Review article: the modern management of autoimmune hepatitis

Aliment Pharmacol Ther 31 , 771–787

Summary

Background The management of autoimmune hepatitis (AIH) continues to be refined. However, several issues remain unresolved, primarily as a consequence of the low incidence of the disease. This factor has contributed both to a lack of understanding of and a paucity of large scale clinical trials involving therapeutic agents. Aim To summarize the latest evidence regarding the pathogenesis, diagnosis, therapy and long‐term management of AIH with a focus on clinical aspects of the disease. Method We searched PUBMED for articles pertaining to AIH, its pathogenesis, treatment and clinical outcomes, combined with the authors’ own knowledge of the literature. Results Standard therapy (corticosteroids and azathioprine) is effective in more than 80% of patients which renders study of novel agents difficult. Budesonide appears to show equivalence to prednisolone. Available, but limited, data suggest that mycophenolate mofetil, tacrolimus and ciclosporin are all variably effective second line agents. Patients with AIH and cirrhosis are at risk of hepatocellular carcinoma (HCC) and require screening. Patients with end stage liver disease represent excellent candidates for liver transplantation. Conclusions Despite ongoing limitations in the understanding of pathogenesis and difficulties in evaluating novel therapies, the management of AIH continues to evolve slowly. Multi‐centre collaboration is necessary to obtain sufficient patient numbers to undertake good quality therapeutic studies.     

Review article: immunopathogenetic and therapeutic aspects of autoimmune hepatitis

Autoimmune hepatitis is a chronic, progressive liver disease that responds well to immunosuppressive therapy, but has a poor prognosis if untreated. Possible triggering factors include viruses, other autoimmune disorders and drugs. The molecular mechanisms contributing to the pathogenesis include: reactions of autoantibodies against their corresponding autoantigens; aberrant expression of histocompatibility antigen class I and II molecules, cell adhesion molecules and cytokines; increased oxidative stress; and the occurrence of angiogenesis. The prevalence of the disease is highest in Caucasians, Europeans and women. The natural history of autoimmune hepatitis shows a poor prognosis, with frequent progression to cirrhosis and hepatic insufficiency in untreated patients. The occurrence of hepatocellular carcinoma is rare and is found only in long-standing cirrhosis. Corticosteroids as monotherapy or in combination with azathioprine are the treatments of choice; different therapeutic schedules and particularities of treatment for pregnant women and children have been established. To avoid treatment-associated adverse effects, alternative therapies have been proposed, including ciclosporin, budesonide, tacrolimus, mycophenolate mofetil, ursodeoxycholic acid, methotrexate, cyclophosphamide, mercaptopurine and free radical scavengers. Liver transplantation is indicated for patients refractory to or intolerant of immunosuppressive therapy.     

Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease

Aliment Pharmacol Ther 2012; 35: 15–36

Summary

Background Thiopurines represent an effective and widely prescribed therapy in inflammatory bowel disease (IBD). Concerns about toxicity, mainly resulting from a wide inter‐individual variability in thiopurine metabolism, restrict their use. Optimal thiopurine dosing is challenging for preventing adverse drug reactions and improving clinical response. Aim To review efficacy and toxicity of thiopurines in IBD. To provide pharmacogenetic‐based therapeutic recommendations. Methods We conducted a query on PubMed database using ‘inflammatory bowel disease’, ‘thiopurine’, ‘azathioprine’, ‘6‐mercaptopurine’, ‘TPMT’, ‘pharmacogenetics’, ‘TDM’, and selected relevant articles, especially clinical studies. Results Thiopurine metabolism – key enzyme: thiopurine S‐methyltransferase (TPMT) – modulates clinical response, as it results in production of the pharmacologically active and toxic metabolites, the thioguanine nucleotides (6‐TGN). Adjusting dosage according to TPMT status and/or metabolite blood levels is recommended for optimising thiopurine therapy (e.g. improving response rate up to 30% or decreasing haematological adverse events of 25%). Other enzymes or transporters of interest, as inosine triphosphatase (ITPase), glutathione S‐transferase (GST), xanthine oxidase (XO), aldehyde oxidase (AOX), methylene tetrahydrofolate reductase (MTHFR) and ATP‐binding cassette sub‐family C member 4 (ABCC4) are reviewed and discussed for clinical relevance. Conclusions Based on the literature data, we provide a therapeutic algorithm for thiopurines therapy with starting dose recommendations depending on TPMT status and thereafter dose adjustments according to five metabolite profiles identified with therapeutic drug monitoring (TDM). This algorithm allows a dosage individualisation to optimise the management of patients under thiopurine. Furthermore, identification of new pharmacogenetic biomarkers is promising for ensuring maximal therapeutic response to thiopurines with a minimisation of the risk for adverse events.     

Review article: current antiviral therapy of chronic hepatitis B

Background The long‐term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma. Aim To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses. Methods A systematic review of the literature, with a focus on recent guidelines, was undertaken. Results Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa‐2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on‐treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross‐resistant is critical to restore suppression of viral replication. Conclusions Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.     

Review article: predicting response in hepatitis C virus therapy

The introduction of combination therapy with ribavirin and of pegylated interferons has improved treatment results in patients with chronic hepatitis C. However, overall rates of sustained virologic response following antiviral therapy of chronic hepatitis C still do not exceed 54-63%. Because of several virus- and patient-related factors, treatment is even less successful in some patient subpopulations. The major viral factors associated with impaired response are hepatitis C virus genotype 1 infection and a high viral load. Among patient-related factors cirrhosis is of special importance. Baseline predictive factors for sustained virologic response become less important for prediction of treatment outcome when quantifications of hepatitis C virus RNA during early therapy are taken into account. This article provides a summary of virus- and patient-related parameters, which are prognostic for response to antiviral therapy in chronic hepatitis C and focuses on the prediction of treatment response by quantification of hepatitis C virus RNA concentration during therapy.     

