Annals of Internal Medicine䊛

In the Clinic®

Hepatitis C Virus Transmission

and Prevention

Screening

H
epatitis C virus (HCV) is the most com-
mon bloodborne pathogen in the United
States, chronically affecting approxi-
mately 2.4 million Americans, most of whom are Diagnosis and Evaluation
unaware of the infection. Highly effective, well-
tolerated therapies are now available with mark-
edly simplified treatment algorithms. Eradica- Treatment
tion of HCV is a national goal. Increased efforts
to extend access to treatment to populations
that traditionally are difficult to treat, such as
persons who inject drugs, are critical to achiev-
Practice Improvement and
ing eradication. Given the magnitude of the dis- Quality Measures
ease burden, an increased role of primary care
providers in screening, patient stratification, and
treatment will be needed.

CME/MOC activity available at Annals.org.

David E. Kaplan, MD, MSc doi:10.7326/AITC202009010

From Perelman School of
Medicine at the University of CME Objective: To review current evidence for transmission, prevention, screening,
Pennsylvania, Philadelphia, diagnosis, evaluation, treatment, practice improvement, and quality measures for
Pennsylvania (D.E.K.). hepatitis C virus.
Acknowledgment: The author thanks Arthur Kim, MD, author of the previous version of this
In the Clinic.
Funding Source: American College of Physicians.
Disclosures: Dr. Kaplan, ACP Contributing Author, reports a grant from Gilead Sciences outside the
submitted work. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest
Forms.do?msNum=M20-1981.

With the assistance of additional physician writers, the editors of Annals of Internal Medicine
develop In the Clinic using MKSAP and other resources of the American College of Physicians.
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sional Partnership Initiative at the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines,
please go to https://www.acponline.org/clinical_information/guidelines/.
© 2020 American College of Physicians
 The rapid evolution of all-oral, Americans are infected, three
1. World Health Organiza- short-duration, well-tolerated, quarters of whom were born
tion. Combating Hepatitis broadly applicable, and highly from 1945 through 1965 (3, 4). A
B and C to Reach Elimina-
tion by 2030: Advocacy effective antiviral therapy for concern is the near quadrupling
Brief. World Health Orga-
nization; 2016. acute and chronic hepatitis C vi- of incidence rates of acute hepa-
2. Buckley GJ, Strom BL, eds. rus (HCV) infection has allowed titis C among men and women
Eliminating the Public
Health Problem of Hepati- eradication of the virus as a pub- aged 18 –39 years, predomi-
tis B and C in the United lic health problem to become an nantly among non-Hispanic
States: Phase One Report.
2016. achievable goal. In 2016, the Whites, related to an increase in
3. Hofmeister MG, Rosenthal
EM, Barker LK, et al. Esti- World Health Organization de- the number of persons who inject
mating prevalence of veloped an international strategy drugs (PWID) resulting from the
hepatitis C virus infection
in the United States, and action plans to neutralize the opioid epidemic (5).
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2019;69:1020-31. [PMID:
30398671] National Academies of Sciences, Sustained virologic response
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Engineering, and Medicine (SVR)—when HCV RNA is unde-
Drobeniuc J, et al. Chronic
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acute hepatitis C virus
universal treatment and, if en- therapeutic landscape has
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growing opioid epidemic acted, is projected to reduce evolved considerably since the
and associated injection
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6. Ghany MG, Morgan TR;
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AASLD-IDSA Hepatitis C
Guidance Panel. Hepatitis among persons currently in- and overall mortality (9). Al-
C guidance 2019 update:
American Association for fected are access to testing, though HCV infection is no lon-
the Study of Liver Diseas-
linkage to care, and access to ger the leading indication for
es–Infectious Diseases
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managing, and treating
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Hepatology. 2020;71:
686-721. [PMID:
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Green PK, et al. Increased
Transmission and Prevention
risk for hepatocellular What factors increase risk for as tattooing and piercing, are
carcinoma persists up to
10 years after HCV eradi- HCV infection? considered to have extremely
cation in patients with Most persons with HCV were in- low risk for transmission as long
baseline cirrhosis or high
FIB-4 scores. Gastroenter- fected via a percutaneous expo- as strict infection control mea-
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1278.e4. [PMID: sure to infected blood. The 2 pri- sures are followed. Higher rates
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Feld JJ, et al. Association transmission are injection drug tients receiving hemodialysis and
between sustained viro-
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cause mortality among Sharing of injection equipment quate infection control practices
patients with chronic hep-
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10. Cholankeril G, Ahmed A.
Alcoholic liver disease results in exposure and transmis- ual activity, given that HCV RNA
replaces hepatitis C virus is occasionally detected in the
infection as the leading
sion. Exposure to blood products
indication for liver trans- before 1992, when screening of semen of viremic patients. How-
plantation in the United
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Hepatol. 2018;16: also a risk factor for HCV infec- ples with discordant serostatus
1356-8. [PMID:
29199144] tion. Cosmetic procedures, such have shown that such transmis-

姝 2020 American College of Physicians ITC34 In the Clinic Annals of Internal Medicine 1 September 2020
sion is extremely inefficient (13). pathogens. Infections within
11. Kim D, Li AA, Perumpail
HCV seems to be transmitted at a households can be minimized by BJ, et al. Changing
higher rate in men who have sex trends in etiology-based
avoiding potential blood expo- and ethnicity-based
with men (MSM), particularly sures via shared toothbrushes annual mortality rates of
cirrhosis and hepatocel-
those who practice unprotected and razors; other activities, such lular carcinoma in the
anal intercourse or have HIV (14). as sharing utensils, do not result United States. Hepatol-
ogy. 2019;69:1064-74.
HCV may be transmitted from in transmission. Persons who are [PMID: 30014489]
mother to child at a rate of ap- 12. Pérez-Álvarez R, Garcı́a-
cured of HCV infection will not Samaniego J, Solá R,
proximately 4%–5% (15). Breast- infect others. However, reinfec- et al. Acute hepatitis C in
Spain: a retrospective
feeding is not associated with tion is possible after achievement study of 131 cases. Rev
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13. Terrault NA, Dodge JL,
How can person-to-person persons most likely to transmit Murphy EL, et al. Sexual
transmission of hepatitis
transmission be prevented? infection to others (19). No vac- C virus among monoga-
PWID should be enabled to ac- cine against HCV is currently mous heterosexual cou-
ples: the HCV partners
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14. Wilkin T. Clinical Practice.
and needle and syringe ex- health care setting? Primary care for men
change. Together, these mea- who have sex with men.
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to-patient transmission, blood
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banks should avoid paid donors 15. Benova L, Mohamoud
The most effective preventive YA, Calvert C, et al. Verti-
strategy is likely to be expanded and should routinely screen do- cal transmission of hepa-
titis C virus: systematic
access to antiviral therapy among nated products. Health care review and meta-
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that prevent reuse of contami- 16. Gartner LM, Morton J,
Tattooing and piercing should be Lawrence RA, et al;
done according to strict infection nated equipment. Abolishing use American Academy of
Pediatrics Section on
control protocols. Condoms are of multidose vials should be con- Breastfeeding. Breast-
not recommended for long-term sidered. Postexposure prophy- feeding and the use of
human milk. Pediatrics.
heterosexual monogamous cou- laxis for needlestick injury to pre- 2005;115:496-506.
[PMID: 15687461]
ples with discordant HCV se- vent transmission from a patient 17. Platt L, Minozzi S, Reed
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preventing hepatitis C
multiple partners and for HIV- infection after a single exposure, transmission in people
positive MSM for prevention of high efficacy of antivirals if infec- who inject drugs. Co-
chrane Database Syst
transmission of HCV and other tion occurs, and excess cost (20). Rev. 2017;9:CD012021.
[PMID: 28922449]
18. Zelenev A, Li J, Mazh-
naya A, et al. Hepatitis C
virus treatment as pre-
Transmission and Prevention... HCV is most efficiently transmitted by vention in an extended
exposure to infected blood. Sexual transmission is relatively inefficient; network of people who
condoms are recommended in the setting of HIV or multiple sexual inject drugs in the USA:
a modelling study. Lan-
partners. Nosocomial transmission in health care settings may be pre- cet Infect Dis. 2018;18:
vented by adequate infection control practices. PWID remain at the 215-24. [PMID:
29153265]
highest risk for new infections; opioid substitution, needle exchange, 19. Buchanan R, Meskarian
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proaches to reduce overall transmission rates. et al. Prioritising hepati-
tis C treatment in people
with multiple injecting
partners maximises
CLINICAL BOTTOM LINE prevention: a real-world
network study. J Infect.
2020;80:225-31. [PMID:
31887323]
20. Naggie S, Holland DP,
Sulkowski MS, et al.
Hepatitis C virus postex-
posure prophylaxis in the
healthcare worker: why
direct-acting antivirals
don't change a thing.
Clin Infect Dis. 2017;64:
92-9. [PMID: 27682067]

