July 2020 Guidelines on antiviral prophylaxis in pregnancy PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HEPATITIS B VIRUS:

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PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HEPATITIS B

VIRUS: Guidelines on antiviral prophylaxis in pregnancy

July 2020

Annex E. Framework for regional verification of the global control goal for

hepatitis B surface antigen prevalence in children by 2020

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Prevention of mother-to-child transmission of hepatitis B virus (HBV): guidelines on antiviral prophylaxis in pregnancy. Web Annex E. Framework for regional verification of the global control goal for hepatitis B surface antigen prevalence in children by 2020

ISBN 978-92-4-000866-3 (electronic version)

© World Health Organization 2020

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Acronyms

cMYP comprehensive multi-year plan

EMTCT elimination of mother-to-child transmission EPI Expanded Programme of Immunization

GHSS Global Health Sector Strategy on viral hepatitis HBIG hepatitis B immune globulin

HepB hepatitis B vaccine HBV hepatitis B virus

HepB1 first dose of hepatitis B vaccine HepB-BD hepatitis B vaccine birth dose

HepB-TBD timely birth dose of hepatitis B vaccine HepB3 third dose of hepatitis B vaccine HBsAg hepatitis B surface antigen HCC hepatocellular carcinoma MCH maternal and child health MTCT mother-to-child transmission

PMTCT prevention of mother-to-child transmission PVST post vaccination serological testing

RVT Regional Verification Team SDG Sustainable Development Goals TBD timely birth dose

UNICEF United Nations Children’s Fund VEP Verification Expert Panel WHO World Health Organization

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1. Background of hepatitis B control

1.1 Burden of HBV infection

The World Health Organization (WHO) estimates that in 2015, globally 257 million people were living with chronic hepatitis B virus (HBV) infection. Of these, about 900 000 died of hepatitis B and its sequelae.¹ Most of these deaths are from cirrhosis or hepatocellular carcinoma (HCC), the consequences of chronic HBV infection.¹ As estimated, 1.1 million people developed chronic HBV infection in the same year and the prevalence of chronic HBV infection in children under 5 years was 1.3% globally, higher in countries with low birth dose coverage (3% in Africa where the 2017 timely birth dose (TBD) coverage was 10%) and/or a high burden of HBV infection. ²

1.2 Importance of universal immunization

WHO recognizes the importance of HCC and other HBV-related diseases as global public health problems and reiterates its recommendation that hepatitis B vaccine (HepB) should be included in national immunization programmes.³ A comprehensive approach to eliminating HBV transmission must address prevention of infections acquired perinatally and during childhood, as well as prevention of infections acquired by adolescents and adults. Therefore, WHO issued a position paper on hepatitis B vaccine in 2004, and updated it in 2009 and 2017.³ WHO recommends that all countries should integrate HepB into routine immunization, and improve vaccination coverage to all children. The first dose should be administered as soon as possible after birth, if possible within 24 hours. As of 2018, HepB for infants had been introduced nationwide in 189 countries. WHO and the United Nations Children’s Fund (UNICEF) estimated the global coverage with three doses of HepB at 84%. In addition, 109 countries introduced one dose of HepB to newborns within the first 24 hours of life, and the global coverage with the birth dose was 43% in 2017.⁴

1.3 From control through immunization to elimination

In 2016, the World Health Assembly examined and endorsed the Global Health Sector Strategy on viral hepatitis (GHSS), 2016–2021.⁵ This calls for elimination of hepatitis as a public health threat by 2030, as defined by a reduction in incidence (–90%) and mortality (–

65%). For HBV, the incidence reduction goals translate into two milestones. The first is less than 1% prevalence of HBV infection in children 5 years of age by 2020. This milestone can be achieved through universal immunization, including timely birth dose (TBD). Achievement of the 2020 target will then pave the way for the ambitious 2030 target of reducing the prevalence of HBV infection to 0.1%.⁶ This may require additional interventions, including prevention of mother-to-child transmission (PMTCT) of HBV. PMTCT of HBV is based on testing pregnant women for hepatitis B surface antigen (HBsAg) followed by additional interventions that may include (1) administration of hepatitis B immune globulin (HBIG) and (2) peripartum prophylaxis with antivirals. Meanwhile, the United Nations also set a Sustainable Development Goal (SDG) indicator for hepatitis, which is defined as the number of new chronic HBV infections per 100 000 population in a given year.⁷ The prevalence of

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chronic HBV infection (defined as the presence of HBsAg) among children 5 years of age is a surrogate indicator of the cumulated incidence of HBV infections in the first five years of life.

