1. ↑ INCIDENCE AND COMPLICATIONS

2. BUT, NOT EVERYONE NEEDS TREATMENT

350 million persons worldwide are chronically

infected with HBV.7 there are an estimated 1.25 million hepatitis B

carriers, defined as persons positive for hepatitis B surface antigen (HBsAg) for more than 6 months.8,9

Carriers of HBV are at increased risk of developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC).

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

2009 Am Assoc Liver Study Grp Practice Guidelines

• A 38-year-old Filipina with HBeAg-positive chronic hepatitis B presents for evaluation. She has had serum alanine aminotransferase (ALT) levels of 80-120 U/L and HBV DNA level of 2 million copies/mL (approximately 400,000 IU/ml) over the past year and no evidence of spontaneous loss of HBeAg. She is asymptomatic and had a normal abdominal ultrasound within the prior 6 months. She has never received therapy for hepatitis B.

http://depts.washington.edu/hepstudy/hepB/mgmt/agents/index.html

2009 Am Assoc Liver Study Grp Practice Guidelines

ANTI-VIRALSentecavir (Baraclude)tenofovir Lamivudine (Epivir HBV)Adefovir dipivoxil, telbivudine,IMMUNE MODULATORSInterferon alfa 2b (Intron A)Peginterferon alfa 2a (Pegasys)Hepatitis C Treatments interferon alfa-2b (Intron A) recombinant interferon alfa-2a

(Roferon) consensus interferon or interferon

alfacon-1 (Infergen) Peginterferon alfa 2a (Pegasys)Peginterferon alfa 2b (Peg Intron)Peginterferon alfa2b and ribavirinRecombinant alfa 2a (Roferon) and

rivavirinVaccines

MOA: induction of gene transcription; Inhibits cellular growth, alters the state of cellular differentiation, interferes with oncogene expression, alters cell surface antigen expression, increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells

reduction in risk of progression to cirrhosis, hepatocellular carcinoma, and liver-related death in long-term responders of interferon

Pkinetics The additon of polyethylene

glycol to the interferon, through a process known as pegylation, enhances the half-life of the interferon when compared to its native form.

administered subcutaneously. IFN alfa: 3 MIU three times a

week (tiw) administered subcutaneously for 12 months (48 to 52 weeks).

Peg-interferon: 180 mcg weekly for 48 weeks

Normalization of serum ALT generally occurs within a few weeks after initiation of treatment in responders.

Approximately 90% of patients who respond to Roferon-A do so within the first 3 months of treatment; however, patients responding to Roferon-A with a reduction in ALT should complete 12 months of treatment.

Patients who have no response to Roferon-A within the first 3 months of therapy are not likely to respond with continued treatment; treatment discontinuation should be considered in these patients.

Durability of response approximately half may relapse when therapy is stopped; longer duration 24 mos vs. 6-12 mos may increase sustained response

Flu-like Symptoms: Fatigue (58%), myalgia/arthralgia (51%), flu-like symptoms (33%), fever (28%), chills (23%), asthenia (6%), sweating (5%), leg cramps (3%) and malaise (1%). *** most common

Central and Peripheral Nervous System: Headache (52%), dizziness (13%), paresthesia (7%), confusion (7%), concentration impaired (4%) and change in taste or smell (3%).

Gastrointestinal: Nausea/vomiting (33%), diarrhea (20%), anorexia (14%), abdominal pain (12%), flatulence (3%), liver pain (3%), digestion impaired (2%) and gingival bleeding (2%).

Psychiatric: Depression (16%), irritability (15%), insomnia (14%), anxiety (5%) and behavior disturbances (3%).

Pulmonary and Cardiovascular: Dryness or inflammation of oropharynx(6%), epistaxis(4%), rhinitis (3%), arrhythmia (1%) and sinusitis ( < 1%).

Skin: Injection site reaction (29%), partial alopecia (19%), rash (8%), dry skin or pruritus (7%), hematoma (1%), psoriasis ( < 1%), cutaneous eruptions ( < 1%), eczema ( < 1%) and seborrhea ( < 1%).

Other: Conjunctivitis (4%), menstrual irregularity (2%) and visual acuity decreased ( < 1%).

