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ABCs of hepatitisSarah Doernberg, MD, MASAssociate Professor and Medical Director of Antimicrobial StewardshipDivision of Infectious Diseases, UCSF
Disclosures
§ Consultant: Genentech
Outline
§ Symptoms§ Hepatitis A § Hepatitis B§ Hepatitis C
Viral hepatitis manifestations
Acut
e • Fever• Fatigue• Anorexia• Nausea• Emesis• Abd pain• Clay-colored stool• Dark urine• Jaundice• Joint pain
Extra
inte
stin
al • Leukocytoclasticvasculitis
• Cryoglobulinemia• Arthritis• Optic neuritis• Transverse myelitis• Myocarditis• Aplastic anemia/red cell
aplasia• Lymphoma• Glomerulonephritis• Thyroid disease• Autoimmune
phenomena
Chr
onic • Cirrhosis
• Hepatic decompensation
• HCC
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Outline: HAV
§ Epidemiology§ Pathogenesis§ Diagnosis§ Prevention
Which of these patients should receive HAV immunization?
A. A healthy 6 month-old infantB. A 25 year-old F who works at a day care centerC. A 55 year-old M who works in a burrito shopD. A 40 year-old F adopting an infant from EthiopiaE. A 33 year-old M working in a sewage treatment plant
Global HAV epidemiology, 2005
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm#fig4
US HAV epidemiology
Vaccine
ACIP rec for universal pedsvaccination
https://www.cdc.gov/hepatitis/hav/havfaq.htm#general
• Recent major outbreaks among PWID and experiencing homelessness
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HAV pathogenesisContamination of food, water or hands w/ HAV1. Fecal-oral2. Common source
Brief viremia
Replication in GI tract
Transported to liver (major replication site)
Shed from liver via bile to intestines
Exits body in feces
Shedding begins 2 weeks before symptoms and continues after resolution (wks to mths)
Incubation: 28 dd(15-50)
Can survive outside the body x months
https://www.cdc.gov/hepatitis/hav/havfaq.htm#generalhttps://commons.wikimedia.org/wiki/File:Uppergi.gif
HAV presentation and management
§ Self-limited, supportive care- sxs ~2 weeks
§ Kids can shed x mths§ Fulminant hepatitis rare
(<2%)- Risks: advanced age,
other liver disease
https://www.cdc.gov/hepatitis/resources/professionals/pdfs/ABCTable.pdf
0%
20%
40%
60%
80%
< 6 years 6-14 yrs > 14 yrs
Incidence of jaundice
HAV diagnosis
MMWR 2001;50[No. RR-2]; https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5304a1.htm
HAV prevention
Hyg
iene • Food/H20
precautions• Sanitation
Vacc
ine • Kids > 1 yo
• Travel• MSM• Homeless• Drug use• Clotting factors• Chronic liver dz• Adoption
Pass
ive
imm
unity • Pre-travel
• @ risk < 2wk• Can’t get
vaccine• Post exposure:
• Older age (>40!)
• Allergy• IC
https://www.cdc.gov/hepatitis/hav/havfaq.htm#general
Vaccine: lasts 20yInfection: lifelong immunity
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Common HAV vaccination questions
§ Can a pt get doses from different manufacturers? Yes§ What if the second dose is delayed? Give ASAP; do not repeat dose #1. 1st
dose protects up to 10 yrs and can protect for travel§ Can it be given to immunocompromised patients? Yes§ Should I send HAV IgG before immunization? Not risky to revaccinate
immune pts but costly. Check in these groups:- Born/lived in high or intermediate endemicity regions- Those in groups w/ ↑ prevalence by ethnicity or behavior
- Adults > 40
§ Should I send serologic tests after immunization? Nohttps://www.cdc.gov/hepatitis/hav/havfaq.htm#generalhttps://www.cdc.gov/mmwr/preview/mmwrhtml/rr5507a1.htm
HAV summary
§ Spread via fecal-oral route§ No chronic phase§ Fulminant disease is rare, jaundice common§ Vaccine-preventable§ Hygiene is critical
Outline: HBV
§ Epidemiology§ Pathogenesis§ Screening, diagnosis, and test interpretation§ Treatment§ Prevention
US HBV epidemiology
• At least ~850K w/ chronic HBV in the US, may be up to 2 millionhttps://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
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HBV prevalence worldwide
https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/hepatitis-b
>350 million chronically infected2 billion have had infections
HBV transmission
§ Blood and bodily fluids (not breastmilk)- Survives outside the body x 7 days
§ Incubation: 1-4 mths§ Most common worldwide:
- Perinatal- Horizontal transmission in childhood
§ In the US:- Sex w/ infected partner- IDU
HBV natural history HBV case
§ New couple seeking care in your office
§ 39 year-old M, no medical issues
- Born in US, parents emigrated from Mongolia
- Does not know immunization history
§ 35 year-old F
- Severe RA failing therapy, rheumatologist planning rituximab
- Born in the US to US-born parents
§ No risky behaviors
B. Schwartz
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Case, con’t. Which patient will you screen for HBV?
