2 Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
Further research should be undertaken to evaluate the clinical and cost effectiveness of hepatitis B surface antigen (HBsAg) quantitative assays in determining treatment duration in hepatitis B e antigen- (HBeAg) negative disease.
In HBeAg-positive disease, HBeAg seroconversion is a predictor of durable response to antiviral treatment and can be used as a milestone after which treatment can be stopped. At present, similar parameters have not been defined in HBeAg-negative disease. Quantitative HBsAg may have a role in determining treatment duration in this setting. Establishing threshold levels for HBsAg titre associated with durable off-treatment control in HBeAg-negative disease would transform current treatment strategies. People on long-term nucleoside or nucleotide analogues could safely stop treatment once they achieved a threshold level of HBsAg. Further research is needed to define these levels of HBsAg and to determine when treatment in HBeAg-negative disease can be safely stopped.
Further research should be undertaken to examine whether the upper limit of normal ALT values for adults (below 30 IU/L for males and below 19 IU/L for females) are appropriate for use in children and young people with chronic hepatitis B when making decisions on when to initiate treatment.
Recent studies have highlighted the imprecision of using biochemical activity as a measure of immune activity in children and young people with chronic hepatitis B. Researchers have found T-cell exhaustion and even HBV-specific immune responses in children and young people considered to have immune-tolerant disease. These findings need to be validated in larger studies to see if upper limit of normal ALT values derived from adults accurately reflect disease activity in children and young people. Further research is needed to investigate whether there is a genuine state of immune tolerance in children and young people reflected in lower levels of biochemical activity and a lower upper limit of normal ALT value.
Further research should be undertaken to determine the long-term safety of tenofovir disoproxil, including the risk of clinically significant hypophosphataemia and related bone toxicity, in people with chronic hepatitis B. The cost effectiveness of routine monitoring for phosphate loss and bone disease in people with chronic hepatitis B who are receiving tenofovir disoproxil treatment needs further evaluation.
Tenofovir disoproxil is recommended as an option for treatment of people with chronic hepatitis B, and is typically prescribed for long-term use. Kidney dysfunction has been reported in people treated with tenofovir disoproxil, including rare cases of proximal renal tubular dysfunction that appear related to long-term exposure but are not well understood. Adverse renal effects such as hypophosphataemia may have an impact on bone architecture which could result in clinical problems such as fragility fractures. Monitoring for phosphate loss and bone disease could have a role in preventing clinically significant bone problems in people with chronic hepatitis B receiving long-term tenofovir disoproxil. However, the cost effectiveness and clinical utility of routine monitoring needs to be established before recommendations can be made about its use.
Further research should be undertaken to determine whether long-term use of mild immunosuppressive agents for autoimmune and allergic problems presents a risk for reactivation of HBV infection in people with previous or current chronic hepatitis B, including occult HBV infection. The cost effectiveness of routine tests for HBV in this population, including HBV DNA for occult HBV infection, and the need for prophylactic treatment with nucleoside or nucleotide analogues needs further evaluation.
Reactivation of HBV may occur spontaneously or arise during immunosuppression. Solid organ transplantation, chemotherapy and immunosuppressive drugs used to treat autoimmune diseases are key causes of HBV reactivation. Antiviral agents can be used as prophylaxis to prevent reactivation of HBV infection in people receiving immunosuppressive therapy but the optimal treatment and duration of therapy are unknown. Decision-making and cost-effectiveness studies are needed to determine optimal screening strategies to identify people at risk of HBV reactivation. People with occult HBV (including people coming from high endemicity regions) might carry a low, but not negligible, risk of viral reactivation. Prospective studies are needed to assess the risk of HBV reactivation in people receiving mild immunosuppressants or biological treatment for autoimmune diseases, to identify risk factors that predict HBV reactivation in this population, and evaluate treatment or pre-emptive strategies using existing nucleoside and nucleotide analogues.