Patients receiving 6 MIU tiw experienced a higher incidence of severe psychiatric events (9%) than those receiving 3 MIU tiw (6%) in two large US studies. In addition, more patients withdrew from these studies when receiving 6 MIU tiw (11%) than when receiving 3 MIU tiw (7%). Up to half of patients receiving 3 MIU or 6 MIU tiw withdrawing from the study experienced depression or other psychiatric adverse events. At higher doses anxiety, sleep disorders, and irritability were observed more frequently. An increased incidence of fatigue, myalgia/arthralgia, headache, fever, chills, alopecia, sleep disturbances and dry skin or pruritus

Dosage adjustment 1) If severe adverse reactions or laboratory abnormalities

develop during interferon alfa-2b therapy, modify the dose (reduce by 50%) or discontinue if appropriate, until the adverse reactions subside. If intolerance persists after dose adjustment, discontinue interferon alfa-2b.

2) For patients with decreases in WBC, granulocyte count or platelet count, reduce the interferon alfa-2b dose 50%

D/C: WBC count < 1.5 × 10 9 /L,

granulocyte count is less than 0.75 × 10 9 /L,

platelet count is less than 50 × 10 9 /L.

-

1. Lamivudine (Epivir-HBV, 3TC)

Figure 5. Image 1. Peginterferon alpha-2a versus Lamivudine alone or in Combination in HBeAg-Negative Patients: Study Features

From: Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-17.

MOA: nucleoside analogue inhibitsHBVreplication at

three different steps: the priming of HBV DNA

polymerase, the reverse transcription of the negative strandHBVDNAfrom the pregenomic RNA, and the synthesis of the positive strandHBVDNA

Ind: indicated for the treatment of chronic hepatitis B virus infection in 1.HBeAg-positive patients2.HBeAg-negative patients3.Decompensated cirrhosis / recurrent hepatitis B after liver transplantation4.Lamivudine-refractory HBV5.Adefovir-resistant HBV

Pkinetics / Efficacy and use not recommended for anyone

less than 16 years old. stomach (at least 2 hours after a

meal and at least 2 hours before the next meal).

primarily eliminated by the kidneys

Dose 0.5 mg orally once daily or 1 g if with resistance

Durability of response/outcomes: 24 wks after seroconversion and

48 wks treatment : suppression of serum HBV to

undetctable levels in 39%, normalizaiton of ALT 79%, seroconversio n 77%

Adv eff: headache, tiredness,

dizziness, and nausea. Exacerbations of hepatitis after discontinuation of treatment.

Lactic acidosis: muscle pain and weakness, dyspnea, fast or uneven heart rate, nausea, vomiting, stomach pain, and numbness

severe liver symptoms such as nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice and severe hepatomegaly with steatosis

.

MOA: nucleotide analogue, first approved for the treatment of HIV infection and approved 2008 for HBV

Tenofovir is structurally similar to adefovir.

In vitro studies showed that tenofovir and adefovir are equipotent.

Because tenofovirappears to be less nephrotoxic, the approved dose is much higher than that of adefovir, 300 mg versus 10 mg daily. This may explain why tenofovir has more potent

antiviral activity in clinical studies.

Efficacy in Various Categories of Patients.

1. HBeAg-positive patients2. HBeAg-negative patients3. Lamivudine-refractory

HBV-greater reductions than adefovir

4. Adefovir-resistant HBV-shares cross-resistance

Adverse Events. Tenofovir has been reported to cause

Fanconi syndrome, renal insufficiency as well as osteomalacia

and decrease in bone density.

MOA: an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).

Ind: 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

Pkinetics:- Taken with or without food- Bioavailability of adefovir is

approximately 59%. C max is approximately 18.4 ng/mL, and T max is approximately 1.75 h.

- Distribution: Up to 4% is protein bound.

Efficacy:1. HBeAg positive chronic hepatitis B- give up

to 6 mos after serovonversion2. HBeAg negative chronic hepatitis – give up

to 1 yr (4-5yrs) 3. Children (under trial but not yet approved

for use)4. Lamivudine resistant hepatitis B- if no

improvement, alternative regimens

Dose: 10 mg daily 1 to 2 yrs

Metabolism Adefovir dipivoxil (prodrug) is

rapidly converted to adefovir (active).

