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CLINICAL REVIEW

Managing hepatitis C virus infection

Kathryn L Nash,1 Ian Bentley,2 Gideon M Hirschfield3
1 Southampton University Hospitals NHS Trust, Southampton 2 Hill Lane Surgery, Southampton 3 Liver Centre, Toronto Western Hospital/Department of Medicine, University of Toronto, Toronto, Ontario M5T 2S8, Canada Correspondence to: G M Hirschfield gideon.hirschfield@uhn.on.ca

Cite this as: BMJ 2009;338:b2366 doi:10.1136/bmj.b2366

Chronic infection with the RNA flavivirus hepatitis C is a major cause of liver disease.1 The Department of Health estimates that in the United Kingdom, chronic infection is present in 200 000 peopleof whom 50% are unaware that they carry the viruswith variations in prevalence between different groups (0.04% in blood donors, 1% in people attending genitourinary clinics, and up to 50% in intravenous drug users). A general practitioner with an average list of 1800 can expect to have eight to 20 patients with hepatitis C infection. If such patients are identified and treated, the virus can be eradicated in more than half of them. We outline this area of hepatology, highlighting risk factors for acquisition, groups to screen, and specialist management of patients with chronic infection.
What is the natural history of hepatitis C infection?

In the UK the main mode of acquisition is recreational intravenous drug use; in developing countries transfusion of blood products and exposure to unclean or unsterilised objects remains importantfor example, during circumcision, scarification, and tattooing (box 1). Outcomes of infection are not uniform (fig 1). 2 Acute infection is usually unrecognised, and 60-85% of patients progress to chronic infection with persistent detection of hepatitis C virus RNA. The major complication of persistent infection is chronic hepatitis, which leads to advanced fibrosis and cirrhosis in about one in five patients over a period of 20 to 30 years. The infection is a leading indication for liver transplantation. Alcohol consumption, coinfection with HIV or hepatitis B virus, obesity, hepatic steatosis, diabetes, male sex, and older age at the time of infection predict more aggressive disease, and consequently complications.3 Patients with cirrhosis have an increased risk of hepatocellular carcinoma, which has an incidence of 1-4% per year in such patients.4 The association of hepatitis C infection with an increased risk of developing insulin resistance and type 2 diabetes, as shown by cross sectional and longitudinal studies, is noteworthy,5 as are rare extrahepatic autoimmune or lymphoproliferative manifestations such as cryoglobulinaemic vasculitis and B cell lymphoma.w1 A systematic review supports the concept that patients with hepatitis C virus infection have clinically significant reductions in health related quality of life.6
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How are patients assessed for hepatitis C infection? Who to screen Acute infection is usually not identified, unless investigation is prompted by symptomatic hepatitis. Chronic infectionfor longer than six monthsmay be identified when evaluating abnormal liver biochemistry, thrombocytopenia (seen with portal hypertension), incidental imaging findings suggesting cirrhosis, or decompensated liver disease. Screening in general practice is recommended (www.dh.gov.uk/en/Publi chealth/Communicablediseases/HepatitisC) for individuals in the following groups.  Unexplained abnormal liver biochemistry tests  Ever injected drugs  Received blood transfusion in the UK before September 1991 or any blood products before 1986  Received medical or dental treatment where infection control may be poor  Children of infected mothers  Sexual partners of infected people  Exposed to blood where a risk of transmission exists  Received tattoos, piercings, or acupuncture with poor infection control procedures. How to test for infection Screening identifies exposure to the virus through testing for specific antibodies. False negatives can occur in patients with acute infection, immunodeficiencies, or end stage renal disease. Ongoing infection is confirmed in those with positive serology by testing for hepatitis C viral RNA, and those with a positive result are usually referred for further assessment. In those who test positive for antibodies but negative for RNA, tests should be repeated once after six months. The features of the disease are similar across the genotypes, but treatment response and duration are related to genotype, with the best responses seen for genotypes 2 and 3. How to assess the severity of liver disease Liver biochemistry is insensitive at predicting disease severity; normal results do not exclude progressive liver disease or cirrhosis.7 Baseline ultrasound to look for focal lesions, splenomegaly (a marker of portal hypertension), or frank features of cirrhosis is appropriate, although normal findings on imaging do not
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Exposure to hepatitis C infection Mean incubation period six to eight weeks Acute infection Serology can take up to six months to become positive; RNA can fluctuate during infection but is usually detectable by one/two weeks ~15-40% clear the infection