1.4 Regional targets to control HBV infection through immunization

Major progress in the global response to HBV infection has been made through the expansion of routine hepatitis B vaccination of infants, including TBD (2017 global HepB3 coverage: 84%; 2017 global HepB-TBD coverage: 43%). This was made possible by a high level commitment to hepatitis B control in all regions. All regions have set regional control targets, but using different target years, ranging from 2015 (WHO Eastern Mediterranean Region), 2017 (Western Pacific Region) or 2020 (African Region, Region of the Americas, European Region, South-East Asia Region). The reference age groups and prevalence levels differed (Table 1).⁸^,⁹The African Region set a <2% of prevalence of HBsAg in children under 5 years by 2020. The Eastern Mediterranean, South-East Asian and Western Pacific regions all decided on <1%, but in different age groups. The European Region decided on 0.5% while the Region of the Americas committed to <0.1% (Table 1). In 2016, the GHSS on viral hepatitis 2016–2021 harmonized these targets to call for <1% prevalence by 2020. This should be achieved by reaching 90% coverage with HepB3 and 50% HepB-TBD by 2020.⁵ The 2030 control goal of 0.1% should be achieved with 90% coverage with HepB3 and 90% coverage of PMTCT services by 2030. ⁵

Table 1: Hepatitis B control goals in the six WHO regions: target, indicators and status of verification by region

WHO

region Year Prevalence Age group Coverage targets Status of verification of

goal

African 2020 <2% <5 years HepB3 ≥90%

≥25 countries introduced HepB-TBD

American 2020 ≤0.1% 5 years HepB-TBD and HepB3

≥95%

Eastern

Mediterranean 2015 <1% <5 years HepB3 ≥90%

HepB-TBD ≥50% ERP Meeting

European 2020 ≤0.5% Vaccinated

cohorts HepB3 ≥95%

HepB-TBD ≥90%

(universal) or HepB-TBD

≥95% (selective)

ETAGE WG:

NLD provisionally

verified South-East

Asian 2020 ≤1% 5 years HepB-TBD and HepB3

≥90% 4/11 verified Western

Pacific 2017

2030 <1%

≤0.1% ≥5 years

vaccinated HepB-TBD and HepB3

≥95% 21/36 verified

Note: First regional HepB control goal was established by the Western Pacific Region in 2005; emphasis on high 3-dose coverage, with introduction of TBD; achievement of goals measured exclusively by nationally representative biomarker surveys (~2000–4000 children)

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1.5 Regional mechanisms to verify control of HBV infection through immunization In 2005, the WHO Western Pacific Region was the first region to establish a hepatitis B control goal, with an initial target of reducing HBsAg prevalence to <2% among children aged 5 years by 2012. In 2013, the Region set more stringent control targets to be achieved by 2017, including reducing HBsAg prevalence to <1% in children aged 5 years. These regional targets and strategies were ahead of those established by the WHO GHSS, which aims to reduce HBsAg prevalence among children aged 5 years to ≤1% by 2020 and to ≤0.1% by 2030.

In 2007, the Western Pacific Region established the Hepatitis B Immunization Expert Resource Panel that independently advises on the status of and strategies for achieving the regional hepatitis B control goal. The Expert Resource Panel convenes verification panels to assess whether countries have met established regional control targets. As of 2019, 21 of the 36 countries/areas were verified by the Expert Resource Panel as having met the regional <1%

prevalence target based on biomarker survey and vaccination coverage data.¹⁰

Following the Western Pacific Region, other regions established their targets and verification mechanisms. In 2018, the Regional Director of the South-East Asia Region appointed a panel of independent experts and established an Expert Panel for Verification of Hepatitis B Control (SEA REP).¹¹ As of 2019, four countries have been verified by the Expert Panel as having met the regional <1% prevalence target based on biomarker survey and vaccination coverage data. The European Region convened the First Regional Consultation on Viral Hepatitis in the WHO European Region in Georgia, on 11–13 February 2019 to discuss all aspects of the response and exchange tools and experiences to address common challenges.

It is a landmark on the road to eliminating the disease by 2030.¹² The Eastern Mediterranean Region was in the process of establishing an Expert Resource Panel in 2019. The African Region has not yet established a mechanism. In the Americas, the situation differs as the Region started from a lower prevalence baseline and launched directly an initiative for triple elimination of HIV, syphilis and HBV that includes a 0.1% HBsAg control goal by 2030. Since 2010, Member States of the Pan American Health Organization have committed to the elimination of mother-to-child transmission (EMTCT) of HIV and syphilis in the Region, and targets were established in 2015. These commitments were renewed and expanded in 2016 through the approved Plan of Action for the Prevention and Control of HIV and Sexually Transmitted Infections. The Plan of Action expands the EMTCT initiative (labelled “EMTCT Plus”), leveraging the maternal and child health (MCH) platform to include elimination of other preventable communicable diseases in the Americas, such as hepatitis B and Chagas disease in 2017.¹³

2. Harmonizing verification frameworks towards the 1% goal

The GHSS on viral hepatitis proposed a harmonized global target of 1% for the prevalence of HBsAg in children under 5 years of age. The achievement of the hepatitis B control target in 2020 is primarily assessed by the prevalence of HBsAg among children measured through serological surveys and immunization coverage. WHO has published technical guidelines to support countries in conducting nationally representative serological surveys to evaluate the impact of hepatitis B immunization programmes.^{14 , 15} The 2019 Consolidated guidelines on strategic information for viral hepatitis ¹⁶ also included a template biomarker survey protocol to facilitate the preparation of biomarker surveys.¹⁷ This document provides an overall framework on verifying a country’s achievement of the 1%

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control goal through immunization. Data and indicators to be used for verification and the verification procedures to be followed are described in the following sections as well as the actual process to be followed. Tools to support the verification process are annexed to this document. While regions with already existing frameworks and mechanisms would keep their arrangements, this framework could constitute the basis of an approach for other regions, such as the African Region.

