The Effects of the COVID-19 Pandemic on Clinical and Laboratory Follow-up of Patients Diagnosed With Chronic Hepatitis B: A Multicenter, Prospective, Observational Study

authors:

avatar Fethiye Akgul ORCID 1 , * , avatar Yusuf Arslan 1 , avatar Mehmet Celik 2 , avatar Omer Karasahin ORCID 3 , avatar Mustafa Kemal Celen 4

Department of Infectious Diseases and Clinical Microbiology, Batman Training and Research Hospital, Batman, Turkey
Department of Infectious Diseases and Clinical Microbiology, Harran University Hospital, Sanlıurfa, Turkey
Department of Infectious Diseases and Clinical Microbiology Erzurum Regional Training and Research Hospital, Erzurum, Turkey
Department of Infectious Diseases and Clinical Microbiology, Dicle University Hospital Department of Infectious Diseases, Diyarbakir, Turkey

how to cite: Akgul F, Arslan Y, Celik M, Karasahin O, Celen M K. The Effects of the COVID-19 Pandemic on Clinical and Laboratory Follow-up of Patients Diagnosed With Chronic Hepatitis B: A Multicenter, Prospective, Observational Study. Hepat Mon. 2022;22(1):e132174. https://doi.org/10.5812/hepatmon-132174.

Abstract

Background:

Chronic hepatitis B (CHB) patients who are under the treatment of antiviral agents should be monitored in routine control visits. However, during the COVID-19 pandemic, the visits were interrupted.

Objectives:

This study aimed to investigate whether these patients were affected regarding clinical, laboratory, and treatment outcomes.

Methods:

This prospective study consisted of CHB patients aged > 18 who were applied to 3 tertiary centers between 14 February and 30 March 2022. The patients were selected from the ones who regularly applied to outpatient clinics and under the treatment of antiviral agents before the pandemic. The demographic and laboratory values, including serologic, biochemistry, and molecular results, were compared between the 2 groups who came and did not come to control visits.

Results:

A total number of 220 patients were included. More than half (n = 142, 64.5%) were female. The median age was 44 years (19 - 73). A hundred and forty-two (64.5%) patients did not come to control visits during the pandemic. The most common reason was anxiety about COVID-19. The tenofovir treatment was replaced with entecavir (ETV) due to osteopenia and with alafenamide due to osteopenia and/or renal failure. The previous agents were re-started in 27 (79.5%) patients who discontinued the treatment.

Conclusions:

The COVID-19 pandemic negatively impacted the follow-up of CHB patients. In this regard, 15.5% of patients stopped their treatments. The patients who stopped their follow-ups and continued tenofovir disoproxil fumarate (TDF) had proteinuria and decreases in bone mineral density (BMD) and estimated glomerular filtration rate (eGFR) levels.

1. Background

Hepatitis B virus (HBV) infection is a significant life-threatening public health problem, affecting approximately 300 million people worldwide (1). The prevalence of HBV infection varies between 0.1% and 20% in different geographic regions of the world (2). Epidemiological studies in Turkey have shown hepatitis B surface antigen (HbsAg) positivity in approximately 4% of the population (3, 4).

COVID-19 has caused illness and death in millions of people worldwide. During the COVID-19 pandemic, the societal restrictions implemented to stop the spread of infection and decrease patient traffic in hospitals hampered access to health care services for individuals with chronic diseases. Patients diagnosed with chronic hepatitis B (CHB) constitute a significant proportion of these patient groups (5).

With the declaration of COVID-19 as a global pandemic, various precautions were taken in hospitals in Turkey as throughout the world. The follow-up and treatment of non-emergency diseases were largely postponed, and many health care personnel were transferred to units where COVID-19 patients were followed up. The Ministry of Health of the Turkish Republic gave permission for patients who were prescribed drugs for a chronic disease to obtain the drugs from pharmacies by extending report dates without a prescription (6). Therefore, patients being treated and followed up for CHB could not regularly attend the Infectious Diseases Polyclinic. From March 2020 (when the pandemic declaration was made) to February 2022, routine blood and imaging tests could not be made for some CHB patients. It was observed that some patients did not take their drugs regularly or even stopped treatment during this period. Obtaining drugs without a prescription was recently terminated (7).

2. Objectives

This study aimed to provide real-life data showing the effect of the COVID-19 pandemic in terms of the follow-up, treatment, and laboratory test results of patients diagnosed with CHB who could not attend the polyclinic for a long time.

3. Methods

3.1. Study Design and Participants

This prospective, observational study included patients aged > 18 years who presented at 3 centers between 14 February 2022 and 30 March 2022. The subjects had been diagnosed with CHB, receiving antiviral treatment for at least 1 year, and attending regular follow-up appointments before the pandemic.

