SAGE IVD recommended including the hepatitis E virus nucleic acid test (NAT) category in EDL 4
• as a disease-specific IVD for use in clinical laboratories (EDL 4, Section II.b);
• using a NAT format;
• using whole blood, plasma, serum and stool as specimen types;
• to diagnose acute hepatitis E virus infection.

Hepatitis E is an acute viral hepatitis caused by HEV infection. Most affected people recover. However, a small proportion – generally less than 5% but much higher in pregnant women – develop acute liver failure. Hepatitis E should always be considered in outbreaks of acute jaundice syndrome, which have occurred more recently across sub-Saharan Africa, and particularly in the context of internally displaced person camps. Definitive diagnosis of hepatitis E is challenging, as causes of acute jaundice are many and include yellow fever, hepatitis A and leptospirosis. For countries experiencing outbreaks, the problem of differential diagnosis is exacerbated by lack of access to hepatitis E assays. The NAT is the gold standard test for diagnosing acute HEV infection. The assay is particularly important for people with immune suppression, including co-endemic HIV and HEV in outbreak situations. Nonetheless, SAGE IVD members expressed concern about the cost of the assay and the level of technology, human skill and workforce capacity needed for broad implementation in LMICs. SAGE IVD members questioned the complexity of the test, its feasibility in a given setting and where it would fit in a referral algorithm linked to the HEV IgM RDT as a screening test. The group noted that NAT provides differential diagnosis when IgM is insufficient, but it is of lesser value than getting good serology for clinical management and is not indicated for surveillance. SAGE IVD further discussed the need to clarify the language of the EDL with reference to the test’s purpose (i.e. “to diagnose” vs “to confirm”) but noted that this issue should resolve once a consolidated algorithm is available under the hepatitis E updated guidance from WHO currently in preparation. Literature cited in the discussion: European Association for the Study of the Liver. EASL clinical practice guidelines on hepatitis E virus infection. J Hepatol. 2018;68:1256–71 (https://www.journal- of-hepatology.eu/article/S0168-8278(18)30155-7/fulltext, accessed 14 December 2022).

This test addresses a significant global health problem. Nucleic acid detection tests for diagnosing HEV infection are included in the WHO guidance (9, 10). The 2018 European Association for the Study of the Liver (EASL) guidelines also recommend a combination of serology and nucleic acid testing for HEV infection (10.1016/j.jhep.2018.03.005). The test allows detection of acute infection, thereby possibly contributing to early warning of an outbreak. There is insufficient evidence to assess clinical diagnostic accuracy and clinical utility/ effectiveness. Given that this test is the gold standard in the diagnosis of HEV, evaluating its clinical accuracy may not be the best way to judge the merits of this test. If studies of clinical effectiveness (on patient outcomes) are absent, other factors may weigh more heavily in eventually deciding to use this test, such as resources required, acceptability and equity.

World Health Organization. (‎2023)‎. The selection and use of essential in vitro diagnostics: report of the fourth meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics, 2022 (‎including the fourth WHO model list of essential in vitro diagnostics)‎. World Health Organization. https://iris.who.int/handle/10665/373322