3. Criteria for verification and indicators

The main evidence needed for verification is a low prevalence of chronic HBV infection among vaccinated cohorts of children and proof of high and sustained HepB immunization coverage in the population. These findings can be demonstrated in the following ways and are considered essential criteria for verification:

✓ Prevalence of HBsAg among children: at least one source of nationally representative data from children 5 years of age or older born after the nationwide implementation of universal hepatitis B infant immunization.

✓ Coverage of HepB-TBD (where applicable) and HepB3 at national and subnational levels for at least 5 years with coverage levels in line with the GHSS targets. Additional data may be required to review coverage before and after impact assessment surveys.

✓ Additional supplementary information may be required as multiple lines of evidence will be considered and should be congruent in indicating that the target has been achieved.

✓ Other sources of information should be provided, if measures have been implemented and data are available:

– Antenatal testing of HBV and prophylaxis for infants born to HBsAg-positive mothers (especially for countries that have not introduced the birth dose).

Relevant information may include:

▪ national policies and guidance on antenatal HBV testing;

▪ coverage of antenatal testing and prevalence of HBsAg among pregnant women;

▪ TBD coverage among infants born to HBsAg-positive mothers;

▪ availability and coverage of HBIG for infants born to HBsAg-positive mothers;

▪ data from post-vaccination serological testing (PVST).

– Surveillance for acute hepatitis, especially among children.

3.1 Seroprevalence of HBsAg among cohorts born after national implementation of hepatitis B vaccination

Symptom-based disease surveillance provides important information about incidence and trends in acute infections as well as risk factors for infection. However, most new HBV infections, especially those in children, are asymptomatic. This limits the use of surveillance data to estimate disease burden. Therefore, population-based biomarker surveys are necessary to estimate the prevalence of infection and to document and plan for effective

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prevention strategies. One of the key requirements for verification will be the analysis of seroprevalence of HBV infection markers. Countries may undertake biomarker surveys of HBsAg based on a representative sampling of population cohorts born after the nationwide implementation of the universal hepatitis B immunization programmeand after continuously sustaining high coverage with HepB3 (and HepB-BD if available). Ideally, the biomarker survey should be conducted within 3 years of applying for verification.

According to the WHO guidelines Documenting the impact of hepatitis B immunization:

best practices for conducting a biomarker survey,¹⁸ the most appropriate study design is a cross-sectional survey of a nationally representative population. To document HepB impact, countries should survey children ≥5 years of age who had an opportunity to be vaccinated and have passed through the period of highest risk of chronic infection. School-based sampling is the most appropriate if school attendance among the target age group for the survey is at least 95%. Otherwise, countries can use community-based sampling. WHO recommends complex survey sampling (for example, a stratified multistage cluster sample with random selection at each stage). This methodology is described in detail in the Sample design and procedures for hepatitis B immunization surveys: a companion to the WHO cluster survey reference manual.¹⁹

Key thresholds for verification and precision are as follows:

➢ The point estimate of HBsAg seroprevalence should be less than the target.

➢ The upper bound of the 95% confidence interval should not go beyond the target.

Further criteria for a valid biomarker survey to verification are included in Annex 1.

3.2 Hepatitis B immunization coverage

Since the biomarker survey measures the prevalence of HBV infection among birth cohorts that were included in the survey, it can be assumed that, with sustained hepatitis B immunization coverage, younger cohorts will not have higher HBsAg prevalence than the surveyed older cohorts. Countries should provide data showing HepB3 and HepB-BD coverage at least for the most recent 3 years. This can be done together with the biomarker survey if children under 5 years are sampled.

Immunization coverage data will be analysed at national, provincial and district levels, as well as for specific subpopulations whose infant cohorts may not be reached by routine immunization. If evidence suggests that certain communities have a high prevalence of HBV infection, for example, certain ethnic groups, it is highly desirable to have information on immunization coverage in these communities.

Immunization coverage data from administrative sources should be corroborated by data from surveys, for example, immunization coverage surveys, Demographic Health Surveys, or Multiple Indicator Cluster Surveys. Countries could also supplement information on data quality from data quality assessments or audits, or immunization programme reviews.

