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REVIEW ARTICLE  
Year : 2011  |  Volume : 8  |  Issue : 1  |  Page : 32-70
Management of chronic hepatitis B


Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

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Date of Web Publication8-Sep-2016
 

   Abstract 

Hepatitis B virus (HBV) is the most important cause of chronic liver disease and hepatocellular carcinoma in India. During the past three decades, considerable advances in the diagnosis and treatment of HBV infection have been achieved. However, despite the remarkable improvements, medical management for HBV induced cirrhosis, and liver cancer remains unsatisfactory. In fact, it is becoming increasingly clear that as of now, there is no "cure" for hepatitis B infection. Management of chronic hepatitis B has changed considerably; currently, emphasis is in identifying and treating patients at high risk of disease progression since effective antiviral therapy arrests disease progression, reduces complications and can potentially reverse liver damage if given for sufficient duration. The treatment should be initiated with drugs that have high potency and high genetic barrier to resistance, and compliance should be ensured once decision to treat is initiated. Resistant patients are difficult to treat and preferably combination treatment with high potency and high genetic barrier drugs should be used to avoid treatment failure. Close monitoring of both treated and untreated patients for disease progression should be done, and early intervention is required to prevent complications in those who show progression over time.

Keywords: Antiviral therapy, hepatitis B virus, hepatitis B virus therapy, interferon, nucleos(t)ide analogues, viral hepatitis

How to cite this article:
Goyal R, Acharya SK. Management of chronic hepatitis B. Hep B Annual 2011;8:32-70

How to cite this URL:
Goyal R, Acharya SK. Management of chronic hepatitis B. Hep B Annual [serial online] 2011 [cited 2019 Oct 15];8:32-70. Available from: http://www.hepatitisbannual.org/text.asp?2011/8/1/32/190079



   Introduction Top


Hepatitis B virus (HBV) is the most important cause of chronic hepatitis, cirrhosis of the liver, and primary liver cancer in India. It is considered to be responsible for 40-60% of patients with chronic hepatitis and cirrhosis in India. [1],[2],[3] About 80-90% of primary liver cancers in India have been reported to be associated with HBV infection. [1],[2],[3] During the last three decades, considerable improvement in the diagnosis and treatment, as well as in monitoring of HBV infection, the sequelae of chronic HBV-associated liver damage and prevention of HBV infection have been achieved. Despite remarkable improvement in therapy, medical management for HBV-induced cirrhosis and liver cancer remains unsatisfactory, while therapy in chronic hepatitis B (CHB) is progressively improving with the availability of better diagnostic techniques as well as newer and effective antiviral chemotherapy. The ultimate goal of therapy in chronic hepatitis is to improve hepatic inflammation and necrosis, as well as prevent its progression to cirrhosis and hepatocellular cancer (HCC). However, it is becoming increasingly clear that as of now, there is no "cure" for hepatitis B infection. Even in patients achieving hepatitis B surface antigen (HBsAg) seroconversion (which is considered as the most desirable therapeutic end point for antiviral therapy), severe hepatitis flare preceded by enhanced HBV replication have been documented when such patients are immunosuppressed. [4] Host immune response is a major determinant of the HBV persistence as well as the natural course of HBV infection in humans. Further, it is by now evident that due to high replication potential and its ability to evade immune surveillance by mutation, the virus itself is highly heterogeneous with many genotypes and mutants. These differences in viral genome resulting in heterogeneous HBV virus in different hosts may influence the natural course of the disease, its transmission and the response to therapy. Therefore, the CHB infection and its outcomes in a given individual are dependent on a dynamic and complex relationship between the virus itself and the host immune system, making therapeutic decisions and prediction of outcomes difficult in a given individual. Before elucidating the effectiveness of various therapeutic strategies against chronic HBV infection, it is important to briefly discuss the natural course and life cycle of HBV infection in humans, because HBV induced disease in humans is due to the result of interaction between the virus and the host immune system [Table 1]. [5]
Table 1: The stages in the natural history of HBV infection


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   Life Cycle and Natural Course of Hepatitis B Virus Infection  Top


0 Under most circumstances, HBV is not cytopathic. An intact immune system is necessary for viral clearance and hepatocyte injury. The severity of liver injury reflects the vigor of the immune response; the most complete immune response is associated with the greatest likelihood of viral clearance and the most severe liver injury. Ninety-five percent of infected neonates with immature immune systems become asymptomatic chronic HBV carriers, as compared to 30% children infected after neonatal period but before 6 years of age. [6] Less than 1% of adults following an acute HBV infection continue to remain chronically infected, and the remaining patients, due to a competent immune system, clear HBV infection. [6] In Asian countries, evidence suggests that most of the chronic HBV infections are acquired in childhood. [6] While in the South East Asian countries, chronic HBV infection predominantly occurs due to vertical transmission from HBV-infected mother to baby, in India it is likely to be due to HBV infections in the postneonatal period through horizontal spread (child to child) before the age of 6 years. [7] In India, about 86% of chronic HBV infections are considered to be due to horizontal infection in the pediatric age group, and the remaining 14% presumably are during neonatal period (vertical transmission). [7] When these HBV-infected children acquire a more robust and complete immune system, they try to clear the HBV from the infected hepatocytes. This effort may succeed or gets obtunded by the various viral strategies to evade the host immune attack. In the latter case, the obtunded immune system causes mild but ongoing injury resulting in chronic hepatitis. Thus, enhancing the immune system further, or decreasing the viral load (so that its tolerising effect on immune system is reduced) causing immune restitution, has become the rationale for present therapeutic strategy. In the following paragraphs, the life cycle of HBV in humans will illustrate the above facts more lucidly which is important to rationalize all therapeutic strategies to remove HBV from the human liver. The life cycle of HBV in humans can be categorized into four stages [Table 1]. [5]

The first stage, following HBV entry into human hepatocyte is considered as the phase of immune tolerance (stage 1), during which the HBV replicates in the liver and starts getting released into the circulation. In the healthy adult, this incubation period lasts for about 2-6 weeks. In contrast, in HBV infection acquired during neonatal period or early childhood, the immune tolerant phase continues till the second and third decades of life. The immune clearance phase (stage 2) ensues with establishment of an active host immune system during adolescence, which tries to clear HBV infected hepatocytes resulting in suppression of HBV replication which is followed by subsidence of hepatic inflammation and onset of low or nonreplication phase or inactive carrier state. However, in about 20-25% of such individuals, the host immune system during the immune reactive phase does not achieve adequate suppression of HBV replication. Such abortive attempts of immune clearance of the virus result in hepatic injury with simultaneous repair (matrix remodeling) causing hepatic fibrosis. Clinically this latter group of individuals is diagnosed as having chronic hepatitis and cirrhosis. This is the group of patients who need therapy with the aim to suppress HBV replication to the minimum for a long duration that is known to improve the hepatic inflammation with a resultant reversal of hepatic fibrosis. However, as mentioned earlier, HBV infection persists throughout life and over 10-30 years period, 20-25% of asymptomatic carriers, due to yet unidentified reasons, may enter a phase of enhanced HBV replication with concomitant liver injury (reactivation/hepatic flare; stage 4) which may occur repeatedly in an individual over long duration and ultimately present with cirrhosis and may even present with substantial liver damage during reactivation with features of liver failure (acute-on-chronic liver failure [ACLF]). Therefore, all efforts during treatment of CHB infection are aimed at maximal suppression of HBV replication and prevention of reactivation of asymptomatic carrier state/early recognition of reactivation. Therefore, all patients with CHB infection should be kept under continuous surveillance with a strategy to suppress HBV replication indefinitely. The clinical presentation of reactivation phase of chronic HBV infection may vary from severe hepatitis flares presenting as "ACLF" to asymptomatic rise in alanine aminotransferase (ALT). However, the determinants of switch between stages are however yet unclear.

