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Approximately one third of the worlds population has serological evidence of current or previous hepatitis B virus infection. Of the 2 billion people who are infected, 350 million people are chronically infected and an estimated 500 000 - 700 000 deaths are recorded each year worldwide. 1, 2, 3
Hepatitis B is an infection of the liver caused by the HBV virus, a partially double-stranded circular DNA virus belonging to a group of hepatropic DNA viruses (hepadnaviruses) 1, 4 This virus is composed of a nucleocapsid covered with the envelope protein and is transmitted by percutaneous and permucosal exposure to infected blood and other body fluids. HBV depend strongly on the viral-host interaction to carry out viral gene expression due to the limited genome size. 5 In the UK, most of new infections are normally acquired in adulthood. The source of infection is usually following blood to blood contact (injecting drugs and 'needlestick' injuries), sexual transmission and perinatal transmission from mother-to-baby. 6
Patients newly infected with hepatitis B are normally sub-clinical or may present flu-like symptoms. 6 However, the outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease (jaundice, dark urine, extreme fatigue, nausea, vomiting and abdominal pain when infected with HBV) or an asymptomatic disease (illness only detected by abnormal liver function test or the presence of serological markers of hepatitis B). 7 Jaundice only occurs in about 10% of the younger patients and in approximately 50% of the adult patients. 6 Patients may become immune to HBV, or they may develop a chronic carrier state. 4, 8
Chronic hepatitis B (CHB) is defined as a chronic necro-inflammatory disease of the liver caused by persistent infection with HBV. This condition can be further divided into HBeAg positive and HBeAg negative CHB. The diagnostic criteria for CHB include hepatitis B surface antigen (HBsAg)-positive for more than six months, serum HBV DNA of more than 20 000 IU/ml, persistent or intermittent elevation of alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels and liver biopsy showing moderate or severe necroinflammation. 9 Patients with CHB are at a higher risk of developing cirrhosis, hepatitis decompensation and hepatocellular carcinoma (HCC). 4, 8 Approximately 20 to 25% of the patients with CHB worldwide have progressive liver disease. 6
The objective of CHB treatment is to achieve sustained suppression of the HBV replication and remission of the liver disease. The ultimate aim is to prevent cirrhosis, hepatic failure and HCC. Currently there are seven drugs available for the treatment of CHB; five nucleoside analogues (NUCs) and two interferon-based therapies. 8, 10, 11 Treatment outcome with these agents have shown dramatic improvement in patients' condition although complete eradication of the HBV infection does not occur. 8
The pre-treatment factors that need to be considered before initiation of treatment with NUCs include low viral load (<107 IU/ml), high serum ALT levels and high activity score on liver biopsy. NUCs suppress viral replication by inhibiting the HBV polymerase and are cleared by the kidneys thus dosing adjustments are recommended in patients with kidney impairment. 8, 11 NUC therapy is preferred in some cases for the good side-effect and safety profile but there is a considerable risk of viral resistance. The long term data on the effect of NUCs are limited due to the fact that they are relatively new to the clinical practice. The drugs under this class of drug are lamivudine, adefovir, entecavir, telbivudine and tenofovir. 8
Lamivudine. Lamivudine is an antiretroviral belonging to the nucleoside analogue reverse transcriptase inhibitors. Lamivudine monotherapy is effective in reducing the risk of liver complication such as cirrhosis and HCC by suppressing HBV replication through chain termination. 9, 12, 13 Treatment with lamivudine provides a substantial reduction of 50% in disease progression during a 32 months treatment. 14 In another study done by Lok ASF eat al, lamivudine treatment for up to 6 years showed a great safety profile in patients with with HBeAg-positive compensated liver disease. 15 According to Holmberg SD et al, the seroconversion of HBeAg after a year treatment with lamivudine is similar to that of a 16 week treatment of a standard interferon-alfa. 9
Lamivudine is phosphorylated in the body to active triphosphate form and this active form will inhibit the HBV polymerase. The absorption of lamivudine occurs rapidly in the gastrointestinal tract with a peak plasma concentration after an hour. This absorption however is delayed when taken with food. Lamivudine crosses the blood brain barrier and placenta and enters breast milk therefore careful assessment by a specialist is required. The product of metabolism of lamivudine is excreted via the urine and the elimination half-life of the drug is approximately 5 to 7 hours.
