Anti-HCV antibody Antibody to hepatitis C virus (HCV), which can be detected in the blood usually within two or three months of HCV infection or exposure. The terms HCV antibody and anti-HCV antibody are equivalent, but in these guidelines HCV antibody is used throughout.
HCV RNA HCV viral genomes that can be detected and quantified in serum by nucleic acid testing (NAT).
HCV core antigen (HCVcAg)
Nucleocapsid peptide 22  of HCV, which is released into plasma during viral assembly and can be detected from early on and throughout the course of infection.

# Natural history of viral hepatitis
Chronic HCV infection The presence of persistent HCV RNA or HCVcAg in serum in association with positive serology for HCV antibody.

# Viraemic infection
Hepatitis C virus infection associated with presence of virus in the blood (as measured by HCV RNA) and often referred to as active, ongoing or current infection.
An advanced stage of liver disease characterized by extensive hepatic fibrosis, nodularity of the liver, alteration of liver architecture and disrupted hepatic circulation.

# Decompensated cirrhosis
A stage at which clinical (or laboratory) signs of cirrhosis are present. Clinical features include portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy), coagulopathy or liver insufficiency (jaundice). Other clinical features of advanced liver disease/cirrhosis may include hepatomegaly, splenomegaly, pruritus, fatigue, arthralgia, palmar erythema and oedema. Laboratory features usually present in those with cirrhosis and portal hypertension include a low serum albumin, low platelet count and a prolonged prothrombin time.

# GLOSSARY xiii

# Measures of treatment response

# HCV sustained virological response (SVR)
Undetectable HCV RNA in the blood at a defined time point after the end of treatment, usually at 12 or 24 weeks (SVR12 or 24).
HCV non-response Detectable HCV RNA in the blood throughout treatment.
HCV relapse Undetectable HCV RNA during treatment and/or at end of treatment, but subsequent detectable HCV RNA following treatment cessation.
HCV viral breakthrough Undetectable HCV RNA during treatment followed by detectable HCV RNA while on continued treatment.

# Diagnostic testing for hepatitis C
Serological assays Assays that detect the presence of either antigens or antibodies, typically in serum or plasma but also in capillary/venous whole blood and oral fluid. These include rapid diagnostic tests (RDTs), laboratory-based immunoassays, for example, enzyme immunoassays (EIAs), chemiluminescence immunoassays (CLIAs), and electro-chemiluminescence immunoassays (ECLs).

# Rapid diagnostic test (RDT)
Immunoassays that detect antibodies or antigens or nucleic acid and can give a result in less than one hour. Most RDTs can be performed with capillary whole blood collected by finger-stick sampling.

# Enzyme immunoassay (EIA)
Laboratory-based serological immunoassays that detect antibodies, antigens or a combination of both. Requires plasma or serum collected by venepuncture as venous whole blood.

# Nucleic acid testing (NAT)
A molecular technology, for example, polymerase chain reaction (PCR) or nucleic acid sequence-based amplification (NASBA) or transcription-mediated amplification (TMA), that can detect very small quantities of viral nucleic acid (RNA, DNA or total nucleic acid (TNA)), qualitatively or quantitatively.
Point-of-care testing Point-of-care testing is conducted at the site at which clinical care is being provided, with the results being returned to the person being tested or care giver on the same day as sample collection and test to enable clinical decisions to be made in a timely manner.
Reflex viral load testing A linked HCV RNA (or HCVAg) test that is triggered among all people who have an initial positive HCV antibody screening test.
Reflex HCV RNA testing may be implemented in two ways: either laboratory-based reflex testing or clinic-based reflex testing.
- Laboratory-based HCV reflex testing refers to a testing algorithm in which patients have only a single clinical encounter and one blood draw or specimen for an initial laboratory-based HCV antibody test (in some cases it may be divided in two tubes), which is then sent to the lab. If the sample for HCV antibody testing in the lab is positive, then the same existing or a duplicate specimen is automatically used for a prompt "reflex" laboratory-based HCV RNA NAT or HCVAg) test. The result returned to the patient/doctor is, therefore, for both the HCV antibody result and, if positive, the HCV RNA result. No further visit or specimen collection is required.
- Clinic-based reflex testing refers to a testing strategy where there is only a single clinical encounter/visit for an initial rapid diagnostic HCV antibody test, but with two blood draws. A capillary (fingerstick) whole blood specimen is first taken and tested using a rapid diagnostic HCV antibody test, which, if positive (after usually a 15-minute wait), is then immediately followed by a "reflex" second blood specimen collection (either venous blood sample or fingerstick) for HCV RNA detection of current infection. The second blood sample for HCV RNA testing may either be sent to a laboratory for HCV RNA NAT (or HCVAg) test or tested onsite using a point-of-care HCV RNA NAT assay.

# Measures of test performance
Clinical/diagnostic sensitivity of a test
The ability of a test to correctly identify those with the infection or disease (that is, true positives/true positives + false negatives).

# Clinical/diagnostic specificity of a test
The ability of a test to correctly identify those without the infection or disease (that is, true negatives/true negatives + false positives). Sensitivity and specificity are usually expressed as point estimates accompanied by confidence intervals.

# Positive predictive value (PPV)
The probability that when a person's test result is positive, they truly have the infection/disease.

# Negative predictive value (NPV)
The probability that when a person's test result is negative, they truly do not have the infection/disease. Predictive values are influenced by the prevalence of the disease in the population.
Analytical sensitivity/limit of detection (LoD)
The lowest concentration of measurement that can be consistently detected in 95% of specimens tested under routine laboratory conditions. It defines the analytical sensitivity, in contrast to the clinical or diagnostic sensitivity.

# Populations terminology

# Age groups
The following definitions are used in these guidelines for the purpose of implementing treatment recommendations for specific age groups in children aged 3 years and above. It is acknowledged that countries may have other definitions under national laws:
- An adult is a person older than 19 years of age (which includes young people 20-24 years old). - An adolescent is a person 12-19 years of age inclusive.
- An older child is a person 6-11 years of age.
- A younger child is a person 3-5 years of age.

# Key populations
Groups of people who, due to specific high-risk behaviours, are at increased risk for human immunodeficiency virus (HIV) blood-borne infections irrespective of the epidemic type or local context. This term may also apply to hepatitis B virus (HBV) and/ or HCV infection. Key populations often have legal and social issues related to their behaviours that increase their vulnerability to HIV, HBV and HCV infection. These guidelines refer to the following groups as key populations: men who have sex with men, people who inject drugs, people in prisons and other closed settings, sex workers and transgender people.
Vulnerable populations Groups of people who are particularly vulnerable to HBV/HCV infection in certain situations or contexts. These guidelines refer to the following groups as vulnerable populations: migrant and mobile workers; refugee and displaced populations; and indigenous populations. They may also face social and legal barriers to access to viral hepatitis prevention and treatment.

# Men who have sex with men
Refers to all men who engage in sexual and/or romantic relations with other men. The words "men" and "sex" are interpreted differently in diverse cultures and societies and by the individuals involved.
People who inject drugs Refers to people who inject psychotropic (or psychoactive) substances for non-medical purposes. These drugs include, but are not limited to, opioids, amphetamine-type stimulants, cocaine, hypno-sedatives and hallucinogens. Injection may be through intravenous, intramuscular, subcutaneous or other injectable routes.

# Sex workers
Includes female, male and transgender adults (18 years of age and above) who receive money or goods in exchange for sexual services, either regularly or occasionally.
Testing approaches Community-based testing: includes using outreach (mobile) approaches in general and key populations; home-based testing (or door-to-door outreach); testing in workplaces, places of worship, parks, bars and other venues; in schools and other educational establishments; as well as through campaigns.
Facility-based testing Includes testing in health care settings such as primary care clinics, inpatient wards and outpatient clinics, including specialist dedicated clinics for HIV, viral hepatitis, sexually transmitted infection (STI) and tuberculosis (TB), in district, provincial or regional hospitals and their laboratories, and in private clinical services.

# Service delivery terminology
The process of delegating significant authority and resources to lower levels of the health system (provincial, regional, district, sub-district, primary health care and community).

# Differentiated service delivery
An approach that simplifies and adapts viral hepatitis services to better serve the needs of people living with viral hepatitis and to optimize the available resources in health systems.
The co-location and sharing of services and resources across different disease areas. In the context of hepatitis C virus infection, this may include the provision of testing, prevention, care and treatment services alongside other health services, such as HIV, noncommunicable disease (NCD) screening, TB, STI, antenatal clinic (ANC), contraceptive and other family planning services.

# Integrated service delivery
Integrated health services are health services that are managed and delivered in a way that ensures people receive a continuum of health promotion, disease prevention, diagnosis, treatment, disease management, rehabilitation and palliative care services, at the different levels and sites of care within the health system and according to their needs throughout the life course.
The rational redistribution of tasks from "higher-level" cadres of health care providers to other cadres, such as trained lay providers, including community members.

# Lay provider:
Any person who performs functions related to health care delivery and has been trained to deliver services but has received no formal professional or paraprofessional certificate or tertiary education degree.
Linkage to care A process of actions and activities that support people testing for HBV/HCV to engage with prevention, treatment and care services as appropriate for their hepatitis B and C status.
Person-centred care Care that is focused on and organized around the health needs and expectations of people and communities rather than on diseases.
xvii EXECUTIVE SUMMARY Hepatitis C virus (HCV) infection is a major public health problem and cause of chronic liver disease that leads to approximately 399 000 deaths annually. In 2019, WHO estimated that 58 million persons were chronically infected and living with hepatitis C, with a disproportionately high burden in low-and middle-income countries (LMICs). In 2016, WHO developed the global health sector strategy on viral hepatitis 2016-2021, with the ambitious goal to eliminate viral hepatitis as a public health threat by 2030. While good progress has been made in several champion countries, there remains a major testing and treatment gap. In 2019, only 21% of the 58 million persons with chronic HCV infection had been diagnosed, and 13%, treated. Achieving HCV elimination will require a radical simplification in care pathways to overcome barriers in access to HCV testing and treatment.
The objective of these guidelines is to provide updated evidence-based recommendations on the priority HCV-related topics from the 2018 WHO Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C infection and the 2017 WHO Guidelines on hepatitis B and C testing. These priority areas are:
- direct-acting antiviral (DAA) treatment of adolescents and children ages 3 years of age
- simplified HCV service delivery (decentralization, integration and task sharing)
- HCV diagnostics -use of point-of-care (POC) HCV ribonucleic acid (RNA) assays and reflex HCV RNA testing.
These guidelines also update existing chapters without new recommendations, such as the inclusion of new manufacturers' protocols on the use of dried blood spot (DBS) for HCV RNA testing and new data to inform the limit of detection for HCV RNA assays as a test of cure, in addition to their use for diagnosis.
Overall, this guideline update is consistent with the modular approach to updating guidelines for diagnosis and treatment of chronic hepatitis B and C virus infections B adopted since 2020 (that is, periodic updating of specific sections or chapters in response to emerging evidence).
In July 2021, the first modular update on hepatitis C self-testing guidelines was launched. This guidelines update represents the second modular update on hepatitis C testing and treatment. In 2023, all updates will be compiled along with existing recommendations into a single consolidated guidelines on prevention, testing, care and treatment of hepatitis B and C, containing all relevant guidance.
xviii Five systematic reviews and meta-analyses were undertaken to address the key research questions, in addition to four values and preferences surveys to assess perspectives of affected communities and health workers, cost-effectiveness analyses and a series of case studies on implementation experience to inform the process of formulating recommendations.
The main areas of new recommendations are:
- Treatment in adolescents and children: Expansion of the 2018 "treat all" recommendation for all adults to now include all adolescents and children with chronic HCV infection ages three years or older, with use of the same pangenotypic DAA regimens already recommended in adults (sofosbuvir/daclatasvir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir).
- Simplified service delivery: Expansion of HCV testing and treatment services, ideally at the same site, through decentralization of care to lower-level facilities; integration with existing services, such as in primary care, harm reduction, prisons and HIV services; and promotion of task sharing through delivery of HCV testing, care and treatment by trained but non-specialist doctors and nurses.
- HCV RNA testing: The use of PoC HCV RNA assays is now recommended as an additional approach to diagnose viraemic infection, especially among marginalized populations, such as persons who inject drugs, and hard-to-reach communities with constrained access to health care and that have high rates of loss to follow-up. Reflex HCV RNA testing in those with a positive HCV antibody is recommended as an additional strategy to promote linkage to care and treatment. This can be achieved either through laboratory-based reflex HCV RNA testing using a specimen already held in lab or clinic-based reflex testing in a health facility through immediate specimen collection for HCV RNA testing following a positive rapid HCV antibody test result, avoiding the need for a second visit and further blood sample.
These guidelines are addressed primarily to national hepatitis programme managers and other policy-makers in ministries of health, particularly in LMICs, who are responsible for the development of national hepatitis testing and treatment plans, policy and guidelines. Implementation of the recommendations in these guidelines should be informed by local context, including HCV epidemiology and prevalence of other comorbidities, availability of resources, the organization and capacity of the health system and anticipated cost-effectiveness.
Existing, updated or new recommendation DAA treatment in adults, adolescents and children Whom to treat?
We recommend treatment using pangenotypic DAA regimens for all adults, adolescents and children ages 3 years and above with chronic hepatitis C infection, regardless of stage of disease:
Adults (18 years) strong recommendation; moderate certainty of evidence Adolescents (12-17 years) 1 strong recommendation; moderate/low certainty of evidence 2 Older children (6-11 years) strong recommendation; moderate/very low certainty of evidence 2 Younger children (3-5 years) conditional recommendation; very low certainty of evidence 1 For consistency, the age groupings are the same as those used in the trials for regulatory submissions. 2 Range of certainty of evidence is based on evidence for different DAA regimens.
Existing New New
What DAA regimens to use?
We recommend the use of the following pangenotypic DAA regimens is recommended in adults (18 years and above), adolescents (12-17 years), older children (6-11 years) (all strong recommendations) and younger children (3-5 years) (conditional recommendation):
- SOF/DCV 1 for 12 weeks: 2 certainty of evidence: high (adults), high (adolescents and older children); very low (younger children) - SOF/VEL for 12 weeks: certainty of evidence: high (adults), low (adolescents and older children); very low (younger children) - G/P for eight weeks: certainty of evidence: high (adults), moderate (adolescents and older children); very low (younger children). 1 Decentralization of services refers to service delivery at peripheral health facilities, community-based venues and locations beyond hospital sites or conventional health care settings, bringing care nearer to patients' homes. 2 The systematic review was based on an analysis by population group (people who inject drugs, prisoners, general population and people living with HIV) rather than setting or services (harm reduction sites, prisons, primary care or HIV/ART clinics), although these were highly related to population group. 3 Integrated service delivery refers to delivery of different health services in a way that ensures people receive a continuum of health promotion, disease prevention, diagnosis and treatment. 4 Task sharing refers to the rational redistribution of tasks from "higher-level" cadres of health care providers to other cadres, such as trained lay providers, including community members.
New New New
xxi HCV RNA testing -Detection of viraemic HCV infection Laboratory-based HCV NAT testing: Directly following a positive HCV antibody serological test result, the use of quantitative or qualitative nucleic acid testing (NAT) for detection of HCV ribonucleic acid (RNA) is recommended as the preferred strategy to diagnose viraemic infection.
(strong recommendation, moderate/low certainty of evidence)
HCV core antigen assay: An assay to detect HCV core (p22) antigen, which has comparable clinical sensitivity to laboratory-based HCV RNA NAT assays, can be an alternative approach to diagnose HCV viraemic infection.
(conditional recommendation, moderate certainty of evidence)

# Detection of viraemia (nucleic acid testing)
The use of DBS specimens to test for HBV DNA and HCV RNA for diagnosis of HBV and HCV viraemia, respectively, may be considered in settings where: - there is a lack of access to sites or nearby laboratory facilities for NAT, or provision for timely delivery of specimens to a laboratory; or - there are persons with poor venous access (for example, in drug treatment programmes, prisons).

# (conditional recommendation, low (HBV)/moderate (HCV) certainty of evidence)
Updated WHO Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations (WHO, 2022) (7) An updated version of the Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations (WHO, 2022) (7) will be published in July 2022. This guidance outlines a public health response to HIV, viral hepatitis and sexually transmitted infections (STIs) for five key populations, notably men who have sex with men, sex workers, people in prisons and other closed settings, people who inject drugs and trans and gender diverse.
The guidelines include a new recommendation on peer navigators to support people from key populations to start HIV, viral hepatitis or STI treatment and to remain in care, as well as a new recommendation on offering online delivery of HIV, viral hepatitis and STI services to key populations as an additional option, while ensuring that data security and confidentiality are protected. It includes new good practice statements on chemsex and behavioural interventions.
There are two recommendations directly relevant to HCV testing and treatment:
- People at ongoing risk and a history of treatment-induced or spontaneous clearance of HCV infection may be offered 3-6 monthly testing for presence of HCV viraemia (conditional recommendation, very low certainty of evidence). - Pangenotypic DAA-HCV treatment should be offered without delay to people with recently acquired HCV infection and ongoing risk.

# Objectives and scope of updated HCV guidelines
The objective of these updated guidelines is to provide updated evidence-based recommendations on key HCV-related topics identified in both the 2018 WHO Guidelines for the care and treatment of persons diagnosed with chronic HCV infection (1) and the 2017 WHO Guidelines on hepatitis B and C testing (4). The three priority areas are:
- use of direct-acting antiviral (DAA) treatment of adolescents and children ages 3 years - simplified service delivery (decentralization, integration and task sharing)
- HCV diagnostics -use of PoC HCV RNA viral load and reflex HCV RNA viral load testing.
These guidelines also include updates to existing chapters without any new recommendations, such as inclusion of new manufacturers' protocols on use of dried blood spots (DBS) for serology and HCV RNA viral load testing and new data to inform limit of detection for HCV RNA viral load assays as a test of cure.
Overall, this guideline update is consistent with the modular approach to updates adopted since 2020 in response to emerging evidence on hepatitis B and C virus infections. The first modular update, on hepatitis C self-testing, was launched in July 2021 (5). This guidelines update constitutes the second modular update on hepatitis C testing and treatment. A modular update on hepatitis B testing and treatment is planned for 2022 based on existing hepatitis B treatment (6) and testing guidelines (4). In 2023, all updates will be compiled along with existing recommendations into a single consolidated guidelines on prevention, testing, care and treatment of hepatitis B and C, containing all relevant guidance.

# Related guidelines
These guidelines are intended to complement existing guidance on the primary prevention of HCV and other bloodborne viruses by improving blood and injection safety, and health care for people who inject drugs and other vulnerable groups, including those living with HIV.
Additional guidance relevant to the prevention, care and treatment of those infected with HCV can be found in the following documents:
- WHO Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection (2018) (1)
- WHO Guidelines on hepatitis B and C testing (2017) (4)
- Recommendations and guidance on hepatitis C virus self-testing (2021) (5)
- Guidelines for the prevention, care and treatment of persons with chronic hepatitis B virus infection (2015) (6) - Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations (2022 update) (7)
- Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach (2021) (2).

# Intended audience
These guidelines are primarily addressed to national hepatitis programme managers and other policy-makers in ministries of health, particularly in LMICs, who are responsible for the development of national hepatitis testing and treatment plans, policy and guidelines. These guidelines will also be useful for laboratory managers in ministries of health, reference laboratories and key hospital laboratories who are responsible for validation of assays, development of national testing algorithms, and national procurement of assays, quality control (QC) and quality assurance (QA). Finally, the guidelines will serve as a reference for health care providers who offer and implement hepatitis testing, care and treatment for persons with hepatitis C virus infection, including those working in community-based programmes.

# Guiding principles
The following principles have informed the development of these guidelines and should guide the implementation of the recommendations.

# The public health approach
The guidelines are based on and are intended to support a public health approach to scaling up the use of antiviral treatment for HCV infection along the continuum of hepatitis prevention, diagnosis, linkage to care and treatment.
In recognition of the importance of streamlined, standardized approaches to scaling up HCV services in settings with limited resources, the public health approach emphasizes strategies such as task sharing, decentralization, integration of HCV testing and treatment services with other public health programmes and patient, and community empowerment. High-income countries with more resources and fewer HCV cases may favour a more individualized approach to care, although the overarching framework of the public health approach provides the setting for scaleup of testing and treatment, within which this more personalized service delivery can occur.

