The shifting burden of mortality among men with HIV in Japan between 2007 and 2024: A single-center retrospective cohort study

The shifting burden of mortality among men with HIV in Japan between 2007 and 2024: A single-center retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The shifting burden of mortality among men with HIV in Japan between 2007 and 2024: A single-center retrospective cohort study Keiji Konishi, Tomoko Uehira, Kazuyuki Hirota, Takashi Ueji, Yasuharu Nishida, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7395984/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Dec, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted 18 You are reading this latest preprint version Abstract Background Antiretroviral therapy (ART) has transformed HIV infection from a fatal disease into a chronic condition and improved the life expectancy of people living with HIV (PLWH). Few studies have examined long-term changes in standardized mortality ratios (SMRs) by age and cause of death among PLWH in Japan. This study investigated the changes in SMR among men with HIV infection in Japan over an 18-year period, focusing on age at death and the contribution of malignancies. Methods We conducted a retrospective cohort study of men with HIV infection who received care at Osaka National Hospital between 2007 and 2024. Data were extracted from medical records. Causes of death were classified according to the Coding Causes of Death in HIV protocol. SMRs were calculated based on the general male population of Japan. Results A total of 3,793 patients were included with 35,007 person-years of follow-up. The median age on enrollment was 36.3 years, and the median follow-up period was 10.1 years. Of the patients, 230 died during the study period, with a median age at death of 53.4 years. The causes of death included 44 deaths from AIDS-defining illnesses, 20 deaths from AIDS-related malignancies, 51 deaths from non-AIDS-related malignancies; and 57 deaths of unknown cause. The SMR decreased from 4.11 in 2007–2011 to 1.27 in 2021–2024, with different patterns in different age groups. The SMRs fell to below that of the general population (< 1.0) in the 20–39-years and ≥ 65-years age groups but remained high in the 40–64-years age group, and in patients with CD4 counts < 200 cells/µL or viral loads ≥ 1000 copies/mL within the calendar year. The SMR for malignancies also remained high in the 40–64-years age group (2.28 in 2021–2024). Conclusions Among men with HIV infection in Japan, the risk of mortality has markedly decreased with the widespread use of ART, approaching that of the general population, particularly in younger and older age groups. However, elevated mortality due to non-AIDS-related causes, particularly malignancies, persists among middle-aged men. Future HIV care should prioritize viral suppression and enhancing age-appropriate cancer screening. HIV infection older adults standardized mortality ratio malignancies retrospective cohort study Figures Figure 1 Figure 2 Figure 3 Background Human immunodeficiency virus (HIV) infection was first recognized as a fatal disease in the 1980s. However, the advent of antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, leading to an improvement in life expectancy [ 1 ]. Cohort studies from several countries have shown a decline in standardized mortality ratios (SMRs) with the widespread use of treatment, and survival now approaches that of the general population [ 2 , 3 ]. Conversely, mortality rates from age-related chronic comorbidities have increased in people living with HIV (PLWH) [ 4 – 6 ], with more than 50% of PLWH dying from non-communicable chronic diseases [ 7 – 10 ]. However, markedly elevated SMRs have been observed among injection drug users and individuals who experienced delays in diagnosis and the initiation of treatment, revealing major disparities in life expectancy among different risk groups [ 11 ]. The aging of the population has had a profound effect on HIV management in Japan, where life expectancy ranks among the highest worldwide. The aging of PLWH in Japan is consistent with that reported in other countries [ 12 – 14 ], and in 2023, more than 10% of individuals with newly diagnosed HIV infection were aged 50 years or older [ 15 ]. This demographic shift has raised concerns about the increasing contribution of non-AIDS-defining malignancies (NADMs) to mortality among PLWH [ 16 ]. Internationally, PLWH aged 50 years and older represent a growing percentage of the patient population and face a number of challenges, including a delayed diagnosis, polypharmacy, comorbidities, and stigma [ 17 ]. Previous studies conducted in Japan have shown that elevated mortality persisted among middle-aged and older PLWH, and those with a CD4 count < 200 cells/µL at time of diagnosis, with a low CD4 count being identified as an independent risk factor for all-cause mortality [ 18 , 19 ]. However, few studies have comprehensively examined the long-term changes in SMR by age group and cause of death, including the impact of the most recent era of integrase inhibitor-based ART on the SMR. Although studies from other countries have highlighted the role of NADMs in contributing to elevated mortality among aging populations [ 11 , 16 ], data on the extent of this phenomenon in men with HIV in Japan remain limited, highlighting the need to re-examine mortality patterns and disparities in prognosis among men with HIV in Japan in the context of improvements in ART. Therefore, this study aimed to assess temporal changes in SMRs by age group and cause of death among men with HIV who received care between 2007 and 2024 by comparing the observed number of deaths with the expected number of deaths in the general male population in Japan to enable the provision of targeted HIV care. Methods Study design and setting To evaluate temporal changes in the SMRs and epidemiological characteristics of men with HIV owing to advancements in ART, we conducted a single-center retrospective cohort study at Osaka National Hospital. Clinical trial number: not applicable. As of the end of 2024, the hospital had provided care for a cumulative total of 4,261 patients with HIV, accounting for approximately 12% of all cases in Japan, thereby serving as a major tertiary care center in the country [ 15 ]. Patients and study period The study period was from January 1, 2007, to December 31, 2024. Men with HIV who received care at Osaka National Hospital were included. Patients who first visited the hospital for the first time during the study period, as well as those who had been attending regular follow-up visits since before January 1, 2007, and had at least one visit during 2007 were included. Female patients and those aged younger than 20 years at their first visit on or after January 1, 2007, were excluded. Female patients were excluded owing to their small representation (approximately 4%) during the study period, which limited statistical power to perform detailed stratified analyses. Because more than 95.0% of newly reported PLWH in Japan are men [ 15 ], focusing this study on men with HIV aligns with national public health priorities and does not markedly compromise the generalizability of the results. This study was approved by the Institutional Review Board of Osaka National Hospital (approval no.25034) and conducted in accordance with the principles of the Declaration of Helsinki. The requirement for individual informed consent was waived because the study was retrospective, and the data were anonymized prior to analysis. Information about the study was posted on the hospital’s website, and an opt-out approach was employed, allowing patients to decline participation in the use of their data. Data collection and variables Data on age and sex, date of the first visit to the hospital, history of AIDS-defining illnesses, details of prescribed ART, plasma HIV-1 RNA levels (viral load), CD4 counts, assumed mode of infection, and date of death, were extracted from medical records. In this study, “at enrollment” refers to the beginning of the follow-up period, defined as the date of the first visit on or after January 1, 2007. The lowest CD4 count and highest viral load values recorded in each calendar year were used as representative, time-varying measures for that year’s analysis. Two HIV care specialists independently reviewed the medical records of patients who had died and classified the cause of death using the Coding Causes of Death in HIV (CoDe) protocol [ 20 , 21 ]. In cases of disagreement, a third reviewer made the final classification. Deaths due to malignancies were confirmed by a histopathological diagnosis. Causes of death were classified as AIDS-related (codes 01.1, 01.2, 01) or non-AIDS-related (codes 02–92) according to the CoDe protocol. The follow-up began on the first hospital visit on or after January 1, 2007, and ended at the earliest of the following: the date of death, the date of the last visit (in patients lost-to-follow-up or referred to another institution), or December 31, 2024. Lost-to-follow-up was defined as no visits for more than 12 months after the last visit, with no confirmation of continued care elsewhere or of death. As part of the established patient follow-up system at our hospital, a coordinator nurse contacted patients who missed appointments to encourage them to return for scheduled visits. Statistical analysis The SMR was used as the primary outcome measure. Person-years of observation were calculated for each patient, and deaths were analyzed according to calendar year. SMRs were calculated by dividing the observed number of deaths in the study population by the expected number of deaths in the Japanese general male population, stratified by 5-year age intervals, based on official national vital statistics [ 22 ]. Endpoints included the annual SMRs (for all-cause and malignancy-related mortality), annual SMRs stratified by the CD4 count and viral load, and age group-specific SMRs (aggregated for 2007–2024). The calculation of 95% confidence intervals (CIs) for SMRs was performed under the assumption that deaths followed a Poisson distribution, using R version 4.5.1 (The R Foundation for Statistical Computing, Vienna, Austria). Results Of 4,196 patients assessed for eligibility, 3,793 who received care at Osaka National Hospital between 2007 and 2024 were included in the analysis (Fig. 1 ), with a median follow-up period of 10.1 years (cumulative follow-up: 35,007 person-years). The clinical characteristics of the participants are summarized in Table 1 . At enrollment, median age was 36.3 years (interquartile range [IQR]: 29.7–44.9 years), the median CD4 count was 274 cells/µL (IQR: 113–420 cells/µL), and the median viral load was 4.7 log 10 copies/mL (IQR: 3.8–5.3 log 10 copies/mL). Of the 3,793 patients, 828 (21.8%) had a history of AIDS. The most common route of infection was male-to-male sexual contact (3,122 participants; 82.3%), and the majority of participants were of Japanese nationality (3,553 participants; 93.7%). The median duration of follow-up was 10.1 years (IQR: 4.1–15.5 years). Table 1 Characteristics of study participants (N = 3793) Variable Value Total person-years 35007 person-years Age at enrollment (years), median (IQR) 36.3 (29.7–44.9) Japanese nationality, n (%) 3553 (93.7%) CD4 count at