Box 2 Recognised adverse effects of peginterferon alfa and ribavirin therapy Pegylated interferon Alopecia Anaemia* Autoimmune features Depression or mood disturbance Diarrhoea Influenza like symptoms* Injection site pain or erythema Retinopathy Sleep disturbances Thrombocytopenia* Thyroid dysfunction Weight loss Ribavirin Haemolytic anaemia* Cough, dyspnoea Gout Nausea Rash Teratogenicity
*Most common adverse effects.

Chronic hepatitis C Genotype and viral load do not generally affect disease progression Factors enhancing progression Alcohol Older age at infection Infection duration Male sex Obesity Diabetes/insulin resistance HIV and/or hepatitis B coinfection

Cirrhosis ~20% at 20-30 years after chronic infection Largely asymptomatic until:

Liver failure ~2-5% of patients with cirrhosis per year

Hepatocellular carcinoma ~1-4% of patients with cirrhosis per year

Fig 1 | Natural history of hepatitis C infection

exclude cirrhosis.8 Traditionally biopsy was universally recommended, but it has limitations, including sampling error and patient reluctance. Biopsy is often used if treatment is to be deferred (for example, in patients with genotype 1 infection and mild fibrosis), if other cofactors may have contributed to liver disease (such as steatosis, iron overload, or alcohol), or if different non-invasive markers of fibrosis are discordant.9 Non-invasive methods for assessing fibrosis are evolving and remain best at differentiating between extremes
Box 1 Risk factors for hepatitis C infection Injection and other illicit drug use Commonest mode of acquisition in developed countries Use of intranasal cocaine has been associated with acquisition History of blood product transfusion Screening of blood and blood products introduced in the UK in 1991; patients who received blood products before that date or in other countries may be at risk History of having had surgery abroad Having had surgery in a country where sterilising of instruments may be suboptimal is a risk factor Haemodialysis Hepatitis C antibody testing was introduced in 1992 Needlestick injuries Incidence of seroconversion following needlestick injury is 3% to 4% Sexual activity People in long term monogamous relationships are at low risk of acquisition (0 to 0.6% per year); those with multiple sexual partners, particularly those engaging in traumatic sexual activity, are at greater risk Tattooing or body piercing Vertical transmission Incidence of infection is about 5% among infants born to women with the infection (risk increased with HIV coinfection); breast feeding does not seem to transmit infection, and babies may carry maternal antibodies until age 18 months

of fibrosis (normal or cirrhosis).10 11 Fibrosis can also be assessed using serum markers, as in the FibroTest (BioPredictive, Paris, France), which associates five biochemical tests2 macroglobulin, haptoglobin, apolipoprotein A1, gamma glutamyl transpeptidase, and total bilirubinadjusting for sex and age. Alternatively, liver stiffness can be measured with transient elastography, in which a shear wave is generated and tracked through the liver using ultrasound. Simple calculations can also give an indication of advanced liver disease; for example, the aspartate aminotransferase to platelet ratio index, calculated as aspartate aminotransferase (U/l)/ upper normal 100/platelet count (109/l), for which scores greater that 1.5 have a positive predictive value for substantial fibrosis of 88%.w2
Other considerations Non-randomised evidence points towards adoption of routine opt-out HIV testing in all patients with chronic viral hepatitis.w3 In people without serological evidence of previous infection with hepatitis A or B, vaccination against these viruses is appropriate. When should hepatitis C infection be treated? Although all patients with chronic infection are candidates for antiviral therapy, the risks and benefits of therapy must be weighed carefully on an individual basis. Treatment is considered successful when hepatitis C viral RNA is undetectable six months after stopping therapy (sustained virological response), and even patients with cirrhosis can benefit, since long term viral
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Hepatitis C virus RNA positive Assessment Viral genotype/pre-treatment viral load Risk factors for disease progression e.g. HIV, Liver disease severity alcohol, hepatitis B Risk factors for poor response e.g. obesity, Contraindications to treatment (absolute v relative) insulin resistance, ethnicity, age Patient preference/motivation Decision to treat