The dosage regimen of lamivudine for adults in HBV infection is 100mg orally daily. Dose reduction is necessary for patient with renal insufficiency and the liver chemistries and HBV DNA level should be monitor every 12 weeks while on therapy. 9, 11 The adverse events reported from the use of lamivudine include headache, fatigue, nausea, vomiting, abdominal pain and diarrhea. 13, 14 Because lamivudine is cleared in the kidney, any drugs cleared renally such as trimethoprim should be used with caution. Lamivudine is well tolerated in patient with decompensated cirrhosis and reported a marked increase in HBeAg seroconversion in patients from various groups. 9
One disadvantage of long-term lamivudine therapy is the development of resistance which increases progressively between 14% and 32% annually. This increases with the duration of treatment to 60% to 70% after approximately five years of treatment. 9, 15,16 There are several factors that increases the risk of resistance in patient on lamivudine therapy and this include high pre-treatment HBV DNA, high pre-treatment ALT levels and incomplete suppression of viral replication. The selection of lamivudine-resistance-mutation is the main concern with this therapy and the most common mutation involves the substitution of methionine in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV DNA polymerase for valine or isoleucine rtM204V/I. 9, 14, 16
Adefovir Dipivoxil. Adefovir dipivoxil is an adenosine monophosphate nucleotide analogue. Adefovir exerts its effect by inhibiting both the activity of reverse transcriptase and DNA polymerase by incorporation into the HBV DNA causing chain termination. 9 Drug therapy with adefovir dipivoxil should only be initiated if treatment with lamivudine has resulted in viral resistance or treatment with interferon-alfa has been unsuccessful or poorly tolerated. In some clinical trials, treatment with adefovir reported a significant histological improvement, HBeAg seroconversion and ALT normalization and the treatment outcome is comparable to lamivudine. Marcellin et al reported histological improvements in approximately 90% of the patients by Week 48. 17, 18, 19
Following oral administration, the pro-drug adefovir dipivoxil is converted to the acyclic phosphonate nucleotide, adefovir which is then phosphorylated into adefovir diphosphate, a competitive inhibitor of the HBV polymerase. It is not metabolized by cytochrome P450 enzyme and approximately 50% of the dose is recovered in the urine as adefovir over 24 hours following a 10mg/day oral dosing. This shows that adefovir is renally excreted by glomerular filtration and tubular secretion. Because adefovir is renally excreted, dose adjustments are required in patient with renal dysfunction and co-concurrent administration of drugs renally excreted should be taken into consideration. The elimination half-life of adefovir is approximately 6 to 8 hours and should be avoided in lactating mothers and pregnant women. 20
Adverse effects most commonly reported from the treatment with adefovir are nausea, flatulence, diarrhea and dyspepsia although nephrotoxicity will also be observed in some patients. 9, 17, 20 Resistance will also develop during the treatment with adefovir although it occurs less frequently as compared to lamivudine. Hadziyannis et al reported an insignificant overall accumulative rate of resistance among the patients at week 48, 96 and 144 as 0%, 3% and 5.9 % respectively. 18 The resistance in adefovir is conferred by substitution of threonine for asparagine and in-vitro studies showed that this resistance decreases treatment susceptibility by 33 to 15 fold. 9, 16
Entecavir. Entecavir is a carboxylic analogue of 2'-deoxyguanosine which inhibits HBV replication at three different steps rendering it different from the mode of action of lamivudine and adefovir. The three steps mentioned are the priming of HBV polymerase, the reverse transcriptase of the negative strand which is acts as a template for the replication of viral mRNA and the synthesis of the positive strand HBV DNA. 9, 22 Entecavir is indicated for adults with evidence of active viral replication and either evidence of persistence elevations in serum ALT or histologically active disease. 21
Several randomised clinical trials showed that entacavir is statistically superior to lamivudine in terms of the number of people with HBV DNA suppression, ALT normalization and histological improvement. Chang et al reported 73% of the patients receiving entecavir in his study showed histological improvement by Week 48 and long term therapy entecavir suppresses viral replication in all patients. 21, 23
Following oral administration, entecavir reaches its peak plasma concentration at about 30 to 90 minutes and this is affected by intake of food. Entecavir is also extensively distributed in tissues and is eliminated by the kidney with urinary recovery of unchanged drug. Therefore, appropriate adjustments to the dosing interval should be made in patients with renal dysfunction. The terminal elimination half-life of entecavir is approximately 128 to 149 hours. The typical dosing of entecavir for an adult patient is 500mcg daily. 21