Review article: current antiviral therapy of chronic hepatitis B

Aliment Pharmacol Ther 2011; 34: 1145–1158

Summary

Background The indications and endpoints for treatment of chronic hepatitis B continue to evolve. The aim of the therapy for chronic hepatitis B is to achieve a long‐term continued suppression of the hepatitis B virus (HBV) DNA to prevent disease progression leading to the development of cirrhosis and hepatocellular carcinoma. Aim To summarise current literature on therapy of chronic hepatitis B, with a focus on indications for therapy, preferred treatment options, and management of resistance and partial responders. Methods A systematic review of the literature, with a focus on international guidelines, was performed. Results Seven drugs are licensed for the treatment of chronic hepatitis B in many countries. The selection of a drug with high potency and low rate of resistance is essential to achieve rapid and long‐term viral suppression. The prevention of the sequelae of antiviral drug resistance and appropriate management of viral breakthrough are major goals of current management. The addition or change to an antiviral agent that is not cross‐resistant is critical to restore suppression of viral replication for patients with breakthrough resistance. Patient adherence to medication is essential to achieve adequate HBV DNA suppression. Conclusions The current treatment strategy of chronic hepatitis B is now standard: initial selection of entecavir, tenofovir, or peginterferon alfa‐2a. Future studies are required to determine if combination therapy using two oral agents or peginterferon with an oral agent with a high genetic barrier to resistance might be superior to standard current monotherapy.     

Review article: indicators and predictors of response to anti-viral therapy in chronic hepatitis C

The complications of chronic hepatitis C, including cirrhosis and hepatocellular carcinoma, are expected to increase dramatically world-wide over the next 10-20 years. Immunomodulatory/anti-viral therapy, employing interferon alfa both alone and in combination with ribavirin, affords the only effective treatment for hepatitis C. Accurate early prediction of response to interferon therapy may decrease or eliminate unnecessary or ineffective treatment, permit greater flexibility in tailoring therapy on an individual basis, and enhance the cost-effectiveness of treatment. Liver biopsy provides valuable information about the baseline severity and subsequent progression of hepatitis C. Severe fibrosis or cirrhosis on the pre-treatment liver biopsy is associated with decreased response rates. The measurement of viral RNA levels and genotyping may be used to optimize individual patient treatment. Genotype non-1 and a low viral load are the most significant pre-treatment indicators of sustained virological response. The most reliable predictor of a poor virological response is continued seropositivity for viral RNA during therapy. Therefore, a decision to stop or continue treatment can be based on a positive viral RNA test at 12 weeks for interferon-naive patients receiving interferon or pegylated interferon therapy.     

Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease

Aliment Pharmacol Ther 2010; 32: 119–130

Summary

Background Immunosuppression is a risk factor for carcinogenesis. Thiopurines specifically contribute to this. As thiopurines are used more aggressively in the treatment of IBD, it is likely that we will see more thiopurine‐related malignancy. Aim To review the literature, exploring how immunosuppression, thiopurines specifically, might cause cancer and which malignancies occur in practice, placing specific emphasis on IBD cohorts. Methods Search terms included ‘malignancy’‘cancer’‘azathioprine’‘mercaptopurine’‘tioguanine (thioguanine)’‘thiopurine’ and ‘inflammatory bowel disease’‘Crohn’s disease’‘ulcerative colitis’. We also searched for specific cancers (lymphoma, colorectal cancer, skin cancer, cervical cancer) and reviewed the reference lists of the articles detected. Results Immunosuppression is associated with an increased risk of cancer. Thiopurines are associated with specific additional risks. In IBD cohorts, very few thiopurine‐related malignancies have been reported. However, studies suggest a relative risk of 4–5 for lymphoma. This still translates into a low actual risk, (one extra lymphoma in every 300–1400 years of thiopurine treatment). Conclusions Whilst we must be aware of this risk and counsel our patients appropriately, thiopurines remain a mainstay of IBD therapy. We present practical advice aimed at minimizing our patients’ risk of developing malignancy, whilst optimizing the benefits that thiopurines can provide.     

Review article: investigational agents for chronic hepatitis C

Background  The need for effective treatment for chronic hepatitis C infection has driven the development of novel antiviral agents that target specific steps in the viral replication cycle.
Aim  To evaluate the current literature concerning investigational agents for chronic hepatitis C virus infection.
Methods  Resources used included PubMed, conference proceedings from the American and European Liver Associations' meetings 2005–2008 and the National Institute of Health's clinical trials website ( http://www.clinicaltrials.gov ). The focus was restricted to investigational agents that have progressed beyond preclinical development.
Results  Over 50 investigational agents for chronic hepatitis C infection are currently in clinical development. Specifically targeted anti-viral therapy for HCV (STAT-C) shows great promise with NS3/4a protease inhibitors now entering phase 3 programmes. New interferon-α and ribavirin formulations aim to optimize anti-viral efficacy yet limit toxicity. Other candidates include novel immunomodulators and therapeutic vaccines.
Conclusions  A new era of therapy for chronic hepatitis C beckons, promising increased cure rates with shortened duration of therapy. However, the era will not be without challenges including viral resistance, drug toxicity and the need to optimize combination therapy in the face of a rapidly evolving therapeutic arsenal.     

Review article: hepatitis B and liver transplantation

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re-infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome. The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re-infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so-called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission). Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.