Long-term Effects of Treatment for Chronic HBV Infection on Patient-Reported Outcomes

Worldwide, viral hepatitis remains the most common cause of chronic liver disease.1Chen C.J. Yang H.I. Natural history of chronic hepatitis B REVEALed.J Gastroenterol Hepatol. 2011; 26: 628-638Crossref PubMed Scopus (211) Google Scholar In this context, hepatitis B virus (HBV) infection and its complications are responsible for a tremendous clinical burden related to cirrhosis and hepatocellular carcinoma.1Chen C.J. Yang H.I. Natural history of chronic hepatitis B REVEALed.J Gastroenterol Hepatol. 2011; 26: 628-638Crossref PubMed Scopus (211) Google Scholar In contrast, long-term HBV suppression can improve hepatic fibrosis and clinical outcomes.2Liaw Y.F. Impact of therapy on the outcome of chronic hepatitis B.Liver Int. 2013; 33: 111-115Crossref PubMed Scopus (57) Google Scholar In addition to the clinical burden, HBV can negatively impact patient-reported outcomes (PROs), while viral suppression leads to their improvement.3Younossi Z.M. Stepanova M. Janssen H.L.A. et al.Effects of treatment of chronic HBV infection on patient-reported outcomes.Clin Gastroenterol Hepatol. 2018; 16: 1641-1649.e6Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Our aim is to assess the sustainability of long-term changes in PROs of HBV subjects with viral suppression. Patients were enrolled in a long-term follow-up registry (2014–2017, NCT02258581) after completing treatment in clinical trials (NCT01277601, NCT02166047, NCT01943799, NCT02174276), and were followed for 96 weeks. Enrolled patients were required to have completed the trial ≤120 days before registry enrollment, not participate in other clinical trials (they were permitted to modify their standard-of-care HBV treatment), and have adequate viral suppression at baseline (<10,000 IU/mL). Patients with significant fibrosis (Metavir stage ≥3); hepatocellular carcinoma; coinfection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus; other significant illness or comorbidity were not included in parent trials which fed into the registry. Patient-reported outcomes were assessed using 36-Item Short Form Survey (SF-36), Chronic Liver Disease Questionnaire (CLDQ), and Work Productivity and Activity Impairment instruments,4Ware J.E. Kosinski M. SF-36 physical and mental health summary scales: a manual for users of version 1.2nd ed. QualityMetric, Inc, Lincoln, RI2001Google Scholar, 5Younossi Z.M. Stepanova M. Nader F. Lam B. Hunt S. The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.Aliment Pharmacol Ther. 2015; 42: 286-295Crossref PubMed Scopus (85) Google Scholar which were self-administered at registry baseline, weeks 24, 48, and 96. Pairwise comparisons were performed using chi-square or Mann-Whitney tests; changes in PRO scores from patients' own registry baseline levels were compared with 0 using a signed rank test. The study was approved by each site's Institutional Review Board. There were 229 patients with HBV enrolled in the registry: age 48.6 ± 10.4 years, 71.2% men, 75.1% Asian, 19.7% hepatitis B e antigen positive, 61.6% enrolled in the United States, and 87.8% receiving a standard-of-care oral antiviral therapy at the registry baseline (adefovir, entecavir, lamivudine, telbivudine, tenofovir, or a combination) (Supplementary Table 1). At baseline, 13 patients had detectable HBV viremia (20-2;160 IU/mL). During follow-up, 15 additional patients developed detectable viremia at least once, but only 2 