# People-centred care
People-centred health services are an approach to care that consciously adopts the perspectives of individuals, families and communities and sees them as participants and beneficiaries of trusted health systems that respond to their needs and preferences in humane and holistic ways. This approach acknowledges the experiences and perspectives of health care providers that may enable or prevent the delivery of people-centred care of high quality.

# Essential strategies for an enabling environment for key populations
Implementation of the guidelines needs to be accompanied by efforts to promote and protect the human rights of people who need hepatitis services, including ensuring informed consent, preventing stigma and discrimination in the provision of services and promoting gender equity.
Several populations are subject to structural barriers to health care, including stigma, discrimination, marginalization, criminalization and violence. This is especially important for women, young girls and adolescents and key populations, who are subject to these barriers across the HIV and hepatitis care cascade. Although primarily intended for developing programmatic guidance to help implement all WHO recommendations, the basic principles underlying these recommendations align with the concepts of people-centred care, the public health approach and a rights-based approach.
The updated WHO Consolidated guidelines on HIV, viral hepatitis and STI prevention, diagnosis, treatment and care for key populations, 2022 update) (7) describe essential strategies to build an enabling environment. They include developing supportive legislation and policy, including working towards decriminalizing drug use and possession, sexual orientation and gender identity addressing stigma and discrimination, empowering communities, and addressing violence against key populations. WHO also supports a strong emphasis on workforce training against stigma and discrimination and strategies to support those that are subject to violence, to ensure that all populations benefit from access to better and safer health care services.

# Adaptation of implementation to local context
Implementation of the recommendations in these guidelines should be informed by local context, including HCV epidemiology and the prevalence of other comorbidities, the availability of resources, the organization and capacity of the health system and anticipated cost-effectiveness.
The public health approach recognizes the importance of streamlined, standardized approaches to scaling up HCV services in settings with limited resources.  1 Elimination is defined as a 90% reduction in new chronic infections and a 65% reduction in mortality compared with a 2015 baseline.
Reaching these targets will require scale-up of currently available prevention interventions as well as testing and treatment to achieve diagnosis of 90% of those infected and treatment of 80% of those diagnosed as infected. Several champion countries have made good progress in the scale-up of treatment access and of highly effective preventative approaches such as assuring blood and injection safety. However, there remain major gaps in the cascade of testing and treatment of those living with hepatitis C. In 2019, of the 58 million persons with HCV infection, 21% had been diagnosed, and 13% had been treated (9).
Major gaps remain in testing and treatment: Only 21% of those infected have been diagnosed, and only 13%, treated.

# Natural history of HCV infection 2.2.1 Disease progression
HCV infection causes both acute and chronic hepatitis. Incident infection is associated with early symptoms in about approximately 20% of persons. Spontaneous clearance in the absence of treatment occurs within six months of infection in around 25% of infected individuals (11).
The remaining 55-85% develop chronic infection, which can lead to progressive fibrosis and cirrhosis. The risk of cirrhosis in those with chronic hepatitis C infection ranges from 15% to 30% after about 20 years of infection with HCV (12)(13)(14). Initially, cirrhosis is usually compensated. Decompensated cirrhosis (liver failure) may subsequently occur, leading to morbidity and mortality from outcomes including variceal haemorrhages, ascites, spontaneous bacterial peritonitis or encephalopathy, and renal impairment (15). Annually, approximately 1-3% of persons with cirrhosis progress to HCC (16). The risk of progression to cirrhosis and HCC varies according to both host and virological factors. Age of acquisition, alcohol use, HBV or HIV coinfection and immunosuppression due to any cause increase the risk of developing cirrhosis or HCC (17,18). In the absence of antiretroviral (ART) treatment, HIV co-infected persons, particularly those with advanced immunodeficiency (CD4 count <200 cells/mm3), progress to cirrhosis, decompensated cirrhosis and HCC significantly faster than do HCV mono-infected persons (17,19,20).

# Extrahepatic manifestations
HCV infection can also lead to extrahepatic manifestations (21). Among HCV-infected persons, the three most common comorbidities are depression (24%), diabetes mellitus (15%) and chronic renal disease (10%). Less common are immune-related extrahepatic manifestations (for example, mixed cryoglobulinemia, B-cell non-Hodgkin lymphoma and idiopathic thromobocytopaenic purpura (ITP). A proportion of these morbidities is directly attributable to HCV infection and is, therefore, referred to as extrahepatic manifestations. Extrahepatic manifestations are likely to improve with treatment. The prevalence of these extrahepatic manifestations is usually independent of the degree of liver fibrosis (22,23).

# Routes of transmission 2.3.1 Health care-associated transmission
In countries where infection prevention and control measures are insufficient, HCV infection is associated with unsafe health care injection practices and procedures such as renal dialysis, surgery, dental care and unscreened blood transfusions (24)(25)(26). Worldwide, in 2010 an estimated 5% of health care injections were given with unsterilized, reused injection devices (27), and unsafe injections were estimated to lead to 315 000 new HCV infections each year (28). Excessive use of injections to administer medications, coupled with poor injection practices, further increases HCV transmission (29). This persisting driver of transmission needs to be addressed through safer health care, introduction of reuse-prevention injection devices (30) and a reduction in unnecessary health care injections.

# Transmission among people who inject drugs
Globally, injection drug use may account for 23% of new HCV infections; 8% of current HCV infections are among people who inject drugs (9). People who inject drugs who are infected with HCV are at increased risk of all-cause mortality, reflecting the combined role of injecting drug use, low socioeconomic status, poor access to health care and environmental factors (31,32).

# Other modes of transmission
Other modes of HCV transmission include mother-to-child transmission, which affects 4-8% of children born to women with HCV infection and 10.8-25% of children born to women with HIV/HCV coinfection (33); other percutaneous procedures, such as tattooing and body piercing (34); and needlestick injuries in health care workers (35,36). Sexual transmission of HCV occurs infrequently in heterosexual couples. It is more frequent in men who have sex with men (37).
Transmission among HIV-negative men who have sex with men is increasing.  (38)(39)(40)(41)(42). Sofosbuvir/velpatasvir retains high efficacy with genotype 4 non-A/D subtypes, which are endemic in some regions of sub-Saharan Africa (43).
Glecaprevir/pibrentasvir is an FDC containing a pangenotypic NS3/4A protease inhibitor with a pangenotypic NS5A inhibitor. The FDA and EMA approved it in 2017. In clinical trials it is associated with high efficacy against infections with genotypes 1-6 and compensated cirrhosis, including in persons with renal insufficiency and end-stage renal disease (44)(45)(46)(47)(48)(49)(50). The regimen is contraindicated in persons with decompensated cirrhosis (Child-Pugh Class C) because of high exposure to the protease inhibitor.
Daclatasvir, an NS5A inhibitor that has been evaluated with sofosbuvir, was approved by the EMA in 2014 and by the FDA in 2015. Clinical trials reported high efficacy of the combination of daclatasvir and sofosbuvir in infections with genotypes 1-4, persons with decompensated liver disease, liver transplant recipients and those with HIV/HCV coinfection (51)(52)(53). Other data showed that the combination is also effective in infections with genotypes 5 and 6. Sofosbuvir/ daclatasvir and also sofosbuvir/ledipasvir may be less effective against certain HCV genotypes, namely genotype 4 non-A/D subtypes, which are endemic in some regions of sub-Saharan Africa, as well as other genotypes elsewhere (including genotypes 1 and 3), which frequently contain resistance-associated substitutions in the NS5A regions (54).
Sofosbuvir/velpatasvir/voxilaprevir is generally considered for use in the retreatment of HCVinfected persons who previously failed a DAA regimen. In some high-income countries, however, it is also registered for treatment-naive HCV-infected persons. An updated review of retreatment of persons with DAA failure is planned for 2022.
These guidelines also include updates to existing chapters without any new recommendations, such as on use of dried blood spot (DBS) for serology and HCV ribonucleic acid (RNA) viral load testing (inclusion of new manufacturers' protocols), and new data to inform limit of detection for HCV RNA viral load assays as a test of cure.
Overall, this guideline update is consistent with the modular approach to updates adopted since 2020 in response to emerging evidence on hepatitis B and C virus infections. The first modular update, on hepatitis C self-testing guidelines, was launched in July 2021 (5). This guidelines update is the second modular update on hepatitis C testing and treatment. A modular update on hepatitis B testing and treatment, based on existing hepatitis B treatment and testing guidelines (4,6), is planned for 2022. In 2023 all updates will be compiled along with existing recommendations into a single consolidated guidelines on prevention, testing, care and treatment of hepatitis B and C, containing all relevant guidance.

# WHO guideline development process
The WHO Department of HIV, Hepatitis and STI Global Programmes led the development of these updated guidelines on priority areas of HCV testing, care and treatment, following the WHO procedures and reporting standards laid out in the WHO handbook for guideline development, second edition, 2014 (56). The recommendations in the guidelines are based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to reviewing evidence and formulating recommendations (57-61).

# Roles (Web Annex A)
A WHO Steering Committee was constituted, which included individuals with relevant expertise from different WHO units, who oversaw the guidelines development process. A Guidelines Development Group was constituted to ensure representation from various stakeholder groups, including members of organizations that represent patients' groups, advocacy groups, researchers and clinicians. Group members were also selected to achieve geographical representation and gender balance. There was an initial scoping and planning process to formulate questions most relevant to LMICs and to define outcomes important to patients. The Guidelines Development Group helped formulate the questions on population, intervention, comparison, outcomes (PICO), reviewed the evidence profiles and decision-making tables, composed and agreed upon the wording of the recommendations, and reviewed drafts of the guidelines document.
The guidelines methodologist ensured that the GRADE framework was appropriately applied throughout the guideline's development process. This included formulation of the populationintervention-comparison-outcomes (PICO) questions, ensuring the comprehensiveness and quality of the systematic reviews, and preparing evidence profiles and decision-making tables, including certainty of evidence. The methodologist also provided guidance to the Guidelines Development Group in formulating the wording and strength of the recommendations. The External Review Group reviewed the draft guidelines document and provided crucial feedback.

# Evidence that informed the recommendations (Web Annex B)
Systematic reviews, meta-analyses, cost-effectiveness analyses, values and preferences surveys and a series of case studies on implementation experience, to inform feasibility, were undertaken to support the process of formulating recommendations and identifying outcomes important to patients.

# Systematic reviews and meta-analyses (Web Annex C)
Five systematic external reviews and meta-analyses of the primary literature were commissioned externally to address the research questions and outcomes important to patients. Outcomes were ranked by the Guidelines Development Group based on their importance to the patient population.
- the efficacy and safety of direct-acting antivirals in children and adolescents with chronic HCV infection;
- decentralization, integration and task-sharing in hepatitis C virus infection testing and treatment;
- impact of HCV PoC HCV RNA viral load testing on uptake of testing and treatment and turnaround times and diagnostic accuracy of PoC HCV RNA viral load assays;
- determining the threshold/lower limit of detection required for HCV RNA viral load assays for test of cure following treatment with direct-acting antiviral (DAA) based treatment regimens;
- laboratory-based and clinic-based HCV viral load reflex testing following an initial positive HCV antibody test result.
Search strategies and summaries of evidence are reported in Web Annex A. GRADE tables for all reviews are reported in Web Annex C. Evidence-to-decision tables appear in Web Annex C. The glossary provides full definitions for diagnostic and analytical test performance.

# Values and preferences and acceptability surveys (Web Annex D)
Simplified service delivery and PoC HCV diagnostics. WHO commissioned three related surveys or in-depth interviews from different partner organizations, which were undertaken among different populations affected by HCV to inform an understanding of the values, preferences and acceptability of different ways of simplifying delivery of care and treatment for chronic HCV infection (that is, decentralization, integration and task sharing of HCV services) and on simplifying HCV diagnostic pathways, including use of PoC HCV RNA viral load diagnostic assays. These included the following:
(i) A multi-country online survey, comprising 42 questions, was conducted by the World Hepatitis Alliance and Coalition Plus in September 2021, disseminated through partner networks and social media. There were 210 respondents from 49 countries.
(ii) A series of peer-driven semi-structured interviews (SSI) or focus group discussions (FGD) conducted by the International Network of People Who Use Drugs (INPUD) from April to June 2021 among four key populations (gay and bisexual men, male and female sex workers, people who inject drugs and transgender people). Some 230 individuals participated from 68 countries.
(iii) A multi-country rapid qualitative assessment using a master protocol across 10 countries, commissioned by FIND in 2020 to understand the values and preferences concerning hepatitis C self-testing (HCVST) as well as perspectives on current hepatitis C testing services among potential service end-users (general population and marginalized populations) and health care workers. Some 460 people from 10 countries participated in individual interviews, and 220, in group interviews.
Treatment of children and adolescents: A further online survey was commissioned and undertaken between August and September 2021 across global, regional and country networks of paediatricians treating HCV-infected children and adolescents. The survey assessed preferences and acceptability regarding which children to prioritize for treatment and which DAA regimens to use. Networks included: PENTA Child Health network, Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) and regional counterparts -the Asian Pan-Pacific Society (APPSPGHAN); the Commonwealth Association of Paediatric Gastroenterology and Nutrition (CAPGAN); the European Society (ESPGHAN); the Latin American Society (LASPGHAN); the North America Society (NASPGHAN); and the Pan Arab Society (PASPGHAN). Some 142 health care workers responded, of whom 94 had treated HCV-infected children or adolescents within the previous three years. Practitioners from all WHO geographic regions were represented; the highest proportions of respondents were from the Western Pacific (43%) and the Americas (19%).

# Feasibility -case studies on operational and implementation experience
Case studies were commissioned from programmes in several countries to obtain information on the operational experience and feasibility of decentralization, integration, and task-sharing; use of PoC HCV RNA viral load assays in outreach clinic services for people who inject drugs and the general population; and use of laboratory-based HCV reflex viral load testing. The case studies focused on description of the model, key outcomes, challenges and operational lessons learned.

# Cost-effectiveness analyses
All commissioned systematic reviews captured relevant literature that had evaluated the costeffectiveness and population health outcomes of different levels of decentralization and tasksharing, use of PoC HCV RNA viral load and use of reflex HCV RNA viral load testing. Also, the Clinton Health Access Initiative (CHAI) was commissioned to undertake a market size analysis of paediatric DAA dosage forms (62) and an assessment of DAA generic supplier status to inform a feasibility assessment of different DAA treatment options for younger children.

# Grading of certainty of evidence and strength of recommendations (Web Annex B)
The certainty of the evidence was assessed and either rated down or rated up based on criteria specified in GRADE methods, modified for diagnostic tests and test strategies (63,64). Summaries of the certainty of evidence to address each outcome were entered in the GRADE profiler software GRADE pro 3.6. The certainty of evidence was categorized as high, moderate, low or very low (Box 3.1 and Table 3.1).
Specific issues with rating the certainty of evidence for studies of diagnostic accuracy For evaluation of POC RNA viral load diagnostics, the Guidelines Development Group considered BOX 3.1 Standard approach to rating the certainty of evidence and strength of recommendations using the GRADE system
The GRADE system separates the rating of the certainty of evidence from the rating of the strength of the recommendation.
The certainty of evidence is defined as the confidence that the reported estimates of effect are adequate to support a specific recommendation. The GRADE system classifies the certainty of evidence as high, moderate, low or very low, indicating the level of confidence in the estimates and findings ( relationship or if all plausible biases would underestimate the effect. The higher the certainty of evidence, the more likely a strong recommendation can be made.
The strength of a recommendation reflects the extent to which the Guidelines Development
Group was confident that the desirable effects of following a recommendation outweigh the potential undesirable effects. The strength is influenced by the following factors: the certainty of the evidence, the balance of benefits and harms, values and preferences, resource use and the feasibility of carrying out the intervention (Table 3.2).
The GRADE system classifies the strength of a recommendation in two ways: "strong" and "conditional" (65).
A strong recommendation is one for which the Guidelines Development Group was confident that the desirable effects of adhering to the recommendation outweigh the undesirable effects.
A conditional recommendation is one for which the Guidelines Development Group concluded that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects but the Guidelines Development Group is not confident about these trade-offs. The implications of a conditional recommendation are that, although most people or settings would adopt the recommendation, some would not or would do so only under certain conditions. The reasons for making a conditional recommendation include the absence of high-certainty evidence, imprecision in outcome estimates, uncertainty regarding how individuals value the outcomes, small benefits relative to harms, and benefits that may not be worth the costs (including the costs of implementing the recommendation).
-utcomes important to patients, diagnostic accuracy (sensitivity, specificity, positive and negative predictive values) and in some cases analytical sensitivity (limit of detection). Although observational studies of interventions start as low certainty in GRADE, cross-sectional and cohort studies of diagnostic accuracy can provide reliable evidence on diagnostic accuracy (63) and, therefore, were initially categorized as high certainty. Evidence was then rated down based on the presence of (i) risk of bias (using a tool designed for assessment of diagnostic accuracy studies, the QUADAS-2 tool) (66); (ii) inconsistency (indicated by heterogeneity); (iii) indirectness (for example, addressing a different population than the one under consideration); or (iv) imprecision. For diagnostic accuracy studies, evaluating inconsistency is a challenge because methods to measure statistical heterogeneity that account for threshold effects are lacking, and statistical heterogeneity is usually high even when diagnostic accuracy estimates are fairly close. Therefore, inconsistency for diagnostic accuracy outcomes was based on whether variability in estimates exceeded pre-defined thresholds (for example, the variability in sensitivity estimates exceeded 0.10). Although diagnostic accuracy is an intermediate outcome, we did not downgrade for indirectness because diagnostic accuracy was a pre-defined outcome of interest.
We are very confident that the true effect lies close to the estimate of effect.
We are moderately confident of the estimate of effect. The true effect is likely to be close to the estimate of effect, but it could be substantially different.
Our confidence in the estimate of effect is limited. The true effect may be substantially different from the estimate of effect.

# Very low
We have very little confidence in the estimate of effect. Any estimate of effect is very uncertain.

# Formulation of recommendations
At the Guidelines Development Group meeting, the results of the systematic reviews, metaanalyses and complementary information were presented, and the evidence profiles and decision-making tables were reviewed to ensure that participants understood and agreed on the scoring criteria (see Web Annex C).
The GRADE method was used to rate the quality of the evidence and determine the strength of the recommendations. The strength of the recommendations was rated as either strong (the panel was confident that the desirable effects of the intervention outweighed the undesirable effects) or conditional (the panel determined that the desirable effects of the intervention probably outweighed the undesirable effects). The certainty of evidence supporting each recommendation was graded as high, moderate, low or very low. Recommendations were then formulated by members of the Guidelines Development Group through discussions based on overall certainty of the evidence, in addition to other considerations, including the balance of benefits and harms,

# Benefits and harm
When a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks or harm), considering any previous recommendation or an alternative. The larger the gap or gradient in favour of the benefits over the risks, the more likely that a strong recommendation will be made.

# Certainty of evidence
High certainty of evidence is likely to lead to a strong recommendation.

# Values and preferences (of providers and stakeholders)
If decisions to use an intervention are unlikely to be affected by differences in how providers, end-users and other stakeholders value various outcomes, it is more likely that a strong recommendation will be made.
If there is a high degree of variability or uncertainty with regard to how providers and stakeholders value various outcomes, that could impact the decision; a conditional recommendation is more likely.

# Acceptability (of providers and stakeholders)
If the recommendation is likely to be widely accepted or highly valued, it is likely that a strong recommendation will be made. If there is a great deal of variability or strong reasons that the recommended course of action is unlikely to be accepted, it is more likely that a conditional recommendation will be made.

# Cost/financial implications
Lower costs (monetary, infrastructure, equipment or human resources) or greater cost-effectiveness contribute to a strong recommendation.
If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is appropriate.

