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Jeffery W. Spray, Pharm.D., BCPS Clinical Pharmacy Specialist Winchester Medical Center Objectives Identify risk factors associated with development of viral hepatitis Explain pathophysiologic mechanisms associated with the development of acute and chronic hepatitis Describe patients most likely to benefit from vaccination against HAV and HBV Design an initial treatment regimen for a treatment naïve patient with HCV List the primary adverse effects associated with agents used in the treatment of viral hepatitis Hepatitis A Risk factors for development Long stays in endemic countries/areas Men who have sex with men Injecting drug users Persons working with nonhuman primates Contact with child or employee in child care center Primarily occurs through person to person contact Oral inoculation of fecally excreted virus Ingestion of contaminated food/water Viral Hepatitis relative modes of transmission Fecal-Oral Sexual Transmission HAV +++ HBV +++ HEV +++ HDV ++ Parenteral HGV + Transmission Perinatal HBV +++ Transmission HCV +++ HBV +++ HDV ++ HCV + HGV ++ HDV + HAV + Unknown HBV + HCV + HAV Pathophysiology Self limiting disease, up to 6 months in duration causing inflammatory damage to the liver 3 stages Incubation Acute hepatitis Convalescence HAV Pathophysiology Incubation Duration: 15-50 days, avg. 25-30 days Peak viral excretion 2 weeks before onset of jaundice Viremia and elevated liver enzymes occurs soon after infection Viral antigens can be found in hepatocytes Host usually asymptomatic HAV Pathophysiology Acute Hepatitis Preicteric phase (before jaundice) 5-7 days ○ Nonspecific influenza-like symptoms – anorexia, nausea, fatigue, fever, and malaise Mild disease – mild elevations of bilirubin, gamma globulin, ALT, and AST Icteric phase 4-30 days ○ Significant liver dysfunction, interruption of bilirubin metabolism and flow ○ Sx’s: fever, RUQ abdominal pain, nausea, vomiting, dark urine, light colored stool ○ AST, ALTs 4x ULN Convalescence HAV Pathophysiology Liver injury is immune mediated through cytotoxic T cells Death of hepatocytes results in viral elimination and resolution of clinical illness IgM is formed shortly after infection (usually detectable 5-10 days) IgG antibodies formed 2-6 months, confer lifelong immunity HAV Treatment Supportive Care Liver Transplant for pt that develop fulminant hepatitis Avoid hepatotoxic agents Acetaminophen, alcohol HAV Prevention Immunoglobulin Administered IM provides 3-5 months of protection ○ Used for patients who might have been exposed or travellers to endemic areas Vaccines Children after 12-18 months routinely vaccinated At risk adults should be vaccinated Pt with chronic liver disease due to higher risk of complications Handwashing Acute HBV Acute HBV Often asymptomatic (70% of adults, 90% of children) Incubation period 1-4 months Sx/Symptoms (last 1-3 months) ○ Nausea, anorexia, fatigue, low-grade fever, right upper quadrant pain ○ Jaundice can occur, but usually when symptoms resolving ○ Myalgias, joint pain, urticaria Acute HBV Treatment - supportive AST and ALT may rise up to 20,000 IU/L ○ Typically peak 2 weeks prior to jaundice Elevated Bilirubin Mild anemia Most of the liver damage is related to immune response, not direct viral damage Fulminant hepatic failure only occurs in 1% of patients Chronic HBV Defined as presence of HBsAg for 6 months 4 phases Immune tolerant ○ High HBV DNA, HBeAg, and transaminases ○ Incubation period, can last for years Immune response ○ Inflammatory cascade ○ Causes destruction of HBV infected hepatocytes ○ High risk of progression to cirrrhosis and cancer Chronic HBV 4 stages cont. Inactive carrier state ○ End of viral replication ○ HBeAg becomes negative and transaminase levels normalize ○ Most adults reach this phase rapidly ○ Can have flares of disease Immune