• IV drug abuse is the principal mode of transmission of hepatitis C. Occasional users are likely to share needles because drug use is usually unplanned and with borrowed equipments.
• Sharing straws for snorting cocaine may be a route of infection due to nose bleeds.
• Blood or blood component transfusion or organ transplants before 1992 are other modes of transmission.
• People who received blood products such as haemophiliacs before 1985 will have at risk of infection.
• Sexual transmission of HCV between monogamous partners is uncommon.  Many authorities do not advise the use of barrier protection among monogamous couples. Nevertheless, between 1% and 5% of monogamous sexual partners of index HCV cases test positive for anti-HCV.
• HCV-infected persons should avoid activities that might result in blood exposure, such as sharing a razor or toothbrush.
• Maternal-foetal transmission- risk is about 6%. Unclear whether it happens in the uterus or during birth. Testing infant should be delayed until 8weeks as HCV PCR may be false negative earlier.
• Kissing/cuddling is fine. Breastfeeding is ok unless mother has cracked nipple and child has a cut in mouth. Breastfeeding is not recommended if there is co- infection with HIV..

Discuss the prevalence of Hep C

1. Hep C was discovered and cloned in 1989
2. Three percent of world population is infected- 180million are affected worldwide
3. 250,000 people infected in UK
4. 50% of active injectors will have hep C

Who should be screened for Hep C

1. IDU (intravenous drug users- past or present)
2. Dialysis
3. HIV infection
4. Transfusion or transplant prior to July 1992
5. Haemophiliacs who received factor clotting factor concentrates prior to 1987
6. Children born to HCV-infected mother
7. Current sexual partners of HCV infected persons
8. Health care worker after needle stick injury or mucodal exposure to HCV positive blood
9. People who have had tattoos or body piercings where infection control procedures are poor
10. People who have received medical or dental treatment in countries where infection control is poor and there is high prevalence of hep C eg Southeast Asia and subsaharan Africa

Discuss the natural history of hepatitis C?

• Hep C is described as chronic when infection persists beyond six months
• Up to 85% of individuals who develop acute hepatitis C will remain HCV-infected.
• The risk of developing cirrhosis ranges from 5% to 25% over periods of 25 to 30 years.
• HCC develops only in cirrhotic liver in hepatitis C (1-3% per year)
• Hepatitis C is the principal cause of death from liver disease and the leading indication for liver transplantation.

Discuss the diagnosis of hepatitis C?

The incubation period of acute hep C is usually between 6-9 weeks. The HCV antibody usually present three months after the initial infection and in some cases up to six months.Serologic assay that detect speci?c antibody to hepatitis C virus (anti-HCV) is used as a screening test. Confirmation is done with HCV RNA (highly sensitive PCR test)

• Anti HCV +ve HCV RNA +ve Diagnosis confirmed.
• Anti HCV +ve HCV RNA –ve This most likely indicates infection has resolved. However, HCV RNA may be falsely –ve in presence of intermittent or low level viremia. So recheck HCV RNA after 4-6weeks. If 2 tests for HCV RNA are negative, it means Hep C infection has resolved.
• In conditions associated with diminished antibody production such as HIV. Transplant recipients & chronic haemodialysis- negative anti-HCV does not exclude HCV – so HCV RNA may be needed.
• If acute infection is suspected then also HCV RNA is to be requested as it might take 8-12 weeks for anti-HCV to be positive, eg needle stick injury with hepC positive blood.
• If HCV RNA assay is positive- the HCV virus should be genotyped. There are 6 genotypes 1-6. Genotype 1 is the most common followed by genotype 2 and 3

Discuss the role of liver biopsy in hepatitis C?

Liver biopsy provides the stage of liver injury and hence the risk of progression. A liver biopsy was previously considered routine in HCV genotype 1 prior to treatment. However the issue is now in a state of flux. The procedure is not considered mandatory at present before deciding treatment.  However, if a liver biopsy is performed and the histology shows minimal to moderate fibrosis (i.e. portal fibrosis with no septa), treatment may be deferred. If performed and treatment is withheld, a common strategy is to repeat the liver biopsy 4 to 5 years later and to reconsider treatment should there be evidence of disease progression.

