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Impact of hepatitis C on health related quality of life: A systematic review and quantitative assessment
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--Many health professionals & patients underestimate the true burden of HCV on quality of life. This study examined a tool used in research, HRQOL (health related quality of life), to see how it can be used to evaluate the affect of HCV on quality of life, and the affect on quality of life when a patient achieves an SVR from treatment for HCV. Investigators performed a comprehensive systematic review to quantify the impact of chronic HCV on HRQOL. The study authors report: HCV diminishes quality of life. Patients achieving a sustained viral response (SVR) achieve an improvement in quality of life. The study found that the impact of HCV is most dramatic in social and physical function, general health, and vitality. Data indicate that HCV not only impacts biological functioning, but also neurological, psychological and social functioning. The authors report the feeling on the part of the patient of being stigmatized for having HCV can have an effect: compared with HCV patients who did not feel stigmatized by their disease, those who felt severely stigmatized scored 8 points lower on average on the total Sickness Impact Profile score. In the Author Discussion, the use of the HRQOL test in clinical practice is reviewed.
The authors conclude: chronic HCV diminishes HRQOL across a wide range of clinical anchors. The impact on HRQOL is highly clinically significant and affects physical, social, and mental health domains. Sustained virological response is associated with improvement in HRQOL, thereby indicating that treatment of HCV may improve patient-oriented outcomes in addition to established biological outcomes. We estimate that a change of 4.2 points on the vitality scale of the SF-36 may represent the minimally important difference in HRQOL in HCV. This value may be used to monitor patient outcomes in clinical practice as well as clinical trials.
Hepatology
April 2005
Brennan M.R. Spiegel 1 2 3, Zobair M. Younossi 4, Ron D. Hays 5 6, Dennis Revicki 7, Sean Robbins 8, Fasiha Kanwal 1 2 3 *
1Division of Gastroenterology, VA Greater Los Angeles Healthcare System
2Division of Digestive Diseases, David Geffen School of Medicine at UCLA
3Center for the Study of Digestive Healthcare Quality and Outcomes
4Center for Liver Diseases, Inova Fairfax Hospital
5UCLA School of Public Health
6RAND Corporation Santa Monica
7MEDTAP International
8Global Health Economics, Amgen, Inc.
Introduction
Abstract
Methods & Materials
Author Discussion
Results
INTRODUCTION
Chronic hepatitis C virus (HCV) infection is a prevalent and expensive condition affecting 4 million people in the United States at a cost of over $700 million annually.[1] HCV leads to cirrhosis in up to 20% of those chronically infected[2] and is the primary indication for liver transplantation worldwide.[3] This economic burden is multiplied by the dramatic impact of HCV on health related quality of life (HRQOL) resulting from complications of advanced liver disease such as encephalopathy, variceal hemorrhage, ascites, and liver transplantation.[4-6] However, these end-stage complications are relatively rare compared with the vast majority of patients with HCV in the absence of clinically significant liver disease. Despite the previous consensus that this majority of patients has asymptomatic seropositivity,[7] evolving data now indicate that HCV itself may diminish HRQOL in the absence of advanced liver disease,[8-20] perhaps as a result of extrahepatic symptoms related to HCV, cognitive dysfunction related to HCV, or a negative synergy between HCV and comorbid psychosocial disorders.[10][21]
As awareness grows of the HRQOL decrement from HCV and its clinical consequences, investigators have become progressively interested in measuring HRQOL in HCV clinical trials. This acknowledgment that the burden of HCV extends beyond its economic impact coincides with recommendations by the National Institutes of Health to conduct studies that measure not only traditional biological outcomes in HCV (i.e., HCV RNA, liver enzyme levels, liver histology), but also patient-oriented outcomes.[22] However, most clinicians are not versed in the interpretation of HRQOL in HCV, and patient-oriented outcomes such as HRQOL may fail to resonate with clinicians in the same way as traditional biological parameters. Failure to understand and interpret HRQOL data in HCV may lead to the myopic view that biological outcomes are of primary importance - a view that likely underestimates the true burden of illness engendered by HCV.
In light of the disconnection between the growing importance of measuring HRQOL in HCV and the inability of many clinicians to readily interpret HRQOL differences, it is imperative to establish the clinical significance (in contrast to the statistical significance) of HRQOL score differences by anchoring them to changes in clinically familiar outcomes. By knowing the clinically important differences in HRQOL, researchers, physicians, and patients can better understand not only the overall health burden of HCV, but also the optimal approach to managing HCV. Nonetheless, despite the increasing awareness of HRQOL in HCV, there has been no attempt to systematically review the HRQOL literature in HCV.
In light of this shortcoming we performed a systematic review and quantitative assessment with the following objectives: (1) to identify and summarize the published literature pertaining to HRQOL in HCV; (2) to compare the HRQOL in patients with HCV versus healthy controls; (3) to compare the HRQOL in HCV patients achieving sustained virologic response (SVR) versus those without SVR; (4) to stratify HRQOL data in HCV by clinically-relevant anchors, including liver disease severity anchors and neurological, psychological, and social anchors; and (5) to establish the minimally clinically important HRQOL difference (MCID) in HCV. These data may provide the basis for appropriate sample size calculations in treatment trials, allow physicians to better monitor patient outcomes in clinical practice, and equip patients with the knowledge to better select between competing management strategies.
Materials and Methods
The authors performed a systematic review of MEDLINE, EMBASE, and published abstracts to identify relevant English-language publications from January 1990 to June 2004.
ABSTRACT
Hepatitis C virus (HCV) diminishes health related quality of life (HRQOL), and it is now common to measure HRQOL in clinical trials. We sought to summarize the HRQOL data in HCV, and to establish the minimally clinically important difference (MCID) in HRQOL scores in HCV. We performed a systematic review to identify relevant studies, and converted HRQOL data from each study into clinically interpretable statistics. An expert panel used a modified Delphi technique to estimate the MCID in HCV.
We found that patients with HCV scored lower than controls across all scales of the SF-36.
Patients achieving sustained virological response (SVR) scored higher across all scales versus patients without SVR, especially in the physical health domains.
HRQOL differences did not correspond with differences in liver histology or ALT levels.
Based upon the published data, the expert panel concluded that the SF-36 vitality scale was most relevant in patients with HCV, and generated a mean MCID of 4.2 points on this scale.
In conclusion, patients with HCV have a clinically significant decrement in HRQOL versus controls, and physical HRQOL improves in patients achieving SVR but not in those without SVR. The data further suggest that traditional outcomes fail to capture the full spectrum of illness related to chronic HCV. A difference of 4.2 points on the SF-36 vitality scale can be used as an estimate of the MCID in HCV, and this value may be used as the basis for power calculations in clinical trials evaluating HRQOL.
AUTHOR DISCUSSION
The burden of disease engendered by chronic HCV extends beyond its impact on traditional biological outcomes to include a negative impact on patient-oriented outcomes such as HRQOL. It is now common practice to include HRQOL as a primary outcome in clinical trials, to incorporate HRQOL in cost-effectiveness analyses, and to monitor HRQOL in everyday clinical practice in HCV. In light of these trends, we performed a comprehensive systematic review to quantify the impact of chronic HCV on HRQOL. Our analysis has five key findings: First, patients with HCV have consistently diminished HRQOL compared with matched controls without HCV. Second, patients with HCV achieving SVR have an improved HRQOL compared with those without SVR. Third, the impact of HCV is most pronounced on the vitality, general health, physical function, and social function scales of the SF-36 Health Survey, thereby indicating an impact across a wide range of HRQOL domains. Fourth, the impact of HCV on HRQOL is likely to be clinically important as measured by proposed criteria for determining the significance of HRQOL effect sizes.[24] Last, traditional outcomes in both clinical management and treatment trials, such as ALT levels and early histological changes, fail to correlate with HRQOL, thereby suggesting that traditional outcomes may fail to capture the full spectrum of illness related to chronic HCV.
The insight that HCV diminishes HRQOL is a necessary first step to understand why it is important to measure HRQOL in clinical practice. However, knowing that HCV diminishes HRQOL is insufficient for knowing how to use this information in clinical practice. This practical challenge can be met by establishing the minimal change in HRQOL that patients with HCV perceive to be important. We therefore convened an expert panel to establish the MCID in HCV using a modified Delphi technique.[27] The panel relied upon existing construct-anchored HRQOL data in HCV to estimate the MCID for the vitality scale of the SF-36, and generated a value of 4.2 with an ES of 0.2. This value can be used in everyday clinical practice and in clinical trials. For example, in clinical practice physicians can measure patient outcomes by routinely administering the 4-item SF-36 vitality scale during office visits. If a patient fails to achieve an increase of 4.2 points over time (corresponding ES = 0.2), then it implies that the ongoing care has failed to perceptively improve the patient's HRQOL. In clinical trials, the MCID can be used as a yardstick to determine whether patients have benefited from the study intervention. Specifically, patients may be defined as responders if they achieve or exceed the MCID of 4.2 or an ES of 0.2 on the vitality scale. This can be used as the basis for power calculations. Table 8 provides the estimated sample sizes needed to detect a difference of 5%, 10%, 15%, 20% and 25% between 2 groups at a power of 80% and 90%.
