ORIGINAL ARTICLE. Received June 16, 2011; accepted November 1, LIVER TRANSPLANTATION 18: , 2012

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1 LIVER TRANSPLANTATION 18: , 2012 ORIGINAL ARTICLE Development and Validation of a Questionnaire Evaluating the Impact of Hepatitis B Immune Globulin Prophylaxis on the Quality of Life of Liver Transplant Recipients Monica Franciosi, 1 Lucio Caccamo, 2 Paolo De Simone, 3 Antonio Daniele Pinna, 4 Giovanni Giuseppe Di Costanzo, 5 Riccardo Volpes, 6 Vincenzo Scuderi, 7 Paolo Strignano, 8 Patrizia Boccagni, 9 Patrizia Burra, 10 and Antonio Nicolucci 1 for the TWINS I Study Group 1 Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Consortium, Santa Maria Imbaro, Italy; 2 Department of General Surgery and Liver Transplantation, Ca Granda-Maggiore Polyclinic Hospital, Scientific Institute for Research, Hospitalization, and Health Care, Milan, Italy; 3 Department of General Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy; 4 Liver and Multiorgan Transplantation, Department of General Surgery, Sant Orsola-Malpighi Polyclinic, Bologna, Italy; 5 Department of Hepatology, A. Cardarelli Hospital for National Relief, Naples, Italy; 6 Mediterranean Institute for Transplantation and High Specialization Therapies, Palermo, Italy; 7 Department of Hepatobiliary Surgery and Liver Transplantation, A. Cardarelli Hospital for National Relief, Naples, Italy; 8 General Surgery and Liver Transplant Center, S. Giovanni Battista Hospital, Turin, Italy; and 9 Hepatobiliary Surgery and Liver Transplantation Unit and 10 Multivisceral Transplant Unit (Gastroenterology), Department of Surgical and Gastroenterological Sciences, Padua University Hospital, Padua, Italy To date, there is still a lack of instruments for specifically assessing the impact of anti hepatitis B virus prophylaxis after liver transplantation (LT) on health-related quality of life (HRQOL) and treatment satisfaction. Focusing on the use of hepatitis B immune globulin (HBIG), we developed and validated the Immunoglobulin Therapy After Liver Transplantation Questionnaire (ITaLi-Q), which includes 41 items and covers 5 domains (side effects, positive and negative feelings, impact on the flexibility of daily activities, support, and satisfaction). The questionnaire was tested by 177 consecutive LT patients [71.8% were male, 38.4% were more than 60 years old, 58.8% were on intramuscular (IM) HBIG, and 41.2% were on intravenous (IV) HBIG]. A factor analysis confirmed the hypothesized structure, and a multitrait, multi-item analysis showed favorable psychometric characteristics for ITaLi-Q: item-scale correlations > 0.40 for all items but 1, high scaling success rates (>90% for all scales but 1), excellent internal consistency (Cronbach s a 0.8 for all scales), and good reproducibility (test-retest > 0.70 for all scales but 2). ITaLi-Q was able to discriminate between subgroups of patients according to their clinical and sociodemographic characteristics. In comparison with patients on IV HBIG, patients on IM HBIG reported significantly better HRQOL scores on the Flexibility ( versus , P ¼ 0.01) and Negative Feelings scales ( versus , P ¼ 0.04), but they reported worse HRQOL scores on the Side Effects scale ( versus , P < 0.001). No differences were found between the route of HBIG administration and the Satisfaction, Positive Feelings, Impact, and Support scales. In conclusion, ITaLi-Q showed adequate psychometric characteristics and revealed that the route of HBIG administration has a significant impact on specific HRQOL domains beyond a patient s satisfaction. Liver Transpl 18: , VC 2012 AASLD. Received June 16, 2011; accepted November 1, Additional Supporting Information may be found in the online version of this article. Abbreviations: HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HRQOL, health-related quality of life; IM, intramuscular; ITaLi- Q, Immunoglobulin Therapy After Liver Transplantation Questionnaire; IV, intravenous; LT, liver transplantation; SF-12, Short Form 12. The members of the TWINS I study group are listed in the supporting information. This study was unconditionally supported by Biotest Italia S.r.l. Address reprint requests to Monica Franciosi, M.Sc., Department of Clinical Pharmacology and Epidemiology, Mario Negri Sud Consortium, Via Nazionale 8/A, Santa Maria Imbaro, Italy Telephone: þ ; FAX: þ ; franciosi@negrisud.it DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2012 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 FRANCIOSI ET AL. 333 The recurrence of the primary disease can have a negative impact on long-term outcomes after liver transplantation (LT). 1 Before the introduction of human hepatitis B immune globulin (HBIG) and the subsequent introduction of nucleos(t)ide analogues, hepatitis B virus (HBV) reinfection was universal after LT and was associated with significant morbidity and mortality. 2 Reinfection prophylaxis is crucial for guaranteeing long-term results, and it is currently accepted as the standard of care after LT for HBV surface antigen positive patients. 