Therefore, the goal of current therapy is to accelerate the transition from stage 2 to stage 3 in hepatitis B e antigen (HBeAg) positive patients, and to downgrade patients from stage 4 (reactivation phase) to stage 3 in HBeAg-negative chronic hepatitis till they lose their surface antigen. The major determinants that may influence effective suppression of HBV replication include age at infection, sex, viral characteristics such as high viral load or development of HBeAg negative strain, and immunosuppression state [Table 2]. Therefore, before treating patients with CHB, evaluation of the above-mentioned factors assists the treating clinician to provide the best possible treatment schedule, as well as monitoring strategy [Table 3]. Liver biopsy is very informative and useful in the management of patients of chronic hepatitis B. The indications for liver biopsy in chronic hepatitis B patients are summarized in [Table 4].
Table 2: Predictors of response in chronic hepatitis B


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Table 3: Baseline workup of patients with chronic hepatitis B


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Table 4: Indications of liver biopsy


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Chronic hepatitis B is a heterogeneous disease

As described earlier, HBV may modify its structure under immune pressure, and selection of such mutant virus associated with progressive liver damage may not respond to therapy well. [8] Therefore, based on viral characteristic, CHB can be grouped into HBeAg positive and HBeAg negative variants. The host characteristics may also influence the natural course of the patients with CHB. For example, CHB infection, among HIV-infected individuals, patients with chronic renal failure or renal transplant, patients with hematological malignancy, patients undergoing chemotherapy for malignancies usually do not behave like CHB patients without associated co-morbid illnesses and usually do not respond well to therapy. [6] While treating a patient with CHB, these factors may influence the outcome of therapeutic interventions. In such patients, therapy should be individualized as per patient and viral characteristics.


   Therapeutic End Points in the Management of Chronic Hepatitis B Top


During the last two decades, experience in the management of CHB has been substantial. Published studies on the therapeutic results in CHB clearly indicate that eradication of HBV or suppression of HBV replication is associated with decrease in hepatic inflammatory process. While, HBsAg loss subsequent to successful treatment has been frequent among Caucasians, such outcome among the Asians is rare. [9],[10] Such differences in therapeutic outcome have been presumed to be due to the age at which HBV infection occurs in these communities. Usually, chronic HBV infection among the former population occurs in adults, whereas, among Asians, persistent HBV infection is a childhood event. [6],[7] Presumably due to the long duration of infection, the HBV genome gets integrated into the host hepatocyte genome that continues to produce HBsAg despite arrest of HBV replication in the latter patients. [11]

The primary aim of therapy in patients with CHB is to eradicate or permanently suppress HBV replication and to prevent reactivation of HBV replication in long term. The terms used to express such successful results are sustained viral response (SVR) and sustained biochemical response (SBR). SVR conventionally indicates persistent and continued arrest of HBV replication (HBeAg seroconversion and HBV-DNA loss) after 6 months of stopping treatment. [12] Similarly, SBR denotes normal ALT beyond 6 months of cessation of therapy. Histological improvement invariably accompanies SVR and SBR. The severity of liver damage among patients with CHB can be objectively assessed during histological evaluation by grading the severity of inflammation and liver cell necrosis and by assessing stage of the disease in which degree of fibrosis is scored on a semiquantitative scale. [13] Certain viral and host factors have been found to be associated with SVR. [14] A low viral load (HBV-DNA level <200 pg/mL or 5.7 × 10 [7] copies/mL), more active immune system (ALT >100 IU/dL), lesser degree of hepatic fibrosis and higher histological activity index (HAI) (HAI >10) have been associated with excellent SVR. On the other hand, co infection with another virus like HIV, advanced hepatic fibrosis, low ALT, male sex, high BMI and associated alcohol consumption are factors associated with the suboptimal therapeutic response. [14] Further, it has been documented that HBeAg-negative CHB are extremely difficult to treat because of a high relapse rate documented in these patients after cessation of therapy, and the relapse rate increases in these patients with passage of time. [12] The role of HBV genotypes and their association with response to therapy is yet to elucidated. However, genotypes A and B appear to be more sensitive to therapy with pegylated (PEG) interferon (IFN) compared to genotypes C and D. [15]


   Therapy in Chronic Hepatitis B Top


By now many immunomodulators and antivirals have been developed to treat patients with CHB. However the results of treatment with IFN, lamivudine, adefovir, telbivudine, entecavir and tenofovir have been well evaluated and the present discussion would be limited to these drugs predominantly.


   Interferon Top


IFN was the first drug to be approved for the treatment of CHB. IFN α was first reported to have beneficial effects in CHB in small uncontrolled studies in the 1970s. [16] A meta-analysis published in 1993 reviewed 15 randomized controlled trials involving 837 adults with HBeAg-positive CHB, who received 5-10 million units (MU) IFN daily or thrice weekly for 4-6 months. [17] HBV-DNA loss was documented in 37% of treated patients compared to 17% of controls, loss of HBeAg occurred in 33% of treated patients compared to 12% in the controls, and the loss of HBsAg was observed in 7.8% of the treated patients while it was 1.8% in the controls [Figure 1]. [17] Another meta-analysis which included 1,200 patients and 22 trials, documented that IFN increased the rates of serum HBV-DNA clearance and aminotransferase normalization by a factor of 3 at 1-year. [18] The accepted conventional dose of IFN is 5 MUd aily or 10 MU 3 times a week. The duration of such a regimen for HBeAg-positive disease has been recommended for 4-6 months. However, the optimal duration of IFN therapy for hepatitis B is not well established. [19] A multicentric trial from Europe demonstrated added benefit of continuing therapy for 32 weeks among patients in whom HBeAg is not cleared by 16 weeks but who had low levels of HBV-DNA (<10 pg/mL). [20] Therapeutic response to IFN α has been reported to be different among various races and ethnic population. However, such differences are difficult to be assessed because trials in Asia have included only Asians while Western trials included mostly white subjects. [11] Published and unpublished trials of IFN α among the Indian HBeAg positive CHB patients revealed HBeAg seroconversion rate of about 30% in comparison to a 9% HBeAg loss among untreated controls. [21] Irrespective of ethnicity or race, patients with normal or minimally elevated ALT have universally been reported to respond poorly (<3%) to IFN. [11] Several methods to increase the response in such patients have been suggested. One of the most popular approaches described was "priming with a short course of steroid." However, convincing and reproducible data on its efficacy particularly on long-term follow-up is lacking. [11] The durability of responses and continued benefit of therapy have been assessed in several long-term follow-up studies. Studies from the West suggest that 95-100% of the responders remained HBeAg negative during 5-10 years follow-up, and 30-80% of them ultimately lose HBsAg. [22],[23],[24] In contrast, studies from South East Asian countries revealed lower rates of durable responses, only rare loss of HBsAg and ultimately a loss of HBeAg in similar proportions of controls and treated patients. [10],[25],[26] Data on long-term durability of response among South Asians (India, Pakistan and Nepal) is not known. IFN therapy is associated with side effects like fever, myalgia and influenza-like symptoms in most (60-90%) of the patients; these tend to ameliorate with continuing use of the drugs. Other problematic side effects include leucopenia, thrombocytopenia, hypothyroidism and behavioral abnormalities. Discontinuation of therapy due to such side effects have been reported in 5-10% of cases. [8],[12]
Figure 1: Outcome of Treatment of Chronic Hepatitis B with IFN a

