NHS Evidence Annual Evidence Updates (AEUs) attempt to draw together recently published, high quality evidence – focusing particularly on systematic reviews and published guidelines - which it is hoped will inform and enhance the decision making and planning of clinicians, commissioners and others involved in the process of health care.
For this Hepatitis B and C AEU updating last year's work, a detailed literature search from 2009-2010 identified 246 potential pieces of evidence (see methods for retrieving and evaluating the evidence for more information). Following a process of filtering and peer review (with thanks to the reviewers listed below) 61 of these form the basis of this AEU.
It is imperative that those involved in commissioning and delivering care are apprised of the best available evidence and guidelines against which to review their service. We hope that the AEU in Hepatitis B and C will provide a prime source of such evidence.
A summary of the methods used for retrieving and evaluating the evidence can be found here. The evidence has been split into sections as follows:
•Economics
•Prevention
•Treatment:
•Adverse effects
•Risk factors
•Other
•Articles in foreign languages and on foreign populations
Click on the sections above to find links to critically appraised systematic reviews, expert commentaries and other information of interest, or download the PDF version.
We have also provided a list of treatment uncertainties, taken from the articles included in the AEU.
This year's update has been put together by the NHS Evidence - gastroenterology and liver diseases Project Team, with expert advice and commentaries provided by our liver disease topic leads. These are:
•Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge
•Andrew Austin, Consultant Hepatologist, Royal Derby Hospital
•Jane Collier, Consultant Hepatologist, John Radcliffe Hospital, Oxford
•Jan Freeman, Consultant Hepatologist and Lead Clinician for Gastroenterology and Hepatology, Royal Derby Hospital
•Martin James, Consultant Hepatologist and Gastroenterologist, Queen's Medical Centre, Nottingham
•Lynda Greenslade, Clinical Nurse Specialist in Hepatology, Royal Free Hampstead NHS Trust, London
•Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London
•Steven Ryder, Consultant Physician and Hepatologist, Queen's Medical Centre, Nottingham
- Economics
Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge and Andrew Austin, Consultant Hepatologist, Royal Derby Hospital
Graeme Alexander: The paper by Sroczynski et al, which is pertinent to the UK, indicates that there is an economic benefit in screening for hepatitis C when the prevalence is sufficiently high. The only failing of this paper is that it doesn’t really define clearly what an adequate prevalence is to make studies cost effective, but it is one of the better papers in the field and the cost of screening and the cost of treatment are very important issues for the UK.
Andrew Austin: With the advent of a number of effective oral antiviral treatments for chronic hepatitis B, both clinical and cost-effectiveness need to be considered. The latest EASL guidelines recommend pegylated interferon, entecavir and tenofovir as first-line treatment for both HBeAg-positive and HBeAg-negative patients with chronic hepatitis B. Buti et al used a Markov model to project lifetime costs in cohorts of 40 year old HBeAg-positive and HBeAg-negative patients treated with six different first-line and two second-line management strategies. Costs were assessed using Spanish data. The analysis found that tenofovir is the most cost-effective oral therapy for both groups of patients. Entecavir was the second most effective strategy and the difference is determined primarily by the difference in purchase price in Spain. When the pricing is similar the two drugs are equally cost-effective and it would be important to check on the real drug cost in your area. Furthermore, longer term modelling (> 5 years) is based on scant data and may be effected by changing resistance patterns, local cost of managing complications of chronic liver disease and unforeseen treatment side effects.
Deuffic-Burban et al compare different approaches to the detection of occupational hepatitis C infection in healthcare workers using a decision-analysis model. In France in 2004, a staggering 41,276 accidental blood exposures occurred in hospitals, 58.7% of which were percutaneous injuries. Of these 6.2% occurred to anti-HCV antibody-positive source patients. The authors compared three existing follow-up strategies from Europe and USA using combinations of ALT and anti-HCV antibody tests with a strategy based on early HCV RNA testing one month after exposure. The study found that although the HCV RNA testing strategy is more expensive than the other strategies examined, it is reasonably cost-effective and the study recommends its use. Given the advantage of early treatment of acute hepatitis C and the likely quality of life benefits from an earlier “all clear”, such a bland conclusion is surprising. I suspect that most clinicians who have been able to confirm the donor is HCV-positive will recommend an early HCV RNA test at one month using a highly sensitive assay for HCV RNA.
Grishchenko et al have used similar methodology to estimate the lifetime cost per quality-adjusted life-year (QALY) of antiviral treatment compared to no treatment for chronic HCV infection. However, rather than using estimates of sustained virological response, costs and transitional probabilities from registration trials, they have drawn estimates from the Trent HCV database, a large representative sample of UK cases. The authors found that pegylated interferon and ribavirin is generally cost-effective when provided in routine clinical practice. Treatment appears cost saving for patients with non-1, and has low costs per QALY for most patients with genotype 1. However, treatment is less effective in older patients with genotype 1 and cirrhosis whose chance of achieving an SVR may be less than 10%. As a member of the Trent HCV cohort study I declare an interest in this paper.
Saab et al use retrospective data to compare switching from HBIG to adefovir one year after successful liver transplantation versus continuing with HBIG/lamivudine. The authors report that the switching strategy leads to significant cost-savings. However, looking to the future it seems unlikely that many patients will come to transplantation who are treatment-naive with respect to either tenofovir or entecavir and the result may be of mainly historical interest.
