Hepatitis B virus infection as a neglected tropical disease

CITATION: O'Hara, G. A., et al. 2017. Hepatitis B virus infection as a neglected tropical disease. PLOS Neglected Tropical Diseases, 11(10): e0005842, doi:10.1371/journal.pntd.0005842.


Background
This document contains supporNng informaNon to corroborate our view that HepaNNs B Virus (HBV) can helpfully be represented within the framework set out for Neglected Tropical Diseases (NTDs) by the World Health OrganizaNon (WHO) [1]. This is in line with aims stated within United NaNons Sustainable Development Goals [2].
We here provide complementary evidence from different locaNons in Africa to illustrate the ways in which HBV infecNon meets the criteria for NTDs. These scenarios, labelled Cases 1 to 9 (C1 --C9), are presented by geography from South to North. They contribute important insights into how the NTD paradigm can be helpful in informing strategies to improve diagnosis, treatment and prevenNon of HBV infecNon, with the ulNmate goal of eliminaNng infecNon as a public health threat.
The resources provided here document real experiences of HBV from paNents, healthcare workers and laboratory staff from urban and rural se^ngs. Although some of them contain references to published data, the primary aim is to capture experience and opinion which are o_en not reflected in convenNonal academic publicaNons. This reflects the true impact of HBV infecNon, and the challenges associated with reducing the burden of cases, ranging from insights into its close relaNonship with poverty, to the sNgma and discriminaNon faced by individuals with the infecNon, through to the first-hand experience of clinicians and laboratory staff who seek --on a daily basis --to improve the standards of care they can offer to their paNents and their communiNes. Alongside the strong poliNcal and strategic arguments that can be made for HBV advocacy, these real life voices represent a unique personal angle.
The case histories are all accurate first--hand representaNons of true events, but we have changed or omiMed certain details in order to protect the anonymity of individuals concerned.

Strategies for tackling NTDs that are relevant to HBV
• ImplementaNon of a combinaNon of several public health approaches that can be delivered locally, and o_en in combinaNon with infrastructure used to tackle other diseases.

•
IntensificaNon of case management. • Improvements in sanitaNon and hygiene (applied broadly to HBV in reflecNng improvements in sterile pracNce).
Due to this paNent's presentaNon with HCC and infecNon with HBV, his family members were subsequently tested. Chronic HBV infecNon was detected in two siblings, who have since been placed on anNviral therapy and on--going HCC surveillance. His mother was HBV--exposed but had cleared the virus. This is a typical example of many young and economically--producNve/promising paNents who present with HCC in South Africa. These paNents frequently present with advanced HCC arising from undiagnosed and untreated chronic HBV infecNon. Timely diagnosis of HBV infecNon remains a rarity. Many HBV--infected paNents remain undiagnosed and at risk of developing HCC.

Relevance to WHO NTD framework
• HBV infecNon is associated with 'important morbidity and mortality' and is associated with high economic costs for individuals, families and society.

•
The morbidity and burden of disease can be diminished through improvements in prevenNon, diagnosis and treatment. She was born in another region of South Africa, and no history was available regarding any perinatal prevenNon of mother to child transmission intervenNons. However, her records indicate that she had received three doses of HBV vaccine as per WHO EPI recommendaNons. Her mother was unwell, and the child had recently been taken into the care of another relaNve.

Hepa&&s B Virus Infec&on as a Neglected Tropical
She was started on ART (Abacavir, Lamuvidine and Efavirenz) without any side effects. Her CD4+ T cell count and HIV viral load were repeated every 6 months but in spite of repeated counselling on adherence her HIV viral load persisted at >10 4 copies/ml. A year later, as a result of introducing HBV screening for all HIV--posiNve children [3], she was found to be HBsAg posiNve. HBeAg was also posiNve and her HBV DNA viral load was 36 x 10 6 IU/ml. Her liver funcNon was normal and she has no symptoms to suggest chronic liver disease. The child's mother was HBsAg negaNve.
On the basis of a high HBV viral load despite lamivudine, and failure of HIV suppression, her ART was changed to tenofovir, emtricitabine and ritonavir boosted lopinavir. Following this, her HIV viral load became suppressed below the limits of detecNon for the first Nme, CD4+ T cell count improved to 863 cells/mm 3 and BMI improved to 17.4 kg/m 2 .
This case illustrates the importance of rouNne screening for HBV, even without a family history of infecNon, and in the absence clinical evidence of liver disease. HBV viral load tesNng and a choice of appropriate therapeuNc agents can be provided from within the infrastructure currently available for HIV.

Relevance to WHO NTD framework
• HBV infecNon is silent -both clinically, where it can be asymptomaNc unNl the very late consequences of chronic infecNon, and as a result of its niche in vulnerable populaNons with liMle voice.

•
There is potenNal for HBV to be effecNvely tackled through exisNng infrastructure; in this case diagnosis and management is nested within HIV services.