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Data on the results of IFN therapy among HBeAg-negative CHB patients are limited and complicated by heterogeneity of the virus, the diseases, and the study designs. Heterogeneity of the disease is reflected through markedly different patterns of serum ALT elevation viz: Continuous (25%), fluctuating (50%), and relapsing (25%). [11] The virus may also be heterogenous; HBeAg negativity in such cases may be due to classical G1896A precore mutation or due to core promoter mutation (A1762T, G1764A). The heterogeneity in a study design is reflected by various types and regimens of IFN, different end points and various types of control populations. [11] All the trials have documented an end of therapy response rate of 40-60%, but with cessation of treatment half the patients relapsed within 6 months. Unlike the durable response rate among HBeAg-positive patients, relapse among HBeAg-negative CHB continues to occur with passage of time and a durable response to a 12 months course of IFN in such patients has been reported to vary from 15% to 25%. [11] Further, unlike HBeAg-positive patients, the predictors of response to treatment in HBeAg-negative patients are not clear. Longer duration of treatment in such patients and early normalization of ALT values have been reported to be associated with better sustained response. [11] Recent data suggest that HBsAg quantification may be helpful in predicting the response to therapy in these patients. [27] In both, HBeAg positive and HBeAg negative patients, SVR has been reported to be associated with lower rates of death and HCC. [28],[29]

IFN α therapy has been shown to be effective and is recommended for use in children above 2 years of age with HBeAg-positive CHB. Two hundred forty children included in 15 studies were treated with a dose of 3-10 MU/m [2] given thrice weekly for 12-48 weeks. SVR of 23% among treated patients and 11% among untreated controls was reported. [29] Predictors of response among children were similar to those in adults. [30] Data on therapeutic results of IFN treatment of Indian children are not available.

IFN has a short half-life of about 4 h only. To increase its half-life and prolong its duration of action, it has been tagged with polyethylene glycol molecule to form PEG IFN. PEG IFN has a longer trough level, weekly dosing and a higher efficacy. [15] PEG IFN is currently the preferred form of IFN to be used in the management of CHB due to its weekly dosing interval that may increase patient compliance and maintain trough levels. In a phase III trial involving 814 patients, response to treatment with PEG IFN α2a with or without lamivudine was higher (seroconversion rates of 32% and 27%) in patients compared to those receiving lamivudine alone (19%) at 6 months after stopping treatment. [31] Similar results have been reported with PEG IFN α2b as well, with response rates of 29% (with or without lamivudine) in one study and 36% (vs. 19% with lamivudine monotherapy) in another study. [32] In HBeAg-negative patients after 24 weeks of therapy, the rates of virological response at 48 weeks were seen in 43%, 44%, and 29% of the patients, respectively. [33] Moreover, the seroconversion rates following IFN therapy tend to be more durable and higher HBsAg seroconversion rates (30% at 3 years) are noted on follow-up of responders as compared to controls or patients treated with nucleos(t)ide analogues. [34]


   Lamivudine Top


Lamivudine (3-thia-cytidine) is a dideoxynucleoside (a pyrimidine nucleoside analogue) which acts by inhibiting viral DNA synthesis by terminating the nascent proviral DNA chains. It is well absorbed orally and has marked antiviral activity against HBV and HIV. Long-term treatment using lamivudine monotherapy for 52 weeks has been evaluated in four large multicentric, randomized controlled trials in patients with HBeAg-positive CHB. In these trials, HBeAg loss and HBeAg seroconversion were documented in 17-32% and 16-18% respectively, in contrast to 11% and 5% respectively in controls after 52 weeks of treatment. [35],[36],[37],[38]

One out of these four trials was conducted among Chinese patients [35] whereas the remaining three were conducted among Western patients with CHB. [36],[37],[38] The factors identified as predictors for response (HBeAg loss/seroconversion) in the above-mentioned studies were similar to those documented among responders to IFN. Patients with CHB having ALT levels 5 times normal had HBeAg loss/seroconversion in 65% of the patients. [35] However, an unresolved issue of lamivudine therapy in CHB is the durability of the response. Even though HBeAg seroconversion has been reported to be associated with durable response in 70-80% of cases in the above studies, a single center study reported a relapse rate of 50%. [39] As a part of the extended follow-up of the Asian multicentric trial, 58 of 357 patients continued long-term lamivudine treatment; cumulative HBeAg seroconversion with loss of HBV-DNA (hybridization assay) was documented in 22% at 1-year, 29% at 2 years, 40% at 3 years and 47% at 4 years of therapy. [40]

Although the initial results with lamivudine were promising, drug resistance has emerged as a problem, occurring in 16-32% patients at the end of 1-year of therapy and increasing with the duration of therapy to 67% at the end of 4 years of therapy. [40] Resistance to lamivudine occurs as a result of selection of the mutant strains of virus, the mutation occurring at the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the DNA polymerase region of the virus. The substitutions were most commonly due to replacement of the methionine at codon 552 with serine, isoleucine or valine. [41] Lamivudine resistance is associated with a rise in ALT/AST value with increase in HBV-DNA level. [42]

Most studies on the therapy in CHB have focused on HBeAg-positive CHB. However in India, approximately 15-30% of patients with CHB are associated with HBeAg-negative CHB. About six studies have evaluated the efficiency of lamivudine for 12 months among patients with HBeAg-negative CHB. [42],[43],[44],[45],[46],[47] HBV-DNA loss by hybridization assay with normalization in ALT values at the end of 12 months of therapy have been documented in 63-96% of the cases. However, with cessation of therapy, relapse frequency was very high with a sustained response of only about 10-12% during 1-year posttherapy follow-up. Therefore long-term or even lifelong lamivudine therapy has been contemplated as an alternative, but long-term treatment with lamivudine for more than 12 months has been associated with progressively increasing virological and biochemical breakthrough indicating lamivudine resistance. Despite the increased frequency of breakthroughs about one-third of such patients on long-term lamivudine treatment have been reported to be associated with HBV-DNA negativity, normal ALT, and improved liver histology. [47]

Thus, lamivudine therapy leads to improvements in biochemical, virological and histological features of the disease in more than three-fourths of the HBeAg-negative CHB patients, but relapse is frequent when therapy is stopped, and long-term treatment is associated with a high rate of viral resistance.

