1. Pharmacotherapy III First Semester 2012/2013
Viral Hepatitis
Pharmacotherapy III
First Semester 2012/2013

2. References Dipiro: Chapter 47 – Viral Hepatitis UpToDate
AASLD Guidelines (
Chronic Hepatitis B: Update_2009 
Diagnosis, Management, and Treatment of Hepatitis C: An Update

3. Introduction
The major hepatotrophic viruses responsible for viral hepatitis are:
hepatitis A,
hepatitis B,
hepatitis C,
delta hepatitis,
hepatitis E.
All share clinical, biochemical, immunoserologic, & histologic findings.
Hepatitides A & E are spread through fecal–oral route;
Hepatitides B, C, & delta are transmitted parenterally.
Infection with delta hepatitis requires coinfection with hepatitis B
Infection with delta hepatitis requires coinfection with hepatitis B.
Although the rates of acute infection have declined, viral hepatitis remains a major cause of morbidity and mortality with a significant impact on healthcare costs in the United States.
Significant therapeutic advances have occurred with hepatitis B with the approval of new agents and updated guidelines for care.
For hepatitis C, the challenge remains of increasing successful outcomes while minimizing side effects of therapy.

6. Hepatitis A
Hepatitis A virus (HAV), or infectious hepatitis, is often self-limiting & acute viral infection of liver posing health risk worldwide.
The infection is rarely fatal.
According to Centers for Disease Control and Prevention (CDC), reported cases of acute clinical hepatitis A infection in the United States in 2007 were lowest in recorded history.
Although vaccine preventable, HAV continues to be one of the most commonly reported infections.

7. Transmission of hepatitis A virus
HAV is spread via the fecal-oral route, personal contact, or ingestion of contaminated water/food
HAV is more prevalent in low socioeconomic areas in which a lack of adequate sanitation and poor hygienic practices facilitate spread of the infection
Risk factors:
Most common is international travel
Sexual & household contact with another person with hepatitis A
Homosexual activity in men
Chronic liver disease
Foods contaminated by infected food handlers
No identifiable risk factor
Children pose a particular problem with the spread of the disease because they often remain clinically asymptomatic and are infectious for longer periods of time than adults. (

8. Etiology
Hepatitis A is RNA virus belonging to genus Hepatovirus of Picornaviridae family.
Humans are the only known reservoir for virus
Virus is stable in environment for at least month & requires heating foods to minimum of 85°C (185°F) for 1 minute or disinfecting with 1:100 dilution of sodium hypochlorite (bleach) in tap water for inactivation.
Genotypes I & III are the most commonly identified in human outbreaks.

9. Pathogenesis of Hepatic Injury
Injury to liver is secondary to host's immune response.
Replication of HAV occurs exclusively within cytoplasm of hepatocyte, where virus causes non cytopathic infection.
Hepatocellular damage & destruction of infected hepatocytes is mediated by:
CD8+ T lymphocytes
natural killer cells.
Interferon gamma appears to have central role in promoting clearance of infected hepatocytes.
Excessive host response (observable clinically by marked degree of reduction of HAV RNA during acute infection) is associated with severe hepatitis
HAV infection is usually acute, self-limiting, and confers lifelong immunity. HAV's life cycle in the human host classically begins with ingestion of the virus. Absorption in the stomach or small intestine allows entry into the circulation and uptake by the liver. Replication of the virus occurs within hepatocytes and gastrointestinal epithelial cells. New virus particles are released into the blood and secreted into bile by the liver. The virus is then either reabsorbed to continue its cycle or excreted in the stool. The enterohepatic cycle will continue until interrupted by antibody neutralization. 7 The exact mechanism of replication and secretion is unknown; however, the initial viral expansion does not seem to be associated with hepatic injury as peak viral fecal excretion precedes clinical signs and symptoms of infection. 2
On biopsy, acute hepatitis is marked by hepatocellular degeneration, inflammatory infiltrate, and hepatocyte regeneration. Hepatocellular degeneration occurs as a result of immune-mediated injury and not as a direct cytopathic effect of the virus. 9 Clinical symptoms of HAV typically identify the onset of the immune response. Cytolytic T cells mediate hepatocyte lysis to eradicate the virus and mark the cellular immune response with rising hepatic enzyme levels. 7

10. Clinical Presentation of Acute Hepatitis A
ic·ter·ic definition
Pronunciation: /ik-ˈter-ik/ Function: adj :  of, relating to, or affected with jaundice

12. Clinical Evaluation HAV infection usually results in an:
acute, self-limited illness
only rarely leads to fulminant hepatic failure which occurs more commonly in patients with underlying liver disease, particularly chronic hepatitis C virus infection.
The manifestations vary with age.
HAV infection is usually silent or subclinical in children.
Infection in adults can vary in severity from mild flu-like illness to fulminant hepatitis.
Incubation period averages 28 days (range days)
prodrome  pro·drome (prō'drōm') n. pl. pro·dromes  or pro·dro·ma·ta  (-drō'mə-tə) An early symptom indicating the onset of an attack or a disease.