A liver biopsy may be unnecessary in persons with genotypes 2 and 3 HCV infection as there is high response to treatment. The need for liver biopsy is uncertain with genotype 4-6.

So in summary, a liver biopsy should be considered in patients if information is needed regarding ?brosis stage for prognostic purposes or to make a decision regarding treatment

Who should be treated for hepatitis C?

Characteristics of persons for whom therapy is widely accepted-

• At least 18 yrs of age and
• HCV RNA positive and
• Liver biopsy showing chronic hepatitis and significant fibrosis (bridging fibrosis or higher)&
• Compensated liver disease (bilirubin <1.5, INR < 1.5, Albumin >3.4, Platelets >75,000)&
• Acceptable haematological & biochemical indices (Hb- normal, neutrophil >1.5, creatinine <1.5)
• No contraindications of interferon or ribavirin
• Patient should be vaccinated against Hep B and Hep A

What are the contraindications for hepatitis C treatment?

• Major uncontrolled depressive illness
• Solid organ transplant (renal, heart, or lung)
• Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peg interferon and ribavirin
• Decompensated liver cirrhosis
• Untreated thyroid disease
• Pregnant or unwilling to comply with adequate contraception
• Severe concurrent medical disease such as severe hypertension, heart failure, signi?cant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease,epilepsy
• Age less than 2 years
• Known hypersensitivity to drugs used to treat HCV

Discuss the treatment for hepatitis C?

The optimal therapy for chronic HCV infection is the combination of peg interferon alfa and ribavirin.

Treatment of HCV genotype 1 and 4

• Treatment with peg interferon plus ribavirin should be planned for 48 weeks;
• Treatment may be discontinued in patients who do not achieve an early virological response (EVR; >2 log reduction in HCV RNA at week 12 of treatment). If an EVR is not seen, there is a less than 2% chance of achieving a SVR
• Patients who do not achieve a complete EVR (undetectable HCV RNA at week 12 of treatment) should be re-tested at week 24, and if HCV RNA remains positive, treatment should be discontinued.
• For patients with genotype 1 infection who have delayed virus clearance (HCV RNA test becomes negative between weeks 12 and 24), consideration should be given to extending therapy to 72 weeks.
• Patients with genotype 1 infection whose treatment continues through 48 to 72 weeks and whose measurement of HCV RNA is negative at the end of treatment should be retested for HCV RNA 24 weeks later to evaluate for a sustained virological response (SVR; HCV RNA negative 24 weeks after cessation of treatment)

Treatment of HCV genotype 2 and 3

• Treatment with peg interferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg (Class I, Level A).
• Patients whose treatment continues through 24 weeks and whose measurement of HCV RNA is negative should be retested for HCV RNA 24 weeks later to evaluate for an SVR

NB:

• Patients with HCV-related cirrhosis who achieve an SVR, regardless of the genotype, should continue to be monitored at 6-12 month intervals for the development of HCC
• Patients with HCV-related compensated cirrhosis can be treated with the standard regimen of pegylated interferon and ribavirin but will require close monitoring for adverse events Patients with HCV-related decompensated cirrhosis should be referred for consideration of liver transplantation.
• Doses- the dose for peg interferon alfa-2a is 180g subcutaneously per week together with ribavirin using doses of 1,000 mg for those < 75 kg in weight and 1,200 mg for those > 75 kg; the dose for peg interferon alfa-2b is 1.5 g/kg subcutaneously per week together with ribavirin using doses of 800 mg for those weighing <65 kg; 1,000 mg for those weighing >65 kg to 85 kg, 1,200 mg for >85 kg to 105 kg, and 1,400 mg for >105 kg.
• Vaccinate against Hep A and B, if HBsAg and anti HAV negative Hep A on chronic C can cause fulminant hepatitis.
• Success with the treatment above: SVR of more than 80% in genotype 2 and 3 and 50% for genotype 1
• Presence of symptomatic cryoglobulinemia (extrahepatic manifestation) is an indication for HCV therapy- regardless of stage of liver disease.
• Achieving an SVR at 6m post treatment is likely to be maintained indefinitely in more than 98% of patients and a 2 year SVR represents a cure in all cases

Discuss the management of non responders and relapsers?

