Viral Hepatitis Elizabeth Perry, Pharm.D. PGY-1 Resident

Viral Hepatitis Elizabeth Perry, Pharm.D. PGY-1 Resident
LSU-HSC Shreveport, LA November 24th, 2009

Objectives Describe the pathogenesis, mode of transmission, risk factors, and epidemiology for Hepatitis A, B, C, D, E, and G Accurately interpret patients serology and other appropriate markers for diagnosis of viral hepatitis Identify patients requiring treatment and formulate treatment plans for each type of viral hepatitis Identify appropriate means for prevention of viral hepatitis including vaccination or passive immunity

Viral Hepatitis Systemic viral infection lasting ≤ 6 months
Acute Systemic viral infection lasting ≤ 6 months Progresses through stages: incubation, hepatitis (symptoms), convalescence Chronic Serologic evidence of hepatitis > 6 months Increases risk for cirrhosis, chronic liver disease and hepatocellular carcinoma Not associated with hepatitis A or E Fulminant Progress quickly from hepatitis to hepatic failure due to hepatic necrosis High mortality (80%) - Hepatitis is a general term meaning inflammation of the liver – viral hepatitis caused by HAV, HBV, HCV, HDV, HEV, HGV; can only be differentiated from other forms of hepatitis by presence of viral antigens and host antibodies - Chronic hepatitis – patient may present 20+ years down the road with symptoms or progression to cirrhosis and HCC; ongoing low grade inflammation - In viral hepatitis the liver damage is actually a result of the bodies immune system attacking the hepatocytes to try and eliminate the virus – so the symptoms and liver damage is a result of our own immune system attacking the liver - Fulminant hepatitis – viral hepatitis is the most common cause worldwide – HBV (1% of pts develop), HAV occasionally, HCV rarely; patients develop signs and sx of acute hepatitis but then rapidly progress to hepatic failure – encephalopathy and coma developing within 8 weeks – signs of impending liver failure may be – altered mental status, hyperexcitability, irritability, rapid decline in LFT, INR increase; death from cerebral edema, bleeding, infection and multi-organ failure; requires transplant for any hope of survival

Viral Hepatitis Pathogenesis
Viruses are not directly cytopathic Host immune response to the virus causes liver inflammation and hepatitis - Cirrhosis – liver cells dies and are replaced with fibrotic tissue which leads to nodule formation; the internal structure of the liver is deranged which leads to obstruction of blood flow and further damage - CD4 and CD8 T lymphocytes directed to hepatitis viruses attack the hepatocytes that harbor the virus and leads to the liver damage - in chronic disease the host immune response is not great enough to overcome and eliminate the disease but a low grade response/inflammation persists which progressively makes the liver become cirrhotic and even leads to HCC Normal liver Cirrhosis Hepatic Carcinoma

Hepatitis A Identified in 1973 RNA virus 7 distinct genotypes
Nonenveloped 7 distinct genotypes Replication in hepatocytes and gastrointestinal cells with RNA polymerase 7 genotypes but all are highly similar – no important biological differences like we may see with other hepatitis viruses infected virions accumulate in hepatic sinusoids and are internalized by hepatocytes – replication occurs exclusively in hepatocytes and gastrointestinal epithelial cells which leads to shedding in bile and stool body’s immune system has to kill hepatocytes to get rid of virus – leads to liver damage

Hepatitis A: Transmission
Fecal – oral route Person to person Food borne or waterborne exposure Less common Sexual contact Blood transfusions IV drug use - virus can survive outside the body for months - community-wide outbreak results from person to person transmission - common source outbreak results in infection of many people from one single source (restaurant, day care, etc.) - developing countries have more infections due to water borne exposure – contaminated drinking water - blood is not screened from HAV but transmission is rare b/c the person must be in the viremic prodromal phase of the infection and HAV concentration in blood is much lower than stool concentration - same with IV drug user – blood concentrations are low but infections via this route are increasing - more likely associated with unconventional sexual practices (MSM, etc) - HAV is not transmitted from infected mothers to newborn infants – anti-HAV antibodies cross the placenta and protect the infant

Hepatitis A: Risk Factors
Travelers to endemic countries MSM Illegal drug users Patients with clotting disorders Primate handlers Medical personnel Close contact with infected persons Day care workers Food – handlers Patients with chronic liver disease - clotting disorder – notice increased rates in people receiving factor 8 - HAV also a simian disease – not known if the simian HAV can be transmitted to humans - no identified risk factor in up to 50% of cases

Hepatitis A: Prevalence
Worldwide – 1.4 million cases annually US – In 2007: 92% decline since vaccine in 1995 2,979 acute cases reported Adjustment for underreporting ~ 25,000 cases Cyclic recurrences Inversely proportional to level of sanitation - Virus reporting peaks during the fall and winter

Hepatitis A: Epidemiology
HAV Endemicity Regions Avg. age of patients Likely mode of transmission Very high Africa, South America, Middle East, SE Asia Under 5 Person – person Contaminated food/water High Brazil’s Amazon basin, China and Latin America 5-14 Outbreaks/ food or water Intermediate Southern and Eastern Europe 5-24 Low Australia, USA, Western Europe 5-40 Outbreaks Very low Northern Europe and Japan Over 20 Exposure during travel to endemic area - typically occurs in children in the high endemic regions and transmission common with food/water and person to person

Hepatitis A: Prevalence
- High in undeveloped countries (Mexico, Africa, etc)

Hepatitis A: The Disease
Patients may have an inapparent or subclinical hepatitis Children OR Patients develop anicteric or icteric hepatitis ranging from mild and transient to severe and prolonged HAV does not cause a chronic hepatitis - With subclinical disease there are no symptoms or jaundice and infection only detected by serology (anti-HAV IgM or IgG) – 70% of children < 5 yrs are asymptomatic - Severity increases with age at time of infection - > 70% of older children and adults will develop icteric hepatitis - typically resolves within 2 months - anicteric – the acute phase of hepatitis with minimal liver damage, patient doesn’t develop jaundice and LFT’s are only increased to about 2x normal - icteric hepatitis – more than 70% of adults and older children; more significant liver damage and hepatocyte destruction that there is an interruption in bile metabolism and flow – leads to jaundice and LFT’s 4-10x higher than normal - will resolve within 6 months – no chronic disease

Incubation – HIGH TRANSMISSION!
10-50 days while patient asymptomatic and virus replicating Prodromal Lasts several days - one week when symptoms appear Fatigue, decreased appetite, abdominal pain, nausea/vomiting/diarrhea, fever Icteric Jaundice develops and bilirubin levels mg/dL within 10 days of initial symptoms Feces still infectious for 1-2 weeks Possible fulminant hepatitis Convalescence - resolution is slow but uneventful Possible relapse in 3-20% of patients with 4-15 weeks - Incubation – avg 28 days; shortly after virus inoculums while virus is accumulating in hepatocytes and replicating; person will not know that they have hepatitis which increases the risk of spreading; virus is shedding in bile and stool Prodromal (Preicteric) – this is the beginning of the acute hepatitis phase – initiation of host immune response but prior to significant liver cell injury; non-specific flu-like symptoms Icteric (if the person goes to icteric, they may have anicteric with no significant symptoms) – RUQ pain, dark urine, pale stools, itching a major complaint, the viremia will terminate shortly after hepatitis develops but the feces will remain infectious; mortality rate is low (0.2%) Convalescence – most patients (98-99%) will have complete recovery without complications; T lymphocytes primarily responsible for hepatocyte destruction and elimination of the virus; most patients fully recover within 8-12 weeks

