication is complete viral suppression of HBV DNA, normalization of ALT, loss of both HBeAg and HBsAg, and attainment of antibodies against HBsAg. Treatment should be tailored to individuals based on serology, ALT, genotype, family history, and current state of health. The occurrence of resistance to nucleoside/nucleotide analogues is unavoidable. With the removal of clevudine from phase III clinical trials in the US, there are no new drugs in early developmental stages focusing on the treatment of chronic hepatitis B. With high rates of resistance to available oral therapies, development of new drugs is necessary to combat inevitable and unavoidable resistance. New agents with different viral targets that vary from those of the currently available drugs will be needed for patients who have failed or ultimately may fail second- or third-line treatment regimens . Phase III studies are currently investigating the use of emtricitabine and its use in combination therapy for treatment of chronic hepatitis B. In preliminary studies, nitazoxanide shows some promise for HBV treatment. Future phase II clinical trials will investigate its antiviral potential for use in treatment. The use of siRNA molecules in vitro shows promise inhibiting hepatitis B expression and replication, but future studies are needed in humans to confirm efficacy and safety. In vitro studies show simvastatin has synergistic interactions with lamivudine and with tenofovir and additive interactions with adefovir against HBV. Future in vivo studies are needed to confirm whether the suggested potential HBV antiviral effect using combined oral nucleoside/nucleotide and simvastatin is successful. With significant concern for drug resistance and with no new drugs on the horizon, future treatment of hepatitis B will be challenging.
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