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Transplantation Publish Ahead of PrintDOI: 10.1097/TP.0000000000002453

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International Liver Transplantation Society Asian Consensus on the

Management of Hepatitis C Virus Infection in Resource Limited Setting –

From Noncirrhotic to Decompensated Disease and Following Liver

Transplantation

Michael R. Charlton, MB, MBBS1, Edward J. Gane, MD

2, Akash Shukla, MD

3,

Bekhbold Dashtseren4, Davaadorj Duger

5, David H. Muljono, MD, PhD

6,

Diana A. Payawal, MD7, Ganbolor Jargalsaikhan, MD

4, Hery D. Purnomo, PhD, MD

8,

Ian H. Cua9, Irsan Hasan

10, Jose Sollano Jr., MD

11, Khin Maung Win

12

Laurentius A. Lesmana, MD, PhD13

, Mohammad Salih, MD, MBBS14

,

Pham Thi Thu Thuy15

, Ravi Shankar16

, Vivek A. Saraswat17

1Professor of Medicine, Director, Transplant Institute, Director, Center for Liver Diseases,

The University of Chicago Biological Sciences, 5841 South Maryland Avenue

2Hepatologist and Associate Director, New Zealand Liver Transplant Unit, 15th Floor

Support Building, Auckland City Hospital, Park Road, Grafton, Auckland 1142, NEW

ZEALAND

3Professor and Head, Department of Gastroenterology, LTMMC and LTMGH, Sion Mumbai

(India),

4 Physician, Liver Center Clinical Research Center, Mongolia & Mongolian National

University of Medical Science (MNUMS)

http://guide.medlive.cn/

wuyingying

英文




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5Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia

6Eijkman Institute for Molecular Biology, Jakarta, Indonesia, Faculty of Medicine,

universitas Hasanuddin, Makassar, Indonesia, Sydney Medical School, University of Sydney,

Australia, National Expert Committee for Hepatitis, Ministry of Health, Indonesia`

7President-Elect, Asian Pacific Study of the Liver Chair, Department of Internal Medicine,

Chair. Digestive Health Center, Fatima Medical University Center, MetroManila, Philippines

8Internist-Consultant of Gastroentero-Hepatology, Head of Division of Gastroentero-

Hepatology, Department of Internal Medicine Dr Kariadi Hospital, Diponegoro University

Semarang Indonesia

9Active Consultant, St. Luke’s Medical Center, Institute of Digestive and Liver Diseases,

Quezon City, Philippines

10Staff of Division of Hepatology, Department of Internal Medicine, Faculty of Medicine

University of Indonesia / Dr Cipto Mangunkusumo Hospital

11Professor of Medicine at the University of Santo, Tomas Faculty of Medicine and Surgery,

Manila, Philippines

12Honorary Professor, Department of Hepatology, University of Medicine (1), Yangon,

Ministry of Health and Sports, Myanmar





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13Professor in Internal Medicine, Consultant Gastroentero-Hepatologist, Department of

Medicine, University of Indonesia, Dr. Cipto Mangunkusumo teaching hospital, Jakarta

14Director Hepatology Quaid e Azam International hospital, Islamabad

15Hepatology Department, Medic Medical Center, Ho Chi Minh City, Vietnam

16Global Center of Excellence Lead for Infectious Disease and Head of Medical Affairs,

Mylan Laboratories Ltd.

17Professor and Head, Department of Gastroenterology, SGPGIMS, Lucknow

Corresponding author:

Prof. Michael R. Charlton

Professor of Medicine,

Director Transplant Institute and Center for Liver Diseases

The University of Chicago

5841 South Maryland Avenue, Rm M-454| Chicago, IL 60637

Email: [email protected]

Phone: 773-702-2395





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Authorship page

Name Contribution

Michael R. Charlton

Conceptualization, synopsis development, presentation

of content during the consensus meeting, participated in

consensus development meeting, involved in manuscript

development, review and final approval of manuscript

Edward John Gane

Conceptualization, synopsis development, involved in

manuscript development, review and final approval of

manuscript

Aakash Shukla, Ravi Shankar, Bekhbold

Dashtseren,

Davaadorj Duger, David H

Muljono, Diana A Payawal, Ganbolor

Jargalsaikhan, Hery D Purnomo, Ian H Cua,

Irsan Hasan, Jose Sollano Jr., Khin Maung Win,

Laurentius A. Lesmana, Mohammad Salih,

Pham Thi Thu Thuy, Ravi Shankar, Vivek A

Saraswat

Participated in consensus development meeting,

involved in outline development, manuscript review and

finalization

Conflict of interest: None to disclose

Funding: The development of the consensus document was supported by an educational

support from Mylan Laboratories Limited.





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Abbreviations Page

ALT – Alanine aminotransferase

APRI – Aminotransferase/platelet ratio index

AST – Aspartate aminotransferase

CBC – Complete blood count

COSMOS – COmbination of SiMeprevir and sOfoSbuvir

CYP – cytochrome P

DAAs – Direct-acting antivirals

DCV – Daclatasvir

DSV – Dasabuvir

EBV – Elbasvir

FDC – Fixed-dose combination

GFR – Glomerular filtration rate

GT – Genotype

GZV – Grazoprevir

HCV – Hepatitis C virus

HIV – Human immunodeficiency virus

LDV – Ledipasvir

OPTIMIST – OPtimal Treatment with a sIMeprevIr and Sofosbuvir Therapy

OMV – Ombitasvir

PAR – Paritaprevir

Peg-IFN – Pegylated interferon

P-gp – P-glycoprotein

RBV – Ribavirin





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RNA – Ribonucleic acid

RTV – Ritonavir

SIM – Simeprevir

SOF– Sofosbuvir

SVR – Sustained virologic response

VEL– Velpatasvir





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Abstract

Background: The population of Asia exceeds 4.4 billion people. Chronic hepatitis C virus

(HCV) infection in Asia is characterized by specific distribution of genotypes, lack of access

to specific therapeutic agents, relatively high cost of treatment, and lack of experienced

healthcare providers. Clear consensus on the diagnosis, management, and monitoring of HCV

infection specific to the Asian region is a major unmet need. The consensus guidelines

documents that have been published to date by major medical societies presume access to an

array of direct acting antiviral agents and diagnostic tests that are not broadly applicable to

resource limited settings, including Asia. Methods: To address the lack of an Asia-specific

set of HCV treatment guidelines, we assembled a panel of 15 HCV experts in the field of

hepatology from India, Indonesia, Myanmar, Vietnam, Pakistan, Philippines, and Mongolia

convened in April 2017 to review the updated literature and provide recommendations on the

diagnosis and management of chronic HCV infection that reflects local conditions. Results:

An evidence-based comprehensive compilation of the literature supported by the graded

recommendations from the expert panel for the optimization of the diagnosis, pre, on, and

posttreatment assessment, and management of chronic HCV infection has been presented in

this article. Conclusions: With the evolving treatment landscape and addition of several new

direct-acting antiviral agents and combination regimens into the therapeutic armamentarium,

the current article may serve as a guide to the clinicians in optimizing the diagnosis and

treatment selection for the management of chronic HCV infection in resource-limited

settings.

Keywords: Asian consensus, Direct-acting antivirals, Genotype, Hepatitis C virus infection.





