Prevalence of Autoimmune Diseases in Individuals Living with HIV in Korea: A Nationwide Population-Based Study

1. Introduction

Human immunodeficiency virus (HIV) infection leads to immune dysregulation, primarily through depletion of CD4+ T cells [1]. HIV infection is associated with alterations in immune homeostasis and lymphocyte subsets, including changes in CD4+ and CD8+ T-cell populations, as well as B cells and natural killer cells. In addition to abnormal numbers of lymphocytes, dysregulation of B and T cells and polyclonal B-cell activation occurs [2]. Chronic immune activation and cytokine imbalance contribute to immune dysfunction and may play a role in the development of autoimmune diseases [2,3]. Differentiation from autoimmune diseases may be more difficult in these patients than in the general population due to increased positivity of autoantibodies, including rheumatoid factor, anti-cyclic citrullinated peptide antibody, and antinuclear antibody, and similar symptoms such as rheumatoid-like arthritis in individuals living with HIV [3,4]. However, the association between HIV infection and specific autoimmune diseases remains unclear.

Previous studies have reported an increased incidence of certain autoimmune diseases in individuals living with HIV, although findings vary according to antiretroviral therapy status [5,6]. Immune system abnormalities are associated with HIV infection and may be partially restored by ART. ART may influence the development and progression of autoimmune diseases. The number of HIV infections continues to increase in Korea. Moreover, more than 90% of individuals living with HIV are receiving ART, which is provided free of charge [7]. In addition to epidemiological and socioeconomic factors, genetic factors may also influence the development of HIV infection and autoimmune diseases. The prevalence and spectrum of autoimmune diseases in Korea may differ from those reported in other countries [8]. Therefore, the prevalence of autoimmune diseases in individuals living with HIV may differ in Korea.

The use of steroids and immunosuppressive agents can affect the progression and treatment of HIV infection [4]. Cardiovascular diseases, renal diseases, bone disorders, and cancers are more common in those living with HIV than in the general population, which overlaps with the comorbidities observed in some autoimmune diseases [9,10]. However, population-based data in Asian populations remain limited. Therefore, investigating the prevalence of autoimmune diseases in individuals living with HIV may provide clinically relevant information for differential diagnosis and management. In this study, we aimed to investigate the prevalence of autoimmune diseases in individuals living with HIV in Korea and to compare these findings with those in the general population.

2. Materials and Methods

2.1. Data Source and Study Subjects

Data were obtained from the National Patient Samples of the Health Insurance Review and Assessment Service (HIRA) from January 2012 to December 2015 (dataset numbers: HIRA-NPS-2012-0133, HIRA-NPS-2013-0143, HIRA-NPS-2014-0152, and HIRA-NPS-2015-0151). HIRA is a nationwide claims database operated by the Korean government. HIRA provides various medical information, including basic information such as patient age and sex, disease information based on diagnostic codes, and medication information through drug codes [11]. HIRA-NPS includes approximately 3% of the total population using a stratified sampling method. The stratification variables were sex and age, with age categorized into 5-year intervals. A stratified probability sampling method with 32 layers was applied [12]. There were a total of 5,755,633 individuals in the 2012–2015 HIRA-NPS dataset. Of these, 4,851,064 individuals aged ≥15 years were included in the analysis (2,332,623 males and 2,518,441 females).

2.2. Definition of HIV Infection and Autoimmune Diseases

The diagnostic codes of HIV infection were identified using B20–24 of the Korean Classification of Disease, 7th edition (KCD-7), which is the Korean version of the International Classification of Disease, 10th revision (ICD-10). Patients with HIV infection were defined as those with the relevant diagnostic codes recorded as either a primary or secondary diagnosis, and the control group was defined as those without these diagnostic codes. The autoimmune diseases and diagnostic codes included in this study were as follows: RA, M05, M06.0, and M06.2–9; AS, M45; SLE, M32; systemic sclerosis, M34; polymyositis, M33.2; dermatomyositis, M33.1 and M33.9; antiphospholipid syndrome, D68.6B; Sjögren's syndrome, M35.0A–D; Behçet's disease, M35.20–22, 28 and 29, and N77.8A; vasculitis except Behçet's disease, M30.0–9; ulcerative colitis, K51.0, 2, 3, 8, and 9, and M07.50–58; Crohn’s disease, K50.00–02, 10–12, 19, 80–82, 89–92, and 99; sarcoidosis, D86.0–3, 8, and 9; psoriasis, L40.00, 08, 1, 4, 5, 8, and 9; Graves’ disease, E05.0–4, and 8; Hashimoto’s thyroiditis, E06.3A; autoimmune hepatitis, K75.4; and primary biliary cholangitis, K74.30–32 and 39. Individuals with an autoimmune disease diagnostic code as a primary or secondary diagnosis were defined as patients with an autoimmune disease; otherwise, they were classified as not having an autoimmune disease