Hepatitis A: Diagnosis
Serologic testing Anti – HAV IgM Always present in acute infection Appear 5-10 days before symptoms appear Anti – HAV IgG Persists lifelong and indicates past infection If BOTH present then ACUTE infection! Liver function assessment Anti-HAV IgM appears during the prodromal period or towards the end of the incubation period IgM will be replaced with IgG after 2-6 months which confers lifelong immunity LFT’s – AST, ALT, alk phos, bilirubin, albumin, PT time

Hepatitis A: Course - incubation phase – right after infection – before clinical symptoms or LFT increase; appears in stool quickly after inoculated and before symptomatic; IgM within about a week or so after inoculum and before symptoms - prodromal phase – prior to peak in ALT; nonspecific symptoms; initiation of host immune response - icteric – Peak in LFT; clearing viremia, but stool still infectious - IgG starts to increase while still acutely infected (around when sx appear) – so can’t r/o acute infection if IgG present -

Hepatitis A: Treatment
Self limiting disease Supportive treatment Diet, rest, fluids, avoidance of alcohol and hepatotoxic drugs Hospitalization typically not necessary INR and LFT’s to identify progression to fulminant hepatitis Mortality 0.1% (children) – 2.1% (> 40 years) - 99% of patients completely recover - hospitalization only necessary if prolonged vomiting, coagulation defects, or fulminant hepatitis - fulminant hepatitis – watch for changes in mental status, may see a decrease in LFT’s rapidly which is sign of liver failure; death occurs in 80% of cases within days to weeks - older age typically associated with more sever and symptomatic disease

Hepatitis A: Prevention
Good hygiene Hand-washing, sanitary diaper handling, proper food preparation, travel precautions Hepatitis A vaccine Immune globulin - travel precautions – avoid water and ice in countries with unknown sanitation, uncooked shellfish and fruits and vegetables - IG – passive transfer of concentrated antibodies (anti-HAV); 85% effective in preventing HAV if given post-exposure - vaccine – 94% effective after 1 dose, 100% after second dose

Hepatitis A: Vaccines 3 inactivated vaccines
HAVRIX®, VAQTA®, TWINRIX® (Hep A and B) Immunity lasts ~ 25 years Vaccine # of Doses Dose Schedule HAVRIX® 12 mo. to 18 yr ≥ 19 years 2 0.5 mL (720 units) 1 mL (1440 units) 0, 6-12 months VAQTA® 0.5 mL (25 units) 1 mL (50 units) TWINRIX® ≥ 18 years 3 or 4 1 mL (720 units) 0, 1, 6 months 0, 7, 21 days, + 1yr - whole virus vaccines – growth of attenuated HAV and inactivation - can be given with hep b, diphtheria, polio, tetanus, typhoid, cholera, rabies, yellow fever - can be given to pregnant women and immunocompromised because it is inactivated - will protect from exposure if given at least 2 weeks prior to HAV exposure - 2 single antigen vaccines are interchangeable - Twinrix – 4 dose schedule for short notice travel or exposure - only side effects are injection site rxn and headache

Hepatitis A: Prevention
Immune Globulin Passive immunity thru transfer of HAV antibodies For travel < 3 months: mL/kg IM Travel 3-5 months: mL/kg IM Alternative prophylaxis for patients who don’t need long term protection IG can interfere with response to live vaccines (MMR, varicella, etc.) Prefer vaccine for prevention but can be used for children < 12 months and patients allergic to vaccine - not effective for prevention if given IV – must be IM - must be repeated if travel > 5 months - less expensive than vaccine - delay MMR vaccine for 3 months after IG, varicella for 5 months after IG - If IG benefit clearly outweigh then if 2 weeks after MMR or 3 weeks after varicella – must revaccinate (after 3-5 months) - no vaccine available for children < 12 months so is alternative for prevention

Hepatitis A: Post-exposure
Persons receiving vaccine within 2 weeks of exposure do not need post exposure prophylaxis Patients not previously vaccinated and within 2 weeks of exposure to HAV 12 months to 40 years: Single age appropriate dose of Hep A vaccine > 40 years, < 12 months, chronic liver disease, allergic to vaccine, immunocompromised Use HVIG mL/kg - IG is 85% effective if given within 2 weeks after exposure - advantage of vaccine is long term protection and equivalent efficacy to IG (healthy persons 1 yr – 40 yr) - more data on IG – just recently (2007) included vaccine as method of post-exposure prophylaxis - efficacy of vaccine in patients > 40 yrs is unknown and HAV is usually more severe in this age group

Hepatitis A: Case AJ is a 47 year old white male who works as a photographer for National Geographic. His most recent expedition is scheduled in 3 weeks to take him to Mali, West Africa. Should AJ receive preventative measures for Hepatitis A? If so, what should we recommend? If AJ did not receive preventative treatment what could be done if he was exposed to HAV? Is AJ likely to have long term consequences of HAV exposure?

Hepatitis B DNA virus 8 major genotypes (A-H)
Double-stranded, enveloped 8 major genotypes (A-H) Replicates in hepatocytes via RNA polymerase Can cause both acute and chronic hepatitis - Virus enters host cell, uncoats and is transported to the nucleus of the hepatocyte where covalently closed circular DNA is repaired and HBC DNA becomes integrated into the host’s genome (makes eradication difficult) - the cccDNA serves as a template for transcription of viral RNA – goes through reverse transcription to form the viral DNA proteins HBsAg and HBeAg - Genotypes may play a role in progression of HBV related liver disease and response to interferon – Genotype B earlier seroconversion and slower rate of progression; A and B better response to interferon compared to C and D

Hepatitis B: Life Cycle

Hepatitis B: Epidemiology
More than 2 billion people worldwide > 350 million with chronic HBV 75% in the Asian Pacific region In 2007, ~43,000 acute cases of HBV in US 800,000 – 1.4 million people in US are chronic carriers Responsible for 60-80% of primary liver cancers Mortality ~620,000 deaths worldwide each year

Hepatitis B: Epidemiology
- Present in up to 20% of people in parts of China and Africa - < 0.5% in US

Hepatitis B: Transmission
Activities that involve percutaneous or mucosal contact with infectious blood or body fluid Sex with infected partner IV drug use Perinatal transmission Contact with open sore Needle sticks Sharing razors, toothbrushes, etc. - HBV can survive on surfaces for 7 days (razors, tabletops, toothbrushes) - Does not cross the skin or mucous membranes, there must be some break in the barrier - Virus does not cross the placenta, but transmission occurs during birth - perinatal transmission is the major mode of transmission in countries with high endemicity (Asia and Africa) and 90% children infected at birth will become chronic carriers compared to 5% of persons infected as older children or adults - in countries with lower endemicity (US) the major mode of transmission is through sexual contact or IV drug use - risk of HBV from needlestick is 30% vs. 0.3% from HIV - HBV is 100x more infectious than HIV

