Hepatitis C

1. Hepatitis C

2. What factors increase the risk for HCV infection? • Injection drug use • Exposure to blood products before 1992 • Hemodialysis in areas w/ poor infection control practices • Narcotic diversion by HCV-infected health care workers • Sexual transmission • Mother-to-child transmission • Tattooing or piercing

3. How can person-to-person transmission be prevented? • For people who inject drugs: opioid agonist therapy and needle and syringe exchange • Tattoos and piercings: strict infection control protocols • Condom use: by those with multiple partners and for HIV-positive MSM • Avoid sharing toothbrushes, razors • People treated and cured of HCV infection: should be aware they can become infected again

4. How can risk be reduced in the health care setting? • Blood banks should avoid paid donors and screen donated products • Health care workers and volunteers should follow infection control practices • Needlestick injury: post-exposure prophylaxis not recommended for healthcare workers • Low infection risk after single exposure • High efficacy of antivirals if infected

5. Should clinicians screen patients for HCV infection? • Screening in certain populations is recommended   • Infection relatively common in certain populations • Acute and chronic phases are mostly asymptomatic • Long latent period before liver disease manifests • Initial HCV serology test is relatively inexpensive • Benefits • Patients can obtain curative treatments • Opportunity for counseling to reduce or eliminate alcohol use and to prevent or detect other infections

6. What populations should be screened? • Persons with history of risk exposures • Persons with ongoing risks (PWID, HIV-positive MSM) • Adults born from 1945-1965 (test once) • Persons donating blood or organs • Persons living in settings with high prevalence rates (jails, prisons)

7. What is the natural history of HCV infection? • Incubation period is typically several weeks • HCV RNA appears in blood weeks prior to rises in alanine aminotransferase or anti-HCV antibodies • Flu-like symptoms, myalgias, dark urine may occur • Jaundice rare, and fulminant disease extremely rare • Spontaneous clearance w/in first 6-12 months in 15-45% • More common in women, younger individuals, and those with certain genetic polymorphisms • Not infectious, no increased risk of liver disease from HCV

8. Chronic infection • Often asymptomatic but may result in extrahepatic manifestations (see next slide) • ALT levels often elevated but normal in ≤20% of individuals • Liver fibrosis can develop, leading to cirrhosis • Liver fibrosis accelerated by other liver insults • Patients may suffer significant morbidity and mortality if cirrhosis develops • Risk for hepatocellular carcinoma due to HCV-related cirrhosis up to 3% per year without successful treatment

9. Extrahepatic manifestations of HCV infection • Fatigue • Sicca syndrome • Lichen planus • Porphyria cutanea tarda • Diabetes mellitus • Hypothyroidism / hyperthyroidism • Cryoglobulinemic vasculitis • Membranoproliferative glomerulonephritis • Membranous nephropathy • Monoclonal gammopathy • Non-Hodgkin’s lymphoma • Arthralgias/arthritis • Raynaud’s phenomenon

10. What diagnostics are available? • Anti-HCV test using enzyme-linked immunoassay • HCV RNA measurement to confirm current infection • Genotype testing guides treatment choice and duration • 6 major viral genotypes, all very similar clinical course • Genotype 1 (subtype 1a) most common in United States • Tests now available for viral mutations associated with resistance and employed under selected circumstances • Additional lab testing: CBC, prothrombin time, albumin, measures of renal function • HIV and HBV screening

11. Why is it important to determine the degree of liver fibrosis? • If present: interventions may prevent disease progression and complications • Advanced fibrosis or cirrhosis: prioritize for antiviral treatment • If decompensation occurs: refer patient for consideration of liver transplantation

12. What are symptoms and signs to look for on physical examination? • Fatigue • Abdominal pain • Anorexia • Signs of extrahepatic manifestations • Signs of chronic liver disease • Scleral icterus, spider nevi, palmar erythema, peripheral edema, gynecomastia, dilated abdominal veins, splenomegaly, ascites • Patients with liver fibrosis can have normal physical exam

13. How is the degree of liver fibrosis determined? • Biopsy • Most accurate measure, historical gold standard • Requires adequate sample and proper interpretation • Invasive, carries small risk of severe pain and bleeding • Noninvasive approaches • Routine imaging (abdominal ultrasonography) • AST to Platelet Ratio Index and Fibrosis-4 calculations • Serum tests (FibroSure, FibroScan) • Lower cost, higher patient acceptance, may be repeated more often than biopsy