stage ○ Clearance of HBsAg, HBV DNA undetectable ○ Only occurs in 3% of patients Lifetime risk of developing cirrhosis or cancer 15%-25% Relative Risk of developing HCC from HBV HBV Prevention Vaccination All children and adolescents, as well as high risk adults ○ Hx STD ○ Household contact with HBV carrier ○ Healthcare workers ○ IV drug users ○ Men who have sex with men ○ Sexual partners of HV infected persons ○ High risk sexual practices 3 injection series ○ Protection achieved in 90% of adults ○ Booster only for immunocompromiseds HBV Prevention Vaccination All children and adolescents, as well as high risk adults ○ Hx STD ○ Household contact with HBV carrier ○ Healthcare workers ○ IV drug users ○ Men who have sex with men ○ Sexual partners of HV infected persons ○ High risk sexual practices 3 injection series ○ Protection achieved in 90% of adults ○ Booster only for immunocompromiseds Immune Globulin BayhepB HyperHEP B Nabi-HB Nabi-HB NovaPlus HepaGam B Goals of Tx for chronic HBV infection Eradication or suppress HBV Short term Limit hepatic inflammation Decrease risk of fibrosis and/or decompensation Long term goals Prevent transaminase flares and long term compensation Prolong survival Loss of HBeAg HBV Treatment Indications for treatment HBeAg and transaminase levels > twice normal Presence of HBV DNA and transaminase levels > twice normal Moderate to severe hepatitis on liver biopsy Presensce of HBV and cirrhosis Goals of Tx Erradicate or permanently suppress HBV HBV Indications for Treatment HBeAG +, ALT > 2x ULN or hepatitis on biopsy – Lamivudine or interferon HBeAG -, ALT > 2x ULN – tx only if hepatitis seen on biopsy or HBV DNA >105 copies/ml Failure to respond to interferon, can tx with lamivudine Decompensated liver disease – only use lamivudine Diagnostic Tests for HBV Test CHB HBeAg CHB HBeAg Inactive Carrier Positive Negative HBsAg + + + Anti-HBs - - - HBeAg + - - anti-HBe - + + anti-HBc + + + IgM anti-HBc - - - HBV DNA >2x104 >2x103 < 2x103 IU/ml(>105 IU/ml(>104 IU/ml(<104 copies/ml) copies/ml) copies/ml) ALT level Elevated Elevated Norma HBeAg HBV DNA ALT Treatment strategy (IU/ML) + > 20,000 <2 x Observe; consider treatment when ALT becomes elevated; ULN Consider biopsy in persons 40 years, ALT persistently high normal-2x ULN, or with family history of HCC.; Consider treatment if HBV DNA 20,000 IU/ml and biopsy shows moderate/severe inflammation or significant fibrosis + > 20,000 >2 x IFN/pegIFN , LAM, ADV, ETV or LdT may be used as initial ULN therapy; End-point of treatment – Seroconversion from HBeAg to anti-HBe Duration of therapy: IFN-: 16 weeks; PegIFN-: 48 weeks; LAM/ADV/ETV/LdT: minimum 1 year, continue for at least 6 months after HBeAg seroconversion; IFN non-responders / contraindications to IFN 3 ADV/ETV; IFN-/peg IFN-, - > 20,000 >2 x LAM, ADV, ETV or LdT may be used as initial therapy; End-point ULN of treatment – not defined; Duration of therapy: IFN-/pegIFN-: 1 year; LAM/ADV/ETV/LdT: 1 year - > 20,000 1-2 x treat if liver biopsy shows moderate/severe inflammation or ULN significant fibrosis - < 20,000 WNL Observe, treat if HBV DNA or ALT becomes higher +/- Detect- Cirrh Comp.: HBV DNA 2,000 IU/ml—Treat, LAM/ADV/ETV/LdT may able osis be used as initial therapy Decomp.: LAM (or LdT) ADV or ETV preferred. Refer for liver transplant Interferon-alpha MOA Interferon induced production intracellular enzymes such as 2'5'-OAS and protein kinase that inhibit of viral replication by activation of endoribonucleases that cleave viral RNA ○ translation of viral proteins is inhibited. Contraindications ○ Neutropenia, Thrombocytopenia, Depression, Decompensate cirrhosis, Alcohol or drug abuse Predictors of response ○ Low HBV DNA levels, Elevated transaminases, Lack of fibrosis, Female, HIV Negative, genotype A or B Dosing IFN alpha Dosing Adults is 5MUdaily or 10 MU thrice weekly