How to improve access to therapy in hepatitis B patients

Despite the availability of a preventive vaccine and active antiviral treatments that stop disease progression and reduce the risk of hepatocellular carcinoma, hepatitis B is still a major public health problem. Only an estimated 10% of the 257 million people living with HBV have been diagnosed and as few as 1% are being adequately treated. Barriers to diagnosis and treatment include: (i) limited awareness and lack of knowledge about HBV infection and HBV‐related diseases; (ii) under‐diagnosis with insufficient screening and referral to care; (iii) limited treatment due to drug availability, costs, reimbursement policies and the need for long‐term or life‐long therapy. These barriers and the actions needed to improve access to treatment are strongly influenced by the prevalence of infection and affect middle‐high vs low‐middle income countries differently, where most HBV carriers are found. In high‐prevalence regions and low‐to middle‐income countries, the main challenges are availability and cost while in low‐prevalence regions and middle‐to high‐income countries low screening rates, public awareness, social stigma and discrimination play an important role. Overcoming these challenges on a global scale is a complex clinical and public health challenge and multilateral commitment from pharmaceutical companies, governments, funders and the research community is lacking. The new WHO 2016 Global Health Sector Strategy on viral hepatitis targets testing and treatment, suggesting that important but strong actions are needed from advocacy groups, scientific societies and funding agencies to foster awareness and access to cure.


| THE GLOBAL BURDEN OF HBV INFECTION AND THE HBV CASCADE
More than 50 years after the discovery of the Australia antigen linked year 4 ) is now twice that of malaria (429 000 deaths/year 5 ) and HBV (hepatitis B, HBV-related cirrhosis and HBV-related liver cancer) represents the seventh highest cause of mortality worldwide. 6 HBV is responsible for >50% of the hepatocellular carcinomas (HCCs) worldwide 7,8 and up to 10% liver transplants. 8 The major burden of morbidity and mortality from HBV is found in low/middle income countries in tropical and subtropical countries. 9 Including chronic HBV among neglected tropical diseases (NTDs), according to WHO definitions, was recently suggested to strengthen a unified global approach for the elimination of HBV using the NTD management paradigm. 10 The prevalence of HBV varies greatly in the different geographical regions with the highest prevalence in sub-Saharian Africa (>8%), the western Pacific (>5% overall and >8% in China, South Korea, Philippines, and Vietnam), the Balkans, the Pacific Islands and the Amazon basin of South America. [11][12][13][14][15][16] The prevalence of chronic HBV infection is low in most European countries (France, Hungary, Italy, The Netherlands, Portugal, Spain, and the UK) (0.5%-0.7%) but this increases to 1%-5% in Turkey, Romania and Serbia and to >5% in Albania and Moldavia, with a clear Eastern to Western gradient. 15,16 In the United States, the prevalence of HBV infection is approximately 0.3% but this varies widely depending on geographic origin and ethnicity with Asian-Americans and African-Americans having the highest prevalence (up to 15%) while Latinos having a prevalence similar to the general US population. [17][18][19] Overall, approximately three-quarters of individuals with chronic HBV are found in the Asia-Pacific region. There are between with up to 70%-95% of the new cases of chronic HBV infection attributed to immigration from regions with moderate to high HBV endemicity. 16,19 It is important to note that the overall prevalence of chronic HBV infection may be greater than the results of sero-epidemiological studies. Not only is overt (HBsAg positive) HBV infection underdiagnosed 2 but so-called "occult HBV infection" (defined as persistence of free and/or integrated forms of HBV-DNA in the liver in the absence of HBsAg in serum 20 ) which is associated with an increased risk of the development of HCC, 21 The absence of robust data on the number of diagnosed HBV patients who have been referred for care, begun and continued treatment and with suppressed viremia, make it difficult to estimate the proportion of patients with chronic hepatitis B (CHB) who are adequately treated worldwide, but the figure could be <1% (Figure 1). It is important to note that without treatment, as many as 25% of patients with chronic HBV infection are at risk of developing cirrhosis, decompensated cirrhosis, liver failure and hepatocarcinoma during their lifetime. 24

| CONTROLLING HBV INFECTION
After decades of relative neglect, the global elimination of HBV infection has recently become a priority in international health agendas, due to a general consensus among doctors, researchers, health agencies and governments that availabe antiviral therapies and vaccines should be sufficient to eliminate HBV if they are adequately implemented. In 2016, the World Health Organization assembly ap- Universal infant HBV vaccination has been shown to reduce not only the incidence of HBV infections but also the incidence of HCC. 27,28 Other preventive measures (ie blood safety, health-care injection safety, harm reduction for PWID) further reduce the transmission of HBV. 2 However, even if the coverage and efficacy of vaccination could be immediately increased to 100%, the need to care for patients with acquired HBV infection and its consequences would remain. The Global Burden of Disease (GBD) project estimates that cirrhosis and HCC account for most viral hepatitis morbidity and