enrollment (cells/µL), median (IQR) 274 (113–420) HIV RNA level at enrollment (log 10 copies/mL), median (IQR) 4.7 (3.8–5.3) History of AIDS-defining illness, n (%) 828 (21.8%) Route of transmission Male-to-male sexual contact 3122 (82.3%) Heterosexual contact 439 (11.6%) Contaminated blood products 69 (1.8%) Injection drug use 5 (0.1%) Other/Unknown 158 (4.2%) Follow-up duration (years), median (IQR) 10.1 (4.1–15.5) IQR, interquartile range During the study period, 230 deaths were confirmed. The median age at death was 53.4 years (IQR: 45.6–64.7 years), and the median time from the first visit to death was 5.0 years (IQR: 0.9–10.7 years) (Table 2 ). The causes of death were diverse: 44 AIDS-related deaths, 20 due to AIDS-defining malignancies, 51 due to NADMs, and 57 from unknown causes. Forty-three deaths occurred outside healthcare institutions, of which 31 were from unknown causes. The detailed causes of death by age group are presented in the additional file (Supplemental Table 1). In the 40–64-years age group, NADMs were the most common cause of death (33 cases), followed by AIDS-related deaths (29 cases) and non-malignant causes, such as cardiovascular disease (10 cases). Table 2 Characteristics of deceased participants (N = 230) Variable Value Age at death (years), median (IQR) 53.4 (45.6–64.7) Time from the first visit to death (years), median (IQR) 5.0 (0.9–10.7) Death during treatment interruption, n (%) 4 (1.7%) Place of death, n (%) In-hospital 105 (45.7%) Other hospital 49 (21.3%) At home 33 (14.3%) Outside hospital/Others 43 (18.7%) Cause of death, n (%) AIDS-related (excluding malignancies) 44 (19.1%) 11 (4.8%) Progressive multifocal leukoencephalopathy 10 (4.3%) HIV encephalopathy 6 (2.6%) Cytomegalovirus infection 3 (1.3%) Cryptococcal meningitis 2 (0.9%) Others 12 (5.2%) AIDS-related malignancies 20 (8.7%) Malignant lymphoma 19 (8.3%) Kaposi’s sarcoma 1 (0.4%) Non-AIDS-related malignancies 51 (22.2%) Lung cancer 14 (6.1%) Gastric cancer 5 (2.2%) Anal canal cancer 5 (2.2%) Hepatocellular carcinoma 5 (2.2%) Hematologic malignancy 5 (2.2%) Colorectal cancer 3 (1.3%) Oropharyngeal cancer 3 (1.3%) Hilar cholangiocarcinoma 2 (0.9%) Others 9 (3.9%) Hepatitis C virus-related 4 (1.7%) Cardiovascular disease 15 (6.5%) Respiratory disease 9 (3.9%) Suicide 9 (3.9%) COVID-19 2 (0.9%) Others 19 (8.3%) Unknown 57 (24.8%) IQR, interquartile range The changes in the crude mortality rates for deaths from all causes and malignancy-related deaths are shown in the additional file (Supplemental Table 2). The overall crude mortality rate for deaths from all causes over the entire observation period was 7.01 per 1,000 person-years. The highest rate (10.58 per 1,000 person-years) was observed in the 2007–2011 period, followed by a decrease to 5.27 per 1,000 person-years in 2017–2020. In the most recent period (2021–2024), the rate increased slightly to 5.80 per 1,000 person-years. The crude mortality rate for malignancy-related deaths during the whole observation period was 2.16 per 1,000 person-years. The crude mortality rates for malignancy-related deaths were 2.78, 2.39, 1.76, and 1.97 per 1,000 person-years in 2007–2011, 2012–2016, 2017–2020, and 2021–2024, respectively. Temporal changes in the crude mortality rates for deaths from causes other than malignancy are shown in the additional file (Supplemental Table 3). The crude mortality rate for AIDS-related deaths decreased markedly from 3.53 per 1,000 person-years in 2007–2011 to 0.44 per 1,000 person-years in 2021–2024. Consequently, the relative importance of non-AIDS-related causes increased. During the most recent period (2021–2024), the mortality rates for respiratory diseases (0.55 per 1,000 person-years) and cardiovascular diseases (0.55 per 1,000 person-years) exceeded that for AIDS-related deaths. During this period, two deaths due to COVID-19 (0.22 per 1,000 person-years) were reported, and the mortality rate from suicide decreased. The overall SMR declined markedly during the study period (Fig. 2 ) from 4.11 (95% CI: 3.11–5.32) in the 2007–2011 to 1.27 (95% CI: 0.95–1.66) in 2021–2024. In the 20–39-years age group, the SMR decreased from 7.28 (95% CI: 4.32–11.51) to 0.68 (95% CI: 0.02–3.77), falling below that of the general population. In addition, the SMR decreased from 3.72 (95% CI: 2.49–5.35) to 1.82 (95% CI: 1.26–2.54) in the 40–64-years age group, and from 2.77 (95% CI: 1.33–5.10) to 0.83 (95% CI: 0.49–1.31) in the ≥ 65-years age group. The SMR for malignancy-related deaths also decreased in all age groups, from 3.46 (95% CI: 1.94–5.71) to 1.36 (95% CI: 0.81–2.15). However, the malignancy-related SMR remained higher in the 40–64-years age group than in the younger and older age groups, decreasing from 3.15 (95% CI: 1.36–6.20) to 2.28 (95% CI: 1.18–3.98). Notably, in the 20–39-years age group, the malignancy-related SMR was 0 in the 2017–2020 and 2021–2024 periods. In the ≥ 65-years age group, the malignancy-related SMR was 0.77 (95% CI: 0.28–1.68) in the 2021–2024 period. The changes in SMR stratified by the CD4 count and viral load, are shown in Fig. 3 . For this analysis, each patient’s person-time contribution was assessed annually based on the lowest CD4 count or highest viral load level recorded within the calendar year. Among patients with CD4 counts < 200 cells/µL, the SMR was highest in the 2007–2011 period (12.76, 95% CI: 9.12–17.38) and decreased to 2.59 (95% CI: 1.12–5.11) in the 2021–2024 period. In contrast, patients with CD4 counts of 200–499 cells/µL and ≥ 500 cells/µL had lower SMRs of 0.82 (95% CI: 0.50–1.26) and 1.05 (95% CI: 0.59–1.74), respectively, in the 2021–2024 period. Similarly, among patients with viral loads ≥ 1,000 copies/mL, the SMR decreased from 8.26 (95% CI: 5.49–11.93) in the 2007–2011 period to 3.37 (95% CI: 0.92–8.64) in the 2021–2024 period. In contrast, patients with viral loads < 50 copies/mL maintained low SMRs, which from 1.42 (95% CI: 0.65–2.70) in the 2007–2011 period to 1.03 (95% CI: 0.72–1.41) in the 2021–2024 period. Discussion This study provides a detailed analysis of the long-term changes in SMRs and mortality patterns among a cohort of men with HIV who received care at a tertiary medical center in Osaka between 2007 and 2024. The marked decline in overall SMR, including a reduction in the mortality rate in the 20–39-years age group to a level approaching that of the general population, suggests that improvements in ART during the study period markedly improved the life expectancy of PLWH in Japan. However, the results of this study revealed that elevated mortality, particularly due to malignancies, persists in men in the 40–64-years age group. The marked reduction in all-cause SMR can be attributed to earlier ART initiation and high rates of viral suppression. These results align with findings of a UK cohort study that demonstrated that a delayed diagnosis markedly shortened life expectancy [ 23 ], and an analysis of 23 European cohorts that showed that mortality rates in PLWH decreased by 50% during this period [ 3 ]. Collectively, these findings suggest that timely diagnosis of HIV infection and early treatment initiation are associated with improved survival, including in Japan. This study revealed that the SMR in men in the 20–39-years age group decreased to below that of the general population. This may reflect the benefits of frequent healthcare access, increased health literacy, and the rigorous management of lifestyle-related conditions. Improved life expectancy has also been reported among younger PLWH in the UK, based on an analysis of national surveillance data [ 24 ], suggesting that the current model of HIV care is effective in younger populations. The median age at death in this cohort was 53.4 years with an IQR of 45.6–64.7 years, indicating that mortality was concentrated in individuals in the 40–64-years age group. This aligns with the finding that whereas the SMR in the 20–39-years age group fell below that of the general population, the mortality rate remained elevated in the 40–64-years age group. The clustering of deaths in this age group suggests that individuals who acquired HIV prior to the widespread availability of ART, and those diagnosed or initiating treatment late, may experience a greater burden of comorbidities and NADMs as they age, leading to increased mortality. A large proportion of deaths, including the majority of deaths from unknown causes, occurred outside a medical institution, which highlights a critical challenge in HIV care in Japan. In a large-scale cohort study conducted by Trickey et al. [ 3 ] in Europe and North America, suicide and accidental deaths were two of the leading causes of death. Although the mortality rate from suicide decreased in our cohort during the study period, the high number out-of-hospital deaths due to unknown causes warrants further investigation. To gain a comprehensive understanding of mortality, collection of more detailed data on out-of-hospital deaths is essential. Among patients aged 65 years and older, the SMR decreased to 0.83, falling below that of the general population. This may be partly explained by the “healthy survivor effect,” whereby individuals who have survived through the pre-ART era and maintained long-term ART adherence may represent a healthier subpopulation in terms of self-management, healthcare access, and lifestyle behaviors. These individuals may be regarded as “selective survivors” who have passed through a natural selection process shaped by disease progression, potentially introducing a bias that leads to a lowering of the SMR in this age group [ 25 ]. Therefore, although the reduced SMR in older adults may reflect the long-term benefits of ART, it requires interpretation in light of possible survivorship bias. Future studies need to consider incorporating statistical models that account for survivorship bias and confirm the data obtained through multicenter collaborative research. Among patients with CD4 counts < 200 cells/µL, the most recent SMR remained high (2.59). This at-risk population likely consists of patients with a late diagnosis and those with insufficient immune recovery (i.e., immunological non-responders) despite long-term ART. This finding is consistent with a prospective cohort study from Japan which reported that a delayed diagnosis doubled the risk of death [ 19 ], supporting the hypothesis that risk is not fully eliminated even after immune reconstitution. Elevated mortality in this group may be attributable not only to opportunistic infections and specific immunodeficiency-related malignancies, but also to the increased severity of NADMs. In Japan, obtaining the public subsidy certificate required to receive financial assistance for HIV treatment costs may take several months [ 26 ]. Many patients delay ART initiation until the certificate is issued, which may contribute to delays in initiating treatment. Although the SMR among those with viral loads ≥ 1,000 copies/mL was 3.37, this was not statistically significant owing to the small absolute number of patients in this group. This group consists primarily of patients with poor adherence to ART and those who have interrupted their care. This result suggests the negative impact of structural and behavioral factors, such as poor medication adherence, psychiatric disorders, and substance use, which are