It is believed that clearance of HBV or prevention of viral replication can reduce further liver damage and progression of disease in patients with HBV-associated decompensated cirrhosis, and may result in development of the "stable cirrhotic state." IFN is contraindicated in this subgroup of patients. Lamivudine treatment has been reported to be associated with a rapid suppression of viral DNA to undetectable levels and a rapid improvement in the biochemical and the clinical profile among such patients with cirrhosis. [48],[49] In a prospective North American study, 80% of those treated with lamivudine had undetectable HBV-DNA levels within 8 weeks at the beginning of therapy. [48] In addition, 35% of patients lost previously detectable HBeAg, and 20% acquired anti-HBe. [48] Yao and Bass from China reported that patients with HBV induced cirrhosis listed for liver transplant and receiving lamivudine were less likely to undergo transplantation. [49] Improvement in hepatic inflammation subsequent to lamivudine therapy may be associated with a reduction in the development of HCC as has been demonstrated in long-term follow-up studies. [50]

Several studies have now demonstrated the efficacy of lamivudine in preventing posttransplant recurrences of HBV infection which can lead to deterioration of graft as well as compromise patient survival. Because of the appearance of lamivudine-resistant HBV with long-term use, most liver transplant centers used to treat transplanted patients having a high risk of HBV re-infections with a combination of lamivudine and hepatitis B immunoglobulin (HBIG). [51] However, long-term use of HBIG is expensive and may be impractical in many countries. A combination of adefovir and lamivudine has been used in place of lamivudine/HBIG combination as maintenance therapy in posttransplant setting and is successful in circumventing the problem of drug resistance and flares associated with monotherapy. [51],[52]

Minimal toxic effects have been reported in most studies on lamivudine. Analysis of lamivudine effect on mitochondrial morphology and functions has not shown any mitochondrial toxicity either after 6 months [53] or 3 years [54] of therapy. Other reported side effects are anorexia, nausea, vomiting, leukopenia, and peripheral neuropathy.


   Adefovir Dipivoxil Top


Adefovir dipivoxil is a synthetic acyclic adenine nucleotide analogue. It is a potent inhibitor of HBV reverse transcriptase in the wild-type HBV as well as in lamivudine-, telbivudine-, and entecavir-resistant mutants. It has an excellent oral absorption and an intracellular half-life that permits once daily dosing. However in large doses (60-120 mg daily) it causes reversible nephrotoxicity such as renal tubular acidosis, renal insufficiency and phosphate wasting. Adefovir is effective in both HBeAg positive and HBeAg negative chronic hepatitis. In the study by Marcellin et al. which included HBeAg positive patients and was conducted in 32 centers across the globe, 512 patients were randomized to receive either adefovir 10 mg, adefovir 30 mg or placebo, and the following results were documented after 48 weeks of therapy. Histological improvement was noted in 53% in the 10 mg arm, 59% in the 30 mg arm and 25% in the placebo group. [55] The reduction of serum HBV-DNA levels was by 3.52 logs, 4.76 logs and 0.55 logs respectively. Undetectable serum HBV-DNA by branched chain assay was documented in 21%, 39%, and 0%, respectively and HBeAg seroconversion in 12%, 14%, and 6%, respectively. Adefovir resistance was not reported in any of the patients who were treated to 48 weeks. Both 10 mg and 30 mg doses of adefovir had a similar efficacy; however nephrotoxicity was more common among the patients who received 30 mg of the drug. Studies on patients with decompensated chronic HBV infection showed increases in serum creatinine levels by 0.5 mg/dl or more from baseline in 16% of them by week 48, 31% by week 96, and 1% required discontinuation due to renal failure. [56]

Another study published at the same time by Hadziyannis et al., [57] included 185 HBeAg negative CHB patients, who were randomized to receive either 10 mg of adefovir daily or placebo. Sixty-four percentage had improvement in the liver histology in the treatment group as compared to 33% in the placebo group. Undetectable HBV DNA was found in 51% of the treated patients and none in the placebo group; the median decline in the HBV DNA levels was 3.91 logs in the treatment group while it was 1.35 logs among the patients receiving placebo. There was no evidence of emergence of viral resistant mutants despite 12 months therapy in these patients. In a follow-up study, up to 240 weeks of adefovir therapy in naive HBeAg-negative patients resulted in HBV DNA <200 IU/mL in 67%, ALT normalization in 69%, improvement in necroinflammation in 83%, and regression of fibrosis in 73% of patients respectively. [58] The overall incidence of adefovir-resistant mutation is low [Table 5]. HBV-DNA<10 [3] copies/mL at week 48 were predictive of the emergence of adefovir-resistant mutations (6% vs. 49% with >10 [3] copies/mL) during 192 weeks of adefovir treatment. [58]
Table 5: Resistance profiles of nucleos(t)ide analogues


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Patients with lamivudine resistance have been treated with adefovir, [59],[60],[61],[62] the majority having a 3-4 log reduction in the serum HBV-DNA levels and a stabilization of their liver disease. Add on adefovir to lamivudine seems to be better than switch to adefovir as the former strategy is associated with lower risk of drug resistance and hence lower risk of disease flares in the long term. A 3 years study of 145 lamivudine-resistant HBV-infected patients showed that add-on adefovir led to undetectable HBV DNA in 80% and normal ALT in 84% of patients, and none developed virologic and clinical breakthrough during 12-74 months of therapy. [60] Add-on adefovir in patients with HBV-DNA>10 [7] copies/mL is associated with insufficient virologic responses, [61],[62] and should, therefore, be instituted as soon as genotypic resistance is detected and before the serum HBV-DNA levels increase to a level too high to be suppressed successfully. [63]


