Guidelines for the Management of Patients with Hepatitis B Infection 2009

Transcription

1 Guidelines for the Management of Patients with Hepatitis B Infection 2009 Acute HBV HBV is a notifiable disease 90-95% Adults (but only 10% children) will clear the virus Incidence of fulminant hepatic failure is 0.5% HBsAg, HBeAg, HB cigm/igg (HBV DNA only in chronics) HBcIgM is not specific for acute HBV and occurs in reactivation, flares and highly replicative state Review regularly beware patient with coagulopathy Vaccinate all close contacts - see below If HBsAg Positive at 6 months - chronic Anti HBs and HBcIgG implies immunity to HBV no further Rx needed. But note new entity of occult HBV, in which markers are of immunity, but circulating HBVDNA persists. Nucleos(t)ide analogues are sometimes used if the patient has acute liver failure with coagulopathy (see later section) Chronic HBV Current Definition: HBsAg positive for more than 6 months after acute infection. Patients can either be HBeAg positive or HBeAg negative. HBeAg HBV DNA ALT Definition Positive >2,000 IU /ml PERSISTENTLY Normal Immunotolerant Positive >2,000 IU /ml Raised eag +ve active chronic HBV Negative >2000 IU /ml Raised eag ve active chronic HBV* Negative <2000 IU /ml PERSISTENTLY Normal Inactive HBsAg carrier state** * anti HBe pos or neg. Probable HBV mutants (precore and core promoter mutants also known generically as eagen negative mutants)

2 ** anti HBe present Treatment is discussed in due course. Shared care protocols for lamivudine, adefovir, entecavir and tenofovir are available and must be sent to the GP so that they can continue to prescribe. Some GPs will refuse to prescribe, in which case discuss with the liver unit pharmacist. Clinic visit #1 Clinical details: duration of diagnosis route of acquisition symptoms alcohol intake Risk factors for co-infection Family Hx of HBV and HCC stigmata of chronic liver disease, splenomegaly and liver volume Investigations: General advice: Hepatitis B markers: HBsAg, HBeAg, antihbe, cigm/igg Hepatitis B viral load (PCR) (5ml in EDTA tube) HCV antibody FBC/clotting screen/u&e s/lft s alpha feto protein (AFP). Not in PREGNANT patients Immunology: liver autoantibodies, immunoglobulins Ferritin If myalgia/cutaneous features of vasculitis: rheumatoid factor and cryoglobulins USS HIV if considering treatment or at risk Genotyping is required if patient has been biopsied and treatment is currently being considered Reassure: most inactive HBsAg carriers will have normal/near normal liver histology and have a low risk of developing complications Spontaneous loss of e can occur Risk of horizontal transmission is high and varies according to DNA levels Approximately 0.5% of inactive HBsAg carriers will clear HBsAg yearly Screen all partners and household contacts with HBcAb, HBsAg and anti HBsAb all HBcAb negatives and anti HBsAb negative vaccinate HBcAb positive and anti HBsAb positive already immune

3 Advice to avoid sharing razors, toothbrushes and appropriate disposal of tampons Avoid heavy alcohol intake (abstinence in cirrhotics) as with NAFLD Advice on weight loss if BMI>26 GP to vaccinate against Hepatitis A Huge risk of vertical transmission - Mother HBsAg +ve eag neg vaccinate baby at birth Mother HBsAg +ve eag +ve vaccinate and HBIG Breast feeding is safe once child is vaccinated Patient should inform Dr and dentists of Hep B status Management of chronic HBV NOTE: When considering treatment of HBV the upper limits of normal for ALT should be considered to be <19 for women and < 30 for men HBV DNA results are given in IU/ml, older results and results from other hospitals may be in copies/ml (to convert from copies/ml to IU/ml divide by 5) Note the different cut off in HBV DNA between eag POS and eag NEG patients Patients, particularly males, age > 40 or family history of HCC may require more intensive follow up HBeAG HBV DNA(iu/ml) ALT Action POS <2,000 POS >2,000 POS >2,000 Persistently Normal Persistently Normal 1-2x upper limit normal (ULN) 6 monthly review initially, then annual review Low efficacy with current treatment Repeat LFTs 3 monthly initially and consider biopsy if ALT rises, if family history of HCC or patient age greater than 40. Consider liver biopsy to determine if ongoing inflammation/fibrosis, otherwise initial 3 monthly LFTs and biopsy if ALT rises to 2xULN POS >2,000 > 2x ULN Will require treatment but consider biopsy to stage disease NEG <2,000 Persistently Observe with repeat LFTs and HBV DNA,

