Relationship of sleep disorders with long-term complications and health-related quality of life in people with well-controlled human immunodeficiency virus

Abstract Although sleep disorders are common in patients with human immunodeficiency virus (HIV) infection, they have not been adequately evaluated under currently advanced treatments, mainly with integrase strand transfer inhibitors. However, the relationship of sleep disorders with long-term complications and quality of life (QOL) status in patients infected with HIV is still poorly understood. Such associations are important in the management of outpatients with HIV. Hence, this study aimed to evaluate these associations. This cross-sectional observational study assessed the QOL changes of patients with HIV before and after the treatment regimen change. Male patients with well-controlled HIV who attended our hospital and changed HIV medications for reasons other than treatment failure between October 2019 and September 2021 were included. At the time of regimen change, sleep disorder status was assessed according to the Pittsburgh sleep quality index (PSQI), and health-related QOL (HRQOL) was assessed using the medical outcomes study 8-item short form health survey. In addition, we collected information on age, blood tests, and long-term comorbid conditions present during the evaluation. The HIV treatment regimen was also reviewed. Out of 45 male Japanese patients with HIV that were included in this study, 24 (53.3%) and 21 (46.7%) were classified into the sleep disorder group and nonsleep disorder group, respectively, according to their PSQI scores. The sleep disorder group had a significantly lower HRQOL mental component summary (P = .0222) than the nonsleep disorder group. The prevalence rates of hypertension, dyslipidemia, and diabetes mellitus were not significantly different between the 2 groups. In addition, a significant correlation was observed between PSQI scores and the HRQOL status (mental component summary, P = .0450; physical component summary, P = .0350). Sleep disorders remain common in patients with well-controlled HIV infection receiving current treatment. Sleep disorder is significantly associated with a low HRQOL in these patients. Hence, sleep status evaluation is necessary to improve HIV management.


Introduction
Sleep is one of the most important factors influencing one's performance.The quality and quantity of sleep affect a wide range of characteristics, from physical and mental performance to general health.Regarding physical performance, sleep significantly contributes to muscle recovery and restoration. [1]leep is also closely related to physical and mental health.In fact, it has been associated with depression, anxiety, and bipolar disorder. [2]leep disorders are common in people living with human immunodeficiency virus (HIV) infection (PLWH). [3]However, the complication rate of sleep disorders remains controversial.Sleep disorders are often evaluated subjectively, making them difficult to diagnose.In recent years, objective measures have been used to evaluate sleep disorders.For instance, Pittsburgh sleep quality index (PSQI) is a comprehensive assessment method based on not only sleep duration but also other sleep parameters, such as sleep efficiency, sleep latency, sleep quality, sleep disturbance, hypnotic medication, and daytime dysfunction. [4][8][9][10][11][12][13][14] Editor: Leonardo Gilardi.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Some of these studies have suggested that sleep disorders reduce the quality of life (QOL) of PLWH. [7,15]ocial background, HIV infection itself, and immune status alteration are the reported factors associated with sleep disorders in HIV infection. [3]Previously, antiretrovirals, such as non-nucleoside reverse transcriptase inhibitors, were often associated with sleep disorders. [10,11]However, considering the significant advances in HIV treatment, the use of non-nucleoside reverse transcriptase inhibitors, which have been linked to sleep disorders as adverse events, has been drastically reduced in recent years, and safer drugs with fewer adverse events are now being prescribed.In addition, the status of sleep disorders in well-controlled PLWH treated with recent safer drugs is still insufficiently evaluated.
The life expectancy of PLWH has dramatically increased, owing to the advancement of therapeutic drugs; as a result, lifestyle-related diseases known as long-term complications occur more frequently in PLWH than in people without HIV infection. [16]Some of these long-term complications include hypertension, dyslipidemia, and diabetes mellitus.The management of these diseases has become important in the outpatient management of PLWH.In addition, regardless of the HIV infection status, the long-term complications of HIV infection are generally associated with sleep disorders, even in younger ones. [17,18]Hence, HIV infection, sleep disorders, and long-term complications may be closely related to each other.
This study aimed to evaluate the actual status of sleep disorder and its association with long-term complications and other parameters in PLWH (virologically stable) treated with currently advanced antiretrovirals.We also examined their health-related QOL (HRQOL) according to patient-reported outcomes to determine the association between sleep disturbance and QOL in well-controlled PLWH.