Key points
• Viral hepatitis and its consequences (HBV-related cirrhosis and HBV-related liver cancer) remain a global health burden.
• HBV is under-diagnosed and only 1% of HBV carriers are adequately treated.
• Cost of diagnosis and treatment are the main challenges in high-prevalence regions and low-to middle-income countries.
• In low-prevalence regions and middle-to high-income countries, low screening rates, public awareness, social stigma and discrimination play an important role.

| BARRIERS TO HBV TREATMENT
The main factors that limit the access to treatment of chronic HBV include:

limited awareness and lack of knowledge about HBV infection
and HBV-related disease,

under-diagnosis with inadequate screening and referral to care
3. limited treatment due to drug availability, costs, reimbursement policies and long-term or life-long therapy

social stigma and discrimination
The impact of these different barriers and the actions needed to improve access to treatment differ in low-middle and middle-high income countries and are strogly influenced by the prevalence of infection and comorbidities. In high-prevalence regions and low-to middle-income countries the main challenges are availability and cost, while in lowprevalence regions and middle-to high-income countries low screening rates, public awareness, social stigma and discrimination play an important role. Globally, knowledge and education is poor among patients, the public, and healthcare workers and the global burden of infection is underestimated. HBV infection and HBV-host interactions are complex resulting in a complicated and wide spectrum of HBV-related diseases. 13,16,17 Moreover, the higher disease burden is in low/middle-income countries, where investment is not a priority and poverty contributes to lack of patient and public involvement. The quality of available regional/ country based data on epidemiology and risk factors is often poor.

| Lack of knowledge and awareness
Infrastructures to collect robust data and provide education, prevention, diagnosis, and treatment are lacking. Evaluations on the feasibility of proposed interventions are often overlooked. The impact of stigma is underestimated. Finally, the extremely limited number of major funding agencies dedicated to HBV has also played a role and this disease has remained out of the scope of agencies such as the Melissa and Bill Gates Foundation and the Global Fund. Several simple actions can be taken to overcome this lack of knowledge and awareness (Table 1).

| Under-diagnosis with limited screening and referral to care
Screening of HBV infection is the cornerstone to identify patients requiring treatment to prevent and/or delay progression of HBV-related liver disease and further transmission. 29 technology that avoids fluorescence reagents 37 and a Nanoplasmonic Electrical field-enhanced Resonating Device (NE2RD). 38 All these assays must be validated for broader dynamic ranges and in different HBV genotypes.
Besides serological testing, assessment of the stage of liver disease must be determined. Liver biopsy is considered to be the gold standard to determine the degree of fibrosis using systems such as the METAVIR or Ishak scores. Liver biopsy is invasive and costly, inconvenient and associated with a small, yet measurable, risk of complications such as significant bleeding (1.1%-1.6%) and sampling errors. 39  Measures that can be implemented or supported to improve HBV screening and patient referral to care are listed in Table 1. This is a significant end-point making it possible to stop therapy.

| Limited access to treatment
In these cases, it is associated with clinical benefit; (iii) the cost and availability of treatment especially in low-middle income countries, and the different reimbursement policies in middle-high income countries (Table 1). In a regional study of patients diagnosed with chronic HBV infection in Italy, 84% of treatment-eligible patients did not undergo therapy. 45 Available treatment options for CHB include pegylated interferon alpha2a (PegIFN) and nucleos(t)ide analogues (NAs). PEG-IFN is a finite treatment that leads to HBsAg loss more often than NAs but is associated with side effects and the need for subcutaneous injec- Europe and the USA, and will remain on patent for another 10 years.

Patients with chronic HBV infection
Specific national programs must be developed to take into account country-specific healthcare policies. The availability of finite treatment will be important to enlarge access to treatment in middle-high income countries, as long as these options are not too expensive.
In low-middle income countries, the cost and availability of existing drugs, as well as the lack of infrastructures and limited medical personnel represent the major barriers to treatment. The feasibility of screen-and-treat programs were assessed in Gambia with an acceptability rate of 60%-80%, a link to care of 40%-80% 47

| Funding limitations and need for the allocation of resources
HBV has attracted far fewer resources for clinical management and research than other chronic infectious diseases such as HIV, HCV or malaria. 10 A recent report in the UK shows that HBV receives 0.7% of total expenditures compared to 3.0% for HCV, 13.9% for malaria and 17.5% for HIV. 49 As mentioned, mortality from HBV is now higher than that of malaria while the latter receives nearly five times more funding.
Hepatitis delta virus (HDV) which co-infects 20 million HBV carriers and results in more aggressive liver disease, receives nearly no resources.

| CONCLUSIONS
To meet the current challenges in patients with HBV, access to diag- Strong actions from advocacy groups, scientific societies and funding agencies should foster awareness and access to cure. Global initiatives by scientists for an HBV cure, such as the ICE-HBV group 50 will play an important role.