• Non-responders to peg interferon and ribavirin with advanced ?brosis should be screened for HCC and varices and be evaluated for liver transplantation. Patients with mild ?brosis should be monitored without treatment.
• In the majority of instances, virological relapse occurs within the ?rst 12 weeks and late relapse, beyond 24 weeks, is extremely uncommon. Patients with virological relapse are likely to respond to the same regimen given a second time but will still experience an unacceptable rate of relapse.
• Retreatment with peg interferon plus ribavirin can be considered for non-responders or relapsers who have previously been treated with non-pegylated interferon with or without ribavirin, or with peg interferon monotherapy, particularly if they have bridging ?brosis or cirrhosis

Discuss management of HCV patients with normal ALT?

A normal ALT does not exclude advanced fibrosis or even cirrhosis. Thus, the decision to treat should be based on the severity of liver disease by liver biopsy, the potential for serious side effects, the likelihood of response, and the presence of co-morbid conditions rather than ALT levels

Discuss treatment of acute hepatitis C?

Acute hepatitis C can be diagnosed based on the clinical presentation: namely the presence of symptoms o r jaundice, and whether or not there was a prior history of ALT elevation and its duration. After acute infection, HCV RNA is usually detected in serum before antibody; HCV RNA can be identi?ed as early as 2 weeks following exposure whereas anti-HCV is generally not detectable before 8-12 weeks.

There is good evidence that treatment reduces the risk of chronic infection and the response rate to treatment is higher with acute than with chronic HCV. Thus patients with acute HCV infection should be considered for interferon-based anti-viral therapy.

Treatment can be delayed for 8 t o 1 2 weeks after acute onset of hepatitis to allow for spontaneous resolution. There is currently limited data on the duration of treatment and addition of ribavirin to the treatment of acute hepatitis C. However, it is reasonable to treat for at least 12 weeks and ribavirin should be considered on a case-by-case basis.

Discuss the side effects of HCV treatment?

Related to IFN

1. Flu-like symptoms
2. Marrow suppression (especially leukopenia and thrombocytopenia)
3. Emotional effects (irritability, difficulty concentrating, memory disturbances, and depression)
4. Autoimmune disorders (especially thyroiditis)
5. Hair loss, Rash, Diarrhea, Sleep disorders
6. Visual disorders (rarely retinal hemorrhages, especially in diabetic & hypertensive patients)
7. Weight loss, Seizures, Hearing loss, Pancreatitis
8. Interstitial pneumonitis, Injection site reactions

Related to ribavirin

1. Hemolytic anemia
2. Chest congestion, dry cough, and dyspnea
3. Pruritus, Sinus disorders
4. Rash, Gout, Nausea
5. Diarrhea, Teratogenicity (Contraception-very imp)

Discuss HCV and needle stick injury?

The likelihood of acute HCV infection after an accidental needle stick is only approximately 3% and because antiviral therapy initiated after the onset of hepatitis C viremia is so effective, treatment to prevent HCV infection need not be initiated prophylactically after needle stick exposure.