1 September 2020 Annals of Internal Medicine In the Clinic ITC35 姝 2020 American College of Physicians
21. Buti M, Domı́nguez-
Hernández R, Casado
MÁ, et al. Healthcare
Screening
value of implementing Should clinicians screen for inexpensive. Moreover, infected
hepatitis C screening in
the adult general popu- HCV infection? patients can receive counseling to
lation in Spain. PLoS
Screening for HCV infection is rec- reduce or eliminate alcohol use
One. 2018;13:
e0208036. [PMID: ommended because both the acute and to minimize the risk for trans-
30485377]
22. Eckman MH, Ward JW, and chronic phases are mostly mission of HCV to others. On the
Sherman KE. Cost effec-
tiveness of universal
asymptomatic. There is a long latent basis of the markedly increased
screening for hepatitis C period—usually decades—before incidence in young PWID and
virus infection in the era
of direct-acting, pange- liver disease manifests, during modeling studies that support uni-
notypic treatment regi- versal screening (21, 22), the
mens. Clin Gastroenterol
which treatment can almost en-
Hepatol. 2019;17:930- tirely prevent complications. Initial American Association for the Study
939.e9. [PMID:
30201597] HCV serologic testing is relatively of Liver Diseases and the Infectious
23. Owens DK, Davidson
KW, Krist AH, et al; US
Preventive Services Task
Force. Screening for
hepatitis C virus infection
in adolescents and
adults: US Preventive Screening Recommendations From the AASLD/IDSA and the CDC*
Services Task Force rec-
ommendation state- General Recommendations
ment. JAMA. 2020.
[PMID: 32119076] One-time, routine, opt-out HCV testing is recommended for all persons
24. Schillie S, Wester C,
Osborne M, et al. CDC aged 18 years or older.
recommendations for
hepatitis C screening
One-time screening for persons younger than 18 years should be per-
among adults – United formed in the setting of behaviors, exposures, and conditions associated
States, 2020. MMWR
Recomm Rep. 2020;69: with increased risk for HCV infection.
1-17. [PMID: 32271723]
25. Aberg JA, Gallant JE,
One-time screening of pregnant women is recommended unless risk fac-
Ghanem KG, et al; Infec- tors indicate additional testing.
tious Diseases Society of
America. Primary care Annual HCV testing is recommended for PWID and for HIV-seropositive
guidelines for the man-
agement of persons
men who have unprotected sex with men. Periodic testing should be of-
infected with HIV: 2013 fered to other persons with ongoing risk factors for exposure to HCV.
update by the HIV Medi-
cine Association of the
Infectious Diseases Soci-
Risk Behaviors
ety of America. Clin In- Injection drug use (current or ever, including those who have injected once)
fect Dis. 2014;58:1-10.
[PMID: 24343580] Intranasal illicit drug use
26. He T, Li K, Roberts MS,
et al. Prevention of hepa-
titis C by screening and
Risk Exposures
treatment in U.S. pris- Persons who have ever received long-term hemodialysis
ons. Ann Intern Med.
2016;164:84-92. [PMID: Persons with percutaneous/parenteral exposure in an unregulated setting
26595252]
27. Grebely J, Page K, Sacks- Health care, emergency medical, and public safety workers after sticks with
Davis R, et al; InC3 Study
Group. The effects of
needles or sharps or mucosal exposure to HCV-infected blood
female sex, viral geno-
type, and IL28B geno-
Children born to HCV-infected women
type on spontaneous Recipients of transfusions or organ transplants, including persons who:
clearance of acute hepati-
tis C virus infection. • Were notified that they received blood from a donor who later tested
Hepatology. 2014;59: positive for HCV infection
109-20. [PMID:
23908124]
• Received a transfusion of blood or blood components or had an organ
28. Kaplan DE, Sugimoto K, transplant before July 1992
Newton K, et al. Discor- • Received clotting factor concentrates produced before 1987
dant role of CD4 T-cell • Were ever incarcerated
response relative to
neutralizing antibody
and CD8 T-cell responses
Other Populations That Should Be Screened
in acute hepatitis C. Persons with HIV infection
Gastroenterology. 2007;
132:654-66. [PMID: Persons planning to initiate preexposure prophylaxis for HIV
17258733]
29. Negro F. Natural history Persons with unexplained chronic liver disease and chronic hepatitis, in-
of hepatic and extrahe-
patic hepatitis C virus
cluding elevated ALT levels
diseases and impact of Solid organ donors (deceased and living)
interferon-free HCV ther-
apy. Cold Spring Harb * Adapted from section on testing and linkage to care at http://hcvguidelines.org.
Perspect Med. 2020;10.
[PMID: 31636094]