factors that have been identified in European multicenter reports as major contributors to disparities in mortality [ 11 ]. Furthermore, a large number of PLWH in Japan remain undiagnosed. At the end of 2015, the most recent year for which an estimate is available, an estimated 14.4% of all PLWH in Japan were unaware of their infection [ 27 ]. This diagnostic gap may lead to missed opportunities for early treatment and consequently worsen their prognosis. The persistently elevated malignancy-related mortality is likely due to a multifactorial interplay between chronic inflammation, immunosenescence, co-infection with oncogenic viruses, and lifestyle factors, such as smoking and alcohol consumption. A recent meta-analysis of NADM risk worldwide found the both NADM incidence and mortality are increasing [ 28 ]. Similarly, a prospective cancer-screening study among PLWH with hemophilia in Japan revealed a high prevalence and incidence of NADM, highlighting the hidden cancer burden and utility of regular screening [ 29 ]. The sustained elevation of the malignancy-related SMR in the 40–64-year age group in this study suggests a need for intensified surveillance in this population. A secondary analysis of the Strategic Timing of AntiRetroviral Treatment (START) trial, conducted in Europe and the United States, revealed that early ART initiation reduced the risk of infection-related cancers [ 30 ]. However, in Japan, approximately 30% of cases of HIV infection are diagnosed after the onset of AIDS [ 15 ], highlighting the need to address diagnostic delays and establish individualized cancer-screening programs. The meta-analysis of NADM by Yuan et al. [ 28 ], highlighted the importance of integrating primary and secondary prevention of major NADMs, such as anal, liver, and lung cancers, into routine HIV care. This includes age-stratified screening strategies that combine human papillomavirus and hepatitis B virus vaccination, antiviral therapy, smoking cessation support, and the use of screening methods, such as low-dose computed tomography and endoscopy. This study suggests that in an aging PLWH population, it is necessary to go beyond cancer screening and incorporate comprehensive geriatric assessment and mental health support into multidisciplinary team-based care. According to an analysis of Japanese health insurance claims data, 13.4% of 28,089 PLWH on ART were using five or more concurrent medications, with rates increasing to 29.9% in those aged 50–59 years and 40.3% in those aged 70 years and older [ 31 ]. Therefore, the systematic management of polypharmacy and drug-drug interactions is a growing challenge in the care of older PLWH. This study has several strengths. The long-term follow-up of a cohort of almost 4,000 individuals at Osaka National Hospital, a central institution for PLWH care in Japan, over an 18-year-period,provides new insights into the epidemiology of HIV in Japan, and a comprehensive evaluation of the long-term changes in mortality risk. Additionally, the use of the CoDe protocol for cause-of-death classification ensured internationally comparable and standardized cause-of-death data, enhancing the reliability of the results obtained. Furthermore, by conducting stratified analyses by age group, CD4 count, and viral load, the study identified age group-specific challenges, such as an improved prognosis in the younger age group, and persistently elevated mortality due to malignancies in the middle and older age groups. This study also has several limitations. Because it is a retrospective single-center cohort study, the possibility of a selection bias, such as overrepresentation of patients with more severe disease owing to referrals, cannot be ruled out. Therefore, the mortality rates and cause-of-death patterns may not be generalizable to all men with HIV in Japan. Furthermore, the cause of death was unknown in approximately 25% of all deaths and was higher among patients with out-of-hospital deaths. The high proportion of deaths due to unknown causes may have affected the accuracy of cause-specific SMRs, especially for non-AIDS-related deaths, and may have led to an underestimation of malignancy-related mortality. Moreover, the minimum CD4 count and the maximum viral load within each year were used as immunological and virological markers, respectively but do not necessarily reflect long-term disease control at the individual level. To evaluate the effects of exposure duration and temporal fluctuations in CD4 count and viral load, longitudinal analyses or analyses using time-weighted averages are required. Another limitation is that this study excluded female patients, and the cohort was predominantly composed of men who acquired HIV through male-to-male sexual contact (approximately 80%); therefore, differences in mortality by sex and route of transmission could not be assessed. Addressing this limitation is important for future research, particularly from a public health perspective of promoting diversity and inclusion. In addition, owing to the retrospective nature of the study and reliance on medical records, it was not possible to systematically capture social factors that affect health, such as smoking, alcohol use, lifestyle behaviors, mental health conditions, and the utilization of medical cost subsidies. The impact of these factors on mortality and prognosis need to be examined in future prospective studies or nationwide database analyses. Conclusions This study revealed that SMRs among men with HIV in Japan improved markedly between 2007 and 2024, which is primarily due to improvements in ART. Although the mortality rates in the younger and older age groups converged toward those observed in the general population, mortality related to malignancies remained elevated in men in the 40–64-years age group. These results highlight the need for a comprehensive approach to NADMs in addition to virological control in proving care for PLWH in Japan and could inform the development of targeted public health and clinical management strategies. Abbreviations AIDS Acquired immunodeficiency syndrome ART Antiretroviral therapy HIV Human immunodeficiency virus NADM Non-AIDS-defining malignancy PLWH Persons living with HIV SMR Standardized mortality ratio Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of Osaka National Hospital (approval no. 25034). The requirement for individual informed consent was waived because the study was retrospective, and the data were anonymized prior to analysis. Consent for publication Not applicable. Availability of data and materials The data used in this study cannot be posted in supplemental files or public repositories because of legal and ethical restrictions. Competing interests The authors declare that they have no competing interests. Funding This work was supported by a Health Labour Sciences Research Grant [23HB2001, acquired by DW; funder URL: https://mhlw-grants.niph.go.jp/]. The funder played no role in the study design, data collection, data analysis, interpretation, or manuscript writing. Authors' contributions KK and DW designed this study. KK, DW, KH, TU, YN, and TU collected data. KK and DW were involved in sample processing. KK participated in the data analysis. KK wrote the paper. DW, KH, TU, YN, TU, and TS critically reviewed and revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript. Acknowledgments Editage, Cactus Communications provided support with English-language editing. References Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008:372:293-9. Tsuda H, Koga M, Nojima M, Senkoji T, Kubota M, Kikuchi T, et al. Changes in survival and causes of death among people living with HIV: Three decades of surveys from Tokyo, one of the Asian metropolitan cities. J Infect Chemother. 2021;27:949-56. Trickey A, McGinnis K, Gill MJ, Abgrall S, Berenguer J, Wyen C, et al. Longitudinal trends in causes of death among adults with HIV on antiretroviral therapy in Europe and North America from 1996 to 2020: A collaboration of cohort studies. Lancet HIV 2024;11:e176-85. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53:1120-6. Hasse B, Ledergerber B, Furrer H, Battegay M, Hirschel B, Cavassini M, et al. Morbidity and aging in HIV-infected persons: The Swiss HIV Cohort Study. Clin Infect Dis. 2011;53:1130-9. Wu PY, Chen MY, Hsieh SM, Sun HY, Tsai MS, Lee KY, et al. Comorbidities among the HIV-infected patients aged 40 years or older in Taiwan. PLoS One 2014;9:e104945. Weber R, Sabin CA, Friis-Møller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632-41. Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145:397-406. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736-88. Weber MSR, Duran Ramirez JJ, Hentzien M, Cavassini M, Bernasconi E, Hofmann E, et al. Time trends in causes of death in people with HIV: Insights from the Swiss HIV Cohort Study. Clin Infect Dis. 2024;79:177-88. Suárez-García I, Gutierrez F, Pérez-Molina JA, Moreno S, Aldamiz T, Valencia Ortega E, et al. Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up. J Cancer Res Clin Oncol. 2023; 149:18161-71. Costagliola D. Demographics of HIV and aging. Curr Opin HIV AIDS 2014;9:294-301. Marcus JL, Leyden WA, Alexeeff SE, Anderson AN, Hechter RC, Hu H, et al. Comparison of overall and comorbidity-free life expectancy between insured adults with and without HIV infection, 2000–2016. JAMA Netw Open 2020;3:e207954. Collins LF, Armstrong WS. What it means to age with HIV infection: Years gained are not comorbidity free. JAMA Netw Open 2020;3:e208023. AIDS Prevention Information Network. The AIDS Surveillance Committee, the Japanese Ministry of Health, Labour and Welfare. Japanese. https://api-net.jfap.or.jp/status/japan/nenpo.html. Accessed 13 July 2025. Vallée A, Majerholc C, Zucman D, Livrozet JM, Laurendeau C, Bouée S, et al. Mortality and comorbidities in a nationwide cohort of HIV-infected adults: Comparison to a matched non-HIV adults’ cohort, France, 2006–18. Eur J Public Health 2024;34:879-84. Mbalinda SN, Lusota DA, Muddu M, Nyashanu M. Ageing with HIV: Challenges and coping mechanisms of older adults 50 years and above living with HIV in Uganda. BMC Geriatr. 2024;24:95. Oka S, Ikeda K, Takano M, Ogane M, Tanuma J, Tsukada K, et al. Pathogenesis, clinical course, and recent issues in HIV-1-infected Japanese hemophiliacs: A three-decade follow-up. Glob Health Med. 2020;2:9-17. Nishijima T, Inaba Y, Kawasaki Y, Tsukada K, Teruya K, Kikuchi Y, et al. Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan. AIDS 2020; 34:913-21. Copenhagen HIV Programme (CHIP). Coding Causes of Death in HIV protocol; version 2.3; August 2013. https://chip.dk/Portals/0/files/Code%20Protocol%202.3.pdf. Accessed 13 Jul 2025. Kowalska JD, Friis-Møller N, Kirk O, Bannister W, Mocroft A, Sabin C, et al. The Coding Causes of Death in HIV (CoDe) Project: Initial results and evaluation of methodology. Epidemiology 2011;22:516-23. e-Stat, Statistics of Japan. Trends in deaths and death rates (per 100,000 population) by sex, age (5-year age groups) and causes of death: Japan. https://www.e-stat.go.jp/en/stat-search/files?page=1&layout=datalist&toukei=00450011&tstat=000001028897&cycle=7&year=20230&month=0&tclass1 =000001053058&tclass2=000001053061&tclass3=000001053065&result_back=1&tclass4val=0. Accessed 13 July 2025. May M, Gompels M, Delpech V, Porter K, Post F, Johnson M, et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 2011; 343:d6016. Croxford S, Kitching A, Desai S, Kall M, Edelstein M, Skingsley A, et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: An analysis of a national observational cohort. Lancet Public Health 2017;2:e35-e46. Engsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, Røge B, et al. Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: A cohort study. BMC Infect Dis. 2010;10:318. Ministry of Health, Labour and Welfare. Reports on the certification of disabilities due to immune deficiency by HIV. https://www.mhlw.go.jp/www1/shingi/s1216-3.html.Accessed 13 July 2025. Iwamoto A, Taira R, Yokomaku Y, Koibuchi T, Rahman M, Izumi Y, et al. The HIV care cascade: Japanese perspectives. PLoS One 2017;12:e0174360. Yuan T, Hu Y, Zhou X, Yang L, Wang H, Li L, et al. Incidence and mortality of non-AIDS-defining cancers among people living with HIV: A systematic review and meta-analysis. EClinicalMedicine 2022, 52:101613. Oka S, Ogata M, Takano M, Minamimoto R, Hotta M, Tajima T, et al. Non-AIDS-defining malignancies in Japanese hemophiliacs with HIV-1 infection. Glob Health Med. 2019;1:49-54. Borges ÁH, Neuhaus J, Babiker AG, Henry K, Jain MK, Palfreeman A, et al. Immediate antiretroviral therapy reduces risk of infection-related cancer during early HIV infection. Clin Infect Dis. 2016;63:1668-76. Naito T, Suzuki M, Fukushima S, Yuda M, Fukui N, Tsukamoto S, et al. Comorbidities and co-medications among 28 089 people living with HIV: A nationwide cohort study from 2009 to 2019 in Japan. HIV Med. 2022;23:485-493. Additional Declarations No competing interests reported. Supplementary Files additionalfilesupplementarymaterials.docx Cite Share Download PDF Status: Published Journal Publication published 05 Dec, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 08 Oct, 2025 Reviews received at journal 05 Oct, 2025 Reviews received at journal 22 Sep, 2025 Reviews received at journal 17 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviews received at journal 15 Sep, 2025 Reviewers agreed at journal 15 Sep, 2025 Reviewers agreed at journal 14 Sep, 2025 Reviewers agreed at journal 13 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers invited by journal 12 Sep, 2025 Editor invited by journal 20 Aug, 2025 Editor assigned by journal 19 Aug, 2025 Submission checks completed at journal 19 Aug, 2025 First submitted to journal 18 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7395984","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":516665218,"identity":"4634bc30-1380-409a-8cf5-5e317ce8b41b","order_by":0,"name":"Keiji Konishi","email":"data:image/png;base64,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","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":true,"prefix":"","firstName":"Keiji","middleName":"","lastName":"Konishi","suffix":""},{"id":516665219,"identity":"74f964f5-8f09-4108-a9df-6662815f2eaf","order_by":1,"name":"Tomoko Uehira","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Uehira","suffix":""},{"id":516665220,"identity":"f072d1fa-97a9-440f-9cc4-ffde7bc6fc0c","order_by":2,"name":"Kazuyuki Hirota","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kazuyuki","middleName":"","lastName":"Hirota","suffix":""},{"id":516665221,"identity":"2c51b38d-3cfe-431b-81d3-c90e7f6fdb72","order_by":3,"name":"Takashi Ueji","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Ueji","suffix":""},{"id":516665222,"identity":"49b3322a-0ad7-4df3-a816-a3fe9bd23013","order_by":4,"name":"Yasuharu Nishida","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasuharu","middleName":"","lastName":"Nishida","suffix":""},{"id":516665223,"identity":"ce6e88c7-071e-4d9f-b91e-9e3eaed2349c","order_by":5,"name":"Takuma Shirasaka","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takuma","middleName":"","lastName":"Shirasaka","suffix":""},{"id":516665224,"identity":"30151593-f7b5-4fa2-ade5-3f557906d190","order_by":6,"name":"Dai Watanabe","email":"","orcid":"","institution":"AIDS Medical Center, NHO Osaka National Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Watanabe","suffix":""}],"badges":[],"createdAt":"2025-08-18 05:38:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7395984/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7395984/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-12114-8","type":"published","date":"2025-12-05T15:57:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91931152,"identity":"6d3534ea-5ac4-4865-aaf3-7b4b2f154503","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119352,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/7745eae800f610fd92997fa0.docx"},{"id":91931153,"identity":"e385736e-4da3-4ab5-8a5b-8195f49bfdea","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"json","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9023,"visible":true,"origin":"","legend":"","description":"","filename":"c20047015f0e4e31a53441170d417c8f.json","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/07b1f192e253e15ca81a713e.json"},{"id":91932836,"identity":"eeb55364-1857-48ab-ac38-abb4c51ceeb1","added_by":"auto","created_at":"2025-09-23 02:36:40","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38379,"visible":true,"origin":"","legend":"","description":"","filename":"additionalfilesupplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/b82e72bf18c006945cf9e644.docx"},{"id":91931154,"identity":"e487b729-e096-4a8e-a7af-a207710b8cde","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97161,"visible":true,"origin":"","legend":"","description":"","filename":"c20047015f0e4e31a53441170d417c8f1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/5620f296a1ca5e130d48f650.xml"},{"id":91932835,"identity":"3fb57d95-aa01-40e4-95ef-1b6ba00edd2b","added_by":"auto","created_at":"2025-09-23 02:36:40","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":290831,"visible":true,"origin":"","legend":"","description":"","filename":"figure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/0720ef37bf6382d9c6eaa541.pdf"},{"id":91931157,"identity":"605b5472-ca53-409a-ac1f-d10cfa8cc399","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"pdf","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":874860,"visible":true,"origin":"","legend":"","description":"","filename":"figure2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/7cdf599546eea5fbd034528a.pdf"},{"id":91931161,"identity":"94f9ff28-c1d1-468d-bb4e-db240f567b0e","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"pdf","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":675302,"visible":true,"origin":"","legend":"","description":"","filename":"figure3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/38c7d71c5bd587792b5c7263.pdf"},{"id":91931160,"identity":"dcff95ce-ce63-4990-84e1-ec7ecb8144ca","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94309,"visible":true,"origin":"","legend":"","description":"","filename":"c20047015f0e4e31a53441170d417c8f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/8c97be795a1e4973f0c53f76.xml"},{"id":91932834,"identity":"6fae4341-338a-4186-b499-56f6ef236deb","added_by":"auto","created_at":"2025-09-23 02:36:40","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":104560,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/da4e39476e215b5d58630d35.html"},{"id":91931148,"identity":"ad96513b-b2e3-4aed-93aa-ece16f1211d6","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":204123,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart showing participant selection\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/4a6952f2e0c82cf319ae866e.jpg"},{"id":91932833,"identity":"4049f55d-1302-4f9c-ab72-1e75a6dfabb7","added_by":"auto","created_at":"2025-09-23 02:36:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":435032,"visible":true,"origin":"","legend":"\u003cp\u003eStandardized mortality ratios (SMRs) by period according to age group.\u003c/p\u003e\n\u003cp\u003e(a) All-cause SMRs by period in the whole cohort and by age group. (b) Malignancy-specific SMRs in the whole cohort and by age group. The error bars show the 95% confidence intervals (CIs). The 95% CIs are wide in the 20–39-years age group owing to the limited number of deaths. The red horizontal line indicates an SMR of 1.0.\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/448d3800c2ece5b8475694ce.jpg"},{"id":91931151,"identity":"c4bbbfbb-c04f-48ac-a4c6-28862e898b97","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":393902,"visible":true,"origin":"","legend":"\u003cp\u003eStandardized mortality ratios (SMRs) by period according to the time-varying lowest CD4 count and highest viral load level within each calendar year\u003c/p\u003e\n\u003cp\u003e(a) SMRs by period according to lowest CD4 count level within each calendar year. (b) SMRs by period according to highest viral load level within each calendar year. The error bars show the 95% confidence intervals (CIs). The red horizontal line indicates an SMR of 1.0.\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/0d0cb99fc5e59fa4194da990.jpg"},{"id":97724527,"identity":"0b53e1ea-5432-4fa0-935a-cc96e8281274","added_by":"auto","created_at":"2025-12-08 16:12:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1565748,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/738dfd5b-d607-4abf-b608-fa0e9d1e6c3b.pdf"},{"id":91931150,"identity":"bc434028-d1a0-42e2-a8ac-e6a7038fb0a2","added_by":"auto","created_at":"2025-09-23 02:28:40","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":38379,"visible":true,"origin":"","legend":"","description":"","filename":"additionalfilesupplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7395984/v1/71a4f895be95e9e18f70dacb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The shifting burden of mortality among men with HIV in Japan between 2007 and 2024: A single-center retrospective cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eHuman immunodeficiency virus (HIV) infection was first recognized as a fatal disease in the 1980s. However, the advent of antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, leading to an improvement in life expectancy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cohort studies from several countries have shown a decline in standardized mortality ratios (SMRs) with the widespread use of treatment, and survival now approaches that of the general population [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Conversely, mortality rates from age-related chronic comorbidities have increased in people living with HIV (PLWH) [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], with more than 50% of PLWH dying from non-communicable chronic diseases [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, markedly elevated SMRs have been observed among injection drug users and individuals who experienced delays in diagnosis and the initiation of treatment, revealing major disparities in life expectancy among different risk groups [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe aging of the population has had a profound effect on HIV management in Japan, where life expectancy ranks among the highest worldwide. The aging of PLWH in Japan is consistent with that reported in other countries [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and in 2023, more than 10% of individuals with newly diagnosed HIV infection were aged 50 years or older [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This demographic shift has raised concerns about the increasing contribution of non-AIDS-defining malignancies (NADMs) to mortality among PLWH [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Internationally, PLWH aged 50 years and older represent a growing percentage of the patient population and face a number of challenges, including a delayed diagnosis, polypharmacy, comorbidities, and stigma [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Previous studies conducted in Japan have shown that elevated mortality persisted among middle-aged and older PLWH, and those with a CD4 count\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/\u0026micro;L at time of diagnosis, with a low CD4 count being identified as an independent risk factor for all-cause mortality [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, few studies have comprehensively examined the long-term changes in SMR by age group and cause of death, including the impact of the most recent era of integrase inhibitor-based ART on the SMR. Although studies from other countries have highlighted the role of NADMs in contributing to elevated mortality among aging populations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], data on the extent of this phenomenon in men with HIV in Japan remain limited, highlighting the need to re-examine mortality patterns and disparities in prognosis among men with HIV in Japan in the context of improvements in ART.