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WHO Guidelines on Hepatitis B and C Testing. Geneva: World Health Organization; 2017 Feb.

Cover of WHO Guidelines on Hepatitis B and C Testing

WHO Guidelines on Hepatitis B and C Testing.

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6ATESTING APPROACHES TO DETECT CHRONIC HEPATITIS B

6.3. Summary of the evidence

The evidence base for different HBV testing approaches (general population or focused testing) remains very limited, especially in LMICs, and relies largely on observational data and modelling. Although there are descriptive data showing that focused testing can increase the uptake of HBV testing, and detection rate of CHB cases, data showing impact on patient-important outcomes are limited (142). There is also a lack of evidence on and uncertainty regarding how successful focused testing is in reaching specific populations. For these reasons, a formal systematic review of the impact and cost–effectiveness of different testing approaches was precluded, and an updated narrative review of evidence was undertaken. The overall quality of evidence was therefore rated as low.

There were 32 published studies of which nine studies met the inclusion criteria – all but one study were from HICs with low HBV prevalence (see Web annex 5.1). Two studies evaluated the cost–effectiveness of offering testing and treatment to the general population (one from the United States (143) and the other from west Africa (144)), and seven studies had examined targeted risk-group testing in migrant populations (145150) or “high-risk” groups (151). Several studies were based on modelling simulations using hypothetical data. Various outcome measures were used, including cost per quality-adjusted life-year (QALY) gained, cost per life-year (LY) saved and cost per case tested.

General population testing. The two studies performed in the United States and West Africa showed that offering HBsAg testing to the general population with provision of antiviral treatment in those eligible is cost–effective in both high-income (143) and low-income settings (144) , even down to a population prevalence as low as 0.3% and 1.5%, respectively. In addition, the feasibility of large-scale testing and treatment in sub-Saharan Africa based on real-world cost and effectiveness data was demonstrated by the PROLIFICA (Prevention of Liver Fibrosis and Liver Cancer in Africa) study in west Africa (152). This study screened almost 10 000 adults for HBsAg using an active outreach method at the community level in the Gambia and Senegal, followed by full clinical assessment of those found HBsAg positive, and provision of antiviral treatment if they met eligibility criteria. They showed this community-based screen-and-treat strategy was cost-effective compared to the status quo.

Focused risk-based testing. Testing and treatment of migrant or refugee populations in HICs was also found to be a cost-effective intervention in seven studies from Canada, the United States and Europe (145150).

Pregnant women. Although the cost–effectiveness of HBsAg testing of pregnant women in ANC to reduce MTCT and benefits to the child has been addressed in several studies, there were none identified that considered interventions and antiviral treatment for the benefit of the mother to reduce her risk of progression of liver disease.

Drivers of cost–effectiveness. These analyses identified several key drivers of cost–effectiveness for countries to consider when planning testing approaches. These include: (i) Drug and testing costs. The key driver of the cost–effectiveness of a test-and-treat strategy reported is the cost of the antiviral drug (144, 146, 147), and to a lesser extent testing costs (145, 147). In the PROLIFICA study, despite an active community-based screening campaign, testing costs were low (US$ 7.43 per person offered screening) and the intervention remained cost-effective even if there was a threefold increase in testing costs (144). (ii) Linkage to care and adherence. Adherence to treatment and linkage to care were reported as key drivers of cost–effectiveness in several studies (148), but not in the PROLIFICA study (152). (iii) Uptake of testing was not identified as a key driver of incremental cost-effectiveness ratio (ICER) in any of the studies. However, this does not imply that high participation levels in screening are not important. The implication of this result is that it is likely to be worthwhile performing screening and providing treatment, even if participation in screening may be low, in part because testing costs are low relative to the costs and health benefits of treatment for those who are infected. HBsAg prevalence also had a relatively small influence on cost–effectiveness across a wide range of prevalence levels examined.

6.4. Rationale for the recommendations on testing approaches for HBV infection

In developing recommendations on which populations to test and what testing approaches to use, the Guidelines Development Group first considered the primary goals of testing (153): (i) to identify those in greatest need of treatment to reduce morbidity and mortality from HBV-related chronic liver disease; (ii) to reduce the risk of acquisition of disease, by vaccinating those who do not have HBV infection but remain at risk; and (iii) to reduce the risk of mother-to-child vertical transmission and so have benefits that extend beyond the person tested to others. These considerations were then balanced with the need for recommendations that are feasible and implementable by health programmes in LMICs.

Overall, there was a very limited evidence base for the impact of different testing approaches (general population or focused high-risk) as well as for different settings (community- versus health facility-based). Therefore, recommendations were formulated based on consideration of evidence mainly from cost–effectiveness analyses together with data on HBsAg seroprevalence in different settings and populations, and in the general population with considerations of feasibility and cost. The caveats of extrapolating cost-effectiveness data from HICs to LMICs were recognized. The Guidelines Development Group recommended the use of three key testing approaches: routine testing in the general population; focused testing in most affected populations because of higher-risk behaviours or exposures; and routine ANC testing. These can be implemented both in health-care facilities and in the community, as appropriate to the local epidemiology and context.

