Clinical Slide Set. Hepatitis C

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in the clinic

Hepatitis C

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

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What factors increase the risk for HCV infection?



Percutaneous exposure to infected blood



Remote or long-term injection drug



Blood transfusion



Tattoo or piercing with contaminated instruments



Accidental needle-stick (health care workers)



Reuse of needles and syringes



Hemodialysis (U.S. rate of infection: 8.9%)



Sexual intercourse with HCV-infected person



Mother-to-child transmission

How can individuals, including those who live with an infected individual, reduce risk?



Avoid high-risk behaviors



Treatment programs for support



Needle-exchange programs



Use condoms



Advised for patients with multiple sex partners



Don’t share razors, toothbrushes, nail clippers

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Follow infection control practices in health care setting



Always use new needle and new syringe to access medication from multidose vials

CLINICAL BOTTOM LINE: Prevention…



Main risk factor for infection: percutaneous exposure



Transfusion of blood products



Injection drug use



Hemodialysis



Other risk factors: sexual transmission, mother-child transmission



To prevent infection, avoid high-risk behaviors



Don’t share or reuse needles



Use condoms



Use infection control practices in health care settings

Who should clinicians screen for HCV infection?

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Those with risk factors



Injection drug use (past or present)



Receipt of clotting factor concentrates before 1987; or of blood or blood components or solid-organ transplantation before July 1992; or of blood from HCV-positive donor



Long-term hemodialysis treatment



Repeatedly elevated serum alanine transaminase levels



Specific high-risk exposure to known HCV-positive blood



Needle-sticks or other sharp exposure; mucosal exposure



HIV infection



Being the child of HCV-positive woman

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History of multiple sex partners or STDs



Being born between 1945-1965 (new CDC recommendation)

What test should clinicians use for screening?



Use ELISA to test for antibody to HCV



Sensitivity 98.9%-100%



Specificity 99.3%-100%



(When performed with second- or third-generation assays)

CLINICAL BOTTOM LINE: Screening…



Screen all persons with risk factors for HCV antibody



Including anyone born from 1945 to 1965



Use ELISA test for HCV antibody

What is the clinical spectrum of HCV infection?



Acute infection



Often asymptomatic or nonspecific: fatigue, nausea, abdominal pain, flu-like



Jaundice



Acute liver failure uncommon



Chronic infection (develops in 74%-86% over time)



Symptoms: Fatigue, jaundice, lower-extremity edema, ascites, altered mental status, GI bleeding



Abnormal liver tests



Cirrhosis, portal hypertension



Hepatocellular carcinoma

Extrahepatic Manifestations

             

Arthritis Porphyria cutanea tarda Leukocytoclastic vasculitis Lichen planus Raynaud phenomenon The sicca syndrome Idiopathic thrombocytopenic purpura Membranoproliferative glomerulonephritis Membranous nephropathy Hypo/hyperthyroidism Diabetes mellitus Essential mixed cryoglobulinemia Monoclonal gammopathy Non-Hodgkin lymphoma

What laboratory tests should clinicians use?



Positive antibody to HCV on ELISA ?



Measure HCV RNA by PCR to confirm chronic infection



Note: quantitative viral load doesn’t predict HCV severity (correlates poorly with hepatic histology)



Considering therapy ?



Obtain HCV genotype (affects Rx response, regimen, duration



Most other liver function studies lack specificity



Reserve other lab tests for those with evidence of cirrhosis or extrahepatic manifestations of HCV

When should clinicians consider liver biopsy?



Once infection confirmed with HCV RNA testing



Identifies those most at risk for disease progression



Moderate-to-severe fibrosis ? Consider treatment



Minimal or no fibrosis ? May defer treatment



Biopsy may show significant fibrosis even if alanine aminotransferase levels normal



Helps assess risk vs. benefit of treatment



Limitations: sampling error + interobserver variability



Repeatedly test hepatic histology over time (to lower error rate and variability + estimate progression)

What other liver conditions have similar clinical presentations?



