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The impact of lipodystrophy (LD) on quality of life is high, but it has not been demonstrated in literature. The objective of the study was to assess the impact of LD on the health–related quality of life (HRQOL) in HIV-infected people on highly active antiretroviral therapy (HAART). Patients with LD phenotype defined by the Multicenter AIDS Cohort Study (MACS) were included. Three different methods were used to define LD severity: both patient and physician evaluation using the HIV Outpatient Study (HOPS) severity scales and the Lipodystrophy Case Definition (LDCD). The HRQOL was evaluated by MOS-HIV Health Survey. Four hundred one patients on HAART for a mean of 108±52 months were evaluated for LD at the Metabolic Clinic of Modena and Reggio Emilia University were enrolled from January 2003 to July 2006. According to self-perceived or physician-based HOPS, 106 (26.5%) and 122 (30.4%) patients had severe LD. Females had significantly more severe LD. Few HRQOL scores correlated to LD severity using the physician-based score (both HOPSph and LDCD), while all the HRQOL scores correlated with LD severity when a patient-based score was used (HOPSpt). In multiple linear regression analysis, Mental Health HRQOL score, gender, body mass index, age, body image satisfaction were independent predictors of patient-based (HOPSpt) LD, while none of the HRQOL scores, but female gender, age, waist-to-hip ratio, limb fat, and body image satisfaction were correlated with physician-estimated HOPSph LD severity. HRQOL was strongly correlated with LD severity when a patient-based score was used. For an overall assessment of the impact of LD on HIV-infected people, both patient-based and physician-based measures are required.
Despite the demonstrated benefits of highly active antiretroviral therapy (HAART), adverse events related to treatment can be a great burden to patients. Body habitus changes, named lipodystrophy (LD), are one of the most frequent clinical disorders associated with antiretroviral therapy. LD phenotype include fat atrophy affecting limbs, buttocks, and face, fat accumulation both intravisceral or subcutaneous and mixed forms as the result of a combination of the two. While lipoatrophy is clearly an HIV- and/or HIV-drug–related phenomenon, fat accumulation seems not specific for either.1,2 Unfortunately, there is neither consensus on the definition of LD, nor agreement on the best method for measuring it. LD is a multidimensional construct and patient versus physician-detected incidence of LD may have variable level of concordance.3 Moreover, it is not known which is the best instrument to measure the subjective impact of LD on people with HIV.
Clinical experience suggests that LD can have a profound impact on quality of life. Changes in body image may stigmatize patients, producing erosion of self-esteem, decreasing social functioning including sexual relations, and leading to anxiety and depression.4,5 LD may result in an involuntary disclosure of HIV status and also appears to be correlated to suboptimal adherence to therapy.6,7
Few studies have addressed quality-of-life issues in HIV-infected patients with LD, and its impact has not been established definitively. Some studies demonstrating effects have used instruments not widely validated in people with HIV infection,8,9 while others have failed to find correlations with health-related quality of life.10,11
The main objective of this study was to identify the impact of LD on the health-related quality of life in HIV-infected people taking HAART. The identification of the best instrument for the assessment of the impact of LD on the health-related quality of life could provide useful tools in clinical practice, both for monitoring the psychosocial effects of LD and evaluating outcomes of interventions to improve or preserve quality of life.
