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1. ↑ INCIDENCE AND COMPLICATIONS 2. BUT, NOT EVERYONE NEEDS TREATMENT  350 million persons worldwide are chronically infected with HBV.7  there are.

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Presentation on theme: "1. ↑ INCIDENCE AND COMPLICATIONS 2. BUT, NOT EVERYONE NEEDS TREATMENT  350 million persons worldwide are chronically infected with HBV.7  there are."— Presentation transcript:

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2 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

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4 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

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8 2009 Am Assoc Liver Study Grp Practice Guidelines

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10 ANTI-VIRALS entecavir (Baraclude) tenofovir Lamivudine (Epivir HBV) Adefovir dipivoxil, telbivudine, IMMUNE MODULATORS Interferon 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 ribavirin Recombinant alfa 2a (Roferon) and rivavirin Vaccines

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12  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

13 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

14  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

15 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. -

16 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.

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18 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 patients 2.HBeAg-negative patients 3.Decompensated cirrhosis / recurrent hepatitis B after liver transplantation 4.Lamivudine-refractory HBV 5.Adefovir-resistant HBV

19 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.

20  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 tenofovir appears 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.

21  Efficacy in Various Categories of Patients. 1. HBeAg-positive patients 2. HBeAg-negative patients 3. 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.

22 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 serovonversion 2. 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

23  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:

24 USES: 1. HBeAg positive chronic hepatitis-1 yr a. Elevated ALT b. Normal ALT c. Children d. 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 children 100 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

25  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 yrs 2. 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

26  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

27  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

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33  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

34 AASLD PRACTICE GUIDELINE

35  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 longer Pkinetic 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

36  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.

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

38  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 response HCV 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

39 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.

40  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)

41  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 & Hepatology Article in press, epub Jan 12, 2007

42  An ounce of prevention…  Any questions?


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