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Introduction

Hepatitis C virus (HCV) is a blood-borne virus belonging to the genus Hepacivirus and

family Flaviviridae.(1) Infection with HCV manifests as acute and chronic hepatitis, with

disease severity ranging from mild, short-term illness to severe, chronic, life-threatening

disease. A total of 7 major genotypes (GT1–GT7) and 67 different subtypes of the virus have

been identified.(1)

A recent systematic review of the literature estimated the global prevalence of HCV infection

to be about 2.5% (177.5 million HCV-infected cases), of which 67% cases (118.9 million

cases) were positive for HCV ribonucleic acid (RNA).(1) The most prevalent HCV genotypes

were GT1 (49.1%), followed by GT3 (17.9%), GT4 (16.8%), GT2 (11.0%), GT5 (2%),

mixed (1.8%), and GT6 (1.4%). GT4 and GT5 are found to be more prevalent in lower

income countries.(2) The population of Asia exceeds 4 billion people, 60% of the World’s

population, with a prevalence of chronic HCV infection in Asia was reported of about 2.8%

(111.6 million cases), accounting for more than 60% of HCV cases worldwide, of which 71.9

million (64.4%) are estimated to have chronic infection.(2) The prevalence of HCV infection

is likely to vary substantially between countries and regions. Although the distribution of

HCV genotypes in Asia is closely aligned to the global pattern, with GT1 being the most

common genotype (46.6%), followed by GT3 (22.4%), GT2 (18.6%), GT6 (7.0%), mixed

genotype (4.3%), GT4 (1.0%), and GT5 (0.1%), there is a wide variation in the genotype

distribution within the 5 major Asian regions studied in this review, that included (1) Asia-

Pacific (high income) (Japan and South Korea), (2) Central Asia (Armenia, Azerbaijan,

Georgia, Kazakhstan, Kyrgyzstan, Mongolia, Tajikistan, Turkmenistan, and Uzbekistan), (3)

East Asia (China and Taiwan), (4) South Asia (Afghanistan, Bangladesh, India, and





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Pakistan), and (5) Southeast Asia (Cambodia, Indonesia, Laos, Myanmar, Malaysia, The

Philippines, Sri Lanka, Thailand, and Vietnam). The prevalence of GT1 was 58.7%, 70.4%,

53.5%, 15.5%, and 35.2% in the Asia-Pacific, Central, East, South and Southeast Asian

regions, respectively.(3) The corresponding prevalence rates for GT3, the second common

genotype were 0.4%, 19.6%, 5.4%, 66.7%, and 19.9%, respectively.(3, 4) The estimates for

GT2 were the highest in the Asia-Pacific (high-income) region (39.7%) and the lowest in the

South Asian region (1.9%).(3, 4) Southeast Asia had the highest estimates of GT6 cases,

whereas there were no cases of this genotype from Central Asia.(3) GT3 is the most prevalent

HCV genotype in Thailand and Malaysia, GT1 is the most common genotype in Singapore,

Philippines, and Indonesia, GT4a is the most commonly reported in Malaysia, Singapore,

Indonesia and the Philippines, and GT6 is most frequently reported in Myanmar, Laos, and

Vietnam.(5)

Unmet needs for the management of HCV in low and middle income countries in Asia

include: (1) lack of awareness of the disease, its risk factors, and modes of transmission,

resulting in under diagnosis; (2) lack of awareness and/or reimbursement coverage for

testing, resulting in low rates of HCV testing; (3) perceived complexity or low success rate of

the treatment; (4) high treatment cost and lack of reimbursement coverage for treatment; (5)

fear of treatment side effects; (6) fear of discrimination on disclosure of drug use or

revelation of hepatitis diagnosis; (7) lack of access to treatment and experienced healthcare

providers, and (8) delayed regulatory drug approvals due to of lack of specific clinical trial

data in the local population or data for the less common genotypes. (3) Consensus guidelines

documents that have been published to date, including those by the European Association of

the Study of Liver Diseases, the American Association for the Study of Liver Diseases

(AASLD) and the International Liver Transplantation Society (ILTS) presume access to an





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array of direct acting antiviral agents and diagnostic tests that are not broadly applicable to

Asia, and to low and middle income countries in general, due to specific local conditions.

Furthermore, the lack of nation-wide treatment guidelines for the management of HCV has

also been acknowledged by most physicians in the Asia-Pacific region in an international,

multidisciplinary survey of HCV treatment providers.(6-9) To address the lack of an Asia-

specific set of HCV treatment guidelines, we assembled a panel of 15 HCV experts in the

field of hepatology from India, Indonesia, Myanmar, Vietnam, Pakistan, Philippines, and

Mongolia convened in April 2017 to review the updated literature and provide

recommendations on the diagnosis and management of chronic HCV infection that reflects

local conditions.

The objective of the current consensus document is to guide physicians on the treatment of

chronic HCV infection with cost-effective regimens in resource-limited settings in Asia to

ensure optimal treatment outcomes.

Methods

Between April 2017 and April 2018, a panel of 15 HCV experts in the field of hepatology

from India, Indonesia, Myanmar, Vietnam, Pakistan, Philippines, and Mongolia convened to

review the updated literature on the management of HCV and provide recommendations to

optimize the:

Diagnosis of HCV infection

Use of cost-effective treatment regimens for the management of HCV infection in

resource-limited settings in Asia

Pre, on-, and posttreatment assessments during HCV management





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The recommendations for the use of optimal treatment regimens in the management of HCV

infection in Asia were graded by the expert panel as Preferred, Alternative, or Not

Recommended (Table 1). DAA availability by region is shown in Table 2.

Diagnosis of HCV Infection

Current guidelines recommend initial HCV serological testing for the detection of anti-HCV

antibodies.(7) A negative test result does not completely rule out the diagnosis of hepatitis as

a negative test result may be possible during the first 6 weeks of exposure or in

immunosuppressed individuals. In such cases, an identifiable source of transmission and/or

clinical signs and symptoms such as alanine aminotransferase (ALT) levels >10 times the

upper limit of normal may be used as an index of suspicion for acute HCV infection.(9-12)

Chronic HCV infection should be confirmed by a nucleic acid test for the detection of HCV

RNA.(9-12) Index values of anti-HCV >10, ALT >40 IU/L, and albumin <3.8 g/dL have

been found to be independently associated with a positive HCV RNA result and the presence

of HCV infection in the setting of positive HCV serological testing.(9-12) Quantification of

HCV core antigen, a marker of HCV replication, may also be used instead of the HCV RNA

test for the diagnosis of infection. Core antigen tests are marginally less sensitive than HCV

RNA assays but have the distinct advantage of being suitable for field testing.(13) As HCV

core antigen is a protein-based assay, HCV core antigen levels are less sensitive to variations

in sample handling conditions (eg, temperature) than HCV RNA assays.

Patients with confirmed HCV infection may be further evaluated to assess the degree of liver

fibrosis and cirrhosis by liver biopsy or other noninvasive tests.(10) In countries with

resource-limited settings, the use of liver biopsy may be limited by the cost, invasiveness, and





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the risk of complications. Furthermore, noninvasive tests such as elastography and FibroTest

may have cost and availability constraints. In such settings, noninvasive tests such as

aminotransferase/platelet ratio index (APRI) or FIB-4, which rely on indirect markers such as

ALT, aspartate aminotransferase (AST), and platelet count, are recommended.(12) An APRI

score greater than 1 has been found to have a sensitivity of 76% and specificity of 72% for

predicting cirrhosis.(12) In addition to the noninvasive tests, testing for genotype is also

recommended before treatment initiation to detect the HCV genotype and tailor the treatment

strategy.(14)

Consensus Recommendations for the Diagnosis of HCV infection

Anti-HCV testing is recommended for screening/initial testing and, if the result

is positive, current infection should be confirmed by sensitive HCV RNA or core

antigen testing.