A. MaleB. FemaleC. Both patientsD. Neither patient
Who to screen (HBsAg)
§ High prevalence area- Born in regions with HBsAg prevalence ≥ 2%
- Born in US to parents from area with HBsAg prevalence ≥ 8%, if unvaccinated
- Born to HBsAg + mothers
§ High-risk activities- IDU, MSM, household contacts, sexual contacts
§ Prevention of transmission- Organ/blood/tissue donors, hemodialysis patients, pregnancy, needlestick
§ Risk of reactivation- Immunosuppression (test for HBcAb and HBsAb as well)
- HIV, HCV
Male
Female
Weinbaum CM et al. MMWR 2008; 57(RR08);1-20. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm
Acute HBV infection with recovery
Window period
Weinbaum CM et al. MMWR 2008; 57(RR08);1-20. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm
Chronic HBV
Weinbaum CM et al. MMWR 2008; 57(RR08);1-20. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm
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HBV serologiesHBsAg HBsAb HBcAb IgM Total HBcAb HBV VL Interpretation- - - - - Susceptible
- + - - - HBV vaccinated
- + - + - “Resolved” infection
+ - + +/- +++ Acute infection
- - + +/- + Window
+ - - + ++ Chronic
+ - - +/- ++ Flare
- - - + +/- Multiple interpretations
Isolated HBcAb+
1. False positive2. Passive txsfer from maternal antibodies or IVIGàNo action
3. Resolved infection with very low-level HBsAb4. Window period/recovery fr acute infection (not yet made sAb)5. Occult chronic HBV with undetectable HBsAg
https://www.cdc.gov/hepatitis/hbv/pdfs/serologicchartv8.pdf
How to sort this out:• Check HBV DNAà#5 (not always +)• Repeat testing in 6 mths (addresses #2, #4)• Can also immunizeàresponse suggests #1; if not, #3
HBV reactivation
§ HBsAg+ or HBsAg- (HBcAb+)§ Inactive or resolved HBVàflare (↑ DNA and ALT)§ At risk (can also be spontaneous):
- Increased HBV replication during IS: Chemo, IS, transplants- Immune reconstitution
§ HIV+ and stop HBV antivirals§ HCV coinfection and treatment
https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
Staging
B. Schwartz
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Our male patient’s results
Characterize viral infection
Disease activity
Stage of disease
Comorbidities
HBV DNA: 130,000KHBeAg+, anti-HBe -
ALT > 2x ULN x 8 months
PT, Bili, Alb - wnlUltrasound: no HCC
Hep A, C, D IgG negative, HIV-, ETOH: minimal
B. Schwartz
What does that mean for our patient?
Chronic active
infection
Chronic hepatitis B infection*
Inactive carrier state
HBeAg+ HBeAg-10-20%/yr
precore mutation
• ↑ HBV DNA (> 20K)• Elevated ALT• Biopsy – inflam
• ↓ HBV DNA , (< 2K)• Normal ALT• Biopsy – no inflammation
Hepatic decompensationCirrhosis
HCC
*
* Must have HBsAg+ x 2, 6 months apart
1-5%/yr
2-5%/yr
3%/yr
0.4%/yr
B. Schwartz
Case, con’t: Which patient should receive HBV treatment?