4 Normal NEG <2, x ULN NEG <2,000 > 2xULN biopsy if HBV DNA rise 3 monthly LFTs and if ALT rises further for liver biopsy Consider liver biopsy to determine if ongoing inflammation/fibrosis NEG 1,000-2,000 Persistently Normal 3 monthly LFTs and if LFTs become abnormal then liver biopsy NEG > 2,000 > 2x ULN Will probably require treatment but consider liver biopsy to determine extent of inflammation/fibrosis Who should be treated? Patients with high (>2,000iu/ml for both eagpos or eagneg) viral load and abnormal LFT s as described as above with liver biopsy if possible prior to starting treatment. Patients who have undergone liver biopsy following the above guidelines whose biopsy shows moderate or severe inflammatory activity or mild activity with Ishak fibrosis score of > 2 or a necroinflammatory score of > 4 Any cirrhotic patient with detectable HBV DNA at any level. Deciding which Treatment Nucleoside analogue naïve patients can be treated with either or entecavir or tenefovir. In female patients of childbearing age tenofovir should be used as there is more evidence of safety in pregnancy (although still limited evidence) If patients have previously been treated with any oral agent the they should have the Hep B resistance profile checked (this can be done by requesting HBV DNA viral genotype and resistance profile on a microbiology request form). If they have any of the lamivudine resistance mutations they should not be treated with entecavir monotherapy as resistance is likely to emerge. In this instance if they are already on lamivudine they should be treated with lamivudine and tenofovir combination therapy

5 If a patient has a high viral load and there is a clinical need to bring this down quickly they should receive entecavir unless previously treated with lamivudine in which case they should be treated with lamivudine and tenofovir combination therapy. Patients treated with nucleos(t)ide analogues should be treated indefinitely but if a patient who was eag POS seroconverts they should be continued on treatment for a further 6 months (with a minimum treatment duration of 1 year in total)when treatment can then be stopped with careful monitoring to ensure there is no post-treatment flare. If a patient is being considered for PegIFN therapy they should have their HBV genotype checked. PegIFN should particularly be considered for young patients with low viral load, high ALT and genotypes A or B (these are all predictors of response to PegIFN). Patients with genotypes C or D have poorer response rates but should not be excluded from PegIFN treatment on the basis of their genotype alone. Patients should be treated for 48 weeks however if there is a less than 1 log drop in viral load after 12 weeks of treatment the treatment should be stopped as the chances of success are poor in this case. Generally this treatment is tolerated better than in patients being treated for Hepatitis C. PegIFN is contraindicated in decompensated cirrhosis If a patient is already established on Lamivudine monotherapy and they have undetectable HBV DNA and normal LFTs then continue Lamivudine monotherapy with initially 3 monthly and then 6 monthly repeat HBV DNA and LFTs. If they have detectable HBV DNA then they should have Tenofovir added to their treatment. Treatment of Hepatitis B Cirrhosis Suspect cirrhosis if patient has signs of CLD. 1 year survival in eag positive cirrhotics is around 80% in compensated patients and 35% in decompensated patients. Survival is 97% at 5 years in eag negative patients. The cirrhotic B will likely come to transplantation at some point. A. Compensated cirrhosis If there is detectable viral load and the patient is nucleoside naïve start either entecavir 0.5mg od or tenofovir 245mg od. If they are nucleoside experienced check for viral resistance mutations and treat as above. Irrespective of viral load treatment should continue indefinitely unless there is loss of HBsAg. Initially monitor 2 monthly (LFT s, viral load).decrease doses of all oral agents in renal impairment (discuss with pharmacist)

