Poor Quality of Life in HIV-Infected Men Who Have Sex with Men is Associated with Excess-Type Constitution of Traditional Chinese Medicine

Introduction This study explored the pathological constitution as it relates to low quality of life in HIV-infected MSM patients, as a reference for clinical treatment. Methods It had a cross-sectional research design using structured questionnaires to collect data, including patient's basic data, CD4+, CD4+/CD8+ ratio, Wang Qi constitution, and WHOQOL-BREF-Taiwan version questionnaires. We considered the association between constitutions and quality of life of HIV-infected MSM patients. Results and Discussion. The project accepted 203 HIV-infected MSM participants. The three most common pathological constitutions were Yang deficiency 15.5%, yin deficiency 13.1%, and qi deficiency 11.2%. The study determined scores for various quality of life domains: psychological (13.44 ± 2.27), social relationship (13.81 ± 2.80), physiological (14.43 ± 2.41), and environmental (14.78 ± 2.21). The TCM constitution is strongly correlated with the quality of life. Excess constitution had the worst quality of life. Comparing the infected time over one year with the time of <0–2 weeks, the adjusted odds ratios (AOR) were determined for abnormal CD4+ and CD4+/CD8+ ratio (OR: odds ratio: 0.03, 0.07, respectively, p < 0.001). Compared with the Gentleness constitution, there is a significant difference between the Deficiency and Excess constitution in sleep status and negative mood by multiple regression analysis (p < 0.001). Conclusion The Excess constitutions was correlated with worse quality of life. Even if the immune system was restored, the psychosocial domain, sleep status, and negative mood were not improved.


Introduction
Quality of life (QOL) can be defned as a person's satisfaction and subjective well-being living in what she or he thinks is the most important area [1]. QOL is an important outcome indicator of HIV treatment. Compared with the general population, HIV-infected patients have lower quality of life due to life-long medications, sufering from side efects and anxiety/ depression [2,3]. A meta-analysis of 9,000 people living with HIV/AIDS (PLWHA) found that nearly 58% of HIV-infected persons have a high degree of sleep disturbance, and those with sleep disturbance also show more depression and health problems [4]. PLWHA in Taiwan have worse QOL in terms of physical, psychological, and social relationships than the general population (all p < 0.001) [5]. On average, published research works indicate that 60% of HIV-infected patients use complementary and alternative medicine (CAM) to treat health problems related to HIV infection [6]. Of these, MSM and HIVinfected patients with severe infection symptoms and longer duration of illness more commonly use CAM to prevent or alleviate HIV-related symptoms, reduce treatment side efects, and improve quality of life [7][8][9][10][11].
Chinese herbal medicine (CHM) is a type of CAM widely used in Taiwan's medical system. Relevant studies have shown that higher cumulative doses taken by HIV-infected/ highly active antiretroviral therapy (HAART) patients increase the risk of hyperlipidemia, cardiovascular disease, respiratory disease, and diabetes [12]. In addition, during HAART treatment, patients who took CHM had a lower incidence of hyperlipidemia and cardiovascular disease than those who did not take CHM [13]. Studies have also shown that traditional Chinese medicine (TCM) can alleviate signs and symptoms related to HIV-infected symptoms, improve quality of life, extend long-term survival, alleviate adverse side efects of antiviral drugs, promote immune reconstitution, and improve laboratory results [14,15].
Constitution is the core value of TCM, and it depends on the result of the innate and acquired environment by integrating the characteristics of physiological functions and mental states. Wang Qi classifed the TCM constitution into nine constitutions, namely, Yang defciency (Yang), Yin defciency (Yin), Qi defciency (Qi), Phlegm-dampness (Pw), Dampness-heat (Dh), Blood stasis (Bs), Special diathesis (Sp), Qi-stagnation (Qs), Gentleness (G). Tese were derived from classifcation standards extracted from complex constitutional phenomena. Constitutional identifcation shows the direction of treatment and provides core techniques for assessing health conditions and supports research on the relationship between constitution and disease [16][17][18][19]. Previous studies used Wang Qi's TCM constitution questionnaire to explore the correlation between cardiovascular disease, hypertension, diabetes and other diseases and specifc TCM Constitution, and the association between moderate and severe cancer fatigue and TCM Constitution. Te constitution identity can be used as an appropriate choice for the basis of TCM to prevent and treat diseases [20,21].
Although the quality of life of HIV-infected patients is lower than that of people in general [3], there is no research discussing the relationship between TCM constitution and quality of life in HIV-infected patients. Tis study explores the correlation between the distribution of HIV-infected MSM patients in TCM constitution and quality of life in Taiwan, and what type of constitution is a risk factor for lower score quality of life, to develop a reference for treatment and preventive strategies.

Data Collection.
Te recruited cases used the last 2 weeks as a reference point to judge their subjective quality of life and constitution related issues. Te following are information from the hospital's medical records database: years, education, occupation, marital status, time of diagnosis, route of HIV infection, and CD4 + , CD4 + /CD8 + ratio. Te inspection time for CD4 + and CD4 + /CD8 + ratio was within 2 weeks before and after the recruited time. CD4 + < 292 cells/µL, CD4 + /CD8 + ratio < 0.6 was regarded as an abnormal value (Beckman Coulter).
Each item uses a fve-point scale to score. Te scores range from 1 (worst condition) to 5 (best condition), except for 3 items (Ph1, Ph2, and Ps6), which have reverse scores. Two scales (0-100 and 4-20, with a higher score indicating better QOL) can be transformed into domain scores for each domain. We used the 4-20 scale in this study, the higher scores indicating better quality of life. Te reliability (0.70 to 0.77) and validity (0.53 to 0.78) of the questionnaire reached statistically signifcant levels (p < 0.01) [23]. Tese 4 domains, common sleep status (Ph5), and negative mood (Ps6), were used as clinical symptoms in this discussion.

TCM Constitution Questionnaire by Wang Qi.
It includes 9 basic types of constitution, Yang defciency (7 items), Yin defciency (8 items), Qi defciency (8 items), Phlegm dampness (8 items), Damp-heat (6 items), Blood stasis (7 items), Special diathesis (7 items), Qi depression (7 items), and Gentleness constitution (8 items). Except for the Gentleness constitution, all others are considered pathological constitutions. One question is judged by Likert fve-point scale from 1 point (none) to 5 (always). Nine kinds of TCM constitution-the constitution type must be judged according to the standards: original score = sum of the scores of items for each constitution, and then the original score is converted into a conversion score [conversion score = ((original score number of answer items)/ answer items × 4) × 100].
Judgment of constitutions: Gentleness is a normal constitution and others are pathological constitutions. Gentleness constitution conversion score ≥60 points and other pathological constitution conversion score <30 points is considered Gentleness constitution; pathological constitution conversion score ≥40 is considered pathological constitution, the higher the conversion score, the more obvious the constitution trend, if any for more than 2 pathological constitutions, the highest score is used to judge the constitution [17,23].
Tis study used these nine constitutions to explore the distribution of constitutions in these subjects. In addition, Yang defciency, Yin defciency, and Qi defciency were combined into the Defcient Constitution, and phlegm dampness, damp-heat, and blood stasis were combined into the Excess Constitution.

Statistical Analysis.
Demographic and other data were collected and analyzed using IBM SPSS Statistics for Windows, version 24.0 (IBM Crop.Armonk, NY). Pearson's chi-square test and Fisher's exact test were used to detect signifcant diferences between years, infected time, CD4 + , CD4 + /CD8 + ratio, and diferent constitution distribution. For all parameters considered in the study, the approximation to normal of the distribution of the population was tested by the Shapiro-Wilk test and statistics for kurtosis and symmetry. As results were asymmetrically distributed, nonparametric tests were used. Data were expressed as median and interquartile range (IQR). Te Kruskal-Wallis test followed by Dunn's post hoc test was used to detect signifcant diferences between years, infected time, and quality of life.
Te Mann-Whitney U Test was used to detect signifcant diferences between CD4 + , CD4 + /CD8 + ratio, and quality of life. Logistic regression used parameters to discuss the odds ratio between CD4 + , CD4 + /CD8 + ratios by years, education, occupation, TCM constitution, and infection time. Multiple linear regression determined correlations between independent variable years, education, occupation, TCM constitution, and infected time as related to the sleep status and negative mood.

Results
Te relevant parameters were as follows: Te total recruited cases was 232, the number of valid cases was 203, and invalid was 26 (including those with incomplete personal basic information, biochemical data and questionnaires). So, the dropout rate was 12.5%.