# Equity and human rights
If the recommendation is likely to increase access to an intervention for those most in need, a strong recommendation is likely.
The greater the acceptability to all or most stakeholders, the greater the likelihood of a strong recommendation values, preferences and acceptability, resource implications and the feasibility of carrying out the intervention. The chairs and methodologist worked to reach consensus during the meeting.
After discussion of all comments and questions from members of the Group, the Chair, to document consensus, asked Group members whether they agreed with the recommendations. Voting was not required, but the group had agreed a priori that two thirds of the votes would be required for a decision. All Group members agreed with all the recommendations. For each recommendation, the Group evaluated also the implementation needs and identified areas and topics requiring further research. Prior to finalization, Guidelines Development Group and an external review group reviewed and further revised the draft guidelines.

# Declarations of interest and management of conflicts of interest
In accordance with WHO policy, all external contributors to the guidelines, including members of the Guidelines Development Group and the External Review Group, completed a WHO declaration of interest form (including participation in consulting and advisory panels, research support and financial investment). Prior to the guideline meeting, a brief biography of each member of the Guidelines Development Group was posted on the website. The WHO Steering Committee reviewed and assessed the declarations submitted by each member and agreed on an approach to assess potential conflicts of interest. At the meeting, declarations of interest were reported according to WHO standard requirements. Individuals from organizations that had received significant funding from private (primarily pharmaceutical) companies and individual researchers or clinicians who had received honoraria above US$ 5000 from pharmaceutical companies were considered to have a conflict of interest if it was related to the guidelines topic and recommendations, and their participation in the Guidelines Development Group was classified as restricted (Web Annex E). The participation of only one group member, Jason Grebely, was restricted for the topic of PoC HCV RNA viral load assays. This group member contributed his technical expertise in reviewing the evidence summaries but was excluded from participation in voting and formulation of the recommendation (Web Annex A).
The declarations of interest forms from members of the External Review Group were reviewed in accordance with the WHO guidelines development policy. For the peer review group, the WHO Secretariat was satisfied that no case necessitated exclusion from the review process. Any conflicts of interest identified were considered when interpreting comments from External Review Group members during the external review process. The external reviewers could not and did not make changes in the recommendations.

# Dissemination and updating of the guidelines
The guidelines update will be disseminated electronically on the WHO HHS departmental website and to WHO regional offices, WHO country offices and ministries of health through webinar series, made available as a print publication on demand and as policy briefs. Dissemination will be further supported by publication of the systematic reviews and evidence in peer-reviewed journals.
The successful implementation of the recommendations in these guidelines will depend on a well-planned and appropriate process of adaptation and integration into relevant regional and national strategies. Implementation of these guidelines can be measured by the number of countries that incorporate them into their national treatment programmes and updated data on uptake of HCV viral load testing and treatment, which is part of the cascade of care monitoring and evaluation framework. WHO monitors numbers of HCV infected adults who have been treated, and now also HCV infected adolescents and children.
These guidelines will be updated in full or in part based on regular scoping exercises of available evidence and experience from country implementation that will guide and trigger the need for new guidance. As the evidence base or user needs change, consideration will be given to producing technical updates on specific subjects.
Short-course, oral, curative direct-acting antiviral (DAA) regimens have transformed treatment for HCV infection in adults, who bear the greatest burden of morbidity and mortality. This result has been due to high efficacy and minimal side effects with short-course treatment compared with the previous era of interferon-based regimens. Until recently, there had been less attention to addressing HCV in children and adolescents, and no DAA regimens were approved for use in children (67,68).
In 2018 there were an estimated 3.26 million (95%, uncertainty interval 2.07-3.90) children and adolescents ages 0-18 years living with chronic HCV infection (69). The predominant mode of acquisition of HCV infection in children is mother-to-child transmission. Older children and adolescents may become infected via unsafe injections and poor infection prevention and control, especially in LMICs (69,70). Regardless of age, most children with HCV infection have asymptomatic or minimally symptomatic liver disease, and cirrhosis, hepatocellular carcinoma or extrahepatic manifestations are rare. Yet, recent evidence suggests that those with perinatal exposure developed cirrhosis at an earlier age (71). HCV infection may also decrease the general health and quality of life of adolescents (72,73). Therefore, early diagnosis and treatment in children is key to preventing long-term morbidity (74).  1 For use in those with genotype 1, 4, 5, or 6 infection or where genotype 3 infection is uncommon. In the SHARED trial, (in adults) a sustained virological response (SVR) with sofosbuvir (400 mg) and ledipasvir (90 mg) was observed in 261 (87%) overall, but in only 56% of those infected with HCV genotype 4r, compared with 93% of those infected with genotype subtypes other than 4r. Realistically, these findings do not support the use of sofosbuvir-ledipasvir as the initial therapy for HCV infection without genotype subtyping in some regions and countries in sub-Saharan Africa. 2 Dosing based on population pharmacokinetic modelling studies 3 Available as tablets (FDC) 100/40 mg and oral pellets or granules 50/20 mg, depending on locally approved product information
Prior to regulatory approval of DAAs for use in children, the standard of care of adolescents and children infected with HCV was dual therapy with pegylated-interferon alpha and ribavirin for 24 weeks for genotypes 2 and 3, and 48 weeks for genotypes 1 and 4 (75)(76)(77)(78)(79)(80)(81)(82)(83). This combination resulted in an SVR rate of around 52% for HCV genotypes 1 and 4 and 89% for HCV genotypes 2 and 3 (75,76,78,80), but it was associated with significant side-effects. At the time of the 2018 WHO HCV guidelines, none of the recommended pangenotypic DAAs for adults (sofosbuvir/ daclatasvir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) had been approved for use in either adolescents or children. Therefore, WHO recommended use of two non-pangenotypic DAA regimens (sofosbuvir/ledipasvir and sofosbuvir/ribavirin) that had received regulatory approval from the FDA and the EMA for use in adolescents (12 years) (84,85) but advised deferral of treatment in those under than 12 years of age until DAA regimens became available for these younger age groups (73,86).
Since 2018, the high rate of HCV viral clearance observed in adults with the various pangenotypic DAA regimens has been replicated among adolescents and children. This led to approvals by the key regulatory agencies, the FDA and the EMA. Among adolescents, the pangenotypic regimens, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir, were approved in 2020 and 2021. Among children ages three years and older, sofosbuvir/ledipasvir was approved in 2019, followed by glecaprevir/pibrentasvir and sofosbuvir/velpatasvir in 2021.
Although the sofosbuvir/daclatasvir regimen is the most widely available and lowest cost pangenotypic DAA regimen in LMICs, and its safety and efficacy in children and adolescents have been reported in multiple observational studies (87,88), there is no regulatory approval for this DAA combination, as the originator companies are no longer collaborating (89). Alignment of WHO-recommended DAA regimens across adults, adolescents and children would simplify procurement, promote access to treatment among children in LMICs and help support global elimination efforts.

# Summary of the evidence for treatment in adolescents and children (Web Annex C)
A WHO-commissioned systematic review and meta-analysis of the efficacy and safety of key DAA regimens was undertaken for adolescents (12-18 years), older children (6-11 years) and younger children (3-5 years) with chronic hepatitis C virus infection, based on the same age groupings used in the trials for regulatory approval. There were 49 studies (three RCTS, 28 non-RCTs and 18 observational studies). Together, they reported treatment experience in 1891 adolescents (35 study arms), 472 older children (13 study arms) and 167 younger children (7 study arms). There were no placebo-controlled RCTs, and findings were based on summary estimates of SVR cure rates by regimen in the three age groups. However, these were considered informative because spontaneous clearance is rare in the absence of treatment. Data on serious adverse events and treatment discontinuations were considered more informative than adverse events alone because of the lack of a comparison group. The majority of participants were non-cirrhotic (1786, 70.6%), treatment-naive (1825, 72.1%), and with non-GT3 infection (1453, 57.4%).
Overall, sustained virological response rates 12 weeks after the end of treatment (SVR12) were high (95%) in all age groups and for the key pangenotypic DAA regimens as well as for sofosbuvir/ ledipasvir. The rate of any adverse event was higher for children ages 3-5 years (72%) than for those ages 6-11 years (53%) or adolescents (50%), but serious adverse events and treatment discontinuations were uncommon (<1%), except in young children (6.6%) because of the poor palatability of the oral formulation of sofosbuvir/velpatasvir in this group. Less than half of the studies (22/49 (44.9%)) reported information on comorbidities. There were 15 persons with cirrhosis across nine studies, 304 persons who were treatment-experienced across 21 studies and 157 persons with GT3 infection across eight studies. There were no studies of sofosbuvir/ daclatasvir in children or adolescents reported from sub-Saharan Africa, where HCV genotype 4 non-a/d subtypes are endemic in some regions, as well as other genotypes (including genotype 1 and 3) that frequently contain resistance-associated substitutions in the NS5A regions. This may contribute to higher rates of treatment failure with sofosbuvir/daclatasvir.
All studies but two were classified as at low risk of bias. Adverse events and treatment discontinuations: Of the studies that reported adverse events, 92 (72%) reported at least one adverse event; the most common were vomiting (21%), cough (14%) and diarrhoea (9%). Treatment discontinuations were rare, but were higher (6.6%) in the sofosbuvir/velpatasvir arms because of relative lack of palatability of the oral formulation.
Strength of evidence: moderate for sofosbuvir/ledipasvir; very low for all other DAAs (sofosbuvir/ velpatasvir, glecaprevir/pibrentasvir). There were no data for sofosbuvir/daclatasvir.
There were insufficient studies that reported on outcomes by cirrhosis, genotype and treatment experience. Only three studies reported the HIV co-infection status of participants. There were five HIV co-infected participants, of whom three were treated with glecaprevir/pibrentasvir; all achieved SVR12 (90)(91)(92). Overall, the small numbers of HCV-infected children means that subgroup analyses will be limited.

# Quality of life assessment
Data from three studies indicate that HCV infection in children has a detrimental effect on quality of life, leading to increased caregiver stress, strain on the family system and poorer health status, including impaired psychosocial and cognitive functioning (93)(94)(95). Three other studies explored the impact of DAA treatment on the quality of life of children and adolescents. They showed improvement in health-related quality of life scores after achieving SVR12 (90,96,97).
- 3.5 Supporting pharmacokinetic (PK) data for use of 200/30 mg sofosbuvir/ daclatasvir in children ages <12 years (101) Sofosbuvir/daclatasvir (400 mg/60 mg) is the pangenotypic DAA regimen of choice for adults and adolescents in many LMICs, as it is highly effective and widely available as low-cost generic formulations. However, there are no direct study data on its efficacy and safety in children ages three to five years. It is recognised that the use of available adult daclatasvir formulations (60 mg and 30 mg) together with approved paediatric doses of sofosbuvir (200 mg and 150 mg) would be an effective way to expand global access to HCV treatment for children.
The use of extrapolation to support paediatric drug development is a well-established practice in regulatory approvals (98), whereby efficacy, safety and PK data in young children is extrapolated from adequate studies in adult, adolescents or older children. This applies when the course of the disease or condition and the response to treatment are expected to be similar in children and adults. Modelling and simulation is a critical step in identifying the correct dose, to be confirmed in a targeted PK study. Extrapolation is specifically cited in FDA guidance as appropriate in development of DAAs for children (67). The PK data were used to complement the available clinical data on SVR rates for older children, but they did not change the quality rating.
A PK analysis was undertaken to predict daclatasvir exposure in children less than 12 years of age and weighing 10 to <35 kg, using existing adult 60 mg and 30 mg doses of daclatasvir, and to determine the lowest body weight at which children could be treated using these doses. Daclatasvir concentration data from 17 HCV-infected adolescents receiving sofosbuvir/ daclatasvir (400 mg/60 mg once daily) who participated in a PK study in Egypt were used for model development (99,100). PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual children weighing 10 to <35 kg receiving 60 or 30 mg once daily, and daclatasvir exposures were compared with ranges seen in adults. Daclatasvir 30 mg once daily was predicted to achieve effective and safe exposures in children 14 to <35 kg and even down to 10 kg (101). Two complementary studies assessed sofosbuvir pharmacokinetics in children relative to adults to establish appropriate dosing in children. Overall, the data suggest that it would be acceptable to use the existing adult dose of sofosbuvir/ daclatasvir (400 mg/60 mg) in children down at least to 25 kg and a half dose (200 mg/30 mg) for those 14-25 kg, potentially down even to 10 kg. Two efficacy, safety and PK studies of sofosbuvir/daclatasvir among children <12 years of age are now planned in Egypt and Cambodia to validate the optimal dosing in the intended paediatric population as the basis for regulatory approval and country adoption. 1. Benefits of earlier treatment in childhood and adolescence include the possibility of achieving a cure before the onset of disease progression, thus preventing HCV-associated liver damage and extrahepatic manifestations. The overall resulting reduction in transmission will reduce the prevalence and incidence in children and adolescents to achieve an HCVfree generation. Although advanced liver disease is uncommon in children and adolescents, liver fibrosis progresses over time and may lead to complications in late adolescence and/ or early adulthood. Other potential reported benefits of early treatment include avoiding stigmatization of infected children and the prevention of transmission to others, particularly among adolescents engaging in high-risk behaviours. It also improves neurocognitive dysfunction that affects school performance and quality of life.
- Treatment of HCV infected children and adolescents (3-17 years of age) is highly effective and safe, with SVR12 rates 95% in all age groups for the key pangenotypic DAA regimens already recommended for adults (sofosbuvir/daclatasvir, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir). This conclusion is based on high, moderate and low certainty of evidence, respectively, for adolescents and older children and very low certainty for all regimens in younger children.
- Serious adverse events and treatment discontinuations were uncommon. Although the frequency of any adverse event was higher for younger age groups (72% for children ages 3-5 years, 53% for those ages 6-11 years and 50% for adolescents), serious adverse events and treatment discontinuations were uncommon. Therefore, the benefit-to-harm ratio is very high in adolescents and older children, but it may be less in younger children, as they experienced more problems with treatment discontinuations due to poor palatability with some regimens and adverse effects. 1. Both direct evidence from a systematic review and meta-analysis of use of these DAA regimens in 1891 adolescents (12-18 years of age) from 35 studies and 472 older children (6-11 years of age) from 13 studies confirmed high efficacy, safety and tolerability, as did indirect evidence from adult treatment studies for all DAA regimens.
- The PK modelling data suggest that it should be possible to use the existing adult dose of sofosbuvir/daclatasvir (400 mg/60 mg) in children down at least to 25 kg.
- This new recommendation replaces ribavirin which requires haematological monitoring, with the use of sofosbuvir in adolescents. Also, ribavirin is a teratogenic agent and contraindicated in pregnancy. This is particularly relevant, as adolescents' pregnancies are more likely to be unplanned.
- Data on treatment in those with cirrhosis remains limited, but recommendations include those with compensated cirrhosis. In those who are treatment-experienced and with compensated cirrhosis, treatment for 24 weeks is recommended.

# Treat children ages 3-5 years
The 2018 HCV guidelines recommended that treatment be deferred in young children until they either reach 12 years of age or DAA regimens were approved for those under 12 years of age. This recommendation was based largely on the low frequency of HCV-related liver disease in childhood and the significant side-effects of interferon alpha -some irreversible (79,80,(105)(106)(107)(108)(109) -and overall low efficacy, prolonged treatment duration (6-12 months), inconvenient administration route (via injection) and high costs. It was recommended that interferon-based regimens should no longer be used for either adolescents or children.
The Guidelines Development Group recognized that the benefits of treatment with DAAs (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, sofosbuvir/daclatasvir) likely outweigh those of deferral even in those less than six years of age, who are at low risk of advanced liver disease (110,111). A conditional recommendation was made to initiate DAA treatment in children ages 3-5 years based on the following rationale:
- Curative short-course oral pangenotypic DAA regimens (sofosbuvir/velpatasvir, glecaprevir/ pibrentasvir) as well as also sofosbuvir/ledipasvir now have regulatory approval for children down to three years of age.
- There was high efficacy and no major safety concerns across these regimens -sofosbuvir/ velpatasvir and glecaprevir/pibrentasvir based on direct studies and sofosbuvir/daclatasvir based on extrapolation from studies in adolescent and older children.
- Overall, the data suggest that it should be possible to use the existing adult dose of sofosbuvir/ daclatasvir (400 mg/60 mg) in children down at least to 25 kg and a half dose (200 mg /30 mg) for those weighing 14-25 kg, potentially down even to 10 kg.
- For sofosbuvir/daclatasvir, the modelling exercise based on PK data in adolescents indicated that half of the adult dose (that is, 200 mg/30 mg) could be used for children weighing 14-25 kg and potentially down even to 10 kg. As noted above, the use of extrapolation to support paediatric drug development is a well-established practice in regulatory approvals (98,112), whereby efficacy, safety and PK data in young children can be extrapolated from adequate studies in adult, adolescents or older children. Extrapolation can be applied when the course of the disease or condition and the response to treatment are expected to be similar in children and adults and matching drug exposure in children to the safe and effective exposure in adults reliably predicts successful treatment. This situation meets all key conditions that support extrapolation of the efficacy observed in adults receiving sofosbuvir/daclatasvir. A PK/efficacy and safety study will be conducted in children to confirm that the proposed dose provides exposure similar to that shown to be safe and effective in adult patients.

# Values, preferences and acceptability (Web Annex D)
The assessment of the Guidelines Development Group was that, given the marked benefits relative to harms, the recommendations were not sensitive to preferences.
An online survey was distributed between August and September 2021 to global, regional and national networks of paediatricians treating HCV-infected children and adolescents. The survey assessed preferences and acceptability regarding which children to treat and prioritize and which DAA regimens to use. Networks included: PENTA Child Health network and the Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) and its regional counterparts -the Asian Pan-Pacific Society (APPSPGHAN); the Commonwealth Association of Paediatric Gastroenterology and Nutrition (CAPGAN); the European Society (ESPGHAN); the Latin American Society (LASPGHAN); the North America Society (NASPGHAN); and the Pan Arab Society (PASPGHAN). Some 142 health care workers responded, of whom 94 had treated HCV-infected for children or adolescents in the preceding three years. All WHO geographic regions were represented among respondents; the highest proportions of respondents were from the Western Pacific (43%) and the Americas (19%). It was not possible to survey end-users such as parents, care-givers or the children themselves, as there is still very limited routine testing and case-finding of children, and therefore most parents would be unaware their child is infected. Even fewer have experience of their child being treated.
Preferences for treating different age groups: The majority (94%) reported strong support for treating (defined as very likely or likely to treat) adolescents (ages 12-17 years), and 81% expressed support for treating those ages 6-11 years; but slightly less (at 60%) supported treating children ages 3-5 years. The most common reasons cited for not treating younger age groups included: the chance of spontaneous clearance (27%), slower disease progression and asymptomatic disease in early childhood (24%), limited clinical trial data (15%), lack of country drug approvals and registration for DAA regimens in younger age groups (22%) and difficulties with administering medication to young children (12%). The majority of respondents (59%) supported inclusion of treatment recommendations in the guidelines for children 3 years of age and older. A further 15% supported inclusion of treatment recommendations only for older children (6 years) and adolescents, and 22% supported treatment for adolescents only.
Preferences for choice of regimen: The most commonly used and preferred DAA regimens for treatment across all age groups among 82 health care workers who reported recent treatment experience were: sofosbuvir/ledipasvir (52% for adolescents and 28% for older children); sofosbuvir/velpatasvir (32% for adolescents and 20% for older children); and glecaprevir/ pibrentasvir (23% for adolescents and 10% for older children). The main reason for their use, given by 95% of respondents, was drug availability, because they were the most commonly available regimens at the respondents' facilities. Other reasons included: good safety data (95%), professional society guidelines recommending their use (88%), suitability of a regimen to treat HCV genotypes prevalent in the country (including pangenotypic) (84%) and high efficacy (72%).
Although there was no commissioned survey of end-users -that is, either parents or HCVinfected children/adolescents, previous surveys have indicated that curative, short-course (that is, 8-12 weeks) oral DAA treatment is highly acceptable to adolescents and children, as well as to their parents or caregivers (96), because of the high likelihood of a cure, and minimal adverse events compared with interferon injections. Cure will enable adolescents and children to live free of a socially stigmatizing infection. It is recognized that some younger children may have issues with palatability, especially if the medication is available only in tablet form, as is sofosbuvir/ daclatasvir.
The approval of DAAs for use in adolescents and younger children is a major opportunity to advance treatment access and cure to a vulnerable group that will benefit from early treatment. With an estimated 3.26 million children living with chronic HCV infection globally, national elimination of HCV will not be achieved unless children and adolescents are also tested and treated (113). There will be a need to ensure equitable access to recommended DAAs for all HCV-infected children and adolescents, including adolescents from stigmatized populations, such as people who inject drugs and men who have sex with men.
National elimination of HCV will not be achieved unless children and adolescents are also tested and treated.

