Update on Hepatitis B Virus Infection: Focus on Treatment

This review article is an update of the current treatment strategies available for chronic hepatitis B. In addition to achieving on-therapy clinical remission and suppression of HBV replication without resistance, the ultimate goal of therapy is the development of sustained remission and HBsAg loss after discontinuation of treatment. This is the closest possible to cure outcome for hepatitis B virus (HBV) infection. These goals can be achieved by response-guided courses of pegylated interferon (peg-IFN)-alpha at rates higher than 30%, both in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. Review of the data regarding discontinuation of long term NA treatment in HBeAg-negative patients revealed that stopping such therapy is safe with high rates of sustained off treatment responses that appear to be immunologically induced. Decreasing hepatitis B surface antigen (HBsAg) titers under therapy to <500, particularly <100 IU/mL, and adding a course of peg-IFN to ongoing long term nucleos(t)ide analogue (NA) therapy increase the percentage of sustained responses following discontinuation of NA treatment.     

Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: a retrospective analysis

Autoimmune hepatitis commonly relapses after corticosteroid therapy, and long-term management strategies have been proposed based on the premise that repeated relapses after drug withdrawal are inevitable. Our goal was to determine the frequency that remission can be sustained after its induction and termination of therapy. A total of 107 patients who had entered remission on conventional regimens were assessed for sustained remission after initial treatment and after relapse and re-treatment. Re-treatment strategies included conventional regimens and long-term maintenance schedules. Twenty-two patients (21%) achieved a sustained remission after initial treatment, and 24 of 85 patients who relapsed and were re-treated (28%) had a similar outcome. The probability of a sustained remission was 47% after 10 years of follow-up. Patients who sustained remission after initial therapy were distinguished only by a lower serum gamma-globulin level at entry. Conventional re-treatment schedules after relapse were able to induce a sustained remission more commonly then long-term maintenance schedules (59% vs. 12%, P =.00002). In conclusion, patients who respond to initial corticosteroid therapy can achieve a sustained remission after treatment withdrawal or after relapse and re-treatment. All patients are candidates for this outcome, and withdrawal of medication, even during maintenance schedules, is necessary to assess its likelihood.     

Can we stop nucleoside analogues before HBsAg loss?

Most of the current guidelines and the existing data suggest that long‐term therapy with nucleos(t)ide analogue(s) [NA(s)] may be stopped in carefully selected chronic hepatitis B patients who remain HBsAg positive. In particular, NA(s) may be discontinued in such patients without pre‐existing cirrhosis who achieved long‐term on‐therapy virological remission (>12 months of HBeAg seroconversion and HBV DNA undetectability for initially HBeAg‐positive cases; ≥3 years of HBV DNA undetectability for HBeAg‐negative cases) and are expected to remain under close follow‐up after NA(s) discontinuation. The majority of patients will develop post‐NA(s) virological relapses and a proportion of them will have biochemical relapses and occasionally flares, but prompt retreatment can reintroduce remission. No reliable predictor(s) of post‐NA(s) relapses have been identified so far. HBsAg loss develops in a progressively increasing proportion of chronic hepatitis B patients who discontinue NA(s) with HBsAg loss rates being higher in Caucasian patients with HBeAg‐negative chronic hepatitis B. Follow‐up at least every 3 months for the first year seems to be appropriate for all chronic hepatitis B patients who discontinue NA(s), while HBeAg‐negative patients need to be followed more closely (monthly) during the first 3 months. Predefined criteria for retreatment are quite important, and the best candidates for retreatment are probably the patients with persistent (≥3 months) liver disease activity and those with severe flares.     

Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy

Acute exacerbations of chronic hepatitis B virus (HBV) infection occur after withdrawal of lamivudine therapy in approximately 16% of patients and are considered of little clinical significance. We observed "lamivudine withdrawal hepatitis" accompanied by jaundice and incipient liver failure, but also followed by complete recovery and viral clearance. To investigate the incidence, severity, timing, and virologic characteristics of "lamivudine withdrawal hepatitis" we monitored 41 patients for at least 6 months after discontinuation of nucleoside analogue therapy. The incidence of hepatitis flares was estimated to be 7 of 41 (17%); in 2 of 41 cases (5%), hepatitis flares were associated with jaundice and incipient liver failure. A noticeable feature of the "lamivudine withdrawal hepatitis" flares were the high HBV-DNA levels at the time of the alanine transaminase (ALT) peak. All were wild-type HBV, even the one that emerged from a lamivudine-resistant strain during therapy. To minimize the risk of liver failure and to enhance the elimination of HBV following flares, lamivudine therapy was reinstituted in an icteric patient. Clinical and biochemical remission ensued, followed by loss of HBV DNA and hepatitis B e antigen (HBeAg) seroconversion. Such a virologic response did not occur in 5 other patients with a nonicteric "lamivudine withdrawal hepatitis," who were not retreated with lamivudine. Hepatitis after withdrawal of lamivudine resembles acute hepatitis B with a predominance of anicteric flares within a time frame of 6 months. Active management of hepatitis flares following withdrawal of nucleoside analogue therapy should be investigated further.     

Sustained remission after corticosteroid therapy of severe hepatitis B surface antigen-negative chronic active hepatitis

To determine the frequency of a sustained remission and to assess the long-term prognosis of relapse and retreatment, 66 patients with severe hepatitis B surface antigen-negative chronic active hepatitis and prolonged follow-up after initial corticosteroid withdrawal (mean, 10 +/- 0.4 yr) were evaluated. Selection of patients was made from among 206 cases of severe disease. Twenty-four patients (36%) sustained remission for at least 5 yr (mean, 11 +/- 0.6 yr) after initial therapy, and 42 (64%) relapsed and were retreated. Patients who sustained remission had shorter durations of illness before therapy (8 +/- 1 vs. 14 +/- 2 mo, p less than 0.05) and they had greater laboratory improvements during treatment. The frequencies of cirrhosis and death were not significantly greater in patients who relapsed. Of the 42 patients who relapsed, 9 (21%) ultimately entered a sustained remission after retreatment. Remission for at least 5 yr was possible in 33 of the 66 patients (50%). Major drug complications developed more commonly in those who relapsed and required retreatment (59% vs. 29%, p less than 0.05). We conclude that 50% of patients who enter remission during initial therapy may ultimately achieve a sustained remission, especially if their disease is of short duration and adequately suppressed during treatment. Relapse does not affect long-term prognosis, but retreatment is associated with more side effects.     

Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B

BACKGROUND: Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19-50% of patients after stopping therapy, some of whom develop liver decompensation. AIMS: To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. SUBJECTS AND RESULTS: Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. CONCLUSION: Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.     

Antiviral therapy for hepatitis B virus‐related decompensated cirrhosis

Antiviral therapy is important in patients with hepatitis B virus (HBV)‐related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child–Pugh or model for end‐stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first‐line therapy for nucleos(t)ide analogue (NA)‐naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug‐resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug‐resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV‐related cirrhosis and a long‐term follow‐up in China, where a large number of such patients are found, are recommended.     

Adefovir dipivoxil is effective for the treatment of cirrhotic patients with lamivudine failure

Background/Aims: Data on the efficacy of adefovir dipivoxil (ADV) in elderly and cirrhotic patients with lamivudine‐resistant (LAM‐R) chronic hepatitis B are scarce. This retrospective cohort study evaluated the safety and efficacy of ADV in this specific patient population. Methods: Sixty‐eight cirrhotic LAM‐R patients, of whom 19 (27.9%) were elderly (≥65 years of age) and nine had severe disease (two post‐orthotopic liver transplantation, four pre‐orthotopic liver transplantation and three decompensated), with hepatitis B virus (HBV) infection received ADV. Virological and biochemical responses to the addition of ADV were analysed. Results: At inclusion, all patients were receiving LAM; ADV was added. 75.4% of patients received a combination of LAM and ADV throughout this study for a median treatment duration of 12.6 months; the remainder received ADV with an overlap with LAM treatment for a median duration of 7.9 months. At the end of follow‐up, 41.2% of patients had undetectable HBV DNA (≤2000 copies/ml) with a median reduction of 3.4 log₁₀ copies/ml. Time to reach undetectable HBV DNA was dependent on baseline alanine aminotransferase (ALT) levels and HBeAg status. Normalization of serum ALT levels was observed in 55.2% (32/58) of patients. In patients who were HBeAg positive at baseline, HBeAg loss and seroconversion occurred in 23% (9/39) and 10% (4/39) respectively. No resistance mutations and no significant side effects were observed during the study period. Conclusion: Adefovir dipivoxil provides effective and safe treatment in cirrhotic and elderly patients who failed LAM therapy.     