Children 6 MU/m2 thrice weekly (max. of 10 MU) Duration HBeAg positive chronic hepatitis B is 16 to 24 weeks HBeAg-negative chronic hepatitis B should be treated for at least 12 months, and one study suggested that 24 months treatment may increase the rate of sustained response IFN Monitoring Blood counts and liver panel monitored every 4 weeks, thyroid stimulating hormone (TSH) and HBV DNA levels every 12 weeks, and, if initially HBeAg-positive, HBeAg/anti- HBe every 24 weeks during treatment. Blood counts, liverpanel, TSH and HBV DNA, and if initially HBeAg positive, HBeAg/anti-HBe should be tested every 12 weeks during the first 24 weeks post- treatment. PEG – IFN alpha PEG molecule allows for longer t50 for the medication and less frequent dosing Dosing 180mcg weekly for 48 weeks Similar AE as regular IFN Growing evidence of improved efficacy over standard IFN Lamivudine MOA synthetic nucleoside analogue, is phosphorylated intracellularly to its active 5'-triphosphate metabolite, this is incorporated into viral DNA HBV polymerase, resulting in DNA chain termination AE Common ○ Endocrine metabolic: Lipodystrophy (less common) ○ Gastrointestinal: Decrease in appetite, Nausea and vomiting, Vomiting ○ Neurologic: Headache ○ Other: Fatigue Serious ○ Endocrine metabolic: Lactic acidosis, Some fatal cases ○ Gastrointestinal: Pancreatitis, Especially children; some fatal cases ○ Hepatic: Hepatomegaly, Some fatal cases, Relapsing type B viral hepatitis Lamivudine Dosing 100mg po qday Predictors of response Elevated transaminase (ALT>100) Low viral loads Response Quicker than Interferon But not always sustained Resistance Can occur after 6mo of work See increase in HBV DNA and ALT Lower durability of response Adefovir MOA phosphorylated to the active metabolite by cellular kinases which inhibits HBV DNA polymerase by competing with the natural substrate and by causing DNA chain termination after its incorporation into viral DNA. AE Common ○ Dermatologic: Pruritus, Rash ○ Gastrointestinal: Abdominal pain, Diarrhea, Flatulence, ○ Neurologic: Asthenia, Headache Serious ○ Renal: Renal failure, Renal impairment Dosing 10mg po qday Adefovir Predictors of Response reduction in serum HBV DNA HBeAg-positive patients with high pretreatment ALT were more likely to undergo HBeAg seroconversion Resistance Resistance occurs at a slower rate during adefovir treatment compared to lamivudine and no adefovir-resistant mutations were found after 1 year of treatment in the patients who participated in the Phase III trials genotypic resistance exceeding 20% after 2 years of treatment Entecavir MOA phosphorylated to the active form which inhibits hepatitis B viral polymerase activities including base priming, reverse transcription of negative strand pregenomic mRNA, and synthesis of positive strand of hepatitis B DNA. AE Common ○ Gastrointestinal: Nausea ○ Neurologic: Dizziness, Headache ○ Other: Fatigue Serious ○ Hepatic: Recurrent hepatitis Dosing Tx naïve: 0.5mg daily Others: 1mg daily Entecavir Predictors of Response HBV DNA levels and in inducing histologic improvement in Asians and Caucasians, and across HBV genotypes A-D and a wide range of pretreatment HBV DNA and ALT levels; HBeAg seroconversion rates were lower in patients with normal ALT, Resistance 7% of patients after 48 weeks and in 16% after 96 weeks of treatment in the phase III trial of lamivudine refractory patients. Telbivudine MOA synthetic thymidine nucleoside analog with activity against hepatitis B virus by competitive inhibition of viral DNA polymerase (reverse transcriptase). Once incorporated into viral DNA by hepatitis B polymerase, DNA chain termination results AE Common ○ Gastrointestinal: Abdominal pain (12% ) ○ Musculoskeletal: Finding of creatine kinase level, grade 3/4 (9% ) ○ Neurologic: Headache (11% ) ○ Respiratory: Nasopharyngitis (11% ), Upper