Box 3 Role of the clinical nurse specialist

 

Support and education of patients, often those with complex problems including substance abuse Nurse led clinics, in parallel with medical clinics, to provide continuity of care from initial referral through treatment, follow-up, and potential discharge to GP Preparing patients for possible side effects of treatment and supporting them through what can be a challenging time Liaising with drugs and alcohol agencies, homeless health care, GP, and mental health teams where needed

Yes

No

Genotype 2, 3 Peginterferon alfa + ribavirin (800 mg) for 24* weeks

Genotype 1, 4, 6 Peginterferon alfa + ribavirin (10001200 mg; weight based) Week 12 review Ongoing clinical follow up Reassessment periodically Clinical trials

Elizabeth Burge, Southampton University Hospitals NHS Trust

Early virological response 2 log10 decline in RNA Continue therapy until week 48* RNA negative 24 weeks post treatment

No early virological response 2 log10 decline in RNA Discontinue therapy *If week 4 RNA available and negative consider shorter treatment: Genotype 1: 24 weeks Genotype 2/3: 12-16 weeks If RNA positive at week 24, cessation of therapy advised as sustained virological response highly unlikely

Yes Sustained virological response

No

Non-responder Null responder: no early virological response Partial responder: early but not sustained virological response Relapser: Negative end of treatment but no sustained virological response (assuming compliance and optimal dose delivered)

Fig 2 | Current treatment algorithms in routine practice

eradication is sometimes also associated with regression of cirrhosis.12 13 Evidence based guidelines developed by the National Institute for Health and Clinical Excellence (www.nice. org.uk/Guidanc/TA106) and the Scottish Intercollegiate Guidelines Network (www.sign.ac.uk/pdf/sign92.pdf) are available, as are practice guidelines.14 All patients

with moderate to severe fibrosis or cirrhosis should be considered for treatment to prevent disease progression; those with mild disease are also eligible for treatment, although some patients may opt to wait until disease reaches a moderate stage. For genotypes 2 and 3, treatment at the stage of mild disease, as well as at more severe stages, is cost effective in all patients. Treatment of mild disease is also cost effective in patients younger than 65 with genotype 1 (and probably 4), but in older patients with these less responsive genotypes treatment should probably be restricted to those with more severe fibrosis.15 Retrospective evidence shows that insulin resistance, along with advanced fibrosis and unfavourable genotype, are independent predictors of nonresponse to treatment.16 Difficult to treat populations such as prisoners17 or those with a history of substance misuse18 remain candidates for treatment. Psychiatric comorbidities can affect treatment, but are not absolute contraindications since tolerability and antiviral responses comparable to best practice can be achieved if tailored psychiatric input is available.19
How is hepatitis C infection treated? The current treatment for chronic infection is combined peginterferon alfa by subcutaneous injection once weekly and oral ribavirin daily (fig 2). Pegylated interferon is formed by attachment of interferon, a naturally occurring cytokine with immunomodulatory, antiproliferative, and antiviral effects, to polyethylene glycol, which improves the pharmacokinetic profile and permits weekly dosing. Two preparations are available: peginterferon alfa-2b, given as a weight based dose of 1.5 g/kg, and peginterferon alfa-2a, given as a fixed 180 g dose. Ribavirin is a purine nucleoside that has antiviral effects against hepatitis C only when combined with interferon alfa, and its addition to treatment reduces rates of relapse. Combination therapy with peginterferon alfa and ribavirin achieves sustained virological responses in almost half of patients with genotype 1 infection and about four fifths of those with genotype 2 or 3 infection. 20 21 Findings of randomised trials show that patients with genotype 1 need 48 weeks of peginterferon alfa therapy with daily ribavirin (1000-1200 mg) according to weight.22 Genotypes 4 to 6, which are uncommon in
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TIPS FOR NON-SPECIALISTS A GP with an average list size of 1800 will have eight to 20 patients with hepatitis C, half of whom are probably undiagnosed Identifying such patients requires a high index of suspicion with assessment for risk factors to which exposure may have occurred many years ago Onwards referral to secondary care is advised to stage liver disease and consider the need for antiviral therapy in those with chronic infection (RNA positive) Prevention of superimposed hepatitis A and B should be recommended through vaccination Once patients are on antiviral treatment the GP has a supportive role in diagnosis and aiding management of side effects (such as mood disorders, rashes, thyroid disorders, infections, gastrointestinal upsets) After successful eradication of virus, patients with substantial fibrosis or cirrhosis still need long term follow-up (for example, to survey for complications such as hepatocellular carcinoma and varices)

