Disease condition and impact on patients HEV is an RNA virus and a leading cause of acute viral hepatitis worldwide (1). Hepatitis E disease presents as acute, viral hepatitis. During the first week of illness, many symptoms are nonspecific, including fever, malaise, nausea and vomiting. After the prodromal phase, patients experience a period of acute, icteric hepatitis, including jaundice, dark urine, pale stools and prolonged cholestasis with elevated liver enzymes. Symptoms can last 4–6 weeks (2). Most cases occur in older adolescents and adults. In general, these cases are mild and self-limiting, yet approximately 1–2% of cases die. However, some populations are more prone to severe disease. Women infected during pregnancy are at increased risk of fulminant hepatic failure and its associated complications, including hepatic encephalopathy, cerebral oedema and disseminated intravascular coagulation. HEV infection during pregnancy also has poor outcomes for the fetus, including low birth weight, small for gestational age, preterm birth and intrauterine death (3). A recent meta-analysis found the case fatality rate of hepatitis E during pregnancy to be 26% (IQR: 17–41%) for the mother, 33% (IQR: 19–37%) for the fetus and 8% (IQR 3–20%) for the neonate (4). HEV is a pathogen of global concern (5). However, the burden of disease is not distributed evenly; HEV is very common in low-income countries, where it causes substantial burden of disease, while relatively few cases are reported from high-income countries (5). There are four genotypes of HEV that infect humans. Genotypes 1 and 2 only infect humans and are thought to be transmitted primarily via contaminated drinking water. These genotypes are most common in South-East Asia and Africa (6). They are responsible for large outbreaks, with cases numbering in the tens of thousands. Outbreaks have been reported from East and South-East Asia, and protracted outbreaks have occurred in Africa, often affecting displaced populations (7). However, genotypes 1 and 2 also cause substantial disease outside of outbreaks (6). In India, between 25% and 50% of clinical hepatitis cases are caused by HEV, even in the absence of an outbreak (6). Genotypes 3 and 4 infect humans and a wide range of mammals, notably wild and domestic swine. These genotypes are usually transmitted zoonotically from eating infected meat and are largely reported from Europe, East Asia and the Americas. Here, HEV is responsible for sporadic cases and small foodborne outbreaks (8). Does the test meet a medical need? Rapid testing has become common practice throughout the world since the development and wide application of COVID rapid test kits. Similar rapid diagnostics exist for influenza, HIV, HCV, malaria and many other infections. Several RDTs for the detection of anti-HEV IgM are available commercially. These tests can be used as a first-line tests, particularly in low-resource settings where HEV diagnostics are not usually performed (9). Anti-HEV IgM antibodies appear early during infection and indicate a current or recent infection. They are detectable in blood about 3–7 days after symptom onset (after approx. 1 month incubation period) and persist for several months (10). Availability of HEV diagnostic tests will improve the differential diagnosis capability in the case of acute jaundice syndrome. Early diagnosis can alert authorities to the possibility of an outbreak, giving critical time to plan mitigation efforts. Due to the lack of diagnostic testing in areas where HEV is most common, the burden of HEV disease is underestimated and often poorly understood at the country level. This lack of awareness and understanding by country officials is thought to be one reason why vaccines have not been used in outbreaks for a decade after the vaccine became licensed, leading to unnecessary mortality and morbidity. There are several benefits of these rapid tests, including that they are simple to perform and therefore can be completed by health and care workers and non-skilled laboratory technicians; they are low cost, facilitating their distribution to health facilities that do not usually have such diagnostic capability; and the tests can be performed in a basic health facility space, as they do not require laboratory equipment. The good performance of anti-HEV IgM RDTs indicates that they can be used as effective tools for routine diagnosis (9, 11, 12, 13, 14). How the test is used Rapid tests are administered at POC and can give results in less than 1 hour, allowing health care providers to make real-time decisions about the future care of the patient. When a suspect HEV case presents at the community level, defined as any person presenting with an acute (recent, new or abrupt) onset of jaundice (yellowing of whites of eyes or skin) or dark urine and pale clay stools, a rapid IgM test should be performed, if available, to determine the diagnosis (15). If the rapid IgM test is positive, this can be considered case confirmation. If the rapid test is positive early in the clinical course of infection, samples may still be sent to a reference lab for PCR or IgM ELISA confirmation, but this is not necessary. If the patient tested negative on the rapid IgM test and no other cause for the acute jaundice has been found, a PCR test to detect HEV RNA or an ELISA to detect anti-HEV IgM should be performed to confirm the negative diagnosis. Note: the following algorithm was provided by the applicant as part of this application and is not a WHO algorithm. Diagnostic algorithm for HEV infection: https://docs.google.com/presentation/d/ 10Yd0I67LoepbYSHxIIZwrMEKUJttU9OA/edit#slide=id.p1 (accessed 1 August 2023).