respiratory infection (14% ) ○ Other: Malaise and fatigue (12% to 18% ) Dosing 600mg daily Predictors of Response week 24 virologic response was the most important predictor of virologic and biochemical responses as well as resistance at week 96 Resistance resistance rate is substantial and increases exponentially after the first year of treatment Tenofovir MOA: structurally similar to adevofir More robust response than adefovir in small studies, also active against HIV Postive results for patients HBeAG + and – Not as much increase in SCr as seen in HIV studies, but did have increased LFTs compared with adefovir Management of Resistance Lamivudine Resistant Add adefovir or tenofovir Switch to emtricitabine/tenofovir Adefovir resistance Continue adefovir and add lamivudine or tebivudine Switch to or add entecavir (if no prior lamivudine resistance) Entecavir Resistance Switch to or add adefovir or tenofovir Swtich to emtrictitabine/tenfovir Telbivudine resistance Continue and add adefovir or tenofovir Swtich to emtrictitabine/tenfovir Oral HBV Treatment Algorithm Special Populations Cirrhosis HBV DNA levels less than 2000 ○ Treat with entecavir or tenofovir ○ Monitor HBV DNA levels above 2000 ○ Entecavir or tenofovir Decompensated ○ Consider treatment Special Populations Cont HIV Coinfection Can have altered biochemical markers of infection ○ i.e. HBV DNA detectable, but HBsAg negative Higher rate of lamivudine resistance HAART must be started in addition to treatment for HBV ○ Tenofovir and lamivudine or emtricitabine ○ Avoid monotherapy for HBV If HAART is not able to be started can treat with IFN Special Populations Cont Immunosuppression/Chemotherapy Pt often under reactivation during chemo, can be life threatening Close monitoring of HBV + during chemo therapy reccomended Can prophylax with lamivudine prior to chemo and for 6 months or longer depending on HBV DNA levels HCV Epidemiology Risk Factors Clotting factor use prior to 1987 Long term hemodialysis Injection drug use Frequent percutaneous exposures Health care workers Blood transfusions or organ transplant prior to 1992 Birth from infected mother Multiple sex partners HCV Pathophysiology Acute HCV Often asymptomatic, 25% of patients develop malaise, anorexia, and jaundice Incubation last 50 days Viremia occurs 3 weeks after exposure ALT elevated within 4-12 weeks 70% of patients will develop chronic disease Detection ○ Antibody linked HCV tests can be negative initially, but usually postive after 3 months HCV Pathophysiology Chronic HCV Usually asymptomatic until develop fibrosis, cirrhosis, ESLD, and HCC ○ 10-30% develop cirrhosis ○ 1-5% develop cancer If symptomatic: fatigue, malaise, anorexia, weight loss DX: anti-HCV via EIA, positive viral RNA Extra-heaptic symptoms ○ Cryoglobulinemia, cutaneous vasculitis, renal disease, neuropathy, lymphoma, Sjogren’s syndrome HCV Treatment Goal Candidates for Eradicated virus Therapy Prevent progression >18yo of cirrhosis + liver biopsy Reduced Abnormal ALT hepatocellular + HCV viral load carcinoma Reduce need to Response transplant Type 1 – 40% Enhance survival Types 2&3 – 80% HCV Treatment Contraindications Major, uncontrolled depressive illness Decompensate cirrhosis Acute substance abuse Autoimmune disease Untreated hyperthyroidism Pregnancy Advanced cardiac or pulmonary disease Known hypersensitivity to drugs HCV Treatment Predictors of Response Genotype 2 or 3 Low baseline viral loads (< 2 million copies/ml) Younger age (<40 yo) Lower body weights (< 75 kg) Early virologic response (EVR) Mild disease on liver biopsy Therapy adherence (>80%) HCV Treatment Standard Interferon Pegylated interferon alfa 2b (Peg Intron) Pegylated interferon alfa 2a (Pegasys) Ribavirin (Rebetol, Copegus) HCV Treatment Optimal treatment Peginterferon alfa and ribavirin Ribavarin Genotype 1 ○ <75kg = 1000mg, >75mg = 