patients had HBV DNA >2000 IU/mL. At baseline, PROs were similar or higher than general population's norms (all 1-sided P ≥ .05),4Ware J.E. Kosinski M. SF-36 physical and mental health summary scales: a manual for users of version 1.2nd ed. QualityMetric, Inc, Lincoln, RI2001Google Scholar with the exception of the worry domain of the CLDQ (P < .01). Despite this, patients with HBV still had a significant impairment in the presenteeism and activity domains of Work Productivity and Activity Impairment Specific Health Problem (P < .0001). In pairwise comparison, there were no significant differences in PRO scores in HBV patients of Asian and non-Asian origin (Supplementary Table 1), as well as between patients enrolled in the United States and in other countries (all P > .05). Male patients with HBV had higher physical functioning score in comparison with female patients (mean 89.6 vs 82.0; P = .03). Patients who were off oral antiviral treatment were more frequently viremic (P < .0001) and had lower scores in the emotional domain of the CLDQ (mean 5.5 vs 6.0; P = .02) at baseline. Although some decrements in the vitality and mental health domains of the SF-36 were noted by week 24 of follow-up for the study cohort (on average, 4.1–5.5 points on a 0–100 scale; both P < .01), these decrements resolved by week 48 of follow-up (Figure 1A, B). In addition, by week 48, significant improvements were observed in the general health and role emotional domains of the SF-36 (on average, 3.2–5.1 points; both P < .05) (Figure 1B). PROs are essential for understanding the comprehensive impact of HBV infection on patients' health. Additionally, PROs are important when assessing the effect of any treatment regimen because PROs are tightly linked to adherence which is critically important for long-term suppression of HBV.6Younossi I. Weinstein A. Stepanova M. Hunt S. Younossi Z.M. Mental and emotional impairment in patients with hepatitis C is related to lower work productivity.Psychosomatics. 2016; 57: 82-88Crossref PubMed Scopus (19) Google Scholar, 7Weinstein A.A. Kallman Price J. Stepanova M. et al.Depression in patients with nonalcoholic fatty liver disease and chronic viral hepatitis B and C.Psychosomatics. 2011; 52: 127-132Crossref PubMed Scopus (99) Google Scholar, 8Younossi Z.M. Stepanova M. Henry L. Nader F. Younossi Y. Hunt S. Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens.Medicine (Baltimore). 2016; 95: e4151Crossref PubMed Scopus (56) Google Scholar [6-8]. Although the positive effect of HBV suppression on PROs have been previously shown,3Younossi Z.M. Stepanova M. Janssen H.L.A. et al.Effects of treatment of chronic HBV infection on patient-reported outcomes.Clin Gastroenterol Hepatol. 2018; 16: 1641-1649.e6Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar the long-term sustainability of these PRO gains has not been established. Our data suggest that HBV patients with effective viral suppression had PROs that were similar or better than the population norms; this was shown with both disease-specific and generic PRO measures and in all demographic and clinical subgroups. Furthermore, during follow-up in the registry, the PRO scores remained largely stable without evidence of long-term worsening, and were not different from those seen in general population. The main limitation of the study is the lack of similar data for patients with advanced fibrosis and cirrhosis, comorbidities, or those seen in real-world practices outside clinical