13. Clinical Evaluation (cont’d)
Peak fecal shedding of virus → clinical symptoms & ↑ liver enzymes.
Acute hepatitis begins with preicteric or prodromal period: abrupt onset of nonspecific symptoms, some very mild.
> unusual symptoms include chills, myalgia, arthralgia, cough, constipation, diarrhea, pruritus, & urticaria – last ~ 2 months.
Liver enzyme levels ↑ within the 1st weeks of infection, peaking ~ in the 4th week & normalizing by the 8th week.
Conjugated bilirubinemia, or dark urine, precedes icteric period.
Concentration of virus ↓ at this point & patients are generally considered noninfectious ~1 week after onset of jaundice.
GI symptoms may persist or subside during this time & some patients may have hepatomegaly.
Duration of icteric period: on average 7-30 days
prodrome  pro·drome (prō'drōm') n. pl. pro·dromes  or pro·dro·ma·ta  (-drō'mə-tə) An early symptom indicating the onset of an attack or a disease. 13

14. Physical Examination
The two most common physical examination findings are:
Jaundice (70%)
Hepatomegaly (80%)
Less common findings include:
splenomegaly, cervical lymphadenopathy, rash, arthritis, & rarely, vasculitis.
Extrahepatic manifestations:
vasculitis, arthritis, optic neuritis, transverse myelitis, thrombocytopenia, aplastic anemia, red cell aplasia.
These conditions are more likely in patients who have protracted illness.
Evanescent: quickly disappearing

15. Laboratory Findings
 Laboratory findings in symptomatic patients are notable for marked elevations of:
serum aminotransferases (usually >1000 IU/dL),
ALT is commonly higher than AST.
serum total & direct bilirubin,
Serum aminotransferase elevations precede bilirubin elevation.
Serum bilirubin levels above 10 mg/dL are common.
alkaline phosphatase.
Other laboratory abnormalities include:
nonspecific elevations of acute phase reactants,
↑ ESR,
increased immunoglobulins

16. Course of hepatitis A
infected individuals are contagious during the incubation period (2-6 wks) and remain so for about a week after jaundice appears.

17. Diagnosis
By detection of anti-HAV antibodies in patient with the typical clinical presentation.
Presence of serum IgM anti-HAV antibodies in adults without clinical features of viral hepatitis does not necessarily indicate acute infection. Other reasons:
previous HAV infection with prolonged presence of IgM anti-HAV,
False-positive result,
Asymptomatic infection (which is > common in children < six yrs compared with older children & adults).
Anti-HAV is positive at onset of symptoms, peaks during acute or early convalescent phase, & remains positive for ~4-6 mths
IgG anti-HAV appears early in convalescent phase, & remains detectable for decades.
A diagnosis of HAV is based on clinical criteria of an acute onset of fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting, jaundice or elevated serum aminotransferase levels, and serologic testing for IgM anti-HAV. Serologic testing is necessary to differentiate the diagnosis from other types of hepatitis.

18. Treatment: Desired Outcome
The ultimate goal of therapy is complete clinical resolution.
Other goals include:
reducing complications from the infection,
normalization of liver function,
reducing infectivity and transmission.

19. General Approach to Treatment
Because disease is usually self-limited, treatment is supportive.
Occasional patients require hospitalization.
Patients who develop fulminant infection require aggressive supportive therapy & should be transferred to a center capable of performing liver transplantation.
~85 percent of individuals who are infected with hepatitis A have full clinical & biochemical recovery within three months,
nearly all have complete recovery by six months.
No specific treatment options exist for HAV infections. Instead, patients should receive general supportive care. In patients who develop liver failure, transplant is the only option. Although hepatocellular damage occurs through immune-mediated responses, steroid use is not recommended. 12 Prevention and prophylaxis are key to managing the virus. The importance of good hand hygiene cannot be overemphasized in preventing disease transmission. Immunoglobulin is used for pre- and postexposure prophylaxis, and offers passive immunity. Active immunity is achieved through vaccination. Vaccines were approved for use in 1995 and implemented in the routine vaccination of children, as well as at-risk adults, to reduce the overall incidence of HAV. 8
Prevaccination serologic testing to determine susceptibility is generally not recommended. In some cases, testing may be cost-effective if the cost of the test is less than that of the vaccine and if the person is from a moderate to high endemic area and likely to have prior immunity. Prevaccination serologic testing of children is not recommended. Similarly, because of high vaccine response, postvaccine serologic testing is not recommended.

20. Prevention
Prevention can be aided by adherence to sanitary practices such as:
Regular hand washing with soap & water after using the bathroom, changing diaper, & before food preparation
highly effective in preventing transmission since hepatitis A virus may survive for up to four hours on fingertips
Heating foods appropriately,
Avoidance of water & foods from endemic areas.
Chlorination & certain disinfecting solutions (household bleach 1:100 dilution) are sufficient to inactivate virus.