3 As a part of any anti- HBV prophylaxis after LT, HBIG can be administered by an intravenous (IV) route or an intramuscular (IM) route. The 2 modalities differ with respect to dosing, timing, schedules, and side effects, and they can have different impacts on the quality of life and satisfaction of patients. 3-7 In the long term after LT, a lack of adherence to medications is a well-known factor limiting outcomes. Particularly in this setting, HBIG is commonly reported to be a cause of discomfort for patients, and in some cases, it is spontaneously withdrawn; this event can eventually lead to HBV reinfection. Efforts toward the definitive acceptance of HBIG by HBV-infected LT recipients are crucial for maintaining the current gold-standard outcome paradigm for HBV-related disease after LT even over the very long term. However, the satisfaction of patients with HBIG is hard to define because of a lack of appropriate instruments for exploring the impact of HBIG and its related side effects on daily activities as well as other aspects of patients quality of life. The aim of this article is the description of the development and validation of the Immunoglobulin Therapy After Liver Transplantation Questionnaire (ITaLi-Q), which was originally designed to evaluate the impact of HBIG on the quality of life and satisfaction of LT patients. MATERIALS AND METHODS The questionnaire was created in 2 successive phases: development and psychometric validation. Development of ITaLi-Q The questionnaire was developed through a multistage procedure that included domain identification, item generation, and questionnaire formatting. 8,9 Domain Identification and Item Generation Four investigators (M.F., A.N., L.C., and P.D.S.) developed a preliminary questionnaire after a careful review of the medical literature on prophylaxis for HBV recurrence after LT. The draft was ultimately discussed by a working group that included LT nurses (1 nurse from each of the 9 participating centers) and 20 delegates from patient associations who were on HBIG prophylaxis for at least 1 year (14 men and 6 women; 9 on IV HBIG and 11 on IM HBIG). Five relevant domains were identified: the side effects of HBIG, the impact of HBIG prophylaxis on patients perception of well-being, the impact of HBIG prophylaxis on the flexibility of daily activities, the support for HBIG prophylaxis, and the satisfaction with HBIG. Among HBIG-related side effects, the following were considered relevant: pain at the injection site, skin reactions (rash, bruises, and swelling), fatigue, and dizziness. Questionnaire Formatting The questionnaire was intended to be self-administered by patients. Therefore, we tried to make it selfexplanatory with very simple item wording and grammatical structures. All items were formulated to avoid discrimination by sex, ethnicity, and race. The recall time for the questionnaire was set at 3 months; this was based on the different schedules of HBIG administration (which usually is weekly or bimonthly with IM HBIG, and monthly with IV HBIG). Responses were based on a 5-point Likert scale to maximize differences between the 2 routes of HBIG administration. The questionnaire was generated in Italian. Two investigators reviewed the draft questionnaire to ensure that the instrument looked like it worked and appeared to measure the target domains (face validity). The questionnaire was eventually submitted to a group of 10 LT patients to determine whether it was easy to understand in clinical practice, and 10 minutes on average was deemed sufficient for its completion. These patients were not involved in the generation process and were not included in the subsequent validation. Psychometric Validation Any instrument designed for the evaluation of clinical outcomes across groups should score the perceived quality of life in a way that allows a clear distinction to be made between patients experiencing well-being and patients not experiencing well-being. Validation is necessary to ensure that the questionnaire meets the required validity, reliability, and discriminative proprieties. To facilitate the comparability of the different scores, all crude scores were expressed as values between 0 and 100, with higher scores indicating better quality of life or higher satisfaction. The formula used to convert the scores was as follows: Converted score ¼½ðScore MinimumÞ=ðMaximum MinimumÞŠ 100 Reliability was assessed with an evaluation of both internal consistency and stability. The internal consistency was measured with Cronbach s a with a minimum accepted level of 0.7, whereas stability was evaluated with the degree of agreement between observations on 2 successive occasions separated by a 2-week interval with 0.5 as the minimum accepted level (test-retest reliability). 8,10