1200mg Genotype 2 ○ 400mg twice daily Interferon Peginterferon-a2a – 180mcg SQ qweek Peginterferon-a2b – 1.5mcg/kg SQ qweek Hepatitis C Candidates for Goal Therapy Eradicated virus >18yo Prevent progression + liver biopsy of cirrhosis Abnormal ALT Reduced + HCV viral load hepatocellular carcinoma Reduce need to transplant Enhance survival Acute HCV Treatment Supportive Healthy diet Maintaining fluid balance Avoid hepatotoxic drugs and alcohol Treatment outcome definitions Response Reduction in HCV RNA to undectable levels and normalization of ALT during treatment and 6mo post completion Non-response HCV RNA remains detectable or ALT fails to normalize during course of tx Relapse HCV RNA becomes undetectable and ALT normalized during treatment, but either ALT or HCV RNA re-emerge in the 6 months after therapy Who to Treat Candidates for Therapy >18yo + liver biopsy ○ Moderate to severe hepatitis with septal or bridging fibrosis Abnormal ALT + HCV viral load Compensated Liver Disease ○ Bili < 1.5g/dL ○ INR < 1.5 ○ Alb >3.4g/dL ○ Plt > 75,000k/mm3 ○ No evidence of encephalopathy Acceptable hematological and biochemical indices ○ Hgb > 13g/dL (12g/dL for females) ○ Neutrophil count > 1.5k/mm3 ○ SCr < 1.5 mg/dL Contraindications Major, uncontrolled depressive illness Decompensate cirrhosis Acute substance abuse Autoimmune disease Untreated hyperthyroidism Pregnancy Advanced cardiac or pulmonary disease Known hypersensitivity to drugs Retinopathy Seizure disorder Immunosuppressive treatment Predictors of Response Genotype 2 or 3 Low baseline viral loads (< 2 million copies/ml) Younger age (<40 yo) Lower body weights (< 75 kg) Early virologic response (EVR) Mild disease on liver biopsy Lack to steatosis Lack of fibrosis Therapy adherence (>80%) Non-African American ethnicity Compliant Which patient would you select for treatment? HCV Patient A 33yof hx of illicit drug use, mother of 5 month old, currently living with parents, limited income, uninsured, facing possible incarceration, highly motivated to begin treatment, lives 10 miles from clinic Labs HCV type 1 Low viral load Moderately elevated AST/ALT Biopsy pending HCV Patient B 45 yof with history of illicit drug use, lives with mother, motivated to begin treatment, lacks insight into disease, PMH significant for severe depression with pyschotic symptoms, currently moderately controlled, has health insurance, lives 20 miles from clinic Labs HCV type 2 Low viral load LFTs normal Biopsy shows active inflammatory process and minimal fibrosis HCV Patient C 55yom, unemployed, lives with wife and mother, hx of depression well controlled and seeing psychiatrist, hx of IV illicit drug use making venipuncture very difficult, lives 45miles from clinic Labs HCV type 2 Low Viral load Mildly elevated AST/ALT Biopsy not done HCV Treatment Standard Interferon Pegylated interferon alfa 2b (Peg Intron) Pegylated interferon alfa 2a (Pegasys) Ribavirin (Rebetol, Copegus) Optimal Treatment Optimal treatment Peginterferon alfa and ribavirin 48 weeks for Genotype 1 24 weeks for Genotypes 2 and 3 Ribavirin Genotype 1 ○ <75kg = 1000mg, >75mg = 1200mg Genotype 2 ○ 400mg twice daily Interferon Peginterferon-a2a – 180mcg SQ qweek Peginterferon-a2b – 1.5mcg/kg SQ qweek Ribavirin (Rebetol, Copegus) MOA: inhibition of the capping of mRNA reduction of intracellular guanosine triphosphate (GTP) pools and inhibition of viral RNA and protein synthesis AE: Common ○ Dermatologic: Pruritus, Rash ○ Gastrointestinal: Indigestion, Loss of appetite, Nausea ○ Neurologic: Headache, Headache, Inhalation; health- care workers administering ribavirin ○ Ophthalmic: Conjunctivitis ○ Other: Fatigue AE Cont ○ Serious Cardiovascular: Bradyarrhythmia, Inhalation, Cardiac arrest, Hypotension Gastrointestinal: Pancreatitis, Fatal and nonfatal Hematologic: Hemolytic anemia, Cardiac and pulmonary events have