Discuss the terminology:

RVR- Rapid virological response- HCV RNA negative at treatment week 4- may allow shortened course for G2&3 and possibly G1 with low virological load

EVR- Early virological response- >= 2 log reduction (100fold decrease) in HCV RNA compared to baseline (Partial EVR) or HCV RNA negative at treatment week 12 (Complete EVR)

ETR- End of treatment response- HCV RNA negative at end of treatment either 23 weeks (for G2&3 or 48weeks for G1)

SVR- Sustained virological response- HCV RNA negative 24 weeks (6months) after cessation of treatment

Nonresponder- Failure to clear HCV RNA after 24 weeks of treatment

Relapse- Reappearence of HCV RNA after therapy is discontinued

Breakthrough- Reappearence of HCV RNA while still on therapy

Partial responder- Two log decrease in HCV RNA but still HCV RNA positive at week 24

Factors indicating favourable response:

1. Viral genotype- non G1
2. Low viral load- less than 600,000IU/ml
3. Dose of peginterferon and ribavirin
4. Female gender
5. Age less than 40yr
6. Non African-American race
7. Lower body weight <75kg
8. Absence of insulin resistance
9. Elevated ALT
10. Absence of bridging fibrosis or cirrhosis
11. Shorter duration of disease

The two different types of peginterferons:

Roche products:

Pegasys- Peginterferon alpha 2a

Copegus- ribavirin

• Doses- 180 micrograms subcutaneously per week together with ribavirin using doses of 1,000 mg for those < 75 kg in weight and 1,200 mg for those > 75 kg;

Schering Plough products:

Viraferon Peg- Peginterferon alpha 2b

Rabetol-ribavirin

• Dose for peg interferon alfa-2b is 1.5 micrograms/kg subcutaneously once a week together with ribavirin using doses of 800 mg for those weighing <65 kg; 1,000 mg for those weighing >65 kg to 85 kg, 1,200 mg for >85 kg to 105 kg, and 1,400 mg for >105 kg.

Duration of treament:

G2/G3- 24 weeks

G1/G4-6 48weeks

Stop treatment if no 2 log drop of HCV RNA at week 12 or HCV RNA detectable at week 24.

Extended duration:

1. G1/4-Cirrhotic patient, partial EVR at 12 weeks- consider 72 weeks provided HCV RNA is negative at 24 weeks
2. G2/3- Cirrhotic patient/partial EVR at 12 weeks – consider 48 weeks

Reduced duration:

1. G1/4 if RVR, young (<40yrs), BMI<25 and baseline HCV RNA <400,000IU/ml, fibrosis mild-moderate- consider 24 weeks.
2. G2/3- if RVR and complete EVR particularly if also young (<40yrs), BMI<25 and baseline HCV RNA <400,000IU/ml, fibrosis mild-moderate- consider 16 weeks

Special group of patients

1. Co-infection- peglylated interferon alpha -2a (180mcg weekly) plus weight based ribavirin for 48 weeks.. Treatment should be withheld if CD4 count is less than 200/ml until this is corrected with highly active antiretroviral therapy.
2. Post liver tranplant- start at low doses peglylated interferon alpha -2b 0.5microgram/kg and Rebetol 200-400mg od and increase every two weeks – duration 48 weeks
3. Renal dysfunction- peglylated interferon alpha -2a 135microgram weekly and copegus 200mg od and (if dialysis patient)- duration 48 weeks

Advise regarding sex:

sexual transmission is rare but does occasionally occur.

Risk is increased if there is history of sexually transmitted disease, anal/rough sex or sex during period or multiple partners.

Oral sex is low risk

Couples if one positive and other negative – if they are in stable relation- unnecessary to use condom. Advise to avoid sex during menstruation.

Advice regarding alcohol:

Patient should not drink alcohol. Research has shown that alcohol aggravates hepatitis C infection and progression from chronic hepatitis C to cirrhosis is hastened in those who drink alcohol. It also reduces the efficacy of combination treatment.