A. MaleB. FemaleC. BothD. Neither
Treatment§ Immunological cure: Loss of HBsAg & HBV DNA suppression§ Virological cure: Currently impossible: covalently closed circular DNA
(cccDNA) still in hepatocytesàcan reactivate
Drug AE CommentsInterferon Flu-like sxs, mood, cytopenias, autoimmunity Fixed durationLamivudine Pancreatitis, lactic acidosis Risk of resistance
Telbivudine ↑CK, lactic acidosis, neuropathy
Entecavir Lactic acidosisAdefovir ARF, Fanconi sx, nephrogenic DI, lactic acidosis
Tenofovir Nephropathy, Fanconi sx, osteomalacia, lactic acidosis
Terrault NA et al. Hepatology 2016; 63(1):261-283
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Which adults to treat
1. Immune-active:- HBeAg neg: HBV DNA > 2000 + (ALT > 2 ULN or +histology)
§ If not meeting criteria: Case-by-case basis- HBeAg pos: HBV DNA > 20,000
2. Cirrhosis + HBsAg3. Pregnancy + HBsAg + DNA > 2K4. Acute HBV-mediated decompensation5. Immune suppression planned- Risk-stratify by HBsAg and type of IS
Male
Female
Terrault NA et al. Hepatology 2016; 63(1):261-283
Who w/ HBV should be screened for HCC?
§ Populations:
- Asian M > 40 y/o, F > 50 y/o- Cirrhosis- Family history of HCC- Africans/African Americans > 20 y/o- Any > 40 y/o w/ persistent or intermittent ALT elevation
and/or HBV DNA > 2000
§ How to screen (similar recs for HCC screening in HCV):- Q6mth ultrasound +/- AFP- CT is not recommendedàhigh false +, radiation, cost
Heimbach JK et al. Hepatology 2018; 67(1):358-380
Prevention
§ Behavioral modification§ Immunization (recombinant HBsAg): Prevention & PEP
- Single Ag and combos available§ HBIG: 3-6 mth protection; used as PEP
- Unvaccinated or nonresponder w/ HBsAg+ exposure (+vaccine)- Infants born to HBsAg+ mothers- Certain transplant recipients
Mast EE et al. MMWR 2006; 55(16)
Who to vaccinate
§ All infants and unvaccinated kids (catch-up): w/i 24 hrs of birth§ Sexual risk: partners, STI testing, MSM, high-risk sexual behavior§ Blood/fluid risk: IDU, household contacts, HCW, incarcerated, DM§ At risk for complications: Liver disease, immunocompromised§ ESRD§ HIV§ Travelers to regions with high or intermediate levels of HBV§ Any adult seeking protection from HBV infection
Abara WA et al. Ann Intern Med. 2017;167(11):794-804.
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Common HBV vaccination questions
§ Can you give doses from different manufacturers? Yes§ If you get off schedule, what do you do? Proceed with next dose, no
need to restart§ Are extra doses or giving to someone with HBV harmful? No§ Can it be given to immunocompromised patients? Yes§ How long does immunity last? > 20 years§ Should I screen for immunity before immunization? Yes, screen all
patients in high-risk groups; no need for infants/kids§ Should I send serologic tests after immunization? Only if it will change
management:
https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm
• HCW• ESRD, HIV, immunocompromised
• Sexual partners• Infants of HBsAg+ moms
Case, con’t: 1 month after she completes her HBV vaccine series, your pt’s HBsAb is negative. What do you do next?
