Zaigham Abbas, FCPS, FRCP, FACP, FACG, AGAF
HBsAg loss and seroconversion is a difficult task to achieve with the currently available nucleos(t)ide analogue (NA) drugs and treatment may be required for an indefinite duration. To determine the length of hepatitis B therapy, we need to define other optimal endpoints. HBeAg loss or seroconversion may be taken as an endpoint in HBeAg positive chronic hepatitis B (CHB) but consolidation therapy is required even after HBeAg seroconversion. To what level and how long HBV DNA suppression in HBeAg negative patients is required remains unanswered. For all patients with advanced fibrosis or cirrhosis, therapy should continue. Thus, patient selection and education are critical in decisions addressing cessation of therapy. Emerging data has made the recommendation of not treating immunotolerant patients controversial. We herewith address these issues with some detail (Figure 1).
Figure 1: Changing Paradigms in HBV Management
It is well known that elevated ALT level is associated with fibrosis in patients with HBeAg-positive CHB. Antiviral therapy leads to reversal of inflammation, regression of fibrosis, reduction of HCC mortality and improves portal hypertension and transplant-free survival. However, there are limitations of long-term suppression with current NA therapy. There are some safety issues related to long-term treatment. Only partial virologic response is seen in highly viremic HBeAg positive patients. Residual HCC risk remains during long-term NA therapy. Moreover, NA stopping rules remain unclear; there are low HBsAg loss rates and the therapy does not eradicate cccDNA or integrated HBV DNA. The long duration of treatment (life-long in some cases) is associated with high costs, potential drug resistance and adverse events. For these reasons, treating immune-tolerant patients is not recommended by the guidelines.
However, 10% of HBeAg-positive patients with normal ALT have advanced fibrosis. REVEAL study showed that higher HBV DNA levels are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC).1 The risk of HCC remains elevated in patients who do not meet HBV therapy criteria laid down in the HBV guidelines.2 HBV treatment reduces the risk of disease progression including decompensation and liver transplant.3 So, those not on treatment require careful monitoring. Newer studies foretell a potential paradigm shift for immune-tolerant patients. Some recent data suggests treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.4
In the Historical Korean Cohort Study, patients without cirrhosis seen at a tertiary referral hospital between 2000-2013 were followed up. The cohort included immune-tolerant, untreated (n = 413) and immune-active (ALT ≥ 80 IU/mL) treated (n = 1497) patients. Cumulative incidence of HCC after 10 years was 12.7% in immunotolerant patients and 6.1% in treated patients. For death or liver transplantation, figures were 9.7% and 3.4%, respectively.5 There are several arguments in favor of treating immune-tolerant chronic HBV infection:
After discussion of rationale and limitations, treatment may be initiated in individual immune-tolerant patients with evidence of fibrosis. Treatment must be regarded as indefinite in absence of new therapies unless seroconversion occurs. Diagnostic liver biopsy or estimation of fibrosis by transient elastography should be considered to assess the degree of fibrosis so that a treatment decision can be rendered. If patients with the immune-tolerant disease have F2 fibrosis or more, antiviral therapy will be suggested.
NA discontinuation in HBeAg positive CHB
Guidelines suggest that NA should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion.6 Therapy may be stopped in non-cirrhotic HBeAg positive CHB patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted. Stopping NA treatment in Caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates. In one study, of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed.7 Fewer relapses occur with a longer duration of consolidation. In one study, patients who stopped treatment in less than 12 months of consolidation, only 26% maintained HBeAg seroconversion and undetectable HBV DNA. This response rate rose to 71% among those who stopped after more than 18 months.8 Relapses are seen more in the older age group of more than 40 years. Duration of consolidation longer than 12 months especially in older patients is preferable.9 After stopping NA therapy monitor for recurrent viremia, ALT flares, seroreversion, and decompensation every 3 months for at least 12 months.9 In those with advanced fibrosis or cirrhosis, treat indefinitely unless a strong competing rationale for treatment discontinuation exists.
