Hepatitis D virus infection: Progress on the path toward disease control and cure.

This article discusses the impact of Hepatitis D virus (HDV) infection as a major cause of liver-related morbidity and mortality in people with Hepatitis B virus (HBV) infection. The article reviews the current knowledge and unanswered questions about the epidemiology, pathogenesis, and natural history of HDV infection. Although effective treatments for HDV infection have been elusive, interferon alfa is recommended for at least 48 weeks. However, response rates with standard-of-care peginterferon alfa are suboptimal, leading to few patients with a sustained virologic response. The article proposes novel approaches to treating HDV and HBV, including targeting reduction or loss of hepatitis B surface antigen (HBsAg) reduction, and discusses potential strategies for achieving HBsAg loss in patients with chronic HBV infection. Finally, the article discusses the landmark decision of accepting viral and biochemical surrogates by regulatory authorities, opening the door for the clinical development of drugs for patients with HDV infection.

Entecavir combined with interferon-α Is superior to entecavir monotherapy in reducing hepatic and extrahepatic cancer in patients with chronic hepatitis B.

BACKGROUND: The objective of this study was to assess whether entecavir (ETV) in combination with interferon-α (IFN-α) could reduce hepatocellular cancer (HCC) and extrahepatic cancers (EHCs) in patients with chronic hepatitis B (CHB). METHODS: The cohort consisted of 4194 patients with CHB treated with ETV combined with IFN-α or ETV monotherapy at a tertiary hospital in Beijing, China, from January 2009 to December 2017. The risks, hazard ratios (HRs), and 95% confidence intervals (CIs) of HCC and EHCs were compared in the 2 groups. RESULTS: In a multivariate Cox regression analysis, a significantly lower risk of HCC (HR, 0.6; 95% CI, 0.3-0.9; P = .0310) and a marginally significantly lower risk of EHCs (HR, 0.2; 95% CI, 0.02-1.3; P = .0854) were observed in the group receiving ETV combined with IFN-α in comparison with the ETV monotherapy group. The annual virological response rates were significantly higher in the combination therapy group versus the monotherapy group (33.8% vs 21.2%; P < .0001), but the hepatitis B surface antigen (HBsAg) seroclearance rates were not (1.2% vs 0.9%; P = .8537). The HRs were consistent with propensity score-based matching, inverse probability weighting adjustments, and adjustments for virological response and HBsAg seroclearance. CONCLUSIONS: ETV combined with IFN-α therapy is superior to ETV monotherapy in reducing the risk of HCC and EHCs for patients with CHB. People who can tolerate and benefit from IFN-α therapy could consider combination therapy.

Can Interferon Therapy Change the Natural Course of Hepatitis Delta Infection?: a Clinical and Pathological Study.

Chronic delta hepatitis (CDH) has a worse outcome than other types of viral hepatitis. High-dose, long-term alpha interferon (IFN-α) is the approved treatment and may ameliorate the course of infection. We evaluated long-term histological outcomes of CDH patients treated with IFN-α. Patients with histologically proved noncirrhotic CDH who were treated with high-dose IFN-α for at least 1 year were classified as cirrhotic or noncirrhotic at the end of treatment. Noncirrhotic patients also had posttreatment liver biopsies. Patients were designated histologically responsive or nonresponsive on the basis of fibrosis status. Histological, virological, and biochemical courses were analyzed. Forty-eight patients were treated with IFN-α (conventional and/or pegylated) for a median of 24 months with a posttreatment follow-up of 5 years. During the follow-up, cirrhosis developed in 24 patients, 5 of whom were decompensated. There was no difference between pre- and posttreatment fibrosis scores for 24 noncirrhotic patients at the end of follow-up. Among patients, 13% (n = 6) had decreased, 21% (n = 10) had steady, and 16% (n = 8) had increased fibrosis scores. Persistent viral response (PVR) was achieved in 16 patients (33%). Twenty percent of the entire group was histologically responsive (decreasing or steady fibrosis scores with improved necroinflammatory scores), while nearly 80% had histological progression/cirrhosis. PVR was significantly associated with histological response. The long-term natural course of patients who were treated with high dose IFN-α for at least 1 year was evaluated clinically and histologically. Despite the association of PVR with histological response, IFN-α treatment did not change the natural course of CDH; clinical and histological progression continued in two-thirds of the cases despite treatment.

Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. METHODS: A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6 months post-treatment and defined as achieving both <2000 IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000 IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. RESULTS: The median follow-up period was 7.2 years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P < .001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P = .01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. CONCLUSIONS: During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.

[Efficacy and safety of bulevirtide in patients with chronic hepatitis D and compensated cirrhosis].

AIM: To study the efficacy and safety of bulevirtide, the HBV and HDV entry inhibitor. MATERIALS AND METHODS: Analysis of the results of using bulevirtide in randomized controlled open-label comparative studies MYR202 and MYR203 in 56 patients with chronic hepatitis D and compensated cirrhosis, in monotherapy and combination with pegylated interferon alpha-2a (PEG-IFN). RESULTS: Monotherapy with bulevirtide for 24 weeks in the MYR202 study in 46 patients with compensated liver cirrhosis demonstrated: 1) a high rate of virological (100%) and biochemical response (alanine aminotransferase normalization rate 45.7%), 2) superiority of bulevirtide in efficacy over the control group (tenofovir), 3) comparability of treatment efficacy in patients with and without cirrhosis, 4) no progression of liver fibrosis with elastometry in most patients. Treatment with bulevirtide in monotherapy and combination with PEG-IFN for 48 weeks in 10 patients with compensated liver cirrhosis in the MYR203 study was accompanied by a high rate of virological response (80%) and normalization of alanine aminotransferase (70%). Bulevirtide was well tolerated, there was no deterioration in tolerability compared with patients without cirrhosis, there were no serious adverse events and cases of treatment cancellation due to adverse events. CONCLUSION: Bulevirtide is recommended as the first line of treatment for chronic hepatitis D in patients with compensated cirrhosis in monotherapy and combination with PEG-IFN.

Pathogenesis of and New Therapies for Hepatitis D.

Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.

Roadmap to functional cure of chronic hepatitis B: An expert consensus.

Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.

Recent developments in biologic therapies for the treatment of patients with systemic lupus erythematosus.

SLE has a complex pathogenesis, and multiple therapeutic targets have been discovered in recent years. In spite of belimumab being approved by the US Food and Drug Administration and the widespread use of rituximab, there have been many failed attempts to treat SLE successfully using biologic agents. In this review, we consider newer biologic approaches that might offer the hope of improving the outcome of SLE patients. These include the fully humanized anti-CD20 mAbs, PEGylated anti-CD40L, IFNα inhibitors, rigerimod and immune complexes blockade.

Interprofessional team-based approach to patients with chronic hepatitis C and personality disorder: Three case studies.

Hepatitis C virus is a blood borne pathogen that infects 130 million people worldwide. After a prolonged period of slowly progressive liver injury, those infected are at risk of advancing to end stage liver disease, with its associated complications, and hepatocellular carcinoma. Rates of past and/or current substance use and behavioral comorbidities are higher among those infected with hepatitis C compared to the general population. A number of patient, provider and system barriers to care and treatment have led to low rates of treatment initiation in this population despite pharmacologic advances that have made hepatitis C a curable disease. Innovation in care delivery is considered a key strategy that will help reach more patients. We present three case studies of patients with chronic hepatitis C and multiple psychiatric comorbidities who were successfully engaged in care and treated for their chronic hepatitis C in our multidisciplinary primary care-based program.

Successful pregnancies in patients with BCR-ABL-positive leukemias treated with interferon-alpha therapy during the tyrosine kinase inhibitors era.

BACKGROUND: Management of pregnant patients with BCR-ABL-positive leukemia is challenging. Managing a patient who has been diagnosed while pregnant requires a different approach as compared to a patient who plans to become pregnant while on the treatment with tyrosine kinase inhibitor (TKI). Interferon (IFN)-alpha is a useful option in both situations due to teratogenic potential of TKIs. METHODS: We presented a series of 12 successful pregnancies in 11 women with BCR-ABL-positive leukemia, whose leukemia was managed with IFN-alpha throughout their pregnancy. RESULTS: All children have normal growth and development. All patients remained at least in hematological response and could start or resume TKI after delivery or breastfeeding. CONCLUSION: Because of the increased risk of teratogenicity and spontaneous abortion in female patient with pregnancy, when receiving TKI, IFN-alpha can be considered a safe drug to be administered throughout pregnancy and could represent the drug of choice in this situation during the era of TKI therapy.