Our analysis has several strengths. First, we performed an explicit and reproducible systematic review to identify relevant data across several sources, including published manuscripts from two bibliographic databases and published abstracts from 4 subspecialty journals. Second, we relied upon a pre-specified conceptual model to guide our data abstraction. Third, in recognition that different clinical anchors have variable impacts on HRQOL, we stratified our analysis across a comprehensive range of neurological, psychological, social, and liver disease severity anchors. Fourth, in accordance with recommendations for interpreting HRQOL, we selected quantitative summary estimates that emphasize clinical relevance over statistical significance.[23] Last, our analysis systematically estimates the MCID in HCV - data that may have important clinical usefulness as described above.
Our analysis has potential limitations. First, we estimated the MCID in HCV indirectly by using the results of existing data rather than directly measuring the MCID according to a standard protocol. Therefore, our data should not be confused with a direct measurement of the MCID. However, the indirect approach has been used in other areas of medicine[26] and, in the absence of a directly measured MCID, is an acceptable strategy for estimating this clinically useful value. Future research should aim to directly measure the MCID using the accepted patient-based methods,[23] not only for the SF-36, but also for a disease-targeted measure such as the Hepatitis Quality of Life Questionnaire (HQLQ).[14][35] Second, our estimate of the MCID only applies to the vitality scale of the SF-36. Although the vitality scale in has a priori and clinical data to support its usefulness in HCV, relying on the vitality scale alone does not capture all of the key aspects of HRQOL in HCV. We have therefore made efforts in our systematic review to abstract data across all 8 scales, and believe that a balanced understanding of the relationship between HCV and HRQOL ultimately requires information from all areas of biological, psychological, and social health, and not just one scale alone. Third, the nature of the HRQOL literature in HCV is itself limited by several factors. For example, most of the studies included patients from tertiary care referral centers, and the resulting data may not be generalizable to community-based cohorts with HCV. However, although the degree of HRQOL decrement may be smaller in community versus referral cohorts, there is no reason to expect that the negative impact of HCV on HRQOL will disappear in community-based cohorts. In addition, most of the studies employed the SF-36 Health Survey, a generic measure of HRQOL, and only one used a disease-targeted measure of HRQOL - the HQLQ.[14][35] Because the SF-36 may fail to capture the full range of HRQOL decrements from HCV, it is important to develop and employ disease-targeted instrument such as the HQLQ in addition to generic measures like the SF-36.
In conclusion, chronic HCV diminishes HRQOL across a wide range of clinical anchors. The impact on HRQOL is highly clinically significant and affects physical, social, and mental health domains. Sustained virological response is associated with improvement in HRQOL, thereby indicating that treatment of HCV may improve patient-oriented outcomes in addition to established biological outcomes. We estimate that a change of 4.2 points on the vitality scale of the SF-36 may represent the minimally important difference in HRQOL in HCV. This value may be used to monitor patient outcomes in clinical practice as well as clinical trials.
RESULTS
Study Selection
The search strategy identified 259 titles, of which 32 met explicit inclusion criteria (Fig. 2). Of the 32 studies, all provided sufficient data to calculate either an HRQOL mean group difference or a DID, 20 provided sufficient distributional data to calculate an ES, and none provided criterion-anchored data to measure the MCID.
Results Stratified by Clinical Anchors
HRQOL in HCV Versus Healthy Controls.
Although HCV may diminish HRQOL through complications of advanced cirrhosis, it may also diminish HRQOL in the absence of clinically significant liver disease.[8-20] The mechanism of HRQOL decrement in the absence of liver damage is unclear. Potential mechanisms include the development of extrahepatic somatic symptoms (e.g., HCV-related arthralgia and myalgia), extrahepatic disorders (e.g., HCV-related cryoglobulinemia, sicca syndrome, glomerulonephritis), or HCV-related subclinical cognitive dysfunction, among others.[10][21]
We identified 15 studies that compared HRQOL in patients with compensated HCV seropositivity versus healthy control subjects without HCV.[5][8-20][28] All 15 studies measured HRQOL with the SF-36 Health Survey (refer to the Technical Appendix for information regarding the SF-36).