Qualitative HCV RNA testing is a reasonable, good, and cost-effective method,

and it can be used in lieu of quantitative testing.

Genotyping is recommended to guide selection of the most appropriate antiviral

regimen.

Pan-genotypic regimens may obviate the need for genotyping when genotype

testing is difficult to obtain or is unavailable.





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Screening of HCV Infection

Considering the high prevalence of HCV in Asia, screening programs should be implemented

based on the local epidemiology to detect infected individuals and provide appropriate

treatment and care. Serological testing for HCV may be offered to adults born from 1945

through 1965, high-risk individuals, and those with a history of HCV risk exposure or

behavior such as: (1) individuals who have undergone medical or dental interventions in

settings with a high prevalence of inappropriate infection control practices; (2) individuals

who have received blood transfusions without HCV serological testing of the donated blood;

(3) patients on long-term dialysis; (4) people who inject drugs (annual testing is

recommended); (5) individuals who have had tattoos, body piercing, or scarification

procedures done with in settings with suboptimal infection control practices; (6) children

born to mothers infected with HCV; (7) persons with human immunodeficiency virus (HIV)

infection (annual testing is recommended for HIV+ men who have unprotected sex with

men); (8) individuals who use/have used intranasal drugs; and (9) prisoners and previously

incarcerated persons. (12) A positive anti-HCV test result should be confirmed with a HCV

RNA or HCV core antigen assay. Rapid diagnostic tests employing serum, plasma,

fingerstick whole blood, or saliva may be used as an alternative to the standard enzyme

immunoassays as a part of the screening programs.(9, 12) Routine HCV screening is not

recommended for the general population, pregnant women, healthcare workers, or nonsexual

contacts of HCV-positive persons.(10)





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Treatment of HCV infection

The goal of HCV treatment is the attainment of sustained virologic response (SVR; defined

as the continued absence of detectable HCV RNA and/or HCV core antigen for at least 12

weeks after the completion of therapy) and subsequent reduction in all-cause mortality, liver-

associated adverse effects such as hepatic cirrhosis, end-stage liver disease and hepatocellular

carcinoma, and severe extrahepatic manifestations. (9)

Pretreatment assessment

Assessment of liver disease severity and virologic parameters before initiating treatment will

help in optimal treatment selection. The contribution of other factors or causes that may

influence the progression of liver disease and subsequent treatment outcomes, such as

alcoholism, hepatitis B virus/HIV co-infection, renal impairment, diabetes mellitus,

autoimmunity, and cardiac diseases, should be assessed to provide appropriate patient

counseling and tailor treatment choices. Assessment of HCV RNA or HCV core antigen is

recommended before initiation of treatment. Staging of cirrhosis or fibrosis and assessment of

potential drug-drug interactions are also important. An important limitation of HCV antibody

followed by PCR testing is that, while providing diagnostic accuracy, this two-step laboratory

process has an inherent temporal gap between results resulting in an inevitable loss of some

patients to follow-up confirmatory testing. In addition, the expense and technical constraints

of PCR methods (eg, difficulty in maintaining samples at ideal temperatures, limited

availability of diagnostic equipment and operators) favor point of care testing that meets the

World Health Organization’s criteria of being affordable, sensitive and specific, user-

friendly, rapid and robust, equipment-free, and delivered to those who need it

(ASSURED).(15) HCV core antigen measurement, using a chemiluminescent immunoassay





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(ARCHITECT-i2000R Immunoassay Analyser, Abbott Diagnostics, Illinois, USA). has

demonstrated high sensitivity and specificity for detection of pretreatment and posttreatment

HCV viremia.(16, 17)

Fibrosis stage may be evaluated using liver biopsy, imaging, and/or noninvasive markers.

Genotype assessment and testing for HCV resistance will help in individualizing the

treatment regimen and optimizing the treatment outcomes. Assessment of HCV genotype is

not a prerequisite for initiating HCV treatment where pangenotypic HCV treatment regimens

are available. When formal assessment of fibrosis stage not possible beyond history and

physical examination, treatment regimen choice should presume the presence of cirrhosis.

Who should be treated?

Pretreatment Assessments

Liver fibrosis assessment: The use of liver biopsy, imaging, and/or

noninvasive markers is recommended for deciding on the regimen and the

need for initiating additional measures for the management of cirrhosis (eg,

hepatocellular carcinoma screening)

Assessment for potential drug-drug interactions with concomitant

medications

Following laboratory tests are recommended:

o Complete blood count (CBC)

o Hepatic function tests (albumin, total and direct bilirubin, ALT, AST,

and alkaline phosphatase levels)

o Calculated glomerular filtration rate (GFR)

o Hepatitis B surface antigen

o Alfa-fetoprotein and INR in patients with cirrhosis





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All patients with chronic HCV infection should be considered for treatment, except for those

with limited life expectancy, which cannot be improved by treatment or transplantation.

Patients with decompensated cirrhosis should be referred to a tertiary care center and should

be managed by an expert with relevant clinical experience.

Treatment of patients with HCV GT1 infection

Six regimens have been proposed for the treatment of patients with chronic HCV GT1

infection (Table 3). A minimal testing schedule is presented in figure 1.

Sofosbuvir + ledipasvir ± ribavirin

Several clinical studies have evaluated the efficacy and safety of sofosbuvir and ledipasvir

with or without ribavirin for the treatment of chronic HCV GT1 infection in a wide range of

patient populations. In the phase III ION-1 trial, this regimen, given for 12 or 24 weeks, was

found to be highly effective with SVR ranging from 97% to 99% in treatment-naïve patients

with chronic HCV GT1 infection (n=865), including 16% with cirrhosis.(9) Similar results

were noted in treatment-naïve patients in the LONESTAR trial (n=60; 95% SVR with

sofosbuvir and ledipasvir for 12 weeks; 100% SVR with sofosbuvir and ledipasvir plus

ribavirin given for 8 weeks)(18) ELECTRON trial (n=25; 100% SVR with sofosbuvir and

ledipasvir with ribavirin given for 12 weeks),(19), and other Asian studies.(20) The SVR rate

noted in a recent real-world, observational study in 4365 treatment-naïve HCV GT1 patients

was found to be high and aligned with the results from clinical studies.(21-23). Furthermore,

8 weeks of treatment with a combination of sofosbuvir and ledipasvir was found to yield high

SVR rates (94%) comparable with the 12-week regimen (SVR: 95%) in previously untreated

patients with HCV GT1 infection without cirrhosis and with HCV RNA <6 million IU/mL in

the ION-3 trial.(24) Similar findings have been noted in recent real-world studies.(25)





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In treatment-experienced patients, including those with cirrhosis, advanced liver disease,

decompensated cirrhosis, or postliver transplantation, who have had treatment failure with

prior peg-IFN and ribavirin, NS3/4A protease inhibitors ± peg-IFN/ribavirin, sofosbuvir and

ribavirin, or NS5A inhibitor therapies, sofosbuvir and ledipasvir with or without ribavirin for