\u003c/p\u003e\u003cp\u003eTherefore, this study aimed to assess temporal changes in SMRs by age group and cause of death among men with HIV who received care between 2007 and 2024 by comparing the observed number of deaths with the expected number of deaths in the general male population in Japan to enable the provision of targeted HIV care.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and setting\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTo evaluate temporal changes in the SMRs and epidemiological characteristics of men with HIV owing to advancements in ART, we conducted a single-center retrospective cohort study at Osaka National Hospital. Clinical trial number: not applicable. As of the end of 2024, the hospital had provided care for a cumulative total of 4,261 patients with HIV, accounting for approximately 12% of all cases in Japan, thereby serving as a major tertiary care center in the country [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePatients and study period\u003c/h3\u003e\n\u003cp\u003eThe study period was from January 1, 2007, to December 31, 2024. Men with HIV who received care at Osaka National Hospital were included. Patients who first visited the hospital for the first time during the study period, as well as those who had been attending regular follow-up visits since before January 1, 2007, and had at least one visit during 2007 were included. Female patients and those aged younger than 20 years at their first visit on or after January 1, 2007, were excluded. Female patients were excluded owing to their small representation (approximately 4%) during the study period, which limited statistical power to perform detailed stratified analyses. Because more than 95.0% of newly reported PLWH in Japan are men [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], focusing this study on men with HIV aligns with national public health priorities and does not markedly compromise the generalizability of the results.\u003c/p\u003e\u003cp\u003e This study was approved by the Institutional Review Board of Osaka National Hospital (approval no.25034) and conducted in accordance with the principles of the Declaration of Helsinki. The requirement for individual informed consent was waived because the study was retrospective, and the data were anonymized prior to analysis. Information about the study was posted on the hospital\u0026rsquo;s website, and an opt-out approach was employed, allowing patients to decline participation in the use of their data.\u003c/p\u003e\n\u003ch3\u003eData collection and variables\u003c/h3\u003e\n\u003cp\u003eData on age and sex, date of the first visit to the hospital, history of AIDS-defining illnesses, details of prescribed ART, plasma HIV-1 RNA levels (viral load), CD4 counts, assumed mode of infection, and date of death, were extracted from medical records. In this study, \u0026ldquo;at enrollment\u0026rdquo; refers to the beginning of the follow-up period, defined as the date of the first visit on or after January 1, 2007. The lowest CD4 count and highest viral load values recorded in each calendar year were used as representative, time-varying measures for that year\u0026rsquo;s analysis. Two HIV care specialists independently reviewed the medical records of patients who had died and classified the cause of death using the Coding Causes of Death in HIV (CoDe) protocol [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In cases of disagreement, a third reviewer made the final classification. Deaths due to malignancies were confirmed by a histopathological diagnosis. Causes of death were classified as AIDS-related (codes 01.1, 01.2, 01) or non-AIDS-related (codes 02\u0026ndash;92) according to the CoDe protocol. The follow-up began on the first hospital visit on or after January 1, 2007, and ended at the earliest of the following: the date of death, the date of the last visit (in patients lost-to-follow-up or referred to another institution), or December 31, 2024. Lost-to-follow-up was defined as no visits for more than 12 months after the last visit, with no confirmation of continued care elsewhere or of death. As part of the established patient follow-up system at our hospital, a coordinator nurse contacted patients who missed appointments to encourage them to return for scheduled visits.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe SMR was used as the primary outcome measure. Person-years of observation were calculated for each patient, and deaths were analyzed according to calendar year. SMRs were calculated by dividing the observed number of deaths in the study population by the expected number of deaths in the Japanese general male population, stratified by 5-year age intervals, based on official national vital statistics [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Endpoints included the annual SMRs (for all-cause and malignancy-related mortality), annual SMRs stratified by the CD4 count and viral load, and age group-specific SMRs (aggregated for 2007\u0026ndash;2024). The calculation of 95% confidence intervals (CIs) for SMRs was performed under the assumption that deaths followed a Poisson distribution, using R version 4.5.1 (The R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOf 4,196 patients assessed for eligibility, 3,793 who received care at Osaka National Hospital between 2007 and 2024 were included in the analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), with a median follow-up period of 10.1 years (cumulative follow-up: 35,007 person-years). The clinical characteristics of the participants are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At enrollment, median age was 36.3 years (interquartile range [IQR]: 29.7\u0026ndash;44.9 years), the median CD4 count was 274 cells/\u0026micro;L (IQR: 113\u0026ndash;420 cells/\u0026micro;L), and the median viral load was 4.7 log\u003csub\u003e10\u003c/sub\u003e copies/mL (IQR: 3.8\u0026ndash;5.3 log\u003csub\u003e10\u003c/sub\u003e copies/mL). Of the 3,793 patients, 828 (21.8%) had a history of AIDS. The most common route of infection was male-to-male sexual contact (3,122 participants; 82.3%), and the majority of participants were of Japanese nationality (3,553 participants; 93.7%). The median duration of follow-up was 10.1 years (IQR: 4.1\u0026ndash;15.5 years).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of study participants (N\u0026thinsp;=\u0026thinsp;3793)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal person-years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35007 person-years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at enrollment (years), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36.3 (29.7\u0026ndash;44.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJapanese nationality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3553 (93.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCD4 count at enrollment (cells/\u0026micro;L), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e274 (113\u0026ndash;420)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHIV RNA level at enrollment (log\u003csub\u003e10\u003c/sub\u003e copies/mL), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.7 (3.8\u0026ndash;5.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of AIDS-defining illness, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e828 (21.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRoute of transmission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale-to-male sexual contact\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3122 (82.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeterosexual contact\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e439 (11.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eContaminated blood products\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (1.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInjection drug use\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (0.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther/Unknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e158 (4.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow-up duration (years), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.1 (4.1\u0026ndash;15.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eIQR, interquartile range\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDuring the study period, 230 deaths were confirmed. The median age at death was 53.4 years (IQR: 45.6\u0026ndash;64.7 years), and the median time from the first visit to death was 5.0 years (IQR: 0.9\u0026ndash;10.7 years) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The causes of death were diverse: 44 AIDS-related deaths, 20 due to AIDS-defining malignancies, 51 due to NADMs, and 57 from unknown causes. Forty-three deaths occurred outside healthcare institutions, of which 31 were from unknown causes. The detailed causes of death by age group are presented in the additional file (Supplemental Table\u0026nbsp;1). In the 40\u0026ndash;64-years age group, NADMs were the most common cause of death (33 cases), followed by AIDS-related deaths (29 cases) and non-malignant causes, such as cardiovascular disease (10 cases).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of deceased participants (N\u0026thinsp;=\u0026thinsp;230)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at death (years), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e53.4 (45.6\u0026ndash;64.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime from the first visit to death (years), median (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.0 (0.9\u0026ndash;10.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath during treatment interruption, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (1.