# Resource and access considerations
DAA treatment in adults has been consistently reported as highly cost-effective and costsaving. There are no published data on paediatric drug costs for LMICs, and no formal costeffectiveness analyses have been undertaken. In general, treatment of adolescents and younger children may avoid the higher costs associated with treating adults with advanced liver disease and related complications. But costs for procurement of paediatric-specific doses are likely to be higher because of the lower volumes.

# Implementation considerations
To be most effective in promoting access, HCV treatment programmes to reach children and adolescents need to be aligned and integrated as much as possible with programmes for adults, with pooled procurement and streamlined supply chain management, but recognizing that the caregivers differ.
Inclusion of case-finding, testing, care and treatment of children and adolescents in national plans and guidelines A major constraint to implementation of these recommendations is that, currently, few LMICs have included adolescents and children in their national viral hepatitis strategic plans or their testing and treatment guidelines (4). As a result, most cases in adolescents and children remain undiagnosed and untreated. There are significant gaps and missed opportunities for diagnosis and documenting the HCV infection status of children of infected mothers or parents. All countries should now include HCV case-finding and testing strategies for adolescents and children and
To be most effective, HCV treatment programmes for children and adolescents need to be aligned and integrated as much as possible with programmes for adults. for treatment of adolescents in their national guidelines, based on the recommendations of the 2017 WHO HCV testing guidelines (4). This includes focused testing of adolescents from populations most affected by HCV infection (for example, people who inject drugs, men who have sex with men, HIV-infected persons and children of mothers with chronic HCV infection, especially if HIV-coinfected) and those with a clinical suspicion of viral hepatitis. It may also include screening of pregnant women in countries with high prevalence/burden with policies for linkage to care and follow-up of infants.
Testing of HCV-exposed infants could be undertaken in a range of services -child health services, immunization clinics, under-5 clinics, malnutrition services, well-child services, services for testing of hospitalized and all sick children, tuberculosis clinics, and services for orphans and vulnerable children. Box 4.1 describes potential testing opportunities to improve hepatitis case-finding among infants and children. The recently reported national scale-up of testing and treatment among school-age children and adolescents in Egypt has demonstrated the feasibility and acceptability of case-finding and treatment among children and their caregivers (114).
There is also a need to raise awareness among both health care workers and the public about the need to screen adolescents and children and the availability of curative treatments.
- Provision of care and treatment by non-specialists: Non-specialist paediatricians can treat HCV-infected children and adolescents. However, although DAA-experienced HCV-infected children and adolescents and those with cirrhosis are rarely encountered in clinical practice, such cases may be most appropriately managed under the supervision of a paediatric specialist. Data that speak to this are few.

# BOX 4.1 Testing approaches to improve hepatitis case-finding among infants and children
- Prioritize testing children of all HBV-or HCV-positive mothers (especially if the mother is HCV/HIV-coinfected) through home-or facility-based testing.
- Consider offering viral hepatitis testing to all children and adolescents attending HIV services, STI clinics and TB clinics or admitted to hospitals in high prevalence regions.
- Offer viral hepatitis testing or retesting to mothers or infants in maternal and child health services, immunization clinics or under-5 clinics.
- Focus HCV testing on children who have had medical interventions or received blood products in countries with a higher prevalence of hepatitis C or where screening of blood is suboptimal or where medical equipment is inadequately sterilized.
- Offer testing to all children and adolescents presenting with signs and symptoms that suggest acute viral hepatitis, including anorexia, nausea, jaundice, right upper quadrant discomfort and abnormal liver function tests.
- Paediatric formulations for young children: Current options include originator product formulations for glecaprevir/pibrentasvir (pellets) and sofosbuvir/velpatasvir (granules) or existing adult 30 mg daclatasvir and 200 mg sofosbuvir tablets. (See section 4.4.5. Resource and access considerations.)
- Service delivery for adolescents
- Delivering adolescent-friendly services: Providing services for adolescents require approaches that are adolescent focussed on and friendly to adolescents. WHO has developed standards for delivering quality services for adolescents (116). Engaging adolescents in testing for both viral hepatitis and HIV, either in health services or in the community, should be based on adolescent-friendly principles to ensure that psychological as well as medical needs are addressed. Services need to be convenient and available, with an absence of financial barriers, offer flexible opening hours and/or walk-in or same-day appointments. Separate hours and special events for adolescents may help overcome concerns that relatives or neighbours will see them seen attending viral hepatitis/HIV services.
- Vulnerable adolescents: Special considerations are needed for particularly vulnerable adolescents, those who are at higher risk of acquiring infection and have poor access to services. These include those who are homeless, those living on the streets, orphans, boys who have sex with men or who are using/injecting drugs, those in multiple or concurrent sexual partnerships and those who are sexually exploited or trafficked (25). Specific campaigns, use of social media or other Web-based approaches, and involving adolescents in identifying appropriate language may help to reach this group in some settings.
- Age of consent: A high age of consent can pose a barrier to adolescents' access to HIV and viral hepatitis testing (117). The age of consent for HIV testing varies from country to country. Testing services should be aware of laws and policies governing the age of consent and develop appropriate procedures based on this legal framework to ensure that children and adolescents have access to testing. WHO also recommends that children and adolescents themselves be involved in the testing decision as much as possible (117).
Countries should revise their age of consent policies in line with best practices, in the best interest of adolescents and in recognition of the heterogeneity and varying levels of maturity among adolescents.
- Disclosure: Adolescents may particularly need support with when and to whom to disclose a positive status (117). When appropriate, and only with the adolescent's specific permission, health care personnel should engage the support of adults -family members, teachers and other community members. Adolescents should be counselled about the potential benefits and risks of disclosure of their HIV or HCV status to others and empowered and supported to determine if, when, how and to whom to disclose.

# Research gaps
Research is particularly needed in the following areas:
- Direct evaluation of sofosbuvir/daclatasvir in children aged 3-5 years and 6-11 years and <25 kg for SVR12, adverse events, tolerability and pharmacokinetics. There is also a need to establish the efficacy of sofosbuvir/daclatasvir in regions where genotypes, including genotypes 1, 3 and 4-non-a/d subtypes, with inherent resistance-associated substitutions that increase treatment failure rates with this regimen are prevalent. In addition, sofosbuvir/ daclatasvir pharmacokinetic data are modelled only against wild type, and dose-related efficacy against genotypes 1, 3 and 4-non-a/d subtypes variants in children is uncertain.
- For forecasts for procurement needs, country serosurvey data to inform updated estimates of prevalence and burden in adolescents and children.
- Implementation research studies on optimal approaches for testing, case-finding and linkage to care for children and adolescents in different settings.
- Follow-up studies to examine the impact of DAA treatment on growth, cognitive function, educational attainment and quality of life among children and adolescents.
- Cohort studies on DAA treatment outcomes in children and adolescents with cirrhosis, prior treatment experience, genotype 3 infection, HIV coinfection, and renal impairment.

# Pangenotypic DAAs in HCV-infected adults without cirrhosis
In combined treatment-naive and treatment-experienced persons treated with sofosbuvir/ velpatasvir, the pooled SVR rates exceeded 96% (92-100%) for all six major genotypes, except for genotype 3 (SVR rate: 89%, 85-93%).
In combined treatment-naive and treatment-experienced persons treated with glecaprevir/ pibrentasvir, pooled SVR rates exceeded 94% (89-100%) for infections with all six major genotypes. For the relatively rare genotype 5, two persons treated reached SVR.
In combined treatment-naive and treatment-experienced persons treated with sofosbuvir/ daclatasvir, the pooled SVR rates exceeded 92% for infection with genotypes 1, 2, 3 and 4. Data from an observational study (manuscript in preparation, MSF demonstration project) provided information on the less commonly reported genotypes 5 and 6. A total of eight persons with genotype 5 and 123 persons with genotype 6 infection were treated with sofosbuvir/daclatasvir for 12 weeks. SVR rates were, respectively, 88% and 94% for genotypes 5 and 6.

# Pangenotypic DAAs in HCV-infected adults with compensated cirrhosis
In combined treatment-naive and treatment-experienced persons with cirrhosis treated with sofosbuvir/velpatasvir for 12 weeks, the pooled SVR rates in those infected with genotypes 1, 2 and 4 were 90%, 86% and 88%, respectively. The pooled SVR rate in genotype 3 infection was 97% in treatment-naive persons and 90% in treatment-experienced persons.
An additional study (published after the systematic review inclusion period ended) (108) reported SVR rates of 100% for both genotype 5 (N= 13) and genotype 6 (N = 20) after 12 weeks of treatment.
In combined treatment-naive and treatment-experienced persons with compensated cirrhosis treated with glecaprevir/pibrentasvir for 12 weeks, SVR rates exceeded 94% for infection with genotypes 1, 2, 3, 4 and 6. Two persons treated for infection with genotype 5 reached SVR.
In combined treatment-naive and treatment-experienced persons with compensated cirrhosis treated with sofosbuvir/daclatasvir for 12 weeks, the pooled SVR rates exceeded 93% for infection with genotypes 1 and 2. SVR rates for infection with genotype 3 were low, ranging from 79% to 82%. However, after 24 weeks of treatment SVR rates increased to 90%. Data from an observational study (manuscript in preparation, MSF demonstration project) provided information on genotypes 5 and 6, and real-world data from Egypt provided information on genotype 4 (118). One cirrhotic person with genotype 5 infection treated with sofosbuvir/daclatasvir for 12 weeks reached SVR. Among 185 cirrhotic persons with genotype 6 infection treated with sofosbuvir/daclatasvir for 12 weeks, 92% reached SVR.
Cirrhotic persons with genotype 4 infection had SVR rates that exceeded 98% after 12 weeks of treatment (118).

# Safety of pangenotypic DAAs
Treatment discontinuation due to adverse events was very low in persons without and with cirrhosis in the regimens discussed above (<1%). Similar results were observed in treatmentnaive and treatment-experienced persons.

# Rationale for the recommendation
The Guidelines Development Group made an overall recommendation to use pangenotypic DAA regimens for the treatment of HCV infection. The Group acknowledged that the potential clinical benefits of pangenotypic regimens are similar to those of non-pangenotypic regimens. However, pangenotypic DAAs present an opportunity to simplify the care pathway by removing the need for expensive genotyping and so simplifying procurement and supply chains. These regimens offer a major opportunity to facilitate treatment expansion worldwide.
The Guidelines Development Group acknowledged that there are countries where pangenotypic formulations may not yet be approved or available. In addition, there are countries where the HCV epidemic is almost entirely caused by one genotype, and where national hepatitis programmes successfully use a non-pangenotypic DAA regimen such as sofosbuvir/ledipasvir. In these cases and when treating adolescents, there remains a role for non-pangenotypic DAAs while national programmes transition to using pangenotypic regimens.

# Balance of benefits and harms
The use of pangenotypic regimens removes the need for genotyping. This simplifies medicine procurement and supply chains, may reduce costs and loss to follow up after diagnosis. Potential harms include the development of rare long-term side-effects of these recently approved medicines, which may not have been identified during post-marketing surveillance, and the potential overtreatment of persons treated with sofosbuvir/daclatasvir if persons are treated for 24 weeks in the absence of genotyping.

# Values and preferences and acceptability
Four identified studies investigated the preferences of HCV-infected persons regarding HCV treatment regimens. For persons infected with HCV, the likelihood of a cure and the lack of adverse events are the most important considerations related to treatment regimens, though factors such as a shorter (e.g. 8-week) course of treatment were also valued (97-100).
Therefore, use of pangenotypic regimens would be acceptable.

# Resource considerations
The resources required to administer HCV therapy can be broadly divided into health system costs (e.g. laboratory and personnel) and the price of medicines. Treating persons with pangenotypic DAAs incurs fewer health system costs as it removes expensive genotyping, which requires specialist laboratories and personnel, saving up to US$ 200 per test in LMICs.
The Guidelines Development Group recognizes, however, that access to pangenotypic DAA regimens remains limited in many LMICs. Prices for sofosbuvir/velpatasvir and glecaprevir/ pibrentasvir are still higher than the older DAA combinations, but it is expected that prices will substantially decrease as the volume of use increases and access policies for HCVinfected persons living in LMICs are optimized.
The WHO 2020 progress report on access to hepatitis C treatment points to the feasibility of widening access to HCV treatment with the use of pangenotypic DAAs (55).
Simplifying the care pathway by using pangenotypic regimens could improve equity and help improve access to populations that currently do not have access to HCV treatment. Integration: 3 We recommend integration of HCV testing and treatment with existing care services at peripheral health facilities. These services may include primary care, harm reduction (needle and syringe programme (NSP)/opioid agonist maintenance therapy (OAMT) sites), prisons and HIV/ART services.
(strong recommendation; certainty of evidence: moderate (people who inject drugs, prisoners); low (general population, people living with HIV))
In 2016, WHO developed the global health sector strategy on viral hepatitis 2016-2021 (10), with a goal of eliminating viral hepatitis as a public health threat by 2030. Elimination was defined as a reduction in hepatitis-related mortality by 65% and in incidence of chronic infections by 90%. Advances in treatment and diagnostics as well as price reductions and WHO guidelines recommendations in 2018 for a "treat all" approach regardless of stage of disease, using a few pan-genotypic regimens (1), have transformed the global response to and feasibility of eliminating HCV infection (119).While impressive progress has been made in several Member States, major testing and treatment gaps remain. As of 2019, only a small proportion of persons with chronic HCV infection have been diagnosed (21%) and even fewer, treated (13%) (9). Reaching the 90% testing and 80% treatment coverage targets will require a substantial simplification in service delivery. Until recently, delivery of viral hepatitis testing and treatment in many countries relied on models of specialist-led centralized care in hospital settings (120,121). Even when testing was undertaken at the community level, there was often significant attrition, as patients needed to attend a different hospital service for confirmatory HCV RNA testing and treatment (122)(123)(124).
Decentralization: Decentralization of services refers to service delivery at peripheral health facilities, community-based venues and locations beyond hospital sites, bringing care nearer to patients' homes. Most of the evidence to inform simplified approaches such as decentralization of care to primary care facilities and task sharing with nurses, non-specialist doctors as well as peers is based on the HIV literature (8). Decentralization of HIV treatment services was a key factor in successful global scale-up, improving uptake of both testing and treatment and reducing loss to follow-up (125,126). It was also shown to reduce transportation cost and waiting time experienced at central hospitals. As a result, decentralization improves linkage to treatment and follow-up. It can also strengthen community engagement by linking community-based interventions with health facilities and optimize access to services, care-seeking behaviour and retention in care (127)(128)(129)(130). In 2021 WHO made a conditional recommendation for initiating ART outside health facilities to reduce delays in starting treatment (2).
Integration of HCV testing, care and treatment with existing services: WHO already recommends integration of hepatitis C testing into a range of other clinical services, such as services for TB, HIV/ART, maternal and child health, screening for noncommunicable diseases, sexual and reproductive health (especially STI clinics), mental health, harm reduction programmes, migrant and refugee services and in prisons (2,3). The primary purpose of integration and such programme collaboration is to create integrated delivery systems that can facilitate access to hepatitis testing and treatment along with other health services. By making hepatitis B and C testing and treatment more convenient for people coming to health facilities it can expand the reach and uptake of viral hepatitis care. Also, for the HCV-infected person, integration of hepatitis testing into other health services may facilitate addressing other health needs at the same time, thereby saving time and money. For the health system, integration may reduce duplication of services and improve coordination (for example, in stock management of diagnostic assays) and linking reporting systems to share information between settings and providers.
Reaching the 90% testing and 80% treatment coverage targets will require a substantial simplification in service delivery. 8. Community engagement and peer support to promote access to services and linkage through the continuum of care, which includes addressing stigma and discrimination.
- Strategies for more efficient procurement and supply management of quality-assured, affordable medicines and diagnostics.
- Data systems to monitor the quality of individual care and coverage at key steps along the continuum, or cascade, of care at the population level.
In the 2018 update to the WHO HCV guidelines (1), WHO described eight key good practice principles to simplify service delivery across the continuum of care and support implementation of the "Treat All" recommendations (Box 5.1). There is now substantial evidence supporting three key interrelated components of HCV simplified service delivery -decentralization of services from specialized centres, integration of hepatitis testing, care and treatment with other, existing services, and task sharing to non-specialist health care workers) -to inform updated WHO recommendations.
The three chapters in this section provide updated recommendations on decentralization to peripheral health facilities: integration of HCV testing and treatment with other services (Chapter 5); and task sharing to non-specialists (Chapter 6); followed by a summary of all strategies to promote uptake of testing and linkage to care and treatment (Chapter 7). These should be considered alongside the existing good practice principles in the following areas: comprehensive national planning, simple and standardized algorithms, differentiated care strategy, community engagement and peer support, strategies for more efficient procurement and supply management, and data systems to monitor the quality of individual care and coverage. Among people who inject drugs, there was higher HCV RNA NAT testing uptake for full decentralization/integration at harm reduction sites than with partial decentralization or no decentralization (ND): respectively, 98% (95% CI 95-100%) versus 81% (69-91%) versus 82% (13-100%), and higher DAA treatment uptake levels: respectively, 73% (63-80%) versus 66% (55-77%) versus 35% (23-48%). Similarly, for those in prison settings, there was higher linkage to care with full decentralization and integration into existing prison services versus partial decentralization: 94% (79-100%) versus 50% (29-71%) and higher DAA treatment uptake: 72% (48-91%) versus 39% (17-73%).
For general populations, with decentralization and integration of HCV testing and treatment into primary care services, there was a high degree of heterogeneity and overlapping confidence intervals in outcomes for HCV RNA viral load uptake, linkage to care and treatment uptake.
The proportion of patients achieving cure (SVR12) was high (>95%) across all levels of decentralization/integration and for all populations.
The findings among people who inject drugs were confirmed in studies with comparator arms, which found higher linkage to care and treatment uptake for full decentralization/integration of HCV testing and treatment at harm-reduction sites versus no decentralization/integration: 88% (77-94%) versus 67% (54-78%) (p=0.008) and 88% (65-100%) versus 33% (25-43%) (p<0.001), respectively. Overall, results were similar across seven studies with comparator arms and non-comparator studies.
The key limitations of the review were that it was based largely on single-arm observational studies with different levels of decentralization. Only 13 studies (9%) had a comparator arm, and only four were RCTs that made possible a direct comparison of different levels of decentralization and integration. There was Also, studies from LMICs were under-represented, and studies with data from the early testing and linkage part of the cascade were compared with the later treatment steps in the treatment cascade. Many studies also included other interventions addressing different steps in the care cascade -for example, use of POC HCV RNA assays, reflex laboratorybased viral load testing, patient navigators or peer workers -alongside decentralization or integrated care, which may have affected outcomes.

# Additional supporting evidence from HIV literature for decentralization and integrated care
Findings from the HIV literature on decentralization also show comparable rates of viral suppression on ART as well as increased uptake of testing and treatment with full decentralization (for example, community-based HIV testing and treatment at lower-level health facilities) (135,(140)(141)(142)(143). The HIV ART literature also demonstrates the beneficial impact of providing integrated HIV care for people who inject drugs (144)(145)(146). The convenient co-location of HIV testing and treatment integrated with OAMT services or primary care/community sites where multiple needs can be met in one easily accessible setting has been an important facilitator of access to care for people who inject drugs (146)(147)(148). WHO currently recommends offering HIV care and ART at OAMT sites (146).
WHO already recommends integration of HIV testing and ART treatment into a range of other clinical services, such as services for TB, HIV/ART, maternal and child health, sexual and reproductive health (particularly STI clinics), OAMT programmes, migrant and refugee services, and in prisons (2). The same integration of services should extend to hepatitis C and B.

# Rationale for the recommendations
The Guideline Development Group made a strong recommendation for adoption of fully decentralized HCV testing and treatment at the same peripheral health care facility and for full integration into existing services. This recommendation was based on evidence of moderate certainty of increased uptake of HCV viral load testing, linkage to care, and treatment at harm reduction sites among people who inject drugs, as well as among prisoners in closed settings, and evidence of low certainty among the general population in primary care settings.

# Overall balance of benefits and harms
The key benefits of expanding delivery of HCV services beyond tertiary or specialist facilities to fully decentralized, co-located and integrated HCV testing and treatment services at the primary and secondary care levels, harm reduction services, prisons and HIV clinics include the following:
- Such expansion will increase access to HCV testing and treatment services and so accelerate progress towards elimination.
- The impact on access of a decentralized, co-located "one-stop shop" for HCV testing and treatment will be greatest among people who inject drugs, who have particular difficulties accessing health services and have high rates of loss to follow-up. Many studies now show the feasibility of improving access to diagnosis and treatment among the marginalised and hardto-reach people who inject drugs and prisoner populations through delivery of integrated care. Surveys of end-users suggest that delivery of HCV testing and treatment at harm reduction sites is associated with less stigma and as a result promotes access.
- For the health system, integration may reduce duplication of services and improve coordination (for example, in stock management of diagnostic assays) and linking reporting systems to share information between settings and providers.
The key challenges with decentralization (148, 149) are that there is usually less specialist expertise at decentralized site, and a good triage system is needed to ensure those in need of more specialist care are identified and referred. Decentralization of HCV testing and treatment and integration with existing primary care may therefore require additional training for health care workers to ensure delivery of client friendly services, particularly for marginalized groups, such as people who inject drugs, and safe treatment for individuals with potentially advanced disease and greater risks of adverse events. The Guidelines Development Group considerd that the benefits considerably outweighed any potential harms.

# Cost and cost-effectiveness
Four studies have evaluated the cost-effectiveness of different levels of decentralization and task sharing (150)(151)(152)(153). A study in Australia examined the integration of HCV treatment and care into community-based care delivered by general practitioners and found that the integrated care improved health outcomes and reduced costs by Australian $42122 per patient, compared with the cost of usual, non-integrated care delivered by specialists (AU$ 64 025) (151). A further modelling study from Australia compared costs and QALYs according to who delivered testing and treatment and found that groups followed by a general practitioner or a combination of a specialist and a nurse resulted in lower costs and better outcomes than those just followed by a specialist (152).

# Acceptability, values and preferences (Web Annex D)
Three related surveys or series of in-depth interviews were undertaken among different populations affected by HCV to inform an understanding of the values, preferences and acceptability of different ways of simplifying delivery of care and treatment for chronic HCV infection (that is, decentralization, integration and task sharing of HCV services). Overall, there was strong support for fully decentralized and integrated HCV services offering testing and treatment at the same community site and near to people's homes rather than in hospitals. The importance of a non-judgmental/non-stigmatizing approach among health care providers was highlighted, especially by people who inject drugs and people living with HIV.
Potential service users and health care providers expressed strong preferences for services provided by community-based organizations.
Multi-country online survey (World Hepatitis Alliance and Coalition Plus) (Web Annex D) Some 210 people in 49 countries participated anonymously in an online survey. Of these, 56% were male, and 71% were between 26 and 55 years old; 23% were living with HCV; 21% were people who formerly injected drugs; 18% identified as "people who inject drugs"; and 16% were living with HIV. Overall, the survey results showed strong support for decentralized and integrated HCV services as well as task sharing. When participants were asked, "Where you would like to test?", the most common responses were: "at a community-based site" (44%) and "at a place of my choice using a self-test" (35%), rather than at a hospital (28%) or primary care (general practice) clinic (28%). Similarly, when asked, "Regardless of your treatment status (treated, not treated), where would you like to receive your treatment?", the most popular sites were "community-based organization centre" (50%), followed by hospital (39%) and general practitioner (29%). Among people who formerly or currently inject drugs, the preferences for testing and treatment at a "community-based organization site" or a "drug user support centre" were even stronger (50%). Overall, the most important reasons given for their choice of testing and treatment locations were "being close to their home or office" (53% and 56%), "reduced costs" (38% and 40%) and having "a non-judgmental/non-stigmatizing approach/atmosphere" (37% and 39%). These percentages were even higher among people who inject drugs and people living with HIV. The great majority of participants (91%) also expressed a strong preference for having testing and treatment in the same place for "convenience" (34%) and "continuation of follow-up from testing to treatment" (33%).
Peer-driven semi-structured interviews or focus group discussions (International Network of People Who Use Drugs (INPUD)) (Web Annex D) Across four key populations (gay and bisexual men, male and female sex workers, people who inject drugs and transgender people), 230 individuals in 68 countries participated in either a semi-structured interview (SSI) or a focus group discussion (FGD) on the themes of decentralization, integration, the role of peer workers, stigma and discrimination. There were several key findings:
- Across all four key populations, there was a universal preference for community-based services for HIV, STIs and HCV. Participants described community-led services as critical to promoting the health and human rights of marginalized groups and a counter-balance to stigmatizing health care settings. The main advantages of community-led services highlighted were: the greater accessibility of services; specific understanding of community health needs and comprehensive approach to key populations' well-being; provision of safe spaces for communities to gather, organize and advocate; and more effective communication with communities in ways that are credible, relevant, nonjudgmental, trustworthy and accessible. Effective community-led service models mentioned by participants included drop-in centres, mobile clinics, peer outreach and one-stop shops.
- Participants expressed strong support for offering HCV testing and DAA treatment in a wide range of settings, including at harm reduction services (NSPs, OAMT clinics, drop-in centres), as well as in general practice and hospital settings, to maximize access and reduce barriers, but also at the same site ("one-stop shops") to reduce loss to follow-up.
- Participants emphasized the importance of offering HCV DAA treatment alongside HCV prevention for people in prisons, where access to harm reduction measures is often completely lacking.
Multi-country rapid qualitative assessment (FIND) (Web Annex D) A survey was undertaken in 2020 among potential end users of HCV services and health care workers to understand their values and preferences concerning hepatitis C self-testing (HCVST) and perspectives on current hepatitis C testing services. Across 10 countries, populations included were: general population and health care workers (in Rwanda, Thailand and Ukraine); men who have sex with men (in Brazil, India and the Philippines), people who use drugs/people who inject drugs (in Costa Rica, India, Indonesia, Kyrgyzstan and South Africa. Among respondents, 460 participated in individual interviews; 220, in group interviews; and 257, in Participatory Action Research. The original analyses were re-reviewed in 2021 to synthesize relevant data on values and preferences relating to decentralization, integration and task sharing of HCV testing and treatment services. Key observations were: Existing HCV services were described as inconvenient, with complex processes, long queues, requirement for immediate payment and lack of information on how to access tests and treatments. Simplification of processes through decentralization and integration with primary care and harm reduction services, especially the "one-stop shop" for same-day testing and treatment, was strongly supported. But there were concerns about the potential for increasing stigma if such HCV test-and-treat services were offered only to vulnerable and already stigmatized populations. Partial decentralization, where only testing is done at a community level, was judged an ineffective approach if prompt access to treatment could not be guaranteed.
The systematic review showed that the impact of full decentralization/integration of HCV testing and treatment has been greatest among people who inject drugs and prisoners -two key populations that have major difficulties in getting tested, linked to care and navigating tertiary care facilities for treatment, with high rates of loss to follow-up (154)(155)(156). The Guideline Development Group, therefore, concluded that providing HCV testing and treatment at lowerlevel facilities integrated with existing harm reduction services would increase equity, as benefits of co-location of services for patient care were greatest among marginalized populations who currently have major difficulties accessing health services.
Compared with HIV care, there are even greater opportunities for decentralization of HCV care to lower-level facilities (139). The simplicity of short-course, curative, pangenotypic DAA regimens with minimal side-effects means that care and treatment require minimal expertise and monitoring. There are now multiple examples of successful models of decentralized viral hepatitis testing and treatment services emerging in high-burden countries, both in primary care for the general population and at harm reduction sites for people who inject drugs (157). We highlight below country case studies of decentralized and integrated HCV care models in primary care in Cambodia, Malaysia and Georgia and, from Medecins du Monde, multi-country peer-based HCV screening and treatment for people who inject drugs integrated into a harm reduction model in Georgia, Kenya, Viet Nam and Myanmar (Boxes 6.1, 6.2, 6.3 and 6.4 -Case studies).

# Implementation considerations
Implementation of the recommendations should be informed by local context, including HCV epidemiology and the prevalence of other comorbidities, the availability of resources, the organization and capacity of the health system and anticipated cost-effectiveness.
- Decentralization and/or integration of HCV testing and treatment services will require additional training and supervision for health care workers (see Task-sharing implementation considerations, section 6.6), access to quality-assured RDTs or collection and analysis of blood specimens, good specimen referral networks and documentation of results, including other features such as enhanced connectivity for return of results and an electronic results system. Planning and coordination are also important for delivery of integrated care, including establishment of integrated data systems and consistent cross-training of health care providers.
- Implementation alongside other existing good practice principles of simplified service delivery (see Box 5.1). These include comprehensive national planning, simple and standardized algorithms, differentiated care strategy, community engagement and peer support, strategies for more efficient procurement and supply management, and data systems to monitor the quality of individual care and coverage.
- Adaptation of service delivery recommendations for different contexts and high-income countries: Decentralization and integration require understanding of context, needs, service gaps and overall costs and benefits and the programmatic data to inform decision-making.
- Decentralization of HCV testing and treatment services and/or integration into existing health services may not be appropriate for all settings or acceptable to all clients, and the relative benefits should be assessed according to the context. For example, decentralization of services may be inefficient and costly in high-income countries with a low burden of HCV infection, and a centralized service delivery model with community linkage may be more appropriate.
- The selection of facilities for decentralization should take into consideration geographic distribution of the most affected populations, and will not be applicable to all primary health care facilities.
- Where care is partially decentralized, ie. testing at a community site and treatment at a different hospital site, it should be accompanied by efforts to strengthen linkage and referral systems. Community-based treatment programmes should be linked with care at health facilities and with adequate laboratory, diagnostics, monitoring and evaluation and drug and supply management systems. Mobile outreach services may also be utilized to address hot spots, which can be identified via routine HCV testing.
Adaptations may be needed for specific populations. Although hepatitis care and treatment services for key populations can be provided in decentralized settings, it should be recognized that not all health care centres are equipped equally to deal with the specialized needs of people who use drugs. The experience of stigma and discrimination is one of the major problems in accessing services for people who inject drugs, and this problem may be greater at some facilities than others. Some may choose to receive their hepatitis care in a facility that is not close to their homes because of concerns about stigma and disclosure.

# Research gaps
- There is a need for more methodologically rigorous studies comparing packages of different service delivery interventions, focussing on different steps in the care cascade. Such studies should assess how well these interventions promote the uptake of HCV testing, linkage to assessment and uptake of treatment, especially in LMICs. Studies should provide a full description of the service delivery model, and evaluation should capture the effectiveness of interventions across the entire continuum of care and not only the treatment-related outcomes.
- Implementation research is especially needed on different models of fully decentralized and integrated HCV testing, care and treatment for the general population in primary care settings, and models of peer supported service delivery.
- Costing and cost-effectiveness data for different decentralized and integrated models of care should be collected, to allow for comparative analyses.
- Examination is needed of various strategies to promote testing and treatment access in LMICs, such as mobile outreach services, especially for homeless populations; pharmacy-led testing and treatment initiation; and Internet-based linkage programmes. Mobile outreach services may also be utilized to target hot spots, identified through routine HCV testing.
SIMPLIFIED SERVICE DELIVERY CHAPTER 6. TASK SHARING 6.1 Recommendation: task sharing 1

# New recommendation
We recommend delivery of HCV testing, care and treatment by trained non-specialist doctors and nurses to expand access to diagnosis, care and treatment.
(strong recommendation; moderate certainty of evidence)
Until recently, delivery of viral hepatitis testing and treatment in many countries relied on specialist-led (usually by a hepatologist or gastroenterologist) and centralized care models in hospital settings to administer complex treatment (120,121). However, many countries affected by HCV infection face shortages of trained health workers and specialists in the management of viral hepatitis. The availability now of short-course oral, curative pangenotypic HCV DAA treatment regimens with few if any side-effects requires minimal expertise and monitoring and has the potential to be safely provided by non-specialists, including primary care physicians and nurses at peripheral or community facilities (158).
Task sharing to non-specialists is a pragmatic response to shortages of the health workforce to support decentralized care. It was strongly recommended in 2014 by WHO for HIV care, based on a comprehensive evidence base, and has been widely adopted to expand access to testing and ART initiation and follow-up globally (143,159). In 2016 WHO also strongly recommended that lay providers who are trained and supervised be able to independently conduct HIV testing RTCs, and nurses, to initiate ART. Effective task sharing for ART delivery by non-specialists or nurses requires appropriate training at the decentralized site and access to additional support or referral to tertiary or specialist sites for complex cases (123,160,161). There is now a substantial evidence base on task sharing HCV care to non-specialist health care workers to inform updated WHO recommendations.

# Summary of the evidence (Web Annex C)
A systematic review and meta-analysis of 142 studies from 33 countries (20 (14%) from LMICs) examined the effectiveness of key simplified service delivery interventions (decentralization, integration and task sharing to non-specialists) on outcomes across the HCV cascade of care (uptake of HCV serologic testing, NAT, treatment, cure assessment and SVR12 (cure). There were 46 (30%) studies with care delivered by non-specialists, 24 (16%) delivered by nonspecialists supported through telehealth and 51 (33%) with care delivered by specialists. Of the 142 studies, 80 (56%) were among people who inject drugs, 20 (14%) among people in prisons, five (4%) in people living with HIV and 37 (26%) in the general population. Some 123 studies (87%) were single-arm observational studies, and 11 (8%) were comparator observational studies. There were only six randomized controlled trials.
Across all populations, task sharing of care and treatment with DAA-based regimens to a nonspecialist (primary care physician, addiction specialist or nurse) was associated with consistently high SVR12 cure rates, similar to those with treatment delivered by specialists, across all populations and settings. This included among people who inject drugs (non-specialist 96%  versus specialist 92%, people in prisons (non-specialist 98%  versus specialist 100%, people living with HIV (non-specialist 98%  versus specialist 100% and the general population (non-specialist 94%  versus specialist 94%. Of note, task sharing of care and treatment was associated with similar SVR12 cure rates even when using the more complex interferon-based regimens. In an analysis of the five studies that had direct within-study comparisons of task sharing to non-specialists versus no task sharing, SVR12 rates with DAA regimens were high for all populations analysed. Results were also consistent between the comparator and non-comparator studies (Table 6.1).
The key limitations of the review were that it was based largely on single-arm observational studies, but there were five studies that had a comparator arm of specialist versus non-specialist care, and results were consistent between comparator and non-comparator studies. There was also an under-representation of studies from LMICs, and there were insufficient data to examine the impact of task sharing on uptake of testing and treatment.

# Additional supporting evidence from the HIV literature
Multiple systematic reviews from different areas of health care support the general conclusion that good health outcomes can be achieved by devolving tasks to nurses and lay or community health workers with appropriate training and supervision (4,162,163). Task sharing has been adopted for around two decades to expand HIV testing and treatment across the globe, especially in resource-limited settings where there is a shortage of health care professionals (164,165). WHO already recommends that lay providers who are trained and supervised can independently perform HIV counselling and testing using RDTs and that nurses can provide HIV testing in pregnancy and, now, initiate ART (166,167). The public health benefits of lay providers distributing ART have also resulted in an overall increase in the number of providers to overcome the shortage of facility personnel, reduced clinic congestion and provided services closer to communities, which supports long-term retention in care (8). 6.4 Rationale for the recommendations

# Balance of benefits and harms
The Guideline Development Group made a strong recommendation for adoption of task sharing to non-specialists, including primary care physicians and nurses, based on moderate certainty of evidence of comparable cure rates between specialists and non-specialists across all populations and in all settings. Task sharing is a key intervention to improve access to HCV diagnosis and treatment, especially among people who inject drugs and people in prisons, who are more challenging populations to reach and treat. There is limited evidence of reported harms with task sharing in HCV service delivery, but adequate training and support is required to ensure referral for more complex cases (139). It is not yet understood how task sharing for hepatitis C care and treatment could apply for children, due to the need to adjust the dosage for younger children.

# Values and preferences and acceptability (Web Annex D)
Given the considerable potential benefits and minimal harms, the Guidelines Development Group considered that the recommendation was not sensitive to variability in preferences/ values regarding outcomes. Three related surveys or series of in-depth interviews were undertaken among different populations affected by HCV to inform an understanding of the values, preferences and acceptability of task sharing of HCV services to non-specialists. In all three surveys, regardless of support for or against task sharing of HCV testing and treatment to community-based health care workers, there was unanimous support for the importance of a non-judgmental/non-stigmatizing approach among health care providers and the need to sensitize and train primary care physicians and other health care workers. However, the majority of respondents thought that task sharing would not increase people's access to testing and treatment unless health care workers' attitudes improved.
Across the three different surveys, there were diverse perspectives on the issues of task sharing of HCV testing and treatment to non-specialists. Respondents recognized that non-specialists (primary care physicians, nurses, community health workers, pharmacists) are already engaged and play important roles in HCV testing and treatment. While many respondents thought that testing uptake and linkage-to-care would increase if people were able to receive HCV care from their trusted regular care provider, others, particularly from marginalized groups, such as people who inject drugs, thought this approach would be a deterrent to seeking care due to the perceived judgemental attitudes of health care workers.
Task sharing is a key intervention to improve access to HCV diagnosis and treatment, especially among people who inject drugs and people in prisons.
Although participants of the World Hepatitis Alliance survey showed a strong preference for testing and treatment in community-based settings outside of conventional health care settings such as hospitals or general practitioner's clinics, they also showed a preference for seeing specialists when discussing health needs related to hepatitis C. In response to the question, "With whom would you prefer to discuss your health needs related to hepatitis C?" (n=166), "specialist doctor" was the most popular choice (48%), followed by "community-friendly medical personnel" (23%), but only 10% indicated "general practitioner" (11%) or "community/ peer worker" (10%). The subgroup of current or former people who inject drugs showed a greater preference for "community/peer workers" and reluctance to discuss their HCV care with a "general practitioner". The survey concluded that providing a mix of culturally competent services delivered by specialist and non-specialist community-friendly medical personnel was valued, and that this would satisfy the preferences of most participants.
The INPUD peer-driven semi-structured interviews (SSI) or focus group discussions (FGD) highlighted the almost universal experience among people who use drugs of stigma and discrimination from health care workers, and the need to sensitize and train primary care physicians and other health care workers. Across regions, peer workers and peer-based services were highly valued, especially by members of key populations, due to their capacity to engage and gain trust. There was strong support for additional peer-based and community-led HIV/STI/ HCV services.

# Resource considerations and access issues
Four studies have evaluated the cost-effectiveness of different levels of decentralization and task sharing (150)(151)(152)(153). The simplified care models with task sharing to nurses or non-specialist doctors resulted in lower costs and either similar or better outcomes and were considered very cost-effective.
Many studies show the feasibility of task sharing of HCV diagnosis and treatment to nonspecialists in primary care and among the marginalized and hard-to-reach people who inject drugs at OAMT and NSP sites (139).