Hepatitis B: Who should be tested?
Individuals born in areas with high or intermediate prevalence rates Patients not vaccinated as children Sexual contact with HBV infected IV drug users (past or current) Patients with STD’s MSM Inmates Chronic elevation of AST/ALT Persons infected with HCV or HIV Hemodialysis patients All pregnant women Patients on immunosuppressive medications - People that are at risk for HBV - test for serology and presence of antigens and antibodies

Hepatitis B: Antigens - partially double stranded DNA is repaired by DNA polymerase to form the cccDNA which serves as template for further viral replication - HBsAg – on the outer lipoprotein coat of the virus (the envelope) – highly immunogenic and induces T-lymph cytotoxic activity - the core encapsulates the viral DNA and DNA polymerase and the HbcAg is the main protein making up the structure of the core capsid – HBcAg does not circulate freely in serum only internal - HBeAg – circulating nucleocapside antigen found in the serum in infected patients

Hepatitis B: Antigens Antigen Meaning HBsAg
Hepatitis B Surface Antigen - Indicates the person is infectious - Found in high levels during acute and chronic infection - Used to make the HBV vaccine HBcAg Hepatitis B Core Antigen - Indicates acute or chronic infection - Not found with vaccine HBeAg Hepatitis B Envelope Antigen - Associated with the nucleocapsid gene found during acute and chronic HBV - Presence indicates replicating virus and high levels of HBV - HBsAg – present in serum for several weeks before onset of symptoms and persists (if > 6 months considered chronic HBV), first marker to appear 1-6 weeks before symptoms - HBcAg – antibodies to core antigen form 1-2 weeks after HBsAg appears (IgM can persist for 6 + months and replaced by IgG) - HBeAg – present in serum; appears during weeks 3-6 and indicates person is in the most infectious period; persistence for > 10 weeks may indicate chronic infection

Hepatitis B: Antibodies
Antibody Meaning Anti-HBs Antibody to HBsAg - Indicates recovery and immunity from HBV - Develops after successful vaccination Anti-HBc - IgM - IgG Antibody to HBcAg - Appears at onset of symptoms and persists for life - Indicates a previous or ongoing infection - IgM suggests acute HBV; IgG usually chronic Anti-HBe Antibody to HBeAg - Seroconversion - Predictor of long term clearance of HBV and low levels of HBV DNA - Anti-HBs – provides lifelong protection from HBV; will peak if virus is cleared; if never shows up then probably chronic infection - AntiHBc IgM – persists for about 6 months and will be replaced by IgG if chronic infection or recovered infection – they do not provide any protection - Anti-Hbe – good prognosis – patient not contagious

Hepatitis B: Lab Results
HBsAg Anti-HBc Anti-HBs Negative Susceptible Positive Immune due to natural infection Immune due to vaccination IgM anti-HBc Acutely infected Chronic infection Unclear - resolved infection, false (+) anti-HBc, low level chronic infection, resolving acute infection 1 – no vaccine b/c no Anti-HBs and no past infection with immunity – so susceptible 2 – Person is not currently infected b/c no HBsAg; not immune due to vaccine b/c has AntiHBc which only comes with natural infection 3 – Vaccine causes Anti-HBs because it is made from HBsAg proteins – will not cause core antigen + 4 – HBsAg + which means patient has either acute or chronic infection; IgM is + so we know it is acute b/c IgM will only persist for about 6 month 5 – HBsAg + so acute or chronic, IgM is negative so it has probably been replaced by IgG and no antibody to HBsAg yet 6 – Also termed the “window period” , not enough time gone by for appearance of Anti-HBs; or if it is a chronic infection the levels of HBsAg are too low for detection

Hepatitis B: Acute Disease
Presence of HBsAg and IgM anti-HBc Incubation period – 45 to 180 days If symptomatic – N/V, abdominal pain, fatigue, arthralgias, with or w/o jaundice Drastically increased LFT’s – specifically ALT ~5% of adults and 90% of infants (perinatal transmission) progress to chronic infection < 1% progress to fulminant hepatic failure No specific treatment for acute HBV - HBsAg will be the first serologic marker to appear; 1-6 weeks before sx - HBeAg will appear after HBsAg and will persist for ~ 6 wks; highest infectivity - Anti-HBc IgM will appear shortly after HBsAg and persist ~ 6 months - longer incubation period than HAV - <10% of children and 30-50% of adults symptomatic - sx typically only last 4-12 weeks - ALT may increase up to 100 fold (typically 3-10 fold increase) - No specific treatments - fulminant hepatic failure – immune system overpowering and causes huge inflammatory response – Alt/AST will drop bc liver is failing but may be interpreted as resolving disease

Hepatitis B: Acute Disease
- incubation period ~ 2-3 months til sx appear - HBsAg 1st followed by HBeAg, and Anti-HBc IgM (lasting ~ 6 mo) - sx lasting about 4-12 weeks - seroconversion of HBeAg and clearance of HBsAg indicate resolution

Hepatitis B: Chronic Disease
Persistence of HBsAg for > 6 months Active carrier – HBeAg (+), HBV DNA > 20,000 IU/mL, AST/ALT elevations Inactive carrier - Anti-HBe (seroconversion) and HBV DNA < 2,000 IU/mL, normal LFT’s 67-80% of patients with seroconversion (Anti-HBe formation) will become inactive carriers ~20% progress to cirrhosis and 5% to hepatocellular carcinoma - with absence of IgM - probability of developing chronic HBV varies according to age – infants have 90% risk while adults have only 5% risk - patients usually do not have the sx of hepatitis; the bodies cytotoxic response of CD4 and CD8 cells is not great enough to clear virus, but is enough to cause persistent inflammation - cirrhosis – liver cells die and are progressively replaced with fibrotic tissue which leads to nodule formation – obstruct blood flow through liver – usually the person is unaware bc no symptoms; 60-90% of all HCC patients have underlying cirrhosis - HBV DNA integrates into host cell DNA and causes mutations and progression to HCC - progression to cirrhosis and HCC may take place over yrs

Hepatitis B: Chronic Disease
- this patient seroconverts

Extrahepatic Manifestations
Seen in 10-20% of patients Transient serum sickness-like syndrome Fever, rash, arthritis – precedes jaundice Acute necrotizing vasculitis Arthritis, renal disease, HTN, heart disease, skin manifestations Membranous glomerulonephritis Papular acrodermatitis Skin lesions with lymphadenopathy Serum sickness – hypersensitivity reaction to proteins (usually foreign or injected proteins) Acute necrotizing vasculitis – autoimmune inflammation of blood vessel walls; vessel may scar or thicken or even die which decrease perfusion Membranous glomerulonephritis – thickening of the glomeruler basement membranes in the kidney; caused by circulating immune complexes which trigger an attack on kidney glomerulus – proteinuria – kidney’s don’t filter properly Papular acrodermatitis – possibly a delayed type hypersensitivity rxn with deposition of immune complexes in the dermis