核苷(酸)类似物抗乙型肝炎病毒达到治疗终点标准停药后复发的相关因素分析

目的 探讨影响核苷(酸)类似物(NA)治疗慢性乙型肝炎(CHB)患者达到治疗终点标准(达标)停药后复发的相关因素.方法 CHB患者81例,接受NA抗病毒治疗.拉米夫定(LAM)治疗38例,阿德福韦酯(ADV)25例,恩替卡韦(ETV)12例,LAM+ADV 6例.HBeAg阳性40例,NA初治患者67例,耐药复治14例.达标停药或延长疗程后停药,分别于基线、病毒学应答前每个月、病毒学应答后每3个月、停药后半年内每个月、半年后每2个月检测HBV DNA、HBV血清学标志物和ALT.将性别、年龄、乙型肝炎家族史、基线HBV DNA、基线HBeAg、基线ALT、病毒学应答时间、总疗程(月)、延长疗程(月)、初治或耐药复治、停药时HBsAg水平、药物种类共12个可能影响复发的因素进行单因素、多因素Cox比例风险模型和分层分析,累计复发率采用Kaplan-Meier法计算.结果 81例患者达标停药后,36例患者在1年内复发,占44.4%.初治或耐药复治、乙型肝炎家族史、病毒学应答时间、停药时HBsAg水平分别是影响停药后复发的独立危险因素.耐药复治者复发率高于初治患者(78.6%比37.3%,χ2=7.983,P=0.005),有乙型肝炎家族史的患者复发率高于无乙型肝炎家族史者(64.5%比15.0%,χ2=12.096,P=0.002),病毒学应答发生在3个月内的患者复发率低于发生在3个月后的患者(34.0%比64.3%,χ2=6.823,P=0.009),停药时HBsAg≤150μg/L的患者复发率低于>150μg/L者(27.6%比53.8%,χ2=5.199,P=0.023).结论 耐药复治、有乙型肝炎家族史、病毒学应答时间晚、停药时高水平HBsAg是导致NA治疗停药后复发的主要因素.对此类患者治疗达标后应适当延长疗程,巩固疗效.

Abstract：

Objective To explore the influence factors on hepatitis B virus (HBV) relapse after nucleos(t)ide analogues (NA) withdrawal in the chronic hepatitis B (CHB) patients who met NA cessation criteria. Methods Eighty-one consecutive CHB patients were treated with NA, 38 with lamivudine (LAM), 25 with adefovir dipivoxil (ADV), 12 with entecavir (ETV), 6 with LAM +ADV. Among recruited patients, 40 were hepatitis B virus e antigen (HBeAg) positive, 41 were HBeAg negative, 67 of them were initial treatment, 14 were retreatment due to resistance to NA at baseline. The treatment was discontinued after meeting China therapeutic end-point criteria. HBV DNA, HBV serological markers, alanine aminotransferase (ALT) were measured respectively at baseline, every month before virological response, every 3 months after virological response, every month within first 6 months and every 2 months over 6 months after drugs withdrawal. Twelve probable influence factors on relapse which were sex, age, HBV family history, baseline HBV DNA,baseline HBeAg status, baseline ALT, virological response time, total duration of treatment, duration of additional treatment, the level of hepatitis B virus surface antigen (HBsAg) at cessation therapy,initial treatment or retreatment, drug category were analyzed with univariate, multivariate Cox regression modle and stratified analysis. The cumulative relapse was calculated by the Kaplan-Meier method. Results A total of 36 patients (44. 4%) relapsed within 1 year. Initial treatment or retreatment, HBV family history, virological response time, the level of HBsAg at cessation therapy were independent risk factors. The relapse rate of retreatment was higher than that of initial treatment (78.6% vs 37. 3% , χ2 = 7. 983, P = 0. 005) , those of patients with HBV family history higher than without family history (64. 5% vs 15.0%, χ2 =12. 096,P = 0.002), those of patients obtained virological response within 3 months lower than after 3 months(34. 0% vs 64. 3% , χ2 =6. 823,P=0. 009) , those of patients with HBsAg≤150 μg/L at cessation therapy lower than >150 μg/L(27. 6% vs 53. 8%, χ2=5. 199,P=0. 023). Conclusions Retreatment, HBV family history, later virological response and higher HBsAg level at cessation therapy are risk factors of relapse after NA withdrawal. Such patients should be treated with prolonged duration after meeting end-point criteria to strengthen the efficacy.     

Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg‐negative chronic hepatitis B

The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg‐negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off‐treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off‐treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed ‘inactive carriers’) served as controls. Results were validated using qRT‐PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long‐term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off‐treatment remission segregated as a distinct out‐group. Twenty‐one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off‐treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78‐0.92. IFNγ, IL‐8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long‐term NA therapy had expression levels of all these four genes below cut‐off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg‐negative CHB who remain in off‐treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL‐8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy.     

Consequences of treatment withdrawal in type 1 autoimmune hepatitis.

BACKGROUND AND AIMS: Drug-related side effects are considered the major consequences of relapse and re-treatment in patients with autoimmune hepatitis. Our goals were to determine whether relapse is associated with disease progression and whether treatment end points can be refined. METHODS: The outcomes of 132 patients with definite type 1 autoimmune hepatitis who had been treated comparably until remission were assessed retrospectively after drug withdrawal. RESULTS: Patients who had relapsed repeatedly after initial treatment withdrawal developed cirrhosis more commonly than patients who sustained remission (18/48 vs 1/22, P=0.004), and those who relapsed once (18/48 vs 2/21, P=0.02). Hepatic death or the need for liver transplantation was also more frequent in the patients who had multiple relapses than those who sustained remission (13/64 vs 0/30, P=0.008) and those who relapsed once (13/64 vs 1/38, P=0.02). Patients who sustained their remission had a higher frequency of normal laboratory indices at drug withdrawal than patients who relapsed (88% vs 46%, P=0.003). Adverse outcomes after relapse did not distinguish patients until after 5 years of observation. CONCLUSIONS: Multiple relapses are associated with a poorer prognosis than sustained remission or single relapse episodes. Initial treatment to resolution of laboratory abnormalities may afford the greatest opportunity to prevent relapse.     

Effect of nucleoside analog‐interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B

Aim: Nucleoside analog (NA)‐interferon (IFN) sequential therapy may enable the long‐term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA‐IFN sequential therapy for acute exacerbation of CHB. Methods: A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN‐α 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN‐α alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results: Four out of nine (44.4%) HBeAg‐positive and all three HBeAg‐negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core‐related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion: NA‐IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment.     

Improving the end point of corticosteroid therapy in type 1 autoimmune hepatitis to reduce the frequency of relapse

OBJECTIVE: Relapse of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to corticosteroid withdrawal, and liver tissue examination prior to the termination of therapy may be insufficient to predict subsequent course. Our goal was to refine treatment end point criteria so as to reduce the frequency of relapse after drug withdrawal. METHODS: One hundred thirty-two patients with definite type 1 autoimmune hepatitis who fulfilled clinical, laboratory, and histological criteria for remission were evaluated. The degree of laboratory improvement at the termination of treatment was correlated with subsequent clinical course in patients who had improved to normal or near-normal histological findings during corticosteroid therapy. RESULTS: Serum aspartate aminotransferase (AST) levels at the end of treatment were higher in patients who subsequently relapsed than in those who sustained remission (32 +/- 2 U/L vs 25 +/- 2 U/L, P= 0.04). Serum gamma-globulin (1.4 +/- 0.1 g/dL vs 1.2 +/- 0.1 g/dL, P=0.03) and immunoglobulin G (IgG) (1,416 +/- 55 mg/dL vs 1,079 +/- 57 mg/dL, P=0.001) levels were also higher in these patients prior to termination of therapy. The frequencies of abnormal serum AST (40%vs 13%, P=0.008), gamma-globulin (25%vs 3%, P=0.009), and IgG levels (36%vs 4%, P=0.001) at treatment withdrawal were also greater in the patients who subsequently relapsed. CONCLUSIONS: Patients who are treated to normal serum AST, gamma-globulin, and IgG levels have a lower frequency of relapse than others despite comparable histological findings.     