Elimination The terminal elimination half-life

is approximately 7.48 h; is renally excreted

Adv effects: asthenia, headache, abdominal

pain, diarrhea, nausea, dyspepsia, flatulence, increased creatinine,hypophosphatemia; exacerbations of hepatitis (ALT elevations 10 times the upper limit of normal or greater) occurred in up to 25% of patients after discontinuation

Durability of response and outcome:- Seroconversion maintained in 91% of

pts on longer durations but for HBeAg negative pts. Only 8% of pts had sustained viral suppression

MOA: a synthetic nucleoside analogue; Incorporation of the monophosphate form into viral DNA by HBV reverse transcriptase results in DNA chain termination-inhibition of DNA synthesis

Absorption and Bioavailability:

- rapidly absorbed after oral administration - may be administered with or without food.

- Binding of lamivudine to human plasma proteins is low (<36%) and independent of dose

- Renal excretion 12 h at 71 %- No significant differences were

observed in AUC∞ or total clearance for lamivudine or zidovudine when the 2 drugs were administered together.

Efficacy:

USES:1. HBeAg positive chronic hepatitis-1 yr

a. Elevated ALTb. Normal ALTc. Childrend. Asian

2. HBeAg negative chronic hepatitis B-1 yr

3. Non-responders to IFN-α –no added benefit

4. Bridging fibrosis and compensated cirrhosis =improved outcomes

5. Decompensated cirrhosis – benefit 3-6 mos

Outcomes: rates of virologic and biochemical response decreased with time; lower rates of hepatic decomp.

Dose: 3mg/kg/day children100 mg daily

Post-marketing experience with lamivudine: Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Anemia (including pure

red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic: Lactic acidosis and steatosis, pancreatitis, posttreatment exacerbation of hepatitis

Hypersensitivity: Anaphylaxis, urticaria. Musculoskeletal: Rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy. Respiratory: Abnormal breath

sounds/wheezing. 16 Skin: Alopecia, pruritus, rash. Others: Posttreatment Exacerbations of

Hepatitis; Pancreatitis

MOA: L-nucleoside analogue telbivudine is more potent than

lamivudine in suppressing HBV replication.

However, telbivudine is associated with a high rate of resistance and telbivudine-resistant mutations are cross-resistant with lamivudine.

Therefore, telbivudine monotherapy has a limited role in the treatment of hepatitis B.

Uses:1. HBeAg positive pts – 1 to 2 yrs2. HBeAg negative pts. -1 to 2 yrs

Adverse eff: cases of myopathy and peripheral neuropathy have been reported. Peripheral neuropathy appears to be more common when telbivudine was used in combination with pegIFN.

Dose: 600 mg daily

potent inhibitor of HIV and HBV replication. FTC has been pproved for HIV treatment as Emtriva (FTC only) and as Truvada (in Combination with tenofovir as a single pill).

Because of its structural similarity with lamivudine (3TC), treatment with FTC selects for the same resistant mutants.

Adv effects: headache Diarrhea, indigestion joint pain unusual dreams depression trouble falling asleep or

staying asleep numbness, burning, or

tingling in the hands, arms, feet, or legs

runny nose

Mech: nucleoside analogue

Durable viral suppresion up to 24 wks after withdrawal of treatment

Adv effects: myopathy in pts treated longer than 24 wks; typically onset after 8 mos; mitochondrial toxicity

55% to 85% of persons who develop acute hepatitis C will remain HCVinfected.

Among these individuals, 5% to 20% are reported to develop cirrhosis over periods of approximately 20 to 25 years.

Even with regimens given 24-48 wks: genotype is the strongest predictor of response

American Assoc Liver Dse Grp, 2004

AASLD PRACTICE GUIDELINE

a nucleoside analogue: inhibits replication of viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis

Txt duration: 24-48 weeks or longerPkinetic considerations Increased absorption with food. The terminal half-life of Ribavirin is

about 120 to 170 hours. There is extensive accumulation of Ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.