3 334 FRANCIOSI ET AL. LIVER TRANSPLANTATION, March 2012 The construct validity was tested to ensure that the questionnaire showed the hypothesized structure. To this end, different statistical approaches were used. The reduction of the questionnaire and the identification of the underlying dimensions were accomplished through a principal component factor analysis with orthogonal varimax rotation. In addition, a multitrait, multi-item method was used to test the convergent and discriminant validity of items. 11 This method allowed us to determine whether each item in a scale was substantially related to the total score computed from the other items in that scale (item convergent validity criterion) and whether each item correlated significantly higher with its corrected scale score versus other scale scores in the instrument (item discriminant validity criterion, r 0.40). 12,13 The criterion validity (ie, the strength of the relationship between 2 or more measures expected to assess the same domains) was evaluated with the generic Short Form 12 (SF-12) questionnaire. 14 Finally, the discriminative properties of ITaLi-Q for IV and IM patients were tested with the Mann- Whitney U test, whereas the Kruskall-Wallis 1-way analysis of variance was used for multiple samples. To confirm the discriminative proprieties, effect sizes across group stratifications were also calculated. The effect size represents the difference in the scores of 2 groups divided by the pooled standard deviation of the scores. The generally accepted benchmarks are 0.20 for a small effect size, 0.50 for a moderate effect size, and 0.80 for a large effect size. 15 The characteristics of the patients were described with means and standard deviations (continuously distributed variables) or with numbers and percentages (categorical variables). Differences in the baseline characteristics were tested with the unpaired t test statistic or the Mann-Whitney U test for continuous variables, and the v 2 statistic or Fisher s exact test was applied for categorical variables as appropriate. Missing Data The completeness of the data was evaluated through an examination of the percentage of responders with missing data for each item and for each scale. If responders answered 50% or more of the items for a scale, the missing data were replaced by personspecific averages. 8,16 Study Population Psychometric validation of the questionnaire was performed in the context of a cross-sectional observational study: the two evaluations about the HBV ImmunoglobuliNS 1 (TWINS 1) study. This study was approved by local ethical committees and was carried out in compliance with the Declaration of Helsinki. Written consent was obtained from each patient. Patients requiring HBV prophylaxis after LT were involved in the study if they satisfied the following eligibility criteria: they were 18 years old or older, at least 1 year had passed since LT, they had been treated with the same HBIG formulation (IM or IV) for at least 6 months, and they had sufficient cognitive capacity to understand the aims of the study and fill out the questionnaire. At study entry, all enrolled patients were requested to complete ITaLi-Q. The questionnaire was selfadministered and anonymous, and it was handed to each patient in a closed envelope. The investigators were asked to also collect a minimum set of clinical and sociodemographic data for each enrolled patient with predefined forms. The questionnaire and all the information were correlated to each patient with a univocal numerical code. A sample of 8 patients per center was scheduled, and the patients were requested to fill out the questionnaire a second time 2 weeks after study entry. A sample of 130 patients was required to detect an effect size 0.5 for differences across scores between patients on IM HBIG and patients on IV HBIG with a statistical power of 80% (a ¼ 0.05). RESULTS As a result of the preliminary phase, a 46-item questionnaire was formed to explore the selected domains. Psychometric Validation The questionnaire was administered to a study population of 177 maintenance LT patients on HBIG prophylaxis, and they were recruited from 9 Italian transplant centers; 104 patients (58.8%) were on IM HBIG, and 73 (41.2%) were on IV HBIG. At study entry, all patients completed ITaLi-Q. The demographic and clinical characteristics of the patients are reported in Table 1. No significant differences were observed between the 2 groups of patients (Table 1). Overall, 49 patients completed the retest questionnaire. Factor Analysis Varimax rotation revealed 12 factors with eigenvalues >1. The scree test indicated a 9-factor solution that accounted for 69.1% of the total variance. All 46 items achieved the required loading of 0.3 (see Appendix 1 in the supporting information). However, 4 items were discarded because the loading was higher on domains different from the hypothesized factors, and 1 additional item was excluded because of a poor item-scale correlation. The psychometric characteristics described hereafter refer to the final version of the questionnaire, which included 37 items grouped in 8 scales and 4 single items (a detailed description of the final version of ITaLi-Q is reported in Appendix 2 in the supporting information, and the full Italian version of ITaLi-Q is presented in Appendix 3 in the supporting information): 1. Side Effects (4 items; Cronbach s a ¼ 0.78). This scale explores the frequency of HBIG-related side effects.