12 or 24 weeks have been found to yield high SVR rates.(26) These findings are aligned to

the results of recent real-world studies in similar patient cohorts.(19, 20, 27-32) High SVR

rates have also been noted in HCV GT1 patients co-infected with HIV-1 (both treatment-

naïve and treatment-experienced patients, including those with cirrhosis) in both clinical trials

and real-world studies.(33, 34) A significant improvement in the quality of life has been

reported with the ribavirin-free sofosbuvir and ledipasvir regimen in Asian patients with

HCV GT1, including treatment-naive or -experienced patients, without cirrhosis or with

compensated cirrhosis, and with or without coinfection with HIV.(35-37) Addition of

ribavirin was found to increase the adverse effect profile of the treatment regimen. (38, 39)

Sofosbuvir + velpatasvir ± ribavirin

The recommendation for the use of this regimen in patients with chronic HCV GT1 infection

is based on the phase III, double-blind, placebo-controlled, randomized (5:1 ratio; n=624 in

the velpatasvir and sofosbuvir combination group and n=116 in the placebo group)

ASTRAL-1 trial.(38, 40, 41) This study enrolled both treatment-naïve and previously-treated

patients with HCV GT1, GT2, GT4, GT5, or GT6 infections (68% and 32%, respectively, in

the active treatment arm), including those with compensated cirrhosis (19% in the active

treatment arm). Treatment with the combination of once-daily sofosbuvir and velpatasvir for

12 weeks resulted in an overall 99% SVR, and 98% and 99% SVR in GT1a and GT1b

patients, respectively, with safety comparable to placebo. In the phase III, open-label

ASTRAL-4 study, treatment-naïve and -experienced patients with HCV GT1 through GT6





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infections (n=267; GT1: 78%) and decompensated cirrhosis were randomized in a 1:1:1 ratio

to receive sofosbuvir and velpatasvir once daily with (n=87) or without (n=90) ribavirin for

12 weeks or sofosbuvir and velpatasvir for 24 weeks (n=90). The corresponding SVR rates in

GT1a-infected patients were 94%, 88%, and 93%, respectively, and in GT1b-infected

patients were 100%, 89%, and 88%, respectively.(42) In the phase III, open-label, single-arm

ASTRAL-5 study in HCV GT1 through GT6 patients with HIV-1 co-infection, including

those with compensated cirrhosis, sofosbuvir and velpatasvir regimen given for 12 weeks was

safe and resulted in 95% SVR in GT1 patients.(43) High SVR rates have also been noted

with the 12-week velpatasvir and sofosbuvir regimen in other randomized clinical studies in

HCV GT1-infected patients, both in treatment-naïve noncirrhotic and treatment-experienced

patients with or without cirrhosis.(44) Furthermore, improvement in patient-reported

outcomes has been noted with the velpatasvir and sofosbuvir regimen, especially in patients

with decompensated cirrhosis.(45, 46) Addition of ribavirin in the ASTRAL-4 study,

however, was associated with a temporary decrease in these outcomes.(30, 47, 48)

Sofosbuvir + daclatasvir + ribavirin

Daclatasvir plus sofosbuvir with or without ribavirin was evaluated in previously untreated

patients with HCV GT1 through GT3 infection for 24 weeks and in previously treated

patients with GT1 infection for 12 or 24 weeks in an open label study. The SVR rates were

98%, both in previously untreated and treated patients with GT1 infection.(47) In the open-

label, phase III ALLY-1 trial that enrolled patients with HCV of all genotypes, daclatasvir

plus sofosbuvir with ribavirin for 12 or 24 weeks was safe and exhibited high SVR rates:

82% in GT1 patients with cirrhosis and 95% in GT1 transplant recipients.(48) The findings

from the multicenter, observational ANRS/AFEF HEPATHER study group suggest the use of

a 12-week daclatasvir plus sofosbuvir in noncirrhotic GT1 patients and a 24-week regimen





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including ribavirin in cirrhotic GT1-infected patients.(49) High SVR rates (97%) have been

noted with daclatasvir plus sofosbuvir given for 12 weeks in HCV GT1 patients co-infected

with HIV-1 in the ALLY-2 trial that enrolled patients with GT1 through GT4 infections.(50)

This regimen given for 24 weeks has been found to be safe and effective for the treatment of

HCV recurrence post liver transplantation in GT1 patients, including those with HIV-1 co-

infection or with decompensated cirrhosis.(51, 52) Recent real-world studies and meta-

analyses support the efficacy and safety of this regimen.(53)

Grazoprevir + elbasvir

Grazoprevir plus elbasvir combination regimen, with or without ribavirin, for 12 weeks has

been found to yield high SVR rates in HCV GT1-infected patients, including treatment-naïve

(SVR range: 92%–99%),(54-56) and treatment-experienced (SVR range: 91%–100%)(57-59)

cirrhotic and noncirrhotic patients, and those co-infected with HIV-1 (SVR: 87%–97%).(59,

60) The SVR rates with the 12-week regimen in HCV GT1b treatment-naïve and -

experienced patient cohorts were noted to be close to 100%.(61, 62)

Sofosbuvir + simeprevir ± ribavirin

The COmbination of SiMeprevir and sOfoSbuvir in HCV-infected patients (COSMOS) study

investigated the safety and efficacy of the combination of sofosbuvir and simeprevir with or

without ribavirin in chronic HCV GT1-infected adult patients (n=167) (both treatment-naïve

and -experienced patients). The combination was well tolerated with high SVR rates (92%–

94%).(58) Two open-label, randomized studies assessed the efficacy and safety of 12 weeks

of sofosbuvir and simeprevir in treatment-naïve and -experienced GT1 patients, without and

with cirrhosis, respectively. SVR rates were 79-97%, with the combination being well

tolerated in both the studies.(63) Other real-world studies and studies enrolling HCV GT1





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patients co-infected with HIV-1 have also proven the efficacy and safety of the 12-week

sofosbuvir and simeprevir regimen with or without ribavirin.(64, 65) Furthermore, the

combination of sofosbuvir and simeprevir without ribavirin was found to achieve 87.5% SVR

rate in chronic HCV GT1 infected patients who failed to achieve SVR on prior treatment with

a daclatasvir-containing, sofosbuvir-free regimen in real-world settings.(66, 67)


The preferred regimens recommended by the expert panel for the treatment of patients with

chronic HCV GT2 infection are given in Table 4.

Sofosbuvir + daclatasvir ± ribavirin

In the AI444040 trial, daclatasvir plus sofosbuvir, with or without ribavirin, given for 24

weeks was associated with an SVR of 92% in previously untreated HCV GT2-infected

patients without cirrhosis.(67) In the ALLY-1 trial, daclatasvir plus sofosbuvir with ribavirin

for 12 or 24 weeks was safe and exhibited 80% SVR rate in GT2-infected patients with

cirrhosis.(48) Furthermore, in HCV patients co-infected with HIV-1 in the ALLY-2 trial, the

overall SVR rates across GT1 through GT4 in previously untreated and treated patients

treated with the 12-week daclatasvir plus sofosbuvir regimen were noted to be 97% and 98%,

respectively.(49)


The effectiveness of this regimen for the treatment of HCV GT2-infected patients is based on

the results of the randomized, phase III, open-label ASTRAL 2 trial. In this study, previously

untreated and treatment-experienced patients, including those with compensated cirrhosis,

were randomized to receive once-daily sofosbuvir and velpatasvir (n=134) or sofosbuvir plus





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weight-based ribavirin (n=132) for 12 weeks. The corresponding SVR rates were 99% and