Dosing: Chronic hepatitis C (in combination

with interferon alfa-2b): 75 kg: 400 mg in the morning, then

600 mg in the evening >75 kg: 600 mg in the morning, then

600 mg in the evening

mutagenic, tumor-promoting, and gonadotoxic.

1% to 10%: Central nervous system: Fatigue,

headache, insomnia Gastrointestinal: Nausea, anorexia Hematologic: Anemia <1% Hypotension, cardiac arrest, digitalis

toxicity, conjunctivitis, mild bronchospasm, worsening of respiratory function, apnea

Headache (51%); conjunctivitis (32%); rhinitis, nausea, rash, dizziness, pharyngitis, and lacrimation (10% to 20%)

>10%: Central nervous system: Dizziness (17% to

26%), headache (63% to 66%)*, fatigue (60% to 70%)*, fever (32% to 41%)*, insomnia (26% to 39%), irritability (23% to 32%), depression (23% to 36%)*, emotional lability (7% to 12%)*, impaired concentration (10% to 14%)*

Dermatologic: Alopecia (27% to 32%), rash (20% to 28%), pruritus (13% to 21%)

Gastrointestinal: Nausea (38% to 47%), anorexia (21% to 27%), dyspepsia (14% to 16%), vomiting (9% to 12%)*

Hematologic: Decreased hemoglobin (25% to 36%), decreased WBC, absolute neutrophil count <0.5 x 10 9 /L (5% to 11%), thrombocytopenia (6% to 14%), hyperbilirubinemia (24% to 34%), hemolysis

Neuromuscular & skeletal: Myalgia (61% to 64%)*, arthralgia (29% to 33%)*, musculoskeletal pain (20% to 28%), rigors (40% to 43%)

Respiratory: Dyspnea (17% to 19%), sinusitis (9% to 12%)*, nasal congestion

Miscellaneous: Flu-like syndrome (13% to 18%)*

strict contraception methods both during treatment and for a period of 6 months after treatment.

TXT PROTOCOL GENOTYPE 1(poor response) TXT PROTOCOL GENOTYPE 2

EVR – early virological response= HCV RNA – at wk 12

RVR –rapid virologic response HCV RNA - wk 4

ETR – end of treatment response HCV RNA – after 24 -48 wks

SVR – sustained virologic responseHCV RNA – 24 wks after txt

Breakthrougjh- reappearance HCV RNA while on therapy

Relapse – reappearance after therapy

Non-responder – failure to clear after 24 wks therapy

Vaccines

HEPATITIS A VACCINE schedule: doses at 0 and 6 to

12 months, 95% protection for at least 10

years (Ib, A); revaccinate after 10 years (IIb, B); however, there is increasing evidence that vaccine-induced immunity may be >20 years and possibly lifelong, so no further booster doses may be needed after the primary course in immunocompetent patients.

HEPATITIS B VACCINE The ultra-rapid 0, 7, 21 day

regimen Test for response (anti-HBs >10

IU/L, ideally >100 IU/L) 4 to 12 weeks after the last dose (Ib, A). Only 80% of ultra-rapid vaccinees will have detectable anti-HBs antibodies at this stage.

If someone is at high risk of acquiring infection and is in the 20% without an early antibody response, consider further booster doses (II, B). They usually respond to further doses (up to three injections), ideally as a repeat course (Ib, A) with response rates up to 100% (Ib, A).

Alternatively, for those at lower risk, offer a booster at 12 months by which time 95% would be anti-HBs-positive.

No effective anti-viral therapy Alpha interferon may yield remission Liver transplant has been helpful for

treating fulminant acute and end-stage chronic hepatities (up to 88% 5 yr survival rate)

several novel agents in clinical development, such as emtricitabine, and clevudine have shown promising clinical profiles in patients with chronic hepatitis B.

Although conventional antiviral and immunomodulatory drugs used for managing chronic HBV infection have provided clinical benefit, these agents have limitations on the basis of unpredictable or suboptimal suppression of HBV viral replication, variable rates of resistance, and poor tolerability

Clinical Gastroenterology & HepatologyArticle in press, epub Jan 12, 2007

An ounce of prevention… Any questions?