Impact of the COVID-19 pandemic on routine surveillance for adults with chronic hepatitis B virus (HBV) infection in the UK

Background To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load). Methods We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts. Results We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient. Conclusions These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic. Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.


Background
To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load).

Methods
We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts.

Results
We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient.

Conclusions
These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic.Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.Any reports and responses or comments on the article can be found at the end of the article.

Introduction
Mortality and morbidity associated with the Coronavirus Disease 2019 (COVID-19) pandemic can be directly attributed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also result from indirect impacts on other conditions.
In order to progress towards elimination targets for Hepatitis B virus (HBV) infection 1 there is an urgent need for improvement of surveillance and treatment coverage.This will necessitate enhanced screening, followed by surveillance of individuals with chronic HBV (CHB) to determine treatment eligibility.Clinical follow-up includes routine monitoring of liver enzymes (e.g., alanine transferase (ALT)), hepatitis B virus (HBV) DNA viral load (VL), elastography, ultrasound, and occasionally liver biopsy [2][3][4] .In those receiving antiviral treatment, laboratory parameters are monitored to ensure virologic suppression is achieved and maintained, and to identify complications.
Surveillance using VL and liver enzymes is recommended, typically at intervals of 3-12 months, and more frequently among males at older age, those with biochemically active hepatitis, risk factors for hepatocellular carcinoma (HCC), complications of liver disease, recent diagnosis, or changing treatment plans 5,6 .COVID-19-attributable disruptions to HBV elimination efforts have been broadly described 7,8 , but we set out to quantify the specific impact on routine HBV surveillance in secondary care services in England using individual-level patient data.

Methods
We undertook longitudinal and cross-sectional analyses using routinely-collected individual-level secondary care data collected across five NHS Trusts in England by the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC), as previously described 9,10 .HBV treatment data were available from three NHS Trusts.We investigated how ALT and VL surveillance varied between pre-COVID-19 (years 2016-2019) to COVID-19 (year 2020 and part of 2021), comparing surveillance metrics in patients on and off antiviral therapy.
We calculated cumulative probabilities of undergoing ≥1 ALT and HBV DNA VL measurement each year using the Kaplan-Meier method, comparing probabilities across years using the log-rank test.We quantified the mean number of ALT and HBV DNA measurements per 100 patients, during pre-COVID-19 and COVID-19 years, with 95% CIs calculated using the normal distribution (whereby standard error (SE) is estimated by s n with n denoting sample size and s denoting standard deviation).Official UK government COVID-19 incidence data are presented 11 .

Ethics approval
The

Amendments from Version 1
Results have been updated to reflect re-analysis on a more upto-date version of the dataset.
The manuscript has been updated to include data covering the entirety of the 2021 calendar year.Therefore, Kaplan-Meier curves (Figure 1) and visualisation of mean numbers of ALT and HBV DNA VL measurements per 100 patients (Figure 2) are updated, as has the Results section, to reflect results from re-analysis of 2016-2021 (inclusive) data.Our results and conclusions have not changed materially.We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years.We can now conclude that these reductions persisted to the end of 2021.
Any further responses from the reviewers can be found at the end of the article surveillance by the end of the calendar year, respectively.COVID-19 incidence data are displayed in Figure 2.
Frequency of testing by HBV treatment status VL and ALT measurements were more frequent in treated (Figure 3 C, D) compared to untreated (Figure 3 E, F) patients throughout the study period.In treated patients pre-COVID, mean number of ALT measurements fluctuated between and within years but remained >35 measurements per 100 patients per month (Figure 3C); hence, treated patients had ALT measured on average once every 4 months (in keeping with the routine interval for clinic visits in patients on treatment).

Discussion/conclusions
These data demonstrate the negative impact of the COVID-19 pandemic on routine clinical surveillance for patients with CHB infection in the UK.Reduction in rates of surveillance closely track SARS-CoV-2 incidence and thus periods of population lock-down.
During lockdown periods, much clinical care was switched to telemedicine 13,14 , intended to maintain contact between patients and healthcare providers, but at the detriment of laboratory monitoring.Although patients may have an option to attend phlebotomy appointments, services have been stretched, and clinicians and/or patients may have elected to defer routine blood tests.Telephone appointments are impractical for certain patients, and contact may have been lost altogether -for example, for those who do not communicate confidently in English.Furthermore, CHB patients who left the UK early in the course of the pandemic may have been unable to return due to travel restrictions, thereby foregoing routine surveillance.
The impact of the pandemic was seen across treated and untreated individuals.However, the impact on ALT measurement was greater in those on treatment during lockdowns.
We were unable to investigate how imaging-based surveillance strategies were impacted due to lack of complete elastography and ultrasound data in our current dataset.Furthermore, as complications of CHB evolve over the long-term (months to years), it is not yet possible to quantify how service disruptions may impact incidence of HCC and other adverse endpoints.Surveillance disruption may be associated with an increased risk of CHB progression and delays in starting antiviral therapy.Further prospective data are required to determine the impact on long-term outcomes.
Our data represent only five large, urban centres, in the South East of England; trends may differ across settings and additional data will be required to determine the extent to which our observations apply in other regions.HIC data collection is being expanded 10 , providing enhanced opportunities to incorporate a wider view of the UK over time.Effort and resources are required to refine telemedicine services and optimise access to laboratory surveillance 15 , re-establish face-to-face services and catch-up on monitoring and interventions.Future analyses are warranted to investigate how imaging surveillance and telemedicine service uptake have been impacted when these data become available in the NIHR HIC database.Longitudinal follow-up is warranted to ascertain how COVID-attributable disruptions will impact the incidence of HCC and other relevant endpoints, and to ensure activity is re-aligned to support progress to elimination goals.