Assessment prior to treatment and monitoring during and after therapy:

1. All patients will have relevant blood tests, liver ultrasound and liver biopsy if clinically indicated
2. Vaccinated against Hep B and Hep A
3. Assess risk of coronary heart disease (ECG), uncontrolled diabetes (fasting glucose) and hypertension
4. Exclude thyroid disease (TSH normal)
5. Assess for depression- referral to liaison psychiatry need to be done if positive history
6. Advise regarding strict avoidance of pregnancy
7. Discussion of potential side effects
8. Active substance use is not a contraindication to treatment but is a factor that is taken into account when assessing the patient’s ability to tolerate therapy.

Monitoring during treatment:

1. Assessment for side-effects and depression-Peg interferon are subject to black triangle system. All suspected drug reactions should be reported to the CSM using a yellow card
2. A reasonable schedule would be monthly visits during the first 12 weeks and then every 8 weeks until the end of treatment
3. At each visit patient should be questioned about side effects, depression and adherence to treatment.
4. Hospital Anxiety and Depression Scale (HADS) is a self screening questionnaire for depression and anxiety. This tool may be a useful supplement to clinical judgement.
5. At each visit the blood test should include FBC, U/E, LFT, and HCV RNA at 4,12,24 weeks and 4-12 weeks interval thereafter , the end of treatment and 24 weeks after stopping the treatment.
6. Eye examination if any concern
7. CXR if any respiratory symptoms

Treatment of common side-effects

1. Flu like symptom and myalgia is very common. Injection should preferably taken in the evening and paracetamol should be given before the injection and for the rest of the day in recommended doses.
2. Mild depression can be treated with a SSRI like citalopram- psychiatric assessment or support might be needed.
3. Insomnia- Zopiclone 7.5mg od (not always prescribed in prison setting)
4. Itchy skin- piriton and E45
5. Sore mouth- Difflam mouthwash

Dose modification

1. If Hb drops to less than 10g/dl or drops by 2g/dl- reduce Ribavirin by 200mg decrement. Might consider erythropoitin injection. If still worsening anamia ? discontinuation of treatment. It is important to minimise ribavirin dose reduction in the first 12 weeks as this has the most effect on SVR
2. If more than one dose reduction is needed for ribavirin – treatment with erythropoietin should be considered (up to 40,000units weekly). Randomised controlled trials have shown this to be effective at preventing large dose reduction and/or discontinuation of treatment, thus increasing SVR. This is recommended by SIGN guidance.
3. If platelet <50,000/mm3, WBC < 1.5X109/L, neutrophil < 750/mm3, progressive increase in ALT- Reduce PEGASYS to 135microgram/week or VIRAFERON PEG to one half dose unit each week
4. Stop treatment if platelet <25,000/mm3, neutrophil <500/mm3, WBC <1x109/L,
5. Stop Ribavirin if Hb drops below 8.5g/L despite dose reduction

Newly licensed drugs for Hep C:

There are currently about 48 treatments in trial. Some are monotherapies (drugs or therapies taken on their own) and some are for use in conjunction with existing HCV treatments. Some of these developmental treatments have shown promising results in clinical trials.

Two drugs that have already been approved for safety by the FDA and the European equivalent are Telaprevir (Janssen) and Boceprevir (Merck/MSD).

Both Boceprevir (Victrelis) and Telaprevir (Incivo, Invivek) have now been licensed but not NICE approved. This means that they can now be prescribed but the NHS may not fund it. Alternatively a patient may pay for it themselves. It is expected that these drugs will be approved by NHS between spring and summer 2012.

Both of these drugs are protease inhibitors, which are treatments that aim to prevent HCV from replicating.

Both Boceprevir and Telaprevir is for patients with Genotype 1. It is a protease inhibitor that helps target the virus and is added to the current treatment of Interferon and Ribavirin. It will mean the patient will be taking a combination of 3 drugs. It can boost the success rate of clearing the virus from 50% to 80% and in some cases will shorten the time that a patient needs to be on treatment.

If a patient has never done treatment before (Treatment Naive) then it is estimated that over 50% of them will only have to do 28 weeks treatment. However, all those who have done treatment before but not cleared the virus (treatment experienced) will still do 48 weeks.

