Decision making in hepatitis B: Q&A with hepatologist Prof Anna Lok
Pearl Toh finds out from Professor Anna Lok, director of clinical hepatology at the University of Michigan in Ann Arbor, Michigan, US, on integrating guidelines, research data, and clinical setting in decision making for management of hepatitis B during the recent Asian Pacific Association for the Study of the Liver Annual Meeting held in Shanghai, China.
Evidence-based medical decision making should integrate three core elements: clinical judgement, relevant scientific evidence beyond RCT, and a patient's values/preferences. Clinicians should aim for potential benefit with little or no harm to the patients when deciding on treatment.
Who should undergo HBV screening?
According to the Centers for Disease Control and Prevention (CDC) recommendations on HBV screening, the following individuals should be screened: [MMWR Recomm Rep 2008;57:1-20]
-Persons born in geographic regions with hepatitis B surface antigen (HBsAg) prevalence of ≥2 percent
-Tissue and blood donors
-Pregnant women, infants of HBsAg+ mothers
-High-risk groups, for example, men who have sex with men, injection drug users, HIV+ persons, dialysis patients, or household or sexual contacts of carriers
-Persons who will be receiving cytotoxic or immunosuppressive therapy
-Persons with elevated alanine aminotransferase (ALT)/ aspartate transaminase (AST) of unknown aetiology/evidence of chronic liver disease
There are situations when there are controversies on whether one should be screened for hepatitis B – Should patients who will be receiving immunosuppressive therapy be screened for HBV?
There is no good quality randomized controlled trial (RCT) comparing screening vs no screening for this population. There have been a few RCTs of prophylactic antiviral vs no antiviral, but they were almost exclusively done in patients with lymphomas. Also, there are scanty data on solid tumours which are more common than haematological malignancies.
While a hepatologist views HBV reactivation as common, can cause serious hepatitis flares, liver failure, and even death, that HBV reactivation can be prevented with oral antivirals, and every one has to be screened because many patients do not have readily identifiable risk factors for hepatitis B; an oncologist may disagree and may be concern about overburdening these patients since they are already getting many tests and medications.
Nonetheless, there is little harm associated with screening them, all we need is a simple blood test. If we screen and pick up someone with HBV, we can then give them prophylactic antivirals.
With regards to vaccination, is booster HBV vaccine needed for adolescents/young adults who have been vaccinated at birth or during early childhood?
A study of 126 young adults (aged 18–23 years) in Taiwan who have been vaccinated at birth but no evidence of immunity when tested (HBsAg-/hepatitis B surface antibody negative [anti-HBs-]) showed that about 25 percent of them have lost their immune memory to HBV vaccine by the time they enter college and that two doses of booster are needed to ensure >90 percent immunity (anti-HBs seroconversion), suggesting booster dose may be necessary at least for those who do not have immunity at young adult. [Hepatology 2010;51:1547-1554]
Again, there is no RCT on effectiveness of booster dose HBV vaccine in preventing HBV infection and sequalae of chronic hepatitis B in adolescents vaccinated at birth. The available data do show that anti-HBV titre decreases with time, immune memory is preserved in most people but not in every one, and that despite undetectable anti-HBs, we do see cases of transient HBV infection although there is no documented case of chronic or symptomatic infection. Therefore, the need for a booster dose 20 years after initial vaccination remains controversial.
I would suggest that there is no harm in giving booster dose to your adolescents, particularly if response after the initial vaccination is unknown. Besides, giving a booster dose to adolescents also comes with the potential benefit of giving a peace of mind for parents.
Should antiviral therapy be administered to prevent mother-to-child transmission (MTCT) of HBV?
AASLD suggests that antiviral therapy be given for HBsAg+ pregnant women with HBV DNA >200,000 IU/mL. Although the antiviral therapy was not specified, tenofovir was mentioned as the preferred antiviral in technical comments. [Hepatology 2016;63:261-283]
Although the level of quality/certainty of evidence is low, and the status of the recommendation is conditional, we should note that at the time the guidelines were developed there were few RCTs on this, with most studies using lamivudine or telbivudine and limited data on tenofovir. [Hepatology 2016;63:261-283]
A recent RCT on tenofovir in preventing MTCT of HBV in highly viraemic mothers (HBV DNA >200,000 IU/mL) aged 20–35 years with 28–30 weeks gestation showed that 6.82 percent of infants of mothers in the untreated group were HBsAg+/had HBV DNA >20 IU/mL at 28 weeks after birth compared with 0 percent in the tenofovir group by per-protocol analysis, suggesting that oral prophylactic antiviral for pregnant women can prevent MTCT. [N Engl J Med 2016;374:2324-2334]
So, what would you recommend in 2017?