Articles:
Buti M, Brosa M, Casado MA, Rueda M, Esteban R. Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B. J Hepatol 2009;51(4):640-6.
Deuffic-Burban S, Abiteboul D, Lot F, Branger M, Bouvet E, Yazdanpanah Y. Costs and cost-effectiveness of different follow-up schedules for detection of occupational hepatitis C virus infection. Gut 2009;58(1):105-10.
Grishchenko M, Grieve RD, Sweeting MJ, De Angelis D, Thomson BJ, Ryder SD, Irving WL, Trent HCV Study Group. Cost-effectiveness of pegylated interferon and ribavirin for patients with chronic hepatitis C treated in routine clinical practice. Int J Technol Assess Health Care 2009;25(2):171-80.
Saab S, Ham MY, Stone MA, Holt C, Tong M. Decision analysis model for hepatitis B prophylaxis one year after liver transplantation. Liver Transpl 2009;15(4):413-20.
Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Mühlberger N, Wright D, Zeuzem S, Siebert U. Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection. Eur J Public Health 2009;19(3):245-53.
- Prevention
Cochrane reviews
The following Cochrane reviews were released or updated this year:
Bar-On ES, Goldberg E, Fraser A, Vidal L, Hellmann S, Leibovici L. Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD005530. DOI: 10.1002/14651858.CD005530.pub2.
Katz LH, Tur-Kaspa R, Guy DG, Paul M. Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No.: CD006005. DOI: 10.1002/14651858.CD006005.pub2.
McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005546. DOI: 10.1002/14651858.CD005546.pub2.
Other reviews
Reviewed by Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London
The paper by Alavian and Tabatabaei reviews the problems of the reduced efficacy of hepatitis B vaccination in patients with end-stage renal disease. Various strategies have been suggested for this group of patients and the authors performed a meta-analysis of controlled clinical trials of levamisole, an immune modulator, in this setting. They identified four studies which suggest a beneficial response and highlight the need for larger randomized clinical trials.
Poorolajal et al have published two meta-analyses (1, 2) on the long term protection of HBV vaccination and the effects of booster doses. Their analyses suggest that although, with time, protective antibodies gradually decrease the risk of subsequent infection is low and, in healthy individuals with a good response to the initial vaccine course, booster doses of vaccine are not required.
Saab et al review 13 studies comparing lamivudine monotherapy with lamivudine/hepatitis B immune globulin (HBIG) after liver transplantation from a hepatitis B core antibody donor. Their analysis suggests that both strategies are effective and that lamivudine monotherapy is as effective as the combination approach.
Articles:
Alavian SM, Tabatabaei SV. Effects of oral levamisole as an adjuvant to hepatitis B vaccine in adults with end-stage renal disease: a meta-analysis of controlled clinical trials. Clin Ther 2010;32(1):1-10.
Poorolajal J, Mahmoodi M, Majdzadeh R, Nasseri-Moghaddam S, Haghdoost A, Fotouhi A. Long-term protection provided by hepatitis B vaccine and need for booster dose: a meta-analysis. Vaccine 2010;28(3):623-31.
Poorolajal J, Mahmoodi M, Majdzadeh R, Nasseri-Moghaddam S, Haghdoost A, Ghalichi L, Fotouhi A. Seroprotection of hepatitis B vaccine and need for booster dose: a meta-analysis. Hepat Mon 2009;9(4):293-304.
Saab S, Waterman B, Chi AC, Tong MJ. Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review. Liver Transpl 2010;16(3):300-7.
- Diagnosis
Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge
Smith and Sterling is a fair review of non invasive methods of assessing fibrosis in chronic hepatitis C virus infection. It has many aspects to commend it, including a comprehensive review, fair assessment with fair conclusions and this is an area that is particularly topical at present.
Articles:
Smith JO, Sterling RK. Systematic review: non-invasive methods of fibrosis analysis in chronic hepatitis C. Aliment Pharmacol Ther 2009;30(6):557-76.
- Treatment Hepatitis B
Reviewed by Steven Ryder, Consultant Physician and Hepatologist, Queen's Medical Centre, Nottingham
Guidelines
NICE has revisited HBV therapies and guidance is available which should be seen in the context of the EASL guidelines for treatment, an excellent and thoughtful document.
Also released this year were revised AASLD guidelines on chronic hepatitis B
Other reviews
There has been a revolution in the therapy of HBV infection with oral agents proving highly effective. Older therapies such as interferon remain an important part of the armoury. In South Asia there have been a number of studies of thymosin alpha. A meta analysis of trials of lamivudine and thymosin (Zhang et al) suggest better outcomes in e antigen positive patients. It is a therapy which we have not seen used in the Western world but the contrast with interferon where combination therapy shows no benefit, is interesting. The effectiveness of interferon alpha treatment in hepatitis B was confirmed and the magnitude of the effect on e antigen seroconversion and surface antigen loss quantified in a meta-analysis of 7 trials (Yang et al), the relative risk of e antigen loss was 0.66 and of surface antigen loss 0.28 over 3-7 years post therapy. A further study confirms that interferon therapy slows progression of hepatic fibrosis (Poynard et al). Another Eastern perspective on HBV is provided by Zhang et al. This summarises the trials of traditional Chinese medicines (TCM) used for HBV as compared to interferon and Lamivudine. The headline was that TCM has greater effect on ALT values than conventional therapies. A health warning concerning the quality of the studies is included but a further view eastwards for effective therapies may be indicated.