Prospective observational study of consecutive HIV-infected adult outpatients attending the Metabolic Clinic (MC) of Modena and Reggio Emilia University, Italy12 from January 2003 to July 2006. This is a referral centre where a multidisciplinary consultant service consisting of infectious disease physicians, cardiologists, endocrinologists nutritionists, personal trainers for physical activities, psychologists and plastic surgeons offer patients a free-of-charge strategy for aesthetic correction of LD as well as cardiovascular risk reduction. Patients with self-perceived body habitus changes may have direct access or may be referred by their physicians for LD evaluation. Both subjective parameters (health-related quality of life, body image evaluation) and objective parameters (fasting lipids and glucose evaluation, anthropometric measures (body mass index [BMI], waist to hip ratio [WHR]), dermal and subcutaneous thickness of both cheeks measured with a high frequency ultrasound transducer (7.5MHz), dual-energy x-ray absorptiometry (DEXA) evaluation of total body, trunk, and leg fat and lean mass, abdominal computed tomography (CT) scan for visceral (VAT) and subcutaneous adipose tissue (SAT) were routinely collected at the time of first encounter of the patients, before providing any medical or surgical treatment. To be included in the present study, patients were required to be clinically stable, to have received more than 1 year of HAART (an antiretroviral regimen containing at least a protease inhibitor [PI] or a non-nucleoside reverse transcriptase inhibitor [NNRTI] or three nucleoside reverse transcriptase inhibitors [NRTIs]), to be able to complete the questionnaires in Italian, and to be willing to participate to the study. All participants provided written informed consent; the research protocol was approved by the Ethics Committee of the hospital.
Patients with body changes LD phenotype defined by the Multicenter AIDS Cohort Study (MACS) were included.13,14 Three different methods were used to define LD severity: both the patient self-assessment and the physician evaluation using the HIV Outpatient Study (HOPS) severity scales,15 and the Lipodystrophy Case Definition (LDCD).16,17 LD definition criteria are summarized in Table 1.
Instruments for the assessment of health-related quality of life and body image included:
All patients underwent a physical examination including anthropometric variables: weight, height by stadiometer, and circumferential measurements of waist, hip, and thigh as the average of three measures.
Body composition was assessed using whole-body DEXA, and single-slice abdominal (L4) CT with standard protocols. DEXA data comprised legs, trunk, and total fat mass, CT data included VAT, SAT, and total adipose tissue volume (TAT) of the abdomen.
The LDCD definition was applied only to the 182 patients for whom all the needed variables for its calculation (age, gender, duration of HIV infection, HIV disease stage, waist to hip ratio, anion gap, serum HDL cholesterol concentration, trunk to peripheral fat ratio, percentage leg fat, and intra-abdominal to extra-abdominal fat ratio) were available.
The primary outcome of the study were the two summary scores PHS and MHS of MOS HIV questionnaire. Effect size for both PHS and MHS among people at different LD degree of severity were calculated. According to the Cohen's definition,22 an effect size from 0 to 0.2 was considered of a small significance, from 0.21 to 0.50 of a medium significance and more than 0.50 of a large significance.
Analysis of variance (ANOVA) and χ2 test were done to identify variables correlated to physician-based or patient-reported LD severity. Spearman rank correlation coefficients were also calculated to confirm results of ANOVA.
As counterproof a backward stepwise logistic regression analysis was done to assess the independent effects of the significant (p<0.1) explanatory variables on the HOPS scales. In particular, purpose of multivariable analysis was to evaluate the correlation among LD severity and health-related quality of life measures adjusting for several potential confounders. Statistical significance was determined at p<0.05. SPSS software package version 13.0 (SPSS; Chicago, IL) was used for statistical analyses.
Demographic and clinical characteristics of the study population are presented in Table 2. Eleven percent of people were receiving their first antiretroviral regimen. A PI-containing regimen was taken by 40.6%, an NNRTI-containing regimen by 30.5% (in 5 people PI and NNRTI were in the same regimen) and a fusion inhibitor-containing regimen by 2.5% of the study subjects; 49 patients (12.1%) were taking three NRTIs and 68 (16.8%) were not taking HAART at the moment of the survey. Table 3 shows the distribution of enrolled people according to the four LD definitions.
According to MACS classification, females had mixed phenotype (both lipoatrophy and fat accumulation) more frequently than men (50.7% versus 33.3%, respectively, p<0.0001), while men had lipoatrophy more frequently than women (29.7% versus 47.6%, respectively, p<0.0001).