A. Recheck HBsAgB. Give 1 booster dose of the vaccineC. Give the whole series againD. Counsel her not to receive ritux
Management of vaccine nonresponse
§ If received the vaccine remotely:- Up to 60% lose detectable Ab over time (though still protected)- Challenge with 1 doseàamnestic response
§ If recent or no response above, give 2nd three-dose series- 15-25% will respond after dose #1, 30-50% after all three
§ Retest 1-2 mths later
§ If still no response:- Check HBsAg- Consider nonresponder (<5%)àPEP if exposed
https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html#diagnosis
HBV take-home
§ HBV is common worldwide; many patients should be screened
§ Vaccinate at-risk populations§ Select patients benefit from treatment
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Outline: HCV
§ Epidemiology§ Pathogenesis§ Screening and diagnosis§ Treatment
- Pre-treatment evaluation- Treatment- Monitoring
HCV: A disturbing trend
• ~30,000 acute HCV annually in the US
• 2.7-3.9 million w/ chronic HCV
https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm#tabs-6-6
HCV pathogenesis
https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm
Populations to screen
§ Ever injection drug use§ Intranasal illicit drug use§ All baby boomers (1945-1965)§ HIV+§ Before PrEP initiation§ Hemodialysis§ Incarceration§ Sxs/signs of hepatitis
§ Transplant or transfusion < 1992, clotting factors < 1987
§ Transplant from high-risk donor§ SOT donors§ HCWs§ Unregulated tattoo§ Children born to HCV+mothers
At least 1 time; Screen more frequently if risk is ongoing
https://w w w .uspreventiveserv icestaskforce.org /P age/D ocum ent/R ecom m endationS ta tem entF ina l/hepatitis-c-screen ing
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https://w w w .cdc.gov/hepatitis /hcv/pdfs /hcv_graph.pdf
When to check HCV RNA:• Reexposure in HCV Ab + pt• Dx of HCV in immunocompromise• Dx of active versus cleared virus
after screening Ab• Antiviral therapy
How to test Case
§ 36M with well-controlled HIV, chronic HCV, and intermittent IV heroin abuse. His HCV has never been treated.
§ He states that he’s been clean for 8 months§ Patient wonders, “Can I qualify for one of those fancy new
hepatitis treatments that I keep hearing about?”
Bryn Boslett, MD
Who to treat?
§ Everyone with chronic HCV should be treated- Except limited life expectancy (12 mths) not reversible by treatment or
transplant
https://w w w .hcvgu ide lines.org /eva luate /w hen-w hom
What studies are necessary in pre-treatment assessment for a patient with HCV?
A. Hepatitis C genotypeB. Hepatitis C resistance testingC. FibroScan (transient elastography)D. All of the above
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Things to know before starting
1) Degree of liver fibrosis2) Genotype3) History of prior treatment: Failed DAAs vs older agents4) Concomitant issues
-Comorbid conditions -Medications
Bryn Boslett, MD
What you need to know about genotypes
M essina JP e t a l. H epato logy. 2015; 61(1): 77–87.
• 7 genotypes• Many subtypes• Affects prognosis & Rx• GT1: 70% of US HCV
• 55% 1a• GT2: 15-20%• GT3: 10%
• Fibrosis progression• Remainder: Uncommon
Staging
Blood tests
• Indirect: Measure hepatic function but not extracellular matrix metabolism
• Direct: Reflex extracellular matrix turnover
Imaging
• Transient elastography (Fibroscan)
• Cross-sectional imaging not needed for staging
Biopsy
• Gold standard, rarely needed anymore
• Discordant results• Concern for
concurrent diagnosies
Case, con’t. Before initiating HCV therapy for the patient, what other information is needed?
A. Current antiretroviral therapyB. Psychiatric evaluationC. Evaluation for varicesD. At least three months of negative urine tox screens
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NS5a NS5b ProteaseTarget Viral assembly and release Viral RNA polymerase Viral proteaseNaming “-asvir" “-buvir” “-previr”
Harvoni Ledipasvir SofosbuvirZepatier Elbasvir Grazoprevir
Epclusa Velpatasvir SofosbuvirMavyret Pibrentasvir Glecaprevir
Vosevi* Velpatasvir Sofosbuvir Voxilaprevir* = for treatment-experienced (including with NS5a inhibitors)
What are the options?
