Overcoming challenges to eliminate HBV infection in Hong Kong
Chronic Hepatitis B Virus (HBV) infection is a global public health challenge in the same scale as tuberculosis, HIV, or malaria.1 Globally, HBV infection causes considerable amount of liver-related morbidity and mortality. In Hong Kong, 7.8% of the population suffers from HBV infection, making it a major public health concern in Hong Kong.2 World Health Organization (WHO) has set goals of eliminating HBV infection as a public health threat by 2030. This article covers an overview of the management of HBV infection and related complications, as well as strategies to achieve the WHO goal of eliminating HBV infection by 2030 in Hong Kong.
Disease burden globally and in Hong Kong
HBV infection is one of the major public health burdens worldwide. According to WHO, in 2015, 257 million people were chronically infected with HBV and attributed to more than 1 million deaths globally.3 Viral induced hepatitis is the 7th leading cause of death globally, and has increased by 63% from 1990 to 2013.4 Despite the HBV vaccination, the prevalence of HBV infection in Hong Kong is 7.8% and comparatively higher than other regional countries like Taiwan, Japan or Korea.2 Furthermore, a higher proportion of HBV reactivation in Hong Kong adults has been observed due to high-risk immunosuppressive regimens.2
Current approaches in the management of HBV
All patients with chronic HBV infection are at an increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The risk for developing HCC depends on the host and viral factors. Therefore, the main goal of therapy is to improve survival and quality of life by preventing disease progression and HCC development. Long-term suppression of HBV replication is considered as the treatment endpoint in HBV infection. However, majority of the patients do not reach treatment endpoint during their lifetime. Management of HBV infection is thus a life-long process of continuous monitoring of HBV levels and screening for HCC. The management outline adapted from The European Association for the Study of Liver Disease (EASL) together with recommendations of The American Association for the Study of the Liver disease (AASLD) guidelines is presented in Figure 1.5,6
The importance of virological markers and liver assessment
Diagnosis of HBV infection is confirmed by the detection of HBV surface antigen (HBsAg) in the serum or plasma. Presence of HBsAg for 6 months or more is an indication for chronic HBV infection. Quantification of HBsAg in serum is optional as the disease level cannot be determined by HBsAg.5 On the other hand, HBV DNA (Deoxyribonucleic Acid) detection and quantification can be used to confirm diagnosis, to decide when to treat, treatment monitoring, and post-treatment follow up. Additional serological markers such as anti-HBs antibodies, HBeAg (hepatitis B e-antigen), anti-HBe antibodies, anti-HBc (hepatitis B core antigen) and anti-HBc antibodies are useful to classify HBV-infected patients into different phases of the disease, guide treatment decisions and characterize the response to therapy.6
Liver screening is a fundamental aspect of the management of HBV infection. Non-invasive methods are replacing liver biopsy to assess fibrosis and HCC. Liver ultrasonography is an essential tool to detect HCC at early stages, and screening every six months has reduced HBV infection-related HCC mortality by 37%.7 If surveillance is only done annually, the mortality benefits may be reduced.8 Thus, it is recommended that patients with high-risk factors for HCC development, such as men aged 40 years and older, women aged 50 years and older, individuals with a family history of HCC, or patients with cirrhosis, should undergo ultrasonographic surveillance every six months.9 Transient elastography has also been validated for liver screening among patients with chronic HBV infection. It has a shorter procedural time and can be done easily in outpatient clinics. As inflammation can interfere the results of transient elastography, it lacks accuracy during the intermediate stages of cirrhosis.
Current and future anti-viral therapies
Oral nucleos(t)ide analogue therapy is the widely used anti-HBV treatment worldwide. Currently, tenofovir alafenamide, a more liver targeted prodrug of tenofovir is being used. It has comparative rates of viral suppression with other oral nucleos(t)ide analogues and has been associated with better renal and bone safety. However, its use is limited during pregnancy and decompensated liver disease.5 Entecavir is considered a suitable alternative in decompensated liver disease.5
It is questionable whether complete sterilization of HBV could be achieved by current therapies. A new strategy called “functional cure” has been proposed as a treatment option for HBV infection, in which elimination of viral infection and prevention of viral spread occurs by controlling the virus or inducing host immune responses.1 Functional cure should also supposedly achieve sustained undetectable HBsAg and HBV DNA in serum, together with suppression of HBV replication in the liver.1 With novel agents targeting functional cure, it is likely to be attained for HBV infection in the future.
