Where are the children in national hepatitis C policies? A global review of national strategic plans and guidelines

Summary Background & Aims It is estimated that 3.26 million children and adolescents worldwide have chronic HCV infection. To date, the global response has focused on the adult population, but direct-acting antiviral (DAA) regimens are now approved for children aged ≥3 years. This global review describes the current status of policies on HCV testing and treatment in children, adolescents, and pregnant women in WHO Member States. Methods We identified national strategic plans and/or clinical practice guidelines (CPGs) for HCV infection from a World Health Organization (WHO) database of national policies from Member States as of August 2019. A standardised proforma was used to abstract data on polices or recommendations on testing and treatment in children, adolescents and pregnant women. Analysis was stratified according to the country–income status and results were validated through WHO regional focal points through August 2020. Results National HCV policies were available for 122 of the 194 WHO Member States. Of these, the majority (n = 71/122, 58%) contained no policy recommendations for either testing or treatment in children or adolescents. Of the 51 countries with policies, 24 had specific policies for both testing and treatment, and were mainly from the European region; 18 countries for HCV testing only (12 from high- or upper-middle income); and 9 countries for treatment only (7 high- or upper-middle income). Twenty-one countries provided specific treatment recommendations: 13 recommended DAA-based regimens for adolescents ≥12 years and 6 still recommended interferon/ribavirin-based regimens. Conclusions There are significant gaps in policies for HCV-infected children and adolescents. Updated guidance on testing and treatment with newly approved DAA regimens for younger age groups is needed, especially in most affected countries. Lay summary To date, the predominant focus of the global response towards elimination of hepatitis C has been on the testing and treatment of adults. Much less attention has been paid to testing and treatment among children and adolescents, although in 2018 an estimated 3.26 million were infected with HCV. Our review shows that many countries have no national guidance on HCV testing and treatment in children and adolescents. It highlights the urgent need for advocacy and updated policies and guidelines specific for children and adolescents.


Introduction
HCV infection is a major cause of chronic liver disease and associated morbidity and mortality worldwide. 1,2 Globally, the World Health Organization (WHO) estimates that, in 2016, 71 million people were living with chronic HCV infection, with lowand middle-income countries (LMICs) disproportionately affected. 1,2 In 2016, the WHO launched the Global Health Sector Strategy (GHSS) on viral hepatitis with a goal to eliminate viral hepatitis as a public health threat by 2030, defined as 65% and 90% reductions in hepatitis-related deaths and new infections respectively. 3 The GHSS promotes Member States to develop national strategic plans (NSPs) to address viral hepatitis, as well as clinical practice guidelines (CPGs). Since this call to action, 5 WHO Regional Offices have developed region-specific plans for prevention and control of viral hepatitis, [4][5][6][7][8] and there has been a steady increase in both national plans as well as national guidelines for HCV testing and treatment. 9 To date, the global scale-up of HCV screening and treatment has mainly been focused on adults, who bear the greatest burden of morbidity and mortality owing to chronic liver disease. Much less attention has been paid to testing and treatment strategies among children and adolescents. A recent systematic review children and adolescents were living with chronic HCV infection in 2018 -23 countries accounting for 80% of this global burden, and Pakistan, China, India, and Nigeria alone accounting for >50%. 10 Transmission routes, disease progression and treatment indications in children differ from those in adults. Globally, vertical transmission is the principal HCV acquisition route among children 11,12 but transmission also occurs through unsafe medical interventions, especially in LMICs. 13 Adolescents may acquire infection through injecting drug use (IDU), 14,15 and high-risk sexual practices especially among men who have sex with men. 16,17 Although the occurrence of severe disease or cirrhosis in children is low at 2%, progression of liver disease occurs in childhood, [18][19][20] and can impact quality of life. 21,22 Early diagnosis can help timely access to treatment and prevention of long-term morbidity. 23 Before the availability of direct-acting antivirals (DAAs), there was limited treatment in selected children with interferon-based regimens which had low rates of viral clearance and significant side effects. DAA regimens have high rates of cure and minimal toxicity, and several regimens are now approved for use in adolescents and children, providing several opportunities to advance access to HCV care and treatment for children. First, the recent approval of several DAA regimens for use in adolescents (> − 12 years), and now children aged >3 years 24,25 and second, specific recommendations for testing and treatment in children and adolescents in guidance from WHO and 4 professional societies. 23,[26][27][28][29][30][31] An assessment of national HCV policies may help identify where gaps exist regarding global guidance and professional society recommendations. Several surveys or reviews of viral hepatitis prevention and control programmes and policies have been undertaken at global 9,24,25,28 or regional level, mostly in Asia and Europe. [32][33][34][35][36][37][38] Their scope ranged from gathering information about national hepatitis responses, 9,32,33,39,40 to perspectives on treatment access and civil society engagement, [34][35][36][37]41 but none included questions specific to children or adolescents. There is also currently no systematic data collection or reporting of coverage of testing and treatment among adolescents and children. 2 We undertook a global review of hepatitis C policies (both NSPs and CPGs) in WHO Member States, to identify specific policies and/or recommendations for testing and treatment in children and adolescents, and also of screening in pregnant women. We also reviewed international and professional society guidelines as the gold standard for comparison. Our aim was to identify areas of concordance and discordance in testing and treatment policies, and highlight critical gaps in advance of rollout of DAAs for children.