trial settings; all these clinical populations may have different PRO trends and will have to be studied separately. This study suggests that viral suppression has a positive impact on PROs, which is sustained in the long term. These PRO data, coupled with clinical outcomes, should inform patients, providers, and payers about the benefit of long-term viral suppression in patients with chronic HBV infection. Supplementary Table 1Baseline Parameters of the Registry ParticipantsAsianNon-AsianPapairwise comparison between Asian and non-Asian.AllN17257229Age, y47.6 ± 10.551.7 ± 9.3.015548.6 ± 10.4Male gender117 (68.0%)46 (80.7%).07163 (71.2%)White0 (0.0%)44 (77.2%)<.000144 (19.2%)Black0 (0.0%)8 (14.0%)<.00018 (3.5%)Enrolled in the United States117 (68.0%)24 (42.1%).0005141 (61.6%)Enrolled in 201411 (6.4%)0 (0%).1011 (4.8%)Enrolled in 201584 (48.8%)23 (40.4%)107 (46.7%)Enrolled in 201677 (44.8%)34 (59.6%)111 (48.5%)BMI, kg/m224.1 ± 3.627.6 ± 4.2<.000125.0 ± 4.0HBV e antibody-positive112 (75.7%)45 (90.0%).0307157 (79.3%)HBV e antigen-positive39 (22.8%)6 (10.5%).043745 (19.7%)HBV DNA titer, log10 IU/mL1.34 ± 0.271.32 ± 0.28.421.33 ± 0.27HBV surface antigen, log10 IU/mL2.66 ± 1.202.94 ± 1.04.04222.73 ± 1.16ALT, IU/L24.9 ± 17.727.2 ± 17.6.5725.5 ± 17.7Creatinine clearance, mL/min99.6 ± 25.0108.4 ± 30.2.07101.8 ± 26.6On oral antiviral therapy:149 (86.6%)52 (91.2%).36201 (87.8%) adefovir1 (0.7%)0 (0%).831 (0.5%) adefovir/entecavir1 (0.7%)0 (0%)1 (0.5%) adefovir/telbivudine/tenofovir2 (1.3%)0 (0%)2 (1%) entecavir58 (38.9%)18 (34.6%)76 (37.8%) entecavir/other3 (2%)0 (0%)3 (1.5%) entecavir/tenofovir1 (0.7%)0 (0%)1 (0.5%) entecavir/tenofovir/other1 (0.7%)0 (0%)1 (0.5%) lamivudine2 (1.3%)0 (0%)2 (1%) lamivudine/adefovir1 (0.7%)0 (0%)1 (0.5%) lamivudine/tenofovir3 (2%)0 (0%)3 (1.5%) telbivudine1 (0.7%)0 (0%)1 (0.5%) tenofovir61 (40.9%)28 (53.8%)89 (44.3%) tenofovir/entecavir1 (0.7%)0 (0%)1 (0.5%) tenofovir/other11 (7.4%)6 (11.5%)17 (8.5%) truvada (tdf/emtricitabine)2 (1.3%)0 (0%)2 (1%)Patient-reported outcomesSF-36 Physical functioning87.0 ± 21.489.1 ± 22.7.3687.7 ± 21.8 Role physical85.8 ± 22.785.5 ± 22.1.4585.7 ± 22.4 Bodily pain84.1 ± 22.482.9 ± 23.8.9883.7 ± 22.7 General health66.8 ± 20.665.8 ± 20.9.9866.4 ± 20.6 Vitality69.6 ± 19.169.6 ± 16.7.9069.6 ± 18.3 Social functioning88.1 ± 19.986.2 ± 23.2.5287.5 ± 21.0 Role emotional87.3 ± 20.189.5 ± 18.2.7888.0 ± 19.5 Mental health79.9 ± 15.479.6 ± 12.2.6279.8 ± 14.4 Psychical component summary53.0 ± 7.252.9 ± 8.7.6553.0 ± 7.7 Mental component summary52.7 ± 7.952.7 ± 6.8.7552.7 ± 7.5 SF-6D utility score0.78 ± 0.150.76 ± 0.13.590.77 ± 0.14CLDQ Abdominal symptoms6.29 ± 0.835.93 ± 1.35.326.16 ± 1.06 Activity6.21 ± 1.096.32 ± 1.13.346.25 ± 1.10 Emotional health5.90 ± 0.975.96 ± 1.08.695.92 ± 1.00 Fatigue5.63 ± 1.165.59 ± 1.22.975.61 ± 1.18 Systemic symptoms6.08 ± 0.886.23 ± 0.83.426.14 ± 0.86 Worry6.06 ± 1.03bP < .05 in comparison to the general population norms.6.03 ± 1.39bP < .05 in comparison to the general population norms..596.05 ± 1.17bP < .05 in comparison to the general population norms. Total CLDQ6.03 ± 0.886.01 ± 1.04.886.02 ± 0.94WPAI:SHP Work productivity impairment0.076 ± 0.1660.041 ± 0.094.580.067 ± 0.152 Absenteeism0.003 ± 0.0220.000 ± 0.000.570.002 ± 0.019 Presenteeism0.073 ± 0.1650.041 ± 0.094.600.065 ± 0.150 Activity impairment0.071 ± 0.1540.107 ± 0.220.620.083 ± 0.177a pairwise comparison between Asian and non-Asian.b P < .05 in comparison to the general population norms. Open table in a new tab