4 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 FRANCIOSI ET AL. 335 TABLE 1. Patient Characteristics Variable Overall (n ¼ 177) IM HBIG (n ¼ 104) IV HBIG (n ¼ 73) P Value Age (years)* [n (%)] 57 (32.2) 32 (30.8) 25 (34.3) [n (%)] 52 (29.4) 29 (27.9) 23 (31.5) >60.0 [n (%)] 68 (38.4) 43 (41.3) 25 (34.2) Male sex [n (%)] 127 (71.8) 70 (67.3) 57 (78.1) 0.11 Status [n (%)] 0.87 Single 19/172 (11.0) 12/100 (12.0) 7/72 (9.7) Married 133/172 (77.3) 77/100 (77.0) 56/72 (77.8) Divorced/widowed 20/172 (11.6) 11/100 (11.0) 9/72 (12.5) Education 5 years [n (%)] 45/171 (26.3) 26/100 (26.0) 19/71 (26.8) years [n (%)] 59/171 (34.5) 37/100 (37.0) 22/71 (31.0) 9-13 years [n (%)] 54/171 (31.6) 32/100 (32.0) 22/71 (31.0) >13 years [n (%)] 13/171 (7.6) 5/100 (5.0) 8/71 (11.3) Years after LT <2 years [n (%)] 44/165 (26.7) 25/97 (25.8) 19/68 (27.9) years [n (%)] 36/165 (21.8) 20/97 (20.6) 16/68 (23.5) years [n (%)] 52/165 (31.5) 30/97 (30.9) 22/68 (32.4) >10.0 years [n (%)] 33/165 (20.0) 22/97 (22.7) 11/68 (16.2) Previous hepatocellular carcinoma [n (%)] 74 (41.8) 42 (40.4) 32 (43.8) 0.53 *The data are presented as means and standard deviations. TABLE 2. Results of Multitrait, Multi-Item Analysis: Psychometric Characteristics of ITaLi-Q Completeness Item-Scale Scaling Scale Items (n) (%) Correlation Cronbach s a Retest Success Rate (%) Side Effects Impact Negative Feelings Positive Feelings Flexibility Support Need for Support Satisfaction Impact (3 items; Cronbach s a ¼ 0.85). This scale is meant to assess the impact of HBIG-related side effects on daily activities. 3. Negative Feelings (6 items; Cronbach s a ¼ 0.90). This scale measures the negative feelings associated with HBIG use (eg, anxiety and fatigue). 4. Positive Feelings (5 items; Cronbach s a ¼ 0.76). This scale explores the positive feelings associated with HBIG use (eg, the perceived importance of one s own health status). 5. Flexibility (8 items; Cronbach s a ¼ 0.90). This scale measures the impact of HBIG on the flexibility of daily activities (eg, planning work or leisure). 6. Support (3 items; Cronbach s a ¼ 0.81). This scale measures the support that a patient receives to comply with the scheduled administration of HBIG (eg, being reminded or being accompanied to outpatient follow-up visits). 7. Need for Support (3 items; Cronbach s a ¼ 0.85). This scale assesses the need for help in complying with HBIG administration as perceived by the patient. 8. Satisfaction (5 items; Cronbach s a ¼ 0.88). This scale explores the degree of satisfaction related to HBIG (eg, overall satisfaction, satisfaction with the route of administration, and flexibility). Item-scale correlations were used to evaluate the internal consistency of items and largely exceeded the minimal accepted value of 0.40 for all items but 1 included in the Side Effects scale (0.38). Item discriminant validity was measured with the scaling success rate, that is, the percentage of times that items correlated significantly more with their corrected scale scores than other scale scores in the instrument. The scaling success rate was high for all ITaLi-Q scales and ranged from 88.6% for the Positive Feelings scale to 100% for the Negative Feelings, Impact, Need for Support, and Support scales (Table 2).