Kohli A et al. JAMA 2014;312(6):631-40. doi: 10.1001/jama.2014.7085.https://www.hcvguidelines.org/evaluate/resistance Bryn Boslett, MD
How to choose
1) Focus on comorbid conditions – some safety concerns2) Focus on other medications – look for interactions3) Focus on insurance requirements – what is covered4) Focus on duration and pill burden – less is more
Genotype 1
Regimen RBV? DurationGlecaprevir/Pibrentasvir (Mavyret) No 8a -12 wks
Elbasvir/Grazoprevir (Zepatier) +/-b 12 -16b wks
Ledipasvir/Sofosbuvir (Harvoni) +/-c 8d-12 wks
Velpatasvir/Sofosbuvir (Epclusa) No 12 wks
Bryn Boslett, MD; http://www.hcvguidelines.org/
a) AASLD/IDSA guidelines rec 12 wks if comp cirrhosis; 8 wks likely OK per Expedition 8 b) GT 1a needs NS5A RAS genotype à 16 wks + RBV if resistance presentc) RBV added if comp cirrhosis AND prior Peg-I/RBV failured) 8 weeks only if non-black, no HIV, HCV RNA < 6 million IU/mL
Genotype 3, including comp cirrhosis
Regimen RBV? DurationGlecaprevir/Pibrentasvir (Mavyret) No 8a-12 wks
Velpatasvir/Sofosbuvir (Epclusa) +/-b 12 wks
Bryn Boslett, MD; http://www.hcvguidelines.org/
a) AASLD/IDSA guidelines rec 12 wks if comp cirrhosis; does NOT include INF failures b) GT3 comp cirrhotic or treatment experienced, perform NS5a RAS testing: If Y93H, ribavirin recommended
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Important Comorbidities
§ Renal disease- Avoid SOF for CrCL < 30- ELB/GRZ (Zepatier) or GLE/PIB (Mavyret) are ok for CrCl < 30 &
ESRD § GERD/Gastritis
- PPI not recommended with LDV or VEL (in Harvoni, Epclusa)§ Anemia
- If ribavirin-containing regimen is indicated§ HBV
- Risk for re-activation; sAg+ should be on HBV-active therapy
Bryn Boslett, MD
Most common drug interactions
§ Elbasvir/Grazoprevir (Zepatier) & Glecaprevir/Pibrentasvir(Mavyret) - Many interactions with HIV anti-retrovirals- Some contraindicated, esp ritonavir-boosted protease inhibitors
§ Ledipasvir and Velpatasvir (part of Harvoni and Epclusa) - ↓ drug levels w/ acid blocking meds (antacids, H2 blockers, PPIs)
§ Sofosbuvir with amiodarone- Black Box!
Bryn Boslett, MD
Resistance§ Resistance-associated substitutions (RAS): Amino acid change
associated with loss of antiviral susceptibility- Drug-class RAS- Drug-specific RAS
§ Associated with virologic failure§ Testing is drug-, genotype-, and treatment-history specific
- Most do not need it- GT1a: if considering Elbasvir/Grazoprevir (Zepatier)- GT3: if cirrhosis or prior IFN + Velpatasvir/sofosbuvir (Epclusa)
https://www.hcvguidelines.org/evaluate/resistance
Summary: Evaluation before therapy§ Stage fibrosis
§ Drug-drug interactions: https://www.hep-druginteractions.org/§ CBC, INR, LFTs, eGFR§ HCV GT and subtype§ NS5a RAS testing
- GT1a: if considering Zepatier- GT3: if cirrhosis or prior IFN failure + Epclusa
§ HCV RNA w/i 12 mths§ Pregnancy test if appropriate (ribavirin planned)§ If planning protease inhibitor:
- Child-Pugh scoreàcontraindicated if ≥7 or decompensated liver disease
§ HBsAg, anti-HBsAb, and anti-HBcAb- If positive, test for HBV DNAàtreat/prophylax or monitor closely, risk for reactivation
https://www.hcvguidelines.org/evaluate/monitoringBrynn Boslett, MD
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Monitoring
§ CBC, eGFR, LFTs at 4 weeks
- More frequent CBCs if on ribavirin- 10-fold ↑ in ALT without symptoms or ↑ ALT < 10-fold w/
sxsàdiscontinue
§ HCV VL at 4 weeks and 12 weeks post-treatment- If detectable at 4 weeks, recheck at 6
- Consider at 24 weeks post-treatment if at risk for failure§ If cirrhotic, needs ongoing HCC screening
§ HCV Ab may remain + àif concern for reinfection, test RNA; con’t to educate re: reinfection
https://www.hcvguidelines.org/evaluate/monitoring
Hepatitis C resources
§ https://www.hcvguidelines.org/§ https://www.hep-druginteractions.org/§ https://www.hepatitis.va.gov/products/patient/sofosbuvir-
simeprevir-handouts.asp- Up-to-date patient education handouts
§ https://www.hepatitisc.uw.edu/
HCV summary
§ The HCV epidemic is growing in the face of the opioid crisis§ Effective treatment is available now; genotype and fibrosis staging
inform treatment decisions§ Continue to monitor after treatment and educate on reinfection
Thank you!Questions?
