- Top of page
- Summary of European guidelines
Interferon alpha has restricted efficacy in as much as only a proportion of patients show a response. However, in appropriately selected HBeAg-positive and HBeAg-negative patients, sustained suppression of viral replication can be achieved, and HBeAg or even HBsAg seroconversion can be attained. Thus, finite course of interferon alpha can be successful, and offer an advantage to patient. Interferon (IFN) remains a benchmark therapy for chronic hepatitis B. The main advantages of IFN-α over nucleoside analogues are the absence of resistance and the possibility of immune-mediated clearance of hepatitis B. Unfortunately, side effects preclude the use of interferon alpha in substantial proportions of patients, and prolonged maintenance therapy to suppress hepatitis B virus (HBV) is not feasible. Nucleoside analogues are given by mouth, once per day, and the safety, potency and efficacy have improved and facilitated treatment. However, maintenance of long-term suppression is required for the majority of patients. In general, treatment of chronic hepatitis B should target patients with active disease and viral replication, preferably before the signs and symptoms of cirrhosis or significant injury has occurred. Current EASL guidelines suggest that treatment be based on the evaluation of three criteria: Serum aminotransferase levels, serum HBV DNA levels and histological grade and stage. Many questions remain unanswered on the optimal treatment of patients with chronic hepatitis B with a nucleoside vs interferon alpha. Both forms of treatment have benefits and the choice should be selected and tailored. Stopping or futility rules can be implemented in patients who fail interferon. Recent data suggest the safety and efficacy of nucleoside analogues in the third trimester of pregnancy to reduce the risk of transmission from mothers to their children.
Hepatitis B is an important disease worldwide. Over one-third of the world's population has been infected with hepatitis B virus (HBV). Low (less than 2% of the population seropositive for HBsAg), intermediate (2–8%) and high prevalence (more than 8%) areas are recognised.
Chronic infection is a cause of considerable morbidity. The disease can be prevented by vaccination. Morbidity is linked to the ongoing HBV replication. Thus, treatment of existing carriers forms an important part of the control of the disease. Over the past three decades, first with interferon alpha, and more recently with the advent of nucleoside analogues, progressively more patients have received treatment. Interferon alpha has restricted efficacy in as much as only a proportion of patients who show a response. However, in appropriately selected HBeAg-positive and HBeAg-negative patients, sustained suppression of viral replication can be achieved, and HBeAg or even HBsAg seroconversion can be attained. Thus, finite course of interferon alpha can be successful, and offer an advantage to patient. Unfortunately, side effects preclude the use of interferon alpha in substantial proportions of patients, and prolonged maintenance therapy to suppress HBV is not feasible.
Nucleoside analogues are given by mouth, once per day, and the safety, potency and efficacy have improved and facilitated treatment. However, maintenance of long-term suppression is required for the majority of patients.
The aim of this article was to review clinical aspects of the management of chronic hepatitis B with either interferon or nucleoside analogues pointing out the indications and role of both classes of compounds.
Perinatal or infant transmission and chronic hepatitis B
In the absence of vaccinations, viraemic mothers, especially those who are seropositive for the HBeAg, almost invariably transmit the infection to their infants. The mechanism of perinatal infection is uncertain, but it occurs probably during or shortly after birth as a result of a leak of maternal blood into the baby's circulation, ingestion or inadvertent inoculation. Such perinatal infections have led to high rates of chronicity, estimated at around 90%, and individuals infected at an early age exhibit a high degree of immune tolerance and may remain viraemic for decades. Perinatal transmission is an extremely important factor in maintaining the reservoir of infection in high prevalence regions.
Chronic hepatitis B is defined as persistent HBsAg in the circulation for more than 6 months. The ‘carrier state’ may persist for life and may be associated with liver damage varying from mild chronic hepatitis to severe, active hepatitis, cirrhosis and primary liver cancer. Several risk factors have been identified in relation to the development of chronic disease. It is more frequent in men, more likely to follow infections acquired in childhood than those acquired in adult life, and more likely to occur in patients with natural or acquired immune deficiencies. In countries where hepatitis B infection is common, the highest prevalence of HBsAg is found in young children, with steadily declining rates among older age groups. HBeAg has been reported to be more common in young than in adult carriers of hepatitis B, whereas the prevalence of anti-HBe seems to increase with age. HBeAg is found in soluble form in virus-positive sera and is related to the core antigen. The HBV genome is DNA and comprised of two strands held in a circular configuration by base-pairing at the 5′ ends (cohesive end region). There is some variation in sequence (up to 12% of nucleotides) between isolates and up to eight genotypes (A–H) have been described on the basis of >8% nucleotide sequence divergence.
Chronic hepatitis B may be divided into several phases. In the first ‘immune tolerance phase’, high levels of viral replication occur and the patient is seropositive for markers of the virion and for HBeAg but lacks biochemical or histological evidence of hepatitis. During the immune clearance phase, viraemia and HBeAg continue but with increasing inflammatory necrosis of hepatocytes, which may lead to clearance of HBeAg and the development of anti-HBe. In the immune control phase, patients are anti-HBe positive with low levels of HBV replication and little inflammatory activity. However, viraemia and hepatitis may occur in the absence of HBeAg, in patients with the circulating HBe-negative virus (precore or core promoter mutants). HBeAg-negative chronic hepatitis has a variable course, often with fluctuating serum aminotransferases and serum HBV DNA levels. HBeAg may also become detectable transiently in these patients during acute flares. Precore variants may be selected by the targeting of an immune response to hepatocytes expressing HBeAg. Direct tests for the virus, in particular detection of viral DNA are more reliable for establishing infectivity.
This replicative phase may persist for years, and may even be lifelong in individuals who were infected perinatally and whose immune systems are tolerant of the virus. Integration of virus DNA into the hepatocyte chromosomes probably occurs throughout virus replication and expansion of the clones of these cells may be a stage in the progression to neoplasia.
Many carriers are detected through routine screening for hepatitis B surface antigen (HBsAg) or the presence of abnormal liver function tests. Older patients may present for the first time with complications of cirrhosis, or even HCC.
The HBV genotypes have been reported to correlate with spontaneous and interferon-induced HBeAg seroconversion, activity of liver disease and progression to cirrhosis and HCC, but further study is required. In China and Japan, where genotypes B and C circulate, there is evidence of increased pathogenicity and likelihood of developing HCC in genotype C compared with B .