   Entecavir Top


Entecavir is a cyclopentyl guanosine analogue with potent selective inhibition of the priming, DNA-dependent synthesis, and reverse transcription functions of HBV polymerase. In a viral kinetic study comparing entecavir to adefovir in HBeAg-positive patients with high viral load, entecavir showed significantly greater HBV DNA reduction as early as day 10. [64] HBV-DNA reduction was 6.23 log versus 4.42 log at week 12 and 7.28 log versus 5.08 log at week 48, respectively. Phase III randomized lamivudine controlled trials have shown superiority of 1-year entecavir (0.5 mg/day) over lamivudine in reducing HBV-DNA in both HBeAg-positive (6.9 log vs. 5.4 log; HBV-DNA <300 copies/mL in 67% vs. 36%) and HBeAg-negative patients (5.0 log vs. 4.5 log; HBV-DNA <3 00 copies/mL in 90% vs. 72%). [65],[66] HBeAg seroconversion rate was 21% (68% in patients with pretherapy ALT >5 times upper limit of the normal range [ULN]). Extending entecavir therapy to 96 weeks for partial responders at week 48 resulted in an increase in the rate of HBV-DNA<300 copies/mL to 74%, ALT normalization increased to 79%, and a cumulative HBeAg seroconversion rate of 31%. [67] The corresponding rate was 91%, 86%, and additional 16%, after extending entecavir therapy to 192 weeks. In addition, long-term data on entecavir confirmed significant regression of fibrosis after 5 years of therapy, including reversal of histological cirrhosis in a subset of treated patients. Switching to entecavir monotherapy (1 mg/day) is initially safe and effective in lamivudine-resistant patients (5.11 log vs. 0.48 log reduction in lamivudine). [68] HBeAg loss was documented in 10% of lamivudine-resistant HBeAg-positive patients (vs. 3% in controls). Entecavir has a high genetic barrier, and resistance requires at least three mutations including rtL180M and rtM204V, plus a mutation at one of the codons rtT184, rtS202, and/or rtM250. However, entecavir therapy in lamivudine-refractory patients is associated with a higher entecavir resistance rate. The cumulative probability of a virologic breakthrough from entecavir resistance through 5 years is at least 0.8% in lamivudine-naοve patients and up to 51% in lamivudine refractory patients. [69] Recent data on long-term entecavir use has documented significant reversal of histological fibrosis and even cirrhosis after long-term use of entecavir (more than 3 years duration). [70] In a study of 10 patients with Ishak fibrosis score of >4 at baseline, after approximately 6 years of cumulative therapy, all patients showed improvement in liver histology. The mean improvement from baseline in Ishak fibrosis and Knodell necroinflammatory scores were 2.2 and 7.6 points respectively. A reduction in Ishak fibrosis score to 4 or less was observed for all four patients with cirrhosis at baseline. [71] In another study with 22 patients of decompensated patients treated with entecavir, the treated patients had improvement in Child's score and model of end-stage liver disease (MELD) score with improvement in HBV DNA levels and ALT levels. [72]


   Tenofovir Top


Tenofovir disoproxil fumarate is an acyclic adenine nucleotide that exerts a strong and early suppression of HBV with or without lamivudine-associated mutations. Tenofovir is a very promising drug and has been recommended as a first-line drug for treatment of CHB. It has also been shown to be as effective in lamivudine-resistant patients as in treatment naοve patients. The drug is also effective in adefovir resistant patients. Tenofovir 300 mg/day is more potent than adefovir 10 mg/day but without comparable renal toxicity. Phase III randomized adefovir controlled trial in HBeAg-positive patients has shown higher efficacy of tenofovir than adefovir with respect to histologic improvement (74% vs. 68%), HBV-DNA reduction to <400 copies/mL (76% vs. 13%), ALT normalization (69% vs. 54%), and HBeAg seroconversion (21% vs. 18%). [73] Tenofovir also achieved combined virologic and histological response in a higher proportion of HBeAg-negative patients (71% vs. 49%). [73] It is also effective in both lamivudine and adefovir resistant patients. [74],[75],[76] Recent studies have also shown improvement in outcomes following therapy with tenofovir in decompensated liver disease and in patients with spontaneous reactivations of CHB presenting as acute on CHB. In patients with HBV-related acute on chronic liver disease, tenofovir improved overall survival (57% vs. 15%) at 3 months with improvement in Child's score, MELD score, HBV DNA levels and HBeAg seroconversion rates in treated patients compared to controls. They also noted that more than 2 log reduction in 2 weeks with therapy is a predictor of response in treated patients. [77] In another phase II study with 112 treated decompensated patients, 90 of whom received tenofovir (45 patients) or tenofovir/emtricitabine combination (45 patients), there was improvement in Childs' score and MELD score in all treated groups. Only 12 patients died or required transplant over a follow-up period of 48 weeks. About 71% in tenofovir monotherapy arm and 89% in tenofovir/emtricitabine arm had undetectable HBV DNA at the end of therapy. HBeAg seroconversion rates were significantly higher in patients treated with tenofovir with or without emtricitabine. [72]


   Telbivudine Top


Telbivudine is an orally bioavailable L-nucleoside with potent and specific anti-HBV activity. In clinical trials, telbivudine gave more potent HBV suppression than lamivudine or adefovir. [78],[79] In the phase III randomized lamivudine controlled trial in 1,371 patients (446 HBeAg negative; 1040 Asians), significantly greater HBV-DNA reduction with telbivudine 600 mg/day was evident by week 12 (5.71 log vs. 5.42 log in HBeAg-positive patients and 4.36 log vs. 4.08 log in HBeAg-negative patients). HBV-DNA reduction persisted through week 52 with greater histological response, larger proportions of patients with undetectable HBV-DNA (60.0% vs. 40.4% in HBeAg-positive patients and 88.3% vs. 71.4% in HBeAg-negative patients), and less resistance (5.0% vs. 11% in HBeAg-positive patients and 2.3% vs. 10.7% in HBeAg-negative patients) than lamivudine. The HBeAg seroconversion rate was similar between telbivudine-and lamivudine-treated patients. The study also showed that 41% of HBeAg-positive patients with undetectable HBV-DNA at week 24 underwent HBeAg seroconversion by week 52 versus 4% for patients with HBV-DNA>10,000 copies/mL at week 24. Only 1% of HBeAg-positive patients with undetectable HBV-DNA and 2% of patients with HBV-DNA<10 [3] copies/mL at week 24 developed drug resistance by week 52, whereas 11% of patients with HBV-DNA>10 [4] copies/mL at week 24 became resistant at week 52. The corresponding figures for drug resistance in HBeAg-negative patients were 0%, 6%, and 30%, respectively. [78] Two years telbivudine therapy was significantly superior to lamivudine in both HBeAg-positive and HBeAg-negative patients for all direct measures of antiviral effect, including serum HBV-DNA reduction (5.7 vs. 4.4 log in HBeAg-positive and 5.0 vs. 4.2 log in HBeAg-negative patients), polymerase chain reaction (PCR) negativity (56% vs. 39% in HBeAg-positive and 82% vs. 57% in HBeAg-negative patients), HBeAg seroconversion in patients with ALT >2 times ULN (36% vs. 27%; P = 0.022), and viral resistance (25% vs. 40% in HBeAg-positive patients and 11% vs. 26% in HBeAg-negative patients). [80] Week 24 HBV-DNA levels also emerged as a strong predictor of week 104 efficacy outcomes. [80] rtM204I and rtA181T/V are the common mutations associated with telbivudine resistance, making cross resistance with lamivudine very likely.