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HAV outbreaks§ 2017: Largest US outbreak since the vaccine (CA and others)§ Unusual strain usu seen in Mediterranean and S. Africa§ Disproportionately affected: Homeless and/or PWID§ Public health approach:
- Hygiene: Handwashing stations, toilet access- Vaccination campaigns State Cases Hospitalized Death
CA 688 449 (65%) 21 (3%)MI 692 564 (82%) 22 (3%)UT 146 80 (55%) 0
https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/Immunization/Hepatitis-A-Outbreak.aspxhttps://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm
HBV virus Phases of chronic HBV
Phase ALT HBV DNA
HBeAg Histology
Immune tolerant Normal ↑↑↑≥1 million
+ Minimalinflammation/fibrosis
HBeAg+ immune active
Elevated
↑↑≥20,000
+ Moderate to severe inflammation/fibrosis
Inactive Normal Low or neg<2000
Neg Minimal necroinflammation, variable fibrosis
HBeAg- immune active
Elevated
≥2000 Neg Mod to severe inflammation/fibrosis
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Perinatal infection course
IMMUNE TOLERANCE(10-30 years)
IMMUNE CLEARANCE
NON-REPLICATIVE PHASE
(Inactive carrier state)
HBV DNA
AST/ALT
Who not to treat and how to monitor
§ Immune-tolerant phase (except markedly abnl biopsy)§ Pregnancy + HBsAg + DNA ≤ 200K
§ Why not to treat:- May not have complications: Inactive carriers
- Not always effective- Can develop resistance- Side effects
§ Monitoring: q6 month ALT (q3 mth if recently stopped)
What to do after making dx of HCV
§ Evaluate comorbidities that accelerate disease (HAV, HIV, HBV, EtOH, obesity)
§ Reduce transmission- Drug use—no sharing paraphernalia
- Sexual counseling: Low but present risk
- Household precautions: Do not share razors or toothbrushes
https://w w w .cdc.gov/hepatitis /hcv/hcvfaq.h tm
APRI = AST to Platelet Ratio Index
§ ((AST/AST ULN)/platelet count) * 100§ > 0.7àpossible “significant fibrosis” (F2+ fibrosis)- Sn 77%, Sp 72%
§ >1.0àpossible cirrhosis (F4) - Sn 76% Sp. 72%
§ >2.0àprobable cirrhosis- Sn 46%, Sp 91%
Lin ZH et al. Hepatology. 2011.
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FIB-4 (fibrosis 4)
§ (age*ALT)/(plt*√ALT)§ < 1.45 à low likelihood of advanced
fibrosis/cirrhosis- NPV 90%
§ > 3.25 à advanced fibrosis/cirrhosis- Sp 97%, PPV 65%
Sterling RK et. al. Hepatology 2006.
Direct Acting Agents
Adopted from Gane, E.J., et al. American Journal of Transplantation. 2014
“-PREVIR”GrazoprevirGlecaprevirVoxilaprevir
à “-ASVIR”Le
dipasvirVel
patasvirElb
asvirPib
rentasvir
“-BUVIR”Sofosbuvir