94%, respectively (p=0.02).(51) In the ASTRAL 1 trial, the SVR rate with this 12-week

combination regimen without ribavirin was 100% in GT2-infected patients.(68) In the

ASTRAL 4 study that enrolled patients with decompensated cirrhosis, the SVR rate was

100% in GT2-infected patients treated with this combination, with or without ribavirin, for 12

weeks.(42) In the ASTRAL 5 trial, which included HCV patients co-infected with HIV-1,

including those with compensated cirrhosis, sofosbuvir and velpatasvir regimen given for 12

weeks resulted in 100% SVR in GT2-infected patients.(43) Greater than 95% SVR rates have

also been noted in other clinical trials evaluating this 12-week combination regimen in HCV

GT2-infected patients.(44)

Sofosbuvir + ribavirin

In the FISSION trial, sofosbuvir plus ribavirin for 12 weeks was associated with 97% SVR in

previously untreated patients with GT2 infection, including those with cirrhosis.(46) This

regimen exhibited 93% and 86% SVR rates in previously treated patients in the POSITRON

and FUSION trials, respectively.(69) In the VALENCE trial, which enrolled 21% cirrhosis

patients, the SVR rate with the regimen was 93% in HCV GT2-infected patients.(70) In the

BOSON study, in treatment-experienced GT2-infected patients, including those with

cirrhosis, 16 weeks of this regimen was associated with 87% SVR rate at 12 weeks.(71)

Furthermore, this regimen was effective in both treatment-naïve and treatment-experienced

HCV GT2-infected patients co-infected with HIV-1 in the PHOTON 1 and 2 trials (SVR:

88% and 92%, respectively, in PHOTON 1; SVR: 89% and 83%, respectively, in PHOTON

2).(72)





22


The preferred and alternative regimens for the treatment of HCV GT3 infection are given in

Table 5.


In the phase II AI444040 trial, the SVR rate with daclatasvir plus sofosbuvir, with or without

ribavirin, for 24 weeks was 89% in previously untreated HCV GT3-infected patients without

cirrhosis.(48) In the ALLY-3 trial, the SVR rates with daclatasvir plus sofosbuvir for 12

weeks in treatment-naïve and treatment-experienced GT3-infected patients were 90% and

86%, respectively. The SVR rate was high in patients without cirrhosis versus those with

cirrhosis (96% vs 63%, respectively).(73) The ALLY-3+ trial assessed the safety and efficacy

of daclatasvir plus sofosbuvir with ribavirin for 12 weeks or 16 weeks in both treatment-naïve

and treatment-experienced GT3-infected patients with advanced fibrosis or compensated

cirrhosis. The overall SVR was 90%, with 88% in the 12-week cohort and 83% in the 12-

week cohort with cirrhosis. The rates were not affected by past treatment history.(74) In the

ALLY-1 trial, daclatasvir plus sofosbuvir with ribavirin for 12 or 24 weeks exhibited 83%

SVR rate in GT3-infected patients with cirrhosis and 91% in GT3-infected transplant

recipients.(49) Furthermore, in the ALLY-2 trial, in HCV patients co-infected with HIV-1,

the overall SVR rates across GT1 through GT4 with daclatasvir plus sofosbuvir for 12 weeks

in treatment-naïve and treatment-experienced patients were noted to be 97% and 98%,

respectively.(51, 52) High SVR rates have also been noted with this regimen in real-world

settings in the European and French Compassionate Use programs, and in a study in

Myanmar in HCV GT3-infected noncirrhotic and cirrhotic patients, including those with

advanced liver disease and decompensated cirrhosis.(54, 75-77)





23


In the ASTRAL-3 trial, sofosbuvir and velpatasvir combination regimen for 12 weeks was

found to be effective with 95% SVR rates in HCV GT3-infected patients. This study enrolled

both treatment-naïve (SVR: 97%) and treatment-experienced (SVR: 90%) patients, including

those with compensated cirrhosis (SVR: 91% in patients with cirrhosis vs 97% in patients

without cirrhosis). The SVR in treatment-experienced patients with cirrhosis treated with this

regimen was 89%.(78) In the ASTRAL-4 study, which enrolled treatment-naïve and

treatment-experienced patients with decompensated cirrhosis, the SVR rate with sofosbuvir

and velpatasvir plus ribavirin for 12 weeks was 85% in GT3-infected patients.(79)

Furthermore, sofosbuvir and velpatasvir once daily for 12 weeks were found to be effective

with 92% SVR rate in HCV GT3-infected patients co-infected with HIV-1.(44)

Sofosbuvir + ledipasvir + ribavirin

Evidence in support of the ledipasvir and sofosbuvir regimen with ribavirin in GT3-infected

patients is limited to very few studies. In a phase 2, open-label trial in patients with HCV

GT3 or GT6 infection, this regimen given for 12 weeks was associated with 100% SVR rate

in GT3-infected patients.(80) Another recent open-label trial revealed an overall 89% SVR

with the regimen in HCV GT3-infected patients, with 79% SVR in patients with cirrhosis and

94% SVR in patients without cirrhosis.(81)


Six treatment options have been proposed by the expert panel for the treatment of patients

with HCV GT4 infection (Table 6).





24

Sofosbuvir + ledipasvir + ribavirin

In the National Institute of Allergy and Infectious Diseases (NIAID) SYNERGY trial,

sofosbuvir and ledipasvir combination for 12 weeks resulted in 100% SVR rate in treatment-

naïve and treatment-experienced HCV GT4-infected patients, including those with

cirrhosis.(82) High SVR rates were also noted with this regimen in other phase 2 studies in

similar patient cohorts.(83) Real-world studies also stand in support of the efficacy of this

combination regimen with high SVR rates (95.4%) in GT4-infected patients, including those

with cirrhosis (SVR: 93.2%).(84) In the SOLAR-2 study, sofosbuvir, ledipasvir, and ribavirin

combination for 12 and 24 weeks was associated with 78% and 94% SVR, respectively, in

HCV GT4-infected patients with advanced liver disease.(85) Furthermore, in the ION-4 trial,

sofosbuvir and ledipasvir fixed-dose combination for 12 weeks was associated with 100%

SVR in GT4-infected patients co-infected with HIV-1. This study enrolled both treatment-

naïve and treatment-experienced patients, including those with cirrhosis.(35)


In the phase III ASTRAL-1 trial, once-daily sofosbuvir and velpatasvir combination for 12

weeks was associated with 100% SVR in GT4-infected patients. This study included both

treatment-naïve and treatment-experienced patients, including those with compensated

cirrhosis.(42) In the ASTRAL-4 study, which included patients with decompensated

cirrhosis, sofosbuvir and velpatasvir combination for 24 weeks or for 12 weeks with or

without ribavirin yielded 100% SVR in GT4-infected patients.(43) Sofosbuvir and

velpatasvir combination for 12 weeks was found to be safe and was also associated with

100% SVR in GT4-infected patients co-infected with HIV-1.(44)





25


Daclatasvir plus sofosbuvir with ribavirin for 12 or 24 weeks was associated with 100% SVR

in GT4-infected patients with cirrhosis in the ALLY-1 trial.(49) In the ALLY-2 trial,

daclatasvir plus sofosbuvir given for 12 weeks was found to be effective in treating GT1

through GT4 HCV patients co-infected with HIV-1, with 100% SVR in GT4-infected

patients.(51, 52)