Combination therapy seemed the likely best option for long term therapy of hepatitis B with oral agents in the era of relatively weak agents with high resistance rates, the effectiveness of combining adefovir and lamivudine was confirmed in a meta-analysis (Chen et al) but with the newer more potent agents such a strategy may not be so compelling or necessary.
Reactivation of HBV in patients undergoing cancer chemotherapy has been a significant problem, and a meta-analysis suggests that lamivudine prophylaxis reduces the risk of reactivation and showed a trend towards reduced mortality. It gives some concrete figures which are useful in discussions with patients (1/1000 mortality given prophylaxis versus 25/1000 if not).
Children with chronic hepatitis B are frequently in the immunotolerant phase of infection which has limited effectiveness of therapy in the relatively small studies which have been undertaken. A summary of the data is included in a review (Giacchino and Cappelli). There are studies of the more modern oral agents ongoing in adolescents but a limited evidence base for other therapies.
Replicating chronic hepatitis B was a contraindication to liver transplantation 15 years ago but the advances in therapeutics have totally reversed this with HBV now a good indication for transplantation with very low recurrence rates. Zhang, Zhou and Zheng provide a concise summary of the evidence for effectiveness of therapy and the history of improvements in outcomes. A review article summarises the current best practice in prevention of recurrent HBV (Papatheodoridis et al).
Also included in this AEU is a health technology assessment on adefovir dipivoxil and pegylated interferon alpha for chronic hepatitis B by Jones et al.
Articles:
Chen EQ, Wang LC, Lei J, Xu L, Tang H. Meta-analysis: adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J 2009;6:163.
Giacchino R, Cappelli B. Treatment of viral hepatitis B in children. Expert Opin Pharmacother 2010;11(6):889-903.
Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, Price A. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation. Health Technol Assess 2009;13(35):1-172, iii.
Papatheodoridis GV, Cholongitas E, Archimandritis AJ, Burroughs AK. Current management of hepatitis B virus infection before and after liver transplantation. Liver Int 2009;29(9):1294-305.
Poynard T, Massard J, Rudler M, Varaud A, Lebray P, Moussalli J, Munteanu M, Ngo Y, Thabut D, Benhamou Y, Ratziu V. Impact of interferon-alpha treatment on liver fibrosis in patients with chronic hepatitis B: an overview of published trials. Gastroenterol Clin Biol 2009;33(10-11):916-22.
Yang YF, Zhao W, Xia HM, Zhong YD, Huang P, Wen J. Long-term efficacy of interferon alpha therapy on hepatitis B viral replication in patients with chronic hepatitis B: a meta-analysis. Antiviral Res 2010;85(2):361-5.
Zhang J, Zhou L, Zheng SS. Clinical management of hepatitis B virus infection correlated with liver transplantation. Hepatobiliary Pancreat Dis Int 2010;9(1):15-21.
Zhang L, Wang G, Hou W, Li P, Dulin A, Bonkovsky HL. Contemporary clinical research of traditional Chinese medicines for chronic hepatitis B in China: an analytical review. Hepatology 2010;51(2):690-8.
Zhang YY, Chen EQ, Yang J, Duan YR, Tang H. Treatment with lamivudine versus lamivudine and thymosin alpha-1 for e antigen-positive chronic hepatitis B patients: a meta-analysis. Virol J 2009;6:63.
Ziakas PD, Karsaliakos P, Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica 2009;94(7):998-1005.
- Treatment Hepatitis C
Guidelines
The following guidelines were published this year:
Diagnosis, management, and treatment of hepatitis C: an update (American Association for the Study of Liver Diseases)
British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010
Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program
Cochrane reviews
The following Cochrane reviews were released or updated this year:
Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic hepatitis C. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD005527. DOI: 10.1002/14651858.CD005527.pub2.
Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD005445. DOI: 10.1002/14651858.CD005445.pub2.
Gurusamy KS, Tsochatzis E, Xirouchakis E, Burroughs AK, Davidson BR. Antiviral therapy for recurrent liver graft infection with hepatitis C virus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD006803. DOI: 10.1002/14651858.CD006803.pub3.
Iorio A, Marchesini E, Awad T, Gluud LL. Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004888. DOI: 10.1002/14651858.CD004888.pub2.
Other reviews
Reviewed by Jane Collier, Consultant Hepatologist, John Radcliffe Hospital, Oxford and Jan Freeman, Consultant Hepatologist and Lead Clinician for Gastroenterology and Hepatology, Royal Derby Hospital
Jane Collier: The current recommended treatment of hepatitis C is pegylated interferon and ribavirin, but very few Chinese patients were included in the large phase 3 trials of this. Zhao et al have reviewed 7 studies, including a total of 398 Chinese patients, comparing this with standard interferon and ribavirin, confirming that the former is superior to the standard combination, with a relative risk of 1.76 (95% confidence interval 1.21 to 2.56).