# Implementation considerations
- Defining roles and standards of care: Standards of care should be defined for different levels of the health system, including the private sector. The role of each cadre of health worker should match their skills and capacity, and the lines of responsibility should be clear and well understood. For example, health care staff at a decentralized facility should be able to identify signs and symptoms of advanced liver disease or interpretation of test (such as APRI or FIB-4) for the appropriate referral of persons in need of a higher level of care, especially among older patients. There is a need to ensure an appropriate mix of health care workers at peripheral facilities.
- Training and mentorship: Effective task sharing with non-specialist doctors or nurses requires provision of appropriate training and ongoing mentorship at the decentralized site and access to additional support or referral to tertiary or specialist sites for more complex cases (148) 168). This should include awareness-raising and training to provide non-stigmatizing, nondiscriminatory health care to key populations.
- Regulatory framework: An appropriate regulatory framework (legislation, regulations, policies and guidelines) is needed to enable tasks to be performed by different cadres of health care workers. In some countries task sharing and delegation may require changes to legislation and rules and procedures (160).
The pilot project and nurse-led initiation (NLI) care model showed that a highly simplified, decentralized model of HCV care with task-sharing to nurses can be integrated with a rural public health system in a low-income country while maintaining high patient retention, treatment efficacy and safety. The project delivered care via accessible, decentralized primary health centres using non-specialist clinical staff, thereby enhancing the efficient use of limited resources and maximizing the potential to test and treat individuals living with HCV infection. Malaysia is an upper-middle-income country with a low HCV burden and prevalence of around 0.3%.
The initial success of the Malaysian HCV programme, with progressive decentralization of HCV screening and treatment, is attributed to a multi-pronged strategy, defined by:

# Government commitment and leadership
- The Ministry of Health in Malaysia committed to a goal of HCV elimination with goals to diagnose 90% of HCV-infected persons and treat 80% of those eligible.
- A 5-year national strategic plan was launched in 2019, with a plan for HCV treatment scaleup based on decentralized and integrated care.
- A series of clinical practice guidelines on HCV management also launched in 2019, providing evidence-based recommendations and simplified algorithms for HCV care.

# Improved access to DAAs
- Malaysia issued a compulsory license for sofosbuvir in September 2017, which resulted in availability of the sofosbuvir/daclatasvir regimen at less than US$ 300 per client in public health facilities across the country.
- The Ministry of Health organized distribution of DAAs across public health facilities in the country through centralized coordination and pooled procurement. - HCV Programme Implementation Review Workshops were also organized periodically, involving family medicine physicians, general medical officers, allied health professionals and officers from correctional settings and civil society organizations (CSOs) to discuss clinical management and service delivery issues related to HCV care and discuss possible solutions.
Following progressive simplification and decentralization of HCV care in the country, as of August 2021, 11 000 HCV patients had been treated with DAAs, despite the impact of the COVID-19 pandemic on health services. October 2021, 2.3 million people had been screened, and of the 150 000 estimated to have chronic hepatitis C virus (HCV) infection, 95 000 have been identified and 76 000 treated. This has been achieved through continuous improvements and simplification in the HCV testing and treatment pathway to overcome key barriers to screening, linkage-to-care and treatment and to decentralize care to primary and non-specialized care sites.

# Expansion of screening
The diagnostic strategy evolved from an initial focus on testing and treatment of people with advanced liver disease to an expanded hospital screening program in November 2016 with the offer of rapid antibody testing to all admitted patients. This led to a threefold increase in screening uptake in the first six months: 14 623 unique persons had screened per month in May-October, 2016 versus 46 648 per month in November 2016-April 2017 (173). In 2018 primary care centres in one region piloted an integrated HCV/HIV/TB testing project, in which all people presenting to the facility were offered screening for all three infections; the project demonstrated a 60% increase in screening coverage in the pilot region (174). By the end of 2020, the integrated testing approach had expanded to 1044 primary care sites nationally, which conducted 636 401 screening tests (31% of total HCV screening tests performed in the country during the same time period) and identified 5185 HCV-positive persons (16.2% of all identified countrywide).

# Simplification of diagnostic pathways
Ensuring high-quality and diversified diagnostic capacity has been one of the important  (177,178).
Successful service decentralization and integration have been possible through simplified diagnostic and treatment algorithms. Complex treatment selection and monitoring algorithms have been gradually simplified as the programme switched to all-oral pangenotypic DAA regimens, with concomitant increased cure rates from 82.1% to 98.9% (179).

# Task sharing
Initially, only infectious disease specialists could treat HCV. By early 2016 other specialists (for example, gastroenterologists) were able to provide care. The programme has adopted further task sharing by allowing primary care physicians to treat patients and, thus, supporting decentralization of HCV testing and treatment as part of the package of services delivered at primary health care and harm reduction.  (181,182). Key features of these projects have been the strong outreach-based approach, providing delivery of treatment at outreach sites on a case-by-case basis. The Viet Nam experience also showed that this model can "plug into" a medium/low-level public health facility and achieve a form of task sharing, with care delivered by an experienced HIV district hospital team without the involvement of a specialist hepatologist. This collaboration between a district-level hospital and a peersupport network enabled 97% of patients to be retained in care during treatment, with a 98% cure rate for those who completed treatment (183). 6.6 Existing 2018 additional good practice principles for simplified service delivery (1)
- 6.1 National planning for HCV elimination
In 2015 WHO published a manual to guide national programme managers in developing or strengthening national viral hepatitis plans (184). The manual is aligned with a health systems approach to disease planning and supports an evidence-based decision-making process. It includes a template for a national hepatitis plan that covers prevention, testing and treatment within the framework of universal health coverage principles and other planning tools. National stakeholders should also use the plan to agree on the service coverage targets for the interventions necessary to achieve elimination.

# Simple standardized algorithms
A simplified algorithm for testing, treatment and monitoring with five key steps that can be adapted for use at the national level has now been updated (see Figure 1). The three updated steps are: alternative option of an HCV point-of-care RNA assay for diagnosis of HCV viraemic infection and as a test of cure; the offer of pan-genotypic treatment to now all adolescents and children 3 years, in addition to adults; and assessment and management of treatment failure.

# Differentiated HCV care and treatment
Currently, the majority of HCV care and treatment during this early phase of scale up is facility-based, and not differentiated according to individual needs. Differentiated care is defined as a client-centred approach that simplifies and adapts services across the cascade, in ways that both serve the needs better of those with more complex problems requiring prompt or specialized clinical care but also relieves overburdened hepatitis clinics in central hospitals. Based on an evidence-based differentiated care framework recommended by WHO and widely adopted in HIV treatment and care programmes (166), a similar approach has been adopted to support decentralized management of HCV infection.
Broadly, three groups of HCV-infected persons with specific needs can be identified. Table 6.2 summarizes these three groups, their anticipated care needs, the most appropriate setting to deliver care and the type of provider needed. The majority of persons with HCV will have early-stage liver disease and can be treated at facility level or potentially even in the community. Only a small proportion will require more intensive clinical or psychosocial support. However, this will vary considerably according to the epidemic profile of the country, and the maturity of the treatment response and diagnosis rate.  The primary purpose of integration is to make HBV, HCV and HIV testing more convenient for people coming to health facilities, and so expand the reach and uptake of viral hepatitis testing. For the HCV-infected person, integration of hepatitis testing into other health services may facilitate addressing other health needs at the same time, thereby saving time and money. For the health system, integration may reduce duplication of services and improve coordination (for example, in stock management of diagnostic assays).

# Integrating the diagnosis of viral hepatitis C with diagnostic platforms and laboratory services used for other infections

# Combination integrated multidisease serological tests
The use of combination integrated fingerstick whole blood-or oral-based multidisease assays allow for integrated testing of HIV, HBV and HCV. Using a single specimen improves the efficiency of testing programmes, especially in populations with a high prevalence of HIV/HCV or HBV/HCV coinfection. While not widely approved or available, preliminary independent evaluation of these combination RDT assays appear promising (185).

# Shared use of HIV or TB multidisease platforms for HCV RNA testing
The introduction of multidisease testing devices or analyzers (also known as polyvalent testing platforms) brings new opportunities for collaboration and integration, and can both increase access as well as provide significant system efficiencies, with cost-savings.
Countries with existing multidisease platforms for HIV viral load, HIV infant diagnosis or TB diagnosis and drug resistance testing, or those that are planning for their introduction can consider collaboration and integration of HCV viral load testing (186). This includes both high-throughput laboratory-based instruments for HIV viral load and HIV infant diagnosis, SARS-CoV-2 and point-of-care NAT instruments such as GeneXpert for HIV and TB.
- 6.7 Community engagement and peer support, including addressing stigma and discrimination in the general population Updated
Peer-led interventions have been effective in increasing access, care and treatment, and supporting adherence to treatment, for both hepatitis and other infectious diseases particularly for marginalized population groups such as people who inject drugs (4,7,146).
In addition to providing services, peers can act as role models and offer non-judgemental support that may contribute to reducing stigma and improving the acceptability of services.

# Strategies for more efficient procurement and supply management of medicines and diagnostics
Access to DAAs for hepatitis C has improved since their initial registration in 2013 (55). In 2017 62% of those infected with HCV lived in countries where generic medicines could be procured. Countries that made use of this possibility and registered multiple medicines from different manufacturers managed to achieve a major reduction in prices (187). However, initial progress in access to pan genotypic DAAs has been mostly for sofosbuvir/daclatasvir combinations ( 3. Registration and inclusion in the national essential medicines list: DAAs need to be registered with the national regulatory authority and included in the national essential medicines list. If access to generic medicines is possible, registration of products from as many manufacturers as possible will increase competition and lower prices.  1 This can be achieved either through laboratory-based reflex viral load testing using a sample already held in a laboratory or in clinic-based reflex testing in a health facility through immediate sample collection following a positive RDT HCV antibody test.
Both uptake of testing and linkage to care are essential initial components of the hepatitis C care continuum. Country-level data on the continuum for viral hepatitis care is still limited, but, as of 2019, WHO estimated that only 21% of the estimated 58 million persons with chronic HCV infection have been diagnosed and 13%, treated. The proportions are even lower in LMICs and among vulnerable populations, such as people who inject drugs, sex workers and migrants. Poor linkage to care and loss to follow-up after a diagnosis of hepatitis C is a further challenge, contributing to a steep fall-off in the continuum between diagnosis and treatment. Also, those who test negative, if at continuing high risk, as well as those who test positive, need linkage to prevention services and HBV vaccination. Without linkage to prevention, treatment and care, testing and learning one's hepatitis C status has limited value. Suboptimal linkage to prevention, care and treatment results in avoidable morbidity and mortality, poorer treatment outcomes, increased cost of care and preventable transmission.
Multiple factors may hinder the successful uptake of testing and linkage to care and prevention. These include patient-level factors, such as lack of social or family support and fear of disclosure, as well as structural or economic factors, such as stigma and discrimination, distance to care sites, lack of or cost of transportation and long waiting times at facilities (189). Also, hepatitis C disproportionally affects individuals with comorbid mental health or substance use issues.
Traditionally, services for hepatitis, mental health and substance use have been provided by separate clinicians or teams often located in separate health facilities and in tertiary care; this separation of services contributes to HCV treatment dropout and/or treatment failure (190).
Optimizing the impact of effective treatments and prevention requires interventions both to expand uptake of testing and to improve linkage to care and retention across the care continuum, from initial screening to treatment initiation and viral suppression (HBV) or cure (HCV). Such interventions may vary based on the local context, including the health care delivery system, geography and target population. There are several well-established, evidence-based interventions that improve linkage to care and treatment of people who have received an HIV-positive diagnosis. These were first recommended in the 2015 WHO HIV consolidated testing guidelines (3) and in the 2016 updated ARV consolidated guidelines (8). They may apply equally to viral hepatitis care and prevention.
The 2017 WHO Guidelines on hepatitis B and C testing recommended that all facility-and community-based hepatitis testing services implement strategies to enhance uptake of testing and linkage to care (strong recommendation, moderate certainty of evidence) (4) (see box above).

# Summary of the evidence for three 2017 recommendations to promote testing and linkage
In 2017, WHO recommended adoption of these strategies (4):
- trained peer and lay health worker support in community-based settings (moderate certainty of evidence);
- clinician reminders to prompt provider-initiated, facility-based HCV testing in settings that have electronic records or analogous reminder systems (very low certainty of evidence);
- provision of hepatitis testing as part of integrated services within a single facility, especially mental health/substance use (very low certainty of evidence).
Evidence supporting these strategies was collected in a systematic review of the impact of different interventions to enhance five key steps along the continuum of care for chronic viral hepatitis -screening, linkage to care, treatment uptake, treatment adherence and,
ultimately, viral suppression. The review included 54 studies, of which 37 addressed interventions and outcomes across the HCV care continuum; 15, across the HBV care continuum; and two, across both (191). Thirty-three studies were included in a meta-analysis that generated pooled effect size estimates for different outcomes. Interventions to address adherence, viral suppression and uptake of HCV testing were the best studied, but there were few methodologically rigorous studies of promoting linkage to car. All studies except one (192,193) were in high-income countries. Most existing studies were judged to be of low or very low methodological quality, because of risk of bias due to study design issues, and there was a high degree of heterogeneity of outcomes across studies.

# Clinician reminders to prompt HCV testing during clinical visits
Unlike interventions to increase HBV testing, which were primarily delivered in community settings, all 11 of the interventions to increase HCV testing either targeted health care providers or took place at established health care facilities (191,(200)(201)(202)(203)(204)(205)(206)(207)(208)(209). Reminder stickers attached to patient charts or in an electronic medical records system prompted providers to order HCV tests if patients belonged to a high-risk birth cohort (204), reported risk behaviour (207) or both (203). These studies found that clinician reminders to prompt HCV screening during clinical visits substantially increased HCV testing rates compared with no clinician reminders (RR = 3.70. The certainty of evidence was rated as very low.

# Integrated care between mental health and HCV treatment specialists
Several studies evaluated interventions providing "coordinated", "integrated", or "multidisciplinary" care to improve treatment adherence and viral suppression in patients with mental health issues (201,(210)(211)(212)(213)(214)(215). Three RCTs demonstrated that interventions facilitating referral to specialist sites and scheduling of visits increased patient attendance at HCV specialist visits (RR = 1.57 moderate-quality evidence).
Individually tailored mental health counselling and motivational therapy to treat mental health and/or substance use issues also increased the number of patients who were regarded as eligible for treatment when compared with usual care (OR = 3.43, 95% CI: 1.81-6.49). 7.4 Rationale for the 2017 recommendations for three strategies to promote testing and linkage
In recommending the three strategies to promote testing and linkage, WHO in 2017 considered the following rationales (4).

# Balance of benefits and harms
The Guidelines Development Group recognized that poor uptake of viral hepatitis testing and linkage to care are major barriers to access to care and treatment. To expand access to testing and treatment, programmes need not only to make use of multiple testing approaches at facility and community levels, but also to adopt interventions to promote optimal linkage to prevention and treatment. The Guidelines Development Group made a strong general recommendation for the adoption and implementation of a series of relatively simple, lowcost but effective strategies -promotion of testing by lay health workers, clinician reminders, and coordinated care between hepatitis and mental health specialists -to enhance uptake of hepatitis testing and linkage to care, although the specific recommendations were based on generally low-quality evidence.
Specifically, promotion of clinician reminders to prompt HCV screening during clinical visits increased HCV testing rates. Coordinated care between hepatitis and mental health specialists along with psychological therapy and counselling for patients with mental health and/or substance use comorbidities also increased HCV treatment initiation and treatment completion and resulted in higher SVR rates. Integration of services among certain populations of individuals with HCV, such as people who inject drugs, may also be useful. The
Guidelines Development Group also considered evidence from recent systematic reviews on interventions to improve linkage to care following HIV testing, which was considered relevant to hepatitis care and treatment services. Integrated care. Integrating HCV screening and treatment with mental health and substance use services is feasible and acceptable to targeted clients (222,223). While the interventions addressing multidisciplinary or integrated care in the evidence review were diverse, a likely key contributor to improved outcomes was co-location and coordination of services.

# Costs and cost-effectiveness
None of the studies identified in the systematic review reported estimates of the direct cost or cost-effectiveness of interventions. However, effective linkage to hepatitis care and treatment following a positive diagnosis would be expected to improve programme effectiveness, support earlier treatment initiation and reduce loss to follow-up before treatment initiation, thus saving costs along the continuum of care.

# Implementation considerations
Policies on linkage to care. Proactive linkage approaches are a critical component of comprehensive hepatitis testing services. Countries should ensure that they have specific policies and strategies to improve and prioritize linkages among hepatitis testing and prevention, treatment and care services. Interventions that strengthen multiple steps along the care continuum will generally be most efficient. The effectiveness of linkage will vary for different testing approaches.
Linkage to prevention services. As for HIV (224), a range of prevention services should be available for those diagnosed with hepatitis, as well as for those who test negative. Linkage to harm-reduction services for people who inject drugs testing HCV negative is not well documented or studied. Supporting linkage to prevention services is particularly important for those with high ongoing risk, such as people who inject drugs and serodiscordant couples.  (11,225). These persons remain HCV antibody positive, but they are HCV RNA negative and no longer infected with HCV. Diagnosis of viraemic HCV infection in those who are HCV antibody positive will distinguish persons with viraemic HCV infection and in need of treatment from those who have cleared the infection (226,227).
A lower level of analytical sensitivity can be considered if an assay is able to improve access (that is, an assay that can be used at the point of care or suitable for dried blood spot  specimens) and/or affordability. An assay with a limit of detection of 3000 IU/mL or lower would be acceptable and, based on available data, would identify 95% of those with viraemic infection.

# Existing recommendations from 2017 WHO Guidelines on hepatitis B and C testing (4)
Laboratory-based HCV NAT testing: Directly following a positive HCV antibody serological test result, the use of quantitative or qualitative nucleic acid testing (NAT) for detection of HCV ribonucleic acid (RNA) is recommended as the preferred strategy to diagnose viraemic infection (strong recommendation, moderate/low certainty of evidence).
HCV core antigen assay: An assay to detect HCV core (p22) antigen, which has comparable clinical sensitivity to laboratory-based HCV RNA NAT assays, can be an alternative approach to diagnose HCV viraemic infection (conditional recommendation, moderate certainty of evidence).

# New 2022 recommendation
Point-of-care (POC) HCV RNA assays: The use of HCV point-of-care (POC) RNA NAT assays can be an alternative approach to laboratory-based HCV RNA NAT assays to diagnose HCV viraemic infection (conditional recommendation, low/moderate certainty of evidence).
This diagnosis is generally made using NAT technologies to detect HCV RNA, but alternatives to laboratory-based NAT assays are to detect HCV core (p22) antigen or to use POC NAT or other assays, which are potentially less costly and can be used at the point of care.
Laboratory-based HCV RNA nucleic acid testing (NAT) Both quantitative and qualitative methods are available for the detection of viraemic HCV infection. Quantitative NAT has been widely used for measuring HCV RNA levels and identifying those in need of treatment, as well as for assessing treatment response (4,228,229). Qualitative NAT allows for rapid and sensitive detection of the virus as well as evidence of a decline in viral RNA level below a defined threshold. There are currently five commonly used quantitative HCV RNA (viral load) assays that operate on close NAT analyzers that are commercially available, with others in the research and development pipeline (62, 230) 1. Although NAT technologies are very sensitive and specific for the detection of viraemia, they require a dedicated analyzer or sophisticated laboratory equipment and skilled staff. Assays to detect HCV RNA that may be used at or near the point of care have recently become commercially available. A comprehensive review of the HCV diagnostics landscape was undertaken by Unitaid in 2019 and the Clinton Health Access Initiative in 2021 (62,230).
HCV core (p22) antigen testing In addition to using NAT, it is possible to assess for viraemic infection by testing for HCVcAg, an HCV nucleocapsid peptide 22 that is released into the plasma during viral assembly and can be detected both early on and throughout the course of HCV infection (231). Serological methods that test for detection of HCVcAg have the potential to be less costly and more decentralized than NAT, but to date their uptake has been limited in low-resource settings. There are now several assays commercially available for stand-alone detection of HCVcAg (232). Detection of HCVcAg has also been used as an additional marker in a fourth-generation HCV Ag/Ab serological assay because HCVcAg is detectable earlier than antibodies to HCV. However, the addition of core antigen was intended to increase sensitivity of the assay in early infection in the context of blood and blood products (and tissue) screening, and not to differentiate seropositivity from viraemic HCV infection.