Grazoprevir + elbasvir

The SVR rate with grazoprevir and elbasvir combination for 12 weeks was found to be 100%

in GT4-infected treatment-naïve patients, including those with cirrhosis.(58) Other phase 2

studies have also supported the efficacy of grazoprevir and elbasvir with or without ribavirin

in GT4-infected treatment-naïve patients without cirrhosis.(86) High SVR rates have also

been noted with the regimen in studies that enrolled GT4-infected, treatment-experienced

patients with or without cirrhosis (SVR with grazoprevir and elbasvir with or without

ribavirin for 12 weeks: 93.3% and 77.8%, respectively).(87) The efficacy of this regimen also

remains proven in GT4-infected patients co-infected with HIV-1.(61)

Sofosbuvir + simeprevir

Combination therapy with sofosbuvir and simeprevir for 12 weeks has been found to be

effective and well-tolerated in chronic HCV GT4-infected patients (n=6211) in a recent real-

world study, with an overall SVR rate of 94% and treatment response rate of 97.6%.(88) In a

separate real-world study, this combination has also been found to be effective as rescue

therapy in chronic HCV GT4-infected patients who failed on daclatasvir-containing

(sofosbuvir-free) regimen, with SVR rate of 87.5%.(67)





26

Treatment of patients with HCV GT5 or GT6 infections

The preferred and alternative regimens for the treatment of HCV GT5 or GT6 infections are

given in Table 7.

Sofosbuvir + ledipasvir ± ribavirin

Evidence in support of this regimen for the treatment of HCV GT5 or GT6 infections is

limited to two phase 2 studies. In the open-label, single-arm trial by Abergel et al, treatment

with the sofosbuvir and ledipasvir combination for 12 weeks in GT5-infected treatment-naïve

and treatment-experienced patients, including those with cirrhosis, was associated with 95%

SVR rate. The SVR rates were 89% and 97% in patients with and without cirrhosis,

respectively. The combination was well tolerated.(84) In another open-label trial in patients

with GT3 or GT6 infection, treatment-naïve and treatment-experienced patients with GT6

infection (n=25) were treated with ledipasvir and sofosbuvir combination for 12 weeks. The

SVR rate with the combination was noted to be 96%.(80) However, in recent real-world

studies, the SVR rates have been found to be low with this regimen in GT6-infected

patients.(75)


In the ASTRAL-1 study, which enrolled patients with GT1, GT2, GT4, GT5, or GT6

infections, treatment with once-daily sofosbuvir and velpatasvir for 12 weeks was associated

with 97% and 100% SVR rates in patients with GT5 and GT6 infections, respectively.(42) In

another phase 2 study that assessed the safety and efficacy of this combination in treatment-

naïve noncirrhotic patients with HCV GT1 through GT6 infections, the SVR rate was 95%-

96% for GT5- and GT6-infected patients.(46) The ASTRAL-4 study, which enrolled both

treatment-naïve and treatment-experienced patients with decompensated cirrhosis, had less

than 1% patients with GT6 infection. Treatment with sofosbuvir and velpatasvir for 24 weeks

in this cohort was associated with 100% SVR rate.(43)





27


Data in support of this regimen for the treatment of GT5- or GT6-infected patients are very

limited. In the ALLY-1 trial, sofosbuvir, daclatasvir, and ribavirin combination was used

across all genotypes in HCV patients with advanced liver disease. Sustained virologic

response was achieved in 1 GT6-infected liver transplant recipient treated with the

combination.(49)

Treatment of patients in whom liver fibrosis assessment is not possible and HCV

genotyping is not available or HCV genotype is indeterminate or GT7

The expert panel recommended the use of sofosbuvir and velpatasvir in combination with

ribavirin for 12 weeks or sofosbuvir plus daclatasvir in combination with ribavirin for 12

weeks, with extended duration of 24 weeks in treatment-experienced patients, as the preferred

regimens for the treatment of these patient cohorts. Evidence in support of this

recommendation is limited. Sofosbuvir and velpatasvir combination for 12 weeks was found

to achieve SVR in a recent HCV case report with GT7 infection.(89)

Renal Impairment

Although the safety and efficacy of sofosbuvir in patients with severe (estimated GFR

<30mL/min) have not been clearly established, there is increasing evidence that treatment

responses remain high and comparable to those without renal impairment.(90, 91)

A report of the safety and efficacy of sofosbuvir-containing regimens in patients with mild to

severe renal dysfunction (eGFR groups: <30 mL/min; 31-45 mL/min; 46-60 mL/min; and

>60 mL/min)(92) found the regimens were well tolerated with comparable SVR rates and no

increased discontinuation among patients with low eGFRs. Progressive deterioration of renal





28

function was observed, however, in patients with an eGFR <30 mL/min, highlighting the

need for close monitoring of renal function in these patients.

Daclatasvir, elbasvir, grazoprevir, ledipasvir, and simeprevir are primarily hepatically

metabolized and do not require dose adjustments in the setting of renal impairment.

Drug-Drug Interactions

DAAs have the potential for drug-drug interactions with concomitant medications, including

important interactions with many commonly used medications, such as proton pump

inhibitors (reduce bioavailability of ledipasvir and velpatasvir), hydroxy-3-methylglutaryl-

coenzyme (HMG-CoA) reductase inhibitors, and antiretrovirals. A detailed review of drug-

drug interactions is beyond the scope of this review. In order to minimize the likelihood of

clinically meaningful drug-drug interactions we strongly recommend cross referencing any

concomitant medication with planned DAA therapy at the publicly accessible, comprehensive

and regularly updated reference site, http://www.hep-druginteractions.org.

On- and Posttreatment Assessments

On-treatment assessments are recommended for monitoring the treatment efficacy and safety

and possible drug-drug interactions, and ensuring medication adherence. Posttreatment

follow-up and assessment helps in confirming the successful elimination of the virus and

preventing relapses. The on- and posttreatment assessments recommended by the expert

panel have been listed in Table 8.

Decompensated Cirrhosis

The preferred and alternative regimens for the treatment of patients with decompensated

cirrhosis are given in Table 9.





29

Patients with decompensated liver cirrhosis, defined by CPT class of B or C, CPT score of

>/=7, are at substantial risk of liver-related morbidity and mortality. Understanding the

potential benefit and risks of treatment in this population is particularly important. Large,

prospective, randomized controlled multicenter clinical trials have consistently demonstrated

a high frequency of SVR (>90%) good tolerability and frequent improvement in clinical and

lab indices of severity of liver disease.(29, 43, 93-95) Improvement can be substantial enough

for patients to be removed from liver transplant waitlists.(96) Although the frequency of SVR

is lower than for patients without HCC, the great majority of patients with HCC achieve

SVR.(97) HCC is not a contraindication to DAA therapy in and of itself. Although some

patients with decompensated cirrhosis will fail to achieve SVR, because access to liver

transplantation is especially limited in resource limited settings, consideration should be

given to treating HCV in patients with decompensated cirrhosis who do not have an obvious

contraindication to treatment with DAAs. Because protease inhibitors are contraindicated in

patients with decompensated cirrhosis, treatment should be with sofosbuvir and an NS5a

inhibitor. There are no data describing the safety and efficacy of DAA therapy in patients

with MELD score >/=30 nor in patients with severe hypoalbuminemia, stage 2 ascites or

stage 2 encephalopathy. The risk to benefit profile of treatment of HCV infection with DAAs

is not known in patients with 1 or more of these characteristics.