14. CLINICAL BOTTOM LINE: Diagnosis and Evaluation... • Acute and chronic HCV infection usually asymptomatic • Suspect HCV if certain extrahepatic manifestations or ALT elevations are present • Diagnosis of current infection relies on a 2-step process • Detecting presence of HCV antibody • Confirming the presence of virus with HCV RNA • Assess the degree of liver fibrosis for prognostic information and to guide the urgency of antiviral treatment

15. How can the patient delay progression of liver disease and avoid liver-related complications? • Avoid alcohol, avoid NSAIDs • Limit acetaminophen intake to 2 grams daily • Drink coffee • Recommended vaccinations: HAV, HBV, pneumococcus, influenza • With HIV: suppressive antiretroviral therapy reduces fibrosis progression • With cirrhosis: screen for esophageal varices via upper endoscopy and for HCC via liver imaging

16. What are the goals of antiviral treatment, and which patients are candidates? • Goal: viral cure or SVR • All patients with active HCV infection benefit from antiviral treatment • Unless life expectancy ≤12mo due to nonrelated conditions • Interferon-based treatments dangerous for those with liver decompensation, but interferon-free regimens may be effective and safe • Additional considerations for PWID with active or recent drug use, but they should not be excluded from treatment

17. What are novel agents, and how are they used? • Genotype 1 • Daclatasvir and sofosbuvir • Elbasvir/grazoprevir FDC • Ledipasvir/sofosbuvir FDC • Paritaprevir/ritonavir/ombitasvir FDC daily plus dasabuvir twice daily • Simeprevir and sofosbuvir • Sofosbuvir/velpatasvirFDC • Note: ribavirin may be added in select circumstances

18. Genotype 2 • Sofosbuvir and ribavirin • Daclatasvir and sofosbuvir • Sofosbuvir/velpatasvir FDC • Note: ribavirin may be added in select circumstances • Genotype 3 • Daclatasvir and sofosbuvir • Sofosbuvir, weight-based ribavirin, pegylated interferon • Sofosbuvir/velpatasvir FDC • Note: ribavirin may be added in select circumstances

19. Genotype 4 • Elbasvir/grazoprevir • Ledipasvir/sofosbuvirFDC • Paritaprevir/ritonavir/ombitasvirFDC • Sofosbuvir/velpatasvirFDC • Note: ribavirin may be added in select circumstances except with sofosbuvir/velpatasvir FDC

20. Novel direct acting antivirals for treatment of chronic HCV • Protease inhibitors • Grazoprevir, paritaprevir, simeprevir • Note: telaprevir and boceprevir neither recommended nor available in the United States. • NS5A inhibitors • Daclatasvir, elbasvir, ledipasvir, ombitasvir, velpatasvir • NS5B polymerase inhibitors • Nonnucleoside: dasabuvir • Nucleotide: sofosbuvir

21. How efficacious are HCV treatments? • Ribavirin added to other DAAs • Increases efficacy or shortens treatment in specific patient subgroups • Pangenotypic regimens have high efficacy against all major HCV genotypes • Sofosbuvirplus ribavirin (but 1st-line therapy against genotype 2 infection only) • Daclatasvirplus sofosbuvir • Sofosbuvir/velpatasvir FDC

22. Genotype 1 • Responds poorly to pegIFN plus RBV • But newer potent combination regimens are effective • Regimen may be influenced by subtype, prior treatment, cirrhosis, resistance-associated variants • Genotype 2 • Sofosbuvir/velpatasvir FDC • Daclatasvir plus sofosbuvir • Sofosbuvir plus ribavirin • Genotype 3 • pegIFN with ribavirin and sofosbuvir • Daclatasvir plus sofosbuvir (cirrhosis: add ribavirin) • Sofosbuvir/velpatasvir (low pill burden, shorter duration)  