6 B. Decompensated cirrhosis Treat as the compensated cirrhotic patient. Interferon is contraindicated. Start work up for OLT. Treatment of HBV-HCV co-infection One of the two usually predominates usually HCV. If HCV treatment is started monitor HBV viral load carefully during treatment. Depending on the genotype of Hepatitis C and Hepatitis B it may be worth considering treating with PegIFN for 48 weeks rather than the shortened courses used in Hepatitis C monoinfection Treatment of HBV and Hepatitis D co-infection Testing for delta virus should always be considered in HBV patients with raised ALT and low viral load, especially with activity on biopsy. The only therapy thought to be of benefit is PegIFN. Patients should be considered for 48 weeks of PegIFN. Ribavirin, lamivudine and adefovir are of no additional benefit. This group of patients are thought to have a higher risk of auto-immune disease and should have their autoantibodies checked. HBV-HIV co-infection DO NOT START THERAPY UNTIL DISCUSSED WITH GUM SPECIALIST HIV treatment frequently includes agents with activity against HBV including agents such as lamivudine and tenofovir. Do not commence therapy without discussion with the GU medicine team even if treatment for the patient s HIV is not needed due to the risk of development of HIV resistance.

7 Pregnancy Treatment should be continued if the patient is cirrhotic. Risks and benefits should be discussed with the patient by a consultant member of the team. There is some data on the safety of lamivudine and tenofovir in pregnancy. Because of limited data patients who are on entecavir should probably be switched to tenofovir.

8 Chemotherapy and immunosuppression See guidelines for prevention of reactivation.treatment should not be discontinued if the patient is cirrhotic. Even patients who are apparently immune, sab+ and cab+ may reactivate on chemotherapy and should be considered for prophylaxis as per guideline algorithm. Post OLT for HBV Patients should continue with their pre-transplant treatment with nucleos(t) analogues and have HBIG to keep a surface Ab titre>100 for a minimum of one year (when requesting in transplant outpatient clinic CLEARLY state that the surface ANTIBODY is needed). After one year consideration can be given to stopping the HBIg therapy but the oral agent may require review and lamivudine monotherapy alone is insufficient (in most cases the patient will require tenofovir adding to the lamivudine). HCC screening HBV carriers are at increased risk of HCC even in the absence of cirrhosis 6 monthly AFP and USS in high risk patients all cirrhotics FH of HCC SE Asian ethnic origin age>40 (if local resources allow) Further clarification of suitable groups to screen is awaited. Treatment of Acute hepatitis B infection The vast majority of patients will receive no treatment.

9 Patients with liver failure, as defined by onset of ascites or INR > 1.6 which does not reverse with vitamin K should receive anti viral therapy. Entecavir at 0.5mg od is the preferred agent in Leeds although tenofovir 245mg od could be considered if the renal function is normal. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those undergoing liver transplantation. PegIFN is contra-indicated. Response to therapy eag POS Lamivudine Adefovir Entecavir Telbivudine PegIFN alpha 100mg od 10mg od 0.5mg od 600mg od 180mcg 48-52wk 48wk 48wk 52wk 48wk Loss HBV DNA 40-44% 21% 67% 60% 25% Loss of HBeAg 17-32% 24% 22% 26% 30-34% HBeAg seroconversion 16-21% 12% 21% 22% 27-32% Loss of HBsAg <1% 0% 2% 0% 3% ALT normalization Histological improvement 41-75% 48% 68% 77% 46% 49-56% 53% 69% 65% 38%

10 Response to therapy eag NEG Lamivudine 100mg od 48-52wk Adefovir 10mg od 48wk Entecavir 0.5mg od 48wk Telbivudine 600mg od 52wk PegIFN alpha 48wk Loss HBV DNA ALT normalization Histological improvement 60-73% 51% 90% 88% 63% 60-79% 72% 78% 74% 38% 60-66% 64% 70% 67% 48% When starting treatment with Nucleos(t)ide analogues some GPs will take on responsibility for prescribing if they are sent shared care guidelines as below: Lamivudine: Shared Care Guidelines Introduction Indication Lamivudine is indicated for the treatment of chronic hepatitis B in adults with: compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and / or fibrosis. decompensated liver disease Lamivudine is also indicated for prophylaxis post liver transplant for hepatitis B.