姝 2020 American College of Physicians ITC36 In the Clinic Annals of Internal Medicine 1 September 2020
Diseases Society of America infection is recommended in 30. Thein HH, Yi Q, Dore GJ,
et al. Estimation of stage-
(AASLD/IDSA) now recommend all adults aged 18 –79 years. specific fibrosis progres-
1-time, routine, opt-out screening Persons at ongoing risk, sion rates in chronic
hepatitis C virus infec-
for all persons aged 18 years or such as PWID and HIV-positive tion: a meta-analysis and
older (6). The U.S. Preventive Ser- MSM, should be screened at
meta-regression. Hepa-
tology. 2008;48:418-31.
vices Task Force (USPSTF) now also [PMID: 18563841]
least yearly (25). Periodic re- 31. Seeff LB. The history of
recommends 1-time screening in the “natural history” of
adults aged 18–79 years (23). The peated screening is recom- hepatitis C (1968 –2009).
Centers for Disease Control and mended for other populations Liver Int. 2009;29 Suppl
1:89-99. [PMID:
Prevention (CDC) concurs with at increased risk for exposure 19207971]
32. Gordon SC, Lamerato LE,
1-time screening for adults (except (see the Box: Screening Rupp LB, et al. Preva-
where regional prevalence is <0.1%) Recommendations From the lence of cirrhosis in hep-
atitis C patients in the
and further recommends screening AASLD/IDSA and the CDC). Be- Chronic Hepatitis Cohort
of all pregnant women (24). cause of high prevalence rates,
Study (CHeCS): a retro-
spective and prospective
accelerated screening in such observational study. Am
What populations should J Gastroenterol. 2015;
be screened? settings as jails and prisons 110:1169-77. [PMID:
26215529]
On the basis of current guide- should be strongly considered 33. Poynard T, Ratziu V,
Charlotte F, et al. Rates
lines, 1-time screening for HCV (26). and risk factors of liver
fibrosis progression in
patients with chronic
hepatitis C. J Hepatol.
Screening... Screening for HCV is essential due to the long latent pe- 2001;34:730-9. [PMID:
11434620]
riod before serious symptoms manifest, the availability of therapies that 34. Fisher DG, Hess KL, Erly-
interrupt the natural history, and the associated public and personal ana E, et al. Comparison
health burden. All adults should be screened at least once. Persons with of rapid point-of-care
tests for detection of
ongoing risk factors should be screened at least annually. antibodies to hepatitis C
virus. Open Forum Infect
Dis. 2015;2:ofv101.
[PMID: 26269795]
CLINICAL BOTTOM LINE 35. Kanwal F, Kramer JR,
Asch SM, et al. Long-
term risk of hepatocellu-
lar carcinoma in HCV
patients treated with
direct acting antiviral
Diagnosis and Evaluation agents. Hepatology.
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What is the natural history of at this phase requires HCV RNA 36. Udell JA, Wang CS, Tin-
HCV infection? testing. mouth J, et al. Does this
patient with liver disease
The incubation period after ex- have cirrhosis? JAMA.
Spontaneous viral clearance (dis- 2012;307:832-42.
posure to HCV is typically 2–12 [PMID: 22357834]
appearance of HCV RNA on re-
weeks, during which time HCV 37. Holmberg SD, Lu M,
peated measurements) in the Rupp LB, et al; Chronic
RNA is detectable and transmissi- Hepatitis Cohort Study
acute phase of infection occurs in (CHeCS) Investigators.
ble but liver enzyme levels, such Noninvasive serum fibro-
approximately 15%– 45% of pa-
as alanine aminotransferase sis markers for screening
tients. It is more common among and staging chronic
(ALT), remain normal. After incu- hepatitis C virus patients
symptomatic patients, those who in a large US cohort. Clin
bation, mild acute hepatitis oc- are infected at younger ages, Infect Dis. 2013;57:
curs, during which most persons women, and persons with certain
240-6. [PMID:
23592832]
remain asymptomatic; 10%–15% genetic polymorphisms (27). 38. Xu F, Moorman AC, Tong
X, et al; Chronic Hepatitis
develop flu-like symptoms, myal- Spontaneous clearance typically Cohort Study (CHeCS)
gias, jaundice, or dark urine. Ful- occurs within 6 –12 months of ini-
Investigators. All-cause
mortality and progres-
minant disease has occurred in a tial infection; in established sion risks to hepatic
decompensation and
few case reports but is extremely chronic infection, cases of resolu- hepatocellular carcinoma
rare. Given this largely asymp- tion without treatment have oc- in patients infected with
hepatitis C virus. Clin
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97. [PMID: 26417034]
majority of persons with acute extremely rare (27). Patients with 39. Chou R, Wasson N.
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fibrosis or cirrhosis in
ical care. Anti-HCV antibodies infectious and do not have in- patients with chronic
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(HCVAbs) may still remain unde- creased risk for HCV-related liver tion: a systematic review.
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1 September 2020 Annals of Internal Medicine In the Clinic ITC37 姝 2020 American College of Physicians
40. Younossi ZM, Zheng L, between undetectable and de- progression is age at the time of
Stepanova M, et al. Mod-
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alcohol consumption: it is important to confirm lack of of persons infected after age 50
each is significantly asso-
ciated with increased viremia on repeated testing be- years progress to cirrhosis within
mortality in patients with
chronic hepatitis C. Ali- fore discontinuing monitoring. 20 years compared with 10% or
ment Pharmacol Ther. fewer of those infected before
2013;37:703-9. [PMID: Most patients without treatment age 40 years. Other liver insults,
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41. Bravi F, Bosetti C, Tavani in the acute phase will progress such as regular alcohol abuse,
A, et al. Coffee reduces
risk for hepatocellular
to chronic infection. During fatty liver, and co-infection with
carcinoma: an updated chronic infection, levels of ALT other viruses (such as HIV or hep-
meta-analysis. Clin Gas-
are usually persistently or inter-
troenterol Hepatol. atitis B virus [HBV]), can also ac-
2013;11:1413-1421.e1. mittently elevated but can be
[PMID: 23660416] celerate fibrosis.
42. Fried MW, Navarro VJ, normal in up to 20% of infected
Afdhal N, et al; Silymarin
in NASH and C Hepatitis
persons. Once cirrhosis develops, the pa-
(SyNCH) Study Group. tient may have significant mor-
Effect of silymarin (milk Chronic infection is usually
thistle) on liver disease bidity and mortality due to portal
in patients with chronic asymptomatic but may result in
hypertension (manifested by as-
hepatitis C unsuccess- extrahepatic manifestations, such
fully treated with inter- cites, gastrointestinal bleeding
feron therapy: a random- as cryoglobulinemic vasculitis,
ized controlled trial. from esophageal or gastric vari-
porphyria cutanea tarda, insulin
JAMA. 2012;308:274- ces, or portal gastropathy), he-
82. [PMID: 22797645] resistance/diabetes, chronic kid-
43. Mohanty A, Tate JP, patic encephalopathy, and hepa-
Garcia-Tsao G. Statins are ney disease, and fatigue (see the
tocellular carcinoma. The risk for
associated with a de- Box: Extrahepatic Manifestations
creased risk of decom- hepatocellular carcinoma due to
pensation and death in of HCV Infection) (29).
veterans with hepatitis HCV-related cirrhosis, in the ab-
C–related compensated sence of successful treatment, is
cirrhosis. Gastroenterol-
ogy. 2016;150:430- as high as 3% per year.
40.e1. [PMID:
26484707] Extrahepatic Manifestations of
What are symptoms and signs
44. Kaplan DE, Serper MA, HCV Infection
Mehta R, et al; VOCAL
Cryoglobulinemic vasculitis
to look for on physical
Study Group. Effects of
hypercholesterolemia Membranoproliferative examination?
and statin exposure on
survival in a large na- glomerulonephritis Symptoms of chronic liver dis-
tional cohort of patients Membranous nephropathy ease can include fatigue, pruri-
with cirrhosis. Gastroen-
terology. 2019;156: Monoclonal gammopathy tus, weakness, hair loss, and an-
1693-1706.e12. [PMID:
30660733]
Non-Hodgkin lymphoma orexia. Signs of cirrhosis include
45. Greub G, Ledergerber B, Arthralgias/arthritis scleral icterus, spider nevi on the
Battegay M, et al. Clinical
progression, survival, Raynaud phenomenon chest or back, palmar erythema,
and immune recovery Fatigue Terry nails, temporal wasting,
during antiretroviral
therapy in patients with Sicca syndrome thenar wasting, reduced body
HIV-1 and hepatitis C
virus coinfection: the
Lichen planus hair, gynecomastia, peripheral
Swiss HIV Cohort Study. Porphyria cutanea tarda edema, dilated abdominal veins,
Lancet. 2000;356:
1800-5. [PMID: Diabetes mellitus/insulin resistance hepatomegaly (or a shrunken
11117912] Hypothyroidism/hyperthyroidism liver), splenomegaly, asterixis,
46. Cardenas A, Mendez-
Bocanegra A. Report of and ascites. However, most pa-
the Baveno VI consensus
workshop [Editorial]. Ann tients with significant liver fibrosis
Hepatol. 2016;15:289-
The major consequence of have normal findings on physical
90. [PMID: 26845610]
47. Bruix J, Sherman M; chronic infection is liver fibrosis examination. Signs of extrahe-
American Association for patic manifestations include pal-
the Study of Liver Dis- that can lead to cirrhosis over
eases. Management of
several decades. On average, pable purpura in patients with
hepatocellular carci-
associated cryoglobulinemic vas-
noma: an update. Hepa- 15%–20% of persons with chronic
tology. 2011;53:1020-2. culitis or vesicular lesions in
[PMID: 21374666] HCV infection develop cirrhosis
48. Younossi ZM, Stepanova those with associated porphyria
M, Nader F, et al. over a 20-year period (30, 31).
cutanea tarda.
Patient-reported out-
comes in chronic hepati-
Because the baby boomer cohort
tis C patients with cirrho- was infected 20 – 40 years ago, What diagnostic tests are
sis treated with
sofosbuvir-containing this group has a particularly high available?
regimens. Hepatology.
2014;59:2161-9. [PMID:
rate of cirrhosis (32). The stron- Patients should be screened with
24710669] gest risk factor for liver disease an anti-HCV (HCVAb) test using