Written informed consent was obtained from all the study participants.

The patients included in the study were categorized into 3 groups according to their presentation status during the pandemic. Group 1 included patients who had checkups regularly and received treatment during the pandemic. Group 2 included patients who did not have checkups during the pandemic and interrupted or stopped taking the drugs. Group 3 included patients who did not have checkups during the pandemic but continued to take their drugs regularly. The patients in groups 2 and 3 were evaluated after social restrictions due to the COVID-19 pandemic at outpatient clinics.

Patients were excluded from the study if they had not taken their drugs regularly or had polyclinic checkups regularly before the pandemic, had a diagnosis of cirrhosis, were taking HBV prophylaxis because of immunosuppression, had started treatment less than 1 year before the pandemic, or were pregnant.

Patients who had checkups and those who did not were compared regarding demographic data and pre and post-pandemic serological and biochemical parameters, including hepatitis B surface antigen (HbsAg), hepatitis b surface antibody (AntiHbs), hepatitis b e antigen (HbeAg), hepatitis b e antibody (AntiHbe), ‎aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, α-fetoprotein (AFP), calcium, phosphorus, creatinine, glomeruli filtration rate (GFR), cell count parameters, international normalized ratio (INR) and hepatitis B virus (HBV) DNA results.

3.2. Statistical Analysis

Data were analyzed using SPSS version 25.0 (IBM SPSS Inc., Chicago, IL, USA). Descriptive statistics were stated as mean ± SD or median (minimum-maximum) values for continuous variables and as number (n) and percentage (%) for categorical variables. In comparing the groups according to the status of having checkups and continuing drug use, a chi-square test was used for categorical data, and non-parametric Kruskal-Wallis and Mann-Whitney U tests were used for continuous data, as parametric test conditions were not met. To compare the repeated measurements of markers used during checkups before and after the pandemic, Wilcoxon signed-rank and McNemar tests were used for dependent groups. P values less than 0.05 were considered statistically significant.

3.3. Ethical Approval

The necessary permission for the study was obtained from the Clinical Research Ethics Committee of Batman Training and Research Hospital (decision No.: 296, dated: 12/01/2022).

4. Results

A total of 220 patients diagnosed with CHB at Batman Training and Research Hospital, Harran University Medical Faculty Hospital, and Dicle University Medical Faculty Hospital were studied in this research. The subjects consisted of 142 (64.5%) males and 78 (35.5%) females, with a mean age of 44 years (range, 19 - 73 years). Of the patients with CHB known to have been present for a mean of 13 years, 167 (75.9%) had a family history of CHB, and 53 (24%) had a family history of cirrhosis of the liver. The treatments before the pandemic were tenofovir disoproxil fumarate (TDF) in 103 (46.8%) patients, tenofovir alafenamide fumarate (TAF) in 40 patients (18.2%), entecavir (ETV) in 75 (34.1%) patients, and lamivudine in 2 (0.9%) patients. It was learned that 22 (10%) patients were being followed up because of comorbidities.

4.1. Basic Characteristics of the CHB Patients Not Having Checkups During the Pandemic

Of the 220 patients who had received treatment and regularly had checkups before the pandemic, 142 (64.5%) did not go to any follow-up visits during the pandemic. The basic characteristics are shown in Table 1 according to the status of having checkups during the pandemic. No significant difference was determined between patients having or not having checkups during the pandemic regarding the basic characteristics. None of the patients who had checkups had any problems regarding their drugs, and 24 (16.9%) of those who did not have checkups experienced problems regarding their drugs.

Table 1.

The Basic Characteristics of Patients According to the Status of Having Checkups During the Pandemic a

VariablesHad Checkups (n = 78)Did Not Have Checkups (n = 142)P Value b
Age (y) 44.5 (19 - 71)44 (19 - 73)0.838
Gender0.847
Male 51 (65.4)91 (64.1)
Female 27 (34.6)51 (35.9)
Education level0.376
No formal education13 (16.7)27 (19.0)
Primary school25 (32.1)56 (39.4)
High school or university40 (51.3)59 (41.5)
Place of residence 0.605
Village 9 (11.5)22 (15.5)
Town 12 (15.4)17 (12.0)
City 57 (73.1)103 (72.5)
Comorbidity present20 (25.6)40 (28.2)0.687
Use of other drugs33 (42.3)60 (42.3)0.994
Time since diagnosis of hepatitis B (y)14 (3 - 30)12 (3 - 30)0.555
Duration of taking hepatitis B treatment (y)6 (3 - 20)6 (3 - 20)0.641
Family history of hepatitis B57 (73.1)110 (77.5)0.467
Family history of cirrhosis16 (20.5)37 (26.1)0.358
Treatment received0.080
ETV22 (28.2)53 (37.3)
TDF34 (43.6)69 (48.6)
TAF21 (26.9)19 (13.4)
Lamivudine1 (1.3)1 (0.7)
Problems in obtaining the drug-24 (16.9)NE
COVID-19 vaccination68 (87.2)123 (86.6)0.907
COVID-19 infection28 (35.9)64 (45.1)0.187