Balance of benefits and harms

General population testing. In settings where there is an HBsAg prevalence ≥2% in the general population, focused testing in higher-risk populations alone will be insufficient to identify many of those infected and in need of treatment. Additional general population testing approaches that use community- as well as health facility-based testing programmes are therefore needed to increase the coverage and impact of HBV testing. Although general population testing was estimated to be cost–effective down to prevalence levels <1%, the Guidelines Development Group proposed a higher threshold of ≥2% to reflect the well-accepted thresholds for defining intermediate (≥2%)/high (≥5%) seroprevalence (154). The Guidelines Development Group recognized that the threshold used by countries will depend on other country considerations and epidemiological context. For this reason, a conditional recommendation was made.

Focused risk-based testing in populations with high-risk behaviour or exposure to HBV infection. Certain populations are well recognized to be at high risk of acquisition and transmission of HBV infection (Table 4.1), and therefore should be prioritized for testing in all epidemic settings. These include people living with HIV, PWID, MSM, sex workers, people in prisons and other closed settings, some mobile/migrant populations from high/intermediate-endemic countries, some indigenous populations, children born to HBsAg-positive mothers, especially if they did not receive timely infant vaccination, and other family members, sexual partners and close household contacts of those with HBV infection; and health-care workers. In high-endemic settings, a clinically guided testing approach among adults and children with a clinical suspicion of chronic viral hepatitis (i.e. clinical symptoms or signs, or abnormal liver function tests or ultrasound scan) will identify a larger proportion of infected persons.

Key benefits of focused testing

  1. Focused testing in health facilities can successfully increase the uptake of viral hepatitis testing, case detection rate, and referrals to specialist-level care and other important services.
  2. Focused testing approaches can use existing opportunities and infrastructure for health facility-based testing (HIV, STI, and TB outpatient clinics, drug treatment programmes, primary care settings, inpatient and outpatient settings), as well as community-based testing.
  3. Focused testing of high-prevalence populations or of those in settings where there is a large proportion of such persons (e.g. harm reduction and drug treatment services for PWID) or a clinically guided approach based on clinical suspicion is likely to be associated with higher rates of case–finding. This approach will generally be cost–effective compared to generalized testing, especially in low- and concentrated-epidemic settings.
  4. It is recognized that many high HBV-prevalence countries currently lack the resources to undertake general population screening, and therefore focused risk-based testing may be more readily feasible and cost–effective, particularly if it makes use of existing health-facility infrastructure and staff.

Despite the limited formal evaluation of focused testing in high-risk groups and low quality of evidence, a strong recommendation was made because of the overall benefits of focused testing approaches.

Pregnant women – routine testing in antenatal clinics. The Guidelines Development Group strongly recommended routine HBsAg testing in ANC, despite limited or low-quality evidence, for several reasons.

  1. To benefit their offspring through interventions to significantly reduce MTCT of HBV infection (6). This is because in high-prevalence, resource-limited settings, HBV is mainly transmitted through MTCT and early childhood horizontal transmissions. Infants born to HBV-infected mothers are at high risk for both acquisition of HBV infection and development of chronic infection (90%). Therefore, key interventions in this group could significantly reduce the burden of disease in the long term.
  2. To enable women to have knowledge of their HBV serostatus (together with their offspring and partners), allowing them to benefit for their own health through linkage to assessment and treatment services.
  3. Although a systematic review of cost–effectiveness studies on routine antenatal testing in LMICs was not undertaken, this would likely be cost-effective, since testing of mothers for HBV infection has benefits for both the child (reduced transmission) and mother (reduced morbidity).
  4. There is already universal HIV testing in ANC which has proved feasible and acceptable in many countries (6, 11, 153), and addition of HBV testing would be relatively low cost. Although many countries recommend routine screening of women for HBV infection in ANC, the proportion who are screened in many LMICs remains low (157).

Couples and partner testing in ANC. HIV testing of the partners of women attending ANC is now a focus in 21 priority countries aiming for elimination of MTCT (eMTCT) of HIV. Since these countries are also all highly endemic for HBV, this provides a unique opportunity to integrate concurrent HBV testing for partners of women with CHB, or chronic HCV infection if risk factors are present, despite the lack of specific evidence for couples and partner testing for hepatitis in ANC.

Blood donor screening. WHO already recommends blood donor screening for HBV, HCV, HIV and syphilis in order to prevent transmission of bloodborne viruses to the recipient (20). However, this is rarely accompanied by the HBsAg or HCV antibody positive donor being informed of this positive result, counselled and linked into care for clinical evaluation and treatment (141). As part of the PROLIFICA study in west Africa, in addition to HBsAg testing and treatment in the community, blood donors who had tested HBsAg positive at the blood bank were linked to specialist care (152). A higher proportion of blood donors were HBsAg positive and requiring treatment, but had a lower rate of linkage to care. Although a formal cost–effectiveness analysis was not done, these factors are likely to make testing, linkage and treatment of blood donors even more cost-effective compared to community-based testing. However, as blood donors constitute only a small fraction of the population, this strategy is likely to be limited in its reach and population-level effectiveness, and probably should be seen as a complementary, rather than an alternative to a wider screening strategy.

Acceptability, values and preferences

A values and preferences survey of 104 stakeholders from 43 (20 high-income, 23 low- and middle-income) countries provided additional strong support for testing of specific populations: blood donors (>85%), children born to HBV-infected mothers (75%), persons living with HIV (65%), pregnant women (78%), MSM (45%), sex workers (45%), prisoners (25%) and those chronically ill (around 25%). General population testing for HBV infection was supported by only one third of respondents.

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