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3.3 Other sources of information if available

WHO recommends that all countries include a HepB-TBD in the national immunization schedule. For countries that have not introduced a universal birth dose, it is recommended to provide evidence that high coverage of antenatal testing of HBV and high coverage with a TBD among infants born to HBsAg-positive mothers have been achieved. Countries should also provide information on national policies or guidance on antenatal testing of HBV and prevention of perinatal HBV transmission, if HBIG is available, and the coverage of HBIG.

Countries may also supplement this information with studies on PVST of infants born to HBsAg-positive mothers.

4. The verification procedure

4.1 Constitution of the verification panel

The Regional Director of WHO is responsible for and appoints an independent verification expert panel (VEP) working in different institutions in various countries with expertise in hepatitis B control, epidemiology, immunization, surveys, laboratory, statistics and other relevant fields. The terms of reference, conflicts of interest and confidentiality policies are outlined in Annex 5. Expert Panel members serve on an honorary basis in the capacity of a WHO temporary advisor. Upon receiving a request from a country for verification, the WHO region secretariat to the VEP for verification of hepatitis B control will establish a regional verification team (RVT) consisting of one chair and two other members from the VEP. The chair will coordinate communication between team members and will summarize the recommendations from the team. All aspects of the VEP will be supported by the WHO region secretariat.

4.2 Initiation of verification

Once confident that the target has been achieved based on an internal evaluation, the country can request initiation of the verification process. The country may form an internal team to assemble and review the biomarker survey and immunization coverage data as well as other information. After this internal assessment, the country may submit a formal request for verification accompanied by the completed verification data package and supporting documents, including a report, to the concerned WHO regional office. Please see Annex 2 for instructions on preparing a verification data package and Annex 3 for the template of the report.

4.3 Verification process

The RVT will perform a detailed desk review of the data submitted in the verification package. The desk review can be done from a distance by members of the verification team working at their places of residence. Discussions are carried out by email or teleconference.

A visit to the country requesting verification or to the WHO office may be undertaken if necessary. The RVT may contact the country’s focal person for verification if additional information or clarification is needed.

The RVT will examine evidence in each country on a case-by-case basis following the criteria and indicators laid out in this document. Some criteria may be adjusted by the Panel after considering the country context, for example, subnational variations in hepatitis B

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epidemiology, other interventions to reduce the risk of HBV infection and demographic characteristics. The RVT may also take additional information into consideration, including information derived from its own literature review. A tool for evaluating country verification data and an outline of reference points for evaluation criteria are included in Annex 4.

The RVT will reach its conclusion by consensus and present this to the VEP for a conclusion. The VEP will submit a report to the Regional Director detailing whether the country has reached the target of reducing HBV infection prevalence among children to the target by 2020, with justification for its finding.

4.4 Report on verification results

The Regional Director will send an official letter to the country informing the country of the verification decision. The WHO Regional Office will report to the technical advisory groups and the WHO Regional Committee as to the countries that have been verified and may feature these achievements in a news release or other form of communication.

4.5 Maintaining verification status

If a country has been verified to have achieved the target (e.g. prevalence of 1%) HBsAg in children 5 years of age or older, conclusions as to whether verification status has been maintained should be made by the national immunization advisory group based on a review of the HepB coverage data submitted each year in the WHO/UNICEF joint reporting forms.

The Regional Office will review the country’s progress and recommend either that they maintain progress for those countries that have been verified and are on the right track, or for those who need support, provide recommendations and advice on policies that should be enhanced to achieve the target.

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5. References

1 Global hepatitis report, 2017. Geneva: WHO; 2017.

2 Progress report on HIV, viral hepatitis and sexually transmitted infections 2019: accountability for the global health sector strategies, 2016–2021. Geneva: World Health Organization; 2019.

3 World Health Organization. Hepatitis B vaccines: WHO position paper, July 2017 – Recommendations.

Vaccine. 2019 Jan 7;37(2):223–5.

4 https://www.who.int/news-room/fact-sheets/detail/immunization-coverage, accessed on 2 Dec 2019.

5 WHO Global health sector strategy on viral hepatitis, 2016–2021: towards ending hepatitis. Geneva: World Health Organization; 2016

(https://apps.who.int/iris/bitstream/handle/10665/246177/WHO-HIV-2016.06-

eng.pdf;jsessionid=C218A471F69D97C680E0940470EB5455?sequence=1, accessed 5 February 2020).

6 Hutin Y, Desai S, Bulterys M. Preventing hepatitis B virus infection: milestones and targets. Bull World Health Organ. 2018 Jul 1;96(7):443-A.

7 Global indicator framework for the Sustainable Development Goals and targets of the 2030 Agenda for Sustainable Development.

(https://unstats.un.org/sdgs/indicators/Global%20Indicator%20Framework_A.RES.71.313%20Annex .pdf, accessed 5 February 2020).

8 World Health Organization. WHO South-East Asia Regional Immunization Technical Advisory Group (SEAR- ITAG). Report of the Seventh Meeting SEAR-ITAG. New Delhi, India, 7–10 June 2016

(http://www.searo.who.int/immunization/documents/sear_itag_2016.pdf, accessed 5 February 2020).