occurred, Thrombotic thrombocytopenic purpura (less than 1%) Hepatic: Hepatotoxicity, Hyperammonemia, Hyperbilirubinemia, Increased erythrocyte destruction, Liver failure, oral, in combination with peginterferon alfa-2a (2%) Immunologic: Bacterial infectious disease, oral, in combination with peginterferon alfa-2a (<1%) Psychiatric: Suicide, oral, in combination with peginterferon alfa-2a (<1%) Respiratory: Complication of respiratory therapy procedure, Drug precipitation, Respiratory arrest preceding cardiac arrest, Inhalation HCV Treatment Interferon IFN-a2a, IFN-a2b, IFN aflacon-1 ○ Non-pegylated forms are no longer reccomended Peginterferon-a2a (Pegasys) and peginterfern-a2b (PEG-Intron) ○ Addition of PEG to structure increased t1/2 MOA – activation of tyrosine kinases and up regulation gene products that produce of immunomodulating, antiviral, and antiproliferative effects HCV Treatment Interferon AE Early Neuropsychiatric Fever, Chills, Irratability, mood myalgias, fatigue, lability, depression, malaise, nausea, tearfulness, delerium, sleep disturbances, parathesisas, abdominal pain, seizures, psychosis diarrhea, Headache, Autoimmune appetite changes Hepatitis, thyroid Hematologic dysfunction, Neutropenia, TCP, thyroiditis, anemia arthropathy, DM, psoriasis HCV Treatment Interferon AE Chronic Fatigue Low grade fevers Infections Decreased libido Increased sleep Alopecia Anorexia Hypertriglyceridemia Weight Loss Irritability Myalgias Anxiety Attention span deficits Depression Monitoring Therapy Baseline Evaluation Liver Evaluation – Liver Biopsy, HCV Genotype, HCV RNA Hematologic Test: WBC, ANC, Plt, Hgb, HCT Liver Function Tests: ALT, AST, Bilirubin Biochemical Tests: Cr, Glucose, BUN, etc Thyroid Tests: TSH, T4 Clinical Evaluation: Mood evaluation, weight evaluation, adverse events, adherence, eye exam, cardiac examination, medical history, Child-Pugh Score Pregnancy screening Monitoring Cont Week 1-2: Hematologic Tests, LFTs, Clinical evaluation Week 4: Hematologic Tests, LFTs, Biochemical tests, Clinical Evaluation, Pregnancy Test Week 6: Hematologic Tests, LFTs, Clinical evaluation Week 8: Hematologic Tests, LFTs, Biochemical tests, Clinical Evaluation, Pregnancy Test Week 12: HCV RNA, Hematologic Tests, LFTs, Biochemical test, Thyroid Tests, Clinical Eval, Pregnancy test Weeks 24, 48, 72: HCV RNA Early Virologic Response Definition At week 12 at least a 2-log decline from baseline HCV RNA level 65% of patients with EVR achieve SVR 97% of patient that do not achieve EVR fail to achieve SVR Efficacy of Treatment Peg-IFN alfa and ribavirin Sustained Virologic Response (SVR) seen in 54-56% of patients overall Genotype 1 ○ 42-52% SVR Genotype 2 or 3 ○ 76-84% Not known is weight based superior to fixed dose regimens Some advocate for pt with high levels of HCV RNA and genotype 3 to be treated for 48 weeks Efficacy of Treatment Need to make case by case determination of duration of treatment Consider predictors of response Genotype 4 PEG-IFN alpha and full dose ribivarin (1000- 1200mg) for 48 weeks ○ No significant trials evaluating this regimen Short Course Therapy PEG-IFN Alfa 2b and Ribavirin for 12 vs. 24 weeks in HCV Genotypes 2 or 3 NEJM 21005; 352:2609-17 Prospective trial that randomized pt with EVR at week 4 to only receive 12 weeks of treatment Results: shorter course was equally effective in achieving SVR PEG-IFN Alfa-2a and Ribavarin for 16 or 24 weeks in HCV Genotype 2 or 3 NEJM 2007; 357: 124-34 Prospective trial comparing 16 vs 24 weeks of treatment Results: 16 week treatment was inferior to 24 weeks in terms of SVR Side effect management Flu Like Symptoms Non-steroidal anti-inflammatories (ibuprofen, naproxen) Insomnia Sleep promoting agents (diphenhydramine, zolpidem) Depression Antidepressants Neutropenia Dose reduction Colony stimulating factors not recommended Anemia Dose reduction EPO