Differential diagnosis is broad



Because symptoms & lab abnormalities nonspecific



Consider HCV when any liver disease causes mild-to moderate transaminase level elevations or cirrhosis



Infection can occur in patients with other liver diseases



Testing for hepatitis C may be warranted even when alternative diagnosis seems secure

CLINICAL BOTTOM LINE: Diagnosis…



Chronic HCV infection usually asymptomatic

 

Liver function tests often abnormal Extrahepatic manifestations or portal hypertension or hepatocellular carcinoma may be present



To diagnose: Use ELISA to test for antibody to HCV



To confirm: use PCR to measure HCV RNA



Consider liver biopsy



Evaluates degree of fibrosis



Guides treatment decisions

Are lifestyle interventions helpful in the management of hepatitis C infection?

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Abstain from alcohol



Increased alcohol hastens development of cirrhosis in HCV-infected individuals



Avoid hepatotoxic drugs



Normal doses of acetaminophen: not contraindicated



Beware overdose thru heavy acetaminophen use



Use care with NSAIDs, which are risky in cirrhosis



Follow low-sodium diet (if cirrhosis and ascites present)



Don’t restrict protein with cirrhosis (malnutrition risk)

Are complementary-alternative therapies useful?



Herbal remedies don’t improve the outcome of infection

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Avoid herbal remedies known to be hepatotoxic



Chaparral



Leaf germander



Jin bu huan



Mistletoe



Pennyroyal



Traditional Chinese herbs

When should clinicians consider drug therapy?



If patient has no contraindications (see next slide) and…



Compensated liver disease and



Detectable serum HCV RNA



Alternate strategy: track liver disease progression



Biopsy every 3 to 5 years



Both strategies have merit



Given substantial side effects of drug treatment



Weigh risk for decompensation of liver disease against decreased Rx response in advanced fibrosis or cirrhosis



Discuss risks & benefits of each strategy with patients

Contraindications to

pegIFN

and ribavirin Rx

        

Uncontrolled major depression, particularly suicide attempts Autoimmune hepatitis or other autoimmune disorders Bone marrow, lung, heart, or kidney transplantation Severe hypertension, CHD, CHF, CVD, or other serious nonliver disorders likely to reduce life expectancy Renal insufficiency Noncompliance with office visits or medications Decompensated cirrhosis or hepatocellular carcinoma Pregnancy or inability to practice birth control methods Severe anemia, thrombocytopenia, or granulocytopenia Controversial contraindications: Active alcohol use, illicit drug use

How should clinicians choose from among available treatment regimens?



Backbone treatment for chronic HCV: pegIFN + ribavirin



pegIFN: subcutaneous injections 1x/wk



Ribavirin: by mouth in divided doses 2x/d



Genotype determines regimen, duration, likely response



Genotype 1



Standard care now includes boceprevir / telaprevir



Regimen improves response rate, reduces treatment time



Genotypes 2 – 6



PegIFN + ribavirin: 24 – 48 wks (depending on genotype)



HIV co-infection



Treat HCV if HIV status is stable (pegIFN-ribavirin only)

Which vaccinations should patients receive?



Hepatitis A vaccine



Ask about prior vaccination / exposure to hepatitis A



Vaccinating empirically may be more cost-effective than measuring for antibodies



Hepatitis B vaccine



Ask about prior vaccination / exposure to hepatitis B



If no vaccination / exposure: measure anti-HBs



If negative: administer HBV series



Annual influenza vaccine



Pneumococcal vaccine



For all patients with cirrhosis, regardless treatment for HCV

What is appropriate clinical management for patients with suboptimal response to therapy?



Null response: <2-log reduction in HCV RNA by week 12 when treated with interferon α–based regimen

 

Partial response: Relapse: >2-log reduction by week 12, but detectable undetectable at treatment end; detectable in follow-up



Evaluate therapy



Perform histologic examination of liver to guide treatment



Genotype 1: if pegIFN-ribavirin regimen failed, retreat with addition of protease inhibitor if protease inhibitor failed, don’t try different one (refer to hepatologist for alternative approaches)



Genotype 2-6: if patient nonadherent, can try a 2 nd course re-treat if previous dosing was incorrect of if inappropriate dose reductions occurred

What are the side effects of hepatitis C drugs?