21. Vaccination

22. Havrix and Vaqta
Both vaccines are inactivated virus and are available for pediatric and adult use.
The differences in the two vaccines are in the use of a preservative and in expression of antigen content.
Vaqta is formulated without a preservative and uses units of HAV antigen to express potency.
Havrix uses 2-phenoxyphenol as a preservative and antigen content is expressed as enzyme-linked immunosorbent assay (ELISA) units.
Both vaccines recommend a booster shot to achieve the highest possible antibody titers.
Both vaccines may be given concomitantly with immunoglobulin and the two brands are interchangeable for booster shots
What are the possible side effects of the vaccines?
What is Twinrix?
The most common side effects of the vaccines include soreness and warmth at the injection site, headache, malaise, and pain. Reported serious adverse events include anaphylaxis, Guillain-Barré syndrome, brachial plexus neuropathy, transverse myelitis, multiple sclerosis, encephalopathy, and erythema multiforme. However, causality of these reported events has not been established. Furthermore, incidence of serious adverse events in the vaccinated population did not differ from the incidence in nonvaccinated populations. It is important to note that more than 65 million doses of the vaccine have been administered and despite routine monitoring for adverse events, there are no data to suggest a greater incidence of serious adverse events among vaccinated people compared to nonvaccinated. The vaccine is considered safe. 8
Twinrix is a bivalent vaccine for hepatitides A and B that was approved by the FDA in The vaccine is approved for people ages 18 and older and is given at 0, 1, and 6 months. Although seroconversion exceeds 90% for HAV after the first dose, the full three-dose series is required for maximal hepatitis B virus (HBV) seroconversion. The combined vaccine offers the advantage of immunization against both types of hepatitis in a single vaccine.

23. Preexposure prophylaxis
Passive immunization with IM polyclonal serum Ig prior to exposure can decrease incidence of HAV infection by > 90%.
Passive immunity lasts for up to six months depending upon dose used, but is effective only if administered within 2 weeks of exposure.
Ig preexposure prophylaxis should be reserved for nonimmune individuals who are at risk for exposure to hepatitis A or who are allergic to hepatitis A vaccine.
HAV vaccination or prophylaxis with Ig is recommended for travelers to countries with high endemic rates of HAV.
Serious ADEs are rare.
Anaphylaxis has been reported in patients with Ig A deficiency.
Patients who had anaphylaxis reaction to Ig should not receive it.
There is no contraindication for use in pregnancy or lactation.

24. Immunoglobulin (Ig)
Ig is used when pre- or postexposure prophylaxis against HAV infection is needed.
Ig provides protection by passive transfer of antibody.
Postexposure prophylaxis
Ig is most effective if given in incubation period of infection.
Receipt of Ig within the first 2 weeks of infection will reduce infectivity & moderate infection in 85% of patients.
Patients who received at least 1 dose of HAV vaccine at least 1 month earlier do not need pre- or postexposure prophylaxis with Ig.
IM route is used.
If given to infants or pregnant women, thimerosal-free formulation should be used.
For people who were recently exposed to HAV & who had not been previously vaccinated, Ig is indicated:
when in close personal contact with HAV-infected person;
all staff & attendees of daycare centers when HAV is documented;
if they were involved in common source exposure;
classroom contacts of index case patient;
schools, hospitals, & work settings where close personal contact occurred with case patient.
International travelers are the major patient population receiving preexposure prophylaxis with Ig. HAV vaccination or prophylaxis with Ig is recommended for travelers to countries with high endemic rates of HAV. Serious adverse events are rare. Anaphylaxis has been reported in patients with Ig A deficiency. Patients who had an anaphylaxis reaction to Ig should not receive it. There is no contraindication for use in pregnancy or lactation.
Dosing of Ig is the same for adults and children. For postexposure prophylaxis and for short-term preexposure coverage of <3 months, a single dose of 0.02 mL/kg is given intramuscularly. For long-term preexposure prophylaxis of 5 months, a single dose of 0.06 mL/kg is used. Either the deltoid or gluteal muscle may be used. In children younger than 24 months of age, Ig can be given in the anterolateral thigh muscle. 8
Ig can be given concomitantly with the HAV vaccine. Although the antibody titer will be lower than if the vaccine were administered alone, the response is still protective. However, Ig can interfere with the response of other vaccines and should be delayed. The measles, mumps, and rubella (MMR) vaccine should be delayed for a minimum of 3 months after receipt of Ig. The varicella vaccine must be delayed for 5 months. Conversely, Ig should not be given to patients who received the MMR within 2 weeks or the varicella vaccine within 3 weeks. In situations where the benefits of Ig outweigh the benefits of the other vaccines, revaccination can be performed after Ig administration. For the MMR, revaccination should be at least 3 months later, and for the varicella vaccine, at least 5 months later. 8 In general, Ig does not interfere with inactivated vaccines and may be administered safely with other vaccines traditionally given to travelers to some developing countries, such as the oral poliovirus or yellow fever vaccine. 8

25. For postexposure prophylaxis & for short-term preexposure coverage of <3 months, single dose of mL/kg is given IM.
For long-term preexposure prophylaxis of 5 months, single dose of 0.06 mL/kg is used.