A recent randomised trial has shown no difference between the efficacy of pegylated interferon 2a and pegylated interferon 2b. In a meta-analysis by Awad et al, 12 studies comparing these 2 drugs were pooled. Although pegylated interferon 2a was superior with a sustained virological response (SVR) experienced by 47% of participants, compared with 41% in pegylated interferon 2b, with a risk ratio (RR) of 1.11, the studies included were heterogeneous: different genotypes were included and not all patients were naïve or given weight based ribavirin. There were also not enough adverse events recorded to conclude a difference between the two drugs. The length of current treatment is dependent on genotype and viral kinetics, and as these drugs are expensive, recent research has been aimed at individualising length of treatment. A recent large study (ACCELERATE) in genotype 2 and 3 patients showed significant lower SVR with 16 weeks versus the conventional 24 weeks of therapy, even in those patients with a rapid virological response (RVR) (i.e. those who were HCV PCR negative at 4 weeks). The meta-analysis by Slavenburg et al looked at 8 studies comparing 24 weeks with 16 weeks treatment. 3 studies were randomised at the start of treatment (as per ACCELERATE) and 5 randomised at 4 weeks in those achieving a RVR. Although SVR were higher in those randomised to 2 weeks at baseline, RR 0.8, the SVR was similar in those patients who were HCV negative at 4 weeks and given 16 weeks compared to 24 weeks (82% versus 83%; RR 1.00). Patients who are not tolerating treatment at 16 weeks with an RVR could stop treatment with a good chance of an SVR. The role of a favourable interferon lambda genotype in identifying which of those with a RVR will achieve at SVR is currently unknown.
In a meta-analysis looking at the cost-effectiveness of 24 weeks of treatment for genotype 2/3 and 48 weeks for genotype 1, Sroczynski et al showed treatment to be cost effective as defined by a 84700 Euro/QALY with a 3-4 year life, excluding patients with mild disease (normal LFTs). This study did not assess if costs could be reduced by individualising treatment, which was done by Siebert et al. They looked at the cost-effectiveness of German guidelines, which include 24 weeks treatment for genotype 2/3 and stopping treatment at 12 weeks in patients with genotype 1 who had < 2 log drop, and use weight based ribavirin dosing. Pegylated interferon and ribavirin increased undiscounted life expectancy by 5 life-years and individualisation of treatment dose was cheaper with a cost saving of 17000 Euros/per QALY. Similar studies will need to be performed when the protease inhibitors become licensed as they are likely to be significantly more costly. A meta-analysis by Singal et al has confirmed improved survival in patients with advanced fibrosis following a SVR with less liver related mortality (RR 0.23). None of the above studies were able to assess reduced liver related mortality in non-cirrhotics with a SVR due to lack of sufficient long-term follow-up data in patients with and without a SVR.
Ribavirin is associated with haemolysis and dose reduction. Ribavirin dose reduction may not lead to poorer outcomes as a recent trial comparing ribavirin with the prodrug taribavirin which, although causing less anaemia, did not lead to a increased SVR. Chan, Partovi and Ensom looked at whether therapeutic drug monitoring (TDM) for ribavirin is warranted in clinical practice. In a review of literature showed not clear that good relationship between drug levels and degree of anaemia, In 53 small studies, 12 in HIV infection and 5 in renal failure, there was no clear relationship between ribavirin concentration and virological response. There are no studies comparing ribavirin TDM versus dose reduction using Hb on SVR. Overall, there is no clear evidence for use of TDM.
Adherence to therapy (compliance) is important in HCV treatment and will continue to be once direct antiviral therapy, i.e. protease inhibitors, are licensed, as poor compliance may lead to drug resistance. Weiss et al identified 8 studies assessing adherence with interferon/ribavirin combinations. 5 studies with pegylated interferon reported missed doses with adherence rates between 74%-92% in the first 12 weeks, falling towards end of treatment, with only 1 reporting effect on SVR. Three further studies, which combined adherence with dose reductions for medical reasons, showed that taking at least 80% of the initial prescribed dose of interferon/ribavirin for 80% of the recommended duration of treatment was associated with increased SVR. Thus these studies show non-adherence is common, but the effects on SVR for PEG-IFN/ribavirin are unknown.
Gentile et al have reviewed the phase 2 data on the protease inhibitor telepravir combined with pegylated interferon and ribavirin for naïve genotype 1 patients and this together with the phase 2 study in treatment experienced patients both show improved SVR over current standard therapy (ie peg-interferon and ribavirin). Telepravir was given at different time points and different length during treatment and the ongoing phase 3 study will dictate the optimum dosing regimen and confirm efficacy data.
Jan Freeman: Camma et al address the issue of retreatment in non-responders, giving good advice on who to select for retreatment rather than indiscriminate treatment of all non-responders. Modest efficacy (16% SVR) of retreatment is achieved in genotype 2 or 3, in the non-obese, and by use of a 24 week stopping rule in those who fail to seroconvert.
Fabrizi et al show that the use of Pegylated interferon does not add any benefit to standard interferon mono-therapy in patients undergoing dialysis.
Gluud, Marchesini and Iorio confirm the utility of PEG interferon and ribavirin in co-infected patients although the study shows that adverse events are more common.
Gordon et al demonstrate factors which give more favourable outcomes in Hepatitis C patients undergoing dialysis – these include the use of larger doses of interferon (greater than 3 million units thrice weekly), treatment completion rates, female gender and early virological negativity.
Hellard, Sacks-Davis and Gold support the active treatment of patients who continue to abuse drugs intravenously as comparable treatment outcomes can be achieved to those who are former IV drug users.
Moreno et al's meta-analysis shows that only HCV-1 patients with a low base line HCV-RNA (less than 50IU/ml) at 4 weeks of therapy do not lose a chance of a sustained virological response if they are treated for 24 weeks - all others should be given 48 weeks of therapy.
