A systematic review of the epidemiology of hepatitis E virus in Africa

Hepatitis E virus (HEV) causes large outbreaks and sporadic cases of acute hepatitis, and an estimated one-third of the world’s population has been infected with HEV [1]. It is the most or second most common cause of acute viral hepatitis among adults throughout much of Asia, the Middle East, and Africa [2‐4] although the true burden of HEV infection remains unknown [1]. HEV infection is usually self-limiting, but may develop into fulminant hepatitis with a case-fatality rate (CFR) between 1 and 2% in the general population [5], which can rise to over 40% in pregnant women, especially during the third trimester of pregnancy [6].

HEV was first identified in 1983 during the search for the causative agent of an outbreak of enterically transmitted non-A, non-B (NANB) hepatitis [7]. Its full-length genome was first cloned in 1991 [8]. It is a spherical, non-enveloped, single-stranded RNA virus belonging to the Hepeviridae family and the Hepevirus genus [9]. The existing evidence suggests all human HEV strains belong to a single serotype [10] although there are at least four genotypes (1–4) [11, 12] with 24 subtypes [3, 12, 13]. Genotypes 1 and 2 are predominantly found in populations in developing countries whereas genotypes 3 and 4 are zoonotic and globally distributed [3]. Two recombinant HEV vaccine candidates have been clinically evaluated [14‐16]. One vaccine candidate, rHEV, showed 95.5% efficacy after three doses in phase II trial in Nepalese military population while the other vaccine, HEV 239, showed 100% efficacy after three doses in phase III trial in a Chinese population. HEV 239 is licensed by China’s Ministry of Science and Technology [17], and is being produced and marketed by Xiamen Innovax Limited [18].

The first retrospectively (serologically) confirmed HEV outbreak occurred in New Delhi, India in 1955–56 with more than 29,000 symptomatic jaundiced persons [19‐21]. Since then, many serologically confirmed outbreaks and sporadic cases [3, 22] and probable outbreaks have occurred, especially in Asia and Africa [23]. Africa has usually been the place where resources for controlling infectious diseases are last deployed although it is among the regions most severely inflicted by infectious diseases [24]. Acknowledging that understanding HEV infection and distribution in Africa can expedite implementation of evidence-based control policies, our overall objective was to characterize the epidemiology of HEV in Africa by reviewing and summarizing relevant, peer-reviewed literature. The authors’ specific objectives were to explore rates of infection (i.e., seroprevalence, outbreaks, sporadic cases), severity (i.e., case-fatality rates), modes of transmission, and circulating genotypes. The authors also identified knowledge gaps in the existing literature and suggested future studies.

The first documented outbreak of HEV infection likely occurred in 1950 in Tunisia [23] and since the 1980’s, when HEV diagnostic assays became available, half of all African countries including nations in north, south, east, west, and central Africa have published articles of Hepatitis E infections. Clearly, these results suggest that HEV infection is not new to Africa and implies that this is a continent-wide public health problem and a potential threat to travelers. This is supported by a recently published study on HEV in low- and middle-income countries in Asia and Africa [131]. HEV infection deserves the attention of local, regional and international agencies.

Since nations lack routine surveillance for HEV infection, it is difficult to estimate the African disease burden. However, these publications suggest that outbreaks are frequent with about one outbreak report published every other year from Africa. As only a few outbreaks are likely identified and even fewer reported in peer-reviewed journals, it is probable that outbreaks in Africa are even more common than these reports imply. To address HEV outbreak control, routine HEV surveillance and response is necessary and could be integrated with measles or poliomyelitis surveillance, which are ongoing activities in most countries.

Among HEV outbreaks, the overall case-fatality rate is comparable to that seen with other diseases such as cholera and measles signifying that these patients require equal attention. Like HEV infections among pregnant woman in Asia, the clinical prognosis is far worse for pregnant women than for men with fatalities reaching four out of 10 infected pregnant women [6]. The concerns for pregnant woman are further amplified when recognizing that HIV prevalence is high among pregnant women in sub-Saharan Africa [132] and co-infection with HIV and HEV as reported here may increase the risk of fulminant or chronic hepatitis. African men co-infected with HIV and HEV are similarly at risk of complications. While appreciating the hardship from all HEV-associated deaths, maternal deaths are the great tragedy of HEV infection likely causing serious adverse consequences for the health and well-being of surviving family members, especially children.

It has been suggested that many hepatitis outbreaks that occurred before the development of diagnostic assays for any hepatitis virus and enterically transmitted NANB hepatitis outbreaks were likely due to HEV as CFRs in pregnant women in these outbreaks were disproportionately high and attack rates were higher in young adults compared to children or adults [23]. This review supports the prior study showing that outbreaks and sporadic cases by NANB reported in Africa, many of which were not considered in the previous study, also display high CFR in pregnant women and high clinical attack rate among young adults (Tables A1-A3 in the Additional file 1).