Adverse effects of treatment with entecavir are headache, fatigue, dizziness and nausea. Resistances to entecavir are associated with mutations in the viral polymerase and were mapped to domain B (rtS184G), domain C (rtS2021) and domain D (rtM250V). Although this situation is observed in clinical practice, it occurs less frequently compared to lamivudine and adefovir. 9, 16, 23
Telbivudine. Telbivudine is a thymidine nucleotide analogue which is used as an antiviral in the treatment of hepatitis B but it is not recommended for CHB. 24 Incorporation of telbivudine into the viral DNA causes chain termination thus reduces viral DNA replication. Clinical trials showed that telbivudine is more potent compared to lamivudine in the treatment of CHB. 9, 25 Lai et al reported more than 6 log10 reduction in serum HBV DNA level in the telbivudine group compared to approximately 4 log10 reduction in the lamivudine group. 26 Although more potent, telbivudine monotherapy has a limited role in the treatment of hepatitis B due to the high rate of cross-resistance with lamivudine.
Following a 600mg daily oral dosing of telbivudine, the steady state peak plasma concentration is recorded at 1 to 4 hours after administration and the terminal half-life is approximately 12 hours. The absorption of telbivudine appears to be unaffected by the intake of food. Telbivudine is primarily excreted by the kidney unchanged as it is not s subtrate of the cytochrome P450 enzyme. Because telbivudine is excreted renally, patients with renal dysfunction require a dose interval adjustment. 25
Treatment with telbivudine monotherapy appears to be well tolerated. Adverse effects such as fatigue, nausea, diarrhea, headache and dizziness were recorded but these are comparable to the safety profile of lamivudine. 26 Peripheral neuropathy occurs in less than 1% of the treatment group but appears to be more common when telbivudine is used in combination with peginterferon-alfa. 9, 24, 25
Tenofovir Disoproxil Fumarate. Tenofovir disoproxil is a nucleotide analogue reverse transcriptase inhibitor marketed for the treatment of CHB in adults with compensated liver disease. Tenofovir disoproxil is a prodrug of tenofovir which reduces HBV DNA replication by blocking the reverse transcriptase. The structure of tenofovir is similar to that of adefovir and in vitro studies showed that these two agents are equipotent. 9, 27, 28
Following oral administration, the serum level of tenofovir reaches a peak concentration at approximately 1 hour. However, administration of tenofovir following a high fat meal will increases the time for the serum level to reach a peak concentration thus increasing the bioavailability. Since tenofovir is not a substrate for cytochrome P450 enzyme, 30% to 40% of the administered dose is recovered in the urine over 24 hours after administration. This shows that, tenofovir is excreted renally therefore there may be competition over elimination for other drugs administered which are also cleared renally. 27, 28
The adverse effects reported in the treatment of tenofovir include headache, diarrhea, abdominal pain decrease in bone density and rash. 9, 27, 28 Because the incidence of nephrotoxicity is much lower compared to adefovir, the typical dose for treatment with tenofovir is 300mg daily to be taken orally as compared to the 10mg daily for adefovir. With this higher dose, tenofovir has a more potent antiviral effect in clinical trials. 9
There are several pre-treatment factors that need to be taken into consideration before initiating an interferon therapy. These include low viral load (<107 IU/ml), high serum ALT levels and high activity scores on liver biopsy. Other predictor of low response include age of >40, men and cirrhosis. 11, 12 Interferons are potent, naturally occurring cytokines that are immune-modulating with antiviral and antiproliferative effects. This class of drugs mediates a variety of inhibitory mechanisms that affect viral replication. The advantages of interferon therapy over the NUCs are the absence of viral resistance, a shorter fixed duration of therapy and the increased chances of HBeAg and HBsAg clearance. The down sides of interferon therapy are the numerous side effects and the route of administration. 12 The conventional interferon-alfa (IFN-α) and the pegylated interferon-alfa (pegIFN-α) are the two drugs under this class. 8, 11
IFN-α. IFN-α is indicated for treatment of CHB in adults with compensated liver disease and those initiated with IFN-α must be HBsAg positive for at least 6 months and show elevated serum ALT. Patients with decompensated liver disease and renal insufficiency should avoid taking IFN-α. 11, 29 In addition to the typical test required when monitoring a patient's progress, the standard hematological test and blood chemistries should also be monitored. IFN-α is normally given as an injection either subcutaneously or intramuscularly in the treatment of CHB. The recommended dosage of IFN-α is 30 to 35 MIU/week, administered subcutaneously or intramuscularly either as 5 MIU daily or 10 MIU thrice weekly for a duration of 16 to 24 weeks. 9, 29
IFN-α exerts their effect by inducing certain cellular enzymes thus inhibiting virus replication in virus-infected cells. In addition, IFN-α also enhance the phagocytic activity of the macrophages and augment specific cytotoxicity of lymphocytes for target cells. The mean serum IFN-α concentration following a 5 MIU/m2 IM and SC injections are comparable with a maximum serum concentration occurring at approximately 3 to 12 hours after administration. The elimination half-life of IFN-α given through these routes are 3 hours. Urine levels of IFN-α were below the detection limit following each of the three routes of administration. 12, 29
The most common adverse effects reported following treatment of IFN-α are fever, fatigue, headache and myalgia while the less common effects include vomiting, diarrhoea, depression and hypotension. In addition to these, the use of IFN-α may cause fatal or life-threatening issues such as neuropsychiatric, autoimmune, ischemic and infectious disorders thus they are not suitable for long-term treatment in CHB. 16, 29 Administration of IFN-α with other chemotherapeutic agents should be used with extreme caution as there is increased risk of toxicity which may be fatal. In addition, the risk of developing peripheral neuropathy should not be ruled out especially when IFN-α is used with telbivudine. 9, 29
PegIFN-α. PegIFN-α is a large recombinant molecule produced using recombinant DNA technology. A cloned human leukocyte interferon gene is inserted into and expressed in an Escherichia coli in this technology. PegIFN-α is indicated for treatment of CHB in adults with HBeAg-positive and HBeAg-negative CHB. In addition to the previous indication, pegIFN-α can also be used in adults with compensated liver disease, increased ALT and histologically verified liver inflammation. PegIFN-α has a slower absorption and excretion profile when compared to the conventional IFN-α due to the presence of the polyethylene glycol strands. With this modification, there is less fluctuation in serum levels 8, 9, 30, 31
Production of effector proteins by PegIFN-α raises body temperature and decreases leukocyte and platelet counts irreversibly. In addition, this interferon also inhibits viral replication and cell proliferation. Following subcutaneous injection, pegIFN-α reaches its peak serum concentration at approximately 72 to 96 hours post-dose with a half-life of approximately 80 hours. The peak concentration can be maintained for up 168 hours. Its dosing regimen is once a week compared to thrice a week in the unmodified form. Renal elimination accounts for most of the pegIFN-α clearance and there is a 25% to 45% reduction in clearance reported in patients with end stage renal disease. 30, 31
PegIFN-α-2a is the only pegylated interferon indicated for the treatment of CHB. The recommended dose is 180mcg weekly subcutaneously for 48 weeks. The adverse effects observed in pegIFN-α is similar to that of those in IFN-α and patients with worsening of symptoms should be immediately withdrawn from the therapy. Decrease in platelet counts and white blood cells are also common. PegIFN-α should be used with extreme caution with drugs metabolized by CYP2D6 and CYP2C8/9, especially those with narrow therapeutic index such as warfarin, phenytoin and flecainide. 9, 31
Combination therapy has been proven to be more effective than monotherapy in some cases. The advantages of combination therapy are the synergistic antiviral effect and also the delayed resistance. However, with a combined therapy of more than one antiviral, the cost, interaction and toxicity profile will increase. Numerous combination therapies have been evaluated but none of them have been proven to be superior to the monotherapy in inducing a higher rate of response although several have shown to decrease the rate of lamivudine resistance. 9, 12
For instances, Lai et al reported an insignificant difference in the reduction in serum HBV DNA when comparing the telbivudine monotherapy and the telbivudine and lamivudine combination therapy. 26 In another study conducted by Schalm et al involving 230 patients with CHB who were randomised to interferon alone, lamivudine alone or the combination of both showed insignificant difference in the rate of seroconversion between all three groups. 12
Nevertheless, combination therapies represent the future of the treatment of CHB as not only it decreases the risk of drug resistant, it could also be used to target different pathways at the same time.
