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In the Clinic Hepatitis C © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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) © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 1545% More common in women, younger individuals, and those with certain genetic polymorphisms Not infectious, no increased risk of liver disease from HCV © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. Extrahepatic manifestations of HCV infection Cryoglobulinemic vasculitis Fatigue Membranoproliferative glomerulonephritis Sicca syndrome Membranous nephropathy Monoclonal gammopathy Non-Hodgkin’s lymphoma Arthralgias/arthritis Lichen planus Porphyria cutanea tarda Diabetes mellitus Hypothyroidism / hyperthyroidism Raynaud’s phenomenon © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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/velpatasvir FDC Note: ribavirin may be added in select circumstances © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. Genotype 4 Elbasvir/grazoprevir Ledipasvir/sofosbuvir FDC Paritaprevir/ritonavir/ombitasvir FDC Sofosbuvir/velpatasvir FDC Note: ribavirin may be added in select circumstances except with sofosbuvir/velpatasvir FDC © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 Sofosbuvir plus ribavirin (but 1st-line therapy against genotype 2 infection only) Daclatasvir plus sofosbuvir Sofosbuvir/velpatasvir FDC © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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) © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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) © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. Can patients who were unsuccessfully treated with DAAs be re-treated? Virus that emerges after relapse may contain resistanceassociated 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1. 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 © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (3): ITC3-1.