# POC HCV RNA NAT testing
To date, laboratory-based NAT testing has generally been the standard-of-care assay for HCV RNA detection and quantitation (233). However, the high cost of these assays and laboratory requirements means that they are not readily available in resource-limited settings. The key limitation of this review was the relatively few studies with direct within-study comparisons between a POC assay arm and a lab-based assay arm (four studies for HCV RNA NAT testing uptake and ten studies for treatment uptake) and the absence of any RCTs. Although we tried to carefully categorize all studies according to the four different models of care, there was still considerable heterogeneity among these care models, as well as among study populations.

# Diagnostic accuracy 1
A complementary systematic review and meta-analysis were undertaken to determine the diagnostic performance (sensitivity and specificity) of POC HCV RNA NAT assays compared with laboratory-based NAT assays.

# Additional, supporting evidence from HIV and other diseases
WHO has previously recommended use of POC NAT molecular assays for the rapid first-step identification of rifampicin-resistant and multidrug-resistant TB and for routine diagnosis of TB (237). In 2021 WHO also recommended use of POC HIV RNA NAT assays for early infant diagnosis of HIV and routine HIV viral load monitoring for people living with HIV on ART (166).
For early infant diagnosis (EID), this was based on high certainty data from RCTs and large wellcharacterized cohorts showing that POC EID infant testing was associated with faster delivery of results and faster ART initiation in HIV-positive infants (166). Infants who received POC testing were eight times more likely to start treatment within 60 days of initial sample collection than those whose blood samples were sent to laboratories (92.8% versus 50.5%; OR=7.9, p<0.001). Same-day treatment initiation was 51% with POC versus none with standard-of-care (238).
Similarly, POC HIV viral load testing for monitoring resulted in faster return of results to patients [same-day versus 28 days, HR 17.7 (13.0-24.
2)] and to clinicians (HR 11.7), and shorter time to clinical action for elevated VL  than standard-of-care comparators (239). These findings on impact of use of POC HIV RNA assays on turn around time and time to treatment for EID in children and in HIV treatment monitoring provides further indirect evidence to support their use in HCV infection.
- 4 Rationale for the recommendations -POC HCV RNA NAT assays 8.4.1 Balance of benefits and harms
The Guidelines Development Group recognized that access to laboratory-based NAT assays is limited in resource-limited settings and that this poses an important barrier to treatment. For several reasons the Group made a conditional recommendation to consider use of POC RNA NAT assays as an alternative to laboratory-based RNA NAT or HCV core antigen assays to diagnose viraemic HCV infection, based on moderate-/low-quality evidence:
- HCV RNA POC platforms can be used in lower levels of health facilities, given their relative ease-of-use and suitability for running single tests without the need to batch test runs. These assays thereore offer an opportunity to confirm viraemia near to where patient is receiving care.
- POC HCV RNA NAT assays can to lead to greater uptake of and faster testing, and shorter time from testing to return of results to the clinician and treatment initiation, especially when used in fully decentralized care models ie. where testing and treatment are available at the same site and potentially on the same day. Where patients need to travel to another site for treatment, overall time to treatment is prolonged regardless of the use of POC RNA assays.
- OIC NAT molecular platforms are already on the market for a number of infectious diseases, including SARS-CoV-2. They are recommended by WHO for HIV EID and ART monitoring (166) and TB diagnosis, including diagnosis of drug-resistant TB (240). The availability of multi-disease testing devices offers potential for integration of HCV RNA testing that may further expand access while achieving significant system efficiencies and cost-savings. POC testing may reduce some operational needs (e.g. specimen transport, and central result return systems).
- The majority of currently available POC HCV RNA NAT assays have high sensitivity and specificity and similar LoD to laboratory-based NAT assays. POC NAT assays can also be used both for HCV diagnosis and as a test of cure.
There are no notable harms with POC HCV testing, but there are several important challenges:
- POC platforms have more limited test throughput compared to laboratory-based platforms. Therefore, depending on daily specimen/patient volumes, health care facilities may need to prioritize who should receive PoC testing results so immediate treatment and care decisions can be made.
- There are still few manufacturers of POC HCV RNA NAT assays and, therefore, limited competition to drive down costs and options for country selection.
- Monitoring, supervision, training, quality assurance and maintenance of a large number of devices would be challenging.
- There are specific requirements of high-temperature incineration for safe waste disposal of guanidinium thiocyanate (GTC) which is contained in some assays, including those for GeneXpert.

# Acceptability, values and preferences (Web Annex D)
In a multi-country online survey of 210 people in 49 countries undertaken by the World Hepatitis Alliance and Coalition Plus, 88% of participants confirmed a strong preference to "do your initial and confirmatory viral load tests on the same day". This preference was even higher, at 96%, among people who currently inject or formerly injected drugs. The main reasons given for this preference were the opportunity to more rapidly confirm diagnosis (81%) and start treatment (76%). There was also a strong preference, from 93% of respondents, to do both the initial screening test and confirmatory viral load testing at the same place, largely for reasons of convenience (70%), and at a community-friendly site (60%).

# Cost-effectiveness of POC HCV RNA assays
Three studies provided robust cost-effectiveness analyses that compared the use of POC and non-POC HCV RNA NAT assays. All three found POC HCV RNA NAT assays to be cost-effective compared with laboratory-based HCV RNA assays (241,242). Two studies used a decision tree model to compare, from a health sector perspective, 12 testing strategies among various population groups in Cameroon, Cote-d'Ivoire and Senegal (243) and among people who inject drugs in Senegal (244). They found that a strategy combining an HCV antibody RDT
POC HCV RNA NAT assays would promote equity if used in settings and populations at high risk of loss to follow-up, which would particularly benefit from the convenience of POC testing and a rapid test-and-treat approach, such as the homeless and people who inject drugs at harm reduction sites and in prisons. In the systematic review, among people who inject drugs/ homeless populations, there was increased HCV RNA NAT testing uptake with use of POC RNA assays on site (93% or in mobile units (84% compared with lab-based high-throughput HCV RNA assays (27%. Similarly, among prisoners there was evidence of increased treatment uptake with use of POC HCV RNA NAT assays on site (89% compared with laboratory-based high-throughput HCV RNA assays (20%. The introduction of multidisease testing devices (polyvalent testing platforms) brings additional potential for integration that may further expand access and achieve significant system efficiencies and cost-savings.
A 2017 survey of hepatitis testing experience in 19 LMICs found that around 40% of respondent countries did not have access to laboratory-based HCV RNA NAT assays for HCV diagnosis in their countries (121). POC testing programmes using similar platforms have been successfully deployed in multiple countries for other uses, such as HIV EID testing, HIV viral load monitoring and TB diagnosis. Countries with existing multi-disease platforms for HIV VL testing or TB, and those that are planning for their introduction may consider collaboration and integration of HCV VL testing (186). This includes both high-throughput laboratory-based instruments for HIV VL and/or HCV RNA measurement and POC instruments for HIV and TB. There is one supplier with WHO-prequalified products (Cepheid). Molbio (India) has a commercially available assay: Truenat HCV RNA, and a Cepheid fingerstick assay is undergoing WHO Prequalification. Molecular POC options continue to increase and should be encouraged.

# Resource considerations
Programmes report varied final costs for HCV RNA assays (Figure 8.1), with many LMICs achieving prices around US$ 10 to $ 30 per HCV RNA test (both centralized laboratory-based and POC testing). The device costs as well as costs associated with operational components should also be considered. Programmes with higher volumes and pooled procurements (including with other disease assays) may achieve lower costs. In the future, increased competition may both increase access and decrease pricing. In 2017, WHO recommended quantitative or qualitative NAT for detection of HCV RNA as the preferred strategy to diagnose viraemic infection following a positive HCV antibody test result (4).
For the 2017 WHO Guidelines on testing for viral hepatitis B and C, two systematic reviews were undertaken that evaluated the diagnostic accuracy for detection of viraemic HCV infection of (i) qualitative versus quantitative NAT and (ii) HCVcAg testing versus NAT (245).

# Diagnostic accuracy and limit of detection

# HCV NAT assays
One of the systematic reviews identified four eligible studies (246)(247)(248)(249) that compared the performance of three quantitative HCV RNA NAT assays with that of a reference qualitative NAT (two assays used). Although early-generation qualitative NAT assays were able to detect the presence of HCV in plasma at concentrations a full log lower (that is, about 10-fold less) than quantitative NAT assays, the lower limit of quantification of new versions of quantitative assays is now comparable to that of most commercial qualitative assays (that is, 15 IU/mL).

# HCVcAg assays
There were 50 studies that evaluated seven commercial HCV cAg assays. There was significant variation in performance among the different assay brands ( The estimates for the ARCHITECT HCV Ag assay were more homogeneous and precise, as this assay has been the most extensively studied. A pooled quantitative analysis of data available from three studies demonstrated a close correlation between HCV Ag and HCV RNA at viral HCV RNA concentrations above 3000 IU/mL. The LoD for the most sensitive assay is 3 fmol/L HCV Ag or 0.06 pg/mL, which equates to a LoD of ~1000-3000 IU/mL by NAT and is consistent with the analytical sensitivity (LoD) reported by the manufacturer. HCV RNA NAT assays are considered the reference standard for the detection of viraemia, but the quality of studies comparing quantitative and qualitative assays for detection of viraemia was rated as low because of small numbers of studies and heterogeneity in populations. The overall quality of the evidence for the recommendation to use HCV cAg was rated as low to moderate because of inconsistency and imprecision.  (especially for hard-to-reach populations and in remote settings) for countries to consider in their plans for national testing/diagnostics infrastructure and national viral hepatitis strategic plans.

# Limit of detection (LoD

# Use of laboratory-based HCV core antigen for detection of viraemic HCV infection
The Guidelines Development Group recognized that there is limited access to HCV RNA NAT assays in resource-limited settings and that this poses an important barrier to antiviral treatment. The Group made a conditional recommendation to consider use of HCV cAg assays as an alternative to HCV RNA NAT to diagnose viraemic HCV infection, based on moderate-quality evidence, for several reasons:
- HCV cAg assays can utilize existing serological testing platforms and potentially cost less than NAT. They could serve as a more affordable replacement for HCV RNA NAT for diagnosis of viraemic HCV infection in the future.
- Although HCV cAg testing is currently limited to only a few platforms and even those with the highest performance do not reach the sensitivity of HCV RNA NAT, some wellperforming HCV cAg assays have high sensitivity (up to 93.4% for certain commercial assays) and high specificity (>98%), and good correlation with HCV RNA to an LoD above HCV RNA levels of 3000 IU/mL, which will detect over 95% of chronic HCV infections.
However, there was wide variation in sensitivity/specificity between assays and also within the same brand of assay for all but the Abbott ARCHITECT.
- HCV cAg assays also offer the potential in the future to be applied as a one-step screening assay, as HCV cAg HCV cAg appears earlier than HCV antibodies (1-2 days after HCV RNA appears), has a high specificity, and so does not require confirmatory testing. However, such a strategy would be cost-effective only in very high prevalence settings.
The risk with the use of HCVcAg is that, due to the lower clinical sensitivity of the HCV Ag test, a small proportion of cases may be missed due to low circulating HCV RNA concentrations.
As a result, the use of dried blood spot testing for HCV Ag is not currently feasible. A further consideration is that it is preferable, in order to simplify the diagnostic pathway, to select an assay that can be used for both diagnosis of current infection and for test of cure. On the basis of the limited current evidence, the HCV cAg assay cannot be recommended as a reliable SVR test of cure compared with HCV RNA NAT assays.

# Acceptability, values and preferences
The values and preferences survey identified respondents' preferences for future HCV testing strategies. A key preference was for a single-step HCV diagnostic strategy with a low-cost POC test for confirming viraemic infection (48% of respondents). Of these, 52% opted for an HCV RNA NAT because of its high sensitivity, and 35% for an HCV cAg assay because of its lower cost and ease of use. More than half the respondents were prepared to compromise on sensitivity down to 95% in order to gain a reduction in the price of the test. Among the respondents, 47% preferred a test that uses capillary blood and, therefore, could be more easily performed in POC settings, even at the expense of test sensitivity. A short turnaround time (at least same-day) was another key consideration to reduce loss to follow-up, save transportation expenses and enable providers to see more patients within a day.
Participants were asked, "Would you prefer to do your initial and confirmatory HCV viral load tests on the same day?" Overall, 88% answered "yes"; among people who currently inject drugs or formerly injected drugs, 96% said "yes". The main reasons were the possibility to more rapidly confirm a diagnosis (81%) and start treatment (76%). There was also a strong preference from 93% of respondents for doing both the initial screening test and then confirmatory VL testing at the same place, for convenience (70%), and at a community-friendly site (60%).
The survey of hepatitis testing experience in 2017 in 19 LMICs found that NAT for HCV RNA was available at one third of the sites, but 40% of respondent countries did not have any access to NAT for HCV diagnosis in their countries. The HCV cAg assay was not available at any site.

# Resource considerations
Programmes report varied final costs for HCV RNA assays -both POC and centralized laboratory testing (Figure 8.1). The resources required for quantitative NAT vary considerably, with the cost per test ranging from US$ 30 to US$ 200. Furthermore, the laboratory equipment is expensive and requires technicians with specialized training. The cost of testing for HCV cAg is currently US$ 25-50 (data from Medecins Sans Frontieres). This cost is comparable to that of qualitative NAT (US$ 43-51) but still a major barrier to its use.

# Implementation considerations
See also Box 8.2 Case study: Operational considerations for implementation of point-of-care HCV viral load testing in community-based HCV clinic in Yangon, Myanmar - Use of laboratory-based versus POC NAT platforms: The decision whether to use POC RNA NAT technologies or laboratory assays will depend on a variety of factors, including cost and ease of use and the characteristics of the testing site, such as storage facilities, infrastructure, level of staff skills and cost. Use of POC assays may also be considered in services caring for specific vulnerable populations such as people who inject drugs or people in prisons, with high loss to follow-up or in remote locations. Although POC assays may promote and expedite confirmation of viraemia, there are also many excellent examples in which a centralized laboratory-based system has been highly effective when supported by efficient specimen transport and rapid electronic delivery of results (254).
- Priority settings for placement of HCV RNA NAT POC platforms are likely to be where there are populations at high risk of loss to follow-up and at risk of greater morbidity, but where testing volume is not large, such as among people who inject drugs at harm reduction sites or those in prisons, where fast-tracking diagnosis and treatment initiation as soon as possible upon entry to prison increases their chance of finishing their treatment regimens before leaving prison (241,(255)(256)(257). There are other innovative strategies for delivering POC HCV RNA NAT assays to hard-to-reach populations -for example, through mobile units (258)(259)(260)(261)(262) that can offer testing and treatment initiation on the same day (263). The systematic review found strong evidence that the best turn-around times and cascade of care outcomes with POC assays are seen when they are, in fact, used at the point of care rather than placed in laboratories distant from the patients.
- The optimal placement of a POC instrument is where testing and treatment are at the same site -a "one-stop shops". Use of POC platforms may not achieve expected outcomes if other aspects of the care pathway require patients to travel to another clinic for treatment, with associated transport and other costs. A recent systematic review (Web Annex A) has shown that one of the most important interventions to promote access and improve uptake of testing and treatment is delivery of fully decentralized HCV care (139). The POC evidence review (Web Annex A) showed that the best results for use of POC assays were when they were placed in clinics where HCV testing and treatment were available at the same site, especially for people who inject drugs at harm reduction sites, among people living with HIV in ART clinics, among prisoners and in primary care.
The best results for use of POC assays were where HCV testing and treatment were available at the same site.
- Reflex HCV RNA testing after a positive HCV antibody result: WHO now recommends reflex HCV RNA testing of those with a positive HCV antibody test result as an additional strategy to promote uptake and reduce time to confirmation of viraemia and treatment (Chapter 9). This can be achieved either through laboratory-based reflex HCV RNA testing using a specimen already held in the lab or through clinic-based reflex testing in a health facility through immediate specimen collection for viraemic testing following a positive HCV antibody RDT result. Efforts should be made to minimalize risk of contamination when reflex testing from a stored specimen.
- Multi-disease testing platform and diagnostic integration across programmes: The introduction of multi-disease testing platforms, both high-throughput lab-based and POC devices, creates additional opportunities for integration that may further expand access and achieve significant system efficiencies and cost-savings.

# Research gaps
- The use of POC platforms for HCV and HBV diagnosis and treatment decisions needs more methodologically rigorous implementation science studies (ideally, comparative RCTs). Use of POC testing should be considered alongside other interventions to promote the uptake of viral hepatitis testing, linkage to assessment and treatment uptake, especially in LMICs. Future studies should fully describe the diagnostic platform and service delivery model, and evaluation should assess effectiveness across the entire continuum of care and not just treatment-related outcomes. Including costs would allow for comparative cost-effectiveness analyses.
- Evaluation of impact of integrated use of multi-disease testing with diagnostic platforms on access or uptake of testing, utilization of platforms, turnaround times, cost and feasibility.
- Evaluation of the diagnostic accuracy, cost, cost-effectiveness and impact of HCV cAg or HCV RNA NAT assays as a one-step diagnostic testing strategy.
- Evaluation of the concordance between whole blood samples and DBS for HCV viremia using POC HCV RNA assays, such as Xpert.
- Regular internal quality control (IQC) and external quality assessment (EQA) checks to ensure the assay works properly (quality control) and that the testing service can return the correct result (external quality assessment). Any issues with the product should be reported to the assay manufacturer as part of their post-market surveillanceappropriate use of the PoC device and identify errors.
- - The laboratory technicians were primarily responsible for phlebotomy and running the device. They reported that the staggered trainings were useful, as they provided several opportunities to ask questions as the technicians became more familiar with the device.
The technicians reported that, with further training, ongoing support and ongoing use of the device, they felt more confident and more familiar with the nature of errors. The HCV RNA result presented in the logarithmic scale ensured clear interpretation of the result.
Nurses and general practitioners were also trained to perform the tests, but they did not maintain competency throughout the study period because they did not run tests often.
- Overall, the staff reported they found the GeneXpert analyserdevice simple and easy to operate, but that it was sensitive to errors during the specimen preparation stage.
They noted that the specimen preparation (for the venous blood specimen plasma test cartridge) required precise pipetting skills to prepare the required specimen amount after centrifuging the whole blood specimen to separate plasma.

# Laboratory set-up
The study was implemented in two shopfront community-based clinics (equivalent to primary care facilities), and rooms were renovated to provide laboratory services. The laboratories had the following equipment: four-module GeneXpert machine, online UPS, GeneXpert laptop, GeneXpert barcode scanner, printer, centrifuge, air-conditioner, table, chair, filing cabinet, clinical waste disposal bins, sink and running water. One site underwent renovations during the study to improve the conditions for the GeneXpert machine, including reducing the dust flowing into the room by installing a sliding door, reducing the number of people entering and leaving the room and reducing the humidity through use of an exhaust fan.
Electricity supply: The facilities were small shopfronts, with only small on-site generators to assist with power back-up. This is in contrast to hospitals or private laboratories, which often have large power back-up systems. These small generators required manual start-up in a power outage. They were used only occasionally, during power outages, due to requiring maintenance, the anticipated short duration of the power outage and fuel costs.
Yangon experiences scheduled and unscheduled power outages prior to monsoon season (April to June) and during monsoon season (June to October). One site experienced recurring errors with a GeneXpert machine due to unstable electricity supply (power outages and fluctuating voltage). The problem was resolved with installation of an online UPS providing voltage stabilizing and 1-2 hours of electricity to ensure the test cycle could be completed. humidity ranges from an average 65% in the dry season to 85% in the monsoon season.
These conditions posed some challenges to test kit/reagent storage and device operations.
Test kits/reagents require storage under 30 C and could be damaged by high humidity.
Sites were advised to store test kits/reagents in the refrigerator prior to the day of use.