11 Therapy should be initiated by a physician experienced in the management of chronic hepatitis but the responsibilities for managing the prescribing lamivudine can be shared between the hospital specialist and general practitioner. Pharmacology Lamivudine is a nucleoside analogue. It is metabolised by both infected and uninfected cells to the triphosphate (TP) derivative which is the active form of the parent compound. Lamivudine-TP acts as a substrate for the HBV viral polymerase. The formation of further viral DNA is blocked by incorporation of lamivudine-tp into the chain and subsequent chain termination. Dosage and administration Lamivudine is available as 100mg tablets and an oral solution containing 5mg/ml. The recommended dose is 100mg orally once a day. Dosage reduction is required in patients with a creatinine clearance of 50ml/min as shown in the table below. Patients receiving lamivudine for concomitant HIV infection should continue to receive lamivudine in a dose appropriate for HIV infection (150mg every 12 hours or 300mg once daily). Creatinine clearance First Dose of lamivudine Maintenance Dose of lamivudine ml/min Once daily 30 to < mg 50 mg (10 ml) * 15 to < mg 25 mg (5 ml) * 5 to < mg (7ml) * 15 mg (3 ml) * < 5 35 mg (7ml) * 10 mg (2 ml) * *oral solution 5mg/ml Treatment is continued indefinitely. In some patients with compensated disease, it may be possible to discontinue treatment, if seroconversion has occurred (refer to SPC for details) Responsibilities of the specialist initiating

12 Summary Assess lamivudine dosage with particular reference to baseline renal function Discuss benefits and side effects of treatment with the patient Initiate lamivudine treatment Continue regular review of the patient every 3 months Advise GP on when and how to discontinue treatment (if necessary) Report adverse events to the CSM Drug & Disease monitoring Perform all monitoring of viral replication markers and liver function tests at 3 monthly intervals and promptly inform GP of results and need for any changes to existing treatment. Parameter HBV DNA HBeAg (if +ve at the start of therapy Liver function tests Electrolytes Frequency of monitoring At baseline and every 3 months* Comments These parameters mainly reflect disease activity, and the response of the infection to treatment. They may indicate when treatment may be stopped. If treatment is discontinued, continued monitoring is necessary in case of exacerbations. Renal function At baseline Dosage reduction is required if creatinine clearance is <50ml/min. *Specialist advice. The SPCs state that ALT should be measured every 3 months, and HBV DNA and HBeAg every 6 months, as a minimum. GP Responsibilities Summary Prescribe lamivudine Follow specialist advice on any changes in treatment Refer back to hospital specialist in the event of deteriorating clinical condition Report adverse events to the hospital specialist Report any identified non-compliance to hospital specialist

13 Adverse drug reactions In clinical studies of patients with chronic hepatitis B, lamivudine was well tolerated. The most common drug-related adverse events, reported with a similar incidence in placebo and lamivudine groups included malaise, fatigue, nausea, vomiting and headache (refer to SPC for full list of adverse effects). Drug Interactions Lamivudine is predominantly excreted by active renal secretion, hence there is a possibility of interactions with other products eliminated via this route e.g. trimethoprim. Co-trimoxazole increases lamivudine exposure by 40%, however lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. No dosage change is recommended. Other products partly eliminated by the active renal secretion route (e.g. ranitidine, cimetidine) have not been shown to interact with lamivudine Communication Hospital Specialist to GP The hospital specialist will inform the GP when they have initiated treatment with lamivudine and will write to request that the GP participate in shared care and take over the prescribing. The hospital specialist will inform the GP of the results taken at each clinic visit. Any action required will be taken by the hospital specialist and information on any changes to medication will be given in the accompanying letter. The hospital will inform the GP when patients have missed clinic visits and hence missed essential monitoring. GP to Hospital Specialist If the GP has concerns over the prescribing of lamivudine, they will contact the hospital specialist as soon as possible. Adefovir dipivoxil:shared Care Guidelines