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlace of death, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIn-hospital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e105 (45.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther hospital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e49 (21.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAt home\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e33 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutside hospital/Others\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43 (18.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCause of death, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIDS-related (excluding malignancies)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e44 (19.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgressive multifocal leukoencephalopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10 (4.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHIV encephalopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6 (2.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCytomegalovirus infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (1.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCryptococcal meningitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e12 (5.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIDS-related malignancies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20 (8.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignant lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKaposi\u0026rsquo;s sarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-AIDS-related malignancies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e51 (22.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLung cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14 (6.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (2.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnal canal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (2.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatocellular carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (2.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHematologic malignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5 (2.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColorectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (1.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOropharyngeal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3 (1.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHilar cholangiocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatitis C virus-related\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4 (1.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiovascular disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (6.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSuicide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCOVID-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e57 (24.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eIQR, interquartile range\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe changes in the crude mortality rates for deaths from all causes and malignancy-related deaths are shown in the additional file (Supplemental Table\u0026nbsp;2). The overall crude mortality rate for deaths from all causes over the entire observation period was 7.01 per 1,000 person-years. The highest rate (10.58 per 1,000 person-years) was observed in the 2007\u0026ndash;2011 period, followed by a decrease to 5.27 per 1,000 person-years in 2017\u0026ndash;2020. In the most recent period (2021\u0026ndash;2024), the rate increased slightly to 5.80 per 1,000 person-years. The crude mortality rate for malignancy-related deaths during the whole observation period was 2.16 per 1,000 person-years. The crude mortality rates for malignancy-related deaths were 2.78, 2.39, 1.76, and 1.97 per 1,000 person-years in 2007\u0026ndash;2011, 2012\u0026ndash;2016, 2017\u0026ndash;2020, and 2021\u0026ndash;2024, respectively. Temporal changes in the crude mortality rates for deaths from causes other than malignancy are shown in the additional file (Supplemental Table\u0026nbsp;3). The crude mortality rate for AIDS-related deaths decreased markedly from 3.53 per 1,000 person-years in 2007\u0026ndash;2011 to 0.44 per 1,000 person-years in 2021\u0026ndash;2024. Consequently, the relative importance of non-AIDS-related causes increased. During the most recent period (2021\u0026ndash;2024), the mortality rates for respiratory diseases (0.55 per 1,000 person-years) and cardiovascular diseases (0.55 per 1,000 person-years) exceeded that for AIDS-related deaths. During this period, two deaths due to COVID-19 (0.22 per 1,000 person-years) were reported, and the mortality rate from suicide decreased.\u003c/p\u003e\u003cp\u003eThe overall SMR declined markedly during the study period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) from 4.11 (95% CI: 3.11\u0026ndash;5.32) in the 2007\u0026ndash;2011 to 1.27 (95% CI: 0.95\u0026ndash;1.66) in 2021\u0026ndash;2024. In the 20\u0026ndash;39-years age group, the SMR decreased from 7.28 (95% CI: 4.32\u0026ndash;11.51) to 0.68 (95% CI: 0.02\u0026ndash;3.77), falling below that of the general population. In addition, the SMR decreased from 3.72 (95% CI: 2.49\u0026ndash;5.35) to 1.82 (95% CI: 1.26\u0026ndash;2.54) in the 40\u0026ndash;64-years age group, and from 2.77 (95% CI: 1.33\u0026ndash;5.10) to 0.83 (95% CI: 0.49\u0026ndash;1.31) in the \u0026ge;\u0026thinsp;65-years age group. The SMR for malignancy-related deaths also decreased in all age groups, from 3.46 (95% CI: 1.94\u0026ndash;5.71) to 1.36 (95% CI: 0.81\u0026ndash;2.15). However, the malignancy-related SMR remained higher in the 40\u0026ndash;64-years age group than in the younger and older age groups, decreasing from 3.15 (95% CI: 1.36\u0026ndash;6.20) to 2.28 (95% CI: 1.18\u0026ndash;3.98). Notably, in the 20\u0026ndash;39-years age group, the malignancy-related SMR was 0 in the 2017\u0026ndash;2020 and 2021\u0026ndash;2024 periods. In the \u0026ge;\u0026thinsp;65-years age group, the malignancy-related SMR was 0.77 (95% CI: 0.28\u0026ndash;1.68) in the 2021\u0026ndash;2024 period.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe changes in SMR stratified by the CD4 count and viral load, are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. For this analysis, each patient\u0026rsquo;s person-time contribution was assessed annually based on the lowest CD4 count or highest viral load level recorded within the calendar year. Among patients with CD4 counts\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/\u0026micro;L, the SMR was highest in the 2007\u0026ndash;2011 period (12.76, 95% CI: 9.12\u0026ndash;17.38) and decreased to 2.59 (95% CI: 1.12\u0026ndash;5.11) in the 2021\u0026ndash;2024 period. In contrast, patients with CD4 counts of 200\u0026ndash;499 cells/\u0026micro;L and \u0026ge;\u0026thinsp;500 cells/\u0026micro;L had lower SMRs of 0.82 (95% CI: 0.50\u0026ndash;1.26) and 1.05 (95% CI: 0.59\u0026ndash;1.74), respectively, in the 2021\u0026ndash;2024 period. Similarly, among patients with viral loads\u0026thinsp;\u0026ge;\u0026thinsp;1,000 copies/mL, the SMR decreased from 8.26 (95% CI: 5.49\u0026ndash;11.93) in the 2007\u0026ndash;2011 period to 3.37 (95% CI: 0.92\u0026ndash;8.64) in the 2021\u0026ndash;2024 period. In contrast, patients with viral loads\u0026thinsp;\u0026lt;\u0026thinsp;50 copies/mL maintained low SMRs, which from 1.42 (95% CI: 0.65\u0026ndash;2.70) in the 2007\u0026ndash;2011 period to 1.03 (95% CI: 0.72\u0026ndash;1.41) in the 2021\u0026ndash;2024 period.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a detailed analysis of the long-term changes in SMRs and mortality patterns among a cohort of men with HIV who received care at a tertiary medical center in Osaka between 2007 and 2024. The marked decline in overall SMR, including a reduction in the mortality rate in the 20\u0026ndash;39-years age group to a level approaching that of the general population, suggests that improvements in ART during the study period markedly improved the life expectancy of PLWH in Japan. However, the results of this study revealed that elevated mortality, particularly due to malignancies, persists in men in the 40\u0026ndash;64-years age group.\u003c/p\u003e\u003cp\u003eThe marked reduction in all-cause SMR can be attributed to earlier ART initiation and high rates of viral suppression. These results align with findings of a UK cohort study that demonstrated that a delayed diagnosis markedly shortened life expectancy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and an analysis of 23 European cohorts that showed that mortality rates in PLWH decreased by 50% during this period [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Collectively, these findings suggest that timely diagnosis of HIV infection and early treatment initiation are associated with improved survival, including in Japan. This study revealed that the SMR in men in the 20\u0026ndash;39-years age group decreased to below that of the general population. This may reflect the benefits of frequent healthcare access, increased health literacy, and the rigorous management of lifestyle-related conditions. Improved life expectancy has also been reported among younger PLWH in the UK, based on an analysis of national surveillance data [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], suggesting that the current model of HIV care is effective in younger populations.\u003c/p\u003e\u003cp\u003eThe median age at death in this cohort was 53.4 years with an IQR of 45.6\u0026ndash;64.7 years, indicating that mortality was concentrated in individuals in the 40\u0026ndash;64-years age group. This aligns with the finding that whereas the SMR in the 20\u0026ndash;39-years age group fell below that of the general population, the mortality rate remained elevated in the 40\u0026ndash;64-years age group. The clustering of deaths in this age group suggests that individuals who acquired HIV prior to the widespread availability of ART, and those diagnosed or initiating treatment late, may experience a greater burden of comorbidities and NADMs as they age, leading to increased mortality. A large proportion of deaths, including the majority of deaths from unknown causes, occurred outside a medical institution, which highlights a critical challenge in HIV care in Japan. In a large-scale cohort study conducted by Trickey et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] in Europe and North America, suicide and accidental deaths were two of the leading causes of death. Although the mortality rate from suicide decreased in our cohort during the study period, the high number out-of-hospital deaths due to unknown causes warrants further investigation. To gain a comprehensive understanding of mortality, collection of more detailed data on out-of-hospital deaths is essential. Among patients aged 65 years and older, the SMR decreased to 0.83, falling below that of the general population. This may be partly explained by the \u0026ldquo;healthy survivor effect,\u0026rdquo; whereby individuals who have survived through the pre-ART era and maintained long-term ART adherence may represent a healthier subpopulation in terms of self-management, healthcare access, and lifestyle behaviors. These individuals may be regarded as \u0026ldquo;selective survivors\u0026rdquo; who have passed through a natural selection process shaped by disease progression, potentially introducing a bias that leads to a lowering of the SMR in this age group [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Therefore, although the reduced SMR in older adults may reflect the long-term benefits of ART, it requires interpretation in light of possible survivorship bias. Future studies need to consider incorporating statistical models that account for survivorship bias and confirm the data obtained through multicenter collaborative research.