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ADDITIONAL EDUCATIONAL RESOURCES Resources for healthcare professionals  National Institute for Health and Clinical Excellence (http://guidance.nice.org.uk/ TA106)UK evidence based guidance on treatment of hepatitis C
  

Box 5 Possible future directions of treatment Modifications to existing regimens Interventions reducing insulin resistance such as exercise, weight loss, insulin sensitisers Weight based ribavirin Modified interferon (such as albuferon) Newer ribavirin (such as taribavirin) Antiviral approaches in clinical trials NS3 protease inhibitors (telaprevir, bocepravirin phase III clinical trials) NS5B polymerase inhibitors (valopicitabine, R1479, and NM107in phase II and III studies) Cyclophilin inhibitors without immunosuppressive properties that regulate hepatitis C virus NS5B-RNA dependent RNA polymerase (such as Debio 025in preclinical and early clinical trials) Thiazolides (such as nitazoxanidein phase II/III studies) Al-trans retinoic acid (in vitro and preliminary clinical observation) Peptide vaccine Preclinical research strategies Cell entry inhibitors targeting the structural protein E2 NS3 helicase inhibitors Inhibition of the p7 ion channel Specific antiviral agents targeting viral RNA (such as small interfering RNA molecules, ribozymes, antisense RNAs)

World Health Organization (www.who.int/mediacentre/factsheets/fs164/en)useful factsheet on hepatitis C Department of Health (www.dh.gov.uk/en/Publichealth/Communicablediseases/ HepatitisC)UK Government webpage on hepatitis C Health Protection Agency (www.hpa.org.uk/webw/ HPAweb&Page&HPAwebAutoListName/Page/1191942171144?p=1191942171144) resources on hepatitis C Gastroenterology and Liver Diseases Specialist Library (www.library.nhs.uk/ Gastroliver)specialist collection of NHS evidence

Resources for patients  The Hepatitis C Trust (www.hepctrust.org.uk)national UK charity for hepatitis C
  

British Liver Trust (www.britishlivertrust.org.uk)national charity working to reduce the impact of liver disease in the UK NHS Choices (www.nhs.uk/hepatitisc)patient orientated advice on hepatitis C) American Liver Foundation (www.liverfoundation.org)American organisation that aims to facilitate, advocate, and promote education, support, and research for the prevention, treatment, and cure of liver disease The Skipton Fund (www.skiptonfund.org/Eng/index.html)UK-wide ex gratia payment scheme established to make payments to certain people who were infected with hepatitis C through treatment with NHS blood or blood products before September 1991