Papular Acrodermatitis Acute necrotizing vasculitis

Chronic HBV: Treatment
Goals of treatment Suppress virus and achieve HBeAg seroconversion and undectable HBV DNA Stop or reduce hepatic inflammation Prevent development of hepatic decompensation Decrease progression to cirrhosis and HCC - biologic response = decreased ALT and inflammation / virologic response = decrease in HBV DNA / histologic = response on liver biopsy, decreased fibrosis - seroconversion usually followed by clinical remission and lifelong inactive state with excellent outcome – reduced inflammation - Decompensation = albumin < 3, bilirubin > 30, PTT> 3 sec, portal hypertension (ascites, encephalopathy, variceal bleed) - once patient has developed cirrhosis if cannot be reversed

Chronic HBV: When to treat?
HBsAg (+) > 6 months ALT < 1x ULN - √ ALT Q 3-6 mos. - √ HBeAg Q 6-12 mos. ALT 1-2x ULN - √ ALT Q 3 mo. - √ HBeAg Q 6 mo. - ? Biopsy (>40 yr, FHx) - * Tx as needed ALT > 2x ULN - √ ALT, HBeAg Q 1-3 months - *Tx if persistent HBV DNA > 20,000 or jaundice HBeAg (+) upper limit of normal ALT for men = 30 women = 19 monitor for 3-6 months prior to tx b/c ~10% of people will have spontaneous seroconversion unless patient is having an icteric flare – promptly tx Chronic HBV due to HBsAg + for 6 months; and not seroconverted (HBeAg +) People in first category with normal ALT should be monitored for any increase in ALT with no current tx – if ALT increases on follow-up then check the HBV DNA - ALT 1-2 x ULN – tx should be initiated if > 40 years, family history of HCC, jaundice or other signs of hepatic decompensation or base on biopsy with moderate-severe necroinflammatory activity or fibrosis - ALT > 2x ULN if they are compensated then can consider watching for 3-6 months; if having a flare with jaundice or ALT spike then tx immediately - should do ultrasound every 6-12 months for screening for HCC in patients susceptible * If HBV DNA > 20,000 IU/mL after 3-6 months of ALT 1-2x ULN consider tx

Chronic HBV: When to treat?
HBsAg (+) > 6 months ALT < 1x ULN HBV DNA < 2000 IU/mL - √ ALT Q 3 month x 1 yr then Q 6-12 months ALT 1-2x ULN HBV DNA 2,000-20,000 IU/mL - √ ALT and HBV DNA Q 3 months - ? Biopsy - * Tx as needed ALT > 2x ULN HBV DNA > 20,000 IU/mL - Tx if persistent - ? biopsy HBeAg (-) - Normal ALT and HBV < 2000 usually means “inactive carrier state” must recheck ALT every 3 months for 1st year to verify this - If ALT > 2 x ULN and HBV DNA 2000 – may consider tx if persistent or consider biopsy * Tx based on results of biopsy or persistent viremia

Chronic HBV: Treatment
Available agents for HBV Interferons (non-pegylated and pegylated) Nucleoside analogs (lamivudine, entecavir, telbivudine) Nucleotide analogs (adefovir and tenofovir) - pegylated interferons have addition of polyethylene glycol side chain which prolongs half like and changes some kinetic parameters

Interferons MOA Place in therapy Doses Antiviral effects
Immunomodulatory effects Antiproliferative effects Place in therapy Best response if high pretreatment ALT and low HBV DNA First line for compensated liver disease Doses INF α-2b: 5-10 MU SQ 3 times weekly HBeAg (+) for weeks HBeAg (-) for months Peg-INF α-2a: 180 mcg SQ once a week HBeAg (+) and (-) = 48 weeks - increases phagocytic activity of macrophages and augments cytotoxic lymphocytes; enhance T-helper cell activity, cause maturation of B lymphs, inhibit T cell suppressors - Also inhibits viral transcription and translation within the hepatocyte - increase the bodies immune response to the virus – will kill the hepatocytes so will see a flare in ALT after 8-12 weeks of therapy but should normalize then patient will seroconvert and lose HBV DNA – without the flare the loss of viral replication hardly occurs - predefined treatment durations for both HBeAg + and -

Interferons Side effects Contraindications
Flu-like syndrome (fever, chills, HA, myalgia), anorexia, hair loss, hepatitis flares, emotional lability (anxiety, irritability, depression), pancytopenia, thyroid function changes, retinal damage Contraindications Decompensated hepatic disease or autoimmune diseases (e.g. rheumatoid arthritis, lupus) ? Uncontrolled psychiatric disturbances Dose limiting toxicities – pancytopenias and flu-like syndrome - Flu like sx occur several hours after administration - Giving NSAIDs dose reduce - depression – may cause suicidal ideations, usually occurs 3-4 months into therapy; not a total contraindication but patient must be monitored closely; can use SSRI’s - patients with decompensated hepatitis – the flare than is caused by interferon therapy puts them at an increased risk of fulminant hepatic failure - autoimmune diseases – IFN increases the activity of the immune system so patients with autoimmune diseases may have flares - reduce dose by 50% is WBD <1500, PLT<50,000; D/C if WBC <1000, PLT<25,000 - hepatitis flares – don’t typically worry until > 5x ULN

Interferons Advantages Disadvantages No drug resistance
Finite treatment duration 80-90% of patients have a durable response Once weekly dosing with PEG-IFN Disadvantages Poor tolerability due to side effects Relapse is common in HBeAg (-) patients Can’t use in decompensated pts Injection - unlike the nucleotide/side analogs no drug resistance has been reported - tx duration 16 weeks for HBeAg + and 1 yr for (-) with IFN and 48 wks with PEG; analogs are based on time to seroconversion and possibly indefinite % will remain HBeAg – if the seroconvert which is a better prognosis with decreased viral replication and better chance of HBsAg clearance - convenience of once weekly PEG - Side effects are a major limiting factor – flulike sx, and pancytopenias may lead to withdrawal of the drug; need to be in pretty good health prior to initiation - HBeAg - patients don’t have as good of outcomes; may have less relapse if tx for longer durations (24 months) - even if pt has cirrhosis that is compensated, still probably not the safest option to use - typically for younger patients to try and spare long term treatment

Nucleoside/tide Reverse Transcriptase Inhibitors
MOA Inhibition of DNA polymerase Premature DNA chain termination Class side effects Lactic acidosis Lipodystrophy Pancreatitis Neuropathy - As a class have a faster onset and viral suppression than interferons but overall similar rates of seroconversion after > 1 yr therapy - does not affect host response to virus or lead to direct clearing of infected hepatocytes, but suppresses viral replication

