10/15/2018 Objectives Hepatitis C Screening, Treatment and the Family Physician Wayne Ghesquiere MD FRCPC Infectious Diseases & Internal Medicine Division of Infectious Diseases Victoria, BC At the end of this session, the participant should be able to: 1. Discuss the epidemiology and natural history of HCV in Canada 2. Describe which persons should be screened for HCV 3. Discuss benefits, options and outcomes of therapy 4. Understand what to include in a specialist referral 5. Discuss any controversies and myths around HCV screening and treatment Five Take Home Pearls 1. Screen patients more liberally for Hepatitis including birth cohort born between 1945-1975. 2. Hepatitis C is curable in 95-99.9% of patients. 3. Curing HCV infection prevents progression to cirrhosis, improves symptoms and has mortality benefit. 4. Treatment is very well tolerated and fully publically funded for all patients with Hepatitis C. 5. If you need help consider referring to an ID or Hepatology specialist to help you cure your patient. Hepatitis C: Screen, Diagnose, Refer Screen Birth between 1945 and 1975 Any history of injection drug use Immigrants (excluding North America and Western Europe) Received blood transfusions, blood products, or organ transplant before 1992 in Canada High-risk sexual behaviour Test and Diagnose Test for anti-hcv antibody (indicates exposure to HCV) If positive Test for HCV RNA (genotype and baseline viral load) If positive Link to specialist care Link to Specialist Care Refer patient to HCV specialist treater Counsel patient (discuss implications of HCV infections, how to avoid transmission, need for alcohol elimination, importance of seeing an HCV specialist) We Can Cure Hepatitis C Infectious diseases we can t cure HIV Hepatitis B Herpes Human papillomavirus Infectious diseases we can cure Hepatitis C Syphilis Gonorrhea Chlamydia Trichomoniasis New Canadian Guidelines Birth Cohort Screening CMAJ June, 2018 Recommends that screening be both risk-based and target the birth cohort of individuals born from 1945 to 1975. Encompasses the majority of persons chronically infected with HCV in Canada (class of recommendation: 2a; level of evidence: C). HIV, human immunodeficiency virus. 1
Patient survival outcomes with and without SVR Cirrhosis (%) 10/15/2018 HCV and Alcohol: Risk of Cirrhosis 100 80 60 40 20 0 10 20 30 40 Years Following Exposure HCV HCV + alcohol -Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men. -Studies suggest >50% of patients with HCV abuse alcohol Wiley TE, et al. Hepatology 1998:28:805-9. Viral Eradication Improves All-cause Mortality Criteria to Screen for HCV: Symptoms Fatigue Nausea, loss of appetite Arthralgia Abdominal pain Hepatosplenomegaly BUT 60-75% of patients are asymptomatic Cure = sustained virological response (SVR) = reduced risk of all-cause mortality; liver-related mortality; HCV-related complications; progression to HCC or liver failure 4 Possible dermatological signs: Mixed essential cryoglobulinemia Lichen planus Porphyria cutanea tarda Maculopapular rash Jaundice (past or present) Other possible extrahepatic manifestations: Membranous or membranoproliferative glomerulonephritis Non-Hodgkin s lymphoma Sjögren s syndrome 1. Ravazi 2012; 2. Burra 2009; 3. Guillouche 2011; 4. Van der Meer 2012. Virological tests to diagnose and confirm HCV infection Anti-HCV HCV-RNA HCV genotype Other bloodwork CBC Liver enzyme & function tests: ALT, AST, GGT, ALP, bilirubin, INR, albumin Normal ALT is not a contraindication to treatment (⅓ have normal test results) Creatinine Evaluation: Laboratory Testing Abdominal ultrasound Evaluate for cirrhosis and exclude HCC Tests to rule out coinfections Hepatitis A (HAV-Ab) Hepatitis B (HBsAg, HBsAb, HBcAb) HIV (Anti-HIV) DAA Regimens These regimens are all oral, varies between one to a few pills daily Treatment course 8-12 weeks Cure Rate 95-100%, based on genotype Well tolerated: in registration studies, have similar side-effects to placebo groups Need to review for drug-drug interactions, as can vary considerably between regimens Publically Funded. No cost to the patients!!!! 2