C2 Case 3: Lusaka Zambia
Clinical experience from Zambia

(i) Rela(onship between HBV, poverty and morbidity
There is a huge overlap between high HIV prevalence, poor economic status, weak health systems, and HBV; the lack of resources makes it difficult to opNmise prevenNon and control measures. HIV-HBV coinfected individuals may also be at risk in other ways; for example, they are more likely to have hazardous alcohol consumpNon [4]. According to preliminary data from the Zambia PopulaNon--Based HIV Impact Assessment (ZamPHIA) study [5], prevalence of HBV infecNon is higher among HIV--posiNve than HIV--negaNve adults (7.1% vs. 5.4%, respecNvely) and children (5.2% vs. 1.3% respecNvely).

(ii) Failure of current HBV vaccina(on schedule
While HBV is integrated as part of the pentavalent vaccine in Zambia delivered at 6, 10 and 14 weeks, the coverage declines with each consecuNve dose. According to the 2013 Demographic Health Survey, coverage of the first dose was 79%, which reduced to 72% for the third dose [6].
No programme is in place to cover special populaNons at increased risk, such as health care workers and incarcerated individuals within correcNonal faciliNes.
While the prevenNon of mother to child transmission (PMTCT) of HIV is being scaled up, no systemaNc screening for HBV is in place and birth dose of the HBV vaccine is rarely provided. In contrast, screening for syphilis and HIV is hugely successful; this infrastructure could be a great opportunity to develop HBV screening and care, including vaccine doses for new--born babies.

(iii) Failure of assessment and treatment for individuals with chronic HBV infec(on
In Zambia, the NaNonal Blood donaNon system screens all blood donors. "We have raw data showing that we discard more much more blood because of HBV than HIV; and yet no linkage to care is provided for those found to be HBsAg--posiNve."

Clinical experience from Malawi
Accurate data on naNonal incidence and prevalence of hepaNNs B in Malawi are lacking, however clinicians are familiar with the clinical consequences of chronic infecNon, as illustrated by the following case.
A 22--year--old man presented to hospital in Blantyre with sudden onset vomiNng of blood. He had reduced consciousness, tachycardia and hypotension at presentaNon, though was successfully resuscitated with intravenous fluid, and blood donated by a family member.
An endoscopy revealed oesophageal varices which were banded, and a liver ultrasound indicated cirrhosis. The paNent was commenced on propranolol to reduce the risk of subsequent gastrointesNnal bleeding. Full hepaNNs serology was unavailable, but HBsAg screening was available via the transfusion laboratory and was posiNve. An HIV test was negaNve.
Whilst anN--viral drugs with acNvity against hepaNNs B were available (lamivudine and tenofovir) in fixed dose combinaNon tablets via the HIV clinic, these were not accessible for paNents with HBV monoinfecNon. The paNent resorted to purchase of lamivudine on private prescripNon, noNng that "I would have got treatment for free if I had HIV, but cannot find the drugs I need for hepaNNs B, even though it is the same medicine".
Although vaccinaNon of household contacts was recommended, staff for contact tracing and supplies of the hepaNNs B vaccine in public hospitals were lacking.

Relevance to WHO NTD framework
• Resources are constrained in comparison to those deployed for other infecNons; access to diagnosis, monitoring, treatment and prevenNon for HBV infecNon lags far behind that provided by HIV programmes. Healthcare workers and pa&ents discuss the socio-economic impact of an HBV diagnosis "Most of the paNents with HBV infecNon only come to the hospital when they are extremely sick. The reason they come late is because they do not have money to seek medical help early enough and stay at home, hoping that they will get beMer. By the Nme they present to the hospital, they are in very bad shape and most of them die in hospital. Some of them die at home."

C4 Hepa&&s B Virus Infec&on as a Neglected Tropical Disease
''A lot of paNents with HBV infecNon present with symptoms suggesNve of malaria or other commonly experienced diseases in the community. Only a_er they are treated for these condiNons, and are not ge^ng beMer, is an HBsAg test is done. The lack of proper invesNgaNons is mainly because the paNent or their relaNves lack the money to do the required invesNgaNons, or the facility is not capable of doing the necessary tests.'' "My cousin started complaining of stomach pain and therea_er started vomiNng blood. He was diagnosed with HBV and died a few weeks later. My aunt was then tested and found posiNve. She goes for her medicaNons weekly, but the cost of managing the condiNon is expensive and it is evident it has affected her lifestyle." "My husband was taking his HBV medicines, though someNmes he missed a week or so when we could not afford to buy them. More recently, we have not been able to buy medicines and his condiNon is ge^ng worse. Some health workers seem not to put that into consideraNon. Some scolded my husband for not taking his medicines and this made me feel so helpless as we have tried to sell our home produce and animals, but the burden conNnues to be heavier. I spend most of my Nme in the hospital with my husband and I have le_ my children in the care of their grandparents. I am worried that they may not have enough to eat as I am the breadwinner." "Not all health care professionals working in public hospitals have been vaccinated against hepaNNs B - the vaccine is not available in some public hospitals, so you have to go to a private hospital to get vaccinated and pay for it from your own pocket, which is very expensive.''