姝 2020 American College of Physicians ITC38 In the Clinic Annals of Internal Medicine 1 September 2020
either a blood-based or point-of- if a new genotype or subtype is
care enzyme-linked immunoas- detected after prior clearance.
49. Martin NK, Vickerman P,
say approved by the U.S. Food Grebely J, et al. Hepatitis
and Drug Administration (FDA). A comprehensive metabolic C virus treatment for
panel with estimation of glomer- prevention among peo-
These tests have high specificity ple who inject drugs:
ular filtration rate, complete modeling treatment
and sensitivity (34). Tests for
blood count, and prothrombin scale-up in the age of
HCVAbs are less expensive than direct-acting antivirals.
time or international normalized Hepatology. 2013;58:
nucleic acid testing (NAT), but 1598-609. [PMID:
ratio should be done in all pa-
they do not differentiate current 23553643]
tients with HCV infection. If renal 50. Foster GR, Afdhal N,
from past infection and can show Roberts SK, et al;
dysfunction is discovered, tests ASTRAL-2 Investigators.
false-positive results. NAT is the
should include measurement of Sofosbuvir and velpatas-
preferred first test in the acute vir for HCV genotype 2
urinary protein and serum cryo- and 3 infection. N Engl J
setting and for immunocompro- globulin. Patients with HCV Med. 2015;373:2608-
17. [PMID: 26575258]
mised persons who may exhibit should be screened for HIV and 51. Radley A, Robinson E,
delayed HCVAb development. HBV (hepatitis B surface antigen
Aspinall EJ, et al. A sys-
tematic review and meta-
Once a positive HCVAb test re- [HBsAg], hepatitis B surface anti- analysis of community
sult is identified, measurement of and primary-care-based
body [HBsAb], hepatitis B core hepatitis C testing and
HCV RNA, usually by polymerase antibody [HBcAb] IgG) because treatment services that
employ direct acting
chain reaction, is used to confirm they share routes of HCV trans- antiviral drug treatments.
current infection (Appendix Ta- mission. Assessment for immu-
BMC Health Serv Res.
2019;19:765. [PMID:
ble, available at Annals.org). Op- nity to hepatitis A (hepatitis A 31660966]
52. Wyles D, Bräu N, Kottilil
timally, laboratory processes virus antibody IgG) is also recom- S, et al; ASTRAL-5 Investi-
should be streamlined to reflex mended. If possible, performing gators. Sofosbuvir and
velpatasvir for the treat-
test HCV RNA by NAT for every abdominal ultrasonography to ment of hepatitis C virus
in patients coinfected
new positive HCVAb test result. assess liver nodularity and spleen with human immunode-
HCVAb tests should not be re- size is often helpful in identifying ficiency virus type 1: an
open-label, phase 3
peated after a positive result— cirrhosis, with the important ca- study. Clin Infect Dis.
the presence of active infection 2017;65:6-12. [PMID:
veat that a normal result does not 28369210]
and response to treatment exclude cirrhosis. 53. Rockstroh JK, Lacombe
K, Viani RM, et al. Effi-
should be determined by NAT. cacy and safety of gle-
Why is it important to caprevir/pibrentasvir in
There is no correlation between determine the degree of liver patients coinfected with
hepatitis C virus and
HCV RNA titers and disease pro- fibrosis? human immunodefi-
ciency virus type 1: the
gression or fibrosis; therefore, Antiviral therapy, in the absence EXPEDITION-2 study. Clin
there is no role for serial assess- of coexisting fatty liver or alco- Infect Dis. 2018;67:
1010-7. [PMID:
ments of HCV RNA unless a pa- holism, can essentially eliminate 29566246]
54. Serper M, Forde KA,
tient is receiving antiviral therapy. the risk for progression to de- Kaplan DE. Rare clinically
compensation in patients with significant hepatic events
There are 6 major viral geno- compensated cirrhosis from hep-
and hepatitis B reactiva-
tion occur more fre-
types, with genotype 1 (specifi- atitis C. However, patients with quently following rather
than during direct-acting
cally subtype 1a) the most com- advanced fibrosis, and more spe- antiviral therapy for
mon in the United States. The cifically cirrhosis, are at increased chronic hepatitis C: data
from a national US co-
clinical course of all genotypes is risk for hepatocellular carcinoma hort. J Viral Hepat. 2018;
very similar. Whereas in the past 25:187-97. [PMID:
(8, 35). Patients with advanced 28845882]
genotype testing was required to fibrosis or cirrhosis remain at 55. Curry MP, O’Leary JG,
Bzowej N, et al; ASTRAL-4
determine the choice of treat- high risk for hepatic decompen- Investigators. Sofosbuvir
ment regimen and duration, sation and liver cancer if concom- and velpatasvir for HCV
in patients with decom-
newer simplified guidelines from itant liver injury is present from pensated cirrhosis. N
Engl J Med. 2015;373:
AASLD/IDSA (http://hcvguide alcohol intake or nonalcoholic 2618-28. [PMID:
lines.org) no longer recommend fatty liver disease; therefore, risk 26569658]
56. Charlton M, Everson GT,
genotype-specific treatment al- factor modification, such as ces- Flamm SL, et al; SOLAR-1
Investigators. Ledipasvir
gorithms for the vast majority of sation or reduction of alcohol and sofosbuvir plus
treatment candidates. Genotype intake, weight loss, treatment of ribavirin for treatment of
HCV infection in patients
testing remains useful for pa- dyslipidemia, and management with advanced liver dis-
tients with cirrhosis. It may also of insulin resistance, should be ease. Gastroenterology.
2015;149:649-59.
be useful to identify reinfection emphasized for these persons [PMID: 25985734]

1 September 2020 Annals of Internal Medicine In the Clinic ITC39 姝 2020 American College of Physicians
 with more than 1 cause of liver
dysfunction. If liver cancer or de- FIB-4 Calculation
compensation occurs, the patient FIB-4 = [age (years) × AST level
should be referred for consider- (U/L)] / [platelet count (×109
cells/L) × √ALT level (U/L)]
ation of liver transplant.
57. Everson GT, Towner WJ, FIB-4 > 3.25: 97% specific for cirrhosis
Davis MN, et al. Sofosbu- What are common laboratory FIB-4 < 1.45: 90% specific for
vir with velpatasvir in
treatment-naive noncir- test abnormalities that might absence of advanced fibrosis
rhotic patients with ge- 1.45 ≤ FIB-4 ≤ 3.25: Indeterminate;
notype 1 to 6 hepatitis C suggest advanced fibrosis or
virus infection: a ran-
additional testing needed
domized trial. Ann Intern
cirrhosis?
Med. 2015;163:818-26. In the absence of splenectomy or
[PMID: 26551051]
58. Feld JJ, Jacobson IM, other causes of bone marrow How is the degree of fibrosis
Hézode C, et al;
ASTRAL-1 Investigators.
dysfunction, platelet count is a determined?
Sofosbuvir and velpatas- highly useful surrogate marker of
vir for HCV genotype 1, Determining the fibrosis stage
2, 4, 5, and 6 infection. portal hypertension. A platelet
helps predict morbidity and mor-
N Engl J Med. 2015;
373:2599-607. [PMID:
count less than 200 × 109 cells/L tality risk (38). There are several
26571066] should raise suspicion; platelet fibrosis scoring systems, but the
59. Zeuzem S, Foster GR,
Wang S, et al. counts less than 160 × 109 cells/L most commonly used is METAVIR,
Glecaprevir-pibrentasvir or less than 110 × 109 cells/L which stages patients from F0 (no
for 8 or 12 weeks in HCV
genotype 1 or 3 infec- have specificities of 88% and fibrosis) to F4 (cirrhosis).
tion. N Engl J Med.
2018;378:354-69.
95%, respectively, for cirrhosis
[PMID: 29365309] (36). Serum albumin levels less The gold standard for assessing
60. Forns X, Lee SS, Valdes J,
et al. Glecaprevir plus than 35 g/L have a 90% specific- liver fibrosis is biopsy, which re-
pibrentasvir for chronic ity for identifying cirrhosis, but mains the most accurate measure
hepatitis C virus geno-
type 1, 2, 4, 5, or 6 infec- levels less than 38 g/L should if the sample obtained is ade-
tion in adults with com-
pensated cirrhosis raise concern. By contrast, HCV quate and properly interpreted.
(EXPEDITION-1): a single- viral levels and absolute values of It can find additional causes of
arm, open-label, multi-
centre phase 3 trial. aspartate aminotransferase (AST) fibrosis, such as steatohepatitis.
Lancet Infect Dis. 2017;
or ALT do not correlate with the However, it is now considered a
17:1062-8. [PMID:
28818546] degree of fibrosis. tarnished gold standard because
61. Younossi ZM, Stepanova
M, Jacobson IM, et al.
of risks for sampling error and
Sofosbuvir and velpatas- Availability of AST level, ALT intraobserver variability. It is also
vir with or without voxil-
aprevir in direct-acting
level, and platelet count allows invasive and carries a small risk
antiviral-naı̈ve chronic rapid calculation at the bedside for severe pain and bleeding.
hepatitis C: patient-
reported outcomes from of 2 indices: Fibrosis-4 (FIB-4)
POLARIS 2 and 3. Ali- (Box: FIB-4 Calculation) and AST- Noninvasive approaches to fibro-
ment Pharmacol Ther.
2018;47:259-67. [PMID: to-platelet ratio index (APRI). sis assessment are increasingly
29181842]
The area under the receiver- being used. These have the ad-
62. Bourlière M, Gordon SC,
Flamm SL, et al; operating characteristic curve for vantages of lower cost, increased
POLARIS-1 and
POLARIS-4 Investigators. identifying cirrhosis with either of patient acceptance, and ability to
Sofosbuvir, velpatasvir,
these simple calculations is be repeated more often than
and voxilaprevir for previ-
ously treated HCV infec- greater than 0.80 (37). FIB-4 is liver biopsy. Routine imaging,
tion. N Engl J Med. such as abdominal ultrasonogra-
2017;376:2134-46. now recommended as a compo-
[PMID: 28564569] phy, can identify advanced cir-
nent of the pretreatment assess-
63. Gane E, Poordad F, Za- rhosis but is insensitive for early
deikis N, et al. Safety and ment by AASLD/IDSA guidelines
pharmacokinetics of cirrhosis.
glecaprevir/pibrentasvir (6) (an online calculator is avail-
in adults with chronic
genotype 1– 6 hepatitis C
able at www.hepatitisc.uw.edu In addition to FIB-4, testing for
virus infections and com- /page/clinical-calculators/fib-4). advanced fibrosis or cirrhosis can
pensated liver disease.
Clin Infect Dis. 2019;69: A FIB-4 score greater than 3.25 be serologic or radiologic. Sero-
1657-64. [PMID: is highly specific for advanced logic tests include the HCV Fibro-
30923816]
64. Tacke F, Boeker KHW, fibrosis, including cirrhosis. Thus, Sure (also called FibroTest [Labo-
Klinker H, et al. Baseline
risk factors determine
risk stratification for advanced ratory Corporation of America]),
lack of biochemical re- fibrosis can easily be initiated the Enhanced Liver Fibrosis
sponse after SVR in
chronic hepatitis C pa- during the first clinical encounter Score (Siemens Healthineers),
tients treated with DAAs. for most patients newly diag- and others that combine com-
Liver Int. 2020;40:539-
48. [PMID: 31241820] nosed with HCV infection. mon laboratory tests with serum