Patient-based and physician-assessed HOPS scores were highly correlated (R=0.31; p<0.0001). However, the definitions sometime categorized patients differently from each other. In particular, in 16% of cases physicians reported no LD, while patients referred a mild to moderate degree of LD, and in approximately 18% of cases physicians estimated a mild to severe LD when patients reported no LD.
Examining health-related quality of life, PHS and MHS mean scores were 50.6 (SD 8.7) and 43.6 (SD 7.3), respectively. Facial VAS score was 4.7 (SD 2.5), body VAS score was 4.4 (SD 2.4). Satisfaction with body image (ALDD7) mean was 3.5 (SD 1.0), while that of body change interference (ALDD8) was 70.3 (SD 17.5).
Tables 4A, ,4B,4B, and and4C4C show correlations among clinical parameters, subjective measures, and health-related quality of life with both patient and physician-assessed HOPS and LDCD. In all the definitions, females had significantly more severe LD than men. When the physician-based score was used, several clinical parameters, but not all the HRQOL scores were correlated with severity of LD. None of the HRQOL were correlated with LDCD. Using the patient-based score, both subjective and quality of life measures were correlated with the severity of LD.
Pain functioning, physical functioning, mental health, energy/vitality, cognitive functioning, current health perception, overall quality of life were the domains significantly correlated with the severity of patient-assessed LD. Both of the two HRQOL summary scores were significantly correlated with the severity of patient-assessed LD.
The effect size of PHS for people with no LD compared to those with severe LD were 0.31 for the patient-based HOPS definition and 0.26 for the physician-based one, while the effect size of MHS for people with no LD compared to those with severe LD were 0.23 for the patient-based HOPS definition and 0.41 for the physician-based one.
In linear regression analysis HOPS was significantly correlated with both PHS (B −0.29; 95% confidence interval [CI]−0.47, −0.11; p=0.002) and MHS (B −0.28; 95% CI −0.43, −0.13; p<0.0001) in patient's estimation, but only with MHS (B −0.50; 95% CI −0.78, −0.21; p=0.001) in physician evaluation.
With regards to a qualitative assessment of LD, using a physician-based classification of LD according to MACS definition, no correlations were found among clinical parameters, subjective measures and health-related quality of life and LDCD score (data not shown). In Table 5 Spearman correlation coefficients are reported confirming the results of the study.
In backward stepwise multiple linear regression analysis, female gender, BMI, age, ALDD8 and MHS were significantly and independently related to patient-based HOPS LD scale while female gender, age, WHR, limb fat, and ALDD8 were significantly and independently correlated with physician-estimated HOPS LD scale (Table 6).
Although it seems intuitively obvious that LD can decrease quality of life in people with HIV infection, to date, this association is not well corroborated in the published literature. This study demonstrates the significant impact of LD on patient-reported health status. The patient-assessed definition better describes the impact of severity of LD on health status compared to the physician-based one.