5 336 FRANCIOSI ET AL. LIVER TRANSPLANTATION, March 2012 TABLE 3. Descriptive Statistics for ITaLi-Q Scale Mean Standard Deviation Lowest Highest At Floor (%) At Ceiling (%) Side Effects Impact Negative Feelings Positive Feelings Flexibility Support Need for Support Satisfaction TABLE 4. Pearson s Correlation Coefficients Across the ITaLi-Q Scales Scale Side Effects Impact Negative Feelings Positive Feelings Flexibility Support Need for Support Satisfaction Side Effects Impact Negative Feelings Positive Feelings Flexibility Support Need for Support Satisfaction Pearson s 1 P value Pearson s P value <0.01 Pearson s P value <0.001 <0.001 Pearson s P value 0.70 < Pearson s P value <0.001 <0.001 < Pearson s P value Pearson s P value < < Pearson s P value <0.001 <0.001 < < <0.01 Completeness of Data The number of missing values was low (<10% for 34 items, 11.0%-14.9% for 3 items on the Impact scale, and 11.0% for 1 item on the Satisfaction scale). Scores were provided by 90% or more of the patients for all the subscales of ITaLi-Q with the exception of the Impact (81.3%) and Support scales (87.7%; Table 2). Floor effects were lower than 10% for all the scales except Support, whereas the ceiling effect was substantially consistent across all scales (ie, >10%; Table 3). Reliability of Scale Scores For all scales, Cronbach s a largely exceeded the recommended value of 0.70 (Table 2), 14 and it ranged from 0.76 for the Positive Feelings scale to 0.90 for the Flexibility and Negative Feelings scales. Apart from the Positive Feelings (0.49) and Need for Support scales (0.48), the test-retest reliability s exceeded the requested value of 0.5. Construct Validity Convergent validity was assessed with a correlational analysis (Pearson s product-moment correlation). The ITaLi-Q scales assessing the impact of the side effects of treatment on daily activities (ie, Flexibility, Impact, and Side Effects) showed higher correlation s than the scales exploring the impact on psychological functioning (ie, Negative Feelings and Positive Feelings) or the Satisfaction scale (Table 4). Concurrent validity between ITaLi-Q and the 2 components of SF-12 was tested with a correlational analysis (Table 5). The mental component of SF-12 showed a moderate-to-mild correlation with the

6 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 FRANCIOSI ET AL. 337 TABLE 5. Pearson s Correlation Coefficients Between the ITaLi-Q Scales and the 2 Components of SF-12 SF-12 Physical Composite Score Mental Composite Score Side Effects Impact Negative Feelings Positive Feelings Flexibility Support Need for Support Satisfaction Pearson s P value 0.08 <0.01 < < Pearson s P value 0.13 <0.01 < < <0.001 Flexibility (0.51, P < 0.001), Negative Feelings (0.35, P < 0.001), Satisfaction (0.28, P < 0.001), and Impact scales (0.33, P < 0.01), whereas the physical component of SF-12 showed a mild correlation with the Negative Feelings (0.35, P < 0.001), Flexibility (0.30, P < 0.001), and Impact scales (0.34, P < 0.01). Discriminant Validity ITaLi-Q was able to discriminate subgroups of patients according to their clinical and sociodemographic characteristics (Supporting Table 1). Patients treated with IM HBIG reported significantly higher health-related quality of life (HRQOL) scores on the Flexibility scale ( versus , P ¼ 0.01, effect size ¼ 0.36) and the Negative Feelings scale ( versus , P ¼ 0.04, effect size ¼ 0.25) but lower HRQOL scores on the Side Effects scale ( versus , P < 0.001, effect size ¼ 0.71) in comparison with patients on IV HBIG. No differences were observed between patients on IV HBIG and patients on IM HBIG with respect to the Satisfaction, Positive Feelings, Impact, Need for Support, and Support scales. Differences between ITaLi-Q and SF-12 scores were also influenced by the sex, age, and level of education. That is, males reported higher HRQOL scores on the Side Effects scale (effect size ¼ 0.41) and on the physical component of SF-12 (effect size ¼ 0.49). In comparison with people who were 55 years old or younger, patients more than 60 years old reported higher scores on the Negative Feelings (effect size ¼ 0.48) and Impact scales (effect size ¼ 0.80), whereas patients with a higher level of education reported lower HRQOL scores on the Flexibility (effect size ¼ 0.97) and Positive Feelings scales (effect size ¼ 0.78). Patients with previous hepatocellular carcinoma reported higher HRQOL scores on the Impact (effect size ¼ 0.45) and Side Effects scales (effect size ¼ 0.41). ITaLi-Q scores by the types of HBIG and the patient characteristics are reported in