9 South-East Asia Regional Vaccine Action Plan 2016–2020. New Delhi: World Health Organization; 2017 (http://apps.who.int/iris/handle/10665/272397, accessed 5 February 2020).

10 Woodring J, Pastore R, Brink A, Ishikawa N, Takashima Y, Tohme RA. Progress toward hepatitis B control and elimination of mother-to-child transmission of hepatitis B virus—Western Pacific Region, 2005–2017. MMWR Morbid Mortal Wkly Rep. 2019 Mar 1;68(8):195.

11 Guidelines for verification of achievement of hepatitis B control target through immunization in the WHO South-East Asia Region. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017.

License: CC BY-NC-SA 3.0 IGO

12 http://www.euro.who.int/en/health-topics/communicable-diseases/hepatitis/news/news/2019/3/first- regional-consultation-on-viral-hepatitis-in-europe-shows-progress-and-reaffirms-countries-commitment-to- elimination (accessed 6 Dec 2019).

13 Framework for elimination of mother-to-child transmission of HIV, syphilis, hepatitis B, and Chagas.

Washington, DC: Pan American Health Organization; 2017.

14 Documenting the impact of Hepatitis B immunization: best practices for conducting a biomarker survey.

Geneva: World Health Organization, 2011 (http://apps.who.int/iris/handle/10665/70808, accessed 5 February 2020).

15 Sample design and procedures for hepatitis B immunization surveys: a companion to the WHO cluster survey reference manual. Geneva: World Health Organization; 2011.

16 Consolidated strategic information guidelines for viral hepatitis: planning and tracking progress towards elimination. Geneva: World Health Organization; 2019

(https://apps.who.int/iris/bitstream/handle/10665/310912/9789241515191-eng.pdf, accessed 5 February 2020).

17 Consolidated strategic information guidelines for viral hepatitis: planning and tracking progress towards elimination. Geneva: World Health Organization; 2019. Web Annex 2

(https://apps.who.int/iris/bitstream/handle/10665/280099/WHO-CDS-HIV-19.3-eng.pdf?ua=1, accessed 5 February 2020).

18 Documenting the impact of immunization: best practices for conducting a biomarker survey. Geneva: World Health Organization; 2011. ( https://www.technet-21.org/en/library/main/5089-documenting-the-impact-of- hepatitis-b-immunization-best-practices-for-conducting-a-biomarker survey, accessed 5 February 2020).

19 Sample design and procedures for Hepatitis B immunization surveys: a companion to the WHO cluster survey reference manual. Geneva: World Health Organization; 2011

(https://apps.who.int/iris/handle/10665/70876, accessed 5 February 2020).

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Appendix 1: Criteria for a valid hepatitis B surface antigen (HBsAg) biomarker survey for the purpose of verification

Representativeness: the survey should be nationally representative. Ideally, the survey should be a household-based survey using probability sampling. Sample methods that may introduce bias should not be considered for verification, although convenience samples or hospital-based samples may be considered as part of pooled evidence. If school enrolment is almost universal (i.e. >95%), conducting a school-based survey may be logistically efficient and satisfy requirements. If school enrolment is not high enough, a household-based survey is recommended as it will ensure that all children in the eligible age group have a chance to be selected. Convenience samples are generally not accepted as the main evidence for verification. However, if the country has strong evidence showing representativeness of the data and can supplement the survey with other evidence that very low prevalence has been achieved, the country may be considered by the verification panel. In some situations, especially when no national but several subnational surveys have been conducted, evidence other than a nationally representative survey may be taken into consideration.

Precision: the survey should have a sample size that is large enough to generate the estimate of the 95% confidence interval with a total width narrower than 1% (i.e. a half width of 0.5%). When using methods that generate asymmetrical confidence intervals,^a it is acceptable that the upper limit of the confidence interval be slightly greater than +0.5%, and the lower limit of the confidence interval be slightly narrower than -0.5%, with the total width within 1%. For regions with a different target, the point estimates and confidence interval have to be identified prior to the verification.

Age group: initially, the concept used in the Western Pacific Region verification process was to focus on a target age group of 5 years of age and older for surveys. Children in this age group have passed through the period when the risk of infection is the highest. Testing children under the age of 5 years may underestimate the prevalence of chronic HBV infection, as some children may still be infected and develop chronic hepatitis B as they grow older. However, these concepts have evolved and a lower risk of horizontal transmission following many years of use of hepatitis B vaccine have led other regions to accept surveys that include children under 5 years of age.

Seromarkers: HBsAg is the marker indicating chronic HBV infection and testing for HBsAg is required for verification. While clinical diagnosis of chronic HBV infection is made with two positive HBsAg test results at least 6 months apart, in cross-sectional surveys (especially surveys among children), HBV infection can be defined as the presence of HBsAg at a single point in time (most children develop chronic infection).^b Antibodies to hepatitis B core antigen can be included in the testing as an indication of past infections.