Prevalence A commonly cited meta-analysis estimated that HEV causes 20.1 million infections, 3.4 million clinical cases, 70 000 deaths and 3000 stillbirths annually due to the epidemic-prone genotypes 1 and 2 (16). While there is increasing recognition of HEV in genotype 3 and 4 endemic areas, the burden of disease has not been well classified. However, the burden of disease of HEV is vastly underestimated due to the lack of diagnostic capabilities in areas where HEV is most common. Socioeconomic impact Poor understanding of the global burden of disease has hindered efforts to implement control and prevention strategies. Few studies have looked at the economic impact of hepatitis E. In Nepal, acute HEV infection led to an average of 10 bedridden days and 22 sick days; wage earners lost nearly 20% of their yearly income (17). An estimated 108 YLL per 1000 individuals, 144 years lived with disability per 1000 individuals and 252 DALYs per 1000 individuals were attributed to an HEV outbreak in Uganda (18). However, this estimate used disability weights for untreated diarrhoeal disease and did not account for differential severity among pregnant women and neonates, therefore underestimating the true economic impact.

Use of the RDT to diagnose acute hepatitis E in suspected cases is supported by WHO guidance on recognition, investigation and control of waterborne outbreaks of hepatitis E (15, 19). The RDT is one of the first-line tests recommended for this purpose.

There are currently no systematic reviews that detail the clinical accuracy of HEV RDTs. For the purposes of this application, it was therefore necessary to conduct a systematic review. To do so, a search was conducted through PubMed using the search terms ((HeV) OR (Hepatitis E Virus)) AND ((RDT) OR (rapid diagnostic test) OR (dipstick) OR (rapid antigen test) OR (antigen test)), calling up 209 results. Results were limited to the English language. Initial searching found it necessary to narrow search results by filtering out articles with (latex) or (Hendra), yielding 147 results. These articles were reviewed by hand, and five were found to be relevant to HEV RDTs specifically. Clinical accuracy was examined in these five studies, with two of three commercially available RDTs: the MP Diagnostics Assure HEV IgM rapid test and the Wantai HEV IgM rapid test. Four studies examined the Assure test (9, 10, 11, 12, 13, 14). Sensitivity was assessed by comparing the rapid test to PCR-positive, acute hepatitis E patients early in the course of symptoms. Specificity was assessed using patients with acute infections from other viruses or healthy, HEV RNA-negative blood donors. One of the four studies used only genotype 3 samples, one used only genotype 1, and two used a mix of both genotypes 1 and 3. Three studies were performed in European populations, and one in South-East Asian populations. Range of sensitivity: 82–93% Range of specificity: 99–100% Range of PPV: 99.5–100% Range of NPV:95.8–98% Two of the five studies examined the Wantai test (9, 11). Sensitivity was assessed by comparing the rapid test to PCR-positive, acute hepatitis E patients early in the course of symptoms. Specificity was assessed using patients with acute infections from other viruses or healthy, HEV RNA-negative blood donors. Both studies primarily used genotype 3 samples, although one of the studies also included several genotype 1 samples. Both studies were performed in European populations. One study compared the sensitivity, specificity, PPV and NPV of immunocompetent individuals with transplant recipients, an immunocompromised population. Although these values were similar, the values for immunocompromised individuals did tend to be lower and were not included in the following ranges. Range of sensitivity: 90–96% Range of specificity: 99–100% Range of PPV: 99.5–100% Range of NPV: 95.8–98%

A systematic search across several databases at the time of submission of this application found no systematic reviews that examined the direct clinical utility of HEV RDTs on patient care and management. However, one recent systematic review examined data on the epidemiology of HEV in LMICs of Africa and Asia based on seroprevalence, outbreaks and risk factors for infection (20). The lack of routine testing is a major limiting factor to understanding the burden of HEV disease in LMICs. Ninety-one studies from 29 countries examined seroprevalence, with seroprevalence generally increasing by age. Forty-nine completed or ongoing HEV outbreaks from 18 countries were reported from 1988 to 2017. However, most outbreaks are not reported in the published literature, and alternative sources were not used for this systematic review. Risk factors for HEV infection included increased exposure to contaminated water sources and poor hygiene (although not all studies found this association). Risk factor data suggested an increased likelihood of current or recent HEV infection and disease associated with faecal-oral transmission of HEV, as well as exposures to blood and animals. However, the authors emphasized that most data on HEV prevalence and risk factors come from specialized studies or outbreak reports. There are no studies specific to the clinical utility of HEV RDT on patient management and care. However, several preventative strategies could reduce the number of future HEV cases and deaths, especially if these preventative measures are introduced early in an outbreak. The applicant identified 12 studies that point to the clinical utility of an HEV diagnosis and greater understanding of the epidemiology and burden of HEV disease in the local context. Better understanding of the local epidemiology and disease burden caused by HEV will allow country officials to make evidence-based decisions on intervention implementation both prior to and during outbreaks.

No data available.

HEV RDTs have been demonstrated to have lower sensitivity in transplant recipients, an immunocompromised population. In areas where HEV is endemic, HIV is likely to be the most common immunocompromising cause. HEV RDTs have not been evaluated in HIV-positive populations. Increased availability of diagnostic testing would allow country officials to better understand the local burden of HEV, and therefore to make evidence-based decisions regarding the use of vaccines both routinely and during outbreaks. No ethical issues were identified.