A conceptual model for chronic hepatitis B and content validity of the Hepatitis B Quality of Life (HBQOL) instrument

Abstract

Background

There is increased emphasis on incorporating patient perspectives and patient-relevant endpoints in drug development. We developed a conceptual model of the impact of chronic hepatitis B (CHB) on patients’ lives and evaluated the content validity of the Hepatitis B Quality of Life (HBQOL) instrument, a patient-reported outcome tool for use in clinical studies, as a patient-relevant endpoint to measure health-related quality of life in patients with CHB.

Methods

A literature review of qualitative studies of patient experience with CHB and concept elicitation telephone interviews with patients with CHB in the United Kingdom were used to develop a conceptual model of the experience and impact of living with CHB. The content validity of the HBQOL was evaluated using cognitive debriefing techniques.

Results

The qualitative literature review (N = 43 publications) showed that patients with CHB experience emotional/psychological impacts. During concept elicitation interviews (N = 24), fatigue was the most commonly reported symptom, and most participants were worried/anxious about virus transmission and disease progression/death. A conceptual model of patients’ experiences with CHB was developed. The conceptual relevance and comprehensibility of the HBQOL were supported, though limitations, including the lack of a self-stigma item and recall period, were noted for future improvement.

Conclusions

The conceptual model shows that patients with CHB experience emotional/psychological impacts that affect their lifestyles, relationships, and work/schooling. The cognitive debriefing interviews support the content validity of the HBQOL as a conceptually relevant patient-reported outcome measure of health-related quality of life.

Background

Hepatitis B virus (HBV) is a major global health issue. Of ~296 million people worldwide living with chronic hepatitis B (CHB) [1], ~20–30% will develop cirrhosis, liver failure, or hepatocellular carcinoma [2]. CHB also has a negative impact on people’s health-related quality of life (HRQoL), including social and emotional functioning [3,4,5]. In addition to improving survival, a major goal of therapy for patients with CHB is to improve HRQoL [2, 6].

The US Food and Drug Administration established the patient-focused drug development (PFDD) initiative [7, 8] to stimulate the systematic study and incorporation of patients’ experiences and needs into drug development and evaluation. Despite this, the assessment of CHB treatments continues to focus on clinical and laboratory outcomes (e.g., HBV DNA suppression, decline in hepatitis B surface antigen [HBsAg], liver biopsy results) while neglecting HRQoL and other patient-focused outcomes (e.g., disease-associated symptoms, treatment experience, impact of living with CHB on HRQoL). Evaluating these patient-focused outcomes is essential to informing patient-centered measurement strategies [9,10,11,12,13,14] and is key to bringing meaningful, effective, and deliverable results to patients with CHB worldwide [4].

One way to capture patient perspectives is through the use of patient-reported outcomes (PROs), defined as any report of health status coming directly from patients without anyone else’s interpretation [15]. PROs play an important role in PFDD and are commonly used to assess the psychosocial and HRQoL outcomes that matter most to patients [16]. They are being considered as emerging biomarkers in the field of chronic liver disease [17].

Recommendations for the design of clinical trials of therapies for CHB focus on the assessment of functional cure endpoints, defined as sustained loss of HBsAg with or without HBsAg seroconversion and undetectable HBV DNA in serum [18]. Such endpoints do not assess the patient experience or changes in HRQoL while on chronic treatment. When we began this study, the Hepatitis B Quality of Life (HBQOL) questionnaire was the only disease-specific PRO measure designed to assess HRQoL in patients with CHB. The HBQOL questionnaire is a 31-item measure organized into 6 domains (psychological well-being, anticipation anxiety, vitality, stigma, transmission, and vulnerability) [3]. More research is needed to investigate the degree to which the HBQOL items and domains are comprehensive and representative of the HRQoL concepts that are important to patients with CHB. Qualitative interviews, the recommended methodology for establishing the content validity of a PRO measure intended to support endpoints in clinical trials, are key to demonstrating the measure’s overall score validity, as outlined in regulatory guidance documents and best practice recommendations [15, 19,20,21,22].

The first objective of this study was to build a conceptual model of the experiences of people living with CHB. The second objective was to evaluate the content validity of the HBQOL instrument.

