Download Clinical Slide Set. Hepatitis C Virus

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.