In Singal et al, pooled data shows a reduced risk of hepatocellular carcinoma in HCV treated patients (RR 0.43) who achieved a sustained virological response, but maintenance interferon therapy in those who failed to achieve a SVR did not reduce the risk of HCC.
Zanini and Lanzini is a good review of strategies to prevent HCV infection and disease progression, attitude and access to therapy amongst IV drug abusers.
Articles:
Awad T, Thorlund K, Hauser G, Stimac D, Mabrouk M, Gluud C. Peginterferon alpha-2a is associated with higher sustained virological response than peginterferon alfa-2b in chronic hepatitis C: systematic review of randomized trials. Hepatology 2010;51(4):1176-84.
Cammà C, Cabibbo G, Bronte F, Enea M, Licata A, Attanasio M, Andriulli A, Craxì A. Retreatment with pegylated interferon plus ribavirin of chronic hepatitis C non-responders to interferon plus ribavirin: a meta-analysis. J Hepatol 2009;51(4):675-81.
Chan AH, Partovi N, Ensom MH. The utility of therapeutic drug monitoring for ribavirin in patients with chronic hepatitis C--a critical review. Ann Pharmacother 2009;43(12):2044-63.
Fabrizi F, Dixit V, Messa P, Martin P. Pegylated interferon monotherapy of chronic hepatitis C in dialysis patients: Meta-analysis of clinical trials. J Med Virol 2010;82(5):768-75.
Gentile I, Carleo MA, Borgia F, Castaldo G, Borgia G. The efficacy and safety of telaprevir - a new protease inhibitor against hepatitis C virus. Expert Opin Investig Drugs 2010;19(1):151-9.
Gluud LL, Marchesini E, Iorio A. Peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus. Am J Gastroenterol 2009;104(9):2335-41.
Gordon CE, Uhlig K, Lau J, Schmid CH, Levey AS, Wong JB. Interferon for hepatitis C virus in hemodialysis--an individual patient meta-analysis of factors associated with sustained virological response. Clin J Am Soc Nephrol 2009;4(9):1449-58.
Hellard M, Sacks-Davis R, Gold J. Hepatitis C treatment for injection drug users: a review of the available evidence. Clin Infect Dis 2009;49(4):561-73.
Moreno C, Deltenre P, Pawlotsky JM, Henrion J, Adler M, Mathurin P. Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: a meta-analysis. J Hepatol 2010;52(1):25-31.
Siebert U, Sroczynski G, Aidelsburger P, Rossol S, Wasem J, Manns MP, McHutchison JG, Wong JB. Clinical effectiveness and cost effectiveness of tailoring chronic hepatitis C treatment with peginterferon alpha-2b plus ribavirin to HCV genotype and early viral response: a decision analysis based on German guidelines. Pharmacoeconomics 2009;27(4):341-54.
Singal AG, Volk ML, Jensen D, Di Bisceglie AM, Schoenfeld PS. A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus. Clin Gastroenterol Hepatol 2010;8(3):280-8.
Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, Sood GK. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2010;8(2):192-9.
Slavenburg S, Weggelaar I, van Oijen MG, Drenth JP. Optimal length of antiviral therapy in patients with hepatitis C virus genotypes 2 and 3: a meta-analysis. Antivir Ther 2009;14(8):1139-48.
Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Mühlberger N, Wright D, Zeuzem S, Siebert U. Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis. C. J Viral Hepat 2010;17(1):34-50.
Weiss JJ, Bräu N, Stivala A, Swan T, Fishbein D. Review article: adherence to medication for chronic hepatitis C - building on the model of human immunodeficiency virus antiretroviral adherence research. Aliment Pharmacol Ther 2009;30(1):14-27.
Zanini B, Lanzini A. Antiviral treatment for chronic hepatitis C in illicit drug users: a systematic review. Antivir Ther 2009;14(4):467-79.
Zhao SH, Chu YL, Cheng DX, Waqar AB, Yu Q, Yang PH, Xue X, Yang HJ, Liu EQ. Treatment with peginterferon plus ribavirin vs. interferon plus ribavirin for 48 weeks in Chinese patients with chronic hepatitis C. Int J Clin Pract 2009;63(9):1334-9.
- Adverse effects
Reviewed by Janice Main, Reader in Infectious Diseases and General Medicine, Imperial College at St Mary's Hospital, London
Frankel et al published a consensus document on treatment issues in patients with psoriasis and hepatitis C virus (HCV) infection. Interferon alpha can exacerbate psoriasis and there are concerns that immunomodulatory therapy used for more severe cases of psoriasis may cause more rapid disease progression of hepatitis C. There are additional issues with drugs such as methotrexate which can cause hepatotoxicity. The authors conclude that data are limited and, where possible, topical therapy should be used.
Slavenburg, Heijdra and Drenth describe a case of pneumonitis in a patient with HCV receiving peginterferon and ribavirin and then review the relevant literature. Although pneumonitis is a very rare side effect of therapy it is important that this is recognized quickly as it can be fatal. Cessation of antiviral therapy is advised and steroid therapy is recommended.
Thyroiditis is a much more common side effect of interferon based therapy and Tran et al describe their experience with 11 patients. All patients subsequently had a sustained virological response (SVR). However larger studies have not demonstrated such a high SVR in these patients. The authors conclude that with this side effect it is reasonable to treat the thyroiditis and to continue with antiviral therapy.