The link between HBV and metabolic risk factors for HCC
The association between metabolic risk factors and complications of HBV infection are yet to be established.10 However, obesity and diabetes mellitus (DM) already exhibit a defined relationship with liver cirrhosis and HCC induced by HBV infection. A body mass index (BMI) more than 30kg/m2 is associated with increased risk of HCC and liver related mortality in HBV patients.11 DM is also another factor that is associated with HCC and liver cirrhosis in HBV patients.12 Even without previously diagnosed diabetes, an increased plasma glucose level by 1mmol/L in the non-diabetes range increases the probability of HCC and cirrhosis in HBV.12 Furthermore, liver fat, hyperlipidemia, hypertriglyceridemia and hypertension may also play a part in inducing liver fibrosis in HBV patients.10
Screening for HCC in HBV patients
HCC was the 5th most common cancer in Hong Kong and accounted for 5.8% of all new cases of cancers in 2016.13 According to global statistics, 85% of liver cancers are due to HBV.14 The incidence rates of HCC have decreased over time in Hong Kong due to the availability and effectiveness of HBV treatment. However, the mortality rates of HCC continue to be higher, and HCC is the third leading cause of cancer deaths in Hong Kong.13 As mentioned earlier, both the AASLD and EASL guidelines recommend ultrasonography of liver for high-risk patients. Inadequate surveillance of liver among HBV-infected patients may lead to identification of HCC at later stages, where the prognosis is poor. Thus, the incidence rates of HCC in HBV-infected patients depend on the effectiveness of liver screening. Routine liver screening is dependent on whether the patient is aware of having the disease, whether the patient perceives it as an important health issue and whether the patient is willing to get the ultrasonography every six months. The main challenge Hong Kong facing now is the difficulty of having biannual monitoring of chronic HBV patients with ultrasonography in public hospitals. Therefore, patient support in terms of willingness to get the ultrasonography in the private sector is necessary to reduce HCC-related mortality.
Strategies to combat HBV in Hong Kong
The first step in eradicating HBV infection is the identification of patients with HBV and bringing them to care (linkage to care). In 2015, among the patients who had HBV infection globally, only 9% were diagnosed and only 8% received the treatment.15 Linkage to care is thus essential in achieving the WHO goal of eliminating HBV infection as a public health threat by 2030.16 WHO recommends that 90% of patients with HBV infection to be diagnosed, 80% of HBV-infected patients to be treated, 65% of HBV infection related deaths and 90% of new cases of HBV infections to be reduced by 2030.16 When considering Hong Kong, only 22% are diagnosed and 27% are under treatment - comparatively lower than other regional countries like Australia, New Zealand, Taiwan, Japan, and Korea. As the linkage to care for HBV patients in Hong Kong is minimal, they are under-diagnosed and under-treated. The main reason for this being primary care physicians are not involved in the management of HBV patients, unlike in Australia or New Zealand, where low-risk HBV-infected patients are managed by primary physicians. In Hong Kong, with 7.8% of people affected with HBV infection, we cannot rely solely on specialists to treat and monitor the total population of HBV-infected patients. Successful models of managing chronic disease by primary care physicians have been implemented in Hong Kong for diabetes and hypertension. If such chronic diseases with complications could be managed by the primary physicians, I am certain that they can manage HBV.
Achieving WHO goals for eliminating HBV in Hong Kong
At the governmental level, a committee has been appointed to address the issues related to HBV. However, relying exclusively on the government will not help to achieve the WHO targets of eliminating HBV infection by 2030 in Hong Kong. More primary care physicians should be involved in managing HBV infection as a shared care pathway to eradicate HBV infection. Shared care models in HBV infection could lead to timely referral, monitoring and surveillance of patients, thereby preventing HCC in the population at risk. This model empowers primary care physicians in the course of caring for their patients with HBV infection in an environment where the patient feels comfortable. It is a collaborative process, not merely transferring the burden of HBV patient care to primary physicians. The door is always open for primary care physicians who are interested in the shared care of HBV-infected patients. In Hong Kong, I truly believe, if we do not involve the primary care physicians in the care of HBV-infected patients, it is impossible to achieve the target set by WHO to diagnose 90% of HBV-infected patients and to treat 80% of HBV-infected patients by 2030. I am willing to travel to primary care settings, provide necessary training as well as help to resolve issues and problems pertaining to the care of HBV patients.I am confident that together we can eliminate HBV infection as a public health threat in Hong Kong by 2030.