Relevance to WHO NTD framework
• These tesNmonies highlight the extent to which the morbidity of HBV infecNon arises as a consequence of poverty; this is significant for paNents, but also has substanNal impact for their extended families.

•
Poverty can also be a barrier to prevenNon; for example, healthcare workers are unable to afford vaccinaNon. The burden from sNgma and discriminaNon may fall disproporNonately on girls and women within the community.

Hepa&&s B Virus Infec&on as a Neglected Tropical
"For healthcare professionals, those infected with HBV are isolated by their colleagues. No--one wants to go where they have gone. This also escalates up to where they stay, because people do not want their children near them." "For paNents with hepaNNs infecNon, some of them believe that they have been bewitched and start taking tradiNonal medicines. They come to the hospital when they are jaundiced and in very bad shape.'' "In our culture what happens to one person becomes the concern of the whole family and the community. Having a Hep B diagnosis will bring shame to one's family. This can cost family members jobs and school places." "HepaNNs B is associated with HIV/AIDS, which means having a diagnosis comes with sNgma and discriminaNon. This starts a trend of finger poinNng, and slowly results in isolaNon. Although there has been a lot of work done to educate people about HIV, there has not been enough work to educate people about HepaNNs B." "Fear of disclosing the diagnosis is a big barrier to the paNent accessing treatment. There is likely to be a danger of coinfecNons that increases fear about ge^ng tested." "Mothers with HBV infecNon would be very keen to seek vaccinaNon for their babies, but those most affected lack educaNon to understand the importance of vaccinaNng a child at birth. There is liMle or even no informaNon in areas worst affected --for example, people sNll believe the myth that vaccines pose more harm than good." "Health care workers are ignorant and don't know how to handle or manage a situaNon when an individual discloses they are HepaNNs B posiNve but HIV negaNve. This confusion creates a situaNon where the health care workers are discriminaNng and sNgmaNsing HBV paNents due to lack of informaNon." In Uganda, there is one central government laboratory where HBV viral loads can now be tested. In pracNce, this facility is not yet rouNnely available and when it is, samples will have to be transported from all over the country to that laboratory. This has worked for HIV viral load tesNng, se^ng a previous precedent; we therefore have reason to be opNmisNc that it is feasible for HBV. One concern, however, is that the quality of the samples may have deteriorated by the Nme they reach the central laboratory. Currently, private tesNng faciliNes or NGOs are frequently used for viral load tesNng with costs of USD $50--60 per sample. This is unaffordable to our paNents, so the majority of those who test HBsAg--posiNve do not get further assessment, and treatment is not taken up.

Hepa&&s B Virus Infec&on as a Neglected Tropical
In Uganda, there is no algorithm for diagnosis of HBV, in contrast to the clear guidelines and policies for diagnosis and management of other condiNons such as malaria, HIV and TB. As such, HBV diagnosis and monitoring has remained a grey area, and informaNon passed onto paNents is o_en unclear. This has created fear and increased the sNgma for individuals with HBV infecNon. There is an urgent need to develop clear policies and guidelines that can be uNlised by laboratory staff and health care workers on diagnosis and treatment.
Tenofovir monotherapy is available in Kampala. This is produced by CIPLA locally under Gilead voluntary licensing, and costs $7 per month of treatment. Despite the fact that this medicine is being manufactured locally, it is not yet reliably accessible for paNents in rural areas. For these populaNons, this therapy can only be accessed through HIV care programmes, but these are lacking structure, manpower, training and guidelines with which to treat chronic HBV. A fit--looking young man with a history of upper abdominal pain going back several months presented at a medical out--paNent clinic. Amongst other invesNgaNons, an endoscopy was performed, revealing a dramaNc picture of advanced oesophageal varices. He was subsequently found to be HBV infected.

C7 Hepa&&s B Virus Infec&on as a Neglected Tropical Disease
OpNons for the treatment of advanced liver disease associated with HBV infecNon are limited in The Gambia, although the condiNon is not uncommon. This paNent was started on medical treatment with propranolol, but died a few months later.
In another case, an otherwise--healthy paNent in their 40s with hepatocellular carcinoma related to HBV infecNon presented at clinic looking pale and drawn. This is a very painful condiNon, due to stretching of the liver capsule. The only treatment to offer was regular, mild analgesia with paracetamol and codeine. However, on reassessment several weeks later, with symptoms now under control, he was a changed person, bounding into the out--paNent clinic beaming with smiles.
Occasionally a physician has the opportunity to revoluNonise a person's life. These occasions are relaNvely few, parNcularly when working in resource--poor se^ngs with a limited therapeuNc armamentarium. The care of people with terminal illness has been revoluNonised by the hospice movement over the course of the last few decades by advances in symptom management. However, new ideas are someNmes slow to be adopted. In The Gambia, doctors are o_en reluctant to offer even simple analgesia such as paracetamol because of the perceived risk of liver damage. Opiates are frequently avoided altogether, or prescibed 'as required' rather than regularly, because of concerns about addicNon or respiratory depression. Sociological factors may restrict progress in health care as significantly as economic constraints.