4.2. Reasons for CHB Patients Not Having Checkups During the Pandemic

It was determined that 39 (17.7%) patients continued to regularly have checkups during the COVID-19 pandemic, 39 (17.7%) had irregularly (once or twice during the 2-year period of the pandemic), and 142 (64.5%) did not have any checkups. The reasons for not having checkups and having irregular checkups are shown in Figure 1. At least 1 reason was stated by 181 patients, 2 by 61 patients, and 3 by 25 patients. The most common reason for not having checkups was concern about COVID-19 infection. Those who had 1 or 2 checkups stated most often that they did not feel the need to continue taking the drugs.

The reasons given by chronic hepatitis B patients for not having regular checkups during the pandemic
The reasons given by chronic hepatitis B patients for not having regular checkups during the pandemic

4.3. Basic Characteristics of CHB Patients According to the Status of Continuing Treatment During the Pandemic

Of the patients receiving treatment because of CHB, 34 (15.5%) stopped treatment during the pandemic. These patients were determined to have remained without treatment for a mean of 9.18 ± 7.55 months. The basic characteristics of CHB patients according to the status of continuing treatment during the pandemic are shown in Table 2. The patients who stopped treatment were determined to have a younger mean age, and the majority were female (P = 0.001 and P = 0.043, respectively). The patients who stopped treatment were seen to have been receiving antiviral treatment for a shorter period than those who continued treatment (P = 0.013). It was observed that most patients with a family history of liver cirrhosis stopped treatment (P = 0.036). A significantly high rate of patients who experienced problems with their drugs stopped treatment (P < 0.001). A higher rate of patients who had had a COVID-19 vaccination was in the group that continued treatment (P < 0.001).

Table 2.

The Basic Characteristics of Chronic Hepatitis B Patients According to the Status of Continuing Treatment During the Pandemic a

VariablesCHB TreatmentP Value b
Continued Treatment (n = 186)Stopped Treatment (n = 34)
Age (y)45 (19 - 73)36.5 (23 - 59)0.001
Gender0.043
Male 125 (67.2)17 (50.0)
Female 61 (32.8)17 (50.0)
Education level0.592
No formal education35 (18.7)5 (14.7)
Primary school70 (37.4)11 (32.4)
High school or university81 (43.5)18 (52.9)
Place of residence 0.624
Village 25 (13.4)6 (11.5)
Town 26 (14.0)3 (15.4)
City 135 (72.6)25 (73.5)
Comorbidity present54 (29.0)6 (17.6)0.170
Use of other drugs82 (44.1)11 (32.4)0.203
Time since diagnosis of hepatitis B (y)12 (3 - 30)12 (4 - 30)0.911
Duration of taking hepatitis B treatment (y)7 (3 - 20)5 (3 - 19)0.013
Family history of hepatitis B138 (74.2)29 (85.3)0.164
Family history of cirrhosis40 (21.5)13 (38.2)0.036
Treatment received0.667
ETV62 (33.3)13 (38.2)
TDF86 (46.2)17 (50.0)
TAF36 (19.4)4 (11.8)
Lamivudine2 (1.1)-
Problems in obtaining the drug10 (5.4)14 (41.2)< 0.001
COVID-19 vaccination168 (90.3)23 (67.6)< 0.001
COVID-19 infection81 (43.5)11 (32.4)0.224

4.4. Changes in the Markers Used in the Follow-up of CHB Before and After the Pandemic According to the Status of Continuing Treatment

Before the pandemic, 219 (99.5%) patients were HBsAg positive. HBsAg loss occurred in 1 patient who stopped treatment and in 2 patients who continued treatment during the pandemic. In the 2 patients who continued treatment, anti-HBs seroconversion developed. Before the pandemic, HBeAg was determined in 18 (8.2%) patients and anti-HBe positivity in 197 (89.5%) patients. Both were positive in 1 patient and negative in 6 patients. HBeAg loss occurred in 1 patient who stopped treatment and in 2 patients who continued treatment during the pandemic, and anti-HBe seroconversion was observed in these 3 patients.