Further information is available in: Epidemiology and prevention of vaccine-preventable diseases (the pink book: course textbook), 13th edition (Atlanta: CDC; 2015).

aThe Wilson confidence interval with continuity correction is recommended for sample size calculation, as it has better probability coverage than the Wald confidence interval when the prevalence is below 1%. A program written in R has been developed for sample size calculation that can be obtained from the WHO Regional Office for South-East Asia. The survey data should be analysed using methods that account for the complex survey design.

b Technical considerations and case definitions to improve surveillance for viral hepatitis. Technical report. Geneva: World Health Organization; 2016 (http://apps.who.int/iris/bitstream/10665/204501/1/9789241549547_eng.pdf?ua=1, accessed 21 June 2016).

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Ethical standards: the survey protocol should be reviewed by an ethics review committee or a research review committee prior to survey implementation. If the survey receives funding from WHO, review by the organization’s Research Ethics Review Committee is required. The survey should be implemented in compliance with the approved protocol.

Quality assurance of laboratory procedures: countries should be able to implement proper quality control and quality assurance of laboratory procedures. WHO has a prequalified laboratory-based enzyme immunoassay as well as rapid tests for HBsAg. The list of WHO- prequalified tests can be found on the WHO’s website.^a If countries choose to use other assays, the sensitivity and specificity of these assays should be evaluated. WHO may facilitate proficiency testing of such assays or retesting of some of the specimens. Surveys using rapid tests with established sensitivity and specificity are acceptable for verification.

Rapid tests offer several advantages, including lower costs, minimal or no need for laboratory and cold chain infrastructure, and small specimen volume requirements (only a few drops of blood). Some rapid tests may be used with capillary blood collected by fingerstick, thus avoiding venepuncture. Please refer to the instructions of the manufacturers for acceptable specimen types and specimen volumes. As of December 2019, seven test products have been prequalified by WHO, of which two are rapid tests.

a WHO list of prequalified in vitro diagnostic products. Available at http://www.who.int/diagnostics_laboratory/evaluations/PQ_list/en/

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Appendix 2: Instructions for countries that request verification of

achievement of the target of hepatitis B control through immunization

Steps Details

1. Prepare verification package

A. Complete verification report (Annex 3)

B. Attach data or graph on national and subnational hepatitis B vaccination coverage (HepB3) and HepB-TBD, ideally since the start of the programme but at least for the past 5 years. Please specify if HepB-BD is given within 24 hours of birth, or within and after 24 hours of birth, and provide data on both, as applicable.

C. Attach a report of the b i o m a r k e r s survey on the prevalence of HBV infection (indicated by HBsAg) among children. This can be an existing published report or an unpublished report that details the following information:

i. Objectives of the serological survey

ii. Methods – including sampling methods (target ages, geographical areas and sample selection method), sample size assumptions (if sample size has been calculated), including design effect, time period of participant enrolment/specimen collection, exclusion criteria if any, laboratory test used, testing algorithm and quality assurance procedures. If the survey is school-based, please include the proportion of children attending school (in percentage).

iii. Results – including HBsAg prevalence and confidence

intervals by age and, if possible, by gender, geographical region, race/ethnicity, urban/rural, socioeconomic status and

vaccination status including </≥24 hours birth dose. The proportion of invalid tests and the survey response proportion should also be included. If possible, include comparison of demographic characteristics between individuals refusing to participate and those participating in the study.

iv. Discussion – including whether the survey represents the vaccinated cohorts of the country, especially about possible groups at high risk of infection (e.g. certain minority groups), and study limitations.

D. Attach a report – if data are available – of antenatal HBV testing coverage and HBsAg prevalence. This is particularly important if the country has not introduced the birth dose for all infants.

E. Attach any other supporting documents that the country would like to submit, including ones reporting optional data.

F. Discuss limitations of the data as applicable.

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verification

A. Contact the Immunization and Vaccine Unit of the WHO Regional Office to assist with the process of verification.

B. Send a letter from the health administration of the country to the Regional Director of WHO, which includes the following:

i. a statement of interest in initiating the verification process;

ii. the name and contact information of the person who will be the country’s contact person during the verification process.

The report to document verification (see Annex 3) and supporting documents provided to be considered for verification of achievement of regional hepatitis B control goals should be enclosed.

3. Assist review team, if needed

i. A team of three experts from the verification expert panel (VEP) will be convened to review the verification package. During this process, the contact person should be available for any clarification that may be requested by the Panel.

ii. The review team should be in touch with the country contact p e r so n within 4 weeks at the latest from the time of receipt of the letter with a request for clarification, if this is needed.

iii. A letter will be written from the VEP to the Regional Director of WHO. The Regional Director will inform the country of the Panel's decision as per established protocols.