Histological responses of peginterferon alpha add‐on therapy in patients with chronic hepatitis B with advanced liver fibrosis after long‐term nucleos(t)ide analog treatment

Although long‐term antiviral treatment with nucleos(t)ide analogs (NAs) can lead to histological improvement in patients with chronic hepatitis B (CHB), a substantial proportion of patients still fail to achieve regression of fibrosis. Here, we investigated whether peginterferon alpha (Peg‐IFNα） add‐on therapy had benefits on fibrosis regression in patients with sustained severe fibrosis even after long‐term NA treatment. We conducted a retrospective analysis of data from 50 patients with CHB receiving 48 weeks of Peg‐IFNα add‐on therapy. All enrolled patients had advanced fibrosis or cirrhosis (S score ≥ 3) at baseline and underwent NA treatment for at least 1 year before Peg‐IFNα addition. Paired liver biopsies before and after Peg‐IFNα add‐on treatment and laboratory tests at baseline, 24 weeks of treatment, 48 weeks of treatment and long‐term follow‐up were analysed. Of the 50 patients enrolled in this study, 34 patients (68.0%) had significant regression of fibrosis, and 42 (84.0%) showed significant remission of inflammation after Peg‐IFNα add‐on treatment. Compared with nonresponders, patients with significant histological improvement showed faster hepatitis B surface antigen (HBsAg) decline and tended to have higher cumulative hepatitis B e antigen (HBeAg) and HBsAg loss rates during long‐term follow‐up. Peg‐IFNα add‐on therapy led to significant regression of fibrosis and resolution of inflammation in patients with advanced fibrosis after long‐term NA treatment.     

Clinical features and management of autoimmune hepatitis

Autoimmune hepatitis（AIH） is a chronic hepatitis of unknown etiology which can progress to cirrhosis.Its clinical manifestations are highly variable and some-times follow a fluctuating course.Diagnosis is based on characteristic histologic,clinical,biochemical and sero-logical findings.Anti-inflammatory/immunosuppressive treatment frequently induces remission but long-term maintenance therapy is often required.Liver transplantation is generally successful in patients with decompensated cirrhosis unresponsive to or intolerant of medical therapy.     

Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues

The clinical relevance of viral blipping during nucleos (t) ide analogue (NA) treatment is unclear in chronic hepatitis B (CHB). We investigated the prevalence, risk factors and clinical outcomes for those with viral blipping during NA treatment. A retrospective cohort study investigated consecutively treated CHB patients from May 2008 to February 2015 on the NAs such as entecavir (ETV), tenofovir (TDF) and lamivudine (LAM). Included patients were previously treatment naive. Viral blipping was defined as serum HBV DNA >20 IU/mL on one occasion, and not >200 IU/mL, with subsequent measurement returning to undetectable levels, that is <20 IU/mL. A total of 242 treatment‐compliant CHB patients were included with 44 (18.2%) experiencing viral blipping. In multivariable Cox regression, Asian race (HR=7.40, 95% CI 1.01–54.29, P<.049), LAM therapy (vs ETV/TDF, HR=2.53, 95% CI 1.29–4.95, P<.007), higher creatinine (per SD, HR=1.47, 95% CI 1.21–1.79, P<.001), HBeAg positivity (HR=2.68, 95% CI 1.39–5.03, P<.003) and longer time to achieve undetectable HBV DNA (per month, HR=1.05, 95% CI 1.02–1.08, P=.001) were associated with an increased risk of viral blipping. Viral blipping did not show any significant association with viral breakthrough, HBsAg loss, ALT flares or disease progression. Viral blipping is a frequent event during NA therapy; however, it did not lead to any clinically significant outcomes. Thus, it may not require more frequent blood work and patient visits in clinical practice.     