23. Other genotypes • Several regimens available for genotype 4 infection • Little data to guide decision making for genotypes 5 or 6 • Patients with cirrhosis • Cirrhosis can influence the duration of ribavirin therapy or determine whether it should be added • Patients with decreased renal function • Sofosbuvir dosing not established for when creatinine clearance <30 ml/min • Elbasvir plus grazoprevir FDC appears safe • Genotype 1b: daily FDC paritaprevir/ritonavir/ombitasvir plus dasabuvir safe because not cleared by the kidney and ribavirin can be avoided (in contrast to genotype 1a) • Ribavirin-containing regimens require careful dosing

24. How safe are HCV treatments? • PegIFN (variety of side effects and contraindications, however rarely used) • Ribavirin • When used with DAAs, several additive toxicities may occur (fatigue, nausea, hemolytic anemia, rash, irritability) • Measure renal function and CBC monthly • Provide counseling regarding pregnancy prevention • Antiviral regimens that don’t contain pegIFN or ribavirin may also have side effects • Decompensated liver disease: certain combinations risky • Compensated cirrhosis: FDC paritaprevir/ritonavir/ ombitasvir poses risk for liver decompensation

25. What are the issues surrounding antiviral treatment in patients co-infected with HIV? • HIV and HCV co-infection: accelerated liver fibrosis risk • Offer antiviral treatment for most cases • Beware drug-drug interactions, particularly with ARVs • Ledipasvir plus sofosbuvir with boosted anti-HIV protease inhibitors increases tenofovir levels • Anti-HCV DAAs do not appear to interfere with HIV suppression • Avoid DAA combinations containing ritonavir unless the patient is on ARV therapy that fully suppresses HIV (in order to avoid generating ritonavir resistance)

26. What are other important drug-drug interactions? • NS5A inhibitor daclatasvir: adjust dosing with certain concomitant medications • Ritonavir: pharmacologic booster for many medications due to potent inhibition of cytochromes CYP3A4, 2D6  • Sofosbuvir or sofosbuvir-containing regimens: avoid with rifampin, St. John’s Wort, or tipranavir • Ledipasvir and velpatasvir: absorption decreased with alkaline gastric pH • Maintain careful medication lists throughout treatment • Counsel patients to contact their provider regarding use of additional medications

27. How should clinicians choose a treatment regimen? • Patient and disease characteristics • Viral genotype • Cirrhosis • Previous treatment • Potential drug interactions • Pill burden • Reimbursement policies for patient’s insurance plan

28. What is the role of monitoring while on therapy? • Monitor adherence to antiviral therapy • Assess for side effects and adverse events • Ascertain addition of concomitant medications • Contact intervals depend on clinical circumstances • Test HCV RNA 4 weeks after initiation to check adherence • Patients on pegIFN or ribavirin-based regimens require more intense lab monitoring, particularly for cytopenias • For ribavirin-associated hemolytic anemia: reduce dose when patient symptomatic or hemoglobin levels <10g/dL

29. What are the important postsurgical considerations? • Patients with risk factors may be reinfected • Provide preventive counseling and interventions and test at least yearly  • If fatigue persists after successful antiviral treatment, pursue work-up for alternate causes • If ALT elevation persists after SVR, further evaluation may be warranted • If ALT newly elevated after normalization, test HCV RNA to diagnose relapse • SVR decreases morbidity from advanced fibrosis or cirrhosis, but ongoing periodic screening recommended

30. Can patients who were unsuccessfully treated with DAAs be re-treated? • Virus that emerges after relapse may contain resistance-associated variants to other agents in same drug class • Exception: sofosbuvir failures may be successfully retreated with regimens including same agent • For other exposures to DAAs: retreatment strategies often include ≥1 alternate class of agent or agent in same class predicted active against viruses with selected mutations

31. When is specialty consultation indicated? • Evaluation for liver transplantation • When decompensation occurs in patients with cirrhosis • When Model for End-Stage Liver Disease score rises • Diagnose or manage extrahepatic manifestations • Treat ongoing or recent substance use disorders • Guide antiviral treatment for active HCV

32. CLINICAL BOTTOM LINE: Treatment... • Cure of HCV infection interrupts further transmission and prevents future HCV-associated complications • Selection of regimen and therapy duration depends on • Viral genotype • Treatment experience • Presence of cirrhosis • Regimens achieve viral cure in most patients • Due to improved safety and efficacy, most persons with HCV should be treated • Specific guidance: http://hcvguidelines.org