Annals of Internal Medicine
World Health Organization Guidelines on Treatment of Hepatitis C
Virus Infection: Best Practice Advice From the American College
of Physicians
George M. Abraham, MD, MPH; Adam J. Obley, MD; Linda L. Humphrey, MD, MPH; and Amir Qaseem, MD, PhD, MHA; for the
Scientific Medical Policy Committee of the American College of Physicians*
I n the United States, the incidence of hepatitis C virus
(HCV) infection is 1.2 per 100 000 persons, the prev-
alence is 2.4 million cases, and annual mortality is more
than 15 000 deaths (1, 2). Eliminating hepatitis will re-
quire diagnosis of 90% of those infected followed by
treatment of 80% of those diagnosed (3). The World
Health Organization (WHO) updated its evidence-
based guideline on chronic HCV infection in July 2018
(Table) (3). Although the WHO guideline is primarily
targeted toward policymakers in low- and middle-
income countries, recommendations are relevant to the
United States, where equity and resource allocation is-
sues are also important considerations. We discuss im-
plications of the WHO recommendations for clinicians
and patients in the United States.
DISCUSSION
The WHO recommends offering treatment to all
persons older than 12 years who have chronic HCV infec-
tion, and it notes 3 major considerations for this “treat all”
strategy: the effectiveness and safety of direct-acting anti-
viral agents (DAAs), the emergence of pangenotypic drug
regimens, and reduction in the cost of treatment (3). In
current treatment regimens, combination therapy with
oral DAAs has replaced interferon and ribavirin. The
WHO recommends pangenotypic regimens that simplify
pretreatment and on-treatment testing. This differs from
guidance from the American Association for the Study of
Liver Diseases and Infectious Diseases Society of America
(4, 5), which recommends specific DAA treatment regi-
mens based on genotype and more intensive labora-
tory testing before and during treatment. The WHO
recommendations offer U.S. clinicians the opportunity
to simplify and reduce the cost of care without compro-
mising care quality.
The WHO defines pangenotypic treatment regi-
mens as those achieving a rate of sustained virologic
response (SVR) greater than 85% across all major HCV
genotypes (3). However, in the United States, the sofos-
buvir– daclatasvir regimen has fallen out of favor given
inferior response rates in non– head-to-head compari-
sons with other regimens in registration trials (6). In pa-
This article was published at Annals.org on 6 October 2020.
* This paper, authored by George M. Abraham, MD, MPH; Adam J. Obley, MD; Linda L. Humphrey, MD, MPH; and Amir Qaseem, MD, PhD, MHA, was
developed for the Scientific Medical Policy Committee of the American College of Physicians. Individuals who served on the Scientific Medical Policy
Committee from initiation of the project until its approval were Linda L. Humphrey, MD, MPH† (Chair); Robert M. Centor, MD† (Vice Chair); Elie Akl, MD, MPH,
PhD†; Mary Ann Forciea, MD†; Ray Haeme†‡; Peter G. Hamilton, MBBCh†; Gregory A. Hood, MD†; Janet A. Jokela, MD, MPH†; Devan L. Kansagara, MD,
MCR†; Mark A. Levine, MD†; James R. Mason, MD†; Maura Marcucci, MD, MSc†; and Adam J. Obley, MD†. Approved by the ACP Board of Regents on 3
November 2019.
† Author (participated in discussion and voting).
‡ Nonphysician public representative.
Annals.org
IDEAS AND OPINIONS
tients with decompensated cirrhosis (Child–Turcotte–
Pugh class C), treatment options are similar to those for
other patients with cirrhosis, but response may be
lower and risk for adverse effects may be higher. In
addition, experts suggest lifelong monitoring for hepa-
tocellular carcinoma for all patients with cirrhosis, even
with SVR (4).
Successful treatment is defined as an undetectable
viral load 12 weeks after completion of therapy (SVR12)
(7). Pangenotypic DAA regimens are highly effective,
and pooled SVR12 rates generally exceed 85% to 90%.
Systematic reviews of studies using interferon-based
treatment indicate that achievement of SVR12 reduces
illness associated with cirrhosis and extrahepatic manifes-
tations of HCV (3, 7). However, direct evidence that DAA
treatment regimens lead to these patient-important out-
comes is sparse, indicating an area for future research.
The WHO estimates that a treat all approach would
prevent 0.57 infections over 20 years for each person
treated (3). Although some of the parameters used in
the WHO model, such as population growth rate and
HCV prevalence, are lower in the United States, the
population benefits of treating all patients with HCV are
still likely to be meaningful. The WHO notes that DAA
regimens are well tolerated and have mild adverse ef-
fects but acknowledges that broader use of DAAs
could uncover more severe adverse effects. It also cau-
tions about the heightened risk for hepatitis B reactiva-
tion during HCV treatment, as well as the possibility
that a treat all approach could divert attention and re-
sources from interventions for HCV harm reduction.
Drug interactions with DAAs are also important to con-
sider, especially because commonly used drugs, such
as proton-pump inhibitors, statins, antidepressants,
and antiretroviral therapy, can inactivate some DAAs (3,
6). Most patients support a treat all strategy, but some
express concern about adverse effects and costs (3).
The WHO recommendations have implications for
high-value care. First, wider adoption of pangenotypic
regimens in the United States would obviate the need
for viral genotyping before treatment is started (except
when using glecaprevir–pibrentasvir [GLE–PIB], in which
case genotyping is necessary to identify genotype 3,
Annals of Internal Medicine © 2021 American College of Physicians 1
IDEAS AND OPINIONS WHO Guidelines on Treatment of HCV Infection: ACP Best Practice Advice