Methods

Study design and patients

A conceptual model captures the experiences that people living with a condition find most important, and the development of a conceptual model is an essential step when selecting PROs for inclusion in clinical studies [23]. The current study developed such a conceptual model by conducting a literature review of qualitative studies of CHB and interviews of people living with CHB, encompassing pre-diagnosis, treatment, and living with a chronic condition [24]. Interviews with patients also served to evaluate of the content validity of the HBQOL, which was first developed in 2005. Though some evidence of content validity for the HBQOL was reported at the time of the measure’s development, the field of clinical outcome assessment has since advanced [15]. The current study expanded on available evidence regarding the content validity of the HBQOL in a number of ways: (1) we fully explored and documented, from the patient perspective, the patient experience of CHB in order to confirm the relevance and comprehensiveness of the assessed concepts, (2) we assessed and documented whether the HBQOL’s wording and response options were comprehensible by patients, and (3) we explored whether potential recall periods were appropriate for addition to the measure in order for it to be usable to monitor longitudinal changes in patient status.

Literature review

A targeted literature review of qualitative studies in patients with CHB was conducted by searching the Embase, Medline, and PsycINFO literature databases using search strings that combined terms such as chronic, qualitative, interview, and hepatitis B (Table S1). Manual searches of relevant conference proceedings were also performed.

Qualitative studies in patients with CHB, published in English from 2000 to 2020 as journal articles, conference abstracts, and gray reports, were selected for inclusion. Studies reporting on the lived experience of patients from the perspective of non-patients (e.g., clinician, family, friend, caregiver) were excluded. The Critical Appraisal Skills Programme checklist [25] was used to assess the quality of the identified publications. The included articles were analyzed using a thematic synthesis approach (facilitated by ATLAS.ti v7 software) to identify symptom/side effect and impact concepts.

Selection of interview participants

Interviews were conducted to (1) supplement the literature review as part of conceptual model development (concept elicitation) and (2) evaluate the content validity of the HBQOL (cognitive debrief). Participants were recruited from the viral hepatitis clinics at Barts Health NHS Trust, London, UK. Eligible participants were identified by recruiting physicians following review of patient medical records at their practice site. According to published evidence [26] and experience, ~12 interviews should be sufficient to achieve concept saturation in a relatively homogenous sample.

The study was open to adults (aged ≥ 18 years) with a diagnosis of CHB of any genotype and adequate knowledge of the written and spoken English language. Additional key inclusion and exclusion criteria are included in the supplementary materials. This study was reviewed by the local ethics committee/institutional review board and was performed in accordance with the ethical principles of the Declaration of Helsinki. All study participants provided written informed consent.

Interview process

Interviews were conducted by phone by a Barts Health NHS Trust–affiliated specialist researcher. During concept elicitation, the interviewer used open-ended questions to explore multiple aspects of participants’ experience of living with CHB. During cognitive debriefing, the interviewer asked participants to complete the HBQOL questionnaire [3] using a “think aloud” technique whereby they spoke their thoughts as they read items and selected an answer. During the HBQOL conceptual framework section, the interviewer asked participants to rank the domains of the HBQOL according to which experience was most important to them.

Interview analysis

Assisted by ATLAS.ti qualitative data analysis software, Clarivate analyzed the concept elicitation interview transcripts using methods based in thematic analysis [27]. Concept elicitation data were then reviewed to assess conceptual saturation, defined as the point at which no new concept-relevant information was identified related to signs, symptoms, or impacts. The cognitive debriefing interview transcripts were analyzed using framework coding [28] whereby a pre-defined code list was applied to identify the relevance and appropriateness of the measurement concept, instructions, item wording, response scale/options, and recall period.

Results

Qualitative literature review

Data examining the experiences of people living with CHB from 36 qualitative studies, reported in 43 publications that met the inclusion criteria, were reviewed (Fig. 1). The publication details are summarized in Table S2. The 43 publications reviewed reported findings from 36 studies worldwide; 42 of 43 publications reported the number of participants (mostly [30/42] published in peer-reviewed journals) and included 3808 participants (range of 4–1838).

Fig. 1

Selection of studies for qualitative literature review

The qualitative literature review (citations listed in Table S2) revealed that although many people with CHB were asymptomatic, symptomatic individuals experienced numerous symptoms, including flu-like/gastrointestinal symptoms, fatigue, weight loss, jaundice, and pain. Throughout life, CHB significantly impacted participants’ emotional and psychological well-being; existing relationships with partners, family, and friends; and development of new relationships. People with CHB experienced social stigma and self-stigma, and work and school were affected. The impact of CHB on work and lifestyle limitations was associated either with the physical symptoms/side effects of CHB and its treatment or with (often considerable) social stigma. Coping strategies included dietary/lifestyle changes and emotional management.