10/15/2018 Potential Drug-Drug Interactions & Monitoring of Labs Number of agents do have Drug-Drug interactions which requires the prescriber to either hold conmeds or select a regimen for HCV infection Rx that is appropriate. Very little monitoring is required while on therapy except in patients who have decompensated cirrhosis and especially if on ribavirin, which may be indicated with those who have cirrhosis and genotype 3 Hepatitis C in 2018 There is now a cure for this infectious disease. Pharmacare now funds treatment for all patients who have HCV infection regardless of the patients stage of disease. More medications are going to be available which will decrease the cost per patient. Nursing clinics help patients and physicians navigate the labyrinth of administrative work, provides education to patients and ensures patient adherence as well as emotional support. Referral Who should be referred? All persons HCV RNA (+) Role of staging by GP: AST to Platelet Ratio Index (APRI); Fibrosis-4 (FIB-4) Referral should include: HCV Genotype & RNA CBC (platelets important consideration) ALT, AST, ALP, GGT, bilirubin, INR, albumin ULTRASOUND Cirrhosis and Hepatocellular Carcinoma There is still an increased risk of developing HCC in patients with cirrhosis, even if they have been cured of HCV infection. Patients with cirrhosis will require q6 month ultrasound screening for HCC long term (life long?), if suspicious will need an MRI Patient Feedback after being Cured of HCV Infection 50-75 % note significant increase in energy level All feel clean again or no longer feel dirty they are free of stigma Significant improvement in emotional well being Feel they can get on with their lives Thank You Questions and Discussion Contact Information Wayne Ghesquiere MD, FRCPC Infectious Diseases and Internal Medicine Consultant 1964 Fort St, Suite 206, Victoria, BC Tel 250-370-7717, Fax 250-370-7739 3
Hepatitis C Infection: Screening and Management for 2018-2019 Compliments of By Wayne Ghesquiere MD, FRCP(C) Infectious Diseases and Internal Medicine Consultant 1964 Fort St, Suite 206, Victoria, BC Tel 250-370-7717, Fax 250-370-7739 Consider screening your patient for Hepatitis C if he/she has any of the following: Baby Boomers i.e. born between 1945-1975 should be screened at least once in their life time Any prior history of IV drug use or snorting cocaine Has received blood products prior to 1992 Born or raised in a developing country Has tattoos or body piercing Persistently elevated ALT or AST or has thrombocytopenia Steps to take if you are considering screening for Hep C: Step 1 Hepatitis C antibody serology. If this is positive this simply demonstrates the patient was exposed sometime in the past, you will then need to confirm if the patient is still infected. If it is positive then move on to step 2. If negative then reassure the patient. Step 2 Hepatitis C RNA and genotyping. If it s positive move onto step 3. If it is negative repeat 3 to 6 months later. If it remands negative then reassure the patient. Step 3 Blood work o CBC, differential, platelets, INR and PTT o Liver enzymes ALT, AST, Alkaline Phosphatase, GGT, T Bili, Albumin o Creatinine, GFR, Fasting Blood Sugar, Ferritin o Alpha Feto Protein level o Serology for Hepatitis A, B and HIV Abdominal Ultrasound Move onto step 4 Step 4 Consider a referral to a clinician who has an interest in further investigation and the management of the treatment of Hepatitis C infection i.e. Infectious Diseases consultant or Gastro/Hepatologist The patient must be free of alcohol abuse or active IVDU drug use for at least 3-6 months before they are considered for treatment. Key Points 1. Remember that people with normal liver enzyme levels can have advanced liver disease. A fibroscan or a liver biopsy is the only reliable way to assess the stage of disease i.e. fibrosis. 2. The risk of cirrhosis and liver cancer increases as the disease progresses. 3. Studies have repeatedly shown that early treatment provides a greater likelihood of cure than waiting until the disease is more advanced