14 Introduction Indication Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with: Compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and fibrosis Decompensated liver disease Therapy should be initiated by a physician experienced in the management of chronic hepatitis but the responsibilities for managing the prescribing adefovir for chronic hepatitis B can be shared between the hospital specialist and general practitioner. Pharmacology Adefovir dipivoxil is an oral prodrug of adefovir, an acyclic nucleotide phosphonate analogue of adenosine monophosphate, which is actively transported into mammalian cells where it is converted by host enzymes to adefovir diphosphate. Adefovir diphosphate inhibits HBV viral polymerases and, after incorporation into viral DNA, causes DNA chain termination. Dosage and administration Adefovir dipivoxil is available as a tablet containing 10mg Adefovir dipivoxil (equivalent to 5.54mg adefovir) The recommended dose is 10mg orally once daily. Adjustments of the dosage interval are required in patients with a creatinine clearance of 50ml/min as shown in the table below (refer to SPC for details) Creatinine Clearance (ml/min) Recommended Dosing 10mg 10mg Every

15 Interval Every 48 hours 72 hours The optimum dose of treatment is unknown. Treatment is usually continued indefinitely but in some patients with compensated disease, it may be possible to discontinue treatment, if seroconversion has occurred(refer to SPC for details) Responsibilities of the specialist initiating treatment Summary Assess adefovir dosage with particular reference to baseline renal function Discuss benefits and side effects of treatment with the patient Initiate adefovir treatment Continue regular review of the patient every 3 months Advise GP on when and how to discontinue treatment (if necessary) Report adverse events to the CSM Drug & Disease monitoring Perform all monitoring of viral replication markers and liver function tests at 3 monthly intervals and promptly inform GP of results and need for any changes to existing treatment. Parameter HBV DNA HBeAg (if +ve at the start of therapy Liver function tests Electrolytes Renal function Frequency of monitoring At baseline and every 3 months Comments These parameters mainly reflect disease activity, and the response of the infection to treatment. They may indicate when treatment may be stopped. If treatment is discontinued, continued monitoring is necessary in case of exacerbations. Adjustment to the dosing interval is necessary if renal function declines (creatinine clearance <50ml/min). GP Summary Responsibilities

16 Prescribe adefovir dipivoxil Follow specialist advice on any changes in treatment Refer back to hospital specialist in the event of deteriorating clinical condition Report adverse events to the hospital specialist Report any identified non-compliance to hospital specialist Adverse drug reactions Adefovir is generally well tolerated. Side effects associated more frequently with adefovir than placebo in trials were asthenia, diarrhoea, anorexia, headache, abdominal pain and pharyngitis. In pre and post transplant patients changes in serum creatinine were observed very commonly. These changes were seen in patients with multiple risk factors for changes in renal function, including concomitant use of ciclosporin and tacrolimus, and were generally mild to moderate in severity, although some cases of renal failure have been reported. Renal function will be monitored every 3 months in clinic. Rash and pruritus have also been observed during post marketing surveillance. Drug Interactions The potential for liver enzyme cytochrome P450-mediated interactions with adefovir is low. Adefovir is excreted renally by both glomerular filtration and active tubular secretion. No clinically relevant interactions have been identified (refer to SPC for further details) Communication Hospital Specialist to GP The hospital specialist will inform the GP when they have initiated treatment with adefovir and will write to request that the GP participate in shared care and take over the prescribing. The hospital specialist will inform the GP of the results taken at each clinic visit. Any action required will be taken by the hospital specialist and information on any changes to medication will be given in the accompanying letter. The hospital will inform the GP when patients have missed clinic visits and hence missed essential monitoring.

17 GP to Hospital Specialist If the GP has concerns over the prescribing of adefovir, they will contact the hospital specialist as soon as possible.