Inhibition of hypoxia-induced macropinocytosis in future cancer therapeutic strategies
In general, the prognosis for liver cancer is poor because patients are often diagnosed with liver cancer in advanced stage, while its cancer cells can still survive in hypoxia.1,2 In a recent study conducted by Wong CL and colleagues from the Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, published in Nature Communications, it was found that hypoxia-induced macropinocytosis is a new metabolic mechanism in liver cancer cells, by which causing the engulfment of extracellular fluid and the subsequent protein digestion to support the unlimited growth of hepatocellular carcinoma (HCC).1 The breakthrough discovery indicates that inhibiting hypoxia-induced macropinocytosis could be a novel and effective therapeutic approach for HCC.1 This study could also be applied to other solid cancer types with hypoxia.1
Evaluation of renal function with TAF in liver transplant patients: A large-scale multicenter study
Prior studies on the effects of tenofovir alafenamide (TAF) in liver transplant recipients were found to be limited to small-scale only.1-2 However, a recent large-scale, multicenter study conducted by Liu JK et al. published in Clinical Gastroenterology and Hepatology compared renal outcomes among liver transplant recipients with chronic hepatitis B virus (HBV) treated with TAF, tenofovir disoproxil fumarate (TDF) or entecavir (ETV).1
Results of CHECKMATE 040 COHORT 5: Long-term efficacy, safety and biomarker analysis of nivolumab
Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B (CPB) cirrhosis have a poor prognosis and are often excluded from clinical trials.1 The overall survival (OS) of sorafenib-treated patients with CPB and aHCC is approximately 4 months.1 Based on the CheckMate 040 trial, which was an open-label, multicohort and phase 1/2 study, nivolumab received accelerated approval in the United States for sorafenib-treated patients with aHCC.1 At a median follow-up of 16.3 months, the investigator-assessed objective response rate (ORR) and median OS were 12% and 7.6 months in CPB (cohort 5) patients, respectively.1 The National Comprehensive Cancer Network (NCCN) guidelines thus recommended nivolumab as a treatment option for certain CPB and aHCC patients.1 The long-term efficacy, safety and biomarker analyses for this CPB cohort were presented, which was probably the first prospective immunotherapy trial in this population.
Potential clinical benefits of ATEZO plus BEV in HCC patients with prior LRTS: update of the IMBrave150
The global incidence of Hepatocellular carcinoma (HCC) has been rising.1 In the meantime, treatment with atezolizumab (ATEZO) plus bevacizumab (BEV) has gained approval in more than 70 countries for unresectable HCC patients who have not received prior systemic therapies.2 Evidence has shown that the combination of ATEZO and BEV significantly improved the overall survival (OS) and the progression-free survival (PFS).3 From the previous primary analysis of IMbrave150, ATEZO plus BEV successfully prolonged the survival safely in unresectable HCC.4 The recent update of IMbrave150 reported on the efficacy and safety of ATEZO plus BEV in patients with prior locoregional therapies (LRTs).
A case of patient with advanced hepatocellular carcinoma - maximizing clinical benefits through timely switching away from failing regimen
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and accounts for approximately 5.7% of all new cancer cases annually.1 In Hong Kong, HCC is the fourth and seventh most common cancer in men and women, respectively, and is the third leading cause of cancer-related death.2 In a
Direct-acting antivirals reduce the need for liver transplantation in HCV-HCC patients
Compared to patients without hepatitis C virus (HCV) infection, those with HCV are associated with a 15 to 20-fold increase in risk of developing hepatocellular carcinoma (HCC) as well as being the most common reason for liver transplantation in Europe and the United States (US).1,2 Prior to 2011, H
Non-alcoholic fatty liver disease: Prevalence and management in Hong Kong
Fatty liver encompasses broad spectrum of conditions that lead to accumulation of fat in the liver. In Asia, the prevalence of non-alcoholic fatty liver disease (NAFLD) and its subsets are increasing due to altered dietary habits and lifestyle factors.1
Tenofovir alafenamide (TAF) and updates on the management of HBV
Chronic hepatitis B (CHB) is effectively managed with nucleos(t)ide analogues (NAs), yet the treatment is given over an indefinite period of time as functional cure is still difficult to achieve.1 Since the aging demographic continues to grow
Efficacy and safety profile of tenofovir alafenamide (TAF) for the treatment of CHB: An inspection of data from global and Chinese subset
Nucleos(t)ide analogues (NAs) have been proven to be highly effective in suppressing the replication machinery of hepatitis B virus (HBV).1 While the first-line NAs effectively suppress the progression of chronic hepatitis B (CHB) infection,