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17

Appendix 3: Report to document verification of achievement of regional hepatitis B control target through immunization

Country:_____________________________ Date: ____________

Contact name and affiliation: ______________________________________________

Email address: ________________________________________Telephone no: _____________________

Section I. Background on country, immunization systems, policies and other control measures for hepatitis B 1. Live births: ___________ in year _______ (source: _________)

2. Percentage of births in health facilities: ______ % (source: _________)

3. Percentage of births attended by a skilled practitioner: ______ % (source: _________) 4. Primary school enrolment: ____ % (source:_________)

5. Do you provide universal hepatitis B vaccination? Yes No

6. If yes, what type of universal hepatitis B vaccination? [Multiple answers possible]

All children <1 year of age receive 3 doses of hepatitis B vaccine (HepB)

All newborns receive timely birth dose of HepB followed by 2–3 additional doses Birth dose administered only to newborns who are at high risk of infection

Please specify which newborns are at high risk: _______________________________________________________

Other Please specify: _________________________________________________________________

7. Universal hepatitis B vaccination schedule history:

Schedules Year Nationwide (yes/no) Age birth dose Age 1st dose Age 2nd dose Age 3rd dose

Age 4th dose (if applicable) First introduced

Revision 1 Revision 2

8. Specify recommended timing of HepB birth dose in national policy (for countries that administer birth dose to all newborns):

<24 hours after birth 1–7 days after birth other not defined 9. Catch-up hepatitis B vaccination: Yes No

If yes, indicate years and age groups that receive catch-up vaccination (add a page if needed):

Year(s): _________ Age(s): ______________ # targeted: ________________ Coverage: ________(%) Year(s): _________ Age(s): ______________ # targeted: ________________ Coverage: ________(%)

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Section II. Hepatitis B immunization coverage data

10. Please provide national vaccination coverage data for at least the last 5 years (complete table with “n.a.” if data are not available):

Year

HepB birth dose coverage¹ (%) First dose of HepB (HepB1)/First dose of

pentavalent vaccine (Penta1) coverage

(%)

Third dose of HepB (HepB3)/Third dose

of pentavalent vaccine (Penta3)

coverage (%)

Indicate data source (WHO/UNICEF, administrative)

HepB3/Penta3 coverage survey⁴ (%) Timely² Total³

1 Only for countries that implement universal newborn vaccination

2 Timely HepB birth dose is defined as receipt within 24 hours of birth

3 Total HepB birth dose is defined as any HepB birth dose administered

4 Include report if coverage survey data are available (Coverage Evaluation Surveys, Multi Indicator Cluster Surveys, Demographic Health Surveys, etc.) 11. If national coverage figures are <90% for particular year(s), please describe reason(s) below or provide report:

_______________________________________________________________________________________________________________________________________

____________________

12. Are there known groups of people or geographical areas with low coverage? If yes, please list these below and provide the plan for improving HepB coverage in these groups or areas:

_______________________________________________________________________________________________________________________________________

___________________________________________

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13. Provide subnational data on HepB birth dose¹ and HepB3 coverage data for the last 3–5 years (if available, data can be provided in another format):

Year: Year: Year: Year: Year:

% Districts in coverage

brackets

HepB birth dose¹

HepB3 HepB birth dose¹

HepB3

≥95%

90–94%

80–89%

50–79%

<50%

Unknown

1 Only for countries that implement universal newborn vaccination

14. Alternatively, attach provincial and district-level administrative or official coverage of HepB birth dose, HepB1 and HepB3 from the past 3–5 years as in Annual EPI Reporting Form.

15. If subnational coverage figures are <80% for a particular year(s), please describe reason(s) below or provide a report providing justification:

_______________________________________________________________________________________________________________________________________

_______________________________

Section III. Hepatitis B vaccination of high-risk groups

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16. Hepatitis B vaccination provided to health-care workers? Yes No

17. Hepatitis B vaccination provided to high-risk groups (e.g. people who inject drugs, sex workers, etc.) Yes No If yes, specify which risk groups, and, if possible, service delivery model:

______________________________________________________________________________________________________________________________________

__________________________________________________

Section IV. Testing of pregnant women for hepatitis B surface antigen (HBsAg) and prevention of perinatal infection among infants who are at high risk of infection 18. Do you implement universal testing of pregnant women for HBsAg? Yes No

a. If no, do you implement selective testing? Yes No

• If yes, specify:

• year started the testing

• ___ ___ care referring to linkage services.