26. Ig can be given concomitantly with HAV vaccine.
However, Ig can interfere with response of other vaccines & should be delayed (unless benefits of Ig outweigh benefits of other vaccines):
MMR vaccine for minimum of 3 months after receipt of Ig.
Varicella vaccine must be delayed for 5 months.
Conversely, Ig should not be given to patients who received MMR within 2 weeks or varicella vaccine within 3 weeks.
Ig does not interfere with inactivated vaccines & may be administered safely with other vaccines traditionally given to travelers to some developing countries, such as oral poliovirus or yellow fever vaccine

28. Chronic infection with HBV is a major public health issue
Hepatitis B
Chronic infection with HBV is a major public health issue
it serves as reservoir for continued HBV transmission & poses a significant risk of death resulting from liver disease.
More than 1 million people per year die from liver cirrhosis & hepatocellular carcinoma (HCC).

29. Epidemiology
Concentration of HBV is high in blood, serum, & wound exudates of infected persons.
Virus is detectable in moderate quantities in semen, vaginal fluid, & saliva, & is present in low concentrations in urine, feces, sweat, tears, & breast milk.
Transmission can occur through contact with infected body fluids in absence of blood, as virus may be stable in environment for a number of days.
HBV is transmitted sexually, parenterally, & perinatally.
The mode of transmission has clinical implications
Chronic infections are associated with infection acquired in younger patients, especially those infected perinatally & in early childhood.

30. Epidemiology High Intermediate Low Carrier rate, percent ≥8 percent
High
Intermediate
Low
Carrier rate, percent
≥8 percent
2-7 percent
≤1 percent
Geographic distribution
Southeast Asia; China; Pacific islands; sub- Saharan Africa; Alaska (Eskimos)
Mediterranean basin; eastern Europe; central Asia; Japan; Latin and South America; Middle East
United States and Canada, western Europe; Australia; New Zealand
Predominant age at infection
Perinatal and early childhood
Early childhood
Adult
Predominant mode of infection
Maternal-infant; percutaneous
Percutaneous; sexual
Sexual; percutaneous
In areas of high HBV prevalence, perinatal transmission from mother to infant is most common,
In areas of intermediate prevalence, horizontal transmission from child to child is most common.
In low-endemic countries, sexual contact, both homosexual and heterosexual, and injection-drug use are the predominant forms of transmission

31. Etiology
HBV is partially double-stranded, circular DNA virus of family Hepadnaviridae.
It typically infects liver cells.
Seven HBV genotypes exist (A to H) with distinct geographic distribution
Genotypes may correlate with clinical course & response to interferon (> severe fibrosis with A,C & D; > benign with B).
4 A noted limitation of studies is frequently small sample sizes and a predominance of research from Asia, primarily comparing genotypes B and C. 24 Nonetheless, a study of a diverse patient immigrant population infected with genotypes A, B, C, D, and E, confirmed that more severe liver fibrosis was significantly higher in HBV genotypes A, C, and D-infected patients. Genotype B may be more benign because it is associated with faster seroconversion. 25 Resistance mutations may contribute to genotype virulence and hence impact severity of liver disease in infection

32. Pathophysiology
Upon infection, replication of virus begins by attachment of virion to hepatocyte cell surface receptors.
Particles are transported to nucleus where DNA is converted into circular DNA that serves as template for pregenomic RNA.
Viral RNA is then transcribed, transported back to cytoplasm where it can serve as reservoir for future viral templates or bud into membrane with viral envelope proteins & infect other cells.

33. HBV Antigens
HBsAg is the most abundant of 3 surface antigens & is detectable at onset of clinical symptoms.
Its persistence past 6 months after initial detection corresponds to chronic infection & poses increased risk for cirrhosis, hepatic decompensation, & HCC.
Development of antibody to HBsAg (anti-HBsAg) confers immunity to virus & clearance of HBsAg is associated with favorable outcomes.
Patients who respond to vaccine will have anti-HBsAg only.

34. HBeAg-negative mutants are refractory to treatment.
Although HBeAg's role in infection is nebulous, it is present in acute infection & is replaced by antibodies (anti-HBeAg) once infection is resolved.
HBeAg-negative mutants are refractory to treatment.
HBcAg is nucleocapsid protein that, when expressed on hepatocytes, promotes immune-mediated cell death.
High levels of antibodies (IgM anti-HBcAg) are detectable during acute infections.
Detection of IgM anti-HBcAg is also a reliable assay for diagnosing fulminant acute hepatitis where HBsAg & HBV DNA are often undetectable. 34

36. Serologic Responses to Acute & Chronic HBV
Acute infection
HBeAg, HBsAg, & HBV DNA preclinical phase.
IgM anti-HBc appears early in clinical phase; combination of this antibody & HBsAg makes diagnosis of acute infection.
Recovery: normalization of serum ALT, disappearance of HBV DNA, HBeAg to anti-HBe seroconversion, → HBsAg to anti-HBs seroconversion & switch from IgM to IgG anti-HBc. Previous HBV infection is characterized by anti-HBs & IgG anti-HBc.
Chronic infection
persistence of HBeAg (for a variable period), HBsAg, & HBV DNA in circulation; anti-HBs is not seen (in ~20% of patients non-neutralizing form of anti-HBs can be detected).
Persistence of HBsAg for >6 months after acute infection is considered indicative of chronic infection.