We noted several limitations with the existing literature. First, there is no diagnostic “gold standard” for HEV infection and existing studies use different assays that vary in sensitivity and specificity adversely impacting the validity and comparability of reports. Second, studies measure the prevalence of HEV infection in dissimilar subpopulations making it difficult to compare seroprevalence. For example, it is difficult to conclude whether the overall seroprevalence of HEV infection in South Africa is higher than that in Morocco when examining studies that show seroprevalence among South Africans with a mean age of 42 years is 10.7% [98] and that among younger population in Morocco is 2.2-6.8% [84, 85]. Third, studies use different criteria to define acute hepatitis. In a study of Egyptian children, acute hepatitis was defined as the acute injury to the liver, manifested by two fold or more increase in the level of aspartate aminotransferase and alanine aminotransferase [47] whereas in another study, acute hepatitis was defined as the patient whose aminotransferase level was 5 times the normal value [133]. Finally, different surveillance methods may lead to different attack rates being determined. Attack rates are exceptionally difficult to determine in un-enumerated populations, which is likely to be the case in many African nations. The limitations noted above could be corrected in future studies by developing and publishing standardized study methods including case definitions and analytical plans and by development of a generic protocol for outbreak and endemic disease investigations. For diagnosis, an enzyme-linked immunosorbent assay for HEV IgG and IgM (Beijing Wantai Biological Pharmacy Enterprise CO., LTD.) shows high sensitivity and specificity compared to other assays including molecular methods [134].

There are knowledge gaps. Serology studies suggest that many Africans are infected with HEV, but except during outbreaks, symptomatic disease is only sporadic implying that case finding is incomplete or that only a few infected cases progress to clinical disease. Pathogenesis studies are needed. While there are a growing number of published reports on the impact of HEV infection, the overall burden of hepatitis E in Africa remains unclear. For example, two studies from South Asia using verbal autopsies suggest that HEV is responsible for 10% or more of pregnancy-associated deaths [135, 136]. The same investigation should also be carried out in multiple sites in Africa. HEV transmission in nations with genotypes 1 and 2 likely occurs from the fecal-oral route. However, the authors in one study on the HEV epidemic in Uganda during 2007–9 claimed that person-to-person transmission played a significant role in the propagation of HEV [120, 137]. Because of the implications for control measures, this report implies that HEV transmission studies should be carried out. Given the high background rates of HEV infection, the effect of co-infections (e.g., HIV, Hepatitis B) on the severity of disease especially in pregnant women are needed. Potential risk factors for HEV infection such as co-infections or pregnancy need to be clarified. Studies of vertical transmission and blood donor screening should be funded.

As these results suggest that acute hepatitis E is fecal-orally transmitted in African countries, the ultimate control of this disease will require increased access to safe water and sanitation and improved personal hygiene. Until these measures are universal, an anti-HEV vaccine is needed. Hecolin™ is a safe and effective anti-HEV vaccine for healthy subjects 16 years of age and older exposed to HEV genotype 4. The vaccine is now licensed in China [14]. This vaccine shows promise for outbreak interventions and control of endemic disease but several epidemiological issues need to be addressed before the vaccine is used widely in Africa. The participants in the efficacy trial used for licensing Hecolin™ were healthy adults, and there is no safety data on persons with chronic liver disease, the immunocompromised, and among children less than 16 years old. While the vaccine has also been found safe in a small number of pregnant women (n = 37) inadvertently vaccinated during a large clinical trial [138], there is a necessity for demonstrating safety in well-powered trials of pregnant women as this population should be included in outbreak response because of the high case fatality rate. While vaccine efficacy has been established for genotype 4, there are no studies in patients with genotype 1 or 2, the prominent strains in Africa. For outbreaks, it is unknown how quickly after the first injection protection will be afforded to those at risk early in the outbreak. There are no published reports on the length of protection. Still, these issues can and should be addressed quickly as there is a potential for this vaccine is be a major component of African HEV control program.

Extensive data suggest that hepatitis E is a major contributor to disease and mortality across much of the African continent, with country-level variability, as expected. Still, it is challenging to make comparisons across these populations, given differing methodologies and assays used to determine HEV etiology. Despite its substantial impact on human health, HEV has, even in hyper-endemic South Asia, been neglected in recognition as a major public health problem since its identification. Given the emerging evidence that HEV could be vaccine preventable, we hope this review will shed light on a pathogen of significance across the African continent.