19. Data for testing of pregnant women for at least 3 years (if available, data can be provided in another format):

Year Total number of pregnant women

Total number of pregnant women screened for HBsAg during pregnancy

Total number of pregnant women that tested positive for HBsAg

20. For countries that do not implement universal newborn vaccination: data for hepatitis B vaccination of newborns who are at high risk of infection for at least 3 years (if available, data can be provided in another format):

Year Timely HepB birth dose coverage in newborns who are at high risk of infection (%)

Completed vaccination (HepB3) coverage among those children (%)

Testing for HBsAg 1–2 months after completion of hepatitis B vaccination series¹(% HBsAg positive)

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1 If available

21. Additional services routinely provided to prevent perinatal transmission of hepatitis B virus (check all that apply):

Hepatitis B immunoglobulin for newborns who are at high risk of infection

Please specify newborns at high risk: _____________________________________________

Antiviral treatment of pregnant women

Please specify which pregnant women receive treatment: _____________________________________

Other, specify: ___________________

No additional activities

22. Any other information considered relevant for the verification review; this may also include information on other hepatitis B control strategies such as measures to ensure blood and injection safety

__________________________________________________________________________________________________________________________________________

_____________________________________________________________________

Section V. HBsAg biomarker survey data among cohorts born after introduction of universal hepatitis B vaccination (SURVEY REPORT REQUIRED). Please complete this section for each survey for which the data are submitted and provide the relevant report(s).

23. Survey year: ____________

24. Geographical scope of the survey: National Subnational Other, specify:________________________

25. Sampling base: General population/community Health-care centres Schools Other, specify: _________________________________________________________

26. Survey design: Probability sample: simple random Probability sample: cluster Classification survey Convenience sample Other, specify: _______________________________________

27. Hepatitis B virus markers: HBsAg only HBsAg with other tests* (Provide algorithm and data):

_______________________________________________________________________________________________________________________________________

___________________________________________

*Please also refer to WHO Guidelines on hepatitis B and C testing, 2017

28. Test kit: Commercially available ELISA kit, specify brand: _______________________________________

Point-of-care, rapid test, specify brand: _______________________________________________

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Other, specify: __________________________________________________________________

29. HBsAg prevalence estimate of survey age groups¹ born after introduction of universal hepatitis B vaccination:²

Age group (years) Sample size HBsAg point prevalence (%) 95% confidence interval

1 Please ensure that HBsAg point prevalence for children aged 5 years is included, if available.

2 Table can be extended to report national and regional estimates, if available.

30. Comment on findings, if any, in specified subpopulations:

__________________________________________________________________________________________________________________________________________

_____________________________________________________________________

31. Study limitations:

__________________________________________________________________________________________________________________________________________

______________________________________________

Section VI. Sustainability

32. Funding source for HepB (check all that apply):

Self-funded (country) Gavi, the Vaccine Alliance Other (specify): _____________________________

33. Please describe plans to sustain or improve hepatitis B immunization coverage:

_______________________________________________________________________________________________________________________________________

___________________________________________

(Optional: if preferable, attach the hepatitis B immunization section of the relevant multi-year plan or other strategic documents/plans)

Section VII. Expert consultation

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Optional: Please list the areas of hepatitis B control for which the country would like the regional expert panel on hepatitis B control verification to provide comments/recommendations:

___________________________________________________________________________________________________________________________________________

___________________________________________

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Appendix 4: Tool for evaluating country verification data

Country: Date:

Programme

categories Programme elements

Not compliant/

weak

Compliant/

acceptable Advanced Suggestions and comments

Immunization systems and policy

Vaccination schedule Timely birth dose Nationwide vaccination programme

Vaccination coverage monitoring systems

Optional: Perinatal hepatitis programme

Optional: Catch-up strategies Optional: High-risk groups Summary comments on systems and policy

Coverage National HepB3 coverage last 5 years

Timely birth dose coverage last 5 years (where applicable)

National HepB1 vs HepB3 coverage (drop-out)

District HepB3 coverage last 3–5 years

Quality of coverage data

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Summary comments on coverage

Serological survey

Conducted after 5 years of high coverage

Relevant age groups targeted Population sampled

Sampling design

Laboratory quality assurance and procedures

Use of standard HBsAg test kit HBsAg prevalence =

Estimate of precision =

Summary comments on survey

Sustainability Plans for sustainability Hepatitis B control in

comprehensive multi-year plan (cMYP) (immunization)

Conclusion on 2020 control target:

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Observations and recommendations (related to verification):

Observations and recommendations on technical programme aspects including sustainability

To national programme:

To TAG:

July 2020 Guidelines on antiviral prophylaxis in pregnancy PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HEPATITIS B VIRUS:

PREVENTION OF MOTHER-TO-CHILD TRANSMISSION OF HEPATITIS B

VIRUS: Guidelines on antiviral prophylaxis in pregnancy

July 2020

Annex E. Framework for regional verification of the global control goal for

hepatitis B surface antigen prevalence in children by 2020

Contents

Acronyms

1. Background of hepatitis B control

2. Harmonizing verification frameworks towards the 1% goal

3. Criteria for verification and indicators

4. The verification procedure

5. References

Appendix 1: Criteria for a valid hepatitis B surface antigen (HBsAg) biomarker survey for the purpose of verification

Appendix 2: Instructions for countries that request verification of

achievement of the target of hepatitis B control through immunization

Appendix 3: Report to document verification of achievement of regional hepatitis B control target through immunization

Appendix 4: Tool for evaluating country verification data