Materials and methods
Search strategy, data sources, and data collection WHO and major hepatology international and regional professional society guidance on HCV testing and treatment of chronic HCV in adolescents and children We used guidelines from 5 professional societies ( [26][27][28]42,43 and the WHO 30,44 to identify those including relevant recommendations for adolescents and children.

NSPs and CPGs from WHO Member States
First, we identified NSPs and CPGs by searching for public documents available online (e.g. ministries of health (MoH) and national or regional hepatology/gastroenterology societies). Second, we performed a comprehensive search of PubMed to identify published guidelines in all languages. We used the search terms ('Practice Guideline' [Publication Type]) AND 'Hepatitis C' [MESH] from Jan 1, 2010 to Jun 30, 2019. Guidelines were found for 19 countries. Third, we searched the WHO repository of NSPs and CPGs on viral hepatitis to supplement the review.
Information on country hepatitis C policies was extracted from the identified documents. We searched each document for use of the following terms: 'child', 'mother', 'pregnant', and 'adolescent'. If these terms were not explicitly mentioned, we searched for other related concepts, such as 'age', 'young/youth', and 'birth'. We abstracted information on policies to address the following questions: Is there a policy on screening for HCV infection in pregnancy and, if so, is this routinely offered to all or targeted to specific high-risk groups? Is there a policy on testing in children and adolescents; if so, what are the criteria for testing and at what ages? What is the diagnostic algorithm for testing for HCV, and use of serological testing and use of HCV RNA? Is there a policy to treat children and adolescents; if so, at what age and with which regimens? Documents available in languages other than English were translated into English using the Google Translate free online language translation service.
Questionnaire to 19 countries with high burden of paediatric HCV infection To complement the above review, we conducted an online survey of HCV policies in the 19 countries with a high-burden of HCV, accounting for 80% of all paediatric HCV infections based on the 2016 estimates available at the time. 45 These included Afghanistan, Algeria, Angola, Bangladesh, China, Democratic Republic of Congo (DRC), Egypt, Ethiopia, India, Indonesia, Iran, Iraq, Kazakhstan, Nigeria, Pakistan, Russian Federation, Syrian Arab Republic, Ukraine, and Uzbekistan. The semi-structured questionnaire focused on national HCV policies in pregnant women, children, and adolescents. Respondents were recruited through a purposive sampling process, and where possible, we identified MoH officials responsible for viral hepatitis. The survey was conducted using Research Electronic Data Capture, a webbased data collection tool. 46 Terminology As the terms 'policy', 'strategy', 'plan', and 'guideline' are used in different ways across various settings, the following definitions were used for the purpose of this review: NSPs were defined as national strategies and action plans that provide overall strategic direction for a country's response to hepatitis C, including those where viral hepatitis is an integrated part of broader health strategies. This definition was adapted from that used in the WHO manual for the development and assessment of national viral hepatitis plans 47 and in a review of HCV policies in Europe. 38 CPGs were defined as systematically developed statements designed to assist practitioners and patients in making decisions about appropriate healthcare (prevention, screening, diagnosis, testing, treatment and/or overall disease management) for individuals with HCV. 48 The term policy was used to collectively refer to NSPs and CPGs. For this review, we defined an adult as a person aged > − 18 years, an adolescent as aged 12-17 years and a child as <12 years of age, unless stated otherwise, to conform with conventions in the literature.