Data availability
Individual-level electronic health record were used to conduct this investigation.Data are anonymised and collected using National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) data resources.In order to ensure patient confidentiality and data privacy, raw underlying data cannot be made publicly available, and data are made available to researchers via a controlled access repository.The NIHR HIC Viral Hepatitis data repository is hosted by Oxford University Hospitals NHS Foundation Trust under a governance framework which includes a data sharing agreement and terms on confidentiality, contractual responsibilities, intellectual property, and publication.A scientific steering committee, comprised of at least one representative from each participating NIHR HIC site, meets regularly to review data collection, feedback progress on active projects, consider updates to the database, and review all data requests.Any potential collaborations are welcomed, and data are available to researchers on request following review by the steering committee.Further details are available at https://hic.nihr.ac.uk.Queries regarding data access should be directed to orh-tr.nihrhic@nhs.net.

James Van Yperen
University of Sussex, Brighton, England, UK The authors present a study on the impact of the COVID-19 pandemic on routine surveillance for adults with a chronic hepatitis B virus infection in the UK.The authors use the Kaplan-Meier method (typically used for survival analysis) to analyse the cumulative probability of patients getting at least 1 test (either monitoring alanine transferase or virus DNA load) over the course of a year, generating estimates for 2016 up to 2021, and used a log-rank statistical test to compare these.Applying standard exploratory data analysis techniques, they provide statistics on the coverage of the two different tests, stratified by whether a patient has received treatment.The data used in the manuscript is not publicly available but can be made available by request to the steering committee (details available in the manuscript).
The manuscript is well-written, but please thoroughly check for typos.The tests are appropriate, the results well represented and clear.Here are some scientific comments that could improve the manuscript: Are surveillance levels going back to normal levels now?And if not, why do the authors think that is? 1.
How could this drop in surveillance levels be mitigated in future pandemics causing lockdowns?For example, using home tests to check the viral load? 2.
It would be interesting to see the distribution of the number of measurements per patient over the year.This could shed light on behaviour (e.g., lockdown caused a bimodal distribution with some not getting any measurements and some getting a lot).The "methods" summary is not indicative of what methods you employed for your analysis, it should include the statistical methods and tests employed.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Thank you for the manuscript.This paper focused on how the pandemic impacted routine care for CHBV patients on treatment and those not on treatment.A number of articles have been published which looked at similar issues for other patients like HIV clients and other sin routine care prior to the pandemic.I am happy about the approach used here where the dataset set used is verifiable and the number of data points is large enough.The analysis has been done rigorously enough and clearly brings out the fact that laboratory services were very much negatively impacted compared with other aspects which telemedicine provided a solution.
I am very happy and did not see any significant point to make to improve this manuscript.It is well written.The authors could propose or give some suggestions as to how this impact particularly on laboratory services could be mitigated in future similar situations.That would be helpful.And again what do you consider as further research that could offer more insight into what has been reported here?I am also wondering why the team did not look at the laboratory results where available and see if there was any trend pre-and during the pandemic?That could have implications for the care received.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Yes

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?Yes Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Virology, infectious disease epidemiology, laboratory science I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Figure 1 .
Figure 1.Kaplan-Meier plots demonstrating the cumulative proportion of adults with chronic Hepatitis B virus (HBV) infection undergoing routine laboratory surveillance.Plots show patients who have had ≥1 alanine transferase (ALT) (panels A, C, E) and ≥1 HBV DNA viral load (VL) (panels B, D, F) measurement each year for pre-COVID-19 (2016-19) and COVID-19 (2020 and part of 2021) years.For both ALT and VL, plots are stratified by treated (panels C and D, respectively) and untreated (panels E and F, respectively)patients.Dashed lines depict median time for 50% of the cohort to have the laboratory assessment undertaken.Cumulative probabilities for each year were calculated using the Kaplan-Meier method, comparing probabilities across years using the log-rank test, with 2016 serving as the reference/baseline year.

Figure 3 .
Figure 3. Mean numbers of ALT and HBV DNA VL measurements per 100 patients per month during pre-COVID-19coronavirus disease 2019 (COVID-19, 2016-19) and COVID-19 (2020 and part of 2021) periods.Data are shown overall and stratified by treatment status for both viral load (VL, panels A, C, E) and alanine transferase (ALT, panels B, D, F).Dates of UK national COVID-19 lockdowns are denoted in overall plots.95% CIs were calculated using the normal distribution (whereby standard error (SE) is estimated by s n with n denoting sample size and s denoting standard deviation).

3 .I
am not sure what Figure 2 is adding to the manuscript right now, other than a reminder on the COVID-19 cases? 4.

Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Yes Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Version 1
https://doi.org/10.21956/wellcomeopenres.19374.r54846© 2023 Obiri-Yeboah D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Dorcas Obiri-Yeboah 1 Clinical Microbiology/Public Health Unit, Cape Coast Teaching Hospital, Cape Coast, Ghana 2 Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana