Hepatitis B is a blood-borne viral infection of the liver. It is transmitted sexually, parenterally and perinatally. Although a vaccine was marketed in 1981, individuals with hepatitis B virus (HBV) infection have been estimated to be 2 billion globally in 2002. Of these, 18% are chronically infected and leading to an annual death of 1 million due to the development of liver cirrhosis and hepatocellular carcinoma (HCC).1
The HBV, a member of the family of Hepadnaviridae, is a DNA virus with an incomplete double-stranded genome which replicates via reverse transcription of an RNA intermediate. They are highly cell-specific that typically infects hepatocytes. Eight HBV genotypes (A to H) have been identified based on geographic distribution.2 Correlations between the clinical outcomes and HBV genotypes have been established with genotype C associated with more severe complications including liver cirrhosis and progression to HCC, whereas genotype is thought to be more benign due to a faster seroconversion. Resistance arises as a result of mutations often contributes to genotype virulence and thus impact on disease severity.3
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Upon infection, HBV attaches to the hepatocyte surface receptor and penetrates into the cell. Once internalized, HBV uncoates to make its genome accessible to host biosynthetic machinery in nucleus so that transcription and translation can take place to produce new viruses. The incomplete DNA is now converted by host RNA polymerase into closed circular DNA (cccDNA) which acts as a template for pregenomic RNA required for viral replication. Viral RNA is reverse-transcribed and transported back to the cytoplasm where it undergoes translation to synthesize viral protein or buds into the cell membrane with its viral envelope protein and readily infect other hepatocytes.2
The virus expresses several open-reading frames to code for various viral proteins essential for their replication and release. Some of these are used as biological markers in clinical diagnosis. Hepatitis B surface antigen (HBsAg) is one of the surface antigens recognized at the onset of clinical symptoms. Individuals whose serum levels of HBsAg remain detectable for more than 6 months are formally defined as having chronic hepatitis B (CHB). They are usually at a higher risk of developing cirrhosis, hepatic decompensation and HCC. Presence of HBsAg triggers the immune system to initiate viral clearance by generating antibodies to HBsAg (anti-HBsAg). Besides, hepatitis B e antigen (HBeAg) also indicates an infection and they replaced by antibodies (anti-HBeAg) once the infection has resolved. Therefore, it is also referred to as a marker of viral replication.4,5 Furthermore, when a hepatocyte expresses hepatitis B core antigen (HBcAg), immune-mediated cell death is activated and results in production of antibodies TgM anti-HBcAg, which is a characteristic feature of acute hepatitis.2
In fact, it is the immune response to the HBV is cytotoxic to the hepatocytes instead of the HBV itself. The release of activated cytotoxic T-lymphocytes and tumour necrosis factors (TNF-α) accounts for the most hepatic injury, which in turn progresses to cirrhosis and HCC.2 If the cytotoxic T-lymphocytes response is adequate to clear the virus, the infection resolves while in the case of inadequate response, chronic infection is likely. In the process of destruction of infected hepatocytes by the immune system, alanine transaminase (ALT) is released (an indication of hepatic injury) and a transient rise in ALT level is often observed in CHB.
CHB may be symptomatic or asymptomatic. Common clinical symptoms include fatigue, ascites, jaundice, variceal bleeding, hepatic encephalopathy associated with hyperexcitability, impaired mentation, confusion, obtundation and eventually loss of consciousness. Age is identified as the most dominant factor to the development of CHB. Perinatally- and childhood-acquired infections have a higher risk of chronicity due to immune tolerance to the virus.
Patients with CHB can be classified into two groups: HBeAg-positive and HBeAg-negative. HBeAg-positive is characterized by increased expression of HBeAg and HBV DNA in serum without an elevation in ALT level. Patients are considered to be in the immune-tolerant phase. HBeAg-negative can be further divided into the active or inactive carrier. The active carriers have high ALT and HBV DNA levels as well as liver necroinflammation. Patients may experience repetitive flare with increased frequency and severity which on long term is associated with cirrhosis and HCC. On the other hand, in the inactive carriers, as the hepatocytes producing HBV are destroyed by immune clearance, causes replication to be suppressed, they tend to have seroconversion from HBeAg to anti-HBeAg, low HBV DNA and normal ALT.
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Most common HBV DNA assay employed in clinical setting is polymerase chain reaction (PCR) amplification with lower limits of detection of 250 to 1000 copies/mL. Quantification of HBV DNA plays an important role in evaluating the efficacy of antiviral therapy. Response to antiviral treatment is also interpreted in terms of biochemical (ALT normalization), virologic (undetectable serum HBV DNA and loss of HBeAg in HBeAg-positive patients) and histologic (≥2 points decrease in histology activity compared with baseline biopsy).
Two classification systems used in assessing the liver function and disease severity as well as predicting patient survival. The Child-Pugh score system has gained worldwide recognition as a means of quantifying the effects of cirrhotic process on the laboratory and clinical manifestation of the disease. It usually serves as a basis for drug dosing adjustment recommendation in patients with liver failure. The Child-Pugh score system utilizes a combination of physical and laboratory examination results, whereas the newer Model for End stage Liver Disease (MELD) takes into account the serum creatinine, bilirubin and etiology of disease, providing a more subjective assessment.
CHB can lead to many complications. However, only two main consequences will be addressed here. Firstly, cirrhosis occurs as the liver attempts to regenerate while under persistent inflammation condition. Alcohol consumption appears to be an exacerbating factor. The classical feature include a small and knobby liver which suggests the irreversible effect of nodules of regenerating cells filled with infiltrates of inflammatory-induced fibrous tissue. It is revealed that of all CHB patients, about 20% develop complications of impaired hepatic function as their compensated cirrhosis progress to decompensated cirrhosis within 5 years. Patients with decompensated cirrhosis usually present with ascites, jaundice, encephalopathy or a combination of symptoms. The damage caused is irreversible and therefore, referral for liver transplantation is needed.
Moreover, HBV is also a risk factor of HCC. Patients with HCC may have no signs of compensated or decompensated cirrhosis. For many, if not majority of cases, HCC results after long term inflammatory processes evoked by ongoing HBV infection. In addition, patients who are of male gender, older age, existing cirrhosis and history of reversion from anti-HBeAg to HBeAg are considered at increased risk of developing HCC. Based on the risk factors mentioned, the patient in this case is likely to progress to HCC. AASLD guideline recommends HCC screening every 6 to 12 months.
TREATMENT OPTIONS AND CLINICAL EVIDENCE
In this clinical scenario, the patient is a 24 year old male with CHB and decompensated liver disease. Unfortunately, CHB is incurable as the HBV template has been incorporated into the host genome. His condition can only be controlled with the aims to minimize further injury by inhibiting viral replication while avoiding the development of drug resistance, decrease the risk of developing HCC and obviate the need for liver transplant.
Approved therapy options for CHB include two classes of drugs: antiviral agents (nucleoside or nucleotide analogue) and immunomodulatory agents (interferon, IFN-α and peginterferon). Each has inherent limitations. Nevertheless, interferon-based therapies are contraindicated in patients with hepatic decompensation due to a high risk of infection. Evidence derived from two studies conducted on IFN-α in patients with decompensated cirrhosis (Child-Pugh class B or C) demonstrated minimal benefit but higher incidence of bacterial infection and exacerbation of hepatic disease even with reduced doses of IFN-α (3 MU every alternate day). Therefore, it is the antiviral agents that constitute the ongoing management plan of this patient.
Lamivudine, an analogue of cytosine pyrimidine base, has antiviral activity against both HIV and HBV (requires lower concentration) infections. Owing to the structure similarity with cytosine, it is incorporated into the elongating DNA chain as a false substrate, inhibiting the action of HBV DNA polymerase and prevents HBV DNA synthesis. In addition to viral suppression, it is also effective in normalizing ALT level and ameliorating liver function. The recommended dose is 100mg daily but dose modification in patients with renal impairment is necessary as it is excreted predominantly by the renal route. From the research, the elimination half life of lamivudine was found to be approximately 5 to 7 hours. Peak plasma concentration was achieved within 0.5 to 1.5 hours post-dose. Response to lamivudine largely depends on baseline ALT level, higher baseline level tends to have greater rate of seroconversion. The rate increases with duration of therapy and can reach up to 50% by the fifth year of therapy. The advantages of lamivudine-based therapy include its safety and efficacy profile with few serious adverse events observed over the past 10 years as well as high patient acceptability and tolerability. High oral bioavailability permits the convenience of lamivudine as an oral tablet. Furthermore, it can be used in immunocompromised and cirrhotic patients. The estimated annual cost of therapy is £1018, which is the lowest among all antiviral agents used in HBV treatment. However, serum HBV DNA returns to baseline upon cessation of therapy. High frequency of relapse due to the appearance of resistant mutants was found in up to 58% of patients. Resistance rate was reported to increase with each subsequent year of therapy (23% after 1 year and 31% after 2 years). The most common mutation is valine or isoleucine substitution of methionine in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV DNA polymerase causes the catalytic site to be altered and reduces the effectiveness of lamivudine. Treatment failure following extended therapy often results in reversion of histological benefits. Patients on lamivudine therapy should have regular monitoring for virologic breakthrough. If lamivudine-resistant HBV emerges during treatment, alternative drug therapy with activity against the resistant strains is required. In the context of drug interactions, trimethoprim may increase the plasma level of lamivudine by inhibiting its secretion by renal tubules. Signs of toxicity such as should be closely monitored. These reasons eventually limit the use of lamivudine as first-line drug for CHB long term therapy.
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A total of thirty-five HBV infected patients with decompensated cirrhosis were enrolled into a small trial. Liver function was assessed in terms of Child-Pugh score and serum bilirubin level. After 9 months of lamivudine treatment, the mean Child-Pugh score decreased from 10.3 to 7.5 associated with a reduction in serum bilirubin level from 67µmol/L to 30µmol/L (p<0.05).
Besides, in another double-blind, placebo-controlled trial in which 139 HBeAg-negative CHB patients were randomized to receive either lamivudine (100mg daily; n=93) or placebo (n=46) for 24 months. The primary measures of efficacy were reported as the normalization of ALT and the suppression of HBV DNA levels to below the limits of detection. The number of complete responders was significantly higher in lamivudine group than placebo (56% vs 11%; RR, 10.8; 95% CI, 3.8-30.2; p<0.001). The determined medians for log10 reduction in HBV DNA levels were 3.21 copies/mL and 0.47 copies/mL in lamivudine and placebo respectively (p<0.001). However, after the next 6 months of follow-up, the rate of complete response in lamivudine group was found to be comparable to those in placebo (26% vs 19%; p=0.38).
Other than that, adefovir dipivoxil is an oral prodrug of adefovir, an acyclic adenosine monophosphate nucleotide analogue yielded via intracellular phosphorylation catalyzed by cellular kinases. The drug inhibits DNA replication by acting as a fraudulent nucleotide. It is dosed at 10mg daily in adults with compensated or decompensated liver disease and patients with lamivudine-resistant CHB. Adefovir has a half life of approximately 7 hours. It is generally well-tolerated but adverse event such as nephrotoxocity and gastrointestinal disturbances had been reported. Therefore, patients with renal impairment should have their dosing interval adjusted (as the drug is renally excreted) and serum creatinine monitored routinely. No significant drug interactions recognized. The estimated cost of therapy per year is £3610. In fact, low incidence of resistance makes it a preferred choice for use in long term CHB treatment. Hadziyannis et al found adefovir-resistant mutations after 3 years of therapy in only 5.9% of 185 HBeAg-negative patients who included in a randomized controlled trial. In comparison, resistance to adefovir develops at a slower rate than lamivudine. This suggests its use as an alternative in cases of lamivudine resistance.
A 48-week open-label study involving 226 patients with decompensated cirrhosis and 241 patients with recurrent hepatitis B after liver transplant was conducted to investigate the efficacy of adefovir in viral suppression. The outcomes were reported as difference in HBV DNA from baseline to week 48, the percentage of patients who demonstrates normalization of ALT levels and who shows a shift in Child-Pugh score. Suppression of HBV DNA and ALT were seen in 81% of the decompensated cirrhotic and 34% of the recurrent attack after transplant (p<0.001) and 76% of the decompensated cirrhotic and 49% of the recurrent attack after transplant (p<0.001) respectively. It was also effective in improving hepatic function marked by a decrease in Child-Pugh score seen in 90% of the decompensated cirrhotic patients (p=0.0001).
The second open-label study (n=128) which measured the end point as the change in serum HBV DNA in terms of log10 reduction at 6 months and 12 months by PCR assay depicted that adefovir significantly reduced HBV DNA levels by 3 to 4 log10 cycle at 6 months (p<0.001).
Apart from that, entecavir, as a highly selective and potent guanosine nucleoside analogue shows its potential as an oral antiviral agent by inhibiting the priming and elongation steps of HBV DNA replication and thus lowering the serum HBV DNA levels. The normal dose indicated for HBeAg-positive or negative CHB patients with hepatic decompensation and lamivudine-refractory patients is 1mg daily. Study found that entecavir had a half life of approximately 24 hours and the peak plasma concentration was observed within 1 hour after dosing. As the other antiviral drugs, entecavir is mainly excreted in the urine, dose adjustment is required in renal impaired patients. In terms of safety, entecavir is comparable to lamivudine with no major side effects but few case reports of lactic acidosis. No potential drug interactions reported. The annual cost associated is estimated to be £4420. Entecavir resistance occurs less commonly in nucleoside naive patients but more likely in patients with existing lamivudine resistance. Lamivudine-resistant patients who switched to entecavir are at risk of experiencing hepatic flares although severe flares are rare.
In a phase II study, 82 HBeAg-positive patients taking entecavir were evaluated and a significant reduction in HBV DNA levels was reported (7.69 log10 copies/mL pre-treatment vs 3.99 log10 copies/mL post-treatment; p<0.05). 80% of patients showed a decline in ALT after 48 weeks of treatment. Additionally, the mean Knodell fibrosis score decreased from 6.06 to 1.44 indicated that necroinflammation or fibrotic changes were reduced (p<0.05).
To compare the efficacy of entecavir in lamivudine refractory patients, a phase III trial was conducted by Sherman et al involving 286 patients who do not respond to lamivudine treatment, 141 stopped lamivudine and switch to entecavir while the rest continued to receive lamivudine. 21% of entecavir-treated patients had undetectable HBV DNA level by PCR assay after 48 weeks of treatment compared to only 1% in those receiving lamivudine (p<0.001). Histological responses were significantly greater in entecavir group than lamivudine group (55% vs 28%; p<0.001). No significant difference in incidene of adverse events had been observed in entecavir group in comparison with placebo and lamivudine group.
Telbivudine, besides having a similar structure to lamivudine, is also a thymidine nucleoside analogue which works by acting as a competitive inhibitor of HBV reverse transcriptase and DNA polymerase. The usual daily dose is 600mg orally. Study found out that rapid absorption took place after oral administration and reached peak plasma concentration within 3 hours. The half-life reported was 15 hours. It is claimed to be well-tolerated without significant clinical adverse events. The estimated cost of therapy per year is £3785. Telbivudine monotherapy is comparable with lamivudine in safety with few cases of myopathy and elevated level of creatinine kinase. Concomitant use of telbivudine and interferon-α is associated with peripheral neuropathy.
Compared with lamivudine, a phase III trial of 290 patients found out that telbivudine has a higher potency in suppressing viral replication with a greater median log reduction of HBV DNA and more patients showing undetectable viral loads by PCR assay (67% vs 38%; p<0.001), ALT normalization (87% vs 75%; p=0.007) as well as HBeAg serconversion (31% vs 20%; p=0.047). Although individuals receiving telbivudine did demonstrate a lower viral resistance compared to lamivudine-treated individuals, the difference was not statistically significant. No evidence showed that patients taking telbivudine were more likely to suffer an adverse event than those on lamivudine, suggesting its safe profile.
Another open-label multicentre study of 135 HBeAg-positive individuals comparing the efficacy of adefovir and telbivudine, 38.6% in telbivudine group showed a drop in viral load to below a detectable level at week 24 compared to 12.4% in adefovir group (p<0.01). During the follow-up period, telbivudine resulted in significantly higher rate of HBV DNA reduction (-6.3 vs -4.97 log10 copies reduction/mL; p<0.01). No significant differences in terms of ALT normalization, seroconversion rate and clinical adverse events were noted.