Table. Summary of the 2018 WHO Recommended Treatments for Adults With Chronic HCV Infection, With Estimated Cost of
Treatment in the United States

Pangenotypic DAAs* Treatment Drug Price per Patient Total Cost of Treating All Also Recommended
Duration, wk in the United States, $† Patients With Chronic HCV by AASLD/IDSA?
Infection in the United States, $‡
Adults without cirrhosis
SOF–VEL 12 10 917 26.05 billion Yes, for genotypes 1–6
SOF–DCV§ 12 兩兩 兩兩 No
GLE–PIB¶ 8 10 196 24.3 billion Yes, for genotypes 1–6

Adults with compensated cirrhosis

SOF–VEL 12 10 917 26.05 billion Yes, for genotypes 1–6
SOF–DCV§ 24 兩兩 兩兩 No
GLE–PIB¶ 12 13 029 31.1 billion Yes, for genotypes 1–6
AASLD/IDSA = American Association for the Study of Liver Disease/Infectious Diseases Society of America; DAA = direct-acting antiviral agent;
DCV = daclatasvir; GLE–PIB = glecaprevir–pibrentasvir; HCV = hepatitis C virus; SOF = sofosbuvir; VEL = velpatasvir; WHO = World Health
Organization.
* Defined as those leading to a sustained virologic response rate >85% across all 6 major HCV genotypes.
† Individual patient drug cost data were obtained from https://healthcarebluebook.com (accessed 19 March 2020).
‡ Based on U.S. prevalence of 2.4 million cases (1).
§ 12 wk may be considered for compensated cirrhosis in countries where genotype 3 distribution is known and prevalence is <5%.
兩兩 As of 2019, DCV is discontinued in the United States. Source: www.drugs.com/history/daklinza.html (accessed 19 March 2020).
¶ WHO recommends treating persons with genotype 3 infection who have previously received interferon and/or ribavirin for 16 wk. As of 2019,
many major insurance plans no longer cover GLE–PIB (www.goodrx.com/mavyret).