Hepatitis B vaccination generally appears very safe but Fraunfelder, Suhler and Fraunfelder highlight 32 case reports of uveitis and possible links to HBV vaccination.
Articles:
Frankel AJ, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF Jr, Gottlieb AB, National Psoriasis Foundation. Treatment of psoriasis in patients with hepatitis C: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol 2009;61(6):1044-55.
Fraunfelder FW, Suhler EB, Fraunfelder FT. Hepatitis B vaccine and uveitis: an emerging hypothesis suggested by review of 32 case reports. Cutan Ocul Toxicol 2010;29(1):26-9.
Slavenburg S, Heijdra YF, Drenth JP. Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature. Dig Dis Sci 2010;55(3):579-85.
Tran HA, Malcolm Reeves GE, Gibson R, Attia JR. Development of thyroid diseases in the treatment of chronic hepatitis C with alpha-interferon may be a good prognosticator in achieving a sustained virological response: a meta-analysis. J Gastroenterol Hepatol 2009;24(7):1163-8.
- Risk factors
Reviewed by Graeme Alexander, Consultant Hepatologist, Addenbrooke's Hospital, Cambridge, and Martin James, Consultant Hepatologist and Gastroenterologist, Queen's Medical Centre, Nottingham
Graeme Alexander: Chen et al is a solid meta-analysis of 37 studies, with well selected patients from two different eras which demonstrate clearly that hepatitis C co-infection with HIV increases mortality. There is not much more that a meta-analysis can conclude but the message here is clear.
Martin James: The link between HBV infection and the development of hepatocellular carcinoma has been well established previously with studies such as the REVEAL cohort study conducted in Taiwan (JAMA 2006), but the proportion of HCC cases related to chronic viral hepatitis (HBV or HCV) elsewhere in the world varies considerably
Franchesci and Raza conducted a meta-analysis of 90 studies including nearly 28,000 cases of HCC from 36 countries to study the worldwide variation in attributable risk of viral hepatitis in causation of HCC. In addition, they attempted to examine and describe the implementation and impact of HBV vaccination programmes and on HCC development.
As expected, most HCC cases (66%) were from Asia and the rest from the Americas (15%), Europe (12%) with relatively few from Africa (7%; over half of these patients originated from Egypt), probably due to difficulties in accurate recording and publication. There was substantial variation in HBVsAg and anti-HCV antibodies in HCC cases across and within different continents. The highest rates of HBV positivity (over 50%) was in Taiwan, China, Korea, Thailand, Vietnam and Turkey. Conversely, the countries with a higher proportion of HCV positivity in HCC cases were Japan (68%), Pakistan (45%) and Mongolia (40%).
In Europe, all countries apart from Greece had a higher proportion of HCC cases positive for HCV (approximately 45%) than for HBV. In Greece, 56% had HBVsAg positivity. HBV/HCV co-infection was relatively uncommon (3%), whereas absence of any chronic viral hepatitis in some northern European countries was common (80% in the study from Sweden). The majority of American studies came from the US, with 22% anti-HCV positive and only 9% positive for HBVsAg. The relatively low level of viral positivity in Western countries suggests that other aetiologies, principally alcoholic liver disease, are likely to be the cause of cirrhosis and predisposition for HCC, although these data were not presented directly.
HBV vaccines were first licensed in 1981 and are now mostly produced by recombinant DNA technology. HBV vaccination programmes were introduced into highly endemic areas such as Taiwan in 1984; this resulted in a substantial fall in HCC in the following two decades and other studies in Gambia and Qidong China are due to report soon. The debate continues in the UK and other low HBV endemic countries whether universal vaccination should be introduced or to continue with targeting high risk individuals. However, with increased immigration from highly endemic areas, the falling price of HBV vaccines and the serious consequences and high cost of treating HCC, the balance may have shifted enough to reconsider this approach to favour universal vaccination.
Liu et al performed a meta-analysis of the association between different HBV mutations and the risk of HCC using 43 studies mostly from East Asia, including over 11,000 patients with HBV infection, and 2800 with HCC. HBV PreS mutations (C1653T, T1753V) and A1762T/G1764A were associated with an increased risk of developing HCC (summary odds ratio of approximately 3-4). These mutations also became more prevalent with increasing duration of infection and were proposed as potential biomarkers for subsequent HCC development. This raises the potential for confounding of duration of infection and presumably the likelihood of increasing liver fibrosis. In addition, not all patients included in the studies had HBV mutation analysis, which may introduce selection bias for those with higher HBV DNA levels, which has been demonstrated to be an important independent risk for future HCC development (REVEAL; JAMA 2006). The precore mutations G1896A and C1858T were not associated with HCC risk in this meta-analysis.
Articles:
Chen TY, Ding EL, Seage Iii GR, Kim AY. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis 2009;49(10):1605-15.
Franceschi S, Raza SA. Epidemiology and prevention of hepatocellular carcinoma. Cancer Lett 2009;286(1):5-8.
Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009;101(15):1066-82.