姝 2020 American College of Physicians ITC40 In the Clinic Annals of Internal Medicine 1 September 2020
markers of fibrogenesis or fibrolysis imaging (ARFI) and point shear-
to estimate liver fibrosis. It is impor- wave elastography (pSWE) are
tant to recognize with serum mark- elastographic technologies that
ers that although there is very good are integrated into many existing
negative predictive value for low sonographic systems. ARFI/pSWE
scores (for example, F1) and very may be obtained at the time of a
high predictive value that high baseline abdominal ultrasonogra-
scores (F4) reflect the presence of phy and may be more readily
cirrhosis, intermediate results, such available than FibroScan in some
as F2 and F3, are indeterminate and locations. There are no convincing
do not exclude the presence of data on superiority of either Fi-
cirrhosis (39). broScan or ARFI, but the latter
Noninvasive radiologic approaches tends to have greater success in
to stage liver disease have be- obtaining valid readings among
come widely available. FibroScan obese patients. Magnetic reso-
(Echosens), an ultrasound-based nance elastography (MRE) is a
imaging method that measures magnetic resonance imaging–
liver stiffness—a correlate of the based assessment of liver fibrosis
degree of fibrosis—was the first of that requires installation of specific
these systems to gain FDA ap- hardware and software but shows
proval, does not require a radiolo- significantly better diagnostic per-
gist to perform the test or interpret formance for identifying advanced
results, and can be deployed in fibrosis or cirrhosis than
the field. Acoustic radiation force ultrasound-based approaches.

Diagnosis and Evaluation... The diagnosis of HCV infection is based

on NAT after a screening antibody test. AASLD/IDSA guidelines rec-
ommend that all patients with chronic hepatitis C be assessed to ex-
clude advanced liver fibrosis before antiviral treatment. A FIB-4 score
greater than 3.25, a FibroScan score greater than 12.5 kPa (or a simi-
lar finding from ARFI/pSWE or MRE), a FibroSure result or Enhanced
Liver Fibrosis Score indicating cirrhosis, sonographic imaging sug-
gesting cirrhosis (nodular liver or splenomegaly, particularly if the
platelet count is <150 × 109 cells/L), or a prior biopsy showing cir-
rhosis are sufficient to rule in cirrhosis. Indeterminate results (F2 or
F3) from any of these tests should prompt additional testing, liver
biopsy, and/or referral to a specialist.

CLINICAL BOTTOM LINE

Treatment 65. Cole AM, Keppel GA,

How can patients delay Data suggest that coffee intake Baldwin LM, et al. Room
for improvement: rates
progression of liver disease and is associated with lower fibrosis of birth cohort hepatitis C
avoid liver-related complications? progression and lower inci- screening in primary care
practices—a WWAMI
Regular alcohol consumption is dence of hepatocellular carci- region Practice and Re-
noma (41). Milk thistle, a search Network study. J
associated with greater fibrosis Prim Care Community
progression, and even moderate common supplement, was asso- Health. 2019;10:
2150132719884298.
use may be associated with poor ciated with neither benefit nor [PMID: 31658872]
harm (42). Other dietary 66. Zuckerman A, Carver A,
outcomes (40). Because a safe Chastain CA. Building a
level of consumption has not been changes and complementary hepatitis C clinical pro-
gram: strategies to opti-
established, abstinence is advised therapies are not proven; cer- mize outcomes. Curr
in HCV-infected persons with ad- tain herbal supplements may Treat Options Infect Dis.
2018;10:431-46. [PMID:
vanced fibrosis or cirrhosis (6). even be hepatotoxic. 30524209]

1 September 2020 Annals of Internal Medicine In the Clinic ITC41 姝 2020 American College of Physicians
For prescribed medications, pa- indefinitely, even if they achieve sive metabolic panel that in-
tients with HCV are at increased cure (8, 47). cludes estimated glomerular
risk for hepatotoxicity from cer- filtration rate, and pregnancy
What are the goals of antiviral
tain antiretroviral regimens and testing in women of childbearing
treatment, and which patients potential (all current direct-acting
antituberculous agents. Persons
are candidates? antiviral [DAA] therapies are
with advanced liver disease
should avoid nonsteroidal anti- The goals of antiviral therapy are pregnancy category C). Before
inflammatory medications be- 2-fold: virologic cure (which ben- treatment, the patient should be
efits the individual) and preven- educated on the need to main-
cause of the risk for nephrotoxic-
tion (which benefits society). tain adherence to daily dosing,
ity and gastrointestinal bleeding.
Acetaminophen is generally safe Benefits to the individual the need for 8 –12 weeks of ad-
as long as intake does not ex- Expert consensus is that all pa- ministration with possible need
ceed 2 g/d. Statins can be used tients with active HCV infection for refills, and the inability to as-
safely in patients with liver dis- would benefit from antiviral treat- sess cure until 12 weeks after
ease and may reduce long-term ment, except those with a short treatment completion. Genotype
complications, such as liver can- life expectancy due to unrelated testing, while not needed to in-
cer, decompensation, and death conditions that would not be re- form treatment options for most
(43, 44). mediated by viral eradication (6). patients, may be required by
For an individual, HCV infection payers.
Vaccination against hepatitis A causes substantial morbidity and
virus is recommended for per- Because treatment selection for
mortality due to both hepatic and patients with cirrhosis with geno-
sons with chronic liver disease extrahepatic manifestations. Suc- type 3 infection still requires test-
in general and specifically for cessful antiviral treatment allevi-
ing for viral resistance, testing for
chronic hepatitis C, where su- ates or obviates many of its
viral genotype is useful for pa-
perinfection can cause more se- consequences (9, 35) and is asso-
tients with cirrhosis, particularly
vere acute liver injury. Those ciated with significant improve-
those with decompensated cir-
with cirrhosis should receive vac- ments in quality of life (48). Bene-
rhosis. Patients with cirrhosis who
cination against pneumococcus fits are especially evident for
are found to be infected with ge-
and annual vaccination against patients with advanced liver dis-
notype 3 should then be tested
influenza due to increased sus- ease, those with comorbid condi-
for nonstructural protein 5A
ceptibility to complications of tions or extrahepatic manifesta-
(NS5A) viral resistance mutations
these infections. For HIV- or tions, those at risk for accelerated
with the HCV Genotype 3 NS5A
HBV-negative persons with HCV progression (such as HIV co-
Drug Resistance Assay (LabCorp
infection, prevention of these infected persons), and those at
test #550603, Quest Diagnostics
co-infecting viruses is important. increased risk for transmission.
#93325). The presence of a Y93H
HBV infection can be prevented Benefits to society resistance mutation may affect
via vaccination. For persons co- Models suggest net benefits of the success of treatment with so-
infected with HIV and HCV, sup- treatment even in persons at high fosbuvir–velpatasvir (50) and the
pressive antiretroviral therapy risk for reacquisition, such as regimen choice for patients with
has been associated with slower PWID. Even when risk for reinfec- genotype 3 only. Patients with
fibrosis progression (45). tion was taken into account, cirrhosis with a genotype other
these models showed a reduc- than genotype 3 do not require
Selected patients with HCV-
tion in overall prevalence and testing for resistance mutations.
related cirrhosis should undergo
transmission (49). Models Are there any drug– drug
screening for esophageal vari-
strongly suggest that to achieve
ces via upper endoscopy (46). interactions that might affect
90% reduction in incidence by
All patients with cirrhosis should treatment?
2030, antiviral therapy must be
have liver imaging (usually ultra- In addition to the assessment of
expanded among active PWID to
sonography, but contrast- fibrosis discussed earlier, clini-
attenuate transmission (18, 19).
enhanced multiphasic com- cians should carefully reconcile
puted tomography or What evaluations are needed all prescribed and over-the-
gadolinium-enhanced magnetic before treatment is started? counter medications the patient
resonance imaging may be Pretreatment laboratory testing ingests. Potential drug– drug and
used) plus ␣-fetoprotein blood should include total HBcAb IgG, drug– herbal interactions can be
testing to screen for hepatocel- HBsAg, HBsAb, HCV RNA, com- evaluated using the Liverpool
lular carcinoma every 6 months plete blood count, comprehen- HEP Drug Interaction tool (www