Data analysis
We tabulated country data according to WHO region and World Bank income country classification. 49 Overall regional HCV burden in adults and in children was sourced from the Global Hepatitis Report 1 and modelling estimates of paediatric HCV prevalence, 10 respectively. We compared findings on availability of policies from countries with a high burden of paediatric HCV with other countries using Fisher's exact test for categorical variables.
Data were collected January-June 2019 and validated through consultation with regional focal points in July to August 2020. We undertook internal validation of our results through crosschecking with findings from the recent policy review of Member States reported in 2019. 9

Data availability
The datasets used during the current study are available from the corresponding author on reasonable request.

WHO and professional society guidelines
Recommendations from 2 WHO guidelines and 5 professional society guidelines for testing and treatment, relevant to children, adolescents, and pregnant women are summarised in Tables 1  and 2. As for adults, WHO recommends testing of high-risk children and adolescents (such as those exposed to medical interventions and treated in hospitals or those at risk of acquiring HCV sexually or through IDU), including those with a clinical suspicion of chronic viral hepatitis and children of infected mothers. 30 Although professional society guidelines recommend testing children of infected mothers, most do not specify other groups of children and adolescents to be tested. 27,31 The exception is the AASLD guidelines which recommend testing siblings of children with vertically-acquired HCV. 26 The 2017 WHO viral hepatitis testing guidelines, 30 the AASLD, 26 EASL, 27 and the NASPGHAN guidelines, 31 recommend serological testing in children only after 18 months of age, with detection of HCV RNA in those less than 18 months of age. Screening in pregnancy to identify children who could have been vertically exposed to HCV was only recommended by WHO and AASLD guidelines.
WHO (2018), AASLD, EASL, and ESPGHAN guidelines recommend use of sofosbuvir/ledipasvir or sofosbuvir/ribavirin for treating adolescents. [26][27][28]44 All guidelines, except the recently updated EASL guidelines, currently recommend deferring treatment in younger children until interferon-free regimens are approved for younger age groups (Tables 1 and 2). Table 1. Comparison of international guidelines for screening and treatment of chronic HCV infection during pregnancy and in children and adolescents. Testing.
Guideline and year of publication Screening in pregnancy HCV testing of perinatally exposed children American Association for the Study of Liver Diseases (AASLD) 2020 26 All pregnant women should be tested for HCV infection, ideally at the initiation of prenatal care.
All children born to HCV-infected women should be tested for HCV infection. Testing is recommended using an antibody-based test at or after 18 months of age.
Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such a test is unknown.
Repetitive testing by HCV RNA is not recommended. Children who are anti-HCV positive after 18 months of age should be tested with an HCV-RNA assay after age 3 years to confirm chronic hepatitis C infection.
Siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother. European Association for the Study of the Liver (EASL) 2020 27 All pregnant women should be tested for HCV infection, ideally at early stages of pregnancy but testing can be carried out at any stage during pregnancy.
All children born to HCV-infected women should be tested for HCV infection from the age of 18 months.  HCV treatment during pregnancy is not recommended in the absence of safety and efficacy data. However, treatment can be considered during pregnancy, or in the case of accidental conception during treatment, on a case-by-case basis. Treatment regimens for use in pregnancy not specified.
Treatment is recommended for all children > − 3 years. GT 1-6: fixed-dose combination of SOF (400 mg) and VEL (100 mg) or fixed-dose combination of GLE (300 mg) and PIB (120 mg) for adolescents aged > − 12 years who are treatmentnaive or treatment-experienced and without cirrhosis or with compensated (Child-Pugh A) cirrhosis. GT

Research article
European region (n = 12) and were high-or upper-middle income (n = 16). Eighteen countries had policies only on testing, and again were more geographically diverse but mostly high-or upper-middle income (n = 12). Nine countries had policies on treatment only and the majority were high-or upper-middle income (n = 7). Fig. 2 shows the policy landscape in 19 countries that accounted for 80% of paediatric HCV burden in 2016 estimates. 45 National policy documents were available for 15 of the 19 countries (9 NSPs, 1 CPG and 5 countries with both). Twenty percent (3/15) had recommendations on screening of pregnant women; 53% (8/ 15) on testing of children born to HCV-infected mothers; and 47% (7/15) on treating children and adolescents for HCV. There were no statistically significant differences in proportion with policies compared with non-high burden countries.