2.3. Antiretroviral Therapy

ART status was defined based on the prescription of one or more antiretroviral drugs, including abacavir, adefovir, amprenavir, atazanavir, bictegravir, clevudine, cobicistat, darunavir, delavirdine, didanosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, fosamprenavir, indinavir, lamivudine, lopinavir, nelfinavir, nevirapine, raltegravir, rilpivirine, ritonavir, saquinavir, stavudine, telbivudine, tenofovir, tipranavir, zalcitabine, and zidovudine. The corresponding drug codes were J05AE01–10, J05AF01–13, J05AG01–06, J05AR01–27, and J05AX07, 08, and 12.

2.4. Statistical Analysis

The prevalence of each autoimmune disease in patients with HIV infection and in control subjects was compared using a Chi-square test, and a P < 0.05 was considered statistically significant. Analyses were stratified by sex. All statistical analyses were performed using SAS Viya (SAS Institute Inc., Cary, NC, USA).

3. Results

3.1. Prevalence of HIV Infection and Autoimmune Diseases

There were 939 males and 84 females with HIV infection, for a total of 1,023 individuals, and the overall prevalence of HIV infection was 0.021% (0.040% in males and 0.003% in females). All patients with HIV infection included in this study were receiving one or more antiretroviral drugs. Among the autoimmune diseases included in the study, RA had the highest prevalence at 2.39% (1.59% in males and 3.13% in females), followed by psoriasis (0.66% overall, 0.78% in males and 0.54% in females), Graves’ disease (0.47% overall, 0.28% in males and 0.65% in females), and Hashimoto’s thyroiditis (0.40% overall, 0.12% in males and 0.66% in females).

3.2. Prevalence of Autoimmune Diseases in Patients with HIV Infection

The prevalence of autoimmune disease in patients with HIV infection was 4.37% in males, higher than in those without HIV infection, and 2.38% in females, lower than in those without HIV infection. However, these differences were not statistically significant. Table 1 presents the prevalence of each autoimmune disease in patients with and without HIV infection. The prevalence of Behçet's disease, ulcerative colitis, and primary biliary cholangitis was significantly higher in males with HIV infection (P = 0.025 and P = 0.008, respectively), and dermatomyositis was significantly more prevalent in females with HIV infection (P < 0.001).

4. Discussion

This nationwide population-based study provides clinically relevant evidence on the prevalence of autoimmune diseases in individuals living with HIV in Korea. The overall prevalence of autoimmune diseases in individuals with HIV infection receiving ART did not differ significantly from that in individuals without HIV infection. However, the prevalence of Behçet's disease, ulcerative colitis, and primary biliary cholangitis in men, and dermatomyositis in women, was higher in individuals with HIV infection.

Behçet's disease is more prevalent in women than in men, whereas in individuals with HIV infection, it appears to be more frequently observed in men. The clinical features of oral aphthous ulcers, genital ulcerations, folliculitis, acneiform eruptions, and arthritis can occur in both Behçet's disease and HIV infection [13]. Since Behçet's disease can be diagnosed based on clinical features without specific laboratory tests, the symptoms of HIV infection may be misattributed to Behçet's disease. Behçet's disease in patients with HIV infection has been reported primarily in individuals not receiving ART [14]. The high incidence of Behçet's disease in untreated patients with HIV infection suggests a possible association between HIV infection and the development of Behçet's disease. In this study, all individuals with HIV infection were receiving ART, and Behçet's disease may have been overdiagnosed. Since Behçet's disease is closely related to the human leukocyte antigen (HLA)-B51 gene [15], genetic tests may be helpful in the differential diagnosis.

Gut-associated lymphoid tissues (GALT) are a critical site of CD4+ T-lymphocyte depletion and play an important role in HIV replication and the development of inflammatory bowel disease, such as ulcerative colitis [16,17]. HIV infection leads to a decrease in CD4+ T cells in the intestinal tract, resulting in disruption of the gastrointestinal mucosa, dysbiosis, and chronic inflammation similar to that observed in inflammatory bowel disease. In addition, diarrhea is a common symptom in patients with HIV infection and ulcerative colitis [18]; thus, HIV-associated colitis and ulcerative colitis may be clinically difficult to distinguish. However, these diseases can be differentiated, as HIV-associated colitis is characterized by less mucosal damage or ulceration and distinct sites of inflammation [19]. ART increases the number of CD4+ T cells and may attenuate ulcerative colitis, whereas ulcerative colitis may worsen in uncontrolled HIV infection [20] and can be fatal due to intestinal bleeding or perforation [21]. Thus, determining the coexistence of HIV infection and ulcerative colitis is important for appropriate management.

Primary biliary cholangitis is a chronic progressive cholestatic liver disease with an autoimmune mechanism [22]. The etiology of primary biliary cholangitis is unknown; however, evidence suggests that human betaretrovirus may be associated with primary biliary cholangitis, and antiretroviral therapy such as lamivudine, zidovudine, tenofovir, emtricitabine, and lopinavir has been investigated in this condition [23]. The relationship between primary biliary cholangitis and HIV infection remains unclear. However, viral infection may induce various cellular responses, and further studies are warranted to clarify the potential role of viral co-infections, including human betaretrovirus and HIV.

Dermatomyositis is an inflammatory myopathy characterized by skin lesions and muscle weakness and is more common in women [24]. Dermatomyositis is mediated by CD4+ T cells and B lymphocytes. The cell-mediated response is led by perifascicular CD8+ T cells and macrophages that invade myocytes expressing major histocompatibility complex (MHC) class I antigens. HIV infection leads to depletion of CD4+ T cells and an inversion of the CD4+/CD8+ T-cell ratio. It may also trigger autoantibody production associated with dermatomyositis [25]. The mechanism underlying the relationship between HIV infection and dermatomyositis remains unclear, and only a few cases of co-occurrence have been reported. However, in patients with HIV infection, especially women presenting with skin involvement and muscle weakness, dermatomyositis should be considered in the differential diagnosis.

HIV infection mainly destroys CD4+ T cells involved in cellular immunity. Although HIV infection has clinical manifestations caused by the virus, secondary diseases also occur due to decreased immune function. Acquired immune deficiency syndrome (AIDS) involves various complications, such as infectious diseases or malignant tumors, which occur as immunity decreases. ART is typically initiated when AIDS is diagnosed or when the CD4+ T-cell count is low, even in the absence of symptoms [26]. HIV activity and ART are closely related to the function and number of CD4+ T cells, which may influence the development of autoimmune diseases. All patients with HIV infection included in this study were receiving ART. The ART regimens used in this study may differ from those reported in other countries [5,6].

Since this study analyzed nearly 5 million individuals, it provides a representative estimate of the prevalence of autoimmune diseases in patients with HIV infection in Korea. In addition, since individuals living with HIV are systematically managed through a national healthcare system, the diagnosis of comorbidities may be relatively reliable. However, this study has some limitations. First, the cross-sectional design precludes causal inference regarding the relationship between HIV infection and the development of autoimmune diseases. Second, diagnoses of HIV and autoimmune diseases based on administrative claims data recorded by physicians or hospitals may be less accurate than those made in a prospective clinical setting. Finally, since the number of patients with HIV infection is much smaller than that of patients without HIV infection, a statistically significant difference may arise even with small case numbers. In particular, since primary biliary cholangitis in men and dermatomyositis in women were each observed in only one patient with HIV infection, these findings should be interpreted with caution.

5. Conclusions

In this nationwide study, we found that certain autoimmune diseases appeared to be more prevalent in patients with HIV infection than in those without HIV infection. In particular, Behçet's disease, ulcerative colitis, and primary biliary cholangitis were more common in men with HIV infection, while dermatomyositis appeared to be more prevalent in women. As the number of patients with HIV infection continues to increase in Korea, clinicians should consider these conditions in the differential diagnosis of patients with HIV.