Treatment time is calculated using a system called response guided therapy (RGT). This means that tests are done at various weeks into treatment that can tell how well a patient is responding to the treatment. This can help ensure that the patient does not stay on treatment longer than necessary.

Ref/Useful website

1. AASLD Practice Guidelines.  Diagnosis, Management, and Treatment of Hepatitis C: An Update 2009
2. Hep C trust

Although most carriers will not develop hepatic complications from chronic hepatitis B, 15% to 40% will develop serious sequelae (cirrhosis/HCC) during their lifetime.

Discuss the modes of transmission of HBV?

HBV is transmitted by perinatal, percutaneous, and sexual exposure, as well as by close person-to-person contact presumably by open cuts and sores, especially among children in hyper endemic areas.
HBV can survive outside the body for prolonged periods, and carriers who are HBeAg positive can shed large quantities of viral particles on environmental surfaces through open cuts or sores. The risk of developing chronic HBV infection after acute exposure ranges from 90% in newborns of HBeAg-positive mothers to 25% to 30% in infants and children under 5 and less than 10% in adults.

Who should be tested for HBV?

Persons born in hyper endemic areas, men who have sex with men, injecting drug users, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons. Testing for HBsAg and antibody to HBsAg (anti-HBs) should be performed, seronegative persons should be vaccinated.

Discuss the diagnostic criterion for chronic hepatitis B?

Chronic hepatitis B

• HBsAg + > 6 months
• Serum HBV DNA >20,000 IU/ml (>105 copies/ml)
• Persistent or intermittent elevation in ALT/AST levels
• Liver biopsy showing chronic hepatitis (necroinflammatory score more than equal to 4)

Inactive HBsAg carrier state

• HBsAg+ > 6 months
• HBeAg-, anti-HBe+
• Serum HBV DNA <2000 IU/ml
• Persistently normal ALT/AST levels
• Liver biopsy confirms absence of significant hepatitis (necroinflammatory score <4)

Discuss the serologic patterns of chronic HBV infection?

• Perinatal transmission- occurs mostly in Asia and the South Pacific Islands. Persistence of HBeAg is longer and seroconversion does not occur in most persons until later in adulthood. Among individuals with perinatally acquired HBV infection, a large percent of HBeAg-positive patients have high serum HBV DNA but normal ALT levels. These patients are considered to be in the “immune tolerant” phase. Many of these patients develop HBeAg-positive chronic hepatitis B with elevated ALT levels described as pattern 2 in later life.
• In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs from person to person in childhood, whereas perinatal transmission is less common. In these populations most children who are HBeAg positive have elevated ALT levels and seroconversion to anti-HBe is common near or shortly after the onset of puberty.
• The third pattern is usually observed in individuals who acquired HBV infection during adulthood. This is most common in developed countries where sexual transmission is the predominant mode of spread. Very little longitudinal data is available on the latter patients but liver disease is generally present in patients with high HBV DNA levels.

Discuss the natural history of HBV?

• The rate of clearance of HBeAg averages between 8% and 12% per year. HBeAg clearance may follow an exacerbation of hepatitis, manifested by an elevation of ALT levels.
• After spontaneous HBeAg seroconversion, 67% to 80% of carriers remain HBeAg negative and anti-HBe positive with normal ALT levels and minimal or no necroinflammation on liver biopsy. This has been referred to as the “inactive carrier state.”
• The course and outcome of the inactive HBsAg carrier state is generally but not invariably benign. Up to 20% of carriers in the inactive state can have exacerbations of hepatitis, as evidenced by elevations of ALT levels to 5 to 10 times the upper limit of normal, with or without seroreversion to HBeAg. Repeated exacerbations or reactivations can lead to progressive fibrosis.
• Approx 0.5% of HBsAg carriers will clear HBsAg yearly; most will develop anti-HBs.

Discuss HBeAg negative chronic hepatitis?