姝 2020 American College of Physicians ITC42 In the Clinic Annals of Internal Medicine 1 September 2020
.hep-druginteractions.org). Key infected with HIV and HCV are
considerations include amioda- Candidates for Simplified identical to those of HCV-
rone, which can cause severe Treatment Regimens monoinfected persons (52, 53).
bradycardia with sofosbuvir- Treatment-naive The only special considerations
containing regimens; strong cyto- No decompensated cirrhosis* required in HIV/HCV co-infected
chrome P450 inducers, such as No concomitant HIV or hepatitis B persons are drug– drug interac-
carbamazepine, oxcarbazepine, Not candidate for kidney transplant tions of HCV DAA and antiretro-
phenobarbital, phenytoin, rifam- Absence of liver cancer viral therapy regimens. Specific
pin, tipranavir, and St. John's No prior liver transplant combinations can be evaluated
wort, which reduce effective Not pregnant using the Liverpool HEP Drug
blood levels; statins, which can * Genotype test helpful for compensated Interaction tool (www.hep-drug
increase to toxic levels with pro- cirrhosis. interactions.org). Studies suggest
tease inhibitor regimens; ethinyl that, if combined correctly, anti-
estradiol– containing oral contra- HCV DAAs do not interfere appre-
ceptives and certain chemother- treatment regimen and the deci- ciably with HIV suppression.
apy medications that may also be sion about whether to add ribavi- HBV/HCV co-infection
increased by protease inhibitors; rin or extend therapy. Choices Hepatitis C typically suppresses
and proton-pump inhibitors that must also be made with the goal hepatitis B replication in patients
may reduce the absorption of cer- of minimizing interactions with who are co-infected. HCV sup-
tain NS5A inhibitors. Careful med- concomitant medications and pression can thus lead to HBV
ication lists must be maintained reducing pill burden. Due to the reactivation (HBVr). Patients who
throughout the treatment course, prices of DAAs, some insurers
are HBsAg-positive should be
and patients should be counseled have placed restrictions on which
treated with an HBV-directed
to contact their provider about regimens can be used or which
patients can be treated. It is im- DAA (entecavir or tenofovir) dur-
use of additional medications.
portant to check the preferred ing and after HCV treatment.
Who might be considered for drug in the formulary for each Patients who are HBsAg-
treatment in the primary care patient's insurance plan. negative but HBcAb-positive
setting, and who should be have less than 1% risk for HBVr,
referred to a specialist? There are 3 components of ap- which can occur years after HCV
proved DAAs: NS3/4A protease treatment (54). These patients
Experts recommend a simplified
inhibitors, NS5A inhibitors, and should be routinely monitored
treatment algorithm for
polymerase inhibitors. Fixed- for HBVr for at least 24 weeks
treatment-naive persons with or
dose combinations include 2–3 after completion of HCV treat-
without compensated cirrhosis agents. Combination therapy is
who do not have concomitant ment and if liver test results be-
required because monotherapy
HIV or hepatitis B, chronic kidney come abnormal thereafter.
with any agent is not efficacious
disease stage IV or V, liver can- due to rapid viral resistance. Be- Decompensated cirrhosis
cer, or prior liver transplant and cause it has the poorest safety Although interferon-based treat-
who are not pregnant (6) (Box: profile of all HCV antivirals, pegy- ments are dangerous for pa-
Candidates for Simplified Treat- lated interferon is no longer tients with liver decompensa-
ment Regimens). Administration used. Ribavirin still has very rare tion, protease inhibitor–free
of treatment in community- or utility when used with other com- all-oral regimens may be highly
primary care– based settings has binations but is seldom required. effective and can be applied
shown preliminary evidence of
Treatment selection previously safely in this population (55).
high uptake and similar SVR rates
required complex algorithms Treatment of patients with de-
relative to treatment in specialist
based on genotype, cirrhosis and compensated cirrhosis should
practices (51). The vast majority
compensation status, HIV status, be managed by hepatology ex-
of treatment-naive noncirrhotic
kidney function, transplant status, perts, ideally at a liver transplant
persons can be treated in the
race, resistance testing, and prior center. Before treatment, candi-
primary care setting.
treatment. dacy for liver transplant must be
How should clinicians choose a assessed; if a patient is a candi-
Are there specific concerns for
treatment regimen? date and is highly decompen-
certain populations?
Whether the patient has cirrhosis sated, it may be appropriate to
and whether he or she has re- HIV/HCV co-infection defer antiviral therapy until after
ceived previous treatment are The success rate and tolerance of transplant. For patients with de-
key determinants in the choice of DAA therapy for persons co- compensated cirrhosis and

1 September 2020 Annals of Internal Medicine In the Clinic ITC43 姝 2020 American College of Physicians
 Table 1. Combination Antiviral Regimens for Treatment-Naive Patients With Chronic Hepatitis C Genotypes 1 to 6*
Combination, by Scenario Use of Duration Notes
Ribavirin
Pangenotypic regimens
Genotypes 1–6, no cirrhosis
Glecaprevir–pibrentasvir No 8 wk –
Sofosbuvir–velpatasvir No 12 wk –
Genotypes 1–6, compensated cirrhosis
Glecaprevir–pibrentasvir No 8 wk –
Sofosbuvir–velpatasvir No 12 wk Includes genotype 3 without baseline Y93H NS5A RAS
Sofosbuvir–velpatasvir Yes 12 wk Genotype 3 with baseline Y93H NS5A RAS
Sofosbuvir–velpatasvir–voxilaprevir No 12 wk Genotype 3 with baseline Y93H NS5A RAS
Genotypes 1–6, decompensated cirrhosis
Sofosbuvir–velpatasvir Yes 12 wk –
Sofosbuvir–velpatasvir No 24 wk –
Nonpangenotypic regimens
Genotypes 1 and 4, no cirrhosis
Sofosbuvir–ledipasvir No 12 wk 8 wk can be considered only for HIV-negative, treatment-naive patients with
METAVIR stages F0–F2 and HCV RNA level <6 × 106 IU/mL;
12 wk only for genotypes 5 and 6
Grazoprevir–elbasvir No 12 wk Genotype 1a without NS5A RAS; all patients with genotypes 1b and 4
Genotypes 1 and 4, compensated cirrhosis
Sofosbuvir–ledipasvir No 12 wk –
Grazoprevir–elbasvir No 12 wk Genotype 1a without NS5A RAS; all patients with genotypes 1b and 4
Genotypes 1, 4, 5, and 6; decompensated cirrhosis
Sofosbuvir–ledipasvir Yes 12 wk –
Sofosbuvir–ledipasvir No 24 wk –

HCV = hepatitis C virus; NS5A = nonstructural protein 5A; RAS = resistance-associated substitution.
* As of April 2020.