The changes in HBV-DNA and ALT values according to the status of continuing treatment during the pandemic are shown in Figure 2. A statistically significant increase was observed in the ALT value of those who stopped treatment compared to the pre-pandemic value (P = 0.006), and no significant change was observed in those who continued treatment (P = 0.158). Following the pandemic, HBV DNA > 2000 IU/mL was determined in 14 (41.1%) patients who stopped treatment and in 1 (0.5%) patient who continued treatment. As the HBV-DNA value was negative in all the patients before the pandemic, no statistical result could be obtained from the changes.

Changes in the hepatitis B virus-DNA and alanine aminotransferase values according to the status of continuing treatment
Changes in the hepatitis B virus-DNA and alanine aminotransferase values according to the status of continuing treatment

The changes in some biomarkers used in the follow-up of CHB according to the status of continuing treatment during the pandemic are shown in Table 3. AST values after the pandemic were determined to be statistically significantly low in the patients who continued treatment and high (but not at a statistically significant level) in those who stopped treatment (P = 0.002 and Pc = 0.081, respectively). The serum calcium level was significantly reduced after the pandemic in the patients who stopped treatment (P = 0.048). When the effect of stopping treatment was evaluated, this decrease was associated with having stopped the use of TDF (the mean calcium value of those who stopped TDF was 9.58 ± 0.31 before the pandemic and 9.40 ± 0.34 after the pandemic, P = 0.049).

Table 3.

The Changes in Some Biomarkers Used in the Follow-up of Chronic Hepatitis B According to the Status of Continuing Treatment During the Pandemic

Variable s and TreatmentPre-pandemicPost-pandemicP Value a
ALT
Continuing28.72 ± 17.0227.87 ± 15.200.158
Terminated27.68 ± 11.3656.62 ± 64.780.006
AST
Continuing27.35 ± 9.7325.71 ± 7.780.002
Terminated26.33 ± 9.2534.45 ± 21.710.081
AFP
Continuing2.94 ± 2.743.11 ± 2.400.085
Terminated2.67 ± 2.313.20 ± 3.040.050
INR
Continuing1.07 ± 0.131.06 ± 0.110.542
Terminated1.08 ± 0.121.11 ± 0.100.098
Thrombocyte count
Continuing236 ± 60241 ± 630.098
Terminated231 ± 59235 ± 640.388
Creatinine
Continuing0.80 ± 0.220.82 ± 0.360.340
Terminated0.73 ± 0.190.70 ± 0.180.346
Phosphorus
Continuing3.06 ± 0.543.04 ± 0,520.746
Terminated3.14 ± 0.393.04 ± 0.510.161
Calcium
Continuing9.40 ± 0.649.43 ± 0.610.605
Terminated9.54 ± 0.619.40 ± 0.350.048
Albumin
Continuing41.21 ± 4.8341.14 ± 4.930.528
Terminated40.87 ± 4.9040.21 ± 4.270.074

The relationship between the status of continuing treatment during the pandemic and the change in GFR and proteinuria is shown in Figure 3. The GFR value was significantly reduced after the pandemic in those who continued treatment (P = 0.003). This decrease was particularly associated with continuing TDF treatment; in these patients, the mean GFR value was significantly reduced (P = 0.001). However, the mean GFR value increased in those who stopped treatment, which was not statistically significant (P = 0.224). A total of 186 patients were evaluated regarding proteinuria before and after the pandemic. In patients who continued treatment, proteinuria was observed in 6 (3.8%) patients before the pandemic and in 14 (9.1%) patients after the pandemic, which was statistically significant (P = 0.039). After the pandemic, proteinuria was observed in 2 patients who stopped treatment, but as proteinuria was not observed in this group before the pandemic, a statistical result could not be obtained. In 9 patients without proteinuria before the pandemic and those who continued to use TDF, proteinuria was observed after the pandemic.

Changes in the mean glomerular filtration rate value and the presence of proteinuria according to A, the status of continuing treatment during the pandemic; and B, the treatment taken by those continuing treatment.
Changes in the mean glomerular filtration rate value and the presence of proteinuria according to A, the status of continuing treatment during the pandemic; and B, the treatment taken by those continuing treatment.

The changes in bone mineral density (BMD) according to the status of continuing treatment during the pandemic (as well as according to the treatment taken by those continuing) are shown in Figure 4. The vertebra T score was found to be significantly higher after the pandemic than before the pandemic in the patients who stopped treatment (P = 0.014), as well as to be significantly lower in those who continued treatment (P = 0.035). The femur T score decreased after the pandemic compared to the pre-pandemic scores in both patients who stopped and continued treatment, but the differences were not statistically significant (P = 0.181 and P = 0.359, respectively). Both the vertebra T score and femur T score were significantly lower after the pandemic than before the pandemic in the patients who continued TDF treatment (P < 0.001 and P = 0.029, respectively).