37. HBV itself does not seem to be pathogenic to cells; rather, it is thought that immune response (triggered by T cells) to virus is cytotoxic to hepatocytes.
Immune response includes MHC class I CD8 cytotoxic T cells & MHC class II CD4 T-helper cells.
In acute infection, cytotoxic T-cell response is critical to viral clearance. If response is weak, chronic infection is likely.
Liver injury is likely caused by secondary, nonspecific inflammation activated by initial cytotoxic lymphocyte response & as attempt by immune system to clear virus by destroying HBV antigen presenting hepatocytes.
→↑ ALT levels
major histocompatibility complex

38. Cirrhosis
Cirrhosis results as liver attempts to regenerate while in environment of persistent inflammation.
Continued alcohol consumption exacerbates hepatocellular damage.
Most patients with compensated cirrhosis are either asymptomatic or have mild symptoms of epigastric pain & dyspepsia.
~20% of all chronic hepatitis B patients progress to decompensated cirrhosis within a 5-year period.
Typically, initial clinical findings of decompensated cirrhosis are ascites, jaundice, variceal bleed, encephalopathy, or combination of symptoms.
The development of cirrhosis is mostly insidious and patients can remain stable for years before disease progression.
During cirrhosis, the liver enters a cycle of ongoing liver damage, fibrosis, and attempts at regeneration.
The classical appearance of a small and knobby liver reflects the irreversible effect of nodules of regenerating cells integrated with infiltrates of inflammatory induced fibrous tissue.

40. Hepatocellular Carcinoma (HCC)
Development of HCC can be insidious, occurring in absence of cirrhosis or in presence of clinically silent, compensated cirrhosis.
In most cases, HCC develops after years of inflammatory processes provoked by ongoing HBV infection.
Same factors influence development of HCC, as well as predict survival (see Table).

41. 3 phases of HBV infection (indistinguishable from other types of viral hepatitis):
initial or acute phase in adults & older children, 4-10-week incubation period, during which antibodies toward HBV core are produced & virus replicates profusely.
Symptoms, if occur, include fever, anorexia, N&V, jaundice, dark urine, clay-colored or pale stools, & abdominal pain. Most neonates & children are anicteric & have no clinical symptoms, whereas up to half of adult patients are icteric.
Initial phase is considered immunotolerant: no hepatic injury, generally normal ALT levels. Patients are highly infectious during this time.
2. Immunoactive phase marks ↓ HBV DNA levels. Patients are symptomatic with intermittent flares of hepatitis & marked ↑ ALT levels. More frequent flares are associated with disease progression. Can last a few weeks in acute disease, & for years in patients with chronic disease.
If infection is self-limiting, HBV DNA quickly subsides
3. Seroconversion is defined by replacement of HBeAg with anti-HBeAg.

42. Clinical Presentation
HW: Factors favoring seroconversion?

43. Clinical Presentation

44. Clinical Presentation
Chronic infections can be controlled in many cases, but cure is not possible because HBV template is integrated into host genome.
Patients can be divided into 2 types of chronic hepatitis B: those who are HBeAg-positive & those who are HBeAg-negative.
Patients are considered to be in "immune tolerant" phase when HBeAg is positive, high serum HBV DNA levels are detected, & ALT levels are normal.
Typically these patients were infected early in life & develop elevated ALT levels later in life.
Spontaneous HBeAg clearance is possible & is associated with older age, higher ALT, & infection with HBV genotype B

45. Clinical Presentation (cont’d)
Patients who are HBeAg-negative can be further subdivided into active or inactive carrier.
Active carriers have high serum HBV DNA, elevated ALT levels, & liver necroinflammation.
Clinical course is worse with low rate of spontaneous remission, recurring flares of hepatitis with increased frequency & severity - can progress to cirrhosis & HCC.
Inactive carriers have detectable HBsAg & anti-HBeAg, normal ALT, & either low or undetectable levels of HBV DNA - more benign course of disease, with possibility of long-term remission, even seroconversion, although reactivation is possible with progression to cirrhosis & HCC. Rarely, patients will resolve their infection.
Patients with undetectable HBsAg but with anti-HBsAg & anti- HBcAg: small portion of patients who are not likely to experience reinfection or reactivation unless immunosuppressed.

