Hepatitis D virus in Africa: several unmet needs
Authors: Michael P Manns
Journal: The Lancet Global Health (2017)

Chronic hepatitis B virus infection is a global disease. More than 240 million people are chronic carriers of hepatitis B virus, which contributes to substantial morbidity and mortality, including liver cirrhosis, liver cancer, and death.1Hughes SA Wedemeyer H Harrison PM Hepatitis delta virus.Lancet. 2011; 378: 73-85Summary Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 2Wedemeyer H Manns MP Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead.Nat Rev Gastroenterol Hepatol. 2010; 7: 31-40Crossref PubMed Scopus (287) Google Scholar The diagnostic hallmark of hepatitis B virus carriers is detectable HBsAg in serum. When patients with chronic hepatitis B virus infection are superinfected with hepatitis D virus (also known as hepatitis delta virus), their disease runs a more progressive course. Hepatitis D virus is a RNA viroid that can only infect people in the presence of hepatitis B virus, which provides HBsAg, the hepatitis B envelope protein, to the virus. Therefore, the hepatitis B virus vaccine protects against de-novo infection with both viruses but does not protect chronic hepatitis B virus carriers against superinfection with hepatitis D virus. 2–8% of chronic hepatitis B virus carriers worldwide are estimated to be co-infected with hepatitis D virus, corresponding to 10–20 million patients. There are eight known hepatitis D virus genotypes, which differ in geographical distribution and presumably in natural course and disease severity. Genotype 1 is predominantly found in Europe, genotypes 2 and 4 in Asia, genotype 3 in South America, and genotypes 5–8 in Africa.1Hughes SA Wedemeyer H Harrison PM Hepatitis delta virus.Lancet. 2011; 378: 73-85Summary Full Text Full Text PDF PubMed Scopus (375) Google Scholar Particularly severe forms of hepatitis D virus infection were reported in the Amazon Basin, where the combination of hepatitis D virus genotype 3 with hepatitis B virus genotype F is prevalent.3Casey JL Niro GA Engle RE et al.Hepatitis B virus (HBV) hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon Basin: the roles of HDV genotype III and HBV genotype F.J Infect Dis. 1996; 174: 920-926Crossref PubMed Scopus (162) Google Scholar The natural course of hepatitis D virus infection and disease phenotype depend on host, virus, and environmental factors. In over 90% of people, chronic hepatitis B virus infection can be controlled long term with oral nucleoside analogues, which inhibit the viral polymerase. However, they do not affect chronic hepatitis D virus infection. Specific therapies for hepatitis D virus infection are not yet available; standard of care for chronic infection is 48 weeks of pegylated interferon alfa, which is associated with clearance of hepatitis D virus RNA in around 25% of patients (with the caveat that long-term relapses are likely to occur).4Wedemeyer H Yurdaydin C Dalekos GN et al.Peginterferon plus adefovir versus either drug alone for hepatitis delta.N Engl J Med. 2011; 364: 322-331Crossref PubMed Scopus (344) Google Scholar, 5Heidrich B Yurdaydin C Kabacam G et al.Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta.Hepatology. 2014; 60: 87-97Crossref PubMed Scopus (187) Google Scholar Various therapeutic targets in hepatitis D virus infection, including prenylation, viral entry, and HBsAg secretion, are under investigation,6Rizzetto M Investigational drugs in development for hepatitis D.Expert Opin Investig Drugs. 2017; 26: 999-1005Crossref PubMed Scopus (7) Google Scholar but these drugs all are in early clinical development. Regulatory authorities such as the European Medicines Agency classify hepatitis D virus infection as an orphan disease and have given orphan drug status to novel therapies. Understanding of the global epidemiology of hepatitis D virus infection is still poor, with many knowledge gaps. The virus was first discovered in Italy by Mario Rizzetto, and was described in 1977 as the third of the five major hepatotropic viruses.7Rizzetto M Canese MG Arico S et al.Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis-B virus in liver and in serum of HbSAg Carriers.Gut. 1977; 18: 997-1003Crossref PubMed Scopus (688) Google Scholar A substantial proportion of the population with hepatitis B virus infection resides in Africa. However, data for hepatitis D virus epidemiology are scarce for sub-Saharan Africa, where the prevalence of HBsAg exceeds 8%.8Schweitzer A Horn J Mikolajczyk RT Krause G Ott JJ Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.Lancet. 