Characteristics of interview participants

Twenty-four adults with CHB living in the United Kingdom participated in qualitative interviews. The mean age of participants was 39 years, with a mean (range) time since diagnosis of 11 (2–30) years (Table 1). Most participants were Asian/Asian British (42%) or Black/African/Caribbean/Black British (33%).

Table 1 Baseline demographics of interview participants

Concept elicitation

Patient-reported symptoms of CHB

Key findings from the concept elicitation interviews are listed in Tables 2, 3, 4, 5, 6, 7, 8, S3, and S4. When asked how CHB had affected them physically, 13 of 24 participants said that they had not generally experienced physical symptoms. When asked about specific physical symptoms, fatigue was the most commonly reported (n = 16). Participants described fatigue in terms of feeling tired/sleepy (n = 14), lack of energy (n = 4), and weakness (n = 3; Table 2). As stated by one patient, “Since I got the virus, I don’t have enough strength and I get really tired. Every time I want to lean on my hand or and I can’t do it because there’s not enough strength and it start hurting to bone. There’s no strength in my body and I’m putting too much pressure on me. Yeah. I get really tired so quickly and that’s so much.” Other symptoms frequently described by participants included abdominal pain (n = 6), cognitive issues (n = 4), and weight changes (n = 3).

Table 2 Symptom concept elicitation—summary of responses and example quotes

Impact of CHB

Participants were asked to describe the initial impacts of CHB diagnosis on their lives and how these feelings might have changed over time (Table S3). Commonly reported experiences included feeling shocked/overwhelmed/devastated (n = 6) and confusion (n = 5).

Then, participants were asked to describe the impacts of CHB on their lives. Example quotes are provided from these interviews related to emotional/psychological well-being (Table 3), social functioning (Table 4), relationships (Table 5), activities of daily living (ADL; Table 6), and work/school (Table 7). In terms of the impact of CHB on their emotional/psychological well-being, most participants were worried or anxious about transmitting HBV (n = 18) and about disease progression/death (n = 17). For instance, one patient stated, “I’m, yeah, constantly worried about what comes next. Am I going to develop something with my liver earlier than expected or soon?” Other feelings expressed included being depressed/down/upset (n = 6), anxious/worried about disclosing their diagnosis/being exposed (n = 5), being annoyed/frustrated/irritable/angry (n = 4), stress (n = 3), and low self-esteem/confidence (n = 3).

Table 3 Impact on emotional/psychological well-being concept elicitation—summary of responses and example quotes

Table 4 Impact on social functioning concept elicitation—summary of responses and example quotes

Table 5 Impact on relationships concept elicitation—summary of responses and example quotes

Table 6 Impact on lifestyle/ADL concept elicitation—summary of responses and example quotes

Table 7 Impact on work/school concept elicitation—summary of responses and example quotes

Having to take precautions to avoid transmission to others (n = 13) was the most reported impact of CHB on participants’ social functioning (Table 4). One participant said, “I’m always conscious about not being too close or not sharing the food or not being able to do as everyone else can do…” and another one said, “So it became a burden on your head for, like, I don’t want to do this, I don’t want to do that…” Other frequently mentioned impacts on social functioning were reduced social life and feeling lonely (n = 6) and being unable to reach personal/life/career goals (n = 5).

Impacts on relationships included impact on family role (n = 6), difficulty dating/starting relationships (n = 5), and impact on intimacy and sexual relationships (n = 4; Table 5).

Regarding the impacts of CHB on lifestyle and ADL, many participants discussed limitations such as the burden of sickness, and appointments/treatments (n = 7) and not being able to eat and drink what they wanted (n = 6; Table 6). Some participants spoke of the need to regularly take medication and attend frequent medical appointments; others discussed the impact of having an incurable lifelong illness governing their choices. Participants who talked about the inability to eat or drink what they wanted usually mentioned alcohol consumption. Other impacts on ADL included physical/exercise limitations, increased napping/resting, and sleeping difficulties.