Treatment Summary of Hepatitis C Treatment of Chronic Hepatitis C infection continues to evolve rapidly. Here is a list of medications that have recently been licensed in Canada for treatment of HCV and are available. The first 4 are available in BC under pharmacare coverage. The 5 th is available with third party coverage but soon will also be covered by pharmacare. Harvoni Zepatier Epclusa Vosevi Mavyret These are oral agents. Interferon is no longer required. These oral agents are remarkably well tolerated. Usually there are little to no side-effects. The success rate of treatment is based on both the genotype as well as the degree of liver disease i.e. amount of fibrosis. Fibrosis is confirmed and scored by way of either a FibroScan or a liver biopsy. There are also non imaging test such as the FIB-4 or APRI score that can be used to assess the degree of fibrosis but are less accurate. The more advanced the liver disease and fibrosis the lower the success rate. There are 6 different genotypes. The most common is genotype 1 (60% of Canadians have this type) followed by 2 and 3. Genotypes 4, 5 and 6 are less common in Canada. Occasionally Ribavirin is required. BC Pharmacare has approved and covers most of these agents. Many other provinces in Canada have done likewise. There are guidelines outlining who qualifies for treatment for Hepatitis C infection. Treatment is also tailored according to the patient s genotype and degree of fibrosis with duration of treatment anywhere between 8-12 weeks. The Cure Rates of Hepatitis C based on Genotyping and Fibrosis: Genotype 1 Stage 1-2 fibrosis ~ 98-99% Stage 3 fibrosis ~ 95-98% Stage 4 fibrosis (cirrhosis) ~ 95-98% Genotype 2 ~ 98-99% Genotype 3 ~ 95-99% Genotype 4 -Similar to genotype 1 Criteria for HCV Infection Therapy BC has liberalized the criteria for Hepatitis C therapy as of 2018. All patients with HCV infection qualify for treatment, regardless of their fibrosis staging. BC Pharmacare has restricted physicians who can order treatment to either infectious diseases physicians, gastroenterologists or other physicians who have demonstrated experience with HCV management and therapy. Special authority forms are still required to access these agents.
Chronic Hepatitis B Infection 2018: How to Investigate, Sort out Serology and When to Refer Compliments of By Wayne Ghesquiere MD, FRCP(C) Infectious Diseases and Internal Medicine Consultant 1964 Fort St, Suite 206, Victoria, BC Tel 250-370-7717, Fax 250-370-7739 Chronic hepatitis B infection continues to be a significant problem despite the universal vaccination program which has been in place in BC and Canada since the early 1990 s. Both immigrants and non-immigrants are being diagnosed with hepatitis B infection regularly. If Hepatitis B is left unchecked, this infection can lead to cirrhosis, liver failure and hepatocellular carcinoma. Consider screening your patient for Hepatitis B virus if he/she has any of the following risk factors: Foreign born or raised in Asia, Pacific Islands, Africa, Middle East, Eastern Europe Parents or sexual partners who have Hepatitis B infection Has tattoos or body piercing Persistently elevated ALT or AST. Thrombocytopenia, lymphopenia Has positive serology for HIV, Hepatitis C or STI s Cirrhosis, ascites or a liver tumor Any past history of IVDU or snorting cocaine Steps to take if you are considering screening for Hep B: Step 1: Serology: Hepatitis B surface antigen (indicative of persistent infection) Hepatitis B surface antibody (indicative of immunity to the Hep B virus) Hepatitis B core antibody (Indicates prior exposure to the Hep B virus in the past) Step 2: If Hepatitis B surface antigen is positive the following investigations are recommended: Hepatitis B DNA titre Hepatitis B e antigen and e antibody CBC, diff, INR Creatinine, Blood sugar, ALT, AST, GGT, T Bilirubin, Albumin Alpha-feto Protein Serology for Hep A, C and HIV Abdominal Ultrasound FibroScan (This will be ordered by the consultant if it is considered necessary) See below.