- Other
Reviewed by Lynda Greenslade, Clinical Nurse Specialist in Hepatology, Royal Free Hampstead NHS Trust, London
Accessing healthcare is currently an important issue for all health care providers and government who are trying to ensure that the current health service ensures that the general public receive equitable quality care. HCV is a case where it is essential for the health service to identify and offer if appropriate treatment in order to reduce the long term burden of HCV disease on the health service in the future. Treloar and Rhodes look at the lived experience of hepatitis C and its treatment among injecting drug users (IDUs) and has several messages for health care professionals about how to engage with IDUs in order to redesign services and pathways that are inclusive and that uses IDUs own experiences of trying and failing to access healthcare so as to avoid current pitfalls and shortcomings in future patient centred services. This review looked at 25 published articles and generated themes that are uniquely drawing on the perspectives of drug injectors rather than others living with hepatitis C. The analysis of the themes using the thoughts and words of the drug injectors themselves challenges our more traditional health care professional views where past personal adversity such as dealing with drug addiction and withdrawal meant that the drug injector was resilient and able to draw on some of the previously used coping mechanisms to get through their hepatitis C treatment. It shows that often drug injectors felt they were not given enough and appropriate information about treatment and were being hurried through as if to get them out of the system and on to someone deemed to be more worthy. This review is important reading for those of us working with patients with HCV and involved in trying to think out of the box when designing pathways to engage all those who need access to testing and treatment. It also shows that there is a need for more research on the lived experiences of coping with not just HCV but all viral hepatitis.
A second paper by Fabrizi, Messa and Martin looked at health related quality of life (HRQOL) in dialysis patients with hepatitis c infection which is linked to a reduced mortality in patients with end stage renal disease. Interestingly it discussed possible links with HCV infection and depression in patients on dialysis and how this was poorly understood. Depression can be seen in any patients being treated with HCV infection and this paper reminds us that HRQOL screening and assessment for the development of depression throughout treatment for HCV infection remains an important part of the role of HCP looking after patients on treatment.
The paper by Cholongitas, Papatheodoridis and Burroughs also reviews the evidence for using liver grafts from anti-hepatitis B core positive donors, and gives clear guidance that these livers can be safely used and this should be added to any future practice guidelines.
Also included in this AEU are reviews by Hosseini-Moghaddam et al on delta hepatitis in haemodialysis patients, and by Kapp, Tilley and Curtis on the effects of hormonal contraceptives in women with viral hepatitis or cirrhosis.
Articles:
Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol 2010;52(2):272-9.
Fabrizi F, Messa P, Martin P. Health-related quality of life in dialysis patients with HCV infection. Int J Artif Organs 2009;32(8):473-481.
Hosseini-Moghaddam SM, Imani AA, Rizzetto M, Alavian SM. Viral hepatitis D among hemodialysis patients: a worldwide underestimated problem. Hepat Mon 2009;9(4):305-9.
Kapp N, Tilley IB, Curtis KM. The effects of hormonal contraceptive use among women with viral hepatitis or cirrhosis of the liver: a systematic review. Contraception 2009;80(4):381-6.
Treloar C, Rhodes T. The lived experience of hepatitis C and its treatment among injecting drug users: qualitative synthesis. Qual Health Res 2009;19(9):1321-34.
- Foreign articles
The following articles were identified by the search as being potentially relevant to the AEU, but were not sent out for appraisal because the full text is in a language other than English. They are included here for interest, and for the sake of completeness.
Almeida AM, Silva DI, Guerra AA Jr, Silva GD, Acurcio Fde A. Efficacy of interferon (conventional, pegylated) and lamivudine for treatment of chronic hepatitis B: a systematic review. Cad Saude Publica 2009;25(8):1667-77.
Language: Spanish
Hu H-B, Xu T, Cheng K, Su N, Tang Y. Lamivudine versus lamivudine-thymosin alpha-1 combination therapy for HBeAg positive chronic hepatitis B: A systematic review. Chin J Evid-based Med 2009;9(8):904-9.
Language: Chinese
Isken LD, Zaaijer HL, van Steenbergen JE. Hepatitis B revaccination not indicated, even for those at increased risk. Ned Tijdschr Geneeskd 2009;153:A415.
Language: Dutch
Qin XK, Han M, Liu JP. Compound Chinese herbal medicines, Chinese herbal drugs and their active extracts for treatment of chronic hepatitis C: a systematic review and meta-analysis of randomized clinical trials. Zhong Xi Yi Jie He Xue Bao 2009;7(10):913-28.
Language: Chinese
Takács IG, Demetrovics Z. The efficacy of needle exchange programs in the prevention of HIV and hepatitis infection among injecting drug users. Psychiatr Hung 2009;24(4):264-81.
Language: Hungarian
Wang Y-F, Wang Y-X, Yu Q-H. Efficacy of peginterferon alpha-2a in HBeAg positive chronic hepatitis B: Meta-analysis study. Chin J Evid-based Med 2009;9(10):1080-6.
Language: Chinese
Zhao SH, Liu EQ, Cheng DX, Xue X, Chu YL. Meta-analysis on peginterferon plus ribavirin in treatment of hepatitis C virus genotype 1 or 4 infection in HIV patients. Zhejiang Da Xue Xue Bao Yi Xue Ban 2009;38(3):315-9.
Language: Chinese
In addition, the following English-language articles were identified by the search but not sent out for review because they were studies of foreign populations:
Alavian SM, Ahmadzad-Asl M, Lankarani KB, Shahbabaie MA, Ahmadi AB, Kabir A. Hepatitis C infection in the general population of Iran: a systematic review. Hepat Mon 2009;9(3):211-23.
Ali SA, Donahue RM, Qureshi H, Vermund SH. Hepatitis B and hepatitis C in Pakistan: prevalence and risk factors. Int J Infect Dis 2009;13(1):9-19.