2015; 386: 1546-1555Summary Full Text Full Text PDF PubMed Scopus (1811) Google Scholar Hepatitis D virus might represent an important additive cause of chronic liver disease in this region. In The Lancet Global Health, Alexander Stockdale and colleagues9Stockdale AJ Chaponda M Beloukas A et al.Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e992-e1003Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar did a systematic review and meta-analysis to assess anti-hepatitis D virus seroprevalence in HBsAg-positive patients in sub-Saharan Africa. This publication contributes substantially to knowledge about localised clustering of hepatitis D virus endemicity across sub-Saharan Africa, with high prevalence particularly in central Africa, but also in west Africa. By contrast, prevalence was very low in east and southern Africa. These data strongly support the hypothesis that hepatitis D virus infection significantly contributes to morbidity and mortality of chronic hepatitis B virus in central and western Africa. Another finding of this study is that, apart from anti-hepatitis D virus antibody testing by commercially available ELISAs, diagnostics (eg, determination of viral replication, genotyping by PCR) are limited or not widely available in most of these regions. In the 30 studies retrieved, HCV RNA testing was reported for only 16 anti-HDV positive populations, a total of 324 patients. This Article also includes new data from two HIV-positive cohorts in Ghana and Malawi, and draws attention to the importance of hepatitis B virus, hepatitis D virus, and HIV co-infection as a life-threatening combination. Further studies of the prevalence, natural history, health burden, and mode of transmission of hepatitis D virus infection in Africa are urgently needed. Screening every patient infected with hepatitis B virus in sub-Saharan Africa is essential. Additionally, access not only to anti-hepatitis D virus antibody testing but also to RNA and genotype testing needs to become available throughout the region. Data for the natural history of hepatitis D virus are absent for sub-Saharan populations (and thus for genotypes 5–8). The Hepatitis Delta International Network published their registry data for 1576 patients from many centres in Europe, Asia, North America, and South America this year.10Wranke A Hardtke S Borzacov LMP et al.Diversity of clinical presentation and virological characteristics of hepatitis delta in different regions world-wide: results of the Hepatitis Delta International Network.J Hepatol. 2017; 66: S257-S258Summary Full Text PDF Google Scholar No data from African centres were included, and only 13 of the included patients were born in Africa. Screening of African populations with hepatitis B virus for anti-hepatitis D virus seroprevalence should become obligatory, and RNA and genotype testing for hepatitis D virus should be provided once treatments become available. Governments and non-governmental organisations including WHO should be encouraged to provide evidence that hepatitis D virus infection is a major threat to the populations of sub-Saharan Africa. Stockdale and colleagues' Article not only fills a major gap in knowledge about the epidemiology of hepatitis D virus infection in sub-Saharan Africa, it also highlights the need to include African populations in future trials of drugs for hepatitis D virus infection, which seems to be a topic of interest in the pharmaceutical industry at present, given that hepatitis B virus infection can be controlled and hepatitis C virus infection can be cured. The pharmaceutical industry should be encouraged to include African centres at a very early stage in their clinical development programmes for novel hepatitis D virus therapies, rather than waiting until the drugs have been developed and approved elsewhere. Finally, promotion and support of vaccination against hepatitis B virus infection are more important than ever, given the continued absence of vaccines against hepatitis D virus infection to protect chronic hepatitis B virus carriers against superinfection. I thank Svenja Hardtke for editorial assistance. I report having received grants and fees for data analysis from Eiger and Roche; grants, personal fees, and fees for lectures, travel support, and data analysis from Gilead; and fees for consulting from Novartis, during the conduct of the study. Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysisFindings suggest localised clusters of hepatitis D virus endemicity across sub-Saharan Africa. Epidemiological data are needed from southern and east Africa, and from patients with established liver disease. Further studies should aim to define the reliability of hepatitis D virus testing methods, identify risk factors for transmission, and characterise the natural history of the infection in the region. Full-Text PDF Open Access