Step 3: Treatment and referral being considered: Indication for referral would be any patient who has chronic Hepatitis B infection and a positive Hepatitis B DNA or elevated ALT Consider a referral to a clinician who has an interest in further investigation and the management of the treatment of Hepatitis B infection i.e. Infectious Diseases consultant or Gastro/Hepatologist. Positive Hep B DNA and increase ALT s are criteria for treatment. The patient must be free of alcohol or continued IVDU drug use for at least 6 months before they are ever considered for treatment. Treatment (often simply a once a day oral tablet which is covered by Pharmacare) is available to reduce the Hep B DNA to undetectable with normalization of ALT. Treatment also results in reversal of liver fibrosis. Step 4: Prevention measures and long term follow-up: Vaccinate family members, household contacts and sexual partners to Hepatitis B virus. Consider vaccinating the patient for Hepatitis A if they are Hepatitis A IgG negative. Patient will need lifelong screening for cirrhosis and hepatocellular carcinoma with abdominal ultrasound yearly and CBC, diff, INR, ALT, alpha-feto protein and Hepatitis B DNA titres every 4-6 months. Treatment Options Lamivudine Adefovir Entecavir Tenofovir (TDA) Tenofovir (TAF) Unfortunately Pharmacare requires patients to start with lamivudine. If it fails (which it does in 60-70% of the time) then patients can access Tenofovir which is far more effective. The good news is Tenofovir is now generic hence often patients will opt for that choice. What is a FibroScan? A FibroScan is a non-invasive imaging study that evaluates the degree of liver stiffness, or scaring, known as fibrosis. FibroScan has a 90% accuracy, it takes 10-20 minutes to perform and is painless. The results of the study do need to be used in conjunction with the history, physical examination and lab data by a physician trained to interpret the results. The wait time for this study is only a few weeks to months. A FibroScan can be requested by infectious diseases, gastroenterology, internal medicine consultant or physicians with extensive experience in liver diseases The scanner has been useful to determine the degree of fibrosis in patients with, Hepatitis B, Hepatitis C, HIV/Hepatitis C co-infection, Alcohol liver disease and NAFLD In certain patients with liver disease it does not replace the need for a liver biopsy which helps to establish a diagnosis
Key Take Home Pearls Hepatitis C 2018-2019 1. Screen patients more liberally for Hepatitis C infection (and hepatitis B). Birth cohort years 1945-1975 especially. 2. Hepatitis C infection is curable in 95-99% of patients. 3. Curing the patient of HCV infection prevents cirrhosis, improves symptoms and reduces mortality. 4. Treatment is very well tolerated and is publically funded. As of 2018 all patients with HCV infection will are eligible for treatment in BC. 5. Refer to an Infectious Diseases or Hepatology specialist to help you cure your patient. Encourage your patients to seek advice.
HEPATITIS B SEROLOGY Hepatitis B surface antigen (HBsAg): A protein on the surface of the hepatitis B virus (HBV); It can be detected in high levels in serum during acute or chronic HBV infection. The presence of HBsAg indicates that the person is infectious. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make Hepatitis B vaccine. Hepatitis B surface antibody (anti-hbs): The presence of anti-hbs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B. Total hepatitis B core antibody (anti-hbc): Appears at the onset of symptoms in acute hepatitis B infection and persists for life. The presence of anti-hbc indicates previous or ongoing infection with HBV in an undefined time frame. IgM antibody to hepatitis B core antigen (IgM anti-hbc): Positivity indicates recent infection with HBV ( 6 months). Its presence usually indicates acute infection. Hepatitis B e antigen (HBeAg): A secreted product of the nucleocapsid gene of the hepatitis B virus that is found in serum during acute and chronic hepatitis B infection. Its presence indicates that the virus is replicating and the infected person has high levels of HBV. Hepatitis B e antibody (HBeAb or anti-hbe): Produced by the immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication. Spontaneous conversion from e antigen to e antibody (a change known as seroconversion) is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV.
Hepatitis B: Frequently Asked Questions about Serology and the HBV Vaccine 1) You have a patient who is positive for anti-hbc (hepatitis B core antibody) but negative for all other hepatitis B serologic markers. Should he receive hepatitis B vaccine? Some isolated positive anti-hbc results are false positives (it is the most common false positive HBV marker). If that can be established, the individual can and likely should be vaccinated, assuming there is an indication or desire to be protected. If the positive anti-hbc is believed to be a true positive, the individual would not require vaccination since they have already (presumably) had HBV infection. They do not need HBV treatment either unless they go onto immunosuppressive therapy in the future. 2) You come across a hepatitis B panel for a new hospital employee from Ethiopia. She had no documentation of having been vaccinated. Her results showed HBsAg nonreactive, anti-hbc reactive, IgM anti-hbc nonreactive, and anti-hbs borderline. We don t know how to interpret these results. Should she be immunized? Most likely this person has a resolved hepatitis B infection and is immune. However, it would be preferable to test her again for all these serologic markers, and also quantify the anti-hbs result. If the results are still positive for anti-hbc, and anti-hbs is less than the immune level of 10mIU/mL, you can give her one dose of hepatitis B vaccine and test again in 1 2 months. If the anti-hbs is positive (10 miu/ml or higher), she is immune. No further action is needed other than to document the results. If the anti-hbs is still negative, complete the vaccine series and test again 1 2 months after the last dose of vaccine. If she is still anti-hbs negative after 3 doses of vaccine, test again for HBsAg to be sure she is not chronically infected (unlikely) and counsel her as a non-responder. 