Europe and North America, are treated as for genotype 1. Care is guided by quantitative monitoring of viral RNA during treatment. Failure to achieve an early virological response (2 log10 decline at week 12) is a good predictor of non-response and treatment should be discontinued. Patients with the more favourable genotypes 2 and 3 need be treated for only 24 weeks with pegylated interferon and ribavirin 800 mg daily.22 In children, treatment is usually delayed until they reach adulthood. Treatment is poorly tolerated in patients with HIV infection, renal failure, haemophilia, or viral recurrence after liver transplantation. Specialised centres manage such groups.
How is treatment monitored in hepatitis C infection? Side effects of peginterferon alfa and ribavivin (box 2) are reported in over half of patients and range from mild, non-specific, influenza-like symptoms to major neuropsychiatric disturbance. Medical treatment in the form of antipyretics, haematological support, and antidepressants is common, and multidisciplinary teamwork, usually coordinated by nurse specialists,
Box 4 Components of treatment management and monitoring
   

has developed as the standard of care, although data from trials are scarce to prove this model of care is better than others (box 3).23 Patients must receive appropriate education before treatment (box 4), including techniques for self subcutaneous injection. In the first month a full blood count is checked weekly; if results are stable blood may then be checked at monthly reviews throughout treatment. Thyroid function needs to be checked before treatment and every three months (or if symptoms develop). Generally the need for dose reduction is based on marked falls in blood count (such as neutrophil count <0.7109/l; platelets <75109/l; haemoglobin <100 g/l or fall by >20 g/l in any four week period). Anaemia occurs in about 10-30% of patients, with interferon causing bone marrow suppression and ribavirin causing haemolysis. Reduction of ribavirin dose may reduce treatment efficacy; the aim should be to maintain a target dose greater than 80% of the original dose, and use of haematological growth factor for anaemia seems cost effective according to pooled data stuSOURCES AND SELECTION CRITERIA The contents of this review were sourced through Pubmed, National Institute for Health and Clinical Excellence (NICE) guidance, guidelines of professional bodies, and personal libraries. Additional studies were taken from the retrieved articles. The articles cited reflect a balance of reviews and relevant original research.

Education of patients, usually by a nurse specialist, is paramount Careful pretreatment evaluation of medical, psychiatric, and social issues, with appropriate pre-emptive intervention Regular clinical and laboratory assessment of patients being treated, with easy access for the patient and their GP to the treatment team for any concerns arising Dose reduction only when absolutely necessary to manage anaemia, neutropenia, or thrombocytopenia, as treatment efficacy can be impaired

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A PATIENTS PERSPECTIVE I had been feeling increasingly tired when a blood test following a sports injury revealed I had hepatitis C. I was concerned but assumed that the condition could be stabilised. I stopped drinking alcohol and began organising my life in order to spend a year taking a course of interferon and ribavirin. I found the treatment difficult: the need to inject myself was disturbing. I was short of energy and experienced a significant slowing of mental ability. I worked closely with a specialist nurse who monitored my medication and was available to provide information and support. The treatment unfortunately had no effect on the hepatitis C and was discontinued after six months. My condition was stable for five years, during which I had regular outpatient appointments and underwent blood tests and ultrasound scans. Eventually I became swollen with ascites and it became apparent that I needed a liver transplant. I was placed on the waiting list and nine months later I had a transplant. I still have hepatitis C as the virus infected my new liver but I am markedly better. I have great optimism that with continuing research, a cure for hepatitis C will eventually be possible.
Michael Baigent