Interferon



Fatigue



Flu-like syndrome



Nausea and vomiting



Headaches



Low-grade fever



Weight loss



Irritability

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Depression



Hair thinning



Injection site Irritation



Bone marrow suppression

Ribavirin



Hemolytic anemia



Fatigue



Pruritus



Rashes

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Cough, dyspnea, bronchospasm

Boceprevir



Anemia



Dysgeuesia

Telaprevir



Anemia



Rash



GI side effects

Uncommon side effects: interferon combination



Autoimmune thyroiditis



Seizures

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Suicidal ideation or attempts



Retinopathy



Sepsis



Myocardial infarction



Pulmonary fibrosis

How can the side effects be managed?



Anemia: reduce ribavirin dose



Thrombocytopenia: try thrombopoietin-receptor agonists



Be alert to possible hepatotoxity, thromboembolic complications



Don’t reduce or interrupt protease inhibitors



Risk for viral resistance

How should clinicians evaluate the response to therapy?

 

Baseline: Assess HCV RNA titers at initiation of therapy Goal: Undetectable viral load for 6 mos after therapy end (SVR) Genotype 1



Boceprevir + pegIFN-ribavirin: assess titers @ 8, 12, 24 weeks



>100 IU/mL at week 12 or detectable at week 24: stop Rx

 

Undetectable at week 8 & 24: ? shorten course of therapy Prior null responders: treat 48 weeks regardless response



Telaprevir + pegIFN-ribavirin: assess titers @ 4, 12, 24 weeks

 

>1000 IU/mL at week 4 & 12 or detectable at 24: stop Rx Undetectable at week 4 & 12: treat 24 weeks if no cirrhosis and treatment naïve, or if patient previously relapsed



With cirrhosis, prior partial responders or nonresponders: treat for full 48 weeks

Genotypes 2 - 3



Assess titers after week 24 of pegIFN-ribavirin therapy



Consider assessing at week 12:



Early virologic response: ≥2-log reduction in titers



If patients don’t achieve, discontinue Rx



If patients do achieve, then titers should be undetectable by 24 weeks (if not, halt treatment)

Are there other drug regimens with documented effectiveness?



Interferon-free regimens



Would be revolutionary advance in treatment



Studies still needed (? best combination, duration)



Concern: relapse after completion of therapy



? Delay treatment for mild disease until newer drug combinations available



Especially significant for regimens w/o pegIFN

Is it possible to cure hepatitis C infection?



Cure = SVR to interferon based therapies ≥2 years



Relapse still possible but unlikely



SVR associated with decreased liver-related morbidity and mortality



Note: Patients can be re-infected after successful treatment

(antibody isn’t protective)

When is liver transplantation indicated?



Model for End Stage Liver Disease (MELD) score ≥10



First major portal hypertension complication occurs



Ascites, hepatic encephalopathy, variceal bleeding



Hepatocellular carcinoma

What is the risk for hepatocellular carcinoma?



Occurrence: 3% per year after development of cirrhosis



Surveillance: ultrasonography every 6 months



Serum α-fetoprotein no longer recommended

When is specialty consultation indicated?



Hepatologist or infectious disease specialist



To distinguish HCV infection from other liver diseases



To determine need for liver biopsy



To guide next step if nonresponse to pegIFN α - ribavirin



To evaluate for liver transplantation

CLINICAL BOTTOM LINE: Treatment…



Individualize decisions on treatment based on…



Stage of disease



Clinical and lab evaluation



Patient preference; any Rx contraindications



Standard treatment: pegIFN α and ribavirin



Genotype determines dose & duration



For patients with genotype 1: boceprevir or telaprevir approved for addition to the treatment regimen