Lamivudine (3TC) Highest levels of drug resistance
Up to 70% after 5 years tx Similar efficacy but limited use due to resistance Dose 100 mg PO QD Dose decreased in renal impairment: 30-49 mL/min – 50 mg QD 15-29 mL/min – 25 mg QD Duration: HBeAg (+) – 1yr (minimum) and continue for 6 months post seroconversion HBeAg (-) – usually indefinite Well tolerated – HA, fatigue, nausea - nucleoside analog (cytosine) incorporated into viral DNA by RT and results in chain termination - seroconversion is greater than standard interferon at one year but less than PEG – does improve with longer treatment duration but at the risk of resistance - resistance occurs starting within 4-6 months of treatment and increases with the longer duration of therapy - resistance increase with high HBV DNA levels - resistance is due to a mutation in the DNA polymerase - resistance may appear as a virologic breakthrough (increase in HBV DNA) followed by biochemical breakthrough (increase in ALT) which may lead to acute hepatitis exacerbation or hepatic decompensation - treatment endpoint in HBeAg seroconversion and for + pts with 2 tests showing Anti-Hbe (must be 1-3 months apart) they can go through 6 months of consolidation and then D/C with 70-90% durable response - endpoint unknown in patients who are HbeAg (-) so treatment is usually indefinite

Telbivudine (TBV) More potent than lamivudine but cross resistance identified Less resistance than lamivudine 25% at 2 years – limits use Dose 600 mg PO QD Renal impairment: 30-49 mL/min – 600 mg Q 48 hours <30 mL/min – 600 mg Q 72 hours Duration HBeAg (+) – 1yr (minimum) and continue for 6 months post seroconversion HBeAg (-) – usually indefinite More peripheral neuropathy and myopathy - nucleoside thymidine analog – premature DNA chain termination - better viral DNA suppression than 3TC but seroconversion rate similar - same resistance pattern and 3TC – YMDD mutation; lower rate than 3TC but increases drastically after the 1st year of tx from 5% year 1 to 25% year 2 - neuropathy observed 1-6 months after initiation and does usually resolve with discontinuation; will get increases in CPK; neuropathy worse when used in combination with IFN

Entecavir (ETV) More potent viral suppression and histologic improvement vs. 3TC and ADF Possible use in 3TC and ADF resistant patients May cause some ETV resistance – stop 3TC Rate of ETV resistance is low (<2% at 5 yrs) Dose 0.5 mg PO QD ; 3TC-resistant: 1 mg PO QD Renal impairment: 30-39 mL/min – 0.25 mg QD 10-29 mL/min – 0.15 mg QD Duration HBeAg (+) – 1yr (minimum) and continue for 6 months post seroconversion HBeAg (-) – usually indefinite - nucleoside analog of guanosine; premature DNA chain termination - the seroconversion rates are similar to other oral nucleotide/side agents - in nucleoside naïve patients resistance is very low (1.2%) but patients who are 3TC refractory the rates of ETV resistance can be up to 16% at 1 yr

Adefovir (ADF) Effective in lamivudine-resistant HBV
Must continue lamivudine indefinitely with addition of adefovir Novel resistance mechanism for adefovir Up to 20% resistance at 5 years Dose 10 mg PO daily Renal impairment: 20-49 mL/min – 10 mg QOD < 20 mL/min – 10 mg every third day Duration HBeAg (+) – 1yr (minimum) and continue for 6 months post seroconversion HBeAg (-) – usually indefinite Nephrotoxicity – check SCr Q 3 months - nucleotide analog of adenosine – premature DNA chain termination - not cross resistant with lamivudine – doesn’t display the same resistance pattern - if using for 3TC resistance you have to continue 3TC which reduces the emergence of ADF resistance - Slower onset of resistance than lamivudine – no resistance at one year, only 3% resistance at 2 years - usually more resistance occurs if tx a patient that had prior lamivudine resistance - nephrotoxcity more common in transplant pts (possibly due to use of other nephrotoxic agents?)

Tenofovir (TDF) High potency and no resistance
Significantly better viral suppression and ALT normalization vs. ADF Effective in 3TC resistant HBV Cross resistant with ADF Dose 300 mg PO QD Renal impairment: 30-49 mL/min – 300 mg Q 48 hrs 10-29 mL/min – 300 mg Q hrs Duration HBeAg (+) – 1yr (minimum) and continue for 6 months post seroconversion HBeAg (-) – usually indefinite Fanconi syndrome, renal insufficiency, ↓ bone density - nucleotide analog of adenosine; similar structurally to adefovir - only been approved for HBV since 2008 so there is a lack of data on long term outcomes – durability of response and resistance - seroconversion rates similar - better results than adefovir in treating 3TC resistance - cross resistant with ADF – patients with ADF resistance had a 3-4 fold decrease in response to TDF - 5-7% loss in bone mineral density has been reported

Chronic HBV: Monitoring
Interferons Thyroid function tests every 3-6 months, CBC every week for 2 weeks then every month, depression screening every visit HBeAg, HBsAg, HBV DNA at baseline, end of therapy, and 6 months post therapy LFT’s every month Nucleoside/tide Inhibitors Drug specific side effects HBeAg + patients – HBeAg and Anti-HBe at the end of 1 yr and every 3-6 months thereafter LFT’s and HBV DNA every 3-6 months

Drug Resistance Increase in HBV DNA > 1 log10 after initial virologic response Elevated ALT Nucleoside analogs (lamivudine and telbivudine) highest resistance YMDD mutation in HBV Limits use No resistance with IFN or TDF - 10 fold increase in HBV DNA - 30% due to noncompliance - good strategy to withhold medications in people who are unlikely to have a response with minimal disease – follow the algorithm; use the most potent NA with the lowest resistance and reinforce the importance of compliance

Drug Resistance: What do I do now?
Treatment Resistance Action 3TC resistance Add Adefovir (continue 3TC) *Add Tenofovir Adefovir resistance Add Lamivudine *Switch or add Entecavir Entecavir resistance Switch to Tenofovir Telbivudine resistance Add Tenofovir or Adefovir - typically if you are resistant to a nucleoSIDE then add nucleoTIDE or vice versa 3tc resistance – could possibly use entecavir and stop lamivudine – but increases the risk of entecavir resistance ADF resistance – if had 3tc resistance prior to ADF then should not go back to 3tc; cant use tenofovir due to cross resistance Entecavir resistance – can’t use 3tc or adefovir bc use may together may actually increase ETV resistance

Advantages Disadvantages - IFN 5-10 MU SQ TIW - PEG-IFN 180 mcg SQ QWk - Finite tx duration - No resistance - Potent - Q week dosing - Adverse effects - Contraindications - Injection Lamivudine 100 mg QD - PO - Well tolerated - High level of resistance - Prolonged tx duration Adefovir 10 mg QD - Effective in 3TC resistance - Resistance rising - Nephrotoxicity Entecavir 0.5 mg QD - More potent - Very little resistance - ? Use in 3TC and ADF resistance Telbivudine 600 mg QD - More potent than 3TC - High resistance - Neuropathy, myalgia Tenofovir 300 mg QD - High potency - Use in 3TC resistance - Cross resistance with ADF