HRQOL Score Differences:
All 15 studies provided cross-sectional group mean HRQOL differences stratified by HCV status - the clinical anchor in this circumstance. Table 1 presents the data across the 8 SF-36 scales and provides the weighted mean and median for each scale. The largest impact of HCV was in the role-physical scale (HCV vs. healthy control weighted mean cross-sectional difference = -15.8 points), followed by the role-emotional scale (-13.0) and the general health scale (-12.6). Three studies measured differences in the Mental Component Score (MCS) and Physical Component Score (PCS).[9][11][17] The weighted mean differences in MCS and PCS were -12.8 and -9.1, respectively. Although there is no established minimally important difference in SF-36 scale scores in HCV, a review of SF-36 data in other diseases revealed that a 3-5 point difference in scale scores may represent a clinically important difference.[29] Although these thresholds are potentially arbitrary and fail to account for the underlying variation in HRQOL scores,[30] they suggest that the 7-15 point differences observed in compensated HCV versus healthy controls represent a clinically important difference across all SF-36 scales.
Effect Sizes:
Ten studies provided sufficient data to calculate cross-sectional ES for HRQOL in compensated HCV versus healthy non-HCV controls.[5][8][12-20] The largest ES for HCV was in the social function and general health scales (both weighted mean ES = -0.7), followed by the vitality and role-physical scales (both -0.6). Two studies measured ES in the MCS and PCS scores. The weighted mean estimates were -1.0 and -0.75 for MCS and PCS, respectively. Although there is no established ES corresponding with a minimally important difference in HCV, the conventional benchmark for a small ES is <0.2.[30] By this standard the 0.3 to 1.0 range in ES (using absolute values) observed in compensated HCV versus healthy controls likely represents a clinically meaningful impact on HRQOL.
Summary of HRQOL in HCV vs. Healthy Controls.
The data consistently reveal that patients with compensated HCV seropositivity have a diminished HRQOL compared with healthy controls. Moreover, the impact of HCV on HRQOL is moderate to large across all SF-36 scales. The impact of HCV is most dramatic in social and physical function, general health, and vitality.
HRQOL Stratified by Sustained Virological Response (SVR) Status.
The traditional short-term goal of treatment in HCV is to achieve SVR. Although SVR is a biochemical rather than clinical outcome measure, it is considered to be a surrogate marker for clinically relevant outcomes including progression to cirrhosis and survival. Therefore, SVR is a relevant clinical anchor for HRQOL data. We identified 9 studies that measured HRQOL stratified by SVR.[8][31-38]
HRQOL Score Differences:
Seven studies measured HRQOL DID scores (see equation [2] in Technical Appendix) stratified by SVR status (Table 3).[8][31-35][38] The largest DID score was in the role-physical scale (weighted mean = 10.4), followed by role-emotional (7.5), general health (7.1), and vitality (6.6). The weighted mean DID scores in the MCS and PCS were 2.7 and 2.6, respectively. Only 2 studies reported cross-sectional mean HRQOL score differences stratified by SVR.[36][37] The largest mean difference was in the physical function scale (11.1), followed by mental health (7.7) and social functioning (7.5).
Effect Sizes:
Six studies provided sufficient data to calculate an ES for HRQOL in patients achieving SVR following antiviral therapy versus nonresponders.[32-36][38] Two studies presented cross-sectional ES data[36][37] and 4 presented longitudinal data.[32-35] Consistent with the DID scores, the impact of SVR was most pronounced on the role-physical and general health scales (mean weighed ES = 0.4), followed by vitality, physical function, and social function (0.3 for latter 3 scales).
Summary of HRQOL Stratified by SVR.
The data indicate that HRQOL is consistently worse in patients that fail to achieve SVR versus patients that develop viral clearance following treatment for HCV. The impact of SVR is most pronounced in the role-physical and general health scales. The data suggest that patients achieving SVR may have clinically significant improvements in these HRQOL domains compared to patients with an unsuccessful treatment course.
HRQOL Stratified by Neuropsychosocial Anchors.
HRQOL Score Differences.
Data indicate that HCV not only impacts biological functioning, but also neurological, psychological and social functioning. These neuropsychosocial effects of HCV adversely impact HRQOL. We identified 6 studies that measured HRQOL stratified by a neuropsychosocial anchor.[9][10][15][39-41] One study measured a strictly neurological anchor (subclinical cognitive dysfunction determined by evoked potentials),[10] 4 measured psychological anchors (including depression, psychiatric comorbidity, and emotional distress),[9][15][39][40] and one measured a social anchor (stigmatization).[41] Five of the 6 studies measured HRQOL with the SF-36 (Table 5),[9][10][15][39][40] and one used the Sickness Impact Profile.[41] The largest impact on HRQOL was in the SF-36 role-emotional scale, with cross-sectional HRQOL differences ranging from -4.0 (subclinical cognitive dysfunction) to -39.0 (emotional distress). Perhaps more surprising, all of the somatic scales (physical function, role-physical, bodily pain) also demonstrated large group mean differences. Zickmund et al. found similarly large effects on Sickness Impact Profile scores stratified by patient-reported stigmatization.[41] Compared with HCV patients who did not feel stigmatized by their disease, those who felt severely stigmatized scored 8 points lower on average on the total Sickness Impact Profile score.
Effect Sizes:
Our review failed to identify any study presenting sufficient distributional data to calculate an ES across a neurological, psychological, or social anchor.
Summary of HRQOL Stratified by Neuropsychosocial Anchors.
The data indicate that there are large HRQOL differences in HCV across neurological, psychological, and social anchors. These results are not unexpected since each of these anchors, when present, may independently diminish HRQOL. It is difficult to determine whether the large impact on HRQOL observed in these studies is primarily related to the specific anchors, or whether there is a negative synergistic effect between these anchors and HCV.
HRQOL Stratified by Liver Disease Severity Anchors.
HCV is associated with a wide-range of extrahepatic manifestations. Nonetheless, its primary biological impact is on the liver. Although liver damage does not always correspond with patient symptoms and overall health status, liver disease severity is an important surrogate outcome in the management of HCV. Traditional markers of liver disease severity include histological activity (e.g., Knodell scores), biochemical activity (e.g., ALT levels), and clinical activity (e.g., Child's class, MELD score). We identified 5 studies that measured HRQOL stratified by one or more liver disease severity anchor(s) (Table 6).[5][8][15][36][42]
Histological Activity Anchors:
Two studies stratified HRQOL by histological anchors.[8][36] McHutchison et al. found no significant difference in HRQOL in patients with a >5 point change in Knodell score (a histologically important change in disease activity) versus no change in Knodell score.[8] The HRQOL DID scores ranged from 0.5 in physical function to 2.4 in vitality. Similarly, Coughlan et al. detected no significant HRQOL difference in patients with a <3 Knodell score versus >4 Knodell score following treatment for HCV.[36] The cross-sectional mean HRQOL differences ranged from -1.8 in role-physical (suggesting a unexpectedly higher HRQOL in patients with worse histological activity) to 2.2 in vitality.
Biochemical Activity Anchors:
Two studies stratified HRQOL by ALT levels.[8][42] McHutchison et al. found no significant difference in HRQOL in patients with a >3 times improvement in the ALT ratio (a clinically important change in biochemical activity) versus no change in the ALT ratio.[8] Similarly, Miller et al. detected no difference in either the MCS or PCS in patients with high versus normal ALT levels.[42] In fact, there was a trend towards lower HRQOL in those with normal levels (cross section mean difference for MCS = -0.1, PCS = -3.3).
Clinical Activity Anchors:
Two studies compared HRQOL in patients with HCV-related Child's class B cirrhosis versus noncirrhotic chronic HCV.[5][15] Both studies revealed large differences in HRQOL across all scales. The cross-sectional mean differences ranged from -7.0 for general health to -44.0 for role-physical and PCS, and the ES ranged from -0.3 for general health to -1.4 for physical function and PCS.
Summary of HRQOL Stratified by Liver Disease Severity Anchors.
The data suggest that subtle histological or biochemical changes are not perceived as clinically important by patients, thereby suggesting that these traditional biological outcomes may fail to capture the full spectrum of illness related to chronic HCV. In contrast, there are large and clinically significant differences in HRQOL in patients with versus without cirrhosis. The large differences in HRQOL stratified by cirrhosis are not unexpected given the well-documented negative impact that cirrhosis itself exerts on HRQOL, independent of concurrent HCV.
Expert Panel Estimate of MCID in HCV
Based upon a priori hypotheses and data from the systematic review, the expert panel concluded that the SF-36 vitality scale captures the HRQOL domain of the SF-36 that is most relevant to patients with HCV. Specifically, because HCV and its treatment are associated with a range of devitalizing symptoms such as tiredness, lack of energy, and lassitude, the SF-36 vitality scale is pertinent in HCV. Moreover, our systematic review revealed that vitality was one of the key domains most affected by HCV. Of the 8 SF-36 scales, the vitality scale ranked in the top 3 for size of HCV impact on HRQOL across all clinical anchors.
Therefore, rather than develop individual MCID estimates for each of the 8 SF-36 scales, the panel focused its estimates on the vitality scale. Based upon independent review of the systematic review, the panel initially generated a mean MCID of 4.9 points (range, 2-6) on the SF-36 vitality scale. After convening in-person and completing the remaining steps of modified Delphi procedure, the expert panel generated a mean MCID of 4.2 points (range, 3-5) on the SF-36 vitality scale, with a corresponding ES of 0.2 (range, 0.15-0.25).
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