The most frequently mentioned impacts of CHB on work/school were related to the need to take time off to attend appointments (n = 6) and the ability to work or study (n = 5; Table 7). Participants talked about the negative effect of incapacitation from increasing viral load and the impact of symptoms (e.g., fatigue, abdominal pain) on performance. Other impacts of CHB on working life included difficulty obtaining employment and fear of losing work.

Coping with CHB

In another portion of the concept elicitation interviews, participants were asked to talk about how they were coping with CHB (Table S4). The most frequently described coping techniques reported by participants were acceptance (n = 14), engaging with regular medical care (n = 10), support from family and friends (n = 7), and improved disease understanding (n = 7). Other coping strategies included taking general health precautions, reducing alcohol intake, seeking emotional support from health care professionals, modifying diet and exercise, emotional avoidance, and ensuring sufficient rest.

CHB-related stigma

The concept elicitation interviewer also asked participants if they had ever felt stigmatized, and/or experienced prejudice or discrimination because of CHB. As summarized in Table 8, 3 categories of stigmatization (i.e., social stigma, self-stigma, institutional/structured stigma) based on a World Health Organization report [29] and published literature were used [30, 31].

Table 8 Experience of CHB-related stigma concept elicitation—summary of responses and example quotes

Among participants, the most frequently reported experiences of stigmatization were self-stigma (n = 18; defined as self-induced, internalized negative belief that affects feelings and function any time an individual thinks negatively about themselves based on what other people might think or believe about them because of their health condition [29,30,31]), including concealment of CHB from others (n = 14), negative thoughts about themselves (n = 8), and expectation of social avoidance from others (n = 7). As described by one participant, “My major worry is really rejection. And I think a lot of people have been naïve or have no idea what it’s all about. And because of that, I’m feeling like I don’t want to be the guy who needs to train people based on what I’ve got. At the initial stage, to convince people to see me as normal and that I’m not going to just pass any disease or anything to them at any time.” Among the participants who described experiences of social stigmatization (n = 9), the most frequently mentioned experiences were misconceptions from others (n = 7) and judgment/being talked about by others (n = 5). Structural stigma, in terms of being denied opportunities, was mentioned by 1 participant.

Conceptual model of experiences of people with CHB

The conceptual model of the experiences of people with CHB (Fig. 2) was based on findings from the qualitative literature review and analysis of concept elicitation interviews of people living with CHB in the United Kingdom. Two new concepts were identified during the interviews of this study that were not identified in the literature review. The first was related to time off to attend appointments (n = 6), captured under work/school impact; the second was general health precautions (n = 6), captured under coping strategy.

Fig. 2

Conceptual model of the experience of patients with CHB. CHB chronic hepatitis B, HBQOL, Hepatitis B Quality of Life, HCP, health care professional.

*Asymptomatic is not a sign/symptom or side effect, but people with CHB who are asymptomatic may still experience stigma and other impacts on their daily life. ^†Concept assessed by the HBQOL. ^‡Concept reported in the study interviews but not identified in the literature.

A total of 59 of 93 symptom/impact/stigma concepts from the conceptual model came up in the first 2 of 3 sets of concept elicitation interviews, with 8 interviews per set that were grouped in sequential order by the date the interviews were conducted (supplemental methods). Of the 7 concepts arising in the last set and the 27 concepts that did not arise in interviews at all, most were symptoms that were experienced heterogeneously among people with CHB, many of whom are asymptomatic. This may reflect that these experiences are individual in nature and not broadly experienced by patients with CHB. The literature review collectively provided qualitative data from many patients from different cultural backgrounds, and thus warrant inclusion in the conceptual model.

Content validity of the HBQOL

Cognitive debriefing of the HBQOL

The review of content validity of the HBQOL [3] included exploration of patient interpretation, understanding and relevance of the questionnaire’s concepts, item wording, instructions, response scales/options, recall period, and evaluation/prioritization of the conceptual framework. Overall, the item wording and response scales/options were understood, and participants were able to use them appropriately to answer the items. Participants had difficulty interpreting words or phrases such as stigmatized (n = 2), anxious (n = 2), influential (n = 3), less productive (n = 2), life expectancy (n = 5), worn out and tired (n = 2), and something serious might be wrong because of your hepatitis B (n = 7).

The results of the cognitive debriefing confirmed the conceptual relevance of the HBQOL items; at least a third of participants endorsed all 31 items as being relevant. Items that assessed worry about disease progression, transmission, worsening health, flare-ups, and life expectancy were endorsed as relevant by ≥ 21 participants (Table 9). However, many participants reported that they did not feel/had never felt isolated from others (n = 12) or stigmatized (n = 10), perhaps a reflection that individuals with CHB do not disclose their HBV status to others. The impact of CHB on self-stigma could be considered a missing item from the measure. Fatigue was commonly experienced by participants, but this concept was not comprehensively assessed by the HBQOL. No other missing concepts were identified.

Table 9 Conceptual relevance of the HBQOL items from cognitive debriefing of the HBQOL

The HBQOL does not ask responders to remember what they experienced during a specific recall period (e.g., the previous day, week, or month). When asked by the interviewer, most participants said that recall periods of 7 days (n = 21), 2 weeks (n = 19), 24 h (n = 21), and 1 month (n = 19) could be easily used.

Conceptual framework exploration

Participants were asked to rank HBQOL domains to explore which ones would be most important to people with CHB. Participants ranked anticipation, anxiety, and transmissibility equally as the most important domains (Table 10), and they most frequently ranked disease stigma as the least important.

Table 10 HBQOL questionnaire domain ranking results

Discussion

This study was performed to build a conceptual model of patient experience of CHB and review the content validity of the HBQOL as a measure of CHB symptoms and impacts. The qualitative literature review indicated that people living with CHB experience emotional/psychological impacts and stigma. CHB affects their lifestyle, relationships, and work/school.

In the concept elicitation interviews, fatigue was the most commonly reported, and most participants were worried or anxious about transmitting the virus and about disease progression/death. Others have also noted the importance of chronic fatigue as a primary concern of people with CHB [32]. In this study, the most commonly reported type of stigmatization was self-stigma. Participants’ social functioning was most impacted by the need to take precautions to avoid transmission to others. Combining the results of the qualitative literature review and concept elicitation interviews, a conceptual model of patients’ experiences with CHB was developed to reflect patient experience and help identify patient-relevant PROs.

This study demonstrates the content validity of the HBQOL, including its conceptual relevance, item wording, and response options, in people living with CHB in the United Kingdom [3]. However, the content validity analysis of this questionnaire suggests several potential areas of improvement. Self-stigma, not assessed by the HBQOL, could be measured by a separate self-stigma PRO. A recall period should be added to the HBQOL measure to enable reliable measurement of longitudinal change in patient outcomes. Participants in this study favored the use of a 7-day or 4-week recall period. Finally, rewording of the hard-to-understand words and phrases could improve comprehension of these HBQOL items by participants.

A strength of the interview portion of this study is that the sample size met published recommendations [33]. However, as this study only included patients in the United Kingdom, concept elicitation interviews from different countries/cultures are recommended to confirm the conceptual relevance of the measure. This was partially mitigated by including data of patient experiences with CHB from the literature review of qualitative studies published worldwide in the new conceptual model. The participants in this study appeared to be representative of the population with CHB living in the United Kingdom, which has a high prevalence of people who moved to the United Kingdom with CHB or who acquired it from family members or communities during childhood in the United Kingdom. The high level of education of participants (71% with bachelor’s degree and above) may be higher than for the UK general and CHB-specific populations.

There are some important implications of the current study that should be noted. The present study further supported that the HBQOL assesses concepts that are relevant to patients and showed that some modifications could make it more usable both by patients and in trials in order to measure longitudinal change in HRQoL in patients with HBV. Furthermore, we identified an important concept (self-stigma) that should be measured in CHB trials, which is not assessed by the HBQOL.

Conclusions

This study demonstrates that CHB has emotional/psychological impacts that affect the HRQoL of patients living with CHB and that their prevalence should not be underestimated. The HBQOL [3] appears to be a conceptually relevant and content-valid PRO measure of the overall HRQoL of patients with CHB. However, some modifications should be considered, such as adding a recall period to evaluate patient outcomes over time and rewording the words and phrases that participants found difficult to understand. In addition, clinical studies using the HBQOL to explore HRQoL should consider including an additional PRO in order to measure self-stigma, which we have identified to be an important concept to patients. For holistic assessment, evaluation of HRQoL aspects that matter most to patients, in addition to functional cure clinical outcomes, should be included in future clinical studies.