Batham A, Gupta MA, Rastogi P, Garg S, Sreenivas V, Puliyel JM. Calculating prevalence of hepatitis B in India: using population weights to look for publication bias in conventional meta-analysis. Indian J Pediatr 2009;76(12):1247-57.
Hung HF, Chen TH. Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and Hepatitis B e Antigen positive prevalence. Vaccine 2009;27(48):6770-6.
Jayaraman S, Chalabi Z, Perel P, Guerriero C, Roberts I. The risk of transfusion-transmitted infections in sub-Saharan Africa. Transfusion 2010;50(2):433-42.
Lehman EM, Wilson ML. Epidemic hepatitis C virus infection in Egypt: estimates of past incidence and future morbidity and mortality. J Viral Hepat 2009;16(9):650-8.
Sun J, Yu R, Zhu B, Wu J, Larsen S, Zhao W. Hepatitis C infection and related factors in hemodialysis patients in china: systematic review and meta-analysis. Ren Fail 2009;31(7):610-20.
Tu HA, Woerdenbag HJ, Kane S, Riewpaiboon A, van Hulst M, Postma MJ. Economic evaluations of hepatitis B vaccination for developing countries. Expert Rev Vaccines 2009;8(7):907-20.
Umar M, Khaar HT, Khurram M, Hasan Z. Anti-HCV antibody positivity of various sections of Pakistani patients. J Coll Physicians Surg Pak 2009;19(11):737-41.
Waheed Y, Shafi T, Safi SZ, Qadri I. Hepatitis C virus in Pakistan: a systematic review of prevalence, genotypes and risk factors. World J Gastroenterol 2009;15(45):5647-53.
- Uncertainties
As part of the process of conducting this Annual Evidence Update, we examined the included papers for treatment uncertainties that could be added to the UK Database of Uncertainties about the Effects of Treatments (UK DUETs), a project aimed at creating a central database of such uncertainties. The following list, which has been submitted to the database, is the results of our search. Click on each title for more information.
•Antiviral therapy for recurrent liver graft infection with hepatitis C virus
•Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccine for primary prevention of hepatitis B
•Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation
•Optimal duration of pegatheron plus ribavirin therapy for chronic hepatitis C in patients with HIV
•Optimal ribivirin dose for chronic hepatitis C when taking in combination with pegylated interferon alpha-2a or alpha-2b
•Peginterferon plus ribavirin versus no treatment for chronic hepatitis C in patients with HIV
•Rate of serious adverse events in antiviral treatment for chronic hepatitis C in patients with HIV
•Relationship between treatment and clinical outcomes in antiviral treatment for chronic hepatitis C in patients with HIV
•Traditional Chinese medicines for chronic hepatitis B
- Methods for retrieving and evaluating the evidence
The last Annual Evidence Update for Hepatitis B and C was published in September 2009. This AEU serves as an update to that one, and includes articles published in 2009 and 2010. As the Specialist Collection focuses only on secondary information of use to NHS staff and patients, our update was focused on guidelines and systematic reviews written in English. However, foreign language articles were included in the search process. As translations for these articles were not available, the article titles have been listed separately. Our search also recovered a large number of studies of viral hepatitis in foreign populations; as these are of limited relevance to UK practice we did not send these out to our reviewers for appraisal, but we have again listed them separately.
Search strategy
Our search strategy has been updated from last year. The following resources were searched:
•MEDLINE
•EMBASE
•CINAHL
•PsycINFO
•AMED
•National Library of Guidelines
•NHS Evidence Specialist Collections
•The Cochrane Library
•Database of Abstracts of Reviews of Effects
•NHS Economic Evaluation Database
•HTA Database
The search strategy for MEDLINE, which was modified for the other resources, appears below. We combined this with a modified SIGN systematic review filter in all cases except the searches of the NLG, the Specialist Collections, DARE, NHS EED and HTA (because they consist entirely of the types of publication that we were interested in).
After de-duplication 246 articles were retrieved.
Inclusion and exclusion criteria
Included articles had to meet the following criteria:
•Publication types: systematic review, consensus report, guideline, protocol, care pathway, economic evaluation, health technology assessment
•Published in 2009 or 2010
•Main condition under investigation was hepatitis B or C virus infection
Once the inclusion criteria were applied, 93 articles were left. Of these, 7 were foreign language articles, 7 were Cochrane systematic reviews, 5 were guidelines, and 10 were studies of specific foreign populations.
The Cochrane systematic reviews and guidelines were automatically included in the Evidence Update. The foreign language and foreign population studies were not sent out to reviewers because of translation difficulties and limited relevance to UK practice, but are listed in a separate section of the Evidence Update. This left 64 articles to be sent to our reviewers for appraisal.
Critical appraisal process
Before sending out, the articles were divided into categories as follows:
•Epidemiology
•Economics
•Prevention
•Diagnosis
•Treatment
•Adverse effects
•Risk factors
•Other
Using these categories as a guide, the papers were divided up and sent to our 8 reviewers. The reviewers then appraised the articles for their validity, relevance and rigour. Following the receipt of their comments, we included in the Evidence Update 49 articles that were deemed to meet the standards.
Publication Date: 26 Jul 2010
Publication Type: Annual Evidence Update
Publisher: NHS Evidence - gastroenterology and liver diseases
Creator: NHS Evidence - gastroenterology and liver diseases
Next Review Date: 23 Jul 2011
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