without loss of efficacy.26 Another randomised controlled study, however, showed that long term therapy with peginterferon in those who do not respond to initial treatment is not clinically advantageous.30 An improved understanding of viral replication has allowed identification of specific viral targets and antiviral compounds.w6 Hepatitis C specific enzyme inhibitors, including protease inhibitors (such as telaprevir and bocepravir) and nucleoside and non-nucleoside polymerase inhibitors, are being evaluated, with new agents presently being added to standard of care. Other drugs, such as the cyclophilin inhibitor Debio 025 and the thiazolide nitazoxanide, have also shown antiviral activity in early studies. Direct antiviral therapies may lead to viral resistance,w7 a concern not relevant with interferon based therapy.
Contributors: KLN, IB, and GMH all contributed to the writing and editing of the article; KLN and GMH approved the final version and act as guarantors. Competing interests: None declared. Provenance and peer review: Commissioned; externally peer reviewed. Patient consent obtained.
1 2 3 Marcellin P. Hepatitis B and hepatitis C in 2009. Liver Int 2009;29(suppl 1):1-8. Seeff LB. The history of the natural history of hepatitis C (19682009). Liver Int 2009;29(suppl 1):89-99. Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008;134:1699-714. Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009;136:138-48. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol 2009;15:1537-47. Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005;41:790-800. Shiffman ML, Diago M, Tran A, Pockros P, Reindollar R, Prati D, et al. Chronic hepatitis C in patients with persistently normal alanine transaminase levels. Clin Gastroenterol Hepatol 2006;4:645-52. Bonekamp S, Kamel I, Solga S, Clark J. Can imaging modalities diagnose and stage hepatic fibrosis and cirrhosis accurately? J Hepatol 2009;50:17-35. Mehta SH, Lau B, Afdhal NH, Thomas DL. Exceeding the limits of liver histology markers. J Hepatol 2009;50:36-41. Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007;7:40. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 2008;134:960-74. Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677-84. Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008;135:821-9. Ghany MG, Strader DB, Thomas DL, Seeff LB. AASLD practice guidelines: diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335-74. Grieve R, Roberts J, Wright M, Sweeting M, DeAngelis D, Rosenberg W, et al. Cost effectiveness of interferon alpha or peginterferon alpha with ribavirin for histologically mild chronic hepatitis C. Gut 2006;55:1332-8. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmern J, Diago M, Fernndez-Rodrguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005;128:636-41. Tan JA, Joseph TA, Saab S. Treating hepatitis C in the prison population is cost-saving. Hepatology 2008;48:1387-95. Litwin AH, Harris KAJ, Nahvi S, Zamor PJ, Soloway IJ, Tenore PL, et al. Successful treatment of chronic hepatitis C with pegylated interferon

dies.w4. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts in patients being treated for hepatitis C infection.w5
What are the new approaches to treatment? There is ongoing interest in optimising duration and dosage of current antiviral regimens to maximise virological response rates, shorten treatment duration in those predicted to be cured, and spare unnecessary cost and side effects if treatment is likely to fail (box 5). Retrospective and randomised studies show that a rapid virological response at four weeks is a better predictor of sustained response than is response at 12 weeks for all genotypes.24-26 Patients with genotypes 2 and 3 who have a rapid virological response may be cured with a shorter duration of treatment, 12-16 weeks, according to randomised controlled trial data.27 A randomised study in patients with genotypes 1 and 4 showed a similar likelihood for both genotypes of reducing treatment duration by half in those with a rapid virological response.28 Gene expression analysis has identified hepatic gene signatures for patients who do not respond to treatment, and eventually it may provide predictive tools.29 Randomised controlled trial data in genotype 1 patients also showed virological response rates at four, eight, and 12 weeks to have value in stratifying treatment duration to 24, 48, or 72 weeks, allowing therapy to be tailored

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SUMMARY POINTS
Chronic hepatitis C infection is a substantial global health problem Strategies to prevent infection through provision of safe blood products and targeting intravenous drug users are essential Many people are unaware that they carry the virus and are at risk of liver disease Complications of liver disease related to hepatitis C infection are expected to increase over the next 10 years Sustained viral eradication and prevention of disease progression is possible through antiviral therapy Optimal treatment is peginterferon alfa and ribavirin tailored to genotype and response to therapy New specific targeted antiviral therapies are being developed

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in combination with ribavirin in a methadone maintenance treatment program. J Subst Abuse Treat 2009;37:32-40. Schaefer M, Hinzpeter A, Mohmand A, Janssen G, Pich M, Schwaiger M, et al. Hepatitis C treatment in difficult-to-treat psychiatric patients with pegylated interferon-alpha and ribavirin: response and psychiatric side effects. Hepatology 2007;46:991-8. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358:958-65. Fried MW, Shiffman ML, Reddy KR, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82. Hadziyannis SJ, Sette HJ, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-55. Shutt JD, Robathan J, Vyas SK. Impact of a clinical nurse specialist on the treatment of chronic hepatitis C. Br J Nurs 2008;17:572-5. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonales FL Jr, et al. Predicting sustained virological responses in chronic

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hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ ribavirin. J Hepatol 2005;43:425-33. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sol R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124-34. Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, et al. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial. Hepatology 2008;47:43-50. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005;352:2609-17. Ferenci P, Laferl H, Scherzer TM, Gschwantler M, Maieron A, Brunner H, et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008;135:451-8. Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008;57:516-24. Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med 2008;359:2429-41.