Different therapies are suited for different patient depending on their condition. For a 32 year old female with CHB, various considerations needs to be accounted for and these include her previous therapies which might give us an indication of the development of resistance, her HBV DNA levels (viral load), ALT levels, liver biopsy, co-infections (HIV and hepatitis C) and HBeAg status (positive/negative). In addition to those mentioned, it is also important to know if she is planning to start a family anytime in the near future or if she is a nursing mother. All these factors will affect the choice of therapy for the patient.
Treatment suitable for patients with hepatitis B is not necessary suitable for patients with CHB. Example of drugs indicated for hepatitis B such as telbivudine and adefovir dipivoxil are indicated but not recommended for the treatment of CHB. 31
PegIFN-α is the first line treatment for patients with CHB who are either HBeAg-positve or HBeAg-negative with compensated liver disease. The treatment with pegIFN-α should not be initiated in patient with decompensated liver disease. The standard treatment with pegIFN-α is normally offered as a 48-week course. 16, 31 After approximately 12-weeks into treatment, the patients' condition should be evaluated and if an unsatisfactory HBeAg seroconversion is observed, a second-line treatment (tenofovir disoproxil) should replace the pegIFN-α. In cases where tenofovir disoproxil is contraindicated, entacavir should be prescribed instead. 22, 28, 31
As a third-line treatment in patients who are HBeAg-positive with compensated liver disease, lamivudine can be added to the tenofovir disoproxil regime provided the patient does not show any history of lamivudine resistance. As for patients who are HBeAg-negative with compensated liver disease, a switch from entacavir to tenofovir disoproxil or vice versa should be offer as a third-line therapy. It is important not to stop treatment with NUCs after achieving undetectable HBV DNA. 22, 28, 31
For patients with decompensated liver disease and cirrhosis, tenofovir disoproxil should be offer as first-line treatment instead of the usual pegIFN-α. However, in patients with high risk of bone toxicity associated with tenofovir disoproxil, entecavir could be offer as an alternative. All in all, it is important to treat patients with decompensated liver disease with reference to a liver transplant center. 28, 31
In patients co-infected with other disease, a different treatment regime should be proposed. Patients co-infected with CHB and hepatitis C should be prescribed with pegIFN-α and ribavirin as the first-line therapy. As for patients co-infected with CHB and hepatitis D, a 48-week course of pegIFN-α should be offered but treatment should be stopped if hepatitis D virus RNA is detectable after a year of treatment. All in all, treatment should be stop after HBsAg seroconversion is achieved. 16, 31
Tenofovir disoproxil should be prescribed to pregnant women in their third trimester to reduce the risk of transmission to the baby. The treatment should be stop after birth unless the mother is indicated for long term treatment on tenofovir disoproxil. It is also important that the infants are given both active and passive immunization. As for nursing mothers, it is important to convince them that there is a near zero risk of transmitting HBV to their infants if proper immunization is followed. 28, 31