Supporting Table 2. In comparison with patients on the IV formulation, patients on IM HBIG reported a higher impact of HBIG-related side effects across all subgroups. Higher scores on the Negative Feelings scale were related to the use of IM HBIG regardless of sex, even if the level of statistical significance was reached only among women. Patients on IM HBIG reported a higher level of flexibility regardless of their age or history of hepatocellular carcinoma. DISCUSSION The aims of the current study were (1) to develop a tool for measuring the impact of HBIG prophylaxis on HRQOL and treatment satisfaction among LT recipients, (2) to test its psychometric properties, and (3) to provide evidence about its validity. The ultimate goal of organ transplantation in general and LT in particular is to help patients return to a productive and fulfilling life. This concept is the core of any HRQOL measurement, and concurrently with improvements in patient survival, recipients HRQOL has become an important focus of both care and clinical outcomes research on the condition that it should be based on reliable and psychometrically robust instruments. Our study shows that ITaLi-Q is a valid, reliable, and feasible instrument for exploring the impact of HBIG prophylaxis on the quality of life and satisfaction of patients after LT for HBV-related disease. Moreover, ITaLi-Q addresses specific HRQOL dimensions relevant to LT recipients, such as flexibility in performing daily life and leisure activities, treatment side effects, and limitations due to HBIG. In terms of feasibility, the response rate was high (all patients completed the questionnaire), and the time required to complete the questionnaire was short (10 minutes on average). ITaLi-Q also showed satisfactory levels of reliability, as indicated by Cronbach s a s (ie, internal consistency) and test-retest s (ie, stability over time). The moderate-tohigh intercorrelation across the scales included in ITaLi-Q confirmed its homogeneous construct of HRQOL. These intercorrelations seemed to be stronger between those scales exploring the impact of HBIG on daily activities and weaker between scales assessing the satisfaction of patients or psychological aspects. The construct validity of ITaLi-Q was further supported by the moderate-to-mild correlation between its scales and the SF-12 components. We found only a minimum floor effect, and this suggests that the questionnaire can perform well once it is used longitudinally to detect the worsening of a patient s HRQOL and/or satisfaction. On the other hand, the high ceiling effect might limit its efficacy for

7 338 FRANCIOSI ET AL. LIVER TRANSPLANTATION, March 2012 detecting improvements over time. A longitudinal validation study might be necessary to better appreciate the utility of this instrument in detecting changes over time. It is noteworthy that the study was conducted before the clinical introduction of subcutaneous HBIG. 17 The inclusion of this route in a future study might further strengthen the evidence supporting the discriminative properties of our questionnaire. Some aspects of HBIG prophylaxis were correlated to broader HRQOL dimensions, such as the mental and physical components of SF-12. The scale assessing the impact of HBIG on the flexibility of daily activities was correlated to the mental component of SF- 12, whereas the impact of HBIG-related side effects on daily activities and anxiety/fatigue secondary to HBIG were related to both the mental and physical components of SF-12. The perceptions of patients about the impact of HBIG on different HRQOL domains were influenced by clinical and demographic characteristics, and conversely, both routes of HBIG administration influenced different aspects of HRQOL. As expected, patients on IM HBIG reported higher levels of local side effects. Nevertheless, the possibility of administering HBIG at home was associated with a favorable impact on daily flexibility and fewer negative feelings (ie, anxiety and fatigue). No differences between IV HBIG and IM HBIG were reported for other dimensions explored by ITaLi-Q. In addition, patients on IM HBIG scored better on the mental and physical components of SF-12 than patients treated with IV formulations. Although these differences did not reach the level of statistical significance, they suggest better perceptions of overall HRQOL among patients using IM HBIG. In our study, women scored lower (ie, a poorer quality of life) than men on the physical component of SF- 12 and on the Side Effects scale, and this indicates that sex is a potential factor influencing HRQOL after LT. These differences could be explained by social and psychological variables. 