Changes in bone mineral density according to A, the status of continuing treatment during the pandemic; and B, the treatment taken by those continuing treatment.
Changes in bone mineral density according to A, the status of continuing treatment during the pandemic; and B, the treatment taken by those continuing treatment.

4.5. Changes in Treatment After the Pandemic

After the pandemic, the treatment of 156 (83.4%) patients was not changed, the treatment of 11 (5.9%) patients was changed to ETV because of the development of osteopenia/osteoporosis, and the treatment of 18 (9.6%) patients was changed to TAF because of the development of osteopenia/osteoporosis or renal side effects. To switch to a more potent drug, the treatment in 1 (0.5%) patient was changed from lamivudine to TDF. Of the patients who stopped treatment, it was re-started with the same drug in 27 (79.5%) patients. Treatment was not re-started at the request of 6 (17.6%) patients, and it was changed to TAF in 1 (2.9%) patient because of the development of osteoporosis.

5. Discussion

In the long-term treatment management of all chronic diseases, maintaining the efficacy of the treatment and monitoring side effects are critical. Therefore, CHB patients receiving treatment should undergo liver function tests once every 3 - 4 months in the first year and every 6 months thereafter. The serum HBV-DNA level should be examined once every 3 - 4 months in the first year and at 6- to 12-month intervals thereafter. When HBV DNA is not determined, the HBsAg and anti-HBs levels should be examined once every 12 months (8). The CHB patients being followed up at 3-month intervals before the pandemic could not be seen for polyclinic checkups because of the COVID-19 pandemic restrictions. The right to be able to obtain the drugs without a prescription laid the foundation for these patients not to see the need to present at the polyclinic. This study showed that a negative effect should be considered on chronic diseases such as hepatitis b infection because of the extension of control visits during pandemics. The aim of this study was to evaluate the clinical, radiological (bone mineral densitometer), serological, biochemical, and molecular results of the patients who did not have polyclinic checkups.

Of the 220 patients who had checkups regularly before the pandemic, 142 (64.5%) had no checkup for approximately 2 years. Only 39 (17.7%) patients had regular checkups. Of the reasons given by the patients for not having checkups, the main reason was concern about COVID-19 infection. Another study reported that pregnant women did not have regular routine checkups during the pandemic as they felt uncomfortable (9). In a study in Wuhan (China), it was seen that 41.9% of pregnant women refused to go to any hospital because of the fear of infection and would postpone antenatal care and admission to the hospital before birth (10). Obstetricians in India reported that the most common concern of pregnant women was that they would contract the infection during hospital visits for antenatal checkups and ultrasounds (11). It can be predicted that this situation would be seen more in CHB patients because most of these patients have no complaints. A previous study reported that one of the main reasons for not having a viral hepatitis test and accessing treatment was the fear of going to a health care facility because of COVID-19 (12).

In the current study, 34 patients (who were young and mostly female) stopped treatment during the pandemic. In the patients who had been receiving antiviral treatment for a longer time, the rate of continuing to take the drugs was higher. It was thought that the importance of the disease could be better understood by those having checkups for a longer period. An interesting finding was that a significantly higher rate of patients with a family history of cirrhosis of the liver stopped treatment. The compliance to the treatment might be low because they may have believed that cirrhosis is the final inevitable outcome of CHB. It was observed that most patients who continued treatment had a COVID-19 vaccination, which was statistically significant. Due to the protection of the vaccination, it can be considered that the patients lost their concerns about COVID-19 and continued the treatment of CHB. These patients might have compliance with both their treatments and COVID-19 vaccinations. In the later stages of the pandemic (when there was an increase in COVID-19 vaccinations), a study conducted in Canada showed that with this effect, there was an increase in hospital presentations (13).

HBsAg seroclearance and its conversion to an antibody against hepatitis B surface antigen (anti-HBs) is uncommon in chronic infections. In an Asian population, the annual incidence of HBsAg clearance was 0.33% - 5.0% with antiviral treatments and 0.5% - 2.66% without antiviral treatments (14-17). In a study in Turkey, HBsAg seroclearance was developed in only 2 of 173 HBeAg-negative patients, and anti-HBs seroconversion was not determined (18). In the current study, HBsAg loss was seen in 1 patient who stopped treatment and in 2 patients who continued treatment, and anti-HBs seroconversion was developed in 2 patients who continued treatment. Similarly, HBeAg loss was observed in 1 patient who stopped treatment and in 2 patients who continued treatment, and anti-HBe seroconversion was developed in 2 patients who continued treatment. Seroconversion was developed more in patients who continued treatment, which is consistent with previous studies. However, the timing of seroconversion developed in patients who did not regularly have checkups could not be determined. It is recommended that treatment be continued for 1 more year after seroconversion (8). As this timing was not clearly known, patients will have to remain in treatment for a longer period.

There are 2 formulations of tenofovir for the treatment of HBV: TDF and TAF. ETV is generally well tolerated in CHB. In patients with a high potential for side effects related to the bones and kidneys, it is recommended that treatment be changed from TDF to TAF or ETV (8, 19, 20). Previous studies have reported that long-term use of TDF results in a decrease in BMD and an increase in renal toxicity (20-22). Patients who changed from TDF to TAF showed a significant improvement in estimated glomerular filtration rate (eGFR) levels and hip and spine T scores (20). In another study, it was observed that after 2 years of TDF treatment, eGFR significantly decreased. In patients who received ETV, eGFR remained stable throughout 3 years and significantly improved after 4 and 5 years (23). Consistent with previous studies, a decrease in eGFR was observed in patients who continued TDF treatment. Moreover, in 9 patients who continued to use TDF and had not been determined by proteinuria before the pandemic, the treatment was changed to ETV or TAF after the pandemic as proteinuria was determined. Previous studies have shown that proteinuria is one of the side effects seen in TDF regimens (24, 25). When proteinuria develops in HBV patients using TDF, it is recommended that the treatment be changed to TAF or ETV (6, 7, 26).

In the current study, the vertebra T score was found to be significantly higher after the pandemic than before the pandemic in patients who stopped treatment, as well as to be significantly lower in those who continued treatment. In addition to not being the only significant factor for the reduction in BMD, drugs seems to have a large effect on it. Both the vertebra T score and the femur T score were significantly lower after the pandemic than before the pandemic in the patients who continued TDF treatment. These results are consistent with previous studies (20).

Of the 34 (15.5%) patients who stopped taking antiviral treatment during the pandemic, 20 (58.9%) were determined by HBV DNA < 2000 IU/mL and 14 (41.1%) with HBV DNA > 2000 IU/mL. Of those with HBV DNA < 2000 IU/mL, 6 did not wish to resume treatment, and in 2 of these patients, the result was negative. Acceptable treatment termination is stated in the guidelines as continuous virological improvement [HBV DNA levels were not determined by sensitive polymerase chain reaction (PCR)] (5, 9). In a previous study of 504 HBeAg-negative, non-cirrhotic patients who were followed up without treatment for at least 30 months after previous ETV or TDF, virological recurrence was determined in 81 patients. Of these 81 patients, HBV DNA > 2000 IU/mL was determined in 52 patients, and following virological recurrence in 29 patients, a permanent virological dominance (HBV DNA < 2000 IU/mL) was seen at least 1.5 years later (27). In another study, of the 250 patients for whom ETV was stopped, there was permanent virological dominance in 71 (28.4%) patients and virological recurrence in 35 (15%) patients. In patients who developed virological recurrence, clinical recurrence did not develop, or there was no need for treatment again (28). Virological recurrence was determined at a higher rate in the current study than in the literature. In addition, a significant increase in the ALT value was determined in patients who stopped treatment. All guidelines state that normalization of ALT is an important factor in the follow-up of CHB and is a marker of biochemical response (7, 25, 29). Such a result seen in patients who stopped treatment is supported by the guidelines.

5.1. Conclusion

The COVID-19 pandemic had negative effects on the follow-up of patients with chronic diseases. The most common reason for not having checkups was concerns about COVID-19 infection. The primary negative effects encountered in the follow-up of patients were biochemical impairment and virological recurrence developed as a result of stopping treatment. Following the use of TDF, a decrease was seen in BMD, a fall in the level of eGFR, and side effects such as proteinuria. Both HBsAg seroconversion and HBeAg seroconversion were observed more often in patients who continued treatment. To continue antiviral treatments and follow up side effects, patients should have regular checkups.

References

  • 1.

    World Health Organization. Hepatitis B. Geneva, Switzerland: World Health Organization; 2022, [cited 18 July 2022]. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b/.

  • 2.

    World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Towards ending viral hepatitis. Geneva, Switzerland: World Health Organization; 2016.

  • 3.

    Tozun N, Ozdogan O, Cakaloglu Y, Idilman R, Karasu Z, Akarca U, et al. Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study. Clin Microbiol Infect. 2015;21(11):1020-6. [PubMed ID: 26163105]. https://doi.org/10.1016/j.cmi.2015.06.028.

  • 4.