In another 1-year randomized adefovir controlled trial in 135 HBeAg-positive patients, there was significantly greater HBVDNA reduction with telbivudine at week 24 (6.30 log vs. 4.97 log; undetectable HBV-DNA in 39% vs. 12%) and week 52 (6.56 log vs. 5.99 log; undetectable HBV DNA 60% vs. 40%). [79] The HBeAg seroconversion rate at week 52 of treatment was also higher in telbivudine-treated patients than in adefovir-treated patients (28% vs. 19%). A predictive analysis of response showed that week 24 serum HBV-DNA <1000 versus >1000 copies/mL correlated with undetectable HBV-DNA (95% vs. 24%) and HBeAg seroconversion rate (41% vs. 14%) at year 1. Increase in creatine kinase levels was observed more frequently in recipients of telbivudine, of whom 7.5% (vs. 3.1% in lamivudine-treated controls) had grade 3 or 4 elevation (a level of >7 times ULN). Two-thirds of grade 3 or 4 creatine kinase elevations decreased spontaneously to grade 2 or lower during continued treatment. Symptomatic myopathy was reported in one patient after 11 months of telbivudine therapy and resolved over a period of 9-12 months after stopping telbivudine.


   Other Drugs Top


Emtricitabine [81] is a fluorinated cytosine analog which inhibits HBV DNA polymerase. It is structurally related to lamivudine and is associated with about 3 log10 reduction in HBV DNA over 1-year in doses of 200 mg/day and has a resistance profile similar to that of lamivudine, with about 13% incidence of YMDD mutations in 96 weeks of monotherapy. It has been used especially in combination with tenofovir in treatment nonresponders with good results. [72],[73],[82],[83] Clevudine [84],[85] appeared to be a promising drug for treatment of hepatitis B infection but was associated with significant risk of myopathy, [86] and has been largely abandoned. Thymosin α is another immunomodulatory agent that appears promising especially in South East Asian studies but is not currently available in India. [87]


   Combination Therapy Top


Since HBV biology is similar to HIV and most of the nucleoside analogues have been developed as a byproduct of HIV research, therapy against HBV may include two or more nucleoside analogues, similar to the highly active antiretroviral therapy (HAART) used for patients with HIV. The first combination reported was that of lamivudine and famciclovir in a small study in which nine patients were treated with lamivudine monotherapy, and 12 were treated with a combination of lamivudine and famciclovir. [88] A 2 log DNA reduction was present in both the groups at the end of 12 weeks treatment; however a relapse was documented in four patients in the lamivudine monotherapy treated patient whereas none relapsed in the combination group after cessation of therapy. [89] Although most of the studies have failed to show an increase in antiviral efficacy with combination therapies, the development of drug resistance is consistently lower in regimens involving combination of drugs. The most commonly used combination is that of lamivudine with adefovir. Studies using this combination have documented that it prevented the onset of resistance to lamivudine to a large extent. One recent study has shown that the efficacy of this combination is actually better that entecavir monotherapy in lamivudine-resistant patients. [90] This combination is also recommended by many authorities as a first line therapy in conditions like cirrhosis and postliver transplant prophylaxis.

As outlined previously, trials involving combination of lamivudine and PEG IFN failed to show the superiority of combination as compared with IFN monotherapy but showed lower incidence of lamivudine resistance compared to monotherapy.

The management of resistant patients is likely to be dominated by combination therapies as more data is likely to be available especially with combinations involving more potent and high genetic barrier drugs like tenofovir and entecavir. The combination of PEG IFN and newer nucleos(t)ide analogues also holds promise of an improved sustained response rate. The superiority of combination therapy and its ability to achieve long-term sustained response among HBeAg positive and HBeAg negative CHB patients compared to monotherapy has not yet been established. At present, there is no evidence to support routine use of combination therapy, at least in treatment naοve patients.


   Baseline Evaluation of Patient with Chronic Hepatitis B Top


The baseline evaluation in a patient with CHB is directed towards determining the disease activity and the extent of fibrosis. The patient should also be screened for the presence of HCC at baseline and periodically afterwards. The screening is generally done using ultrasonography (USG) every 6-12 months in patients who are more than 40 years of age, and in patients with family history of liver cancer. Most of the current guidelines do not recommend routine use of alpha fetoprotein (AFP) for HCC screening due to its low sensitivity and specificity in picking up early HCC. However, it may be used as an adjunct to USG, as the latter is operator dependent, and early lesions may be missed if they are not carefully looked at by the radiologist. In addition, we do a baseline dual phase computed tomography scan of abdomen in all cirrhotic patients presenting to us at baseline and afterwards if the patients clinical status deteriorates.

All the patients of CHB should undergo a baseline workup that includes liver function tests, prothrombin time, USG and viral markers including HBsAg, HBeAg, HBV DNA quantification. HBV genotyping may be required in selected patients like those being considered for IFN therapy but is not routinely indicated in clinical practice outside research protocols. AFP levels are generally recommended in addition to USG in patients eligible for HCC screening but have been done away with in many recent guidelines due to their poor sensitivity and specificity. Fibroscan, if available should be done in all patients at baseline to look for liver stiffness. Upper gastrointestinal endoscopy should be done in patients who have high index of suspicion for advanced fibrosis based on platelet counts, albumin levels, evidence of portal hypertension on USG in the form of dilated portal vein or retroperitoneal collaterals, high liver stiffness on fibroscan and advanced fibrosis on liver biopsy. Liver biopsy should be done in patients who are scheduled for therapy. In addition, it should be considered in patients who are more than 40 years of age, have HBV DNA levels more than 10 [4] copies/mL (HBeAg negative) or 10 [5] copies (HBeAg positive) or have persistently raised ALT levels above upper limit of normal. Liver biopsy should be done in all patients prior to therapy.

Patients with mild CHB should have their ALT levels measured at least once in 6 months. Treatment should be instituted when there is a sustained rise in the level of transaminases. Those with newly diagnosed CHB should be monitored with 1-3 monthly ALT levels for 6 months before starting therapy. This period is not needed for those with HBeAg-negative diseases. In those receiving therapy, aminotransferases should be monitored every 1-3 months during the first 6 months and every 6 months thereafter.

Those with moderate to severe chronic hepatitis should be monitored irrespective of the fact whether they are being treated or not. Those with cirrhosis should be monitored to minimize the risk of variceal bleeding and HCC. HCC screening should be done 6 monthly with AFP and ultrasound examination as outlined above.