Agents on the Horizon Protease Inhibitors Polymerase-nucleoside/nonnucleoside inhibitors Telaprevir (Vertex) Boceprevir PF00868554 (Pfizer) (Schering Plough/Merck) Idenix 184/-IDX136/316 TMC435350 (Tibotec) ANA598 (Anadys) ITMN-191/R7227 (Roche) BI 207127 NNPI (BI) MK7009 (Merck) MK-3281 NNPI (Merck) B1201355 (BI) ABT-072/333 NNPI (Abbott) SCH 900518 (Schering) GS-9190 NNPI (Gilead) BMS790052 (BMS NS5A) Other Novel Agents •IV Silibin – silimarin (milk thistle) •Debio025, NIM811, SCY635 (cyclophilin inhibitors) •Nitazoxanide (unknown mode of action) •Taribavirin (ribavirin analogue) Protease Inhibitors MOA – interrupt catalytic site or blocking protein interactions Agents: Telaprevir 750mg po q8h ○ In people with hepatitis C who were new to treatment (treatment-naive): Up to 75% achieved a viral cure with telaprevir-based combination therapy, compared to 44% of people who received pegyalted interferon and ribavirin alone A majority (58% in ADVANCE and 65% in ILLUMINATE) were eligible to reduce their treatment time by half -- from 48 weeks to 24 weeks Data showed there was no benefit to extending total treatment from 24 weeks to 48 weeks in people whose virus was undetectable at weeks 4 and 12 with telaprevir-based therapy Bocepravir – 800mg po Q8H Respond 2 Trial ○ Standard therapy without boceprevir: SVR 21% ○ Response-guided therapy with boceprevir 59% (37% improvement) ○ Fixed-duration therapy with boceprevir: 67% (45% improvement) Sprint 2 trial ○ Standard therapy without boceprevir: 38% (40% for non- blacks and 23% for blacks) ○ Response-guided therapy with boceprevir: 63% (67% and 42%, respectively) ○ Fixed duration therapy with boceprevir: 66% (69% and 53%, respectively). Polymerase Inhibitors MOA – similar to antiretrovirals Nucleoside inhibitors target catalytic sites and act as chain terminators Nonnucleosides are allosteric inhibitors Agents R7128 – 85% of pt achieved SVR compared to placebo R7128 and R7227 (INFORM-1 Trial) – combo of agents for 14 days, followed by 48 weeks of SOC Ribavarin Analogues Taribavirin under investigations Still trying to figure out an optimal dose to achieve efficacy Early studies did not show benefits Ongoing trials showing initial benefits with less anemia Other direct acting agents/ Novel Compounds Debio 025 – synthetic, cyclosporine analogue Has shown significant ability to lower RNA levels Still evaluating need for loading doses Nitazoxanide Patients receiving nitazoxanide had higher response rates than those taking placebo by 12 weeks, but not at 4 weeks: RVR: 12% in nitazoxanide arm vs 19% in placebo arm; SVR: 44% vs 32%, respectively. SVR rates were consistently higher for nitazoxanide recipients in difficult-to-treat patient sub- groups: High baseline viral load (> 800,000 IU/mL): 41% vs 29% respectively; African-Americans: 38% vs 20%, respectively Proposed New Treatment Algorithm Class I: treatment naïve, IT, G2/3, G1 low viral load, and/or CC allele Class II: treatment naïve, IT, G1 high viral load, or CC/TT allele Class III: G1/4 and G 2/3 relaspers and nonresponders to current SOC who became undectable by week 12 Class IV: Class IIIs who do not become undectable by week 12, IFN interolerance and treatment failure Proposed treatment Regimens Class 1: SOC x 24 weeks Class 2: PI + SOC x 24 weeks Class 3: PI + SOC x 48 weeks Class 4: PI + other agents – lifetime suppression Other Hepatitis Viruses HDV – aka Delta hepatitis Causes acute or chronic infection Usually associated with HBV coninfection Similar transmission modes at HBV Treatment ○ Possibly role for low dose interferon HEV Acute infection only Rare in US Associated with oral fecal contamination HGV Similar to HCV in structure Transmitted via blood exposure Seen in 6% of HBV cases and 10% of HCV infections Unknown pathology in humans Questions?
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