    Gurol E, Saban C, Oral O, Cigdem A, Armagan A. Trends in hepatitis B and hepatitis C virus among blood donors over 16 years in Turkey. Eur J Epidemiol. 2006;21(4):299-305. [PubMed ID: 16685581]. https://doi.org/10.1007/s10654-006-0001-2.

  • 5.

    Pley CM, McNaughton AL, Matthews PC, Lourenco J. The global impact of the COVID-19 pandemic on the prevention, diagnosis and treatment of hepatitis B virus (HBV) infection. BMJ Glob Health. 2021;6(1). [PubMed ID: 33402334]. [PubMed Central ID: PMC7786543]. https://doi.org/10.1136/bmjgh-2020-004275.

  • 6.

    Turkish Medicines and Medical Devices Agency. [İl Sağlık Müdürlüklerinin ve Eczacıların Dikkatine]. Ankara, Turkey: Turkish Medicines and Medical Devices Agency; 2022, [cited 2022]. Turkish. Available from: https://www.titck.gov.tr/duyuru/il-saglik-mudurluklerinin-ve-eczacilarin-dikkatine-22042020124529.

  • 7.

    Türk Eczacilari Birliği. [KRONİK HASTALIĞI NEDENİYLE SAĞLIK RAPORU OLAN HASTALARIN İLAÇ VE TIBBİ CİHAZ TEMİNİ HAKKINDA]. Ankara, Turkey: Turkish Pharmacists' Association; 2022, [cited 2022]. Turkish. Available from: https://www.teb.org.tr/news/9560/KRON%C4%B0K-HASTALI%C4%9EINEDEN%C4%B0YLE-SA%C4%9ELIK-RAPORU-OLAN-HASTALARIN-%C4%B0LA%C3%87-VE-TIBB%C4%B0-C%C4%B0HAZ%20TEM%C4%B0N%C4%B0-HAKKINDA.

  • 8.

    Lampertico P, Agarwal K, Berg T, Buti M, Janssen HL, Papatheodoridis G, et al. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-98. https://doi.org/10.1016/j.jhep.2017.03.021.

  • 9.

    Kahyaoglu Sut H, Kucukkaya B. Anxiety, depression, and related factors in pregnant women during the COVID-19 pandemic in Turkey: A web-based cross-sectional study. Perspect Psychiatr Care. 2021;57(2):860-8. [PubMed ID: 32989798]. [PubMed Central ID: PMC7537279]. https://doi.org/10.1111/ppc.12627.

  • 10.

    Liu X, Chen M, Wang Y, Sun L, Zhang J, Shi Y, et al. Prenatal anxiety and obstetric decisions among pregnant women in Wuhan and Chongqing during the COVID-19 outbreak: a cross-sectional study. BJOG. 2020;127(10):1229-40. [PubMed ID: 32583536]. [PubMed Central ID: PMC7362035]. https://doi.org/10.1111/1471-0528.16381.

  • 11.

    Nanjundaswamy MH, Shiva L, Desai G, Ganjekar S, Kishore T, Ram U, et al. COVID-19-related anxiety and concerns expressed by pregnant and postpartum women-a survey among obstetricians. Arch Womens Ment Health. 2020;23(6):787-90. [PubMed ID: 32839898]. [PubMed Central ID: PMC7445074]. https://doi.org/10.1007/s00737-020-01060-w.

  • 12.

    Sun J, Aghemo A, Forner A, Valenti L. COVID-19 and liver disease. Liver Int. 2020;40(6):1278-81. [PubMed ID: 32251539]. https://doi.org/10.1111/liv.14470.

  • 13.

    Mandel E, Peci A, Cronin K, Capraru CI, Shah H, Janssen HLA, et al. The impact of the first, second and third waves of covid-19 on hepatitis B and C testing in Ontario, Canada. J Viral Hepat. 2022;29(3):205-8. [PubMed ID: 34820967]. https://doi.org/10.1111/jvh.13637.

  • 14.

    Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63(8):1325-32. [PubMed ID: 24162593]. https://doi.org/10.1136/gutjnl-2013-305517.

  • 15.

    Kobayashi M, Hosaka T, Suzuki F, Akuta N, Sezaki H, Suzuki Y, et al. Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up. J Gastroenterol. 2014;49(3):538-46. [PubMed ID: 23783839]. https://doi.org/10.1007/s00535-013-0821-2.

  • 16.

    Kim JH, Lee JH, Park SJ, Bae MH, Kim JH, Kim DY, et al. Factors associated with natural seroclearance of hepatitis B surface antigen and prognosis after seroclearance: a prospective follow-up study. Hepatogastroenterology. 2008;55(82-83):578-81. [PubMed ID: 18613411].