18 Leeds Entecavir for chronic hepatitis B Shared Care Guidelines Indication Introduction Entecavir is indicated for the treatment of chronic hepatitis B in adults with: Compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and/or fibrosis In patients with HBeAg positive and HBeAg negative HBV infection, nucleoside naive patients and patients with lamivudine-refractory hepatitis B Therapy should be initiated by a physician experienced in the management of chronic hepatitis B but the responsibilities for managing the prescribing of entecavir can be shared between the hospital specialist and general practitioner. Pharmacology Entecavir is a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP, entecavir-tp functionally inhibits the 3 activities of the viral polymerase: (1) priming of the HBV polymerase, (2) reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and (3) synthesis of the positive strand HBV DNA. Dosage and administration Entecavir should be taken orally, once-daily. Entecavir is available as 1mg and 500 microgram tablets and a 50micrograms/ml oral solution.

19 Nucleoside naïve patients: The recommended dose is 0.5 mg once daily, with or without food. Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance: The recommended dose is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal). Adjustments of the dose are required in patients with a creatinine clearance of 50ml/min as shown in the table below. For doses less than 500micrograms the oral solution is recommended. Creatinine clearance (ml/min ) Nucleoside naïve patients Lamivudine-refractory patients mg once daily 1 mg once daily mg once daily 0.5 mg once daily OR 0.5 mg every 48 hours mg once daily 0.3 mg once daily OR OR 0.5 mg every 72 hours 0.5 mg every 48 hours < mg once daily 0.1 mg once daily Haemodialysi

20 s or CAPD OR OR 0.5 mg every 5-7 days 0.5 mg every 72 hours The optimum duration of treatment is unknown. Treatment is usually continued indefinitely but in some patients with compensated disease, it may be possible to discontinue treatment, if seroconversion has occurred(refer to SPC for details) Responsibilities of the specialist initiating treatment Summary Assess entecavir dosage with particular reference to prior treatment and baseline renal function Discuss benefits and side effects of treatment with the patient Initiate entecavir treatment Continue regular review of the patient every 3 months Advise GP on when and how to discontinue treatment (if necessary) Report adverse events to the CSM Drug & Disease monitoring Perform all monitoring of viral replication markers and liver function tests every month for 3 months followed by 3 monthly intervals and promptly inform GP of results and need for any changes to existing treatment. Parameter HBV DNA HBeAg (if +ve at the start of therapy Liver function tests Electrolytes Frequency of monitoring At baseline then every month for 3 months, then Comments These parameters mainly reflect disease activity, and the response of the infection to treatment. They may indicate when treatment may be stopped. If treatment is discontinued, continued monitoring is necessary in case of exacerbations.

21 Renal function 3 monthly Adjustment to the dosing interval is necessary if renal function declines (creatinine clearance <50ml/min). GP Responsibilities Summary Prescribe entecavir Follow specialist advice on any changes in treatment Refer back to hospital specialist in the event of deteriorating clinical condition Report adverse events to the hospital specialist Report any identified non-compliance to hospital specialist Adverse drug reactions/ special warnings (refer to SPC for full list of adverse effects) In clinical studies the most common adverse reactions with a possible relation to entecavir were headache, fatigue, dizziness and nausea. Spontaneous exacerbations in chronic hepatitis B can occur relatively commonly and are characterised by transient increases in serum ALT, as serum HBV DNA levels decline. Exacerbations among entecavir-treated patients had a median time of onset of 4-5 weeks. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy. (relevant laboratory tests will be carried out in clinic).

22 Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. (hepatic function will be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy). Drug Interactions Since entecavir is predominantly eliminated by the kidney, coadministration with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either drug. No clinically relevant interactions have been identified (refer to SPC for further details) but patients should be monitored closely for adverse reactions when entecavir is coadministered with such drugs. Entecavir is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes, therefore CYP450 mediated drug interactions are unlikely to occur with entecavir. Communication Hospital Specialist to GP The hospital specialist will inform the GP when they have initiated treatment with entecavir and will write to request that the GP participate in shared care and take over the prescribing. The hospital specialist will inform the GP of the results taken at each clinic visit. Any action required will be taken by the hospital specialist and information on any changes to medication will be given in the accompanying letter. The hospital will inform the GP when patients have missed clinic visits and hence missed essential monitoring. GP to Hospital Specialist