There are several ways changes in body image may affect patients' psychosocial function and quality of life. A recent paper found that 85% of patients with LD reported the changes have been noticed by family, friends, or work colleagues.23 Disfigurement may cause stigma, erosion of self-esteem, decrease of desirability, attractiveness; it may influence social relations, and lead to anxiety and depression.1 People experiencing LD report a drastic decrease of sexual activity.24 LD may lead to forced disclosure of the diagnosis or increase the fear of adverse events related to antiretroviral treatment25–27 and it can be a crucial determinant for cessation of treatment.6,7
Results from the present study demonstrated that individuals with more severe LD had not only a worsen satisfaction with body image, but also a worse level of quality of life in almost all the investigated domains. Even the two HRQOL Summary Scores showed the same tendency, and effect size among patients at different LD degrees was considered “moderate”23 revealing a significant difference among the strata of LD severity. These findings support a wider use in both routine care and research settings of both patient- and physician-based definition of LD to obtain a complete assessment of impact of LD on health status
Up to now, correlations between LD and quality of life have been obscured by the lack of specificity of the used instrument and by studies small sample size. No differences in quality of life were found between Spanish people with or without LD8 using a quality-of-life questionnaire not previously validated in patients with HIV infetcion. Even though the sample size was small, men scored lower on negative mood and homosexual men scored lower on psychological functioning. On a subsample of this study8 applying a different questionnaire, Blanch and coauthors9 found that changes in the breast, face, or legs were significantly associated with greater impairment of psychosocial functioning. In the multivariate analysis only changes in the breast remained significant. However, once again, authors did not use standardized questionnaires for measuring quality of life in HIV-infected people. Another recent paper11 failed to demonstrate a correlation between a LD score, as assessed by a new specific instrument, and the domains of quality of life. Anyway, few items of quality of life were considered for the study. In a recently published paper,10 the total LD score was not found to be correlated with any domain of MOS-HIV Health Survey or HAT-QoL subscales except for physical function areas, while the LD score was strongly correlated with the patient-perceived body image score. Unfortunately the sample size of the study was too small (77 patients) to derive definitive conclusions. A recent analysis of factors correlated with lower quality of life in the HAART era in a large cohort28 did not include LD as possible predictor of both physical and mental health. A dramatic association was found only between LD severity and dissatisfaction with body image.10,24
Previous studies demonstrated lack of concordance between physicians and patients in symptoms estimation.29 Indeed, although patient experiences the lipodystrophy syndrome, only features that providers recognize and report affect treatment decision in most clinical settings. Actually we demonstrated that patients and physicians were not totally concordant on the definition of LD. According to the present study in more than 13% of cases physician found moderate to severe LD, when patient did not perceive it and in more than 6% a moderate to severe patient-estimated LD was not captured by physician. It should be taken into account that the physicians involved in the present study had several years of experience with the MC model, and are likely to be more skilled on the assessment and management of LD manifestations. Then, even though data on comparison between patient- and physician-assessment of LD are scarce in the literature, the discordance between patient and physician could be even greater in other populations.
Results from the present study suggest that women have a more severe LD and a mixed phenotype (both lipoatrophy and fat accumulation) more frequently than men. We cannot rule out that including fat accumulation in the definition for LD we may have led to a gender bias. Women have more body fat than men and fat accumulation may not be more than the background of HIV-negative women. But it may also be possible that women perceived their syndrome as more severe than men. Since it is well demonstrated that body image is markedly influenced by gender,30 we believe that gender-focused counseling for LD at the beginning or at an antiretroviral regimen switching is warranted.
A limitation of the published literature and of the present study is the lack of consensus on the definition of LD. Several classifications have been proposed for use in both the research setting and in clinical practice.13–17 Each focuses on different aspects of LD (phenotype, severity), but all show limitations. Using both patient- and physician-based definition of LD according to the classification proposed by Lichtenstein et al.15 seems to capture a wider description of the syndrome; moreover it is easy to assess. Since groups are disproportionately different in size, in our analysis we did not discriminate between lipoatrophy (n=164) and lipoaccumulation (n=31). It is possible that the impact on quality of life may differ for the two phenotypes. Finally, results of our study may not be generalized to other HIV-infected populations even though mean values of health-related quality of life were similar to that from other HIV cohorts.10
In conclusion, the importance of lipodystrophy lies not only in actual changes in body shape and in the association with lipid abnormalities, but also in the impact of changes on the patient's quality of life. Negative impact on quality of life may also decrease motivation and adherence to therapy and even lead to discontinuation of the treatment. The best overall assessment of the impact of LD may require both patient- and physician-based measures. Better measurement will help us be most effective in implementing strategies to reduce the burden of LD.31
This study was supported by Istituto Superiore di Sanità, Rome (Italy), IV Programma nazionale ricerche AIDS. “Azione concertata per lo studio degli effetti indesiderati della terapia antiretrovirale.”
Dr. Wu was supported in part by the Adult AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (U01AI38858), and the Johns Hopkins University Adult Clinical Trials Unit (U01A127668).