   Decision to Treat Top


All patients of CHB should ideally be treated. However, presently the available treatment options have limitations-no treatment is presently able to completely eradicate the HBV infection and are at best able to suppress the viral replication. The most acceptable end point for therapy is HBsAg seroconversion that is achieved only in a minority of patients. In HBeAg-positive patients, HBeAg loss with anti-HBe formation (HBeAg seroconversion) with undetectable HBV DNA in sera is considered to be an acceptable end point for stopping the therapy as it has been shown to be associated with decreased disease activity and better long-term outcomes than patients who remain HBeAg positive for prolonged periods. This endpoint, unfortunately, is achieved in only a minority of patients and may be followed by seroreversion to HBeAg positive state in some patients after the drug is stopped. Hence, for all practical purposes, the decision to treat should be carefully taken after considering the likelihood of disease progression as well as the chances of achieving the treatment end points in a particular patient.

The following groups should be considered for antiviral treatment

Patients with severe liver diseases including HBV-related acute liver failure, acute on chronic liver disease, severe acute hepatitis, disease flare (reactivation) with evidence of viral replication, decompensated cirrhosis and compensated cirrhosis with high HBV DNA loads or detectable HBV DNA. [12] The data to support the use of antivirals in each of these indications is sparse, but nonetheless, the use of antivirals in each of these settings is associated with clinical improvement as shown in small case series. Antiviral therapy with nucleos(t)ide analogues has been also shown to reduce the risk of mortality and improve Child's scores in decompensated liver disease, ameliorating the need for liver transplant in a few patients. Moreover, the currently used antivirals like entecavir and tenofovir are generally well tolerated without significant side effects and should be considered for use in each of these conditions considering their potential benefits in prevention of disease progression and reducing mortality.

In patients without clinical or radiological evidence of cirrhosis or advanced fibrosis, the decision to treat depends predominantly on two factors: Likelihood of disease progression without treatment and chances of improvement on treatment. The most important determinants of progression are HBeAg-positive status, serum ALT levels and HBV DNA load. In addition, other factors like patients age, family history of HCC, presence of other viral coinfections, and economic status of the patient also determine the treatment decisions in clinical practice. In most guidelines, there is a consensus that the patients with high ALT (>2 times upper limit of normal) should be considered for treatment if they have high HBV DNA load (>10 [5] copies/mL for HBeAg-positive patient and >10 [4] copies/mL in HBeAg-negative patients). In addition, patients who have ALT >ULN and show evidence of disease activity (HAI >4) and/or advanced fibrosis (metavir score >1 and/or Ishak score >1) are also generally considered for antiviral therapy. There is good amount of data which suggests that treating these patients leads to improvement in serum ALT levels, suppression of HBV DNA and histological improvement in a majority of these patients. In addition, HBV DNA has been shown to determine the risk of complications like cirrhosis and HCC in patients with HBV infection irrespective of their ALT levels and HBeAg status. Hence, there may be a case for treating all patients with high HBV DNA levels irrespective of other parameters. The problem with these data is that the study was conducted in South East Asia with the mean age of the target population being more than 40 years. High DNA loads in this select population means exposure to high HBV DNA loads and possibly multiple abortive attempts at HBV immune clearance and therefore ongoing necroinflammation over extended periods of time, creating a good platform for development of cirrhosis and HCC. Moreover, the response to treatment in these cases appears to be low in patients with normal ALT. Hence, treatment in this group is believed to be associated with lower chances of success with associated risk of drug resistance in patients who fail to respond. The efficacy of newer agents like entecavir and tenofovir in this subgroup of patients is not known. It is possible that if an agent has good therapeutic efficacy with low long-term resistance profiles, it may be considered for use in this select subgroup of patients. However, current recommendations do not include the use of antivirals in these patients.

Another group of patients encountered in clinical practice are those with normal ALT. These patients may further have high DNA load, the approach to which bas been discussed above. The other subgroup of patients may be those with low DNA levels and evidence of disease on liver biopsy. In this subgroup, it is not known that whether these patients have a residual histological activity in response to the viral clearance and would improve with time or they have a progressive disease which may worsen with time despite their low viral loads. At this point of time, it would probably be justified to keep these patients on long-term follow-up without treatment and reassess them periodically with ALT, HBV DNA and probably liver biopsy or fibroscan to look for disease progression, if any. The treatment should be considered if evidence of disease progression is documented during follow-up. Patients who have inactive disease without evidence of disease progression need to be followed up with 6 monthly ALT levels and USG with or without AFP with an objective to detect disease flare and occurrence of HCC. If these patients require immunosuppression at any point of their life, they should be considered for prophylactic antiviral therapy to prevent disease flares that should continue for 6 months beyond the withdrawal of immunosuppression.


   Current Treatment Recommendations Top


After a number of consensus meetings of the Asian Pacific Association for the Study of the Liver (APASL), [91] European Association for the Study of the Liver [92] and American Association for the Study of Liver Diseases [12] liver societies, various consensus recommendations have been made for the treatment and monitoring of patients with chronic hepatitis. Recommendations by the APASL for the treatment of CHB are provided below [Table 6].
Table 6: Recommendations for the treatment of Chronic Hepatitis B


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Who should be treated?

First line antivirals for all categories are entecavir and tenofovir; due to the high risk of resistance, and lower efficacy, telbivudine, adefovir and lamivudine monotherapy is not preferred - if used careful monitoring for drug resistance should be done. Use of roadmap concept may circumvent the problem of resistance in these patients.

Doses and duration of therapy

The recommended dose for IFN is 5 MU daily or 10 MU thrice weekly for 4-6 months for HBeAg-positive chronic hepatitis and for 12 months for HBeAg-negative chronic hepatitis. The recommended dose for PEG IFN α2a is 180 μg/day while that for IFN α2b is 1.5 ug/kg/day. The duration of therapy for both is 6 months for HBeAg-positive patients and 1-year for HBeAg-negative patients.

In HBeAg-positive patients, HBeAg seroconversion is an acceptable end point for stopping the treatment. In addition, many authorities consider HBV DNA negativity by PCR to be an additional desired end point before the treatment is stopped. A consolidation treatment for about 6 months after seroconversion is generally recommended in those treated with nucleos(t)ide analogues to prevent early relapses. Postseroconversion, generally the disease goes into a quiescent phase. However, there are about 25% patients who have HBeAg seroreversion after stopping the treatment and another 10-20% continue to have persistent necroinflammation despite having seroconversion or in other words, progress to HBeAg-negative disease. These are the patients who should be considered for alternative treatments.

In HBeAg-negative patients, the treatment end points are less clear, and probably these patients require lifelong therapy. The ideal endpoint for these patients is HBsAg seroconversion that unfortunately is achieved in less than one-fifth of patients even after prolonged antiviral therapy. APASL guidelines suggest that one may consider stopping the therapy in these patients if they are HBeAg negative and HBV DNA negative on three consecutive occasions 6 months apart. However, the response rates following this approach are low, and no validation studies exist to comment on the appropriateness of this approach.