Chronic HBV: What agents do you choose?
Patient Specific Circumstance Preferred Agents HBeAg (+) or HBeAg ( - ) Peg-IFN, Entecavir, Tenofovir Decompensated liver disease Tenofovir or Entecavir (lack of data) Lamivudine/Telbivudine + Adefovir/Tenofovir NO INTERFERON! Compensated Cirrhosis Tenofovir or Entecavir Pregnancy Tenofovir or Telbivudine (Category B) HIV Co-infection If desire to tx HIV – use combination of 2 HIV/HBV active drugs (3TC + TDF) If not desiring HIV tx – use IFN or ADF - Compensated cirrhosis – IFN in not contraindicated but there have been reports of patients developing fulminant hepatitis when tx with IFN - Decompensated (albumin < 3 bili > 30, prolonged PTT) or sx of jaundice - HIV – IFN and ADF have no activity against HIV so they will no induce resistance if used when not desiring tx; TBV has no HIV activity but may cause resistance; ETV has some activity

Hepatitis B Prevention: Who should be vaccinated?
All infants Children < 19 yrs not previously vaccinated Susceptible sex partners Person getting treated for any STD MSM IV drug users Health care workers Dialysis patients Travelers to high risk areas Persons with chronic liver disease HIV infected persons Do not have to have any risk factor to be vaccinated - Vaccines became available in 1982 and if became policy to vaccinate all infants at birth in 1991 – since then the rate of acute HBV in the US has decreased by 81% from 1991 – 2006 - ~ 160 countries now have mandatory infant vaccinations for HBV - if one dose is given at birth it greatly increases the likelihood of children receiving the full vaccine schedule

Single Antigen Hepatitis B Vaccines Combination Hepatitis Vaccines
Age Dose Schedule Engerix-B Infant – Adult Infant – 19yrs: 10 mcg >20 yr: 20 mcg HD and IC: 40 mcg 0, 1, 6 months (40 mcg – 0,1,2,6) Recombivax HB Infants – 19 yrs: 5 mcg >20 yr: 10 mcg HD and IC: 40 mcg Combination Hepatitis Vaccines Comvax (HBV& Hib conjugate) 6 wks – 71 months 5 mcg 2, 4, months Pediarix (HBV, DTaP, IPV) 6 wks – 7 yrs 10 mcg 6 wk, 10 wk, 6 months Twinrix (HAV& HBV) > 18 yrs 20 mcg - should not be given if yeast allergy - larger doses needed for HD patients and immunocompromised to be able to induce formation of antibody - does not have to be restarted if you get off schedule - can be given during pregnancy - immunity lasts ~ 20 years but does not have to be repeated unless you are immunocompromised or hemodialysis patient - should check HD patients annually for antibody levels and give booster when Anti-Hbs < 10 miU/mL ** Single antigen vaccines composed of HBsAg subunits derived from baker’s yeast

Post-exposure prophylaxis: HBIG
Passive immunity – immediate with 3-6 month duration Should be administered within 48 hours of exposure Administer in conjunction with HBV vaccine Recommendations Neonate born to HBsAg (+) mothers within hours Sexual exposure Susceptible healthcare workers post-exposure Liver transplant patients - unlike Hep A IG the HBIG is not used for preexposure prophylaxis – much more cost efficient and protective to give vaccine - if mom is HBsAg + and HBeAg + baby has 90% chance of being + if no prophylaxis - when give HBIG with vaccine it is 85-95% effective in preventing HBV infection in infants born to + mothers; the vaccine alone is 70-95% effective

Hepatitis B: Case JM is a 54 year old Asian female who presents to her family physician complaining of unusual fatigue, N/V, and abdominal pain. Since the patient takes care of her mother, who is chronically infected with HBV, the physician decides to do a complete HBV workup along with the routine labs. PMH: Rheumatoid arthritis, hypothyroidism, IBS, dysthymia HBV Panel: HBsAg +, Anti-HBc IgM +, HBeAg +, Anti-HBs – ALT = 29 AST = 18 WBC = 8.9 x 103 RBC = 3.2 HGB = 12.4 g/dL CrCL = 89 mL/min What is JM’s diagnosis? Does she require therapy?

Hepatitis B: Case JM’s symptoms resolve over the next month and she feels back to normal. Her physician asked her to follow-up with him in 6 months to recheck her lab work. Upon recheck her labs are as follows: HBsAg +, Anti-HBc IgM - , HBeAg +, Anti-HBs – AST = 42 ALT = 63 WBC = 4.2 x 103 RBC = 3.1 HGB = 11.9 g/dL What is JM’s diagnosis? Should JM be treated? If so, what agent should we recommend? - Need more labs to know if she should be tx (HBV DNA = 29,000) if they say wait 3 months then HBV DNA after 3 months is 31,000 and HBeAg still + and ALT = 67 -

Hepatitis B: Case The physician ignores your recommendation (punk!) and starts the patient on lamivudine (3TC) 100 mg daily. After 3 months of therapy JM’s HBV DNA=2,100 and ALT=18. How long should therapy be continued? At JM’s 6 month visit her HBV DNA=32,000 and ALT=54. What happened? What should you recommend? What adverse effects should you counsel the patient/physician to look out for? - Virologic breakthrough – add Tenofovir 300 mg daily

Hepatitis C – Jazzy’s Story

Hepatitis C Identified in 1989 RNA virus
Enveloped 11 genotypes and > 50 subtypes identified 6 major genotypes Vary in responsiveness to treatment Prohibits vaccine development Can cause both acute and chronic disease - HCV is a “sneaky” virus - highly mutable even when person is infected – undergoes constant mutation and really exists as a collection of quasiviruses in the host - this gives HCV the ability to escape host immunity b/c it is rapidly changing in the body - so this makes the host more susceptible to chronic infection due to bodies inability to efficiently eradicate the virus - also prohibits vaccine development bc the virus is constantly mutating and antibodies to one genotype or subtype does not confer resistance to another genotype

Hepatitis C: Epidemiology
Genotype 1a & 1b most common 60% of global infection Type 3 endemic to SE Asia Type 5 exclusive to South Africa Type 6-11 in Asia - genotypes are associated with response to therapy and virulence - constantly changing – to make a vaccine you would have to include antigens from all known genotypes and then hope that it didn’t mutate even more

Hepatitis C: Prevalence
About 3% of world’s population has HCV Leading cause for liver transplantation Most common chronic blood borne infection in the US 3.2 million persons in US have chronic Hep C Most prevalent in people years old 849 cases of acute hepatitis in US in 2007 Approximately 17,000 adjusted for under reporting - 170 million worldwide chronic carriers - HCV is the cause of 40% of the all chronic liver diseases in the US - the number of people with chronic HCV is expected to have a 4 fold increase by 2015 due to the number of people infected earlier progressing to chronic stage - about 10,000/yr die from HCV related deaths in US