PostLiver Transplantation

The preferred and alternative regimens for the treatment of patients with decompensated

cirrhosis are given in Table 10.

Left untreated, recurrence of HCV infection can be a major cause of posttransplant graft

failure and mortality, with one third of patients with posttransplant HCV infection developing





30

cirrhosis or losing their graft by the fifth postoperative year. HCV infection should be treated

early (by the fourth postoperative month) following liver transplantation, regardless of

fibrosis stage. Because of the potential for hepatotoxicity and for exacerbated drug-drug

interactions, all protease inhibitors should be avoided in patients with decompensated

cirrhosis.

Treatment

Two large, multicenter, open-label, phase 2 trials of nearly 400 liver transplant recipients

across a wide spectrum of severity of HCV recurrence reported an SVR frequency of >95%

with 12 weeks of treatment with sofosbuvir and ledipasvir with low (600mg/day) initial dose

ribavirin, for disease severity up to compensated (CPT-A) cirrhosis. SVR rates were lower,

~85 and 60,% among patients with CTP class B and C cirrhosis respectively.(98) Sofosbuvir

and ledipasvir with ribavirin are thus recommended for the treatment of HCV genotypes 1, 4,

5, and 6 following liver transplantation in patients who are noncirrhotic or who have

compensated cirrhosis. Sofosbuvir with daclatasvir has also been reported to be safe and

effective in liver transplant recipients, including those with HCV genotypes 2 and 3,(99)

Although there are no published data in liver transplant recipients, because of the superior

efficacy observed in the nontransplant setting and because of the similar drug-drug

interaction profiles of velpatasvir and ledipasvir, we recommend sofosbuvir with daclatasvir

or velpatasvir with ribavirin for 12 weeks for patients with HCV infection with genotypes 2

and 3 following liver transplantation. Although there are reports of similar efficacies with

and without ribavirin in retrospective analyses, (100, 101) we recommend ribavirin at an

initial dose of 600mg/day in treating posttransplant HCV infection unless contraindicated.

Longer (24 weeks) duration of treatment should be considered in patients who DAA

treatment experienced, have cirrhosis or who are intolerant or ineligible for ribavirin therapy.





31

Treatment of severe/decompensated liver disease following liver transplantation should be

managed in the same fashion as in the nontransplant setting.

Risk of Rejection and Alloimmune /Plasma Cell Hepatitis

Improved hepatic function can lead to altered pharmacokinetics of immunosuppressive agents

following eradication of HCV infection,(102) increasing the risk of acute cellular rejection

and alloimmune / plasma cell hepatitis, necessitating and usually responding to responding to

increased immunosuppression.(103, 104) For these reasons, we recommend increased

frequency of monitoring of calcineurin inhibitor trough levels and liver biochemical profile in

the first 3 months following end of DAA therapy.

Drug Interactions Between DAAs and Immunosuppressive Agents

Drug-drug interactions, which are complex and can be unpredictable in the setting of

polypharmacy and labile hepatic and renal function, are an important consideration in liver

transplant recipients. Careful assessment of potential drug-drug interactions should be

performed in all liver transplant recipients before initiation of DAA therapy. We recommend

the HEP Drug Interactions website as a resource for screening for potential drug-drug

interactions (http://www.hep-druginteractions.org). All protease inhibitors are contraindicated

in patients who are receiving cyclosporine. Cyclosporine and tacrolimus increase daclatasvir

area under the curve (AUC) by amounts that are not clinically significant (40% and 5%,

respectively). Sofosbuvir, ledipasvir and daclatasvir do not cause clinically meaningful

changes in calcineurin inhibitor, mammalian target of rapamycin (mTOR) inhibitor, steroid,

or mycophenolate levels.(105) Based on the metabolism of grazoprevir and elbasvir, a 15-

fold increase in grazoprevir AUC and a 2-fold increase in elbasvir AUC can be expected with

cyclosporine co-administration. Therefore, this combination should be avoided. Since a 40%





32

to 50% increase in tacrolimus level is predicted during co-administration with grazoprevir, no

dosing adjustments are anticipated but tacrolimus levels should be monitored.

Summary and Future Directives

The treatment landscape for HCV infection has been greatly affected by the introduction of

several new DAAs and combination regimens, access to which is highly variable between

geographic areas. The selection of an appropriate combination regimen for achieving optimal

outcomes should take into consideration both patient-related factors (genotype, affordability,

access to treatment, and treatment adherence) and treatment-related factors (efficacy, duration

of therapy, safety, drug-drug interactions, formulation type, and dosing regimen) at a local

level. In addition to optimizing the treatment regimen, simplification of HCV management at

various levels, including screening, treatment, and monitoring, is an essential prerequisite for

achieving successful treatment outcomes in resource-limited settings in Asia where disparate

epidemiology is a major challenge. Furthermore, improving patients’ access to newer,

effective, and safer treatments and enhancing patients’ awareness to the disease, testing, and

treatment will help in early detection and successful management of the HCV infection in

these settings.

The current consensus document is a joint effort by key hepatology experts from Asia and is

aimed at providing guidance to the physicians in the region for the management of HCV

infection with optimal treatment regimens. Evidence-based recommendations from the expert

panel on the diagnosis, treatment, and pre, on-, and posttreatment assessment of patients with

HCV infection in the focus settings have been comprehensively summarized in this article.

Acknowledgement: We would like to thank BioQuest Solutions Pvt. Ltd for their editorial

services.





33

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87. Kwo P, Gane EJ, Peng CY, et al. Effectiveness of Elbasvir and Grazoprevir

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Table 1: Definitions of the grading of the recommendations

Grading of the recommendation Definition of the grading

Preferred Treatment can be used in most patients and

recommendation is based on optimal efficacy,

favorable tolerability and toxicity profiles, duration,

and pill burden.

Alternative Treatment can be the one that is effective but with

potential disadvantages/limitations for use in certain

patient populations or with less supporting data as

compared with the recommended regimens. In certain

situations, an alternative regimen may be an optimal

regimen for a specific patient population.

Not Recommended Treatment is clearly inferior compared with

recommended or alternative regimens because of

factors such as lower efficacy, unfavorable tolerability

and toxicity, longer duration, and/or higher pill

burden. Unless otherwise indicated, such regimens

should not be administered to patients with HCV

infection.

HCV, hepatitis C virus.





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Table 2. Direct-acting antiviral treatment regimens available in specific Asian countries

Country SOF LDV/SOF DCV SOF/VEL SIM GZV+EBV

Mongolia √ √ √

Indonesia √ √a √

a √ √

c

Philippines √ √ a √

a

India √ √ √ √

Pakistan √ √ a √

a √

a

Vietnam √ b √

b √

b √

Myanmar √ √ √ aAvailable under special access;

bAvailable under quota;

cExpected launch in early 2018 for HCV genotype 1.

DCV, daclatasvir; EBV, elbasvir; GZV, grazoprevir; LDV, ledipasvir; OBV/PTV/r:

ombitasvir/paritaprevir/ritonavir; SIM, simeprevir; SOF, sofosbuvir; VEL, velpatasvir; 3D,

ombitasvir/paritaprevir/ritonavir plus dasabuvir.