CORRECTIONS AND CLARIFICATIONS

Managing UK research data for future use
Because of an editorial error this article was wrongly titled and should have had the title Sharing the raw data from medical research (BMJ 2009;338:b1252, print publication 28 March 2009, pp 729-30). February 2009, pp 467-71). In the Treatment section, under the Pharmacotherapy subsection (p 470), the article stated that all three cholinesterase inhibitors are available in patch form. This statement is wrong: only rivastigmine is available in patch form. As the BMJ follows the BNFs style for drug names we should also have referred to cholinesterase inhibitors as acetylcholinesterase inhibitors.

High vitamin C intake may help prevent gout

In this Short Cuts item by Alison Tonks (BMJ 2009;338: b1078, print publication 21 March 2009, p 685) the units of vitamin C given in the first and final paragraphs should be in milligrams not grams. The labelling on the graph is correct.

Does acupuncture relieve pain?

Because of an administrative error, Adrian White and Mike Cummings, the authors of this editorial (BMJ 2009;338: a2760; print publication 7 February 2009, pp 303-4), cited data from a previous version of the linked research paper. The standard mean difference between placebo acupuncture and conventional care was 0.42 (95% confidence interval 0.60 to 0.23), corresponding to a reduction of 10 mm (not 9 mm, as was stated) on a100 mm visual analogue scale. The difference between needling classic points and control points was 0.17 (0.26 to 0.08), and the overall effect size of acupuncture in relation to usual care was 14 mm (not 12 mm) on a visual analogue scale.

Sexual violence must be treated as medical emergency, charity says

A digit (1) was missing from the start of two numbers cited in this article by Jacqui Wise (BMJ 2009;338:b850, print publication 7 March 2009, p 560). The first sentence of the fifth paragraph should read: MSF [Mdecins sans Frontires] teams provided health care to 12 791 victims of sexual violence in 127 projects worldwide in 2007.

Shaky foundations: compromising the NHS

In this Observations article by Nigel Hawkes (BMJ 2009;338:b789, print publication 28 February 2009, p 508), the following sentence about the compromise on topup payments by the national cancer director, Mike Richards, should have started: This [the compromise] involves NHS patients [not private patients, as was stated] being allowed to pay for drugs that havent been recommended by the National Institute for Health and Clinical Excellence (NICE), so long as they are administered in another part of the hospital. The whole point, of course, is that NHS patients are being allowed to pay for drugs privately.

Managing health problems in people with intellectual disabilities

In the Additional educational resources box in this clinical review by Henny M J van Schrojenstein Lantman-de Valk and Patricia Noonan Walsh (BMJ 2008;337:a2507, print publication 13 December 2008, pp 1408-12), Beyond Words should read Books Beyond Words. The article wrongly said that these books were available from the British Institute of Learning Disabilities. Relatives and care staff can, however, obtain information about Books Beyond Words and order them from the Royal College of Psychiatrists (at www.rcpsych.ac.uk/bbw).

Entanglement in Scotland
David R Ball and colleagues have alerted us to an error in their letter (BMJ 2009;338:b763, print publication 28 February 2009, p 494). In describing how often the anaesthetics departments held sponsored meetings, the authors should have said that four [not three, as stated] departments held less than one meeting a month.

Endgames: Acute breathlessness and metastatic cancer

As a result of an editorial processing error, the title of this case report (BMJ 2008;337:a1405, print publication 20 September 2008, p 699) was wrong: it should have been Breathless beyond obvious. Additionally, we inadvertently omitted three authors from the authorship list. The full list should have been: Chloe I Bloom, L C Price, E F Bowen, and M E Roddie.

Alzheimers disease
An error occurred in this Clinical Review by Alistair Burns and Steve Iliffe (BMJ 2009;338:b158, print publication 21

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