18 The difference in the Side Effects scale may also be attributed to higher symptom sensitivity among women, which is defined as a readiness to perceive physical sensations as symptoms of illness, 19 and this seems to be consistent with previous literature data. 20 As expected, age and education level were also associated with different perceptions of HRQOL, and these differences were probably mediated by less demanding work responsibilities and different social roles associated with older age and a lower degree of education. In our study, older people reported better perceptions of HRQOL on domains assessing the impact of side effects on daily activities and negative feelings (eg, anxiety and fatigue), whereas patients with a higher education level reported lower HRQOL with respect to positive feelings and flexibility of daily activities. Interestingly, patients with hepatocellular carcinoma as an indication for LT reported a lower impact of HBIGrelated side effects (overall and on daily activities). These results might be explained by a lower perception of the impact of treatment and prophylaxis on HRQOL domains among patients affected by malignancies versus patients without malignancies. In conclusion, the development of an instrument specifically focusing on LT recipients receiving HBIG prophylaxis might improve the assessment of HRQOL and lead to a more nuanced understanding of the factors influencing the well-being of transplant recipients. REFERENCES 1. Busuttil RW, Farmer DG, Yersiz H, Hiatt JR, McDiarmid SV, Goldstein LI, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a singlecenter experience. Ann Surg 2005;241: National Institutes of Health consensus development conference statement: liver transplantation June 20-23, Hepatology 1984;4(suppl):107S-110S. 3. Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis B virus recurrence after liver transplantation: a systematic review. Liver Transpl 2011;17: Han SH, Ofman J, Holt C, King K, Kunder G, Chen P, et al. An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recurrent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin monotherapy. Liver Transpl 2000;6: Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 2000;32: Lok AS. Prevention of recurrent hepatitis B post-liver transplantation. Liver Transpl 2002;8(suppl 1):S67-S Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl 2000;6: Spilker B. Quality of Life and Pharmacoeconomics in Clinical Trials. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1995: Stone DH. Design a questionnaire. BMJ 1993;307: Cronbach LJ. Coefficient alpha and the internal structure of tests. Psychometrika 1951;16: Ware JE Jr, Harris WJ, Gandek B, Rogers BW, Reese PR. MAP-R for Windows: Multitrait/Multi-Item Analysis Program Revised User s Guide. Boston, MA: Health Assessment Lab; Howard KI, Forehand GG. A method for correcting itemtotal correlation for the effect of relevant item inclusion. Educ Psychol Meas 1962;22: Campbell DT, Fiske DW. Convergent and discriminant validation by the multitrait-multimethod matrix. Psychol Bull 1959;56: Kodraliu G, Mosconi P, Groth N, Carmosino G, Perilli A, Gianicolo EA, et al. Subjective health status assessment: evaluation of the Italian version of the SF-12 health survey. Results from the MiOS project. J Epidemiol Biostat 2001;6: Samsa G, Edelman D, Rothman ML, Williams GR, Lipscomb J, Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics 1999;15:

8 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 FRANCIOSI ET AL Gandek B, Ware JE Jr, Aaronson NK, Alonso J, Apolone G, Bjorner J, et al. Tests of data quality, scaling assumptions, and reliability of the SF-36 in eleven countries: results from the IQOLA project. International Quality of Life Assessment. J Clin Epidemiol 1998;51: Yahyazadeh A, Beckebaum S, Cicinnati V, Klein C, Paul A, Pascher A, Neuhaus R. Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. Transpl Int 2011;24: Gove WR. Gender differences in mental and physical illness: the effects of fixed roles and nurturant roles. Soc Sci Med 1984;19: Gijsbers van Wijk CM, van Vliet KP, Kolk AM, Everaerd WT. Symptom sensitivity and sex differences in physical morbidity: a review of health surveys in the United States and the Netherlands. Women Health 1991;17: Jin S, Yan L, Li B, Wen T, Zhao J, Zeng Y, et al. Quality of life and psychologic distress of recipients after adult living-donor liver transplantation (LDLT) a study from mainland China. Transplant Proc 2010;42: