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Recent scientific advances, including the development of curative therapies for HCV and the establishment of global cure initiatives for HIV, have led to international calls seeking a cure for chronic infection with HBV.1 ,2 Over 240 million people live with chronic HBV, resulting in up to 780 000 deaths annually due to hepatic fibrosis/cirrhosis and hepatocellular carcinoma (HCC).3 ,4 Persons chronically infected with HBV who do not receive treatment have a lifelong risk of developing HCC, the third most common cause of disease globally.5–7 Along with scaled-up approaches to preventing and treating chronic HBV infection, having a safe and effective cure for HBV infection promises to minimise the global burden of HBV-related morbidity and mortality and reduce the economic and other burdens of lifelong treatment. Nevertheless, as HBV cure research proceeds, it is critical to anticipate and address the associated ethical issues to best protect the rights, interests and welfare of those who participate in the research as well as those who are or will become chronically infected with HBV. In this paper, after describing briefly the rationale for work aimed at achieving HBV cure, we delineate some of the key ethical issues that are especially salient for HBV cure research: (1) risks of interventions; (2) outcome measures, monitoring and modelling; (3) selection of study population; (4) language and consent; and (5) fairness.
Seeking an HBV cure
HBV infects hepatocytes and can establish a long-lived persistent reservoir through unintegrated covalently closed circular (ccc)DNA (and to a lesser extent integrated HBV DNA) that can continually produce HBV DNA and viral proteins, particularly hepatitis B surface antigen (HBsAg).8 Following the administration of nucleos(t)ide reverse transcriptase inhibitors or interferon α, the main strategies for treating chronic HBV infection,9 ,10 HBV DNA declines to often undetectable levels and liver inflammation improves, but cccDNA and integrated DNA persist as does high levels of secreted HBsAg. Persistence of HBsAg is associated with progression to HCC, even in the absence of productive viral replication.11 In a small proportion of individuals, an effective immune response occurs following treatment, with loss of HBsAg and the emergence of antihepatitis B surface antibodies (anti-HBs).12
HBV cure can be defined as either ‘complete cure’ (elimination of all viral replicative intermediates including cccDNA or infected cells) or ‘functional cure’ (undetectable plasma HBV DNA, loss of HBsAg and the emergence of anti-HBs with persistence of cccDNA and integrated viral sequences).1 ,2 Functional HBV cure is scientifically plausible given that it occurs spontaneously in 90% of adults requiring hospitalisation for acute HBV infection and following treatment in a small proportion of chronically infected patients. Complete cure presents a greater challenge, as neither current therapies nor spontaneous resolution of infection eliminate the cccDNA or integrated HBV DNA that leads to expression of antigens, including HBsAg.
Risks of interventions
Multiple interventions to achieve an HBV cure are being considered. Among others these include: (1) antiviral agents acting at sites other than reverse transcriptase, including entry inhibitors and capsid assembly modulators; (2) cccDNA targeting agents, including gene editing; (3) short interfering (si)RNA to silence HBsAg production; and (4) immunotherapeutics and host targeting agents.1 ,2 ,13–16 Since trials obviously should be designed to minimise risks, the least toxic agents should be employed where feasible with monitoring tailored to the nature of specific interventions. While it is beyond the scope of this paper to address each type of intervention in detail, consider for example, particular concerns about modifying the immune response to HBV with interventions such as immune check point blockers, such as antibodies to programmed death-1 (eg, nivolumab or pembrolizumab). These antibodies, now licensed for the treatment of melanoma and other cancers, have a range of adverse effects and could theoretically increase liver inflammation through recruitment of HBV-specific cytotoxic T-cells to HBV-infected hepatocytes. Hence, specialised monitoring needs to be built into studies evaluating these agents. In addition, the selection of viral resistance variants will need to be closely monitored in evaluating many of these approaches.9 Such resistance should be managed or prevented with the use (in combination) of nucleos-(t)ide analogues with a high barrier to resistance. Furthermore, if interventions are combined (as is commonplace in treatment of hepatitis C and HIV where a single intervention alone may not be effective), the possibility of both patient benefits as well as adverse events need to be carefully addressed.
Finally, while most of the risk will be borne by patient-participants, the risks to others need to be considered and minimised. For instance, in studies that involve cessation of antiviral therapy and a risk of viral reactivation the risks to sexual and drug use partners need to be minimised with appropriate counselling regarding safer behaviours and the provision of effective vaccination of known contacts.
Outcome measures, monitoring and modelling
In designing trials, careful consideration needs to be directed at selecting relevant outcome measures and the appropriate time to assess them. Sound proximal virologic end points of HBV cure trials would be HBsAg seroconversion and undetectable serum DNA, which may suggest that it is safe to stop treatment with antiviral agents. Of note, the times at which to measure these end points are dependent in part on the properties of the agents being evaluated. For example, agents that directly target HBsAg expression such as siRNA can only be evaluated for efficacy after a period of time off therapy, which will depend upon the half-life of the agent. Nevertheless, since the ultimate goal of an HBV cure would arguably be to achieve a durable cure and to minimise or eliminate the long-term sequelae of chronic HBV infection, assessing durability, fibrosis and the development of HCC would be desirable. Unfortunately, the time needed to complete such trials would seriously impede progress in the field. On the other hand, using surrogate end points may lead researchers to prematurely conclude that a particular intervention is safe and effective. Consequently, while research is directed at assessing the validity of specific biomarkers to assess durable cure and the reduction of long-term complications of HBV infection, it is essential that researchers and other stakeholders be alert to the potential hazards associated with them (especially prematurely or erroneously concluding that a durable cure has been achieved). However, assessing virologic outcomes is critical in the short-term to determine whether there is sufficient evidence to proceed to late stage clinical trials.
Accordingly, at least for the current generation of HBV cure trials, it is likely to be scientifically desirable to obtain serial liver samples (eg, fine-needle aspirations or liver biopsies) to assess the effects on HBV persistence in hepatocytes, the validity of biomarkers and to demonstrate (or not) a novel mode of action in a proof-of-concept study. Obviously, such techniques are not without risks and burdens for patients and their use must be justified.
Moreover, long-term follow-up is needed to determine the durability of cure and the development of HBV-related sequelae. Even if HBV cure is achieved, those with cirrhosis are likely to require continued monitoring for HCC detection. However, efforts should be directed at minimising the burdens associated with long-term monitoring.
Finally, while clinical trials are needed to evaluate HBV cure strategies, it will not be possible with these studies to assess all of the outcomes relevant to cure (ie, potential for later toxicities, potential relapse). Thus, the overall risks and benefits, as well as costs, associated with any HBV cure strategy will be difficult to capture in short-term clinical trials. Furthermore, an effective HBV cure will probably require a combination of approaches and this will be challenging to evaluate in any single trial. The potential implications of combining several investigational interventions also need to be considered. To facilitate this work, simulation modelling approaches might be used, in conjunction with early data from clinical trials, to assess the impacts of different strategies on long-term outcomes with strategies that vary based on efficacy, early and late toxicity, relapse and cost.17 Modelling provides a framework within which the maximum amount of information may be derived from all available sources on the natural history of a disease, as well as the best and most up-to-date information concerning the efficacy and toxicity of interventions. Consequently, it is possible to assess the effectiveness/toxicity tradeoffs of individual and/or combinations of HBV cure interventions.
Selection of study population
Trials should be appropriately powered to involve the fewest number of participants necessary to answer the relevant research questions. In addition, the nature of the study population itself raises important ethical considerations primarily because there are currently available therapies that are safe and effective for the majority of patients who have access to them. Thus, it is important to consider whether the study population includes those who have not yet initiated antiviral treatment for chronic HBV infection compared with those who have; and perhaps with patient populations that are not yet considered appropriate for treatment in current guidelines with available drugs such as individuals with high HBV DNA levels but no clinical evidence of liver inflammation or liver disease (so-called ‘immune-tolerant’ patients), patients in the low replicative phase of HBV natural history or those who are co-infected with hepatitis D. While those patients who already have signs of long-term sequelae of HBV infection arguably have ‘less to lose’ with an experimental intervention, it is conceivable that certain interventions may not work as well in such people or pose greater risk to them. The ethical implications of stopping therapy in patients where there is a risk of hepatic flare also need to be considered. At any rate, it is essential that such risks be assessed on a case-by-case basis as trials are being designed and efforts taken to minimise them.
Furthermore, since current treatments are generally well tolerated, evaluating the risk-benefit relationship of new experimental potentially curative therapies is critical. In patients receiving standard oral therapy with HBV replication and HBsAg levels already suppressed, there may be little direct personal benefit from a potential HBV cure except those related to not having to take daily treatment with its associated costs. In turn, there may be risks associated with stopping such therapy or intervening in some other manner related to toxicities or otherwise, depending upon the trial design. In contrast, patients who have not started standard oral therapy have a safe and effective option, assuming it is locally available, and deciding to enrol in HBV cure research may preclude access to these benefits while also assuming the risks of an experimental HBV cure option. Nevertheless, in evaluating risks and benefits in research, it must be recognised that the primary benefits at issue are related to the potential scientific value of the research.
Given the ethical mandate that HBV cure clinical research trials be scientifically informative, in deciding which particular strategies to pursue in particular populations it could be useful to conduct a value of information analysis.18 Value of information analysis is an assessment aimed at determining whether based on the potential new information that one may acquire through a trial or trials, is a trial ‘worth’ doing, and what would be its value?
Additionally, in some settings chronic HBV may be especially prevalent among those in stigmatised groups, such as people who inject drugs, men who have sex with men and indigenous and migrant populations. Such stigma may make it difficult to identify and recruit research participants. Regardless, research with such populations is an important part of the HBV cure agenda. In order to conduct research with stigmatised populations, meaningful community engagement will be needed. Meaningful engagement includes developing relationships with community members and involving them in the entire life-cycle of the research effort from planning to implementation to reporting of results. Such a process of engagement, which is now a familiar part of research in many settings including HIV-related research and research concerning genetic conditions, can help to make sure the research is relevant to the community as well as identify locally appropriate ways of overcoming barriers related to stigma during the research process.19 ,20
Studies in adolescents and children must also be carefully considered. Here, attention will need to focus on balancing protection from risks and access to potential benefits where meaningful consent may be infeasible.
Language and consent
For early HBV cure trials, where there are certain risks to participants without the likelihood of offsetting personal benefits, it is essential that patients being recruited understand the nature of the research and give informed consent for it. Here, particular attention should focus on the language used to describe the research, especially the use of the term ‘cure’. While the term ‘cure’ is used to describe related efforts regarding HIV, cancer and in other diseases, it may mislead people to believe that there is some certainty associated with the proposed research, when realistically it may be years before it is known whether complete cures versus even functional cures occur. Such beliefs may exacerbate the possibility of research participants holding a ‘therapeutic misestimation’ or ‘preventive misconception’.21 ,22 A therapeutic misestimation is an erroneous belief that the experimental interventions will necessarily be effective resulting in cure, whereas a preventive misconception would entail a mistaken belief about the certainty of preventing the onset of long-term complications of chronic HBV infection.
In particularly risky research, consideration should be given to empirically developing recruitment and consent materials with patient input. This could include conducting in-depth interviews or focus groups to identify patients' informational needs and to determine the best means of communicating accurately information about the trial. Materials designed in this way could undergo cognitive testing prior to implementation. In addition, measures should be taken to ensure adequate comprehension of this information during the informed consent process.
The ethical principle of justice underscores the requirement to consider fairness in the search for an HBV cure. For example, fairness involves the need to work with people infected with different HBV genotypes. Different genotype are associated with regions of the world with different burdens of HBV infection and comorbidities, and there is also considerable evidence that HBV natural history, disease progression and treatment response differs markedly across HBV genotypes23 and it is likely that responses to curative therapies may also differ. Assuming that a particular HBV cure strategy is not especially risky or burdensome, while it would be valuable to cure anyone with chronic HBV infection, such an approach would be most welcome where the disease is highly prevalent and where health infrastructures are poor. Here, an HBV cure might have population-level benefits by reducing HBV prevalence. Along these lines, as the scientific understanding of feasible approaches matures, consideration should be given to the scalability of interventions where patients with different HBV genotypes seek care. For example, when considering testing of combined interventions, attention should also be given to the scalability of such approaches, especially in resource-limited settings if they are proven to be safe and effective. In addition, fairness requires developing safe and effective strategies to promptly treat children who have acquired infection through vertical transmission as these infections are associated with a long-term risk of HCC.
In addressing such issues related to fairness, it will be essential to meaningfully engage patients, their families and communities, clinicians, policy-makers and other relevant stakeholders to understand their perspectives in developing appropriate interventions and to enhance the likelihood that they ultimately would be acceptable for clinical use. Finally, while it may be premature to assess the cost and cost-effectiveness in early stage trials, efforts should be made to do so at the earliest opportunity.
The potential benefits at an individual and societal level of achieving HBV cure argue for continued multinational collaborative research efforts, which bring the necessary expertise and perspectives to this complex issue. While the current HBV cure research agenda does not seem to pose insurmountable challenges to standard approaches to ethics oversight of research, appreciating the types of ethical issues associated with this research is needed for these approaches to work as intended. Nevertheless, as HBV cure research is implemented, it would be prudent to monitor these efforts to help identify emerging issues that may raise concern. For instance, it would be valuable to capture the experiences of HBV cure research participants through surveys and in-depth interviews to help ensure that they understand the nature of the research, they are satisfied with the research procedures and they did not encounter any avoidable social harms as a result of participation.24 Gathering such data, and developing interventions to overcome problems that may be encountered, provides an additional safeguard for those who are asked to participate in this research.
Contributors JS and SRL designed and conceived this manuscript. All authors were involved in the analysis and interpretation of data. JS wrote the initial version of the manuscript. All authors provided critical revisions of the manuscript and approved of its final submission.
Funding This work was partly supported by the National Health and Medical Research Council (NHMRC) of Australia; SRL is an NHMRC Practitioner Fellow.
Competing interests JS receives fees for travel and expenses as a member of the Merck KGaA Stem Cell Research Oversight Committee and Bioethics Advisory Panel; receives fees for travel and expenses as a member of the Quintiles Ethics Advisory Panel and received fees from Novartis for his role as a consultant on bioethics issues. PR received research funding from Gilead Sciences. FZ received consulting fees from Roche, Gilead Sciences, Janssen, Arbutus, Contravir; and research grants from Roche, Gilead Sciences, Janssen, Sanofi and Assembly Bioscience. YY has received travel grants, honoraria for presentations at workshops and consultancy honoraria from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, Johnson & Johnson and ViiV Healthcare. HLAJ received grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Janssen, Medimmune, Merck, Novartis and Roche; and he is a consultant for AbbVie, Benitec, Bristol-Myers Squibb, Gilead Sciences, GSK, Janssen, Medimmune, Merck, Novartis, Roche and Arbutus. SGL is on advisory boards for Abbott, Gilead Sciences, Novartis, Merck Sharpe and Dohme, Bristol-Myers Squibb and AbbVie; he is on speakers' bureaus for Abbott, Bristol-Myers Squibb. Novartis, Roche, Gilead Sciences, AbbVie and receives educational/research funding from Abbott, Bristol-Myers Squibb, Merck Sharpe and Dohme, Gilead Sciences. SRL's institution has received funding from the National Health and Medical Research Council of Australia, National Institutes for Health, American Foundation for AIDS Research; Merck, ViiV Healthcare, Gilead Sciences and Tetralogic for investigator initiated research and Merck, ViiV Healthcare and Gilead Sciences for educational activities.
Provenance and peer review Not commissioned; externally peer reviewed.
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