Most patients with HBeAg negative chronic hepatitis B harbour HBV variants in the precore or core promoter region. The most common precore mutation, G1896A, creates a premature stop codon in the precore region thus abolishing production of HBeAg.
Patients with HBeAg-negative chronic hepatitis B tend to have lower serum HBV DNA levels than those with HBeAg-positive chronic hepatitis B and are more likely to run a ?uctuating course. These patients are also older and have more advanced liver disease since HBeAg-negative chronic hepatitis B represents a later stage in the course of chronic HBV infection.

Patients with compensated cirrhosis who were HBeAg-negative had significantly better 5-year survival (97%) than those who were HBeAg-positive (72%).

Discuss the evaluation of patients with chronic HBV infection?

• History and physical examination
• Family History of liver disease, HCC
• Laboratory tests to assess liver disease—complete blood counts with platelets, liver screen, and prothrombin time
• Tests for HBV replication—HBeAg/anti-HBe, HBV DNA
• Tests to rule out viral coinfections—anti-HCV, anti-HDV and anti-HIV in those at risk
• Tests to screen for HCC–AFP at baseline and, in high risk patients, ultrasound
• Consider liver biopsy to grade and stage liver disease – for patients who meet criteria for chronic hepatitis.
• All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. Prevaccination screening for antibody to hepatitis A should be considered if the prevalence of infection in the population is likely to be greater than 33%.

Who would you consider for treatment?

The following patients should be considered for treatment:

• HBsAg+, HBeAg+ and ALT > 2 times the upper limit of normal
• HBsAg+, HBeAg- , HBV DNA > 20,000 IU/ml and ALT > 2 times the upper limit of normal.

Liver biopsy is optional in the above two groups. Also, HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment.

A liver biopsy should be considered if the ALT in either of the above two groups is persistently more than 1-2 times the upper limit of normal (especially in age above 40). Consider treatment if biopsy shows moderate/severe in?ammation or signi?cant ?brosis.

Discuss follow up of patients not considered for treatment?

• HBeAg-Positive Patients with High Serum HBV DNA but Normal ALT Levels. These patients should be monitored at 3 to 6 month intervals.
• HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL (inactive carriers) should be tested for ALT every 3 months during the ?rst year to verify that they are truly in the “inactive carrier state” and then every 6-12 months.

What is the goal of HBV treatment?

The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC. Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.

Discuss the drugs available for HBV?

Current therapy of chronic hepatitis B has limited long-term efficacy. Thus, careful balance of patient age, severity of liver disease, likelihood of response, and potential adverse events and complications is needed before treatment is initiated.
The ?rst-line drugs recommended for treatment of hepatitis B are pegIFN, entecavir or tenofovir. In view of the high rate of drug resistance during long-term treatment, lamivudine and telbivudine are not preferred. Since adefovir is less potent than other NA and is associated with increasing rate of antiviral resistance after the ?rst year of therapy, it is best utilized as a second line drug in treatment-naive patients.
The advantages of IFN- include a finite duration of treatment, more durable response, and the lack of resistant mutants. The disadvantages of IFN- are the costs and side effects.

Discuss the treatment of HBV?