[Clinical value of pegylated interferon-α plus ribavirin-based therapy in antiviral treatment of chronic hepatitis C in China].

Chronic hepatitis C virus (HCV) infection is one of the most common causes of liver cirrhosis and hepatocellular carcinoma in China. The older standard treatment regimen for chronic hepatitis C was the pegylated interferon-alfa plus ribavirin(PR). Now newer oral medications called direct antiviral agents (DAAs) has been gradually changed to PR-based DAAs and interferon-free, oral DAAs; making chronic hepatitis C a curable disease. This article intends to expound the advantages and disadvantages of PR-based therapy and provide reference for the treatment of chronic hepatitis C.

[Clinical timing and benefit of antiviral treatment for hepatitis C].

Current treatments for hepatitis C include pegylated interferon-α (Peg-IFNα) and ribavirin (RBV) combination therapy and direct antiviral agents (DAAs). Antiviral treatment can be initiated after 4 to 6 months of clinical observations for patients with acute infections, but should be started as early as possible for those with chronic infections. However, for patients who are ineligible for Peg-IFN and RBV combination therapy and have no unrestricted access to DAAs, it is advised that they wait for the approval of DAAs in China if their medical condition is under control. Though, antiviral therapy should be started immediately if the disease progresses. It has been reported that there are numerous clinical benefits of antiviral treatment for hepatitis C. However, the long-term impact of DAAs treatment including efficacy and safety is limited and remains to be explored.

[HBsAg SEROCONVERSION IN THE TREATMENT OF CHRONIC HEPATITIS B WITH PEGYLATED INTERFERON].

The ideal goal of antiviral therapy or cure of chronic hepatitis B is HBsAg clearance and HBsAg seroconversion. According to modern guidelines of all Associations for liver diseases pegylated interferon alfa-2a and nucleos(t)ide analogues (entecavir, tenofovir) are first choice in the treatment of chronic hepatitis B. The aim of the study was to evaluate the success of the treatment of patients with chronic hepatitis B who received pegylated interferon. At the end of ten year period, HBV DNA <50 IU/ml and HBsAg seroconversion achieved 4 (4/55, 7.00%) patients. All were HBeAg negative. Additionally, is presented the case of patients, who, after the treatment, had the shortest period of healing. Patient is a man, aged 47 years, with the newly discovered HBeAg negative chronic hepatitis B and pronounced activity of serum aminotransferases. He was treated with pegylated interferon alfa-2a, 180 µg once a week, for 48 weeks. After antiviral therapy, the patient is HBV DNA negative, HBsAg negative and neat aminotransferases, and 12 months after completion of antiviral therapy comes to HBsAg seroconversion. The degree of cure of chronic hepatitis B, unfortunately, has not been entirely satisfactory, with the exception of the few individual cases.

[Diagnosis and treatment of chronic hepatitis B and D. National consensus guideline in Hungary from 15 October 2016]. / A hepatitis B- és D-vírus-fertozés diagnosztikája, antivirális kezelése. Magyar konszenzusajánlás. Érvényes: 2016. október 15-tol.

Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2017 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2017, 158(Suppl. 1) 23-35.

[Management and treatment of patients with hepatitis B]. / Manejo clínico y tratamiento de los pacientes con hepatitis B.

Chronic hepatitis B is a major cause of morbidity and mortality worldwide. Approximately one third of the world's population has serological evidence of past or present infection by hepatitis B virus (HBV) and 350-400 million people are chronic HBV surface antigen carriers. The aim of therapy is to prevent the onset of liver fibrosis and development of cirrhosis or hepatocarcinoma by sustained suppression of viral replication. Currently there are 2 strategies for the treatment of chronic hepatitis B: the pegylated interferon and long-term treatment with nucleoside/nucleotide analogues. Pegylated interferon has the advantage of being a treatment of limited duration, and is particularly suitable for patients with chronic hepatitis with positive HBeAg (hepatitis B e antigen), but the unfavorable adverse event profile and route of parenteral administration makes it less used than nucleoside/nucleotide analogues. Tenofovir and entecavir have shown to be potent inhibitors of HBV with a high genetic barrier to resistance and few adverse effects, so are considered as the first line therapy.

Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.

Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.

Optimal therapy of chronic hepatitis B: how do I treat HBeAg-positive patients?