# Summary of the evidence 1
Based on results of the earlier multi-cohort analysis mentioned above (250), HCV RNA assays with a LoD of around 1000 IU/ml would identify at least 95% of viraemic infections (271). A similar analysis has now been undertaken to establish the LoD for HCV RNA assays as test of cure. No studies were identified that examined the use of POC HCV RNA NAT assays as test of cure.
The LoD of HCV RNA NAT POC assays are 10 IU/mL for GeneXpert using venous blood (251,252) or 100 IU/mL using fingerstick capillary blood. The reported LoD for Genedrive instrument is 2362 IU/mL (253).
The reported LoD for core antigen assay is 1000-3000 IU/mL. The accuracy of HCV cAg for treatment monitoring and to confirm successful viral clearance (test of cure) was assessed by descriptive analysis of five studies (273)(274)(275)(276)(277) of two HCV cAg assays in comparison with HCV RNA NAT (qualitative and/or quantitative). All studies involved patients with mainly genotype 1b infection and on interferon-based therapy. SVR was assessed in only two studies, with 100% sensitivity and with specificity ranging from 94% to 100%. There were only three studies that evaluated the same assay -the Abbott ARCHITECT HCV Ag assay. There were no studies that evaluated the use of HCV cAg assay for monitoring response to DAA treatment regimens.

# Rationale for the recommendations 9.4.1 Balance of benefits and harms
Use of qualitative or quantitative HCV RNA as a test of cure -existing recommendation The Guidelines Development Group recommended the use of either qualitative or quantitative NAT detection of HCV RNA as a test of cure at 12 weeks after completion of treatment (or at 24 weeks if 12 weeks is not possible). These assays have a broad dynamic range, from 12 to 7 700 000 IU/mL. All the WHO prequalified laboratory-based quantitative HCV PCR assays have an LoD under 20 IU/mL (and the reviews showed analytical sensitivity as low as 5 IU/mL for qualitative HCV RNA detection by NAT) and would, therefore, capture 99% of individuals with treatment failure. The reviews also showed analytical sensitivity as low as 5 IU/mL for qualitative HCV RNA by NAT. Although either assay was recommended, the lower cost of qualitative assays for HCV RNA makes them preferable to quantitative NAT as a test of cure at 12 weeks (278)(279)(280)(281).

# Use of POC HCV RNA NAT -new recommendation
The Guidelines Development Group recognized that dependence on detection of HCV RNA by laboratory-based NAT to assess response to HCV antiviral treatment and test of cure, especially in remote settings, could be a barrier to setting up hepatitis C treatment and testing services. The LoD of HCV RNA POC assays are 10 IU/mL for GeneXpert using venous blood (251,252) and 100 IU/mL using fingerstick capillary blood (282). This assay can also accommodate DBS specimens with a detection rate similar to that of fingerstick blood, although the manufacturer does not report an LoD specifically for this approach (283). The Genedrive instrument has reported an LoD of 2362 IU/mL (253) and, therefore, might miss some cases of treatment failure. The Guidelines Development Group recommended the use of POC HCV RNA NAT assays as a test of cure that have LoD comparable to laboratory-based assays.
Use of HCVcAg as a test of cure -existing recommendation The LoD for core antigen assay is 1000-3000 IU/ml. The data on HCVcAg in treatment monitoring and assessment of test of cure (SVR) was considered too limited to recommend its use as a substitute for HCV RNA NAT as a test of cure at SVR12.
In the values and preferences survey, HCV cAg assay was reported as not available at any of the sites, and 40% of respondents also reported that they did not have access to HCV NAT in their countries. The increasing availability of validated POC NAT assays and further reduction in costs of both qualitative and quantitative NAT will be critical to improve access to diagnosis and monitoring in LMICs.

# Implementation considerations
- Timing of test of cure. A test of cure at 24 weeks (SVR24) after completion of treatment may be considered as an alternative SVR time-point if SVR12 is not possible. Similarly, in populations for which there are limited data on the correlation between SVR12 and SVR24 -for example, patients with cirrhosis, HIV/HCV coinfection and other immunocompromised states -SVR24 may be considered.
Training, service and maintenance are considerations for both laboratory-based and POC technologies.

# Research gaps
- The kinetics of HCV cAg with DAA treatment should be evaluated, and an optimal time point identified to test with HCVcAg for cure with DAA regimens.
- The correlation between SVR12 and SVR24 should be evaluated in populations where there are limited data, for example, patients with cirrhosis, HIV/HCV coinfection and other immunocompromised states.
- Further studies are needed in different settings and populations to establish the frequency, severity and predictors of HBV reactivation during or after DAA therapy in HBV/HCV coinfected patients.
- The evolution of HCV RNA in patients with viremia >15 IU/mL and <1000 IU/mL 12 weeks following completion of treatment needs further study. - Laboratory-based HCV reflex testing refers to a testing algorithm in which patients have only a single clinical encounter and one blood draw or specimen for an initial laboratory-based HCV antibody test (in some cases it may be divided in two tubes), which is then sent to the lab. If the sample for HCV antibody testing in the lab is positive, then the same existing or a duplicate specimen is automatically used for a prompt "reflex" laboratory-based HCV RNA NAT or HCVAg) test. The result returned to the patient/doctor is, therefore, for both the HCV antibody result and, if positive, the HCV RNA result. No further visit or specimen collection is required.
We recommend reflex HCV RNA testing in those with a positive HCV antibody test result as an additional key strategy to promote linkage to care and treatment.
This can be achieved either through laboratory-based reflex HCV RNA NAT testing using a specimen already held in the laboratory or clinic-based reflex testing in a health facility through immediate specimen collection following a positive HCV antibody RDT.
(conditional recommendation, low quality of evidence)
- Clinic-based reflex testing refers to a testing strategy where there is only a single clinical encounter/visit for an initial rapid diagnostic HCV antibody test, but with two blood draws. A capillary (fingerstick) whole blood specimen is first taken and tested using a rapid diagnostic HCV antibody test, which, if positive (after usually a 15-minute wait), is then immediately followed by a "reflex" second blood specimen collection (either venous blood sample or fingerstick) for HCV RNA detection of current infection. The second blood sample for HCV RNA testing may either be sent to a laboratory for HCV RNA NAT (or HCVAg) test or tested onsite using a point-of-care HCV RNA NAT assay.  10.4 Rationale for the recommendations

# Balance of benefits and harms
The Guideline Development Group made a conditional recommendation for the adoption of HCV RNA reflex testing (either laboratory-based or clinic-based) as an additional strategy to promote uptake of HCV RNA testing following a positive HCV antibody test result and so to promote linkage to care and treatment initiation. This recommendation was based on evidence of low certainty that reflex testing significantly increased the uptake of HCV RNA testing. There was also a non-significant increase in linkage to care and some evidence of reduced turnaround time to treatment initiation with laboratory-based and clinic-based reflex testing, compared with routine non-reflex testing strategies (Web Annex B). Laboratory-based reflex HCV viral load testing is already performed routinely in many laboratory services in high income countries. Clinic-based reflex testing following a positive HCV antibody RDT is also common practice now in low-income countries. Based on the programme survey and costing analysis reported by Public Health England, laboratory-based reflex testing is potentially cost-saving, feasible to implement and has the potential for wide adoption, even in resource-limited settings, to promote HCV testing and treatment uptake. Laboratory-based reflex testing also avoids the need for additional venepuncture and blood draws, which maybe particularly preferred by persons who inject drugs, who are more likely to have compromised veins (287).

# Costing and cost-effectiveness
All respondents to the laboratory-based reflex case survey reported that reflex testing was costsaving compared with conventional two-step testing, even in the absence of formal economic evaluations. Savings were the result of reduced numbers of clinic visits and clinician time. In a 2013 analysis by Public Health England of their laboratory-based reflex testing experience, the estimated annual savings gained from reflex RNA NAT testing of an anti-HCV positive sample was 166 500, due to the reduction in the number of persons being referred from 6001 in the non-reflex pathway to 3781 in the reflex pathway. Since these cost savings did not include the additional cost of referral to treatment in the non-reflex pathway, the total savings are likely to be even higher. There is potential for further savings, as one specimen could be used to test for multiple pathogens, such as HBV and HIV, on high-throughput laboratory machines (288,289).

# Values and preferences (Web Annex D)
In a multi-country online survey of 210 people in 49 countries undertaken by the World Hepatitis Alliance and Coalition Plus, 88% of participants confirmed a strong preference to "do your initial and confirmatory HCV RNA tests on the same day". This level of preference was even higher, at 96%, among people who currently inject drugs and who formerly injected drugs. The main reasons given were the possibility to more quickly confirm diagnosis (81%) and start treatment (76%). There was also a strong preference, from 93% of respondents, for doing both the initial screening test and confirmatory HCV RNA NAT testing at the same place, for convenience (70%), and at a community-friendly site (60%). A further consideration in favour of HCV reflex testing is that, as noted, persons who inject drugs may prefer a testing strategy that requires only one standard venepuncture (287).
Overall, strategies to promote uptake and linkage to care, such as laboratory or clinic-based reflex testing, will likely further promote equity in access if used in settings and populations at high risk of loss to follow-up, who benefit from the convenience of a single sample collection approach, such as the homeless and people who inject drugs at harm reduction sites and people in prisons.
There are multiple examples, mainly in high income countries, of the feasibility of routine laboratory-based reflex HCV RNA NAT testing. The experiences of three laboratories are presented as case studies in boxes 10.1-10.3. Our findings also support the feasibility of implementing clinic-based reflex testing. The systematic review included 19 studies that used HCV RNA reflex testing in POC or near POC settings (that is, HCV clinics and drug treatment sites) and did not send samples to a laboratory for confirmation testing. Compared with standard laboratory-based HCV RNA testing, reflex testing or one-time sample collection simplified the care pathway and reduced the need for additional clinic visits and time to POC HCV RNA NAT test and linkage to care.

# Implementation considerations
Adaptation of reflex HCV RNA testing recommendations for different country contexts
Countries should incorporate routine reflex HCV RNA testing into their national testing guidelines and testing infrastructure. The choice between laboratory-based reflex testing and clinic-based reflex testing with POC HCV RNA tests will depend on national testing policies, budgets, infrastructure and human resources, as well as the extent of reliance on centralized high-throughput laboratories, the available sample transport network and location of testing and treatment services.
While a laboratory-based reflex testing strategy will be more appropriate in settings with large testing volumes supported by extensive sample transport networks, clinic-based reflex sample collection for HCV RNA testing may be the preferred testing algorithm for populations such as key populations (such as people who inject drugs and men who have sex with men) and migrants and refugees who receive health care in community-based settings or in primary care and may have limited access to full-range phlebotomy and laboratory services. Instead, clinic-based reflex testing with initial HCV antibody RDTs followed by reflex sample collection for HCV RNA testing of those testing antibody-positive and then use of clinic-based POC HCV RNA testing may maximize linkage to care for such populations. To meet the needs of different populations or regions in a country, a mix of clinic-based and laboratory-based reflex testing strategies may be optimal.
Key steps to initiate laboratory-based reflex HCV RNA testing
- Train outpatient clinic phlebotomy and laboratory staff on new procedures for specimen collection and processing of HCV RNA NAT testing.
- Update electronic laboratory order forms for anti-HCV and RNA testing to list reflex-only testing options and develop laboratory guidance for HCV reflex testing.
- Design the laboratory process to preserve specimen integrity and limit risk of crosscontamination.
- Plan for additional costs as needed, that is, additional tubes, transport and storage, if collecting two tubes for anti-HCV and NAT/cAg testing.
- Combine laboratory-based reflex HCV RNA NAT testing with other strategies, for example, clinic-based reflex testing, to meet the needs of different populations.
- Evaluate HCV laboratory-based reflex testing programmes, providing feedback to providers and laboratory managers for quality improvement.

# Other operational considerations
- Training for phlebotomists will be required to sensitize new protocols: If the reflex testing protocol requires two separate specimen tubes and phlebotomists are used to only collecting one specimen tube for HCV testing, appropriate training and quality management assurance systems are needed to sensitize phlebotomists to collecting two tubes and using two tube labels.
- Electronic ordering system updates must be comprehensive to disable all non-reflex testing options. Electronic ordering systems are not necessary for reflex testing, but they can help streamline the transition to a new clinical process.
- Designing the clinical process to collect one versus two specimens may depend on the assessed risk of contamination in the laboratory. Laboratory managers should assess the risk of cross-contamination for available testing platforms and develop procedures to minimize this risk.

# Previous testing protocol
Between January 2017 to February 2018, only 52% (n=1412/2176) of positive HCV antibody tests resulted in a request for viral load HCV RNA testing in the primary care clinics (290).
The percentage was even lower in the drug addiction care centres. The conventional testing strategyalgorithm required five visits to receive a confirmatory diagnosis, which could take at least four weeks. In the report of a positive anti-HCV test returned to the clinician, the laboratory promoted the ordering of an HCV viral load HCV RNA test for patients who tested positive for HCV antibody. However, this strategy proved ineffective to increase the uptake of viral load HCV RNA testing.

# Initiation of reflex testing
In March 2018, as recommended by the European Association for the Study of the Liver (EASL), Valld'Hebron implemented reflex testing.

# Clinical process
Valld'Hebron implemented a one-step testing process that involved collecting two specimens at the initial clinic visit. This reduced the time from specimen collection to HCV diagnosis from four weeks to about two days. The first specimen collected by the phlebotomist was a serum sample for HCV antibody testing. The second specimen was plasma with EDTA used for blood count determination. In patients with first specimens that tested positive for HCV antibody, the second specimen was also used to test for HCV RNA. Results of HCV RNA testing were provided within 24 hours after the positive HCV antibody test result Monday through Thursday, and within three days if the antibody test was performed on a Friday.
In some settings under the Valld'Hebron University Hospital umbrella, DBS and plasma separation cards were used to collect samples from patients.

# Laboratory protocol
Serological testing (for HCV antibody) was performed on the Cobas 8000 platform (Roche Molecular Systems, USA) with single-use (that is, disposable) tips. The second specimen for reflex HCV RNA testing was processed unopened (flow cytometry). Determination of HCV RNA was performed with a Cobas 6800 analyser (Roche Molecular Systems, USA). The blood count analysis prior to determination of HCV RNA was performed by flow cytometry with a Sysmex XN-20 analyser (Sysmex Corporation, Japan). This protocol was possible because the Sysmex XN-20 analyser can perform hematimetric measures without de-capping blood tubes. (The rubber cap is punctured by a needle.)
Valld'Hebron ruled out the use of one specimen for both serological and virologic testing due to the assessment of a high-risk for contamination across serological and virologic testing.
Because the Roche Cobas 6800 analyser used for serological testing centralizes serological determinations, the system tends to concentrate specimens with serologic evidence of HCV infection (that is, potentially anti-HCV positive). Although the Cobas 8000 analyser uses disposable tips, specimens reach the analytical system uncapped and, therefore, are vulnerable to environmental aerosols and occasional hand manipulations, which may increase the risk of contamination. As a precautionary measure, the laboratory decided that the serological specimens should not be used for virologic determination. By comparison, all blood count determinations are randomly processed (more than 5000 a day), meaning that potential anti-HCV-positive cases (about five to 10 a day) would be randomly distributed among these 5000 samples, statistically reducing the probability of cross-contamination associated with that of two anti-HCV-positive cases being next to each other, where one positive HCV RNA specimen could contaminate a nearby negative HCV RNA sample.

# Impact of HCV reflex testing
Based on a comparison of the conventional, non-reflex testing protocol from January 2017 to

# Note on cost implications
No formal economic analysis has been done to compare the cost of HCV reflex testing in the Valld'Hebron laboratory network with conventional two-step testing strategy algorithms. Still, laboratory representatives have noted that the cost of a viral RNA determination (less than  30) is much less than the cost of a second physician appointment and blood collection.
The British Columbia Centre for Disease Control Public Health Laboratory (BCCDC PHL) is the primary public health and reference diagnostic testing facility for the province of British Columbia, Canada.

# Previous testing protocol
At the end of 2019, analyses of the British Columbia (BC) Hepatitis Testers Cohort (HTC)
found that approximately 16% of people in BC who had tested HCV antibody positive, and were alive and living in BC, had never had an HCV RNA NAT test (n=8491 people as of end of 2019) (291). Introducing automated HCV RNA NAT reflex testing was proposed to address this gap in assessment for active HCV infection following positive screening results. This improvement in HCV virologic testing could also facilitate better progress along the HCV care cascade, by reducing visits for patients, reducing the number of blood collections and potentially reducing physicians' workload.

# Initiation of reflex testing
HCV laboratory-based reflex testing was introduced in January 2020. The main start-up investments to implement HCV NAT reflex testing were developing laboratory standard operating procedures and mapping process changes. Training for laboratory staff and clinicians was required. No capital investments were required.
Four main challenges were overcome:
- validation of performance of serum specimens on HCV RNA NAT assay and ensuring that there was a process to request a follow-up ethylenediamine tetraacetic acid (EDTA) venous whole blood specimen if there were concerns regarding false negative HCV RNA NAT results due to serum-related specimen integrity concerns 2. revision of laboratory testing and resulting workflows, including laboratory information system updates 3. training laboratory staff and development of job aids and standard operating procedures for implementation 4. educating clinicians on the fact that, if patients have had a previous HCV RNA NAT assay, they will not be picked up in the HCV RNA reflex pathway from an anti-HCV test.

# Clinical process
All clinical settings in the laboratory network, both in-patient and out-patient, are eligible for reflex testing. HCV RNA NAT results from a reflexed test are reported to the ordering provider, who is then responsible for returning all results to the patient. The HCV RNA NAT results from a reflexed test are reported separately from the initial anti-HCV results (that is, two separate result reports are sent), but results are viewable on the patient's electronic testing record. The typical turn-around time between specimen receipt and return of test results is five days (BCCDC PHL medically accepted standard).

# Laboratory protocol
Serum specimens are received and accessioned for test requested (that is, anti-HCV) in the Laboratory Information System. Serum specimens are stored in a refrigerator at 4 C prior to being sent for anti-HCV screening on the Siemens Centaur XP System analyser (Siemens Healthineers, USA). Anti-HCV screening using primary serum tubes on the Siemens Centaur does not result in carryover because individual pipets are used. If the anti-HCV screen is positive, the specimen then undergoes supplemental testing for anti-HCV on the Abbott ARCHITECT HCV Ag analyser (DENKA SEIKEN CO., LTD., Japan for Abbott GmbH & Co.
KG, Germany). If the result of supplemental testing is positive for anti-HCV and the screen index value was >11 on the Siemens Centaur XP Centaur, then the technician looks up that patient's previous HCV testing history. If the patient is a new anti-HCV positive or has never previously had an HCV RNA NAT test performed at the lab, then the HCV RNA NAT (reflex) test is accessioned, and the specimen is sent for the HCV RNA NAT test.
The HCV RNA NAT testing is conducted using either the Abbott m2000 or Abbott ALLINITY platforms. If an EDTA plasma specimen was collected from that patient at the same time as the serum specimen and there is specimen left, that will preferentially be used for the HCV NAT, however, if EDTA plasma is not available, the original serum specimen that was used for anti-HCV test will be used. If serum was used for testing and HCV RNA is not detected, a follow-up EDTA blood HCV RNA test is requested to minimize the risk of a false negative HCV RNA result due to concerns about serum sample integrity. The storage time limit for virologic testing of samples is 14 days. After testing, any remnant anti-HCV or HCV RNA positive specimens are aliquoted and stored indefinitely at 20 oC. Reflex testing is conducted as specimens arrive.

# Economic considerations
On average a consultation with a family physician is billed at CA$ 91.94. Therefore, for two separate visits (standard HCV testing algorithm), the total cost to the payer would be

# Economic considerations
In the 2013 Public Health England analysis, the estimated annual savings gained from automatic RNA testing of an anti-HCV positive specimen was 166 500, attributable to a reduction in the number of persons being referred from 6001 in the non-reflex pathway to 3781 in the reflex pathway. This calculation does not include the additional referral cost to treatment in the non-reflex pathway.
Public Health England found that patients diagnosed via reflex testing received treatment more quickly than those who were RNA NAT tested between one week and six months later (average 167.5 days versus 282.5 days, p<0.0001).