46. Prevention of Hepatitis B
Vaccination
the most effective strategy to prevent infection
a comprehensive vaccination strategy
Vaccines use HBsAg for antigen via recombinant DNA technology using yeast to prompt active immunity.
Considered safe.
Licensed vaccines either contain none or trace amounts of thimerosal as a preservative.
Available vaccines include:
two single-antigen products: Recombivax HB & Engerix-B
three combination products: Twinrix (for adults), Comvax & Pediarix (used for children).
Passive immunity in form of anti-HBsAg
offers temporary protection against HBV
is used in conjunction with hepatitis B vaccine for postexposure prophylaxis.

47. Recommendations for HBV Vaccination

48. Prevention of Transmission
Recommendations for infected persons regarding prevention of transmission of HBV to others
Persons who are HBsAg-positive should:
Have sexual contacts vaccinated
Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune
Not share toothbrushes or razors
Cover open cuts & scratches
Clean blood spills with detergent or bleach
Not donate blood, organs or sperms
Children & adults who are HBsAg-positive:
Can participate in all activities including contact sports
Should not be excluded from daycare or school participation & should not be isolated from other children
Can share food, utensils, or kiss others

49. Carriers should be counseled regarding transmission prevention of HBV
Recommendations for counseling & prevention of transmission of hepatitis B from individuals with chronic hepatitis B virus (HBV) infection:
Carriers should be counseled regarding transmission prevention of HBV
Sexual & household contacts of carriers who are negative for HBV seromarkers should receive hepatitis B vaccination
Newborns of HBV-infected mothers should receive HBIG & hepatitis B vaccine at delivery & complete recommended vaccination series
Persons who remain at risk for HBV infection such as infants of HBsAg- positive mothers, health care workers, dialysis patients, & sexual partners of carriers should be tested for response to vaccination
Postvaccination testing should be performed at 9-15 months of age in infants of carrier mothers & 1-2 months after the last dose in other persons
Follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients
Abstinence or only limited use of alcohol is recommended in carriers
Persons who are positive only for anti-HBc & who are from low endemic area with no risk factors for HBV should be given full series of hepatitis B vaccine

50. Treatment: Desired Outcome
HBV infections are not curable
The goals of therapy are to:
increase chances for seroclearance,
prevent disease progression to cirrhosis & HCC,
minimize further injury in patients with ongoing liver damage.
Primary treatment endpoint
Decrease serum HBV DNA level to low or undetectable
Secondary treatment endpoints
Decrease or normalize serum ALT
Induce HBeAg loss or seroconversion
Induce HBsAg loss or seroconversion
Undetectable serum HBV DNA
Improve liver histology
Clinical trials only; not routinely assessed in practice

51. General Approach to Treatment
Recommendations for treatment - consider:
patient's age,
serum HBV DNA & ALT levels,
histologic evidence
clinical progression of disease.
Not all chronic HBV patients are candidates for treatment. Some patients may be best managed with periodic monitoring for disease progression because the chances for therapeutic response are unlikely and do not outweigh the risks and costs associated with treatment.
Many factors should be considered when selecting first‑line therapy for the treatment of hepatitis B. These considerations include the goals of therapy, whether the patient is a good candidate for antiviral therapy, the baseline patient factors (ie, HBeAg positive vs HBeAg negative, hepatitis B virus [HBV] genotype, HBV DNA level, alanine aminotransferase [ALT] level, presence or absence of cirrhosis, and comorbidities), the expected duration of therapy, efficacy of available therapies, and the resistance profiles of the available treatment options.

52. Nonpharmacologic Therapy
All chronic HBV patients should be counseled on preventing disease transmission.
Sexual & household contacts should be vaccinated.
To minimize further liver damage, all chronic HBV patients should avoid alcohol & be immunized against HAV. No level of alcohol use has been established as safe.
Moreover, patients are encouraged to consult their medical provider before using any new medications, including herbals & OTC.
Herbal medicines:
Phyllanthus,
milk thistle,
glycyrrhizin (licorice root extract),
mixture of herbs known as Liv 52.
not recommended for patients with chronic hepatitis B

53. Pharmacologic Therapy
Because hepatic damage is sustained by ongoing viral replication, drug therapy aims to suppress viral replication by either immune mediating or antiviral agents.
Interferon (IFN)-2b, lamivudine, telbivudine, adefovir, entecavir, & pegylated IFN-2a are all approved as first- line therapy options for chronic HBV.

55. Treatment algorithm for chronic HBV infection based on recommendations of AASLD

56. Treatment algorithm for chronic HBV infection with cirrhosis based on recommendations of AASLD

57. Ifn & Peg-Ifn
Patients who respond to Ifn therapy tend to have more durable response than that seen with lamivudine.
Seroconversion rates are 30-40% & are often permanent, although relapse is more likely in HBeAg-negative patients.
Optimal duration of treatment is unclear (minimum of 12 months)
Additional benefits of Ifn-based therapy in responsive patients: reduction in cirrhosis, HCC, & death.
Pegylated interferon (Peg Ifn): ease of administration (once weekly) →↓ side effect profile, & improvements in efficacy.
For HBV treatment, approved peg-interferon formulation is pegIFN- 2a.
pegIFN-2a–lamivudine combination caused greater HBV DNA suppression than pegIFN-2a monotherapy; pegIFN-2a monotherapy better achieved HBeAg seroconversion than lamivudine monotherapy with no difference in combination therapy; combination therapy resulted in less lamivudine resistance than lamivudine monotherapy