There is no explicit evidence reflecting that telbivudine is superior to entecavir as the mean reduction in serum HBV DNA, suppression of ALT levels and HBeAg seroconversion rate in telbivudine-treated patients were found to be comparable to entecavir-treated patients.
Tenofovir disoproxil fumarate is an oral prodrug that undergoes hydrolysis and phosphorylation to give the active component, tenofovir diphosphate which targets HBV DNA polymerase and thus inhibiting viral replication. It was first approved for use in HIV treatment and licensed for HBV infection in 2008. Tenofovir is structurally related to adefovir but without the nephrotoxicity seen with adefovir, therefore permitting a higher dose of 245mg to be used. It exhibits a long half life of 17 hours allowing once daily administration. No significant drug interactions reported. Tenofovir treatment costs approximately £3103 per year. At present, there are limited data on tenofovir resistance. Findings noted that tenofovir can overcome treatment failure by adefovir but adefovir mutants can still persist, implicating cross resistance.
In two comparative, double-blind phase III studies, one involved HBeAg-positive and the other involved HBeAg-negative patients. The subjects were randomly allocated in tenofovir or adefovir group. The primary endpoint was determined as suppression of serum HBV DNA to below the limit of detection and histological improvement in terms of Knodell necroinflammation score (decrease by ≥2 points considered favorable) within 48 weeks after the initiation of treatment. At week 48, the proportion of HBeAg-negative patients who achieved primary endpoint were 93% for patients receiving tenofovir and 63% for those who received adefovir (p<0.001). Similar results were seen in HBeAg-positive patients (76% vs 13%; p<0.001). Moreover, among HBeAg-positive patients, significantly more tenofovir-treated patients had ALT normalization (68% vs 54%; p=0.03) and loss of HBsAg (3% vs 0%; p=0.02) than the adefovir-treated group. In addition, earlier and greater extent of HBV DNA suppression was found in tenofovir compared to adefovir, suggesting the effectiveness of tenofovir in lamivudine-resistant CHB.
A study with follow up period of 12 months was undertaken in 2012. 72.3% of patients assigned to tenofovir and 69% patients assigned to entecavir had their HBV DNA remains suppressed to undetectable level. However, p-value of 0.75 indicated that the difference did not reach statistical significance. This finding corresponds to the observation by King's College cohort which documented no significant difference in the proportion of patients with sustained suppression of HBV DNA over 12 months in patients taking entecavir compared with tenofovir (76% vs 80%; p>0.05).
The combination of adefovir and lamivudine was proposed to be greatly superior to the corresponding monotherapy as it lowered the resistance rate and produced better responses in lamivudine-refractory patients. A randomized trial of 60 lamivudine-resistant HBeAg-negative CHB patients investigated the combination of adefovir and lamivudine compared with adefovir monotherapy. The outcomes were illustrated as the number of patients with serum HBV DNA less than 400 copies/mL and normalization of ALT levels. After a median follow-up duration of 53 months, 84.4% of patients with combination therapy and 73.3% of patients with monotherapy achieved targeted virologic response. However, this did not reach statistical significance (p=0.56). Improvement in ALT normalization seemed to be more pronounced in the combination rather than the monotherapy (90.9% vs 57.1%; p=0.01).
Long term therapy is required in this patient to maintain virologic suppression, thus high genetic barrier to resistance forms one of the specifications of the treatment regimen. Tenofovir appears to be a cost-effective option. It showed superior efficacy, sustained virological suppression with minimal resistance, comparable safety with minor side effect and affordable cost. Therefore, on the basis of the advantages, disadvantages and evidence presented, the recommended regimen for this 24 year old male patient with CHB infection and decompensated liver disease is tenofovir monotherapy (245mg once daily). Monitor the response to therapy and liver function at three months interval. The patient should be encouraged to avoid alcohol and counseled on the way to prevent disease transmission. Referral for liver transplantation is required in the case of treatment failure.