Hepatitis C: Prevalence

Hepatitis C: Transmission
Contact with infected blood or blood products Sharing needles and blood transfusions (prior to 1992) Less commonly spread through sexual contact Monogamous sexual transmission is rare Perinatal transmission less common < 5% of babies born to HCV + mothers are infected - IV drug users account for 60% of the HCV cases; 30% due to sexual, HD, occupational or perinatal exposure; 10% have no known risk factor - possibly even sharing razors, tattoos, body piercing - spread thru sexual contact more common when multiple partners but still low – not higher in MSM - perinatal transmission < 6% but increases in mothers that are HIV positive – unlike HBV were perinatal transmission is most common route

Hepatitis C: Risk Factors
Injection drug users Blood transfusions or solid organ transplants prior to 1992 Recipients of clotting factors prior to 1987 Chronic hemodialysis Known exposure to HCV Healthcare workers Recipients of blood or organs from HCV (+) donors HIV infected persons Children with HCV (+) mothers - 1/3 of drug users are HCV positive - didn’t start screening blood for HCV until 1992 which was a major mode of transmission prior to this time (1 in 200 units infected) - coinfection with HIV increases the risk perinatal transmission

Hepatocellular Carcinoma
Hepatitis C Acute Hepatitis Incubation period 6 – 10 weeks 80% of patients have are asymptomatic Insidious onset of fatigue, N/V, jaundice, abd. pain P R O G E S I N MORTAL I TY 70 – 90 % Chronic Hepatitis 60 – 80 % are asymptomatic Liver biopsy only way to assess progression 10 – 20 % Cirrhosis Symptoms appear up to 20 years after acute phase – hepatomegaly, splenomegaly, ascites - person is contagious from 1-2 weeks before onset of symptoms and persists almost indefinitely - More likely to be asymptomatic during the acute phase – less jaundice than HBV (~25%) ; fulminant disease is rare (not enough of an immune rxn) % will progress to chronic disease due to the viruses ability to evade the host immune system ; spontaneous elimination of the virus is rare - Chronic HCV diagnosed with elevated ALT and Anti-HCV for > 6 months - cirrhosis cases due to HCV are leading cause of liver transplantation - HCC is rare if the person does not have cirrhosis ; unlike HBV the virus does not integrate into the host cell – the cancer may be due to repeated hepatocyte death and regeneration over years 3-5% ~25% Hepatocellular Carcinoma

Hepatitis C Extrahepatic manifestations (1-2% of patients)
Cryoglobulinemia Cutaneous vasculitis Renal disease Neuropathy Lymphoma Sjogren’s syndrome - If person has extrahepatic manifestations tx should be considered cryoglobulinemia – cryoglobulins are antibodies that become thick or gel-like in cold temperatures leading to blockage of vessels throughout the body; marked by skin rashes, joint and muscle aches, and neuropathy, and glomerulonephritis; the majority of persons that have cryoglobulinemia are HCV positive so if a person has cryo then they need to be tested for HCV Cutaneous vasculitis – inflammation of the vessels in the skin and subcutaneous tissue that usually results from deposition of immune complexes - Sjogren’s – autoimmune disorder resulting in decreased production of tears and saliva leading to dry eyes and mouth

Cryoglobulinemia and Cutaneous vasculitis

Hepatitis C: Diagnosis
Liver function tests: AST, ALT, alk phos, bilirubin, PT/INR, albumin, CBC Initial screening test: Anti-HCV using enzyme immunoassay May not be (+) for up to 6-9 months after onset False negatives common Confirmation test: HCV RNA Present within 1 week of infection IgG and IgM unreliable for diagnosis of acute vs. chronic disease - LFTs may be normal! - anti-HCV may not be present until 2-8 weeks (up to 6-9 months) after initial liver injury - IgM is not a reliable marker of acute infection b/c it can be found in up to 70% of chronic cases

Hepatitis C: Serology - incubation period 6-10 weeks
- HCV RNA the first marker to appear usually within 1-2 weeks of infection - anti-HCV will appear later after sx appear - if chronic disease the patient will still have persistence of HCV RNA and ? ALT increases

Hepatitis C: Treatment
Determine patients HCV genotype first! Influences treatment regimen and duration Treatment goals – reduce inflammation, prevent progression to fibrosis, cirrhosis, and HCC Responses Early virologic response (EVR): 2-log drop or loss of HCV RNA 12 weeks into therapy Sustained virologic response (SVR): absence of HCV RNA in serum at end of treatment and 6 months later Nonresponders: HCV RNA levels remain stable on tx Genotype 1 typically associated with a worse response to tx compared to genotype 2 and 3 (2-3x more likely to respond to therapy) Failure to achieve and EVR is the most accurate predictor of not achieving SVR SVR – best predictor of long term clinical response; usually regarded as a “virologic cure” but HCC can still occur if cirrhosis developed prior to tx Nonresponders fail to suppress HCV RNA by at leas 2 logs after 24 weeks of therapy Virologic breakthrough is reappearance of HCV RNA while still on therapy while relapse is a recurrence after therapy was discontinued

Hepatitis C: Viral Responses

YES NO Who should we treat? Transplant recipients > 18 years
Autoimmune hepatitis Untreated hyperthyroidism Pregnant Severe HTN, HF, CAD < 3 years old > 18 years Abnormal ALT Normal ALT?? Liver biopsy with fibrosis Compensated liver disease Hgb > 13 g/dL for men > 12 g/dL for women Previously treated HCV Normal ALT treatment – based on liver biopsy, presence of HCV RNA, potential for SE, likelihood of response, comorbidities

Predictors of good response Genotype is strongest predictor SVR higher in genotype 2 and 3 (76-82% vs. 42 to 46% of genotype 1) Lower pretreatment HCV RNA Younger age (< 40 yrs) Lower body weight (< 75 kg) Absence of cirrhosis and fibrosis - HCV RNA < 600,000

Genotypes 1 & 4 Interferon alfa – 2a or 2b 3 million units SQ three times a week - Or - **Peginterferon alfa-2a (Pegasys) 180 mcg SQ weekly **Peginterferon alfa-2b (Peg-Intron) 1.5 mcg/kg SQ weekly PLUS Ribavirin 1,000 mg (if < 75 kg) or 1,200 mg (>75 kg) PO divided BID - 3 trials that show that PEG IFN is superior to IFN; more convenient with prolonged half life and less frequent dosing – currently the optimal tx for HCV - EVR = 2 log reduction in HCV DNA at 12 weeks – in genotype 1 patients with no EVR % of them will not reach a SVR after tx; these patients can discontinue therapy without much risk of compromising their chances of SVR - if patient does not have a complete EVR may continue therapy and recheck EVR at week 24 (if still not complete response then DC) - can consider extending therapy for patients who have a delayed response (HCV RNA becomes negative b/w weeks 12-24) to 72 weeks total - HCV RNA 24 weeks post therapy is to test for SVR – “virologic cure” HCV RNA at 12 weeks No EVR consider D/C EVR– 48 weeks total tx HCV RNA 24 weeks post tx