23 If the GP has concerns over the prescribing of entecavir, they will contact the hospital specialist as soon as possible. Contact names and details If you have any concerns regarding individual patients, see consultant letter for medical contact details or contact one of the following: Faye Milner Liver Pharmacist or via switchboard bleep (office hours) Ward 71 Liver Unit, St James s University Hospital (24 hours) The on-call liver unit registrar is available at all times via switchboard if advice is needed out of hours. The registrars have access to an on-call Consultant Hepatologist at all times. LGI Switchboard SJUH Switchboard Cost per month Prepared by Faye Milner Date Jul 2007 Date for review Jul This information is not inclusive of all prescribing information and potential adverse effects. Please refer to the SPC (data sheet) or BNF for further prescribing information. The Shared Care Guidelines are also available electronically via Leeds Health Pathways on nww.lhp.leedsth.nhs.uk

24 Leeds Tenofovir Disoproxil Fumarate Shared Care Guideline for the treatment of chronic Hepatitis B infection Introduction Indication Tenofovir is indicated for the treatment of chronic hepatitis B in adults with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis. Therapy should be initiated by a physician experienced in the management of chronic hepatitis B, but the responsibilities for managing the prescribing of tenofovir can be shared between the specialist initiating treatment and other prescribers. Licensing Information Tenofovir is licensed for the above indication. Pharmacology Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovir diphosphate. Tenofovir diphosphate inhibits HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination. Dosage and administration Tenofovir is available as film-coated tablets containing 245 mg of tenofovir disoproxil (as fumarate). The recommended dose is 245 mg (one tablet) once daily taken orally with food. Treatment is long-term.

25 Dosage adjustment is advised for renal impairment according to creatinine clearance as detailed below: Creatinine clearance (ml/min ) Dose of tenofovir Disoproxil Fumarate mg once daily mg every 48 hours mg every hours (2 x per week) < 10 Avoid < 10 on Haemodialysis 245mg once weekly after haemodialysis Responsibilities of the specialist initiating treatment o Summary To assess the suitability of the patient for treatment. Assess tenofovir dosage (and length of treatment). Baseline renal function should be considered. Discuss benefits and side effects of treatment with the patient. Initiate tenofovir treatment. To ask the GP whether he/she is willing to participate in shared care and discuss the shared care arrangement with the patient. Continue regular review of the patient every 3 months. To adjust treatment as clinically necessary. Advise the GP regarding when and how to discontinue treatment (if necessary). To monitor the patient for adverse events and report any to the Commission on Human Medicines/MHRA (Yellow Card Scheme) and. Supporting and advising GPs Drug & Disease monitoring Perform all monitoring of viral replication markers, liver function tests, renal function and phosphate levels prior to initiation of treatment, every month for 3 months followed by 3 monthly intervals. Promptly inform GP of results and need for any changes to existing treatment. Advise GP to monitor renal function at monthly intervals for the first

26 year (when the patient is not being seen within the hospital setting for these tests). In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir, consideration should be given to more frequent monitoring of renal function. Responsibilities of other prescribers Summary Prescribe tenofovir. Follow specialist advice on any changes in treatment. Refer back to hospital specialist in the event of deteriorating clinical condition. Identify and report adverse events to the hospital specialist and CSM. Report any identified non-compliance to hospital specialist. To ensure that there are no interactions with any other medications initiated. To adjust the dose of tenofovir as advised by the hospital specialist. To stop treatment on the advice of the hospital specialist. To perform any additional blood tests (e.g full blood counts, urea & electrolytes, liver function tests) if requested by the specialist. To continue monitoring of hepatic function for at least six months after discontinuation of the hepatitis B therapy. Adverse drug reactions, Precautions and Contraindications and Interactions Adverse drug reactions (Refer to SPC for full list of adverse effects) Very common ( 1/100 <1/10) Headache Diarrhoea, nausea, vomiting, abdominal pain, flatulence ALT increase o Fatigue Rare ( 1/10,000 <1/1,000) renal failure, acute renal failure, proximal tubulopathy (including Fanconi syndrome), increased creatinine