3) How long is hepatitis B vaccine protective? Studies indicate that immunologic memory remains intact for at least 20 years and confers protection against clinical illness and chronic HBV infection, even though anti-hbs levels that once measured adequate might become low or decline below detectable levels. If one is challenged with HBV, people whose immune systems are competent will mount an anamnestic response and develop protective anti-hbs. Studies are ongoing to assess whether booster doses of hepatitis B vaccine will be needed in the future. At this point it s considered the vaccine is good for life. 4) An adolescent received the first dose of hepatitis B vaccine at age 11 years but did not return for subsequent doses at school. If the patient comes back at age 18 years, is it necessary to repeat the first dose of the series? It is not necessary to restart or add doses to the hepatitis B series (or any other routine vaccine series including Hepatitis A) because of a prolonged interval between doses. Just continue the series from the point where it was interrupted. The same holds true for an adult. 5) Is post-vaccination testing needed for adults who receive hepatitis B vaccine? Serologic testing for immunity after vaccination is recommended only for people whose subsequent clinical management depends on knowledge of their immune status. Testing is not necessary after routine vaccination of adults. Post-vaccination testing is recommended for the following: healthcare and public safety workers at a reasonable risk of continued exposure to blood on the job; immune compromised people; and sex or needle-
sharing partners of HBsAg-positive people. Testing should be performed 1 to 2 months after the last dose of vaccine. 6) What about the need for testing if the hepatitis B vaccine series was completed many years ago. All healthcare personnel (HCP) with risk of exposure to hepatitis B should be tested 1 to 2 months after receiving the third dose of hepatitis B vaccine. Health Canada does not recommend testing healthcare personnel who were not tested within the 1 to 2 month post vaccination time frame. HCP who are exposed to Hepatitis B can be tested as part of post exposure management, if indicated. 7) A patient who is certain they had three doses of the Hep B vaccine in the past (but did not get tested for anti-hbs 1-2 months later) is found to be anti HBs negative. What should be done about the vaccine? If the test was not done after a high risk exposure you could give them 1 single adult dose of the Hep B vaccine and test their anti-hbs titre 1 month later. If it s positive you can now say they have been boosted and are immune. If it s negative you can have them finish the 3 dose series. Test them 1-2 months later. If the anti- HBs is positive then document they responded. It it s still negative they can be considered a non-responder. 8) In what situation should routine screening for anti-hbs and HBsAg be performed for HBV? The following would require the screen: high risk exposure to HBV (current STI s, MSM, active IVDU, sexual partners or household contacts of patients with positive HBSAg, sexual assault, needle stick injury), entering training or starting a new job as a HCW or a medical lab, about to undergo immunosuppression therapy, prenatal screening, patients about to start hemodialysis, patients with chronic liver disease, HIV infection, residents and staff of facilities caring for the developmentally challenged, those working in corrections facilities, immigrants (especially those born in Asia, Pacific Island, Africa) and refugees. 9) You ve identified a patient in your obstetrical practice who is HBsAg positive. Should she be evaluated for liver disease during her pregnancy, or should the evaluation wait until the postpartum period? What should you recommend for her husband and her children? How urgent is the time frame? The earlier the evaluation is done, the better. Consultation with or referral to a liver disease specialist (such as an infectious diseases specialist or Hepatologist,) should be done. The consulting/referral physician should be completely aware of the patient's obstetrical status. In addition, the patient's sex partner and children or other household contacts should be tested for HBV infection (total anti-hbc and HBsAg) as soon as possible. If any are susceptible to HBV infection (total anti-hbc and HBsAg negative), they should be vaccinated. If any are HBsAg positive, they should be referred to or have consultation with an infectious diseases or liver disease specialist. The newborn baby at time of delivery will need HBIG and initiation of the HBV vaccine series. 10) How often should you test HCW after they've received the hepatitis B vaccine series to make sure they're protected? For immunocompetent HCW, periodic testing or periodic boosting is not needed. Post-vaccination testing (anti-hbs) should be done 1 2 months after the last dose of the hepatitis B vaccine series. If adequate anti- HBs (at least 10 miu/ml) is present, nothing more needs to be done. This information should be made available to the employee and recorded in the employee's health record. If post-vaccination testing is less than 10 miu/ml, the 3-dose vaccine series should be repeated and anti-hbs testing done, 1 2 months after the last dose of the second series. If they are still less than 10mIU they are considered a non-responder and at risk of HBV infection. They should be counselled and take appropriate precautions.