58. Homework
Common Side Effects Associated with Peginterferon Therapy

59. Lamivudine
Nucleoside analog, has antiviral activity against HIV & HBV.
Dose is 100 mg/d in adults; optimal duration is unknown.
Higher baseline ALT levels correspond to greater likelihood of seroconversion.
+ Excellent safety profile, patient tolerability
+ Can safely be used in immunosuppressed & cirrhotic patients.
- Serum HBV DNA levels return to baseline upon cessation of therapy.
- Seroconversion rates are <20% after 1 year of therapy & will relapse in up to 58% of patients (poorest prognosis in Asians).
Patients on lamivudine therapy require monitoring for breakthrough infection.
If confirmed lamivudine-resistant mutations, therapy should be changed to agents active against lamivudine-resistant HBV.

60. Adefovir
Adefovir dipivoxil: acyclic nucleotide analog of adenosine monophosphate.
Acts by inhibiting HBV DNA polymerase.
Dose is 10 mg daily for 1 year in adults, optimal duration is unknown.
Improves histologic findings, ↓ serum HBV DNA & ALT levels & ↑ HBeAg seroconversion
Further suppression of HBV DNA & ALT levels occurred in long-term therapy over 4-5 years with improved histologic findings.
In patients with developing lamivudine resistance as demonstrated by rising HBV DNA levels, addition of adefovir was more effective if done while ALT levels were still normal.
To prevent adefovir resistance, lamivudine should be continued even in patients with lamivudine-resistant HBV, although optimal duration for combination therapy is not known.

61. Entecavir
Guanosine nucleoside analog that acts by inhibiting HBV polymerase.
Is more potent than lamivudine & adefovir in suppressing serum HBV DNA levels & is effective in lamivudine-resistant HBV.
Rates of HBeAg seroconversion are higher in patients with elevated baseline ALT.
Treatment response in lamivudine-resistant patients is lower overall
Entecavir-resistant mutants can develop during course of treatment, most likely to occur in patients with preexisting lamivudine resistance
Patients on lamivudine who develop resistance & are switched to entecavir should stop lamivudine therapy (resistance to both lamivudine & adefovir is risk factor for entecavir resistance).
Safety is comparable to that of lamivudine.

62. Combination therapy
AASLD recommends combination therapy with lamivudine or telbivudine plus adefovir, tenofovir, or entecavir for decompensated cirrhotic patients with chronic HBV regardless of HBV DNA levels or HBeAg status.
Moreover, current guidelines suggest combination therapy with two or more agents in patients who develop antiviral resistant HBV

65. New Drugs
The safety and efficacy of other antiviral agents for the treatment of chronic HBV infection, including emtricitabine and clevudine, are under investigation.
Emtricitabine has been associated with significantly higher rates of histologic, virologic, and biochemical responses at week 48 compared with placebo. However,rates of HBeAg seroconversion were the same in both groups(12%), with emtricitabine resistance rates occurring in 13% of treated patients.
Clevudine is well tolerated with undetectable serum HBV DNA levels at the end of treatment in 59% of HBeAg-positive and in 92% of HBeAg-negative patients. A unique characteristic of clevudine is the durability of viral suppression, which persists up to 24 weeks after therapy is discontinued.

66. Viral Hepatitis C

67. Introduction HCV is the most common blood-borne pathogen.
HCV is most often acquired through:
IV drug use (The most important risk factor)
clotting factors (in the past)
sexual contact;
hemodialysis;
household, occupational, or perinatal exposure.

68. Screening
Screening for HCV infection is recommended in selected groups who are at high risk for infection.

69. Etiology
HCV is a single-stranded RNA virus, family Flaviviridae notable for lacking proofreading polymerase & enabling frequent viral mutations.
Virus replicates within hepatocytes & like hepatitis B, is not directly cytopathic.
The most widely distributed genotypes are 1 & 2, with genotype 1 the most common
Genotypes 2 & 3 are at least twice as likely to respond to therapy as genotype 1.
Genotypes 4, 5, & 6 are not well understood but are expected to respond with rates similar to genotype 1.

71. Pathophysiology
In vast majority of cases, acute HCV infection leads to chronic infection.
Immune response in acute HCV infection is mostly insufficient to eradicate virus.
During the early phases of infection, natural killer cells are activated as HCV RNA levels rapidly rise.
Eradication of HCV by cytotoxic T lymphocytes may occur either as result of induced apoptosis by infected hepatocytes or by release of interferon to stifle viral replication.
Liver damage & HCC are associated with high levels of hepatocyte apoptosis.
Low levels of apoptosis are associated with viral persistence.
Resolved cases of HCV are defined by vigorous T-cell response with highly active CD8 & persistent CD4 cell response.