On treatment monitoring and viral resistance

The patients who are on treatment need to be monitored for drug compliance, side effects and development of drug resistance. A 3 monthly follow-up is suggested with monitoring of liver function tests, renal functions (especially for patients on adefovir and tenofovir and with underlying renal dysfunction), serologies (HBeAg, anti HBe) and HBV DNA levels. Noncompliance or drug resistance are considered if there is more than 1 log rise in HBV DNA levels from the nadir value at any point of time, confirmed on two occasions more than 4 weeks apart. Patients who show evidence of resistance should be considered for alternative therapies. In addition, HBV DNA or HBsAg quantification at 6 months of therapy may indicate a subset of patients who are unlikely to respond to continued therapy, and switch or addition of alternative agents should also be considered in these patients based on the results.

For those treated with IFN, HBeAg, anti-HBe and HBV-DNA should be done at the end of therapy, and 6 months thereafter, to assess the virological response. Patients treated with Lamivudine and adefovir should be tested every 3 months after the transaminases are normal. For patients with HBeAg-negative disease, HBV DNA is the only way of assessing the response to therapy. Durability of virological response should be established by testing 1-3 monthly for 12 months after stopping therapy and every 6-12 months thereafter. It is not clear whether liver biopsy should be repeated in those showing a sustained biochemical and virological response.

Roadmap concept in management

As more and more data are emerging regarding the predictors of response in patients on therapy for hepatitis B, it may be possible to predict treatment failure early in the course of therapy in a significant number of patients. It has now become well known that using HBV DNA quantification at 6 months, the likelihood of response to therapy can be predicted in many patients who are on antivirals especially adefovir or telbivudine. In these patents, if HBV DNA is more than 104 copies at 24 weeks of therapy, there may be a case for switching to a more potent agent or to add another agent to reduce the risk of emergence of drug resistance and to possibly improve the therapeutic efficacy. Data is emerging which suggest that HBsAg quantification may be helpful in predicting response to therapy in patients who are on IFN too. This information is useful in early identification and intervention in patients who are likely to be the nonresponders to a particular therapy based on these parameters. This approach is likely to come up in routine clinical practice in near future.


   Drug resistance and Virological Breakthrough Top


The resistance profiles of the nucleos(t)ide analogues, and the principles of management are outlined in Table 5. The patient is considered to have drug resistance if he has virological breakthrough as outlined above despite good compliance. Such patient requires switch to another drug to which the virus is sensitive. However, as outlined above, patients with resistance to one of the antivirals is likely to have cross-resistance to drugs with similar resistance profiles. For example, patients with lamivudine resistance are likely to develop cross resistance to telbivudine and entecavir, especially after long-term use. Similarly, patients with adefovir resistance may have cross-resistance to tenofovir over long term though short-term data does not suggest significant cross-resistance between the two drugs. To prevent the problem of drug resistance, it is recommended that the treatment should be initiated with drugs that have a high efficacy and high genetic barrier to resistance. Tenofovir and entecavir fulfill most of these criteria and should be considered as first line nucleos(t)ide analogues for antiviral therapy. Lamivudine monotherapy should be discouraged especially in patients who require long-term therapy as it is associated with very high resistance rates especially in the long term. Adefovir also is a low potency drug with relatively high resistance rates and should be avoided as monotherapy, especially in patients with high baseline HBV DNA loads. However, a combination of lamivudine and adefovir is associated with low resistance rates and relatively good long term efficacy and may be considered in selected patients with economic constraints or nonavailability of other agents.

PEG IFN has a major advantage of being free of risk of drug resistance and being effective in patients with resistance to other antivirals. It should be strongly considered in selected patients with favorable profile of high ALT levels with low HBV DNA levels, where it may lead to sustained remission in a significant proportion of patients. It may also be considered in selected treatment nonresponders with high ALT levels and/or significant necroinflammation on liver biopsy as these patients have a relatively good chance of successful therapy with IFN.


   Management of Special Subgroups Top


Management of special subgroups is in itself a vast subject. This would not be discussed in detail in this review; however, the broad principles of management are outlined below.

HBV/hepatitis C virus (HCV) and HBV/hepatitis D virus (HDV) coinfections: PEG IFN/ribavirin combinations seems to be efficacious in treating HCV co-infections, whereas high dose IFN (9 MU, 3 times/week) or PEG IFN for 1-year is recommended for HDV coinfections and has been shown to improve long-term outcomes in these patients.

HIV coinfection: The disease course is accelerated in the presence of HIV, and the response to IFN is reduced. PEG IFN should be considered if the patient has CD4 counts >500/μL. Adefovir is another option that has minimal efficacy against HIV but has minimal risk of resistance on long-term use in co-infected patients. Entecavir and telbivudine should be avoided to prevent the emergence of drug-resistant mutations. Lamivudine monotherapy should not be used due to high risk of drug resistance. Treatment in patients who have advanced disease is with emtricitabine/tenofovir based HAART.

Patients who require immunosuppressive therapy should be given prophylactic antiviral therapy to prevent reactivation of disease. Patients who require finite course of antivirals should be evaluated at baseline. If their HBV DNA load is low and if anticipated duration of immunosuppression is <1-year, lamivudine or telbivudine are acceptable antivirals and should be stopped after 6 months of immunosuppression withdrawal. If baseline viral load is high and/or the anticipated duration of immunosuppression is longer, more potent regimens like lamivudine/adefovir combination; entecavir or tenofovir monotherapy should be considered.

Women of childbearing age who are on IFN should avoid pregnancy. Telbivudine and tenofovir are category B drugs and can be continued during pregnancy. Lamivudine, adefovir and entecavir are listed as category C drugs. However, there is considerable data to show safety of lamivudine, tenofovir and emtricitabine during pregnancy in HIV-infected females.


   Conclusions Top


Management of CHB has changed considerably over the last decade due to advances in diagnostic modalities. The present emphasis is in identifying and treating patients at high risk of disease progression as effective antiviral therapy arrests disease progression, reduces complications and can potentially reverse liver damage if given for sufficient duration. The treatment should be initiated with drugs that have high potency and high genetic barrier to resistance and compliance should be ensured once decision to treat is initiated. Resistant patients are difficult to treat and preferably combination treatment with high potency and high genetic barrier drugs should be used to avoid treatment failure. Close monitoring of both treated and untreated patients for disease progression should be done, and early intervention is required to prevent complications in those who show progression over time.

 
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Correspondence Address:
Subrat K Acharya
Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.190079

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    Abstract
   Introduction
    Life Cycle and N...
    Therapeutic End ...
    Therapy in Chron...
   Interferon
   Lamivudine
   Adefovir Dipivoxil
   Entecavir
   Tenofovir
   Telbivudine
   Other Drugs
   Combination Therapy
    Baseline Evaluat...
   Decision to Treat
    Current Treatmen...
    Drug resistance ...
    Management of Sp...
   Conclusions
    References
    Article Figures
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