Methods
This cross-sectional observational study, which was approved by the ethics committee of Teikyo University (No. TUIC-COI.19-175), assessed all patients who participated in a clinical study on QOL changes before and after treatment regimen modification.Male PLWHs who attended our hospital and changed their antiretrovirals medications for reasons other than treatment failure between October 2019 and September 2021 were enrolled in the study.The reason for the change in antiretrovirals medication is to remove the booster drug (emtricitabine) and to change to a single-tablet regimen.There were no cases of change due to adverse drug reactions.In particular, only well-controlled cases under anti-HIV treatment for at least 6 months and maintaining an HIV viral load of less than 200 copies/mL, were included.
At the time of regimen change, we assessed the participants' sleep disorder status and HRQOL using the PSQI and the Japanese version of medical outcomes study 8-item short form health survey (SF-8), respectively.Both assessments were conducted using a questionnaire.In addition, we collected information on age, blood tests (white blood cell, hemoglobin, alanine aminotransferase, bilirubin aspartate aminotransferase, urea nitrogen, creatinine, and CD4-positive lymphocyte count), and long-term comorbid conditions present during the evaluation.The HIV treatment regimen was also reviewed.
According to the PSQI scores (sleep disorder: PSQI > 5), the patients were classified into 2 groups: sleep disorder group and nonsleep disorder group.
The 2 groups were assessed for differences in the presence or absence of complications, significant differences between each parameter, and significant differences in HRQOL.As mentioned, HRQOL was assessed with the Japanese version of SF-8. [19]The SF-8 is an 8-scale HRQOL assessment tool that generates 2 summary measures: a physical component summary and a mental component summary (MCS).The higher the score, the better the HRQOL status.For discontinuous parameters, the significant factors related to sleep disorders were identified using the factorial square test or Fisher exact test.Fisher exact test does not rely on distributional assumptions; therefore, it is particularly appropriate for the analysis of small samples.Furthermore, the direct association of sleep disorder with PSQI values was evaluated using correlation analysis.StatFlex version 7 (Artech Co., Osaka, Japan) was used for all statistical analyses.

Results
This study included 45 male PLWHs.Table 1 presents the clinical features of patients classified into sleep disorder and nonsleep disorder groups according to their PSQI scores.Age, treatment duration, time since diagnosis, CD4 levels, and the HIV medication type were not significantly different between the 2 groups.The prevalence rates of hypertension, dyslipidemia, and diabetes mellitus also showed no significant differences between such groups.In the HRQOL measured by the SF-8, the MCS was significantly lower in the sleep disorder group than in the nonsleep disorder group.
In the correlation analysis between the PSQI score and each item, a significant inverse correlation was observed between HRQOL, MCS, and physical component summary (Table 2).

Discussion
11,20] Hence, the sleep disorder rate was high, even in the setting of recent treatment mainly with integrase inhibitors and in a virologically stable state.
Moreover, time since diagnosis, treatment duration, and age were not significantly associated with sleep disorders.In general, sleep disorders are more common in the older population.Sleep status evaluated by PSQI is significantly associated with age. [6,21,22]However, sleep status was not associated with age in this study, possibly because the participants were mostly relatively young.Given that aging is increasingly becoming an issue among PLWHs, the rate of sleep disorders will likely increase further in the future.
Our study also showed no association between HIV treatment regimen and CD4 levels as HIV-related factors, and sleep disorders.High or low CD4 levels have been associated with sleep disorders, although no definitive views exist. [8,11,21,23]mmune statuses was also not associated with sleep disorders.Regarding therapeutic drugs, integrase inhibitors, which have been widely used in recent years, exhibit some psychological side effects. [24]In our study, most of the participants (35 cases [77.8%]) used integrase inhibitors, which may explain the high rate of sleep disorders.However, the rate of sleep disorders in patients treated with integrase strand transfer inhibitors (INSTIs) was not significantly different compared with those treated with other drugs.[27] However, we found no significant difference between the firstand second-generation INSTI users (data not shown).Thus, we could not determine whether integrase inhibitors had effects on the status of sleep in our study population.
Furthermore, complications such as hypertension, dyslipidemia, and diabetes mellitus were not associated with sleep disorders.Considering that most of our participants were relatively young, the rate of complications may have been relatively low; consequently, this study showed no association between sleep disorder and long-term complications.In general, the relationship between sleep disorder and lifestyle-related diseases has already been shown. [28,29][32] Further large-scale studies are needed to confirm whether sleep disorder is associated with long-term complications in PLWHs.
Our study also revealed that sleep disturbance is significantly associated with HRQOL, consistent with several studies. [7,15]aintaining a good HRQOL status has recently become one of the long-term goals of PLWHs. [33]Although HIV survival improved because of HIV treatment advancement, the HRQOL of PLWHs remains significantly lower than that of the general population, indicating a major problem. [34]Sleep disorder control may be important for improving the HRQOL status of PLWHs, and sleep disorder evaluation is essential to achieve long-term goals in PLWH management.
Although this study has a single-center cross-sectional design with a small sample size, it is still clinically valuable because it reveals that sleep disorders are still common in stable PLWH with current treatment and that these disorders are an important problem in achieving future patient goals.We hope that more data will be accumulated in the future and that the actual status of sleep disorders in PLWH will be evaluated in detail to help improve HRQOL.

Table 2
Correlation analysis between the PSQI score and each item.

Table 1
Clinical features of 2 groups of people living with HIV: sleep disorder group and nonsleep disorder group.