In HBeAg-positive patients, progression to cirrhosis occurs at an annual rate of 2–5.5%, with a cumulative 5-year incidence of progression of 8–20%. Progression to cirrhosis is generally faster in HBeAg-negative patients, at an annual rate of 8–20%. Patients who are more likely to progress are characterised by recurrent exacerbation and bridging fibrosis with severe necroinflammatory changes. Recent retrospective studies have examined survival in compensated cirrhosis from hepatitis B. The reported yearly incidence of hepatic decompensation is about 3%, with a 5-year cumulative incidence of 16%. In a European multicentre longitudinal study to assess the survival of 366 cases of HBsAg-positive compensated cirrhosis, death occurred in 23% of patients, mainly because of liver failure or HCC. The cumulative probability of survival in this cohort was 84 and 68% at 5 and 10 years respectively. The worst survival was in HBeAg and HBV DNA–positive subjects . Chinese patients who remained HBeAg positive were more likely to develop HCC.
In general, treatment of chronic hepatitis B should target patients with active disease and viral replication, preferably before the signs and symptoms of cirrhosis or significant injury have occurred . Eradication of infection is only possible in a minority of patients and the optimal treatment for hepatitis B is still being defined. Recombinant interferon alpha, pegylated interferon (PEG-IFN) alpha and a number of new nucleoside and nucleotides have been licensed. The choice of therapy depends on a number of factors predictive of treatment response, clinical circumstances and stage of disease, the potency of different agents and the likelihood and consequences of resistance to treatment. Current guidelines are not always constant or consensual and must be rapidly updated as new therapies become available (4–6).
A single measurement of ALT (and HBV DNA) is not useful in a disease as dynamic as hepatitis B, and there is no agreement on the level below which HBV DNA concentrations indicate ‘inactive’ disease, or a threshold for initiating treatment.
Summary of European guidelines
- Top of page
- Summary of European guidelines
The European Association for the Study of the Liver (EASL) guidelines have been published and updated to guide therapy [7, 8]. In these guidelines, the indications for treatment are generally the same for both HBeAg-positive and HBeAg-negative CHB. Treatment is based on the evaluation of three criteria: Serum aminotransferase levels, serum HBV DNA levels and histological grade and stage. Thus, these guidelines suggest that patients should be considered for treatment when serum ALT levels are above the upper limit of normal (ULN) for the laboratory and/or HBV DNA levels are above 2000 IU/ml (i.e. approximately 10 000 copies/ml), and liver biopsy (or possibly a non-invasive method) shows moderate to severe active necroinflammation and/or at least moderate fibrosis. Hepatitis B virus DNA detection and HBV DNA levels are essential for the diagnosis and decision to treat, and subsequent monitoring.
Patients with mild disease and normal ALT may not require immediate treatment and should be carefully monitored at appropriate intervals. Most clinicians feel that therapy should only be considered if there is evidence of moderate to severe activity, as well as disease progression.
These guidelines imply that the trend in the disease pattern must be documented. In HBeAg positive patients under 30 years of age with persistently normal ALT levels and high HBV DNA levels, without evidence of liver disease, immediate biopsy or therapy is not required. HBeAg-positive and -negative patients require careful longitudinal monitoring to determine the pattern of disease. Besides the staging of fibrosis, there are several established methods of scoring histology and measuring activity (necroinflammation). However, there are several limitations to biopsies including sampling errors, subjectivity and reproducibility and of course cost, risks and discomfort to the patient. Non-invasive methods of assessing fibrosis including serum markers and transient elastography may prove helpful.
Response rates with either PEG interferon or nucleosides are known. A full discussion of the guidelines is beyond the scope of this article.
Most clinicians feel that therapy should only be considered if there is evidence of moderate to severe activity. HBeAg-positive patients should be followed for a few months to determine their status, and antiviral therapy should be considered if there is active HBV replication (HBV DNA greater than 2000 IU/ml) and elevated ALT after observation, with a biopsy showing active hepatitis, i.e. inflammation, necrosis or accumulating fibrosis. HBeAg-positive patients with greater disease activity may have a better chance of seroconverting to anti-HBe within 1 year of treatment.
The HBeAg negative patients should be considered for antiviral therapy when serum ALT are increased, and there is active viral replication (HBV DNA above 2000 IU/ml) and active hepatitis, i.e. inflammation, necrosis or accumulating fibrosis. The threshold for treatment is the subject of debate. No definite consensus criteria have been established for initiating treatment in this group. Anti-HBe-positive patients with persistently normal ALT and low levels of DNA (<2000 IU/ml) should be monitored. Indeed, both HBeAg-positive and -negative patients require careful and regular monitoring to identify any change in the disease pattern.
Many clinicians feel that a liver biopsy is helpful in determining the degree of necroinflammation and fibrosis in HBeAg-positive and -negative disease. Many centres would propose a biopsy to assess the stage and grade of inflammation, because liver morphology can help determine the decision to treat. There are several methods of scoring histology and measuring activity (necroinflammation) separate from stage (fibrosis). However, there are several limitations to biopsy, including sampling errors, subjectivity and reproducibility, and of course cost, risks and discomfort to the patient. The progression of disease often includes episodes of activity that injure the liver. There is growing interest in the use of non-invasive methods including serum markers and transient elastography to assess liver fibrosis. Transient elastography offers high diagnostic accuracy for the detection of cirrhosis.
The major goals of hepatitis B therapy are to prevent disease progression to cirrhosis, end-stage liver disease or HCC. If HBV replication can be suppressed, the accompanying reduction in histological chronic active hepatitis reduces the risk of cirrhosis and HCC. Patients may request treatment to reduce infectivity. Extra-hepatic manifestations of hepatitis B such as glomerulonephritis or polyarteritis nodosa require treatment. The immediate objectives depend upon the stage of disease, but cirrhosis can be prevented, or decompensated cirrhosis can be prevented in patients with established cirrhosis.
The end points of treatment are not clearly defined, and differ for HBeAg-positive and negative disease. However, improvement is a reasonable outcome if HBV replication is suppressed with accompanying improvement in serum ALT and hepatic necroinflammatory disease. The accompanying reduction in histological chronic active hepatitis reduces the risk of cirrhosis and HCC (Niederau et al., 1996).