• HBeAg+ chronic hepatitis- IFN?/PEG IFN? or one of the nucleoside analogues (NA) may be used as initial therapy. Entecavir or tenofovir is preferred.
  • Duration of therapy:
    • IFN? 16 weeks
    • PegIFN?- 48 weeks
    • NA’s- Treatment should be continued until the patient has achieved HBeAg seroconversion (at least 12 months)and undetectable serum HBV DNA and completed at least 6 months of additional treatment after appearance of anti-HBe.
  • Efficacy of treatment
    • IFN- Loss of HBeAg and HBV DNA in approx 1/3 rd of the cases. Response is durable in 80-90% of cases.
    • NA treatment for 48-52 weeks- loss of e antigen-around 30%. Loss of HBV DNA- 60-70% with entecavir and tenofovir. Response is durable in 50-80% of patients.
  • IFN non responders or contraindications to IFN- use NA’s
• HBeAg negative chronic hepatitis- treatment options are as above, however endpoint of treatment is not defined.
  • Duration of treatment
    • IFN- ?/pegIFN-?: 1 year
    • NA’s: more than 1 year. Treatment should be continued until the patient has achieved HBsAg clearance.
  • Efficacy of treatment
    • IFN- loss of HBV DNA 60-70%
    • NA for 48-52 weeks treatment- 90% or more with entecavir or tenofovir. However durability of response is only 10-20% with both IFN and NA
  • IFN non responders or contraindications to IFN- use NA’s
• Compensated cirrhotic patient with HBV DNA > 2000IU/ml with or without e antigen positivity- consider treatment with NA’s. These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have con?rmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have con?rmed HBsAg clearance. IFN should not be used because of the risk of hepatic decompensation associated with IFN- related flares of hepatitis.
• Decompensated cirrhosis- Treatment should be promptly initiated with a NA (coordinate care with the transplant centre). Life-long treatment is recommended.
  NB
• Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment or receive additional treatment.

Discuss the dose regimens?

• IFN- 5 MU SC daily or 10 MU thrice weekly. PEG IFN- 180mcg SC weekly.
• All NA’s are administered orally.

Discuss HCC surveillance in HBV infection?

HBV carriers at high risk for HCC such as Asian men over 40 years and Asian women over 50 years of age, persons with cirrhosis, persons with a family history of HCC, Africans over 20 years of age, and any carrier over 40 years with persistent or intermittent ALT elevation and/or high HBV DNA level >2,000 IU/mL should be screened with US examination every 6-12 months.

Discuss antiviral prophylaxis of HBV who receive immunosuppressive or cytotoxic therapy?

• Reactivation of HBV replication with increase in serum HBV DNA and ALT level has been reported in 20% to 50% of hepatitis B carriers undergoing immunosuppressive or cancer chemo therapies. In most instances, the hepatitis flares are asymptomatic, but icteric flares, and even hepatic decompensation and death have been observed.
• HBsAg and anti-HBc testing should be performed in patients who are at high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy.
• Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a ?nite course of immunosuppressive therapy.
• Patients with baseline HBVDNA<2,000IU/mL level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy.
• Patients with high baseline HBV DNA (>2,000 IU/mL) level should continue treatment until they reach treatment endpoints as in immunocompetent patients.
• Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months) and baseline serum HBV DNA is not detectable.
• Tenofovir or entecavir is preferred if longer duration of treatment is anticipated.
• IFN should be avoided in view of the bone marrow suppressive effect.

Discuss management of pregnant women with HBV?

Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. (With this strategy- a recent study showed no increased risk with breast feeding).

Discuss precautions for infected persons regarding prevention of transmission of HBV to others?

Persons who are HBsAg-positive should:

• Have sexual contacts vaccinated
• Use barrier protection  if partner not vaccinated or naturally immune.

• Not share toothbrushes or razors
• Cover open cuts and scratches
• Clean blood spills with detergent or bleach
• Not donate blood, organs or sperms

Children and adults who are HBsAg-positive:

• Can participate in all activities including contact sports
• Should not be excluded from day care or school participation and should not be isolated from other children
• Can share food, utensils, or kiss others

Discuss treatment of acute hepatitis B?

• Antiviral therapy is generally not necessary in patients with symptomatic acute hepatitis B because 95% of immunocompetent adults with acute hepatitis B recover spontaneously.
• Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B (increase in INR and deep jaundice persisting for more than 4 weeks).
• Lamivudine or telbivudine may be used when the anticipated duration of treatment is short; otherwise, entecavir is preferred.
• Treatment should be continued until HBsAg clearance is con?rmed or inde?nitely in those who undergo liver transplantation.
• IFN is contraindicated.

Ref

1. AASLD Practice Guidelines. Chronic Hepatitis B: Update 2009