Management of chronic hepatitis B before and after liver transplantation

Liver transplantation remains the only curative option for eligible patients with complications of chronic hepatitis B (CHB) infection, including severe acute hepatitis flares, decompensated cirrhosis, and hepatocellular carcinoma. In general, all patients with CHB awaiting liver transplantation should be treated with oral nucleos(t)ide analogs (NAs) with high barriers to resistance to prevent potential flares of hepatitis and reduce disease progression. After liver transplantation, lifelong antiviral therapy is also required to prevent graft hepatitis, which may lead to subsequent graft loss. Although combination therapy using NA and hepatitis B immune globulin (HBIG) has been the regimen most widely adopted for over a decade, recent studies have demonstrated that newer NAs with low rates of resistance are effective in preventing graft hepatitis even without the use of HBIG, achieving excellent long term outcome. For patients without pre-existing resistant mutations, monotherapy with a single NA has been shown to be effective. For those with resistant strains, a combination of nucleoside analog and nucleotide analog should be used. To date, clinical trials using therapeutic vaccination have shown suboptimal response, as CHB patients likely have an immune deficit against HBV epitopes. Future strategies include targeting different sites of the hepatitis B replication cycle and restoring the host immunity response to facilitate complete viral eradication.     

Add‐on combination therapy with adefovir dipivoxil induces renal impairment in patients with lamivudine‐refractory hepatitis B virus

Summary. Combination therapy with adefovir dipivoxil (ADV) and lamivudine (LAM) is recommended for patients infected with LAM‐refractory hepatitis B virus (HBV). However, the effects of such therapy on renal function and serum phosphorus levels have not been fully evaluated. Combination therapy with ADV and LAM was given to 37 patients infected with LAM‐refractory HBV, including 17 with hepatic cirrhosis. Serum HBV DNA levels decreased to below 2.6 log₁₀ copies/mL in 23 (62%) of 37 patients at 12 months, 25 (78%) of 32 patients at 24 months, and 16 (84%) of 19 patients at 36 months. Except for one cirrhotic patient, serum alanine aminotransferase levels were below 50 IU/L in all patients during combination therapy. Serum creatinine levels increased in 14 (38%) of 37 patients, and serum phosphate levels decreased to below 2.5 mg/mL in 6 (16%) of 37 patients during combination therapy. Patients who received combination therapy for 36 months or longer had a significantly incidence of elevated serum creatinine levels. Fanconi syndrome occurred in a 57‐year‐old woman with cirrhosis after ADV was added to LAM. Combination therapy with ADV and LAM can maintain biochemical remission in patients with LAM‐refractory HBV. However, the dosing interval of ADV should be adjusted according to renal function and serum phosphate levels in patients receiving long‐term treatment.     

The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1–infected patients who do or do not achieve sustained virological response to therapy

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost‐effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium‐term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS ‘Payment by Results’ database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non‐SVR) with mean follow‐up of 3.5 (SVR) and 4.9 (non‐SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non‐SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5‐year post‐treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13‐fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56‐fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real‐life data for future cost‐effectiveness analyses related to the treatment for chronic HCV infection.     

Highly active antiretroviral therapy improved persistent lamivudine‐resistant viremia in acute hepatitis B virus genotype Ae infection with coinfection of human immunodeficiency virus

A 57‐year‐old man developed acute hepatitis B virus (AHB), caused by HBV genotype Ae. Lamivudine (LAM) therapy was started at 8 months after the disease onset, because the infection was persistent, but not self‐limited. Despite LAM therapy, the hepatitis became chronic. Further, virological breakthrough developed due to the emergence of LAM‐resistant YMDD mutants at 11 months after LAM therapy. Adefovir dipivoxil (ADV) was combined with LAM against breakthrough hepatitis at 28 months after LAM therapy. Sequential genetic analysis revealed that rtL217R, a mutation potentially diminishing the ADV efficacy, was detected before and after the combination therapy. During the follow‐up period, the patient unexpectedly turned out coinfected with human immunodeficiency virus (HIV) by measuring anti‐HIV‐1 antibody. At that time, LAM‐resistant HIV mutation, M184V, had been already detected. We switched from the combination therapy with LAM plus ADV to highly active antiretroviral therapy (HAART), which included tenofovir disoproxil fumarate. HAART drastically improved LAM‐resistant viremia and breakthrough hepatitis as well as HIV viremia and CD4 counts. Even in Japan, HBV genotype and HIV coinfection should be determined early in the treatment of AHB, and early induction of nucleotide analogs should be taken into consideration, because the proportion of AHB patients with HBV genotype A and the number of patients horizontally coinfected with HBV and HIV are increasing.