which requires longer treatment). Second, pretreat-
ment testing is required only to distinguish patients
with cirrhosis from those without to determine treatment
duration, a distinction reliably made with inexpensive,
noninvasive tests (8). When clinical circumstances require
a more refined assessment of the degree of precirrhotic
fibrosis, noninvasive techniques, such as vibration-
controlled transient elastography, can be considered in
lieu of liver biopsy (4, 9). Third, many patients with uncom-
plicated HCV infection do not require specialist involve-
ment, and laboratory monitoring can be limited to the
beginning and end of treatment. Patients with decom-
pensated cirrhosis, hepatitis B or HIV co-infection, or
chronic kidney disease; pregnant women; and those in
whom a prior DAA regimen has been unsuccessful
should be managed in consultation with a specialist and
likely require more careful laboratory monitoring.
Although the WHO guidance provides several op-
portunities to improve hepatitis C care, affordability still
poses a barrier to DAA treatment, and price varies
globally. Recognizing this, the WHO has developed a
calculator (www.hepccalculator.org/hepccalc) that esti-
mates the cost-effectiveness of HCV treatment in 28
countries that it has deemed high-priority by applying
its customary willingness-to-pay threshold of 3 times
the per capita gross domestic product of the country.
The cost of a 4-week DAA regimen in the online model
ranges from $15 in Pakistan to $73 944 in Romania.
Although the United States is not represented in the
WHO cost-effectiveness calculator and the cost of DAA
treatment in the United States can vary greatly on the
basis of several factors, the average cost of treatment
has decreased and may now be less than $15 000 per
patient. In comparison, the total lifelong cost of HIV
treatment with darunavir, cobicistat, emtricitabine, and
tenofovir alafenamide is $1.2 million. In addition, the
2 Annals of Internal Medicine
opportunity to prevent the transmission of HCV must
be considered when cost-effectiveness is discussed.
Treatment of chronic hepatitis C disease has reached
a stage where pangenotypic regimens with shorter dura-
tions of therapy (8 to 16 weeks) can achieve virologic cure
rates (SVR12) of more than 90% (6). Improving affordabil-
ity and availability worldwide are important next steps in
universal reduction in the prevalence of this disease.
Given the simplicity of the testing and treatment regi-
mens, particularly with sofosbuvir–velpatasvir, referral to a
subspecialist is not necessary.
BEST PRACTICE ADVICE
Viral genotyping is unnecessary when treating HCV
with pangenotypic medications unless planning treat-
ment with GLE–PIB. Invasive testing to establish the de-
gree of fibrosis is not necessary, and inexpensive labo-
ratory tests can reliably identify patients with cirrhosis.
Patients aged 18 years or older without cirrhosis should
receive sofosbuvir–velpatasvir for 12 weeks or GLE–PIB
for 8 weeks (16 weeks in cases with known genotype 3
infection) (3, 10). Those with compensated cirrhosis
should be treated with sofosbuvir–velpatasvir for 12
weeks or GLE–PIB for 12 weeks (16 weeks in cases with
known genotype 3 infection) (3). Laboratory monitoring
can be limited to the beginning and end of the treat-
ment in adults with no or compensated cirrhosis. Pa-
tients with decompensated cirrhosis will need closer
monitoring. The simplification of treatment and moni-
toring enables patients with uncomplicated HCV infec-
tion to receive treatment in primary care settings.
From University of Massachusetts Medical School and Saint
Vincent Hospital, Worcester, Massachusetts (G.M.A.); Portland
Veterans Affairs Medical Center and Oregon Health & Science
University, Portland, Oregon (A.J.O., L.L.H.); and American
College of Physicians, Philadelphia, Pennsylvania (A.Q.).
Annals.org
WHO Guidelines on Treatment of HCV Infection: ACP Best Practice Advice
Financial Support: Financial support for the development of
this commentary comes exclusively from the ACP operating
budget.
Disclosures: Authors have disclosed no conflicts of interest.
Forms can be viewed at www.acponline.org/authors/icmje
/ConflictOfInterestForms.do?msNum=M19-3860. The authors
and Scientific Medical Policy Committee declared all financial
and intellectual disclosures of interest, and potential conflicts
were discussed and managed. No committee members were
recused from participation because of a conflict of interest. A
record of disclosures of interest is kept for each Scientific Medical
Policy Committee meeting and conference call and can be viewed
at www.acponline.org/clinical-information/high-value-care.
Corresponding Author: Amir Qaseem, MD, PhD, MHA, Amer-
ican College of Physicians, 190 N. Independence Mall West,
Philadelphia, PA 19106: e-mail, aqaseem@acponline.org.
Current author addresses and author contributions are avail-
able at Annals.org.
Ann Intern Med. doi:10.7326/M19-3860
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Annals of Internal Medicine 3
Current Author Addresses: Dr. Abraham: 123 Summer Street,
Suite 370, North Worcester, MA 01608.
Dr. Obley: 3030 SW Moody Avenue, Suite 250, Portland, OR
97201.
Dr. Humphrey: 3710 SW U.S. Veterans Hospital Road, Port-
land, OR 97201.
Dr. Qaseem: 190 N. Independence Mall West, Philadelphia,
PA 19106.
Annals.org
Author Contributions: Conception and design: G.M. Abra-
ham, A.J. Obley, A. Qaseem.
Analysis and interpretation of the data: A.J. Obley, L.L. Hum-
phrey, A. Qaseem.
Drafting of the article: G.M. Abraham, A.J. Obley, A. Qaseem.
Critical revision of the article for important intellectual con-
tent: G.M. Abraham, A.J. Obley, L.L. Humphrey, A. Qaseem.
Final approval of the article: G.M. Abraham, A.J. Obley, L.L.
Humphrey, A. Qaseem.
Administrative, technical, or logistic support: A. Qaseem.
Annals of Internal Medicine