HCV screening in pregnancy
Overall, of the 122 countries with policy documents available, most (n = 90, 74%) did not include any recommendation to screen for HCV during pregnancy. Of 32 countries with a recommendation, 19 countries recommended routine HCV screening for all pregnant women (Table 4), whereas in a further 13 countries, the national policy was targeted antenatal screening in high risk groups. This included HCV screening of pregnant women with clinical suspicion of infection and/or known risk factors such as IDU history (n = 11). Of the 32 countries recommending any form of screening in pregnancy, only 8 specified any service delivery details, such as how to test (first-line diagnostic test), when to test (e.g. first antenatal visit) and where to test, and these varied by country (Table 4).  Table S2). Most of these countries did not have any pregnancy screening guidance (n = 23). Of the 32 countries recommending some form of screening in pregnancy, only 19 had a policy on testing of their infants.

When to test children of HCV positive mothers
In the 42 countries which recommended testing children of HCV-infected mothers, 30 included a specific recommendation on timing and choice of assay. Eight countries (Argentina, Australia, Belgium, Germany, Ireland, Myanmar, Russian Federation, and United Kingdom) recommended HCV RNA testing between 1 and 6 months of age, as the primary diagnostic test. Three countries (Bahrain, Kyrgyzstan, and Singapore) recommended use of antibody tests at 12 months, and 18 countries recommended antibody testing at 18 months or above. Only 6 countries (Argentina, Australia, Germany, Hungary, Ireland, and Kyrgyzstan) recommended different diagnostic algorithms for children based on the mother's HCV viraemic status, with RNA testing recommended as the initial test for children of HCV-RNApositive mothers and anti-HCV testing for infants of seropositive, HCV-RNA-negative women. Exceptionally, guidelines from Kyrgyzstan did not recommend testing in children born to seropositive mothers with a negative HCV RNA test; infants of HCV-RNA-positive mothers were recommended to undergo antibody testing at 12 months of age.

HCV treatment in children and adolescents
Twenty countries had policies that included a broad recommendation to 'treat all' for HCV but without specific guidelines for treating children or adolescents. Another 33 countries specifically indicated that children and/or adolescents could be treated for HCV infection (Table 5).

Treatment in children
Nine country policies recommended treating children (minimum age of eligibility for treatment was 2-3 years); all recommended interferon/ribavirin-based regimens. An additional 4 countries recommended treatment with DAAs for age groups in which DAAs were available (without specifying the age groups).

Treatment in adolescents
Twenty national policies specifically recommended treating adolescents for HCV infection; 13 with DAAs, 6 with interferon/ ribavirin-based regimens and 1 did not mention the regimen. Of note, the policies recommending DAAs were recent having been published between 2017 and 2020. Nine countries (China, Czech Republic, Hungary, Malaysia, Maldives, Mongolia, Nepal, Philippines, and Sweden) included details of DAA regimens for adolescents > − 12 years in the guidelines; sofosbuvir/ledipasvir was recommended by the majority. Some guidelines also included sofosbuvir/ribavirin, sofosbuvir/velpatasvir, and glecaprevir/pibrentasvir (Table 5).

Discussion
Overall, this policy review showed that although many countries have made progress in developing national strategies for elimination of viral hepatitis, there are significant gaps in specific policies for testing and treatment in children and adolescents. Although 122 of 194 (63%) WHO Member States had NSPs and/or CPGs on HCV, of these, only 26% included recommendations on HCV screening in pregnancy and only 42% had any policies relating to testing and/or treatment for HCV in children and/or adolescents. Only 24 countries included recommendations for both testing and treatment of children in their national policies. As with other aspects of the global hepatitis response, little attention has been paid to designing policies that include children and adolescents, and country-level policies remain focused on adults.