27 In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients, ontreatment ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a 2 log 10 copies/ml reduction in viral load that preceded or coincided with the ALT elevation. The most common adverse effects reported from the use of tenofovir are mild gastrointestinal effects, particularly diarrhoea, nausea and vomiting, abdominal pain, flatulence, dyspepsia, and anorexia. Serumamylase concentrations may be raised and pancreatitis has been reported rarely. Hypophosphataemia occurs commonly. Skin rashes may occur. Lactic acidosis, usually associated with severe hepatomegaly and steatosis, has been associated with treatment with nucleoside reverse transcriptase inhibitors Drug Interactions Tenofovir should not be administered with adefovir, or any combination products containing tenofovir. Co-administration of tenofovir and didanosine is not recommended. If the patient is co-infected with HIV, interactions with other antiviral medications may need to be considered. Since tenofovir is primarily eliminated by the kidneys, co-administration with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hoat 1, hoat 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products. Use of tenofovir should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.

28 Use in pregnancy and lactation There is limited clinical data on the use of tenofovir in pregnancy. Animal studies do not indicate direct or indirect harmful effects of tenofovir with respect to pregnancy, foetal development, parturition or postnatal development. Given that the potential risks to developing human foetuses are unknown, the use of tenofovir in pregnancy is not recommended. Women of childbearing potential taking tenofovir must use effective contraception In animal studies it has been shown that tenofovir is excreted into milk. It is not known whether tenofovir is excreted in human milk. Therefore, it is recommended that mothers being treated with tenofovir do not breast-feed their infants. As a general rule, it is recommended that HBV infected women do not breast-feed their infants in order to avoid transmission of the virus to the infant. Communication Specialist to GP The hospital specialist will inform the GP when they have initiated treatment with tenofovir and will write to request that the GP participate in shared care and take over the prescribing. Results of any tests will be sent to the GP. The hospital specialist will inform the GP of the results taken at each clinic visit. Any action required will be taken by the hospital specialist and information on any changes to medication will be given in the accompanying letter. The hospital will inform the GP when patients have missed clinic visits and hence missed essential monitoring. GP to Hospital Specialist If the GP has concerns over the prescribing of tenofovir, they will contact the hospital specialist as soon as possible.

29 Contact names and details If there are any concerns regarding individual patients, see consultant letter for medical contact details or contact one of the following: Faye Croxen Liver Pharmacist (0113) or via switchboard (0113) bleep (office hours) Ward 71 Liver Unit, St James s University Hospital (0113) (24 hours) The on-call Liver Unit Registrar is available at all times via switchboard if advice is needed out of hours. The registrars have access to an on-call Consultant Hepatologist at all times. LGI Switchboard (0113) SJUH Switchboard (0113) Cost per month (MIMS August 2008) 255 (30 tablet pack) Written by Smita Bhikha, Medicines Information/Liver Pharmacist should include details of both a pharmacist and consultant This information is not inclusive of all prescribing information and potential adverse effects. Please refer to the SPC or BNF for further prescribing information. The Shared Care Guidelines are also available electronically via Leeds Health Pathways on References

30 Summary of Product Characteristics of Viread (tenofovir). Gilead Sciences Ltd. Date of revision of text 04/2008. Accessed 18/08/2008. Martin J (Editor). British National Formulary. No. 55 March The British Medical Association and the Royal Pharmaceutical Society of Great Britain.

31 Appendix 1: Levels of evidence Level and type of evidence to be included for off-label or unlicensed drugs Level of evidence Type of evidence 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort studies. High quality case control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal 3 Non analytic studies (for example, case reports, case series) 4 Expert opinion, formal consensus (Reference: - Reviewing and grading the evidence, NICE guidelines manual, April 2006) 31 Management of Patients with Hepatitis B Infection 2009

32 Guideline Provenance Guidance first written by Dr Mark Aldersley for WYHN following network meeting in 2008, revised in Kept as joint network/sjuh guidance due to inclusion of Leeds based shared care guidance for general practitioners, which gives some guidance as to monitoring of drugs etc. Other treatment teams may find it useful to adapt to local needs. Review date October Management of Patients with Hepatitis B Infection 2009