Treatment of cirrhosis
Immediate, prolonged and profound suppression of viraemia is beneficial and reduces the risk of progression to decompensated liver disease, and possibly HCC. Clinical studies indicate that prolonged and adequate suppression of viraemia may stabilise patients and delay or even prevent the need for transplantation. Recent longer term studies have suggested the clinical utility of HBV DNA suppression: Kaplan–Meier estimates of disease progression after 3 years treatment in patients with cirrhosis are reduced from 5% in treated vs 21% in placebo recipients. However, the development of resistance to nucleosides significantly limits the clinical benefit in treated patients. HCC remains a persistent risk, although it is reduced. Hepatic decompensation or lactic acidosis may occur with exacerbations of disease after nucleoside analogues have been begun, and these patients should be monitored carefully.
Treatment of patients with compensated cirrhosis is possible with IFN. However, IFN alpha in contraindicated in patients with decompensated or decompensating cirrhosis. Prophylactic therapy with a nucleoside is recommended in all patients undergoing liver transplantation for end-stage hepatitis B, to reduce levels of HBV DNA to at least less than 105 copies/ml before transplantation. End-stage liver disease should be considered an emergency. Patients may have slow clinical improvement over a period of 3–6 months. However, some patients with advanced liver disease, a high Child-Pugh score and jaundice will not benefit from this treatment. All these patients require long-term therapy, with careful monitoring for resistance and flares. Regression of fibrosis has been reported. There is less data on the efficacy and safety of newer potent agents such as entecavir, telbivudine and tenofovir in this group, but these could be used.
Recurrent HBV infection in the transplanted liver was previously a major problem. Nucleoside analogues for pre-transplant prophylaxis, in combination with hepatitis B immunoglobulin (HBIG) greatly reduces the risk of graft reinfection as long as the HBV virus is suppressed before transplantation. With the advent of entecavir and tenofovir, outcomes have improved further.
Interferon (IFN) remains a benchmark therapy for chronic hepatitis B. Alpha interferons are naturally occurring intercellular signalling proteins to induce an antiviral state in cells, inhibit cellular proliferation and immunomodulation. The IFNs have been classified into two types, based on receptor specificity. Type 1 IFNs (viral IFNs) include IFN alpha (leucocyte) IFN beta (fibroblast) and IFN omega. Type II IFN is also known as immune IFN, i.e. IFN gamma. The cellular activities of IFN alpha are mediated by the products of the IFN inducible genes. The natural IFN alpha-producing cell is the precursor dendritic cell . IFN gamma is produced by cells of the immune system including natural killer cells, CD4 TH1 cells and CD8 T cells following antigen-specific stimulation, and acts via a separate cell receptor. IFN gamma is critical for innate and adaptive immunity.
The main advantages of IFN-α over nucleoside analogues are the absence of resistance and the possibility of immune-mediated clearance of hepatitis B. A meta-analysis of 15 randomised controlled trials in HBeAg-positive patients showed 33% HBeAg seroconversion after 16 weeks of IFN-α treatment compared to 12% in untreated control patients. The incidence of HBsAg loss was 7.8 and 1.8% respectively. Pre-treatment factors predictive of response to IFN-α are low viral load, high serum ALT levels, increased activity scores on liver biopsy, and shorter duration of infection. The HBeAg seroconversion rate correlates with baseline ALT levels and reaches 30–40% for baseline ALT greater than five times the upper limit of normal (ULN). An increase of ALT levels during the second or third month of therapy may occur.
Polyethylene glycol-linked interferons (PEG IFN)
The knowledge that IFN exerts an important endogenous antiviral effect led to their use in patients with chronic viral hepatitis. Recombinant IFN alphas have since been approved for clinical use worldwide. However, the efficacy of interferon alpha therapy is restricted by protein characteristics including poor stability, a short half-life and immunogenicity. The half-life varies from 4 to 16 h with peak concentrations 3–8 h following i.m. or s.c. injection. By 24 h, little IFN alpha remains in the circulation. Thus, frequent dosing is required to achieve effective therapeutic concentrations in plasma. Large fluctuations in serum concentrations occur resulting in peaks and troughs of drug concentration. Polyethylene glycol is an inert non-toxic polymer which can be used to modify the pharmacological properties of biologically active proteins without completely inactivating their intrinsic biological activity. Recent technology has enabled activation of the polyethylene glycol moiety through substitution of the hydroxyl group by an electrophilic functional group. The reactive functional group of activated PEG can be attached to a specific site e.g. amine, sulphydryl group or other nucleophile on the protein. Until recently, mono functional PEG derivatives used for protein pegylation were linear with molecular weights of 12 kD. New advances in pegylation technology have resulted in the development of branched PEGS of high molecular weights [up to 60 000 kD]. The PEG polymer increases the half-life of the conjugated protein, protecting the protein from proteolysis and reducing renal clearance. This enables once a week dosing.
Reduced clearance of PEG-IFN results in increased circulation time and sustained systemic exposure of the pegylated compound. When the biological activity of a pegylated protein is measured in vivo, a direct relationship between the mass of the PEG conjugate and its biological activity frequently is observed, with increasing mass associated with increased activity.
Relative or absolute contraindications to interferon alpha therapy include severe depression, Childs B/C cirrhosis, cirrhosis and hypersplenism, autoimmune hepatitis, hyperthyroidism, coronary artery disease, renal transplant, pregnancy, seizures, concomitant drugs, including several herbal remedies, diabetes/hypertension and retinopathy, thrombocytopenia, leucopenia, anaemia, high titres of autoantibodies and hyperthyroidism. The side effects of alpha interferon are relatively common, but are acceptable in most patients. Toxicity can be predicted in patients with low baseline white cell counts or thrombocytopenia, or pre-existing thyroid disease . The risk of serious complications from alpha interferon is rare. However, serious idiosyncratic complications such as immune disorders, pneumonitis, retinal disease, renal disease or deafness can occur and the drug always must be prescribed with caution. Close monitoring is required throughout therapy. Monitoring requires regular clinical examinations, vital signs, urinalysis and usually monthly measurement of serum chemistries, complete blood counts, and thyroid function tests including thyroid stimulating hormone. A serum pregnancy test should be done to exclude pregnancy before starting treatment.
A study in HBeAg-positive patients compared treatment with PEG-IFN α–2a for 48 weeks, PEG-IFN alpha2a and lamivudine in combination and lamivudine monotherapy. At the end of 24 weeks follow up, HBeAg seroconversion rates were 32, 27 and 19% respectively. The ALT normalisation occurred in 41, 39 and 28% of the same groups. HBeAg levels above 100 IU/ml at weeks 12 and 24 were highly predictive of failure to achieve seroconversion. Conversely, low HBeAg levels at baseline, week 12, and week 24 were correlated to improved rates of seroconversion.