Who to test
Although the WHO recommends routine screening in pregnant women if the general population prevalence is > − 2%, or if pregnant women are from a high-risk group 30 and the AASLD and EASL guidelines recommend testing all pregnant women, 26,27 the majority of country policies and guidelines reviewed (74%) did not include any recommendation for routine or targeted HCV screening during pregnancy. Currently, the main purpose of testing for HCV in pregnancy is to identify those in need of treatment after delivery/breastfeeding for their own health benefit, as well as to prioritise testing of HCV-exposed infants. Routine testing of pregnant women is likely to expand if ongoing trials establish the safety of DAA treatment in pregnancy 50,51 providing an opportunity for prompt treatment of mothers and prevention of HCV vertical transmission.

Research article
Although there was largely consensus in recommendations for testing and treatment of children and adolescents in WHO and professional society guidelines, there was heterogeneity in the recommendations in country policies. WHO recommends HCV testing for all children, adolescents, and adults at high-risk or with clinical suspicion of chronic viral hepatitis, 30 and 3 professional society guidelines recommend testing of all children born to HCV-infected women. 26,27,31 However, only 34% of the country policies reviewed recommended testing children born to HCV-infected mothers. Notably, other groups of children and adolescents potentially at high-risk (such as those exposed to medical interventions in settings with unsafe injecting practices) were only included in 5 country policies.
Diagnostic algorithms for children born to HCV-infected women WHO guidelines and professional society guidelines recommend testing children of infected mothers using HCV RNA in children <18 months of age serological tests after 18 months. Although 42 countries recommended testing children born to mothers with HCV, only 6 specified differential diagnostic approaches based on maternal serological and virological status. This lack of detail is consistent with findings from a recent survey of WHO Member States which reported that although most countries have testing policies, these are not necessarily comprehensive particularly regarding key populations. 9 Methods to identify children with vertically-acquired HCV, and optimal timing of tests are needed given that the current screening and case identification practices are inadequate in pregnancy. 52,53 Our findings also highlight a gap in other case-finding strategies for children, such as testing siblings of confirmed paediatric cases, who may also be at risk of vertical transmission or intra-familial transmission.

Who to treat
The WHO and 4 professional society guidelines recommend deferring treatment for younger children until DAA regimens are approved for their age groups and treating children and adolescents for whom DAAs are licensed. [26][27][28]31,44 These updated recommendations are not yet reflected in national policies as 9 country policies still recommended treating children with interferon/ribavirin-based regimens. Only 20 country policies specifically recommended treating adolescents for HCV infection.

Limitations of review
There were several limitations to this review. First was the challenge of accessing reliable and up-to-date information, as some national guidelines were under revision during the data collection process. When available, these unpublished/draft guidelines were reviewed. The policy situation may have since changed in some countries. National policy documents relating to overall paediatric and adolescent health which may have included reference to viral hepatitis were not reviewed. Our review only addressed current status of policies at the national level and not their level of adoption and implementation, which may lag. [59][60][61] It is therefore important to exercise caution in drawing conclusions about implementation and service delivery from the data included.
What are the policy implications of our findings? This review has demonstrated a 'pregnancy and paediatrics policy gap' in country-level policies, which needs to be addressed if global and regional elimination targets are to be achieved. Almost half of the countries with a high paediatric HCV burden lacked policy recommendations for testing or treatment of children and adolescents (7/15 for which policy documents were available). This highlights the need for further advocacy to ensure countries update their policies and guidelines to include HCV testing and treatment among children and adolescents and provide access to pan-genotypic DAA regimens. Data from studies in the USA indicate that even when maternal HCV infection is identified, most children at-risk of vertically-acquired HCV remain untested at 18 months of age. 52,53,62 Current practices for paediatric case finding and linkage to medical care are inadequate and HCV-exposed children need to be identified systematically for appropriate counselling, testing, treatment, and follow-up. Absence of policies that outline case finding strategies for pregnant women and children contribute to the high proportion of children with HCV who remain undiagnosed. 52 There is also the need for updating of WHO and professional society guidelines to include appropriate case-finding strategies in children and adolescents, and recommendations for use of DAA regimens in adolescents and younger age groups. 63 This can be facilitated by leveraging existing antenatal and maternal and child health services to reach pregnant women and children, with a compilation of examples of good practices identified in case-finding and treatment of children. Recent progress in clinical studies of different DAA regimens in adolescents and children and regulatory approval together with development of paediatric formulations for those aged <6 years provide an opportunity to include children more comprehensively in the global hepatitis elimination response. accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors.

Data availability
The dataset used in this study is available from the corresponding author on reasonable request.