72. Clinical Presentation
Patients with acute HCV are often asymptomatic & undiagnosed.
1/3rd of adults will experience some mild & nonspecific symptoms, including fatigue, anorexia, weakness, jaundice, abdominal pain, or dark urine.
The most common symptom of chronic HCV infection is persistent fatigue.
Estimated 20% of patients with chronic HCV infection will develop cirrhosis & half of those patients will progress to decompensated cirrhosis or HCC.
In vast majority of patients (up to 85%) acute HCV infection leads to chronic infection defined by persistently detectable HCV RNA for 6 months or more.

73. Diagnosis
The diagnosis of HCV infection is confirmed with a reactive enzyme immunoassay for anti-HCV.
Serum transaminase values are elevated within 4 to 12 weeks after exposure.

74. Treatment
Goal is to eradicate HCV infection, which prevents development of chronic HCV infection & sequelae.
Treatment for HCV infection is necessary because high percentage of acutely infected patients develop chronic infections.
All patients with chronic HCV infection should be vaccinated for hepatitis A & B.
Patients should be advised to:
maintain good overall health,
stop smoking,
avoid alcohol & illicit drugs.
Reduce weight (obese respond poorly to Ifn)

75. Indications & Contraindications to Treatment
patients previously untreated who have:
chronic HCV,
circulating HCV RNA,
increased alanine transaminases levels,
evidence on biopsy of moderate to severe hepatic grade & stage,
compensated liver disease.
Contraindications
autoimmune hepatitis,
decompensated liver disease,
pregnant or unwilling to comply with contraception
untreated thyroid disease
SrCr >1.5 mg/dL or on HD
major, uncontrolled depression
severe concurrent medical disease
solid organ transplant including renal, heart, or lung

76. Treatment Response Treatment response is best in:
patients with HCV genotype 1
those who take at least 80% of their medications for at least 80% of the treatment time.

79. Interferons are proteins that are normally produced by the body in response to viral infection. They inhibit viral replication and cell proliferation, and participate in the immune process. Pegylated interferon alfa is a standard fixture in all HCV treatment regimens. The two available products are peginterferon alfa-2b (Pegintron) and peginterferon alfa-2a (Pegasys). Although they are pharmacologically very similar, their dosing is quite different. Pegasys is given as a standard 180 mcg/week injection that's available in prefilled syringes, autoinjectors, or by the vial. Pegintron is dosed by weight and is available in vials or a variety of prefilled syringe strengths (50 mcg/0.5 mL, 80 mcg/0.5 mL, 120 mcg/0.5 mL, 150 mcg/0.5 mL).

80. Ribavirin works as an antiviral agent, although it's not clear exactly how it works. As with peginterferons, ribavirin is a component of all HCV treatment regimens. It's an oral agent and is available as a tablet, a capsule, or an oral solution.
The confusing part is that the approved dosage regimens differ depending on the product. That's because each product was studied differently. Ribavirin tablets were primarily studied with Pegasys and the ribavirin was dosed based on patient weight for more difficult to treat hepatitis, genotypes 1 and 4. Ribavirin capsules were primarily studied with Pegintron and ribavirin was weight-based for all genotypes. In practice is doesn't matter which product is used as long as the dosing is appropriate to the regimen being used

81. Protease inhibitors reversibly inhibit the NS3/4 protease enzyme, an enzyme critical for hepatitis C viral replication. Adding one of these agents to a pegylated interferon/ribavirin regimen can shorten treatment duration for a genotype 1 infection from 48 weeks to 24 weeks. It also significantly increases the likelihood of achieving an SVR from approximately 40% to nearly 70% in newly treated patients. These agents are challenging for patients to take. Right now there are only two on the market, boceprevir (Victrelis) and telaprevir (Incivek ). They're dosed three times daily...every 8 hours, which in this case means each dose must be taken between 7 and 9 hours from the last one. Strict adherence to therapy is critical to achieving a cure and avoiding the development of viral resistance.
These agents should NEVER be used as monotherapy. resistance develops quickly. It's feared that HCV which is resistant to one protease inhibitor will render the entire class ineffective for HCV, including any future agents.

82. Pharmacological management
Current standard of treatment for chronic HCV infection is combination of:
once-weekly PEG-IFN +
daily oral dose of ribavirin.
Sustained virologic response rates are 54-56%.
Therapy is optimized based on: genotype, patient weight, response to therapy.
Homework:
Side effects to these agents.

83. PEG-IFNs Two PEG-IFNs are available, It is unclear which is superior.
Pegasys
PEG-Intron
It is unclear which is superior.

86. Prevention No vaccine is available for HCV.
It is unlikely that vaccine will be developed in the near future because of mutagenesis of virus.
Patients infected with HCV should be counseled on not being blood, organ, or semen donors.
Patients should minimize risks of household transmission by avoiding possible blood or mucus exposure, such as not sharing razors or toothbrushes & covering open wounds.
Patients who continue to use illegal drugs should avoid sharing all drug paraphernalia, as risk of transmission is not limited to needles & syringes.