those with hepatocellular enced with either sofosbuvir or rates exceed 95% for treatment-
carcinoma, remaining viremic an NS5A inhibitor, cure may be naive, noncirrhotic patients with any
may preserve the ability to ac- attempted with sofosbuvir–velpa- genotype infection.
cept a liver from an HCV- tasvir or sofosbuvir–ledipasvir
plus ribavirin for 24 weeks. Sofosbuvir–velpatasvir
infected donor and thereby In the ASTRAL-1 trial, 12 weeks of therapy with
shorten waitlist time. Chronic kidney disease once-daily sofosbuvir–velpatasvir achieved 99%
Patients with chronic kidney dis- efficacy in 624 treatment-naive and interferon-
Decompensated persons, with experienced patients with genotypes 1, 2, 4, 5,
rare exceptions, cannot be pre- ease stage 4 or 5 can be treated
with any standard first-line DAA. and 6, including 121 patients with compensated
scribed a DAA containing an cirrhosis. Serious adverse events were reported in
NS3/4A protease inhibitor. Similar to potential liver trans-
2% of patients receiving medication. None of the
Therefore, the only drug options plant candidates, there may be
116 patients who received placebo achieved SVR
for patients with decompen- advantages for some patients (58).
sated cirrhosis are sofosbuvir– who are candidates for kidney
velpatasvir (all genotypes) or transplant to remain viremic to In the ASTRAL-2 trial, SVR was achieved in 99% of
sofosbuvir–ledipasvir (genotype shorten time on the transplant patients with genotype 2 who were treated with
1, 4, 5, or 6). For treatment-naive waitlist. Given the high mortality and sofosbuvir–velpatasvir for 12 weeks (50). In the
patients with decompensated ASTRAL-3 trial, 12 weeks of daily sofosbuvir–vel-
morbidity associated with dialysis
cirrhosis who are candidates to patasvir was compared with 24 weeks of sofosbu-
and long wait times for HCV- vir plus weight-based ribavirin for patients with
receive ribavirin (hemoglobin
negative donors, it may be more genotype 3 infection, including both treatment-
level >100 g/L and estimated
appropriate to defer treatment naive and treatment-experienced patients. Sofos-
glomerular filtration rate ≥50
mL/min/1.73 m2), a 12-week until after transplant. The risks and buvir–velpatasvir achieved 95% SVR (95% CI,
course of sofosbuvir–ledipasvir benefits of treatment before trans- 92%–98%) in 277 patients, compared with 80%
or sofosbuvir–velpatasvir plus plant must be individualized. (CI, 75%– 85%) in 275 patients receiving sofosbu-
vir plus ribavirin. Eighty (29%) patients had cir-
weight-based ribavirin results in How efficacious are HCV rhosis in the sofosbuvir–velpatasvir group, and
cure in more than 85% of cases
treatments? these patients achieved a 91% rate of SVR com-
(55, 56). For noncandidates for
Sofosbuvir–velpatasvir, sofosbuvir– pared with 66% in 73 patients who received so-
ribavirin, sofosbuvir–velpatasvir
velpatasvir–voxilaprevir, and pibren- fosbuvir–ribavirin (50).
or sofosbuvir–ledipasvir can be
used for 24 weeks without ribavi- tasvir–glecaprevir (Table 1) are Glecaprevir–pibrentasvir
rin. For patients with decompen- FDA-approved treatments for all In ENDURANCE-1, 703 noncirrhotic patients with
sated cirrhosis who are experi- major HCV genotypes (57). Efficacy genotype 1 who were treatment-naive (62%) or

姝 2020 American College of Physicians ITC44 In the Clinic Annals of Internal Medicine 1 September 2020
had previously been treated with an interferon- sustained or severe enough to related monitoring. Patients with
based regimen (38%) were randomly assigned to require medication discontinua- cirrhosis require surveillance for
receive either 8 or 12 weeks of glecaprevir– tion (63). Certain combinations liver cancer indefinitely with ul-
pibrentasvir (59). SVR rates were 99.1% (CI, 98%– should be avoided in decompen- trasonography and ␣-fetoprotein
100%) and 99.7% (CI, 99%–100%) in the 8- and sated liver disease, such as pro- measurements every 6 months.
12-week groups, respectively. tease inhibitor– containing regi-
mens (glecaprevir–pibrentasvir, The durability of SVR has been
In ENDURANCE-3, 348 treatment-naive partic- shown in large prospective stud-
sofosbuvir–velpatasvir–voxilapre-
ipants with genotype 3 infection without cir-
vir, or grazoprevir– elbasvir). ies, with greater than 99% con-
rhosis were randomly assigned in a 2:1 ratio to
tinued HCV RNA negativity after
glecaprevir–pibrentasvir for 12 weeks versus What is the role of monitoring
sofosbuvir plus daclatasvir; an open-label
up to 5 years of follow-up. Pa-
in patients receiving therapy? tients with risk factors may be
group evaluating 8 weeks of glecaprevir–pi- Clinic visits and telephone con-
brentasvir was later added and enrolled 157 reinfected after successful ther-
tacts with patients receiving anti- apy, so HCV RNA should be
patients. SVR rates in both the 8- and 12- week viral therapy are useful for moni-
groups were 95% (CI, 93%–98%) (59). tested at least yearly. Preventive
toring adherence but should be counseling and interventions
In EXPEDITION-1, treatment-naive or interferon- individualized. Patients with dia-
described in the previous sec-
experienced patients with genotype 1, 2, 4, 5, or 6 betes should be counseled that
tion should be provided for
and compensated cirrhosis were given 12 weeks of antiviral therapy may improve
those with ongoing risk.
glecaprevir–pibrentasvir, with a 99% (145 of 146) insulin sensitivity, leading to risk
SVR rate (60). for hypoglycemia. Therapy for Fatigue, a common symptom in
diabetes may need to be ad- patients with chronic hepatitis C,
Sofosbuvir–velpatasvir– justed periodically. Patients re- may decrease after successful
voxilaprevir ceiving warfarin may also exhibit antiviral treatment (48). If it per-
Sofosbuvir–velpatasvir–voxilaprevir changes in international normal- sists, the patient should be
can be used as either the primary ized ratio requiring dose modifi-
worked up for alternate causes.
regimen or a salvage regimen for cation. Otherwise, due to the ex-
patients who had relapse with cellent safety profile of DAAs, no SVR is also associated with re-
prior treatment. specific laboratory monitoring is duced liver inflammation due to
required for candidates for sim- normalization of ALT levels. If
POLARIS-2 and POLARIS-3 evaluated sofosbu- plified treatment. HCV RNA test- ALT elevation persists after
vir–velpatasvir–voxilaprevir in 611 treatment- ing at week 4 after initiation of achievement of SVR, further
naive patients, of whom 34% had cirrhosis. therapy is a useful marker of ad-
SVR with 12 weeks of therapy ranged from
evaluation may be warranted.
herence because, at this point,
95%–98% across all genotypes (61). HCV RNA should almost always Many patients with chronic hep-
be undetectable or detectable atitis C have more than 1 chronic
In POLARIS-1 and POLARIS-4, 264 patients
(46% with compensated cirrhosis) who had re-
only at the limit of quantification. liver disease, such as concomi-
lapsed after receiving an NS5A-containing or Higher values suggest subopti- tant nonalcoholic fatty liver dis-
non–NS5A-containing prior treatment, respec- mum adherence. However, many ease, alcoholism, or chronic
tively, had SVR rates of 96%–98% with a 12- clinicians do not routinely per- hepatitis B. Patients with coexist-
week regimen (62). form laboratory testing during ing liver disease may continue to
therapy and retest patients for have abnormal ALT levels (64).
How safe are HCV treatments? SVR only at week 12 after discon- These patients should be coun-
Pegylated interferon and ribavirin tinuation of therapy. Patients with seled to avoid alcohol, maintain
are associated with various ad- prior exposure to hepatitis B
optimal body weight, control
verse effects and contraindica- (HBcAb-positive, HBsAg-
diabetes, and modify lipid-
tions. Regimens containing these negative) are at low risk for HBVr
related risk factors for vascular
medications, now uncommonly when HCV viremia resolves and
should undergo testing for reac- disease not only to prevent pro-
used, and safety concerns may
tivation (HBsAg) at weeks 12 and gressive liver fibrosis but also to
be reviewed in the previous ver-
24 after completion of DAA reduce risk for cardiovascular
sion of this In the Clinic (7).
therapy (54). disease. New elevations after
Most antiviral regimens that do normalization should also pre-
not contain pegylated interferon What is the role of monitoring cipitate HCV RNA testing to de-
or ribavirin can still cause such in patients who have stopped termine whether relapse (usually
adverse effects as fatigue, head- therapy? within the first 12 weeks after
ache, and nausea. These typically Patients who achieve SVR (cure) stopping therapy) or reinfection
occur in only a few patients and before development of cirrhosis (at any time after cessation of
may be transient; they are rarely require no posttreatment liver- therapy) has occurred.

1 September 2020 Annals of Internal Medicine In the Clinic ITC45 姝 2020 American College of Physicians
 Treatment... Cure of HCV infection can interrupt further transmission
and prevent future HCV-associated complications. Selection of the regi-
men and duration of therapy has become simplified for most patients.
Efficacy of the preferred regimens in achievement of viral cure exceeds
95%. Improved safety and efficacy of antiviral treatments have led to
recommendations that all persons with HCV infection be treated.
Specific guidance from major professional societies can be found at
http://hcvguidelines.org.

CLINICAL BOTTOM LINE

Practice Improvement and Quality Measures

Adherence to prior USPSTF ble performance measures,
birth cohort screening recom- adapted from Zuckerman and
mendations has been shown to colleagues (66), are shown in
be poor (65). Additional possi- Table 2.