NA discontinuation in HBeAg negative CHB
Several studies have shown that NA discontinuation after HBsAg loss with or without seroconversion is the best possible stopping rule for NA therapy. It is safe and effective and HBsAg loss is sustained off treatment. However, HBsAg loss is unlikely to be achieved with NA alone. Can we stop NA before HBsAg loss? Recent guidelines suggest that discontinuation of NA may be considered in selected non-cirrhotic HBeAg-negative patients who have achieved long-term virological suppression (>3 years) if close post-NA monitoring and adequate safety rules for retreatment are followed.6 Calculated withdrawal of NA leads to a relapse of HBV DNA in most patients. There is evidence that this sudden exposure of viral antigens can trigger immune control in some patients which may result in HBsAg loss or a form of immune control with sustained low HBV DNA levels and normal ALT.10
DARING-B study included 57 non-cirrhotic patients with HBeAg-negative CHB who stopped entecavir or tenofovir DF therapy after a median virological remission of 5.3 years and remained under close follow-up. They were retreated with entecavir or tenofovir disoproxil fumarate (TDF) if they fulfilled predetermined criteria. The cumulative probability of retreatment was 18% and 26% at 3 and 12 months. Cumulative rates of HBsAg loss were 5%, 16% and 25% at 6, 12 and 18 months, being higher in patients with lower HBsAg levels at treatment discontinuation.11 In the FINITE study, non-cirrhotic HBeAg-negative patients who had received TDF for ≥4 years, with suppressed HBV DNA for ≥3.5 years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy.12 Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to week 144. 19% (4/21) achieved HBsAg loss at week 144.
When stopping NA, a virologic relapse is nearly universal. After the “lag phase” for weeks to months, the “reactivation phase” starts where most patients show some level of HBV DNA rebound, which is often followed by an increase in ALT levels. Severe immune flares may occur in this phase and need immediate re-treatment (ALT > 10 x ULN or ALT > 5 x ULN and bilirubin > 2 mg/dL and/or prolonged prothrombin time). In the third phase, some patients after transient flares enter a low-replicative “carrier” state. Some retain a degree of disease activity requiring retreatment (ALT > 3x ULN and HBV DNA > 100,000 IU/mL) while others can still be in an intermediate state with ALT > ULN and HBV DNA > 2000 IU/mL for ≥ 3-6 months and require treatment later on. These cut off need validation in future studies.13, 14
In conclusion, therapy can be discontinued in non-cirrhotic HBeAg-negative CHB patients who have received effective NA for more than 4 years. The probability of relapse decreases after 6 months. Despite common virological relapses, most patients, particularly those with mild to moderate pretreatment fibrosis, remain without retreatment, at least in the first 18 months, and a substantial proportion of them clear HBsAg and the majority eventually enters into an inactive carrier state. So NA withdrawal strategies appear promising, but it is premature to recommend as the standard of care. 20% achieve HBsAg loss; 60% remain off therapy. Close monitoring is needed as flares can be severe.
Identifying true inactive carrier status is essential to decide whether to start treatment or continue monitoring only. Fluctuating HBV DNA and ALT in HBeAg negative CHB patients may mimic inactive carrier status with risk of progression and HCC. Quantitative HBsAg is a marker for the amount and activity of covalently closed circular DNA inside hepatocytes. HBV DNA plus quantitative(q) HBsAg can help identify true inactive carriers. HBV DNA ≤ 2000 IU/mL and qHBsAg < 1000 IU/mL identifies inactive carriers with 94.3% diagnostic accuracy.15 Hepatitis B core-related antigen (HBcrAg) comprising HBeAg, HBcAg, and a core-related protein (p22cr) is found in virion-like particles without HBV DNA. It may reflect intrahepatic cccDNA transcriptional activity and levels.16 In HBeAg-negative patients, HBcrAg may help to distinguish between inactive carriers and those with active disease. Inactive or quiescent carriers patients of HBV genotype D usually have HBcrAg levels <3 log U/mL.17 Another marker to distinguish inactive carriers is HBV RNA that is a measurable marker of transcription of cccDNA.18
A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors.19 Bulevertide binds to sodium taurocholate co-transporting polypeptide (NTCP), the uptake cell membrane transporter that allows HBV entrance into the hepatocyte. The drug has been recently approved in Europe as a treatment for viremic patients with hepatitis delta.20 The drug is undergoing phase III studies where monotherapy or in combination with interferon are investigated in patients with hepatitis B. The advances in hepatitis B therapeutics will influence the management guidelines in future.
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