Genotypes 2 & 3 Interferon alfa – 2a or 2b 3 million units SQ three times a week - Or - **Peginterferon alfa-2a (Pegasys) 180 mcg SQ weekly **Peginterferon alfa-2b (Peg-Intron) 1.5 mcg/kg SQ weekly PLUS Ribavirin 800 mg PO divided BID - likelihood of SVR is 70-80% Continue tx for 24 weeks HCV RNA at 24 weeks post tx

Retreatment Relapsed patients – initial SVR but subsequent increase in HCV RNA Re-treat with peg-IFN + ribavirin if initially treated with IFN Try second round if already used peg-IFN + ribavirin Nonresponders – no initial SVR Try peg-IFN if previously on IFN Do not re-treat with peg-IFN if already tried Decompensated cirrhosis Liver transplantation Low doses of antiviral therapy % of patients will not respond (have SVR) to PEG-IFN and ribavirin combination – can be due to nonresponse, virologic breakthrough, or relapse - poor adherence and inappropriate dose reductions can contribute - Patients usually relapse in the first 12 weeks after therapy and are likely to respond if retreated (42%) - Nonresponders – retreatment with same regimen leads to an SVR in <5% of patients – not recommended; in patients that were tx with IFN + ribavirin may have about 10% with SVR when change to PEG-IFN Usually will not respond if had 12 months of therapy 3 trials currently assessing the use of low dose maintenance PEG-IFN ; one trial published shows that the rates of decompensation were similar between the two groups (tx with 90 mcg per week of PEG alfa 2a or placebo)

Hepatitis C: Ribavirin
MOA: Synthetic nucleoside analog which inhibits HCV DNA polymerase Dose: Based on weight and genotype (refer to algorithm) AE’s: Hemolytic anemia, neutropenia, decreased Hgb, fatigue, itching, rash, sinusitis, hyperuricemia, insomnia, depression, myalgias - not effective at eradicating HCV on its own but when added to IFN it increases the rate of SVR 2-3 fold - doses from mg /day - Hgb usually decreases between 2-3 g/dL starting within 1-4 weeks of therapy; patients may develop sx of anemia including SOB, fatigue, palpitations; may precipitate an angina attack and MI and strokes have been reported in patients with preexisting CV disease - sinusitis due to a histamine effect

Hepatitis C: Ribavirin
CI: Pregnancy, CrCL < 50 ml/min, severe heart disease, bone marrow suppression Monitoring: CBC, LFTs, uric acid at initiation and every 2 weeks for 8 weeks then every 4 weeks, TSH every 12 weeks Pregnancy test at initiation & Q month until 6 months after D/C Toxicity: Dose decreased for Hgb < 10 D/C if Hgb drop to < 8.5 in patients w/o cardiac history or if Hgb < 12 after dose adjustment Category X known to cause birth defects; must use strict contraceptives for at least up to 6 months after therapy discontinued Excreted by the kidney and decreased excretion can lead to increase in hemolysis Patients with preexisting heart disease may be at increased risk of MI or stroke due to anemia and symptomatic ischemia caused by ribavirin Patients with Hgb < 11 prior to therapy should not be treated Possible use of growth factors – filgrastim for neutrophils and erythropoeitin for RBC’s but the benefit vs. cost is still under question – does not improve SVR and doubles cost (does reduce the need for ribavirin dose reductions)

Hepatitis C: Prevention
There is no vaccine or IG for HCV No post exposure prophylaxis Screening and treatment of blood products Safe injection practices Monogamy Adequate sterilization of reusable instruments (dental equipment) - since HCV is highly mutable (even within the body can change envelope antigens to avoid host immune system) and there are so many genotypes and serotype of the disease it is difficult to make a vaccine that would stay current with the disease mutations - screening of blood started in 1991 and has drastically reduced transmission via this modality - IV drug use is the major risk factor for developing HCV

Hepatitis C: Case NK is a 34 year old, 65 kg, white female who is a single mom of 2 working as a high school chemistry teacher. During her college days at LA Tech, NK “experimented” a few times with IV heroin. She says she was young and stupid and always thought her friends were healthy so she didn’t mind sharing needles. She says she only used heroin about 5 times and 15 years ago. Today she presents to her physician with generalized fatigue (which she attributes to her busy schedule as a single mom) and some abdominal pain. Her physician performs a full work-up. PMH: Appendectomy at 15 yr, allergic rhinitis, hypertension WBC = 5.4 x 103 RBC = 2.9 HGB = 13.1 g/dL AST = 25 ALT = 29 CrCL = 100 mL/min Anti-HBs +, Anti-HBc - , HBeAg – Anti-HCV +, HCV RNA 5.8 log10 IU/mL

Hepatitis C: Case What is NK’s diagnosis? Does she need treatment? If so, what information do you need before recommending a treatment regimen? What treatment regimen do you recommend? What drug specific problems should we monitor for? When does NK need to return for monitoring for response? Genotype 1b

Hepatitis C: Case NK returns to the office for her follow-up labs. WBC = 4.4 x 103 RBC = 3.1 HGB = 11 g/dL AST = 21 ALT = 23 Anti-HCV + , HCV-RNA = 2.5 log10 IU/mL Is NK responding to therapy? How much longer should she be treated? What should be done after NK finishes treatment?

Hepatitis D RNA virus Requires HBV to replicate
Prevalence similar to HBV Blood borne or sexual transmission Either a coinfection or superinfection with HBV Coinfection usually acute and self limiting with <5% progressing to chronic HDV Superinfection severe acute hepatitis and 80% progress to chronic HDV 60-70% will develop cirrhosis - requires the HBsAg for its own encapsulation – outer envelope proteins entirely provided by HBV - with HBV - can be a coinfection or superinfection (nonactive HBV) - coinfection is a simultaneous infection with both viruses - superinfection is infection with HDV in an already chronically infected HBV; also has a high rate of fulminant hepatic failure - while infected with HDV the HBV virus is suppressed - mortality rate is 2-20% which is 10x higher than just HBV alone

HBV – HDV Superinfection
- Suppression of the HBV DNA

Hepatitis D Persons at risk: Prevention & Treatment
Anyone with chronic HBV infection Same risks for HBV (IV drug use, sexual promiscuity, blood products, etc.) Patients not vaccinated against HBV Prevention & Treatment No vaccine specifically for HDV HBV vaccination prevents HDV No IG for HDV Treatment not currently recommended If never been infected with HBV – the HBV vaccine will prevent HDV

Hepatitis E RNA virus Transmission via fecal-oral route
Waterborne spread Causes an acute hepatitis similar to HAV Not associated with chronic inflammation or HCC High mortality rate in pregnancy (~20% in 3rd trimester) No vaccine or IG Treatment not usually required

Hepatitis G RNA virus Transmitted via infected blood products, sexually, perinatally Usually presents as a coinfection with HBV, HCV, or HIV Patients don’t display typical hepatitis symptoms ? If this is a “true” hepatitis virus No vaccine or prophylaxis Also known as GB-virus

Viral Hepatitis Elizabeth Perry, Pharm.D. PGY-1 Resident

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Viral Hepatitis Elizabeth Perry, Pharm.D. PGY-1 Resident

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