Current agents for the treatment of chronic hepatitis B (CHB) can be classified into interferon-α (standard or pegylated) (IFN) and nucleos(t)ide analogues (NAs). IFN therapy has the advantage of a finite duration (48 weeks) with a chance for durable sustained off-treatment response in HBeAg positive CHB patients. However, these benefits are limited to approximately 30% of HBeAg positive patients, while parenteral administration and potential side effects are common patient concerns. Thus, patients who can benefit from IFN therapy must be carefully selected and monitored. Recently, stopping rules for IFN non-responders were developed based on 12-week HBsAg levels. NAs are currently used in most CHB patients. They are administered in one tablet daily and can be used in all patients with excellent tolerability and a good safety profile. The current first-line options, entecavir (ETV) and tenofovir (TDF), are highly potent with a minimal risk of resistance during long-term monotherapy. Prolongation of entecavir or tenofovir maintains the initially high virological remission rates in adherent HBeAg positive patients and modifies the long-term outcomes. The need for a long-term, perhaps indefinite, treatment duration is the main limitation of ETV or TDF, which may sometimes be safely discontinued in HBeAg positive patients who achieve stable HBeAg seroconversion. Since there will always be safety concerns and family planning issues with long-term therapy, NAs should be used carefully particularly in young HBeAg positive patients with minimal-mild liver disease.

Optimal therapy of chronic hepatitis B: how do I treat my HBeAg-negative patients?

HBeAg negative chronic hepatitis B (CHB) is a frequent, progressive and difficult-to-cure phase of CHB. The end-point of therapy is to persistently suppress viral replication to halt progression of liver disease. Two different treatment strategies are currently available: a short-term course of pegylated interferon alpha (PEG-IFN) or long-term therapy with nucleot(s)ide analogues (NA), i.e. entecavir or tenofovir. Young patients with mild-to-moderate stages of liver disease can benefit from a 48-week course of PEG-IFN, while NA may be preferred in patients with more severe liver disease, in older patients, and in those who do not respond, are unwilling or have contraindications to PEG-IFN. Nucleot(s)ide analogues provide persistent viral suppression and biochemical normalization in almost all patients, together with the regression of fibrosis and the prevention of decompensation, but the effect on hepatocellular carcinoma rates is limited. Thus, NAs have become the most popular treatment strategy worldwide but lifelong administration is associated with high cost, unknown safety and adherence issues and an unknown risk of drug-resistance over time as well as limited rates of HBsAg seroclearance. On the other hand, PEG-IFN treatment may achieve a SVR in nearly a quarter of patients ultimately leading to HBsAg loss in almost 30-50%. Interestingly, response rates to PEG-IFN may further increase with more careful patient selection based on age, ALT and HBV DNA levels at baseline and by applying early on-treatment stopping rules based on HBV DNA and HBsAg kinetics. The combination of NA and PEG-IFN is not currently recommended but numerous studies are ongoing.

[PEG-IFN/IFN monotherapy].

Pegylated-interferon(PEG-IFN)/interferon monotherapy for patients with chronic hepatitis C has been used for two clinical aims; one is for the elimination of hepatitis C virus (HCV), and the other is for the inhibition of hepatocarcinogenesis. In patients with a rapid viral response to PEG-IFN, PEG-IFN monotherapy can efficiently eradicate HCV with decreased side effects. A low dose treatment of interferon is suggested to inhibit hepatocarcinogenesis in patients whose ALT or alpha-fetoprotein (AFP) was reduced in response to the treatment, although the benefits and adverse events of IFN therapy have to be carefully evaluated.

Therapy of acute and fulminant hepatitis B.

Although new hepatitis B virus (HBV) infections are decreasing due to improving vaccination coverage, patients without vaccination coverage can still suffer from manifestation of acute hepatitis B with jaundice and (although rarely) liver failure. No treatment is indicated for mild acute hepatitis B; however, antiviral therapy should be initiated for patients showing signs of significant liver impairment as exemplified by deterioration of prothrombin time to an equivalent of 1.5 or 50% of the 'Quick test'. For fulminant hepatitis, there is no complete agreement on whether antiviral treatment would alter the course, but it should still be started, as it would reduce the risk of reinfection in case there is a need for liver transplantation. Patients in danger of progression towards acute liver failure should be referred to transplant centers as early as possible.