With new data coming from RCT, I would suggest that pregnant women who are HBsAg+ and have HBV DNA of 15 million IU/mL should receive antiviral therapy, such as tenofovir disoproxil fumarate (TDF) from 28 weeks of gestation onwards to allow sufficient time for HBV DNA suppression to prevent MTCT of HBV by the time of delivery.
Data also suggest that TDF is most likely to be safe during breastfeeding as TDF is a prodrug and its concentration in breast milk is low.
With regards to when to stop therapy, if the aim is to protect the baby, therapy can be stopped any time after the baby is born.
Moving on to HBV treatment, when should one start treatment after being diagnosed with HBV infection?
Whether a clinician decides to treat a patient immediately, to consider between immediate treatment vs monitor first, or to monitor and defer treatment until indicated depends on the current activity and stage of the liver disease, and a patient’s predicted risks of cirrhosis, liver failure, and HCC.
The patients most desperately in need of HBV treatment are those with the most urgent cases such as fulminant hepatitis B, severe exacerbations of chronic hepaitis B, and decompensated cirrhosis. Although there are limited high quality data (only few RCTs conducted with small sample size), treatment is recommended in clinical practice due to its potential for benefit with minimal to no adverse effects in starting treatment for this group of patients.
For patients of less desperate need, the AASLD guideline recommends that: [Hepatology 2016;63:261-283]
-For HBeAg+ patients who are immune tolerant, no treatment is recommended except for those aged >40 or in the 3rd trimester of pregnancy; while those who are in the immune active should be phase treated, particularly those with HBV DNA >20,000 IU/mL, ALT >2x ULN or moderate-to-severe inflammation/fibrosis
-For HBeAg- patients, no treatment is recommended for those in the inactive subphase, particularly if their disease state has been shown to be stable during several follow-ups with low levels of liver enzymes and HBV DNA; while those who are immune active should be treated, particularly those with HBV DNA >20,000 IU/mL, elevated ALT or moderate-to-severe inflammation/fibrosis
-For patients with compensated cirrhosis, treatment is recommended regardless of ALT levels, especially if HBV DNA >2000 IU/mL; those with decompensated cirrhosis were recommended treatment regardless of ALT and HBV DNA levels.
In summary, for noncirrhotic patients we recommend treatment for those who are immune active but not those who are inactive carriers in the immune tolerant phase.
Can HBeAg+ patients in the immune tolerant phase wait?
Data have shown that the majority of patients have minimal inflammation/fibrosis, no to low risk of cirrhoosis and HCC during 10 year follow-up, possibility of spontaneous HBeAg seroconversion and durable remission, while response to both IFN and nucleos(t)ide analogue is low and not sustained.
In the REVEAL study, 187 of the 431 (43.4 percent) HBeAg+ patients had spontaneous HBeAg clearance over a mean follow-up duration of 7 years, at a rate of 6.2 percent/year. [Hepatology 2014;60:77-86]
On the other hand, a study on tenofovir vs tenofovir+emtricitabine showed that HBeAg+ patients in the immune tolerant phase showed low rate of HBeAg seroconversion, no HBsAg loss, and universal relapse when treatment was stopped. [Gastroenterology 2014;146:1240-1248]
Coming back to the question, can HBeAg+ patients in immune tolerant phase wait?
With the exception of the following cases:
-Patients of ≥40 years (persistent presence of HBeAg/high serum HBV DNA beyond age 35 or 40 have been associated with increased risk of cirrhosis and HCC)
-Family history of HCC (although there is no evidence that initiating antiviral therapy early can prevent HCC in those who are genetically predisposed)
-Advanced fibrosis based on noninvasive tests or histology