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Table 3. Recommended treatment regimens for HCV GT1 infection (ordered

alphabetically within categories, not by preference)

Recommendation

category

Treatment

option/s

Treatment regimens

Preferred 1. LDV + SOF ±

RBV

LDV + SOF for 12 weeks

In treatment-naïve patients having HCV RNA <6 million

IU/mL in whom cirrhosis has been conclusively ruled out by

transient elastography (Fibroscan) or biopsy: LDV + SOF for

8 weeks

In treatment-experienced cirrhotic patients/patients with

decompensated liver disease/postliver transplant patients:

LDV + SOF + RBV for 12 weeks OR LDV + SOF for 24

weeks if RBV is ineligible

2. SOF + VEL ±

RBV

SOF + VEL for 12 weeks (addition of RBV may be

considered in difficult to treat [treatment-experienced,

cirrhotic] patients)

In patients with decompensated cirrhosis (currently treated

hepatic encephalopathy or ascites or Child-Pugh-Turcotte

class B or C): SOF + VEL + weight-based RBV for 12 weeks

Alternative 1. SOF + DCV ±

RBV

SOF + DCV for 12 weeks (addition of RBV may be

considered if cirrhosis has not been conclusively ruled out)

In patients with compensated cirrhosis: SOF + DCV ±

weight-based RBV for 24 weeks

In patients with decompensated cirrhosis: SOF + DCV +

RBV for 12 weeks (OR) SOF + DCV for 24 weeks if RBV is

ineligible

2. GZV + EBV GZV + EBV for 12 weeks for only patients with GT1b

infection

(Since RAS testing is not available in resource-limited settings,

this regimen is not recommended for GT1a infection)

Other alternatives 1. SOF + SIM ±

RBV

SOF + SIM for 12 weeks

o In patients with cirrhosis (Child-Pugh-Turcotte class A):

SOF + SIM ± RBV for 24 weeks

o This regimen is not recommended in patients with

decompensated liver disease

o As rescue therapy (without RBV) in patients who failed

on daclatasvir-containing (sofosbuvir-free) regimen

DCV, daclatasvir; DSV, dasabuvir; EBV, elbasvir; GT, genotype; GZV, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OMV,

ombitasvir; PAR, paritaprevir; RBV, ribavirin; RNA, ribonucleic acid; RTV, ritonavir; SIM, simeprevir; SOF, sofosbuvir; VEL, velpatasvir.





50



Recommendation

category

Treatment

option(s)

Treatment regimen

Preferred 1. SOF + DCV

± RBV

SOF + DCV for 12 weeks

o In decompensated cirrhosis: SOF + DCV + RBV

for 12 weeks

2. SOF + VEL

± RBV

SOF + VEL for 12 weeks (addition of weight-based

RBV may be considered for decompensated cirrhosis)

3. SOF + RBV SOF + RBV for 12 weeks (data are not available for

patients with decompensated cirrhosis)

DCV, daclatasvir; HCV, hepatitis C virus; GT, genotype; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.





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Recommendation

category

Treatment

option(s)

Treatment regimen

Preferred 1. SOF + DCV

± RBV



In patients with compensated cirrhosis

o Treatment-naïve patients: SOF + DCV + RBV for

12 weeks

o Treatment-experienced patients: SOF + DCV +

RBV for 24 weeks

In patients with decompensated cirrhosis

o SOF + DCV + RBV for 12 weeks

o If RBV ineligible: SOF + DCV for 24 weeks

2. SOF + VEL

± RBV


considered based on the physician’s discretion in

treating difficult-to-treat patients [treatment-experienced

patients, patients with cirrhosis])

o In patients with decompensated cirrhosis: SOF +

VEL + weight-based RBV for 12 weeks

Alternative 1. LDV + SOF

+ RBV

LDV + SOF + RBV for 12 weeks (should be considered

only when preferred regimens are not available)

DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir





52



Recommendation

category

Treatment

option(s)

Treatment regimen

Preferred 1. LDV + SOF

± RBV

LDV + SOF for 12 weeks (addition of RBV may be

considered based on the physician’s discretion in treating

difficult-to-treat patients [treatment-experienced patients,

patients with cirrhosis])

o In case of previous SOF treatment failure: LDV +

SOF + RBV for 12 weeks

2. SOF + VEL

± RBV







Alternative 1. SOF + DCV

± RBV



o Cirrhosis of any class: SOF + DCV + RBV for 12

weeks

o If RBV is ineligible, SOF + DCV for 24 weeks

2. GZV + EBV GZV + EBV for 12 weeks

o Not recommended in patients with decompensated

cirrhosis or liver transplant recipients

Other

alternatives

1. OMV +

PAR + RTV +

RBV

OMV + PAR + RTV + RBV for 12 weeks

o Recommended in noncirrhotic patients only

2. SOF + SIM SOF + SIM for 12 weeks

o In treatment-naïve patients with or without

cirrhosis

o As rescue therapy (without RBV) in patients who

failed on daclatasvir-containing (sofosbuvir-free)

regimen DCV, daclatasvir; EBV, elbasvir; GT, genotype; GZV, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OMV, ombitasvir; PAR,

paritaprevir; RBV, ribavirin; RTV, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; SIM: Simeprevir.





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Table 7. Recommended treatment regimens for HCV GT5 or GT6 infections (ordered


Recommendation

category

Treatment

option(s)

Treatment regimen


± RBV







2. SOF + VEL

± RBV








± RBV




weeks

o If RBV is ineligible, SOF + DCV for 24 weeks DCV, daclatasvir; HCV, hepatitis C virus; GT, genotype; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir; VEL, velpatasvir.





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Table 8. On- and posttreatment assessments during the management of HCV infection

Assessments Expert recommendations

On-treatment In patients with cirrhosis: CBC, creatinine level, calculated

GFR, and hepatic function panel may be repeated after 4

weeks.

HCV RNA testing (qualitative/quantitative) may not be

required, as there are no current recommendations for

response-guided therapy. Testing may be done at the end of

treatment, but it is not mandatory.

Assessment for potential drug-drug interactions with

concomitant medications is recommended.

Periodic review on therapy compliance and general condition

of the patient is recommended.

Posttreatment Assessment for SVR should be done at 12 or 24 weeks after

the end of the treatment.

In patients who have failed therapy:

o Disease progression assessment (hepatic function panel,

CBC, and INR) should be done once in 6 to 12 months.

o In patients with advanced fibrosis (METAVIR stages F3 or

F4), screening for hepatocellular carcinoma with ultrasound

examination is recommended every 6 months.

o Endoscopic screening for esophageal varices is

recommended in cirrhotic patients.

In patients who achieve SVR:

o In patients with advanced fibrosis (Metavir stage F3 or F4),

screening for hepatocellular carcinoma with ultrasound

examination is recommended every 6 months.

o Endoscopic screening for esophageal varices is

recommended in cirrhotic patients.

o AFP and PIVKA II as a screening test for HCC CBC, complete blood count; GFR, glomerular filtration rate; HCV, hepatitis C virus; INR, International normalized ratio; RNA, ribonucleic

acid; SVR, sustained virologic response; AFP, alpha fetoprotein; PIVKA II, prothrombin induced by vitamin K absence-II; HCC,

hepatocellular carcinoma.





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Table 9. Recommended treatment regimens for Decompensated Cirrhosis (ordered


Recommendation

category

Treatment

option(s)

Treatment regimen


± RBV







2. SOF + VEL

± RBV








± RBV




weeks






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Table 10. Recommended treatment regimens for Liver Transplant Recipients (ordered


Recommendation

category

Treatment

option(s)

Treatment regimen


± RBV







2. SOF + VEL

± RBV








± RBV




weeks





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