  • 17.

    Zhu L, Zhai X, Wang Q, Jiang J, Peng H, Song C, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance and seroconversion in hepatitis B e antigen-negative chronic infection patients: A population-based prospective cohort. J Viral Hepat. 2018;25(12):1588-98. [PubMed ID: 30112835]. https://doi.org/10.1111/jvh.12978.

  • 18.

    Ozdemir YE, Sahin Ozdemir M, Bayramlar OF, Surme S, Yildiz Kaya S, Karaali R, et al. Long-term follow-up of treatment-naive HBeAg-negative patients with chronic hepatitis B. Ir J Med Sci. 2022. [PubMed ID: 35715665]. https://doi.org/10.1007/s11845-022-03066-y.

  • 19.

    Chen YC, Su YC, Li CY, Hung SK. 13-year nationwide cohort study of chronic kidney disease risk among treatment-naive patients with chronic hepatitis B in Taiwan. BMC Nephrol. 2015;16:110. [PubMed ID: 26199000]. [PubMed Central ID: PMC4508999]. https://doi.org/10.1186/s12882-015-0106-5.

  • 20.

    Akdemir Kalkan I, Karasahin O, Sarigul F, Altunisik Toplu S, Aladag M, Akgul F, et al. Comparison of Tenofovir Alafenamide and Entecavir Therapy in Patients with Chronic Hepatitis B Initially Treated with Tenofovir Disoproxil: A Retrospective Observational Survey. Hepat Mon. 2022;21(10). https://doi.org/10.5812/hepatmon.118721.

  • 21.

    Hamzah L, Jose S, Booth JW, Hegazi A, Rayment M, Bailey A, et al. Treatment-limiting renal tubulopathy in patients treated with tenofovir disoproxil fumarate. J Infect. 2017;74(5):492-500. [PubMed ID: 28130143]. https://doi.org/10.1016/j.jinf.2017.01.010.

  • 22.

    Koklu S, Gulsen MT, Tuna Y, Koklu H, Yuksel O, Demir M, et al. Differences in nephrotoxicity risk and renal effects among anti-viral therapies against hepatitis B. Aliment Pharmacol Ther. 2015;41(3):310-9. [PubMed ID: 25982037]. https://doi.org/10.1111/apt.13036.

  • 23.

    Tsai MC, Chen CH, Tseng PL, Hung CH, Chiu KW, Wang JH, et al. Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience. Clin Microbiol Infect. 2016;22(1):95 e1-7. [PubMed ID: 26055419]. https://doi.org/10.1016/j.cmi.2015.05.035.

  • 24.

    Nickolas TL, Barasch J, Mugwanya KK, Branch AD, Heffron R, Wanga V, et al. Kidney injury biomarkers during exposure to tenofovir-based preexposure prophylaxis. AIDS. 2021;35(7):1147-9. [PubMed ID: 33710023]. [PubMed Central ID: PMC8102362]. https://doi.org/10.1097/QAD.0000000000002865.

  • 25.

    Gupta SK, Post FA, Arribas JR, Eron JJ, Wohl DA, Clarke AE, et al. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019;33(9):1455-65. [PubMed ID: 30932951]. [PubMed Central ID: PMC6635043]. https://doi.org/10.1097/QAD.0000000000002223.

  • 26.

    Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-83. [PubMed ID: 26566064]. [PubMed Central ID: PMC5987259]. https://doi.org/10.1002/hep.28156.

  • 27.

    Tseng TN, Kuo YH, Hu TH, Hung CH, Wang JH, Lu SN, et al. Kinetics in HBsAg after Stopping Entecavir or Tenofovir in Patients with Virological Relapse but Not Clinical Relapse. Viruses. 2022;14(6). [PubMed ID: 35746660]. [PubMed Central ID: PMC9227936]. https://doi.org/10.3390/v14061189.

  • 28.

    Chen CH, Hung CH, Wang JH, Lu SN, Lai HC, Hu TH, et al. The Incidence of Hepatitis B Surface Antigen Loss Between Hepatitis B E Antigen-Negative Noncirrhotic Patients Who Discontinued or Continued Entecavir Therapy. J Infect Dis. 2019;219(10):1624-33. [PubMed ID: 30689910]. https://doi.org/10.1093/infdis/jiy697.

  • 29.

    Türk Karaciğer Araştırmaları Derneği; Viral Hepatitle Savaşım Derneği. [TÜRKİYE VİRAL HEPATİTLER TANI VE TEDAVİ KILAVUZU]. Ankara, Turkey: Viral Hepatitle Savasim Dernegi; 2017. Turkish.