\u003c/p\u003e\u003cp\u003eAmong patients with CD4 counts\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/\u0026micro;L, the most recent SMR remained high (2.59). This at-risk population likely consists of patients with a late diagnosis and those with insufficient immune recovery (i.e., immunological non-responders) despite long-term ART. This finding is consistent with a prospective cohort study from Japan which reported that a delayed diagnosis doubled the risk of death [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], supporting the hypothesis that risk is not fully eliminated even after immune reconstitution. Elevated mortality in this group may be attributable not only to opportunistic infections and specific immunodeficiency-related malignancies, but also to the increased severity of NADMs. In Japan, obtaining the public subsidy certificate required to receive financial assistance for HIV treatment costs may take several months [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Many patients delay ART initiation until the certificate is issued, which may contribute to delays in initiating treatment. Although the SMR among those with viral loads\u0026thinsp;\u0026ge;\u0026thinsp;1,000 copies/mL was 3.37, this was not statistically significant owing to the small absolute number of patients in this group. This group consists primarily of patients with poor adherence to ART and those who have interrupted their care. This result suggests the negative impact of structural and behavioral factors, such as poor medication adherence, psychiatric disorders, and substance use, which are factors that have been identified in European multicenter reports as major contributors to disparities in mortality [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Furthermore, a large number of PLWH in Japan remain undiagnosed. At the end of 2015, the most recent year for which an estimate is available, an estimated 14.4% of all PLWH in Japan were unaware of their infection [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This diagnostic gap may lead to missed opportunities for early treatment and consequently worsen their prognosis.\u003c/p\u003e\u003cp\u003eThe persistently elevated malignancy-related mortality is likely due to a multifactorial interplay between chronic inflammation, immunosenescence, co-infection with oncogenic viruses, and lifestyle factors, such as smoking and alcohol consumption. A recent meta-analysis of NADM risk worldwide found the both NADM incidence and mortality are increasing [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Similarly, a prospective cancer-screening study among PLWH with hemophilia in Japan revealed a high prevalence and incidence of NADM, highlighting the hidden cancer burden and utility of regular screening [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The sustained elevation of the malignancy-related SMR in the 40\u0026ndash;64-year age group in this study suggests a need for intensified surveillance in this population. A secondary analysis of the Strategic Timing of AntiRetroviral Treatment (START) trial, conducted in Europe and the United States, revealed that early ART initiation reduced the risk of infection-related cancers [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. However, in Japan, approximately 30% of cases of HIV infection are diagnosed after the onset of AIDS [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], highlighting the need to address diagnostic delays and establish individualized cancer-screening programs. The meta-analysis of NADM by Yuan et al. [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], highlighted the importance of integrating primary and secondary prevention of major NADMs, such as anal, liver, and lung cancers, into routine HIV care. This includes age-stratified screening strategies that combine human papillomavirus and hepatitis B virus vaccination, antiviral therapy, smoking cessation support, and the use of screening methods, such as low-dose computed tomography and endoscopy. This study suggests that in an aging PLWH population, it is necessary to go beyond cancer screening and incorporate comprehensive geriatric assessment and mental health support into multidisciplinary team-based care. According to an analysis of Japanese health insurance claims data, 13.4% of 28,089 PLWH on ART were using five or more concurrent medications, with rates increasing to 29.9% in those aged 50\u0026ndash;59 years and 40.3% in those aged 70 years and older [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Therefore, the systematic management of polypharmacy and drug-drug interactions is a growing challenge in the care of older PLWH.\u003c/p\u003e\u003cp\u003eThis study has several strengths. The long-term follow-up of a cohort of almost 4,000 individuals at Osaka National Hospital, a central institution for PLWH care in Japan, over an 18-year-period,provides new insights into the epidemiology of HIV in Japan, and a comprehensive evaluation of the long-term changes in mortality risk. Additionally, the use of the CoDe protocol for cause-of-death classification ensured internationally comparable and standardized cause-of-death data, enhancing the reliability of the results obtained. Furthermore, by conducting stratified analyses by age group, CD4 count, and viral load, the study identified age group-specific challenges, such as an improved prognosis in the younger age group, and persistently elevated mortality due to malignancies in the middle and older age groups.\u003c/p\u003e\u003cp\u003eThis study also has several limitations. Because it is a retrospective single-center cohort study, the possibility of a selection bias, such as overrepresentation of patients with more severe disease owing to referrals, cannot be ruled out. Therefore, the mortality rates and cause-of-death patterns may not be generalizable to all men with HIV in Japan. Furthermore, the cause of death was unknown in approximately 25% of all deaths and was higher among patients with out-of-hospital deaths. The high proportion of deaths due to unknown causes may have affected the accuracy of cause-specific SMRs, especially for non-AIDS-related deaths, and may have led to an underestimation of malignancy-related mortality. Moreover, the minimum CD4 count and the maximum viral load within each year were used as immunological and virological markers, respectively but do not necessarily reflect long-term disease control at the individual level. To evaluate the effects of exposure duration and temporal fluctuations in CD4 count and viral load, longitudinal analyses or analyses using time-weighted averages are required. Another limitation is that this study excluded female patients, and the cohort was predominantly composed of men who acquired HIV through male-to-male sexual contact (approximately 80%); therefore, differences in mortality by sex and route of transmission could not be assessed. Addressing this limitation is important for future research, particularly from a public health perspective of promoting diversity and inclusion. In addition, owing to the retrospective nature of the study and reliance on medical records, it was not possible to systematically capture social factors that affect health, such as smoking, alcohol use, lifestyle behaviors, mental health conditions, and the utilization of medical cost subsidies. The impact of these factors on mortality and prognosis need to be examined in future prospective studies or nationwide database analyses.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study revealed that SMRs among men with HIV in Japan improved markedly between 2007 and 2024, which is primarily due to improvements in ART. Although the mortality rates in the younger and older age groups converged toward those observed in the general population, mortality related to malignancies remained elevated in men in the 40\u0026ndash;64-years age group. These results highlight the need for a comprehensive approach to NADMs in addition to virological control in proving care for PLWH in Japan and could inform the development of targeted public health and clinical management strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAIDS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acquired immunodeficiency syndrome\u003c/p\u003e\n\u003cp\u003eART\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Antiretroviral therapy\u003c/p\u003e\n\u003cp\u003eHIV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Human immunodeficiency virus\u003c/p\u003e\n\u003cp\u003eNADM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Non-AIDS-defining malignancy\u003c/p\u003e\n\u003cp\u003ePLWH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Persons living with HIV\u003c/p\u003e\n\u003cp\u003eSMR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Standardized mortality ratio\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of Osaka National Hospital (approval no. 25034). The requirement for individual informed consent was waived because the study was retrospective, and the data were anonymized prior to analysis.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe data used in this study cannot be posted in supplemental files or public repositories because of legal and ethical restrictions.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by a Health Labour Sciences Research Grant [23HB2001, acquired by DW; funder URL: https://mhlw-grants.niph.go.jp/]. The funder played no role in the study design, data collection, data analysis, interpretation, or manuscript writing.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eKK and DW designed this study. KK, DW, KH, TU, YN, and TU collected data. KK and DW were involved in sample processing. KK participated in the data analysis. KK wrote the paper. DW, KH, TU, YN, TU, and TS critically reviewed and revised the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eEditage, Cactus Communications provided support with English-language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAntiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008:372:293-9.\u003c/li\u003e\n\u003cli\u003eTsuda H, Koga M, Nojima M, Senkoji T, Kubota M, Kikuchi T, et al. Changes in survival and causes of death among people living with HIV: Three decades of surveys from Tokyo, one of the Asian metropolitan cities. J Infect Chemother. 2021;27:949-56.\u003c/li\u003e\n\u003cli\u003eTrickey A, McGinnis K, Gill MJ, Abgrall S, Berenguer J, Wyen C, et al. Longitudinal trends in causes of death among adults with HIV on antiretroviral therapy in Europe and North America from 1996 to 2020: A collaboration of cohort studies. Lancet HIV 2024;11:e176-85.\u003c/li\u003e\n\u003cli\u003eGuaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53:1120-6.\u003c/li\u003e\n\u003cli\u003eHasse B, Ledergerber B, Furrer H, Battegay M, Hirschel B, Cavassini M, et al. Morbidity and aging in HIV-infected persons: The Swiss HIV Cohort Study. Clin Infect Dis. 2011;53:1130-9.\u003c/li\u003e\n\u003cli\u003eWu PY, Chen MY, Hsieh SM, Sun HY, Tsai MS, Lee KY, et al. Comorbidities among the HIV-infected patients aged 40 years or older in Taiwan. PLoS One 2014;9:e104945.\u003c/li\u003e\n\u003cli\u003eWeber R, Sabin CA, Friis-M\u0026oslash;ller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632-41.\u003c/li\u003e\n\u003cli\u003eSackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med. 2006;145:397-406.\u003c/li\u003e\n\u003cli\u003eGBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980\u0026ndash;2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736-88.\u003c/li\u003e\n\u003cli\u003eWeber MSR, Duran Ramirez JJ, Hentzien M, Cavassini M, Bernasconi E, Hofmann E, et al. Time trends in causes of death in people with HIV: Insights from the Swiss HIV Cohort Study. Clin Infect Dis. 2024;79:177-88.\u003c/li\u003e\n\u003cli\u003eSu\u0026aacute;rez-Garc\u0026iacute;a I, Gutierrez F, P\u0026eacute;rez-Molina JA, Moreno S, Aldamiz T, Valencia Ortega E, et al. Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up. J Cancer Res Clin Oncol. 2023; 149:18161-71.\u003c/li\u003e\n\u003cli\u003eCostagliola D. Demographics of HIV and aging. Curr Opin HIV AIDS 2014;9:294-301.\u003c/li\u003e\n\u003cli\u003eMarcus JL, Leyden WA, Alexeeff SE, Anderson AN, Hechter RC, Hu H, et al. Comparison of overall and comorbidity-free life expectancy between insured adults with and without HIV infection, 2000\u0026ndash;2016. JAMA Netw Open 2020;3:e207954.\u003c/li\u003e\n\u003cli\u003eCollins LF, Armstrong WS. What it means to age with HIV infection: Years gained are not comorbidity free. JAMA Netw Open 2020;3:e208023.\u003c/li\u003e\n\u003cli\u003eAIDS Prevention Information Network. The AIDS Surveillance Committee, the Japanese Ministry of Health, Labour and Welfare. Japanese. https://api-net.jfap.or.jp/status/japan/nenpo.html. Accessed 13 July 2025.\u003c/li\u003e\n\u003cli\u003eVall\u0026eacute;e A, Majerholc C, Zucman D, Livrozet JM, Laurendeau C, Bou\u0026eacute;e S, et al. Mortality and comorbidities in a nationwide cohort of HIV-infected adults: Comparison to a matched non-HIV adults\u0026rsquo; cohort, France, 2006\u0026ndash;18. Eur J Public Health 2024;34:879-84.\u003c/li\u003e\n\u003cli\u003eMbalinda SN, Lusota DA, Muddu M, Nyashanu M. Ageing with HIV: Challenges and coping mechanisms of older adults 50 years and above living with HIV in Uganda. BMC Geriatr. 2024;24:95.\u003c/li\u003e\n\u003cli\u003eOka S, Ikeda K, Takano M, Ogane M, Tanuma J, Tsukada K, et al. Pathogenesis, clinical course, and recent issues in HIV-1-infected Japanese hemophiliacs: A three-decade follow-up. Glob Health Med. 2020;2:9-17.\u003c/li\u003e\n\u003cli\u003eNishijima T, Inaba Y, Kawasaki Y, Tsukada K, Teruya K, Kikuchi Y, et al. Mortality and causes of death in people living with HIV in the era of combination antiretroviral therapy compared with the general population in Japan. AIDS 2020; 34:913-21.\u003c/li\u003e\n\u003cli\u003eCopenhagen HIV Programme (CHIP). Coding Causes of Death in HIV protocol; version 2.3; August 2013. https://chip.dk/Portals/0/files/Code%20Protocol%202.3.pdf. Accessed 13 Jul 2025.\u003c/li\u003e\n\u003cli\u003eKowalska JD, Friis-M\u0026oslash;ller N, Kirk O, Bannister W, Mocroft A, Sabin C, et al. The Coding Causes of Death in HIV (CoDe) Project: Initial results and evaluation of methodology. Epidemiology 2011;22:516-23.\u003c/li\u003e\n\u003cli\u003ee-Stat, Statistics of Japan. Trends in deaths and death rates (per 100,000 population) by sex, age (5-year age groups) and causes of death: Japan. https://www.e-stat.go.jp/en/stat-search/files?page=1\u0026amp;layout=datalist\u0026amp;toukei=00450011\u0026amp;tstat=000001028897\u0026amp;cycle=7\u0026amp;year=20230\u0026amp;month=0\u0026amp;tclass1\u003cbr\u003e=000001053058\u0026amp;tclass2=000001053061\u0026amp;tclass3=000001053065\u0026amp;result_back=1\u0026amp;tclass4val=0. Accessed 13 July 2025.\u003c/li\u003e\n\u003cli\u003eMay M, Gompels M, Delpech V, Porter K, Post F, Johnson M, et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) Study. BMJ 2011; 343:d6016.\u003c/li\u003e\n\u003cli\u003eCroxford S, Kitching A, Desai S, Kall M, Edelstein M, Skingsley A, et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: An analysis of a national observational cohort. Lancet Public Health 2017;2:e35-e46.\u003c/li\u003e\n\u003cli\u003eEngsig FN, Gerstoft J, Kronborg G, Larsen CS, Pedersen G, R\u0026oslash;ge B, et al. Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: A cohort study. BMC Infect Dis. 2010;10:318.\u003c/li\u003e\n\u003cli\u003eMinistry of Health, Labour and Welfare. Reports on the certification of disabilities due to immune deficiency by HIV. https://www.mhlw.go.jp/www1/shingi/s1216-3.html.Accessed 13 July 2025.\u003c/li\u003e\n\u003cli\u003eIwamoto A, Taira R, Yokomaku Y, Koibuchi T, Rahman M, Izumi Y, et al. The HIV care cascade: Japanese perspectives. PLoS One 2017;12:e0174360.\u003c/li\u003e\n\u003cli\u003eYuan T, Hu Y, Zhou X, Yang L, Wang H, Li L, et al. Incidence and mortality of non-AIDS-defining cancers among people living with HIV: A systematic review and meta-analysis. EClinicalMedicine 2022, 52:101613.\u003c/li\u003e\n\u003cli\u003eOka S, Ogata M, Takano M, Minamimoto R, Hotta M, Tajima T, et al. Non-AIDS-defining malignancies in Japanese hemophiliacs with HIV-1 infection. Glob Health Med. 2019;1:49-54.\u003c/li\u003e\n\u003cli\u003eBorges \u0026Aacute;H, Neuhaus J, Babiker AG, Henry K, Jain MK, Palfreeman A, et al. Immediate antiretroviral therapy reduces risk of infection-related cancer during early HIV infection. Clin Infect Dis. 2016;63:1668-76.\u003c/li\u003e\n\u003cli\u003eNaito T, Suzuki M, Fukushima S, Yuda M, Fukui N, Tsukamoto S, et al. Comorbidities and co-medications among 28 089 people living with HIV: A nationwide cohort study from 2009 to 2019 in Japan. HIV Med. 2022;23:485-493.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HIV infection, older adults, standardized mortality ratio, malignancies, retrospective cohort study","lastPublishedDoi":"10.21203/rs.3.rs-7395984/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7395984/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eAntiretroviral therapy (ART) has transformed HIV infection from a fatal disease into a chronic condition and improved the life expectancy of people living with HIV (PLWH). Few studies have examined long-term changes in standardized mortality ratios (SMRs) by age and cause of death among PLWH in Japan. This study investigated the changes in SMR among men with HIV infection in Japan over an 18-year period, focusing on age at death and the contribution of malignancies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e We conducted a retrospective cohort study of men with HIV infection who received care at Osaka National Hospital between 2007 and 2024. Data were extracted from medical records. Causes of death were classified according to the Coding Causes of Death in HIV protocol. SMRs were calculated based on the general male population of Japan.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 3,793 patients were included with 35,007 person-years of follow-up. The median age on enrollment was 36.3 years, and the median follow-up period was 10.1 years. Of the patients, 230 died during the study period, with a median age at death of 53.4 years. The causes of death included 44 deaths from AIDS-defining illnesses, 20 deaths from AIDS-related malignancies, 51 deaths from non-AIDS-related malignancies; and 57 deaths of unknown cause. The SMR decreased from 4.11 in 2007\u0026ndash;2011 to 1.27 in 2021\u0026ndash;2024, with different patterns in different age groups. The SMRs fell to below that of the general population (\u0026lt;\u0026thinsp;1.0) in the 20\u0026ndash;39-years and \u0026ge;\u0026thinsp;65-years age groups but remained high in the 40\u0026ndash;64-years age group, and in patients with CD4 counts\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/\u0026micro;L or viral loads\u0026thinsp;\u0026ge;\u0026thinsp;1000 copies/mL within the calendar year. The SMR for malignancies also remained high in the 40\u0026ndash;64-years age group (2.28 in 2021\u0026ndash;2024).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eAmong men with HIV infection in Japan, the risk of mortality has markedly decreased with the widespread use of ART, approaching that of the general population, particularly in younger and older age groups. However, elevated mortality due to non-AIDS-related causes, particularly malignancies, persists among middle-aged men. Future HIV care should prioritize viral suppression and enhancing age-appropriate cancer screening.\u003c/p\u003e","manuscriptTitle":"The shifting burden of mortality among men with HIV in Japan between 2007 and 2024: A single-center retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:28:35","doi":"10.21203/rs.3.rs-7395984/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-08T09:44:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-05T18:44:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-22T23:24:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-17T17:02:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"217456733298398470868299205048117871714","date":"2025-09-17T10:02:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T08:44:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T08:32:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-15T08:50:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154769258062635264950404000967694916014","date":"2025-09-15T07:02:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"162445540664030582536212459341446152173","date":"2025-09-14T15:22:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"120888363761211718393543074101685285248","date":"2025-09-13T10:13:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"208957416455285957127216467994891680402","date":"2025-09-12T18:24:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"307694987617677025696254226812641673984","date":"2025-09-12T15:49:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-12T11:27:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-20T06:21:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-19T23:29:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-19T23:29:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-08-18T05:24:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ad9b104-def6-4cd9-8376-c43cdf6bb92c","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:08:36+00:00","versionOfRecord":{"articleIdentity":"rs-7395984","link":"https://doi.org/10.1186/s12879-025-12114-8","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-12-05 15:57:35","publishedOnDateReadable":"December 5th, 2025"},"versionCreatedAt":"2025-09-23 02:28:35","video":"","vorDoi":"10.1186/s12879-025-12114-8","vorDoiUrl":"https://doi.org/10.1186/s12879-025-12114-8","workflowStages":[]},"version":"v1","identity":"rs-7395984","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7395984","identity":"rs-7395984","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}