Demography and Baseline Characteristics.
Tere are 203 participants. Average age is 32.5 years, with a range from 20 to 49 years. Te period of illness is divided into 3 stages (according to the date of diagnosis), ≤2 weeks, >2 weeks to one year, and more than one year. 73.9% of patients has been diagnosed for more than 1 year, 46% is 30-39 years, 61.5% has college education or above, 12.8% is unemployed, 5.4% and 23.6% has abnormal CD4 + or CD4 + /CD8 + ratio, respectively, for more than one year of infection (see Table 1).

TCM Constitution Distribution.
In the overall distribution of the TCM constitution, Gentleness accounted for 21.7%, and the pathological constitution was mainly composed of Yang defciency, Yin defciency, and Qi defciency, accounting for 15.8%, 13.3%, and, 11.3%, respectively. Te Excess constitution of Qi depression and phlegm dampness were the most common, accounting for 9.4% and 8.9%, respectively.
In Table 2, the authors divide the constitution into Defciency, Excess, Special diathesis, and Gentleness constitution. 40.4% has Defciency constitution, 27.6% has Excess constitution, 10.3% has Special diathesis, and 21.7% has Gentleness constitution. Tere is no signifcant relationship between the distributions of years, rank, infection time, and constitution (Fisher's exact test, p � 0.63 and 0.18). Tere is also no signifcant relationship between CD4 + , CD4 + /CD8 + ratios and the distribution of constitutions (ANOVA, p � 0.62 and p � 0.58).

Quality of Life Scores in Diferent Constitutions.
Comparisons between diferent constitutions in each quality of life domain score are shown in Table 4. In all domain scores of quality of life, the Excess constitution is lower than that of Special diathesis and Gentleness constitutions. (Kruskal-Wallis test: Ph, Ps, So, and p < 0.001).
Comparing the total and environment average score of quality of life in diferent constitutions, the Excess constitution is lower than the Defciency constitution and the Defciency constitutions are lower than the Special diathesis and Gentleness constitutions (one-way ANOVA: En, total, p < 0.001). Te Excess constitution had the worst quality of life.

Multiple Linear Regression of Sleep Status and Negative
Mood. Multiple linear regression examined correlations between years, education, occupation, constitution, and infected time in relation to the sleep status and negative mood ( Table 6).
Tere are no signifcant diferences between years, education level, occupation, and infected time in the sleep status and negative mood. However, comparing Defciency and Excess with Gentleness constitution in the sleep status and negative mood, there are signifcant diferences.
Te associations between Defciency and Excess constitution in relation to the sleep status and negative mood are signifcantly diferent by multiple regression analysis. Sleep in Defciency constitution (standardized regression coefcient β � −0.322, regression coefcient β � −0.701, p � 0.001) and Excess constitution (standardized regression coefcient β � −0.358,    Tus, sleep status in the constitutions of Defciency and Excess is worse than in the Gentleness constitution. Negative mood in the Defciency and Excess constitution is higher than in the Gentleness constitution, but there is no diference between special diathesis and Gentleness constitution in the sleep status and negative mood.

Tis Study Considers HIV Infection/AIDS in MSM.
According to Taiwan's CDC statistics, HIV-infected/AIDS males account for 94.79% of all cases and MSM infection rout for 65.56%, which is the largest group [24].

HIV-Infected/AIDS MSM Quality of Life.
Tis study fnds that the overall HIV-infected/AIDS MSM quality of life has an average score of 14.09 ± 2.37, 13.13 ± 2.83, 13.69 ± 2.94, and 14.26 ± 2.19 in the physical, psychological, social, and environmental domains. At the psychological, physical, and social level, the scores are lower than the general population in Taiwan (physical: 15.4 ± 1.81, psychological: 13.7 ± 2.07, social: 14.0 ± 2.10, and environmental: 13.1 ± 2.18) [25]. Te lowest aspect of quality of life in this study is the psychological domain, followed by the social domain, consistent with previous studies on HIV-infected/ AIDS persons in Taiwan: physical 13.6 ± 2.35, psychological 12.3 ± 2.63, social 12.9 ± 2.23, and environmental 13.4 ± 2.24 [4]. MSM people worry about losing their social status and feel guilty for their family, lonely, and immoral, therefore leading to lower scores in the psychosocial domain of MSM, compared to the general population. Tey are more likely to sufer from severe depression, anxiety, stress, low self- Kruskal-Wallis test unusual distribution, without mother number. b One way ANOVA: normal distribution defciency constitution: Yang defciency, Yin defciency, and Qi defciency. Excess constitution: phlegm-wetness, wetness-heat, and blood stasis constitution; Sd: special diathesis constitution; G: gentleness constitution.  Evidence-Based Complementary and Alternative Medicine esteem, and social isolation [26,27]. Terefore, HIV-infected/AIDS MSM persons need more care in the psychosocial domain.

Relationship between TCM Constitution and Quality of
Life. In this study, Defciency constitution accounts for a relatively large proportion, especially Yang defciency constitution, but we found that the four quality of life domains, Excess constitution aspects (phlegm dampness, damp-heat, stagnation of qi, and blood stasis) are lower than those of the Defciency constitution (Yang defciency, Yin defciency, and Qi defciency). Previous studies have explored the relationship between the constitution and quality of life after chemotherapy of cancer and diabetes, the physical and psychological quality of life with blood stasis has also signifcantly deteriorated. A higher blood stasis pattern score was signifcantly associated with a lower PCS (physical component score) (β � −0.60, 95% CI: −0.73 to −0.46), lower MCS (mental component score) (β � −0.65, 95% CI: −0.81 to −0.49) in cancer patients [28], and lowest for the RE (role emotional) scale (F statistic � 22.94) in diabetes patients [29]. However, this study shows that the quality of life with the Excess constitution is lower than that of the Defciency constitution. We need more research and treatment to improve the quality of life of HIV-infected\AIDS patients who are with the Excess constitution.
4.4. Discussion on CD4 + , CD4 + /CD8 + , Sleep Status, and Negative Mood. Tis study also considers correlations between abnormal CD4 + and CD4 + /CD8 + values with the patient's years, education level, occupation, TCM constitution, and infected time (see Table 5). Results show that the immune response CD4 + and CD4 + /CD8 + ratio are related to the length of time of illness. Clearly, with the intervention of HAART drugs, the rate of recovery of CD4+ and CD4 + / CD8 + ratios after illness for more than 1 year has increased, and the recovery of immunity is not closely related to the TCM constitution. Tis is consistent with previous studies in mainland China. Yang-defciency constitution is related to liver toxicity, nephrotoxicity, side efects, and total mortality, but Yang defciency is not related to CD4 + , CD8 + , and annual changes [30]. Tis study also selects the sleep status (Ph5) and negative mood (Ps6), which are the common clinical symptoms of HIV-infected/AIDS MSM, and examines their relationships with years, occupation, time of illness, and TCM constitution. Table 6 shows that although with longer HARRT treatment time, the CD4 + and CD4 + /CD8 + ratio can be improved [31], but the sleep status (Ph5) and negative mood (Ps6) will not improve because of the longer illness. Immune recovery can improve with the intervention of HAART, but there is no improvement in the sleep status and negative mood. TCM constitution has a signifcant relationship with sleep status and negative mood. Terefore, the intervention of traditional Chinese medicine through the restoration of TCM constitution can reduce the incidence of negative mood, insomnia, and improve the quality of life of HIVinfected/AIDS patients.

Limitation.
Tis study focuses on the relationship between constitution with immune cells and quality of life. We have additionally explored the relationship between sleep and depression with constitution in quality of life. It may be possible to further use the depression and sleep questionnaires to explore the relationship with the constitution in more detail. In our hospital, most of the patients are MSM, Evidence-Based Complementary and Alternative Medicine so the study of HIV cases is limited, if there is a chance, we can make cooperation with other hospitals to make the scope of the study wider and more comprehensive.

Conclusion
Yang defciency constitutions were the highest ratio in this study, but the Excess constitutions Blood stasis, Qi depress, Phlegm dampness and Damp-heat are correlated with worse quality of life. Even if the immune system is restored, the psychosocial domain, sleep status, and negative mood will not improve. Terefore, in addition to antiretroviral therapy, intervention measures to improve HIV-infected/AIDS constitution through TCM may elevate the quality of life of HIV-infected/AIDS MSM patients.

Data Availability
If you need our original data, you can directly contact the frst author, the e-mail address is: DAI55@tpech.gov.tw.

Ethical Approval
Te study design was reviewed and approved by the Institution of Taipei City Hospital Research Ethics Committee (IRB number: TCHIRB-10707110). Wang Qi, nine kinds of TCM constitution Questionnaire, and WHOQOL-BREF-Taiwan version Questionnaire were authorized by Wang Qi and Yao Kaiping professor, respectively.