The PEG-IFN α–2b has also been shown to be active in HBeAg-positive patients, with similar seroconversion rates. There may be a genotype effect and of other baseline factors in the response to PEG-IFN α–2a by HBeAg-positive chronic hepatitis B patients: genotype A and B patients tend to respond better than those with genotypes C and D.
In a similar study in HBeAg-negative patients, after 48 weeks follow up, HBV DNA >400 copies/ml) was maintained in 17% of an observational subset of PEG-IFN α–2a -treated patients followed for 3 years post-treatment. Baseline ALT and HBV DNA levels, patient age, gender and infecting HBV genotype significantly influenced response at 24 weeks post-treatment (Bonino et al., 2007). The HBsAg loss occurred in 8% of the long-term cohort after 3 years.
Frequent side effects and the necessity of monitoring patients closely are the main disadvantage of PEGIFN treatment. There is no role for alpha IFN in the treatment of acute or fulminant hepatitis B. The role of IFN in patients with decompensated hepatitis B is more problematic, because of their effect on platelets and neutrophils, and the pro-inflammatory effects. Interferon should be used with caution and regular monitoring in patients with compensated cirrhosis, since there is a risk of hepatic decompensation with prolonged treatment. Moreover, the occurrence of serious bacterial infections has been reported in this group of patients.
Licensed NUCs for the treatment of chronic hepatitis B
Nucleoside analogues have similar structures to the natural nucleotides and compete at the HBV polymerase catalytic site during synthesis of viral DNA. They lack a hydroxyl group, preventing the formation of a covalent bond with the adjoining nucleotide, causing chain termination of the elongation of DNA. Although all nucleotide analogues act on HBV polymerase, their mechanism differs; thus adefovir inhibits the priming of reverse transcription, lamivudine and emtricitabine inhibit the synthesis of the viral (−) strand DNA . Entecavir inhibits three major stages of HBV replication ([12-15].) Nucleic acids in general are less effective against cccDNA formation after viral entry in the hepatocyte, and thus residual viraemia persists during antiviral treatment [16-18].
The patterns of response observed with nucleosides are broadly similar, although these agents have different structures, and inhibit different phases of hepatitis B replication including priming of reverse transcription, elongation of minus-strand DNA, DNA-dependent DNA polymerase activity and plus-strand synthesis. Nucleosides and nucleotides have variable mechanisms of action and their pharmacokinetics, inhibitory capacity, onset of action, resistance patterns and rates of HBeAg seroconversion vary during the first year of treatment. The current array of nucleosides includes the licensed therapies (lamivudine, adefovir, entecavir, telbivudine, tenofovir, emtricitabine (licensed for HIV).
Lamivudine (2′,3′-dideoxy-3′thiacytidine or 3TC) is a cytidine analogue. Lamivudine competes for cytosine in the synthesis of viral DNA. It is a (−) enantiomer and a phosphorylation step is required for the transformation to active drug. The drug has a strong track and safety record, and reliably reduces HBV DNA concentrations in serum by 2–4 log10. Elevated serum ALT levels have also been shown to predict a higher likelihood of HBeAg loss in patients with chronic hepatitis B treated with lamivudine. Lamivudine is a relatively inexpensive drug, and the lack of side effects in patients with advanced disease is attractive. As a result, lamivudine has become a widely used first line drug for the treatment of HBeAg and anti-HBe-positive disease. The major disadvantage of lamivudine treatment is the high rate of resistance observed in both HBeAg and anti-HBe-positive patients.
The addition of lamivudine to PEG-IFN α2a has not improved seroconversion rates compared with PEG-IFN α2a alone. However, in HBeAg-positive patients, a–7.2 log additive suppression of HBV DNA at the end of 48 weeks in patients with lamivudine plus PEG-IFN α2a was found, compared to a – 4.5 log suppression of HBV DNA in patients treated with PEG-IFN α2a. Resistance to lamivudine was reduced.
The HBV DNA became ‘undetectable’ with a non-standardised assay in HBeAg-negative patients after 1 year of treatment with lamivudine in 70% of patients, serum ALT normalised in 75% and histological improvement was noted in 60% . However, most patients relapsed after treatment cessation.
Long-term lamivudine therapy can prevent the complications of HBV-related liver disease as long as viral suppression is maintained . Thus, the progression of liver disease can be prevented with a prolonged viral response but this response is reduced in those with a virological breakthrough i.e. resistance. There has been extensive experience with lamivudine in the prevention of hepatitis B exacerbations associated with chemotherapy. Lamivudine is effective in preventing reactivation although the latter event can be unpredictable. The argument for ‘deferred’ or ‘pre-emptive therapy’ probably favours early treatment and prolonged therapy.
Resistance to lamivudine
Lamivudine-resistance is conferred through acquired selection of HBV with mutations of the YMDD motif of the HBV DNA polymerase gene . The rates of resistance to lamivudine are higher with HIV-HBV co-infection  and develop more rapidly in patients with HBV genotype A compared with genotype D during the first year of infection . Variants emerging during lamivudine therapy display mutations in the viral polymerase, within the catalytic domain (C domain), which includes the YMDD motif, (e.g. M204V or M204I), and within the B domain (e.g. L180M or V173L). These mutants have a reduced replicative capacity compared with the wild-type virus. The most common mutation is the substitution of methionine to isoleucine or valine (rtM204V/I) at the highly conserved YMDD motif of the reverse transcriptase. Four major patterns have been observed: L18OM + M204V; M204I; L180M + M204I; V173L + L180M + M204V; and occasionally L180M + M204V/I. L18OM + M204V occurs most frequently. Although viral ‘fitness’ may be reduced, as lower levels of HBV DNA occur, recent studies have suggested that the disease can progress . The incidence of lamivudine resistance is 15–20% per year, with 70% of patients becoming resistant after 5 years of treatment.
The value of lamivudine monotherapy is under question because of the likelihood of subsequent resistance to a lineage of drugs including entecavir, telbivudine and possibly adefovir. Telbivudine shares cross-resistance with lamivudine (25, 26). Emtricitabine shares cross-resistance with lamivudine, with mutations emerging at the C, B and B domains respectively.
Adefovir dipivoxil is an orally bioavailable prodrug of adefovir, a phosphonate acyclic nucleotide analogue of adenosine monophosphate  adefovir diphosphate acts by selectively inhibiting the reverse transcriptase-DNA polymerase of HBV by direct binding in competition with the endogenous substrate deoxyadenosine triphosphate (dATP) . Adefovir lacks a 3′ hydroxyl group and, after incorporation into the nascent viral DNA, results in premature termination of viral DNA synthesis. Unlike other nucleoside analogues such as lamivudine, adefovir is monophosphorylated and is not dependent on initial phosphorylation by viral nucleoside kinases to exert its antiviral effect. Clearance of adefovir is by renal excretion. Adefovir pharmacokinetics are substantially altered in subjects with moderate and severe renal impairment (creatinine clearance < 50 ml/min) [29, 30].
Nephrotoxicity is the major side effect of higher doses of adefovir. Adefovir causes a proximal convoluted tubule lesion characterised biochemically by an increase in urea and creatinine. However, in the two largest hepatitis B phase three trials involving 695 patients, no renal toxicity was found at the 10 mg dose.
Adefovir in HBeAg positive disease
The efficacy of adefovir has been assessed in patients with HBeAg-positive and negative disease and other settings of chronic hepatitis B infection. Adefovir 10 mg daily resulted in significant improvement compared with placebo: improvement in liver histology (53% vs 25%), reduction in HBV DNA (3.52 vs 0.55 log copies/ml), normalisation of ALT (48% vs 16%), and HBeAg seroconversion (12% vs 6%). There were no significant side effects and no resistance was found. As a result, adefovir 10 mg daily is the recommended and approved dose. A dose effect of 10 mg vs 30 mg in the pivotal phase III trial was apparent. 10 mg resulted in a 3.5 log suppression of HBV DNA vs a 4.5 log suppression with 30 mg at 48 weeks. The 10 mg dose was chosen because of the more favourable risk benefit ratio, but this dose is not optimal for certain patients.
A certain proportion of patients, in particular HBeAg-positive patients with a higher body mass index (BMI) and high viral load have slower and poor primary responses. In one analysis 25% of patients had less than 2.2 log10 reduction; the third quartile had a 2.2–3.5 log10 reduction. These effects may be seen in routine clinical practice where poor compliance and a higher BMI may affect susceptibility to adefovir resulting in poor primary responses.
Adefovir in HBeAg negative chronic hepatitis B
These patients require long-term treatment to suppress viraemia. In the pivotal anti-HBe positive adefovir study  185 patients were randomised to placebo or adefovir 10 mg daily for 48 weeks. At 48 weeks the adefovir-treated group significantly improved compared with placebo: improvement in liver histology (64% vs 33%) reduction in HBV DNA (3.91 vs 1.35 log copies/ml), undetectable HBV DNA (<400 copies/ml) in 51% vs 0%), normalisation of ALT (72% vs 29%). No significant side effects were reported compared with placebo and no genotypic resistance was found. Thus, adefovir is an agent that has low rates of resistance and good long-term viral suppression, which is especially beneficially in HBeAg-negative HBV infection. Preliminary data suggests that it may be possible to stop adefovir in patients with prolonged continuous suppression, although an HBV DNA flare may occur .
There are a number of structural differences between lamivudine and adefovir that predict lower rates of resistance with adefovir . Firstly, adefovir diphosphate more closely resembles its natural substrate deoxyadenosine triphosphate (dATP) than lamivudine, which contains an L-sugar ring . In contrast to lamivudine, adefovir diphosphate has a minimal acyclic linker in place of the L-sugar ring that closely matches the D-sugar ring of dATP. This similarity between adefovir diphosphate and dATP means that a mutation in HBV DNA polymerase not binding adefovir diphosphate would also impair dATP binding. It also results in more flexibility, allowing adefovir to bind lamivudine-resistant HBV DNA polymerase without steric hindrance (12, 13). Secondly, because adefovir is monophosphorylated, it requires only two phosphorylation steps compared to three for lamivudine. Nevertheless, the development of resistant mutations has been reported with adefovir monotherapy in both HBeAg-positive and HBeAg-negative patients. Sequencing of the RT domain of the HBV polymerase has suggested that mutations and rtA181V/T (the B domain) rtN236T in the D domain confer resistance to adefovir . The reported mutations correlate with HBV DNA rebounds of > 1 log above nadir, suggesting phenotypic resistance.
These studies have been based on careful genotypic analysis of the entire reverse transcriptase region of the HBV genome [36-38]. Life-table analysis has suggested a cumulative incidence of 3.9–5.9% (in naïve patients) after 3 years of treatment. A figure of 18% at 4 years of therapy has been reported. However, in clinical practice, higher rates than this are being reported . Patients with prior lamivudine resistance are at greater risk of adefovir resistance . Adefovir mutants remain sensitive to lamivudine, emtricitabine, telbivudine and entecavir [37, 38]. The A181V mutation has a greater effect on subsequent sensitivity to lamivudine than N236T; this compares with observed in vitro effects on fold sensitivity.
Adefovir has been an important drug for the treatment of lamivudine-resistant HBV infection. Its use has largely been replaced by tenofovir.
Entecavir, also known as BMS-200475, is a cyclopentyl guanosine analogue. Early studies in animals and humans indicate that entecavir is a potent inhibitor of viral replication. Recently, activity against HIV has been suggested [41-44]. Trials in woodchucks – an animal model of chronic hepatitis B infection – indicated that cccDNA was undetectable in liver samples several months post-treatment. Entecavir has been licensed for the treatment of chronic hepatitis B.
Entecavir inhibits all three activities of the HBV polymerase/reverse transcriptase: base priming, reverse transcription of the negative strand from the pregenomic messenger RNA and synthesis of the positive strand of HBV DNA. Phase III trails have been completed.
Phase II trials confirm the efficacy of entecavir . A randomised study of entecavir 0.5 mg daily vs lamivudine 100 mg daily for 52 weeks in 715 naive patients showed that histological improvement was observed in 72% of entecavir and 62% of lamivudine-treated patients. HBV DNA was suppressed to < 300 copies/ml in 67 and 36% of entecavir and lamivudine-treated patients . The mean change from baseline was –6.9 log and – 5.4 log respectively. HBeAg seroconversion occurred in 21 and 18% of entecavir and lamivudine-treated patients.
A recently completed phase III trial of 638 patients treated with 0.5 mg daily entecavir or lamivudine 100 mg for 52 weeks showed that histological improvement was achieved in 70 and 61% of entecavir and lamivudine-treated patients. HBV DNA suppression to less than 300 copies/ml occurred on treatment in 90% of entecavir and 72% of lamivudine-treated patients. The mean change from baseline of HBV DNA was −5.0 log and −4.5 log. ALT normalised in 78 and 71% respectively. Rebound to PCR detectable levels occurs in most patients after cessation of treatment .
A complex picture of entecavir resistance is emerging suggesting that new reverse transcriptase changes may be necessary in combination with those conferring lamivudine resistance to reduce susceptibility to entecavir. Entecavir resistance requires M204V/I + L180M mutations + T 184, s202 or M250 mutations . After 4 years of follow up, a cumulative resistance rate of approximately 1.2% of a subset of naïve-treated and monitored patients has been reported. At 5 years, resistance rates remain low in virological responders on continued treatment. Entecavir thus confers a high genetic barrier to resistance. The rate of resistance in virological non-responders was not evaluated in this registration trial protocol.
Entecavir in lamivudine-resistant patients
Entecavir shows partial efficacy against lamivudine-resistant HBV, and higher doses of entecavir (1.0 mg) are required. Virological rebound and resistance has been reported in 43% of lamivudine-resistant patients after 4 years of switching to entecavir. Lower rates of HBV suppression were reported in this group with 1.0 mg of entecavir. In a phase III trial, 286 lamivudine-resistant patients were treated with 1.0 mg entecavir daily for 48 weeks. HBV DNA was suppressed to less than 300 copies/ml in 19 and 1% of entecavir vs lamivudine patients respectively. The ALT normalised in 61 and 15% respectively. HBeAg seroconversion was observed in 8% vs 3% respectively. Entecavir resistance is thus common in lamivudine-resistant patients.
Entecavir is thus a potent inhibitor of HBV replication. Initial studies suggest that entecavir is safe and well tolerated, with a similar frequency of adverse events to that of lamivudine. Since the drug is excreted by the kidneys, dose adjustments are required in cases of renal impairment, starting at creatinine clearance below 50 ml/min. Although viral suppression is better with entecavir than lamivudine, 1-year HBeAg seroconversion rates are not different between the two analogues (21 and 18% respectively), although these could increase with time (but not at a linear rate) because of the lower rates of resistance to entecavir. Careful monitoring is required if entecavir is used to treat lamivudine resistance because resistance and breakthrough is likely in many [49-51]. Entecavir (and lamivudine)-resistant HBV remains susceptible to adefovir. Carcinogenicity after exposure to levels more than 35-fold greater than the dose administered in humans has been reported in rodents. These lesions include lung adenomas and carcinomas, and liver adenomas and carcinomas. The cumulative human risk will require post-marketing surveillance . As for all antiviral agents, resistance might be encountered in clinical practice in slow or incomplete responders, although at a relatively low rate . Interestingly mycophenolic and ribavirin may potentiate the effect of entecavir .
Telbivudine is a thymidine analogue and belongs to a new class of β-L-configuration nucleoside analogues with specific activity against hepadnavirus [55-57]. Preliminary studies have shown pronounced inhibition of HBV replication with a safe profile and no effect on mitochondrial metabolism. Pharmacokinetic studies indicate once-daily dosing [58-68]. Telbivudine is cleared by the kidneys, and dosing adjustments are recommended in patients with estimated creatinine clearance <50 cc/min. Drug concentrations are comparable in patients with varying degrees of hepatic impairment. A phase II study in HBeAg-positive patients compared 1-year treatment with two different doses of telbivudine (400 and 600 mg/day), lamivudine 100 mg/day and their combination. A combination of telbivudine and lamivudine was not better than telbivudine alone. The median decrease in HBV DNA levels was 6.01, 4.57 and 5.99 log10 copies/ml in the telbivudine, lamivudine and combination group respectively. HBV DNA was undetectable in 61, 32 and 49% respectively, while HBeAg loss occurred in 33, 28 and 17% respectively .
Phase III studies of telbivudine vs lamivudine in HBeAg and anti-HBe have been completed. (The study included 1367 HBeAg-positive or -negative patients randomised to receive telbivudine 600 mg/day (n = 680) or lamivudine 100 mg/day (n = 687) .
A greater therapeutic response with telbivudine at week 104 was noted in HBeAg-positive patients (64% of those receiving telbivudine vs 48% of those with lamivudine). The mean log10 decline was –5.7 log vs –4.4 log in recipients of telbivudine vs lamivudine respectively. In particular, HBV DNA was not detectable by PCR in 56% of the HBeAg-positive patients receiving telbivudine vs 39% of those on lamivudine. HBeAg seroconversion occurred in 30% at year 2. Seventy per cent had normal ALT.
No differences were noted by HBV genotype B or C among HBeAg-positive patients in those receiving telbivudine or lamivudine. A clear relationship between viral load at week 24 and clinical efficacy at week 104 was shown in HBeAg-positive patients . For lamivudine and telbivudine patients combined, histological responses, ALT normalisation and HBeAg loss were greatest in patients whose week 24 HBV DNA was below the quantitative level (46% in the combined lamivudine/telbivudine groups) or between the quantitative level and 3 log10 compared to those whose level of HBV DNA at 24 weeks was >4 log10 (45% of HBeAg-positive patients and 80% of the HBeAg-negative patients treated with telbivudine had undetectable HBV DNA by 24 weeks of treatment). Limited follow-up information suggests that patients may discontinue treatment after HBeAg seroconversion. Responses are durable in approximately 80% . Other studies have been completed .
Telbivudine in anti-HBe negative patients
The mean log10 decline was –5.0 and –4.2 in telbivudine and lamivudine recipients respectively. At 2 years, HBV DNA was undetectable by PCR in 82% of HBeAg-negative patients vs 52% of lamivudine recipients. Seventy-eight per cent had normal ALT.
In this study, viral breakthrough was defined per protocol as HBV DNA >105 after being <105. Viral resistance was defined as resistance mutations documented in HBV DNA amplified from serum from patients with viral breakthrough. 17.8 and 7.3% of the HBeAg-positive and -negative patients showed resistance at 2 years respectively. Only M204I or M204I + L180I/V sequence changes were observed in telbivudine-treated patients. Lamivudine-associated resistant mutations were a mixture of M204V, M204I and + L180M double mutants. The explanation for this lies in the pathways of selection for tyrosine-methionine-aspartate-aspartate–mediated HBV resistance and the fact that telbivudine is active against M204V, whereas lamivudine has reduced activity against both M204V and M204I mutants.
Response at week 24 also predicted resistance. Resistance at 2 years was observed in 4% of HBeAg-positive patients and 2% of HBeAg-negative patients who had undetectable HBV DNA at 24 weeks but the rates of resistance increased substantially in patients with higher levels of viraemia at this time point.
Discontinuations up to week 52 were similar for telbivudine and lamivudine-treated patients (8.1 and 12.8% respectively). Creatinine kinase elevations were observed in 13% at year two. This side effect seems related to a non-specific effect noted with some nucleosides.
Thus, the optimal use of telbivudine has not been defined. The combination of telbivudine and lamivudine is unfavourable. Telbivudine selects for rtM204I and effectively shows cross-resistance with lamivudine . Telbivudine is active against N236T and/or A181V mutant HBV. Adefovir and tenofovir should thus be tested in combination with telbivudine.
Tenofovir and adefovir are related molecules with a similar mechanism of action. Tenofovir disoproxil fumarate is the prodrug of tenofovir (PMPA). Tenofovir diphosphate inhibits the activity of HIV-1 rt by competing with the natural substrate deoxyadenosine 5′ triphosphate, and after incorporation into DNA by DNA chain termination. The drug is approved at a dose of 300 mg for the treatment of HIV. There is strong clinical evidence of the efficacy of tenofovir in chronic hepatitis B, with less nephrotoxicity. The drug is active against wild-type and pre-core mutant hepatitis B, as well as lamivudine-resistant HBV in vitro [73-79]. It is possible that tenofovir's greater efficacy is a result of the higher active dose. Earlier small studies in HBV mono-infected and HIV – HBV co-infected patients have demonstrated the activity of tenofovir against HBV. In the ACTG 5127 study, 26 HIV – HBV co-infected patients with lamivudine resistance were randomised to tenofovir vs 25 with adefovir. Tenofovir-treated patients showed a greater time weighted average DNA change (DVAG48) and log suppression of HBV with tenofovir 300 mg (4.0 log vs −3.1 log compared to adefovir 10 mg). Recent trials show a favourable effect of tenofovir (72–130 weeks) and adefovir (60–80 weeks) in patients with lamivudine-resistant HBV infection and high baseline HBV DNA (> 106 copies/ml) [80, 81].
A phase 3, randomised, double-blind, multicentre clinical trial that compared the efficacy, safety, and tolerance with TDF 300 mg and ADV 10 mg once daily among HBeAg-positive and -negative patients has recently been reported. Both these studies show that tenofovir is more effective than adefovir. The overall incidence of adverse events was comparable in patients receiving tenofovir or adefovir. The most common adverse events in both studies were headache, nasopharyngitis, back pain, nausea and fatigue. There were no deaths in the study.
Tenofovir in HBeAg-positive patients
In a pivotal phase III trial, a total of 266 patients were randomised in a 2:1 ratio to receive either TDF (n = 176) or ADV (n = 90). The primary efficacy endpoint of this study was the portion of patients with a complete response at Week 48, defined as serum HBV DNA < 400 copies/ml and histological improvement characterised by at least a ≥ 2 point reduction in the Knodell necroinflammatory score with no worsening of fibrosis. At Week 48, 66.5% of patients in the TDF arm had a complete response compared with 12.2% in the ADV arm (P < 0.001). At 48 weeks 13% of adefovir-treated patients and 76% of tenofovir-treated patients had HBV DNA concentrations below 400 copies/ml. 20.9 and 17% of patients, respectively, seroconverted to anti-HBe at 48 weeks. No subject developed resistance mutations within this time frame.
Tenofovir for HBeAg-negative patients
The aim of the study was to compare the efficacy and safety of tenofovir vs adefovir in HBeAg-negative patients with CHB. Treatment naïve HBeAg-negative patients were enrolled. A total of 375 patients were randomised in a 2:1 ratio to receive TDF (n = 250) or ADV (n = 125). The primary efficacy endpoint of this study was the proportion of patients with a complete response at Week 48, defined as serum HBV DNA < 400 copies/ml and ≥ 2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis. Results at Week 48 showed that significantly more patients in the TDF arm had a complete response than those in the ADV arm (70.8% vs 48.8%; P < 0.001). At 1 year (48 weeks) 56% of adefovir-treated patients and 91% of tenofovir-treated patients had HBV DNA concentrations below the limit of quantitation (<169 copies/ml). Adefovir-treated patients were crossed to receive tenofovir after 48 weeks of treatment. Among patients randomised to tenofovir, 235 continued therapy beyond Week 48. At Week 72, 94% (222/235) subjects had HBV DNA concentrations of <400 copies/ml. Results of efficacy at week 72 of treatment have recently been presented. Resistance to TDF 300 mg was not observed after 2 years of treatment in either of these studies. There are as yet no data to indicate an advantage of de novo combination data in naïve patients receiving tenofovir.
Thus, tenofovir is a far more consistent and potent suppressor of hepatitis B replication than adefovir [82-84]. Levels of suppression in both HBeAg-positive and anti-HBe-positive patients are similar to those observed with other newer potent nucleosides such as entecavir although these two drugs have not been compared in head-to-head comparisons. This agent will also be a more useful agent than adefovir for the treatment of lamivudine resistance. Tenofovir has been shown to be useful for the management of delayed or suboptimal responses to adefovir. A rapid switch to tenofovir or entecavir for these patients is recommended. In cases of resistance appropriate rescue therapy should be initiated with the most effective antiviral agent to minimise the development of multiple drug-resistant strains. Tenofovir is effective against lamivudine-resistant strains of hepatitis B as well as the A181T/a strain of adefovir-resistant hepatitis B. Tenofovir shows intermediate activity against the N236T variant associated with adefovir resistance and is effective against entecavir-resistant hepatitis B.
The pharmacokinetics of tenofovir are altered in patients with renal impairment, and it is recommended that tenofovir dosing intervals be adjusted for creatinine clearance. Patients who have pre-existing renal impairment may have a low risk of nephrotoxicity from tenofovir and appropriate monitoring of renal function is required in all patients. The tenofovir dose should be adjusted according to renal function as this nucleoside analogue is cleared by the kidneys. Rare decreases in bone mineral density have been reported in HIV-positive patients treated with tenofovir.
Lactic acidosis, hepatomegaly, steatosis and renal impairment have been rarely reported in patients with HIV infection treated with antiretrovirals and tenofovir. Exacerbations of hepatitis B may occur. As patients with high levels of replication or cirrhosis may be at theoretical risk of developing resistance and its long-term consequences, clinicians may need to exercise discretion in combining tenofovir and lamivudine for selected patients.
NUCs are cleared by the kidneys, and appropriate dosing adjustments are recommended for patients with reduced creatinine clearance. Drug concentrations are comparable in patients with varying degrees of hepatic impairment but this has not been extensively studied. The long-term effects, safety and tolerance to nucleosides (i.e. after 5–10 years) are still unknown. Long-term studies on safety are needed. Long-term monitoring for carcinogenesis with entecavir is ongoing. Myopathy has rarely been reported in CHB patients treated with telbivudine. Peripheral neuropathy has been observed in patients treated with PEG-IFN and telbivudine.
Different patterns of viral resistance require effective treatment. Resistance should be identified as early as possible before a clinical breakthrough (increased ALT) by HBV DNA monitoring, and if possible identification of the pattern of resistance mutations should be used to adapt therapeutic strategies. Indeed, clinical and virological studies have shown the benefits of early treatment adaptation as soon as viral load increases. In case of resistance, an appropriate rescue therapy should be initiated with the most effective antiviral effect and the least risk of inducing multiple drug-resistant strains. Therefore, adding-on a second drug without cross-resistance is the only effective strategy. The long-term safety of some combinations is unknown.
The continued use of single nucleosides with low potency and a low barrier to resistance, in sequence, as in the past, may lead to the presence of multidrug-resistant hepatitis B. The efficacy of combination therapy has not been fully explored, but there could be disadvantages to using monotherapies with drugs that induce high rates of resistance.
Use of nucleoside analogues in pregnancy
Recent studies suggest that lamivudine therapy in pregnant women with high levels of viraemia during the last trimester of pregnancy reduces the risk of transmission to newborns who receive HBIG and the vaccine at birth. A level of > 108 copies/ml has been associated with a higher risk of transmission despite HBIG and vaccine use, but strict guidelines for the use of nucleosides in pregnancy have not been issued. Based on their use as anti-retrovirals in HIV-positive women nucleosides such as tenofovir appear safe, but limited data are available .
Delta hepatitis was first recognised following detection of delta antigen (HDAg), a novel protein, by immunofluorescent staining in the nuclei of hepatocytes from patients with hepatitis B . Hepatitis delta virus (HDV) is now known to be defective and require a helper function from HBV for its transmission. HDV is coated with HBsAg which is needed for the release from the host hepatocyte and for entry in the next round of infection. The agent is unique among human viruses and consists of a particle measuring 35–37 nm in diameter, with an internal nucleocapsid comprising the genome surrounded by the delta antigen and enveloped by an outer protein coat of HBsAg. The genome consists of a single-stranded, circular RNA of around 1700 nucleotides, the delta antigen being encoded by antigenomic RNA.
Two major modes of delta hepatitis infection are known. In the first, a susceptible individual is co-infected with HBV and HDV, often leading to a more severe form of acute hepatitis caused by HBV. Vaccination against HBV prevents these infections. In the second, an individual infected with chronic HBV becomes superinfected with HDV. This may accelerate the course of the chronic liver disease and cause overt disease in asymptomatic HBsAg carriers. HDV may be cytopathic, and HDAg directly cytotoxic. A less common type of infection has been seen in HDAg-positive patients who have received liver transplants. Hepatocytes in the graft become infected with HDV circulating at the time of transplantation. In the absence of HBsAg, there is no cell-to-cell spread of the virus but HDV replication persists in isolated hepatocytes.
The mainstay of treatment remains long-term IFN or PEG-IFN. A proportion of patients become HDV RNA negative, or even HBsAg negative, with accompanying improvement in histology. To date, treatment with nucleoside analogues has been disappointing. IFN remains the only feasible treatment. Newer agents, such as prenylation inhibitors may prove useful. Patients with decompensated liver disease should be considered for transplantation with prophylaxis against reinfection with HBV [87, 88].
- Top of page
- Summary of European guidelines
Many questions remain unanswered on the optimal treatment of patients with chronic hepatitis B with a nucleoside vs interferon alpha. Both forms of treatment have benefits and the choice should be selected and tailored. For example, which antiviral is most appropriate for particular patients and how can treatment be tailored to optimise response? In whom should a combination therapy be considered de novo, and for whom might monotherapy or an add-on therapy suffice? Which patients can realistically expect a finite course of treatment, compared with those requiring long-term maintenance suppression? In whom will a strategy of simply continuing viral suppression eventually result in HBeAg seroconversion, and thus discontinuation of therapy?
The majority of patients except those in whom interferon is contraindicated should be given the option of interferon treatment. Many patients will express a preference for either: (a) a trial of a relatively short term, (1 year) circumscribed course of treatment with interferon ; or (b) a preference for long-term treatment with an oral nucleoside without the side effects of interferon injections. In HBeAg-positive patients, HBeAg seroconversion rates during interferon treatment are low in patients with higher levels of HBV DNA (> 108 IU/ml) and normal serum ALT concentrations. However, young individuals, including women of childbearing age, with raised serum ALT concentrations (>5 × ULN), inflammatory activity on biopsy and perhaps genotype A or B infection have a greater likelihood of response to interferon. This requires emphasis. The EASL guidelines indicate that in HBeAg-positive patients, a HBV DNA decrease to less than 20 000 IU/ml at 12 weeks is associated with a 50% chance of anti-HBe seroconversion, while HBsAg levels of >20 000 IU/ml or no decline of HBsAg at 12 weeks are associated with a very low likelihood of subsequent HBeAg seroconversion. Thus, stopping or futility rules can be implemented in patients who fail interferon. Therefore, interferon is the treatment of choice, if acceptable, for patients with active HBeAg-positive or -negative hepatitis B. However, it is a treatment best directed towards selected patients. The pros and cons of the different modalities of treatment require explanation, and baseline factors may help to individualise recommendations [89, 90].
It is also likely that the same pre-treatment predictive factors, i.e. high-baseline ALT may also portent a higher likelihood of HBeAg seroconversion after starting treatment with a nucleoside- Thus patient's choice should be sought. Moreover, recent data suggest the safety and efficacy of nucleoside analogues in the third trimester of pregnancy to reduce the risk of transmission from mothers to their children, although women should be informed of the potential risk of nucleoside analogues in pregnancy .
As yet there are no data to indicate the benefits of de novo combination treatment with NUCs in naive patients receiving either entecavir or tenofovir. Therapeutic trials of combination therapy with these NUCs are in progress.
The efficacy and place of potent and appropriate therapies must be determined, but this requires large and expensive trials. Thus, the efficacy of potent monotherapies including interferon vs the combination of interferon and a nucleoside will need to be gleaned from direct clinical experience and learning in the next few years [91, 92].