Table 2. Potential Quality Metrics for Hepatitis C Care

Recommendation, by Domain Brief Description
Screening and diagnosis
Guideline-recommended screening All adult patients aged 18–79 y should have 1-time, opt-out HCVAb testing
All patients with ongoing risk factors should have periodic HCVAb testing
Linkage and access to care
Patient navigation Rapid contact for education and appointment scheduling
Use of patient navigators to prevent loss to follow-up may be useful
Telehealth Use telecommunications, such as an electronic portal, videoconferencing, and telephone calls, to engage patients in care beyond a
clinic visit
Nonspecialist care Treatment by primary care providers, experienced advanced practice practitioners, or clinical pharmacists to expand treatment capacity
Treatment access
Patient navigation program Specialists/patient navigators should work closely with the patient and pharmacy to ensure all steps for medication approval are
completed
Cost management Patient access programs and other resources should be accessed to reduce copayments
Fibrosis assessment
Calculation of FIB-4 Online calculator available
FIB-4 score >3.25 should prompt long-term liver cancer surveillance and cirrhosis-related care
Noninvasive assessment of fibrosis ARFI/pSWE ultrasound, FibroScan, magnetic resonance elastography, FibroSure, or Enhanced Liver Fibrosis Score
Positive results should prompt liver cancer surveillance and regimen choice appropriate for cirrhosis
Liver biopsy Only in cases when noninvasive assessments are indeterminate
Genotype testing For patients with cirrhosis only
NS5A RAS testing Only for patients with compensated cirrhosis and genotype 3 infection
Treatment monitoring
Patient navigation program Linkage to additional support (e.g., mental health professional, social worker) may be necessary to overcome barriers to treatment
completion
Guideline-recommended monitoring Patients should be monitored according to the AASLD/IDSA treatment guidance, focusing on continued assessment of adherence,
drug–drug interactions, and adverse events while receiving treatment
Posttreatment engagement
Patient education All patients should be educated about the clinical implications of SVR, the fact that SVR cannot be determined in 12 wk after completion,
the risk for reinfection, and the need for further liver disease care depending on fibrosis status
Advanced liver disease care All patients with advanced fibrosis should be linked to liver disease care, including surveillance for hepatocellular carcinoma and
screening for esophageal varices (if they meet Baveno VI criteria)

AASLD = American Association for the Study of Liver Diseases; ARFI = acoustic radiation force imaging; FIB-4 = Fibrosis-4;
HCVAb = hepatitis C virus antibody; IDSA = Infectious Diseases Society of America; NS5A = nonstructural protein 5A; pSWE =
point shear-wave elastography; RAS = resistance-associated substitution; SVR = sustained virologic response.

姝 2020 American College of Physicians ITC46 In the Clinic Annals of Internal Medicine 1 September 2020
 In the Clinic Patient Information

https://medlineplus.gov/hepatitisc.html

Tool Kit Patient information and handouts on hepatitis C from the

National Institutes of Health's MedlinePlus.

www.niddk.nih.gov/health-information/liver-disease
/viral-hepatitis/hepatitis-c
www.niddk.nih.gov/health-information/informacion
Hepatitis C Virus -de-la-salud/enfermedades-higado/hepatitis-viral
/hepatitis-c
Patient information on hepatitis C in English and Spanish
from the National Institute of Diabetes and Digestive
and Kidney Diseases.

www.cdc.gov/hepatitis/hcv/cfaq.htm
Frequently asked questions on hepatitis C for the public
from the Centers for Disease Control and Prevention.

https://gastro.org/practice-guidance/gi-patient-center
/topic/hepatitis-c-hcv
Information for patients on hepatitis C testing and treat-
ment as well as general advice on living with hepatitis C
from the American Gastroenterological Association.

IntheClinic
Information for Health Professionals
www.hcvguidelines.org
Recommendations for testing, managing, and treating
hepatitis C from the American Association for the Study
of Liver Diseases and the Infectious Diseases Society of
America.

www.cdc.gov/hepatitis/HCV/GuidelinesC.htm
Recommendations for hepatitis C screening from the
Centers for Disease Control and Prevention.

https://easl.eu/publication/easl-recommendations
-treatment-of-hepatitis-c
2018 treatment recommendations for hepatitis C from the
European Association for the Study of the Liver.

www.cdc.gov/hepatitis/hcv/hcvfaq.htm
Frequently asked questions on hepatitis C for health pro-
fessionals from the Centers for Disease Control and Pre-
vention.

www.who.int/hepatitis/publications/hepatitis-c
-guidelines-2018/en
World Health Organization 2018 guidelines for the care
and treatment of persons diagnosed with chronic hepa-
titis C virus infection.

1 September 2020 Annals of Internal Medicine In the Clinic ITC47 姝 2020 American College of Physicians
 WHAT YOU SHOULD KNOW In the Clinic
Annals of Internal Medicine
ABOUT HEPATITIS C
What Is Hepatitis C?
Hepatitis C is an infection of the liver caused by a
virus. It is the most common blood infection in
the United States and is now easily cured with
medications. If undetected and untreated, hepa-
titis C can cause major damage to the liver over
time and increase your risk for liver cancer.

Am I at Risk?
Hepatitis C can spread from one person to another imaging options, like ultrasound, are available.
through blood or bodily fluids. You are at highest risk Sometimes, if these tests do not provide
for infection if you inject drugs and share needles. enough information, you might need a liver
Other factors that increase your risk include: biopsy. For this test, a small needle will be
• Having a blood transfusion before 1992 used to take a sample of your liver for testing.
• Having long-term kidney dialysis
• Being born to a mother with hepatitis C How Is It Treated?
• Having unprotected sex with multiple partners • It is important to treat hepatitis C as soon as
• Being a man who has unprotected sex with it is diagnosed. This will limit the damage to
other men or has HIV your liver and decrease your risk for liver
• Tattooing and piercing with unsterilized cancer and death. However, even if you have
equipment had hepatitis C for many years, you can still be
• Being a health care worker who is exposed to cured with treatment.
contaminated needles or bodily fluids • There have been many changes in the way
hepatitis C is treated. New antiviral medicines
What Are the Signs and are safe and well tolerated and can almost
always cure hepatitis C. “Cure” means that the
Symptoms? virus is no longer in your body 3 months after
When first infected with hepatitis C, most people you finish your medications.
do not have any symptoms. In fact, it can take • Talk to your doctor about which antiviral
years to feel sick after you have been infected. medications are right for you. Ask which ones
Some symptoms of chronic liver disease from are covered by your insurance plan because

Patient Information
hepatitis C include: these medications can be expensive.
• Feeling tired • The medications are taken by mouth for about
• Loss of appetite 2–3 months. If your liver is damaged or you
• Itching have other infections, you might need a
• Weakness longer treatment course.
• Jaundice (yellow skin or dark urine) • You should avoid alcohol. Even moderate
• Leg swelling drinking may further damage your liver when
• Rashes you have hepatitis C.
• Talk to your doctor about getting vaccinated
How Is It Diagnosed? against other types of hepatitis (A and B),
• Because few people have symptoms when they pneumonia, and flu.
are first infected, doctors now recommend that
everyone older than 18 years be tested for Questions for My Doctor
hepatitis C at least once. Pregnant women should • Should I be tested for hepatitis C?
be tested during each pregnancy. If you have any • Is my liver damage reversible?
of the risk factors mentioned above, you should be • What are the risks or side effects of antiviral
tested for hepatitis C every year. medication?
• Your doctor will order a blood test to see if you • Will any of the medications I'm currently taking
have hepatitis C. If you have the virus, you will interact with my hepatitis C medications?
need additional blood tests. These will help your • What should I do to protect others from
doctor learn more about your hepatitis C and see catching hepatitis C?
how well your liver is working. • Will my insurance plan cover the cost of my
• You may need to have pictures taken of your treatment? If I can't afford my medications, are
liver to see if it is damaged. Noninvasive there programs that can help me?

For More Information

National Institute of Diabetes and Digestive
and Kidney Diseases
www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis
/hepatitis-c
MedlinePlus
https://medlineplus.gov/hepatitisc.html

姝 2020 American College of Physicians ITC48 In the Clinic Annals of Internal Medicine 1 September 2020
 Appendix Table. Interpretation of Test Results for HCV Infection
Antibody to HCV HCV RNA Infection Status
Positive Positive Acute or chronic HCV infection, depending on clinical context
Positive Negative Resolved HCV infection, or acute HCV infection during low viremia*
or HCV-related cryoglobulinemia
Negative Positive Early acute HCV infection, or
Chronic HCV infection in immunosuppressed patient, or
False-positive HCV RNA*
Negative Negative No HCV infection*

HCV = hepatitis C virus.

* Retest in 4 – 6 mo to confirm status.

1 September 2020 Annals of Internal Medicine 姝 2020 American College of Physicians