Japan Agency for Medical Research and Development, Research Program on HIV/AIDS
The study group on "A study on the management of opportunistic infections associated with early and prolonged use of ART"
Principal investigator: Katsuji Teruya
Questionnaire results
Trends in Opportunistic Complications and Malignancies Associated with Human Immunodeficiency Virus Infection in Japan: Analysis of the 2023 Data
| Investigators： | Koichi Izumikawa (Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences) |
| Research coordinator： | Takeshi Tanaka (Nagasaki University Hospital Infection Control and Education Center) |
| A. Objective… | To analyze the current status and national trend of opportunistic complications in HIV carriers in Japan. |
| B. Method… | A questionnaire was sent to 3376 HIV core hospitals across Japan to collect information on patients diagnosed with any of the 23 AIDS-defining diseases between January 1, 2056, and December 31, 2023. The data obtained were combined with corresponding data from previous surveys conducted between 1995 and 2023 for analysis. |
| C. Results… | Response recovery status in 2023; Questionnaire sent to: 376 hospitals Response received from: 230 hospitals (recovery rate: 61.2%) No. of affected patients: 251 Total no. of episodes: 348 |
Abstract
We have been investigating the trend for opportunistic complications associated with human immunodeficiency virus (HIV) infection since 1995. In the current fiscal year, we investigated cases encountered in 2023 and analyzed them together with those cases that were previously investigated. We sent a questionnaire to 376 core hospitals specializing in HIV treatment across Japan and received responses from 230 (response rate, 61.2%). In total, 251 patients and 348 episodes were reported. The incidence of opportunistic complications has decreased since 2012. According to a report by the AIDS Surveillance Committee of the Japanese Ministry of Health, Labour and Welfare, 291 patients were newly diagnosed with acquired immunodeficiency syndrome in 2023 (compared with 252 patients in 2022). Although the annual number of new patients has been 400 or more since 2006, it has been decreasing since 2018. The estimated capture rate in the present study was 79.0%. As observed in previous years, the largest proportion of patients developed opportunistic complications within 3 months after being diagnosed with HIV; this proportion included patients diagnosed with opportunistic complications before being diagnosed with HIV. Similarly, the largest proportion of patients were not undergoing anti-HIV therapy at the onset of complications. In patients who had been treated for 6 months or more, the cumulative incidences of complications, in descending order, were 19.2% for cytomegalovirus infection, 12.4% for Pneumocystis pneumonia infection, 11.0% for non-Hodgkin’s lymphoma, 10.8% for candidiasis, 9.0% for nontuberculous mycobacteriosis, 7.7% for active tuberculosis, and 5.8% for Kaposi’s sarcoma.
In terms of the incidences of all reported opportunistic complications, similar to those observed over the previous few years, the most common complication in 2023 was Pneumocystis pneumonia infection (40.3%), followed by candidiasis (13.3%) and cytomegalovirus infection (12.7%). The order of the remaining complications varied slightly, as follows: non-Hodgkin’s lymphoma (6.1%), Kaposi’s sarcoma (4.6%), nontuberculous mycobacteriosis (3.7%), progressive multifocal leukoencephalopathy (3.7%), HIV encephalopathy (3.2%), and active tuberculosis (2.3%). The overall mortality rate was 5.5% in 2023. The cumulative disease-specific mortality rates remained high for malignancies and diseases of the central nervous system.
For all major infections except tuberculosis, the time from diagnosis of the opportunistic complications to the initiation of antiretroviral therapy (ART) tended to decrease each year from 2010 to approximately 2013. However, from 2014, the proportion of patients who began ART 15 days or more after an opportunistic infection was diagnosed has increased.
When we analyzed the association between the time to initiating ART and outcomes, the overall mortality rate was significantly higher among patients who started ART within 14 days after diagnosis of an opportunistic complication than among those who started ART 15 days or more after diagnosis. A similar trend was observed for Pneumocystis pneumonia and cytomegalovirus infections.
A．Objective
Antiretroviral therapy (ART) has been widely adopted and tends to be initiated in the early stages of human immunodeficiency virus (HIV) infection; however, efforts have been made to improve the prognosis of HIV infection. In Japan, the numbers of newly reported patients with HIV and those with acquired immunodeficiency syndrome (AIDS) have plateaued in recent years and have been decreasing since 2016. According to the AIDS surveillance data provided by the Japanese Ministry of Health, Labour and Welfare, 30% of patients with HIV and or AIDS are detected after the onset of opportunistic complications. Early detection of HIV infection is an important prognostic factor because the mortality rate after the onset of AIDS is approximately 10%. Considering immune reconstitution inflammatory syndrome, the time at which ART should be initiated after starting treatment for opportunistic complications should be carefully determined for each complication. However, based on the guidelines of the Department of Health and Human Services and the findings of the ACTGA5614 study, ART should be introduced soon after the onset of opportunistic infections. Thus, understanding the trends in opportunistic complications in Japan is important, and continuous investigation is needed. Therefore, in the present study, we aimed to continue the nationwide survey of trends in opportunistic complications, which had been conducted by Study Group Kimura, and to analyze the latest trends in opportunistic complications together with previous data.
B．Methods
Under the current setting of treatment for HIV infection in Japan, most patients diagnosed with HIV infection are referred to core hospitals that specialize in HIV. Thus, the present study included 376 core HIV hospitals (designated as core hospitals in 2023) across Japan. The questionnaires (
Appendix 1 [in Japanese]) were mailed to the target hospitals, and we requested that the questionnaires be completed and returned. The survey took place from January to December 2023. We requested that hospitals report those cases of AIDS-defining diseases that were diagnosed during this period, after the final diagnosis was confirmed.
The questionnaire items were designed to be as simple as possible, and the number of items was kept to a minimum to improve the response rate and reduce the burden on treating physicians. The questionnaire could be completed without the medical records being reviewed in detail. This approach is disadvantageous because using it limits the volume of information collected. We used it, however, because we focused on elucidating the exact trend in opportunistic complications, not detailed individual complications, in the present study. To improve the response rate, we sent a written request for a response to hospitals from which no completed questionnaires had been received by the set deadline. The collected data were entered into and compiled with existing data in a database constructed using Microsoft Access 2010. The database was refined as needed for the present study. Specifically, menu and entry pages were created, and queries were developed to facilitate the necessary compilation.
This study was conducted in compliance with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects, as partially revised on December 22, 2017. Special consideration was given to ensuring that no personal information was collected from the participating hospitals. Therefore, the questionnaires were designed to contain no initials, patient numbers, or any other data that could identify individual patients through data linking. The study protocol was reviewed and approved by the Ethics Committee of Nagasaki University Graduate School of Biomedical Sciences. Although the data collected in the questionnaire survey did not contain personal information, the data were handled with due care and maintained in a controlled laboratory environment in which only the study investigators could access them because they were clinical data on HIV infection.
C．Results
We sent a questionnaire to 376 core HIV hospitals across Japan and received responses from 230. The response rate was 61.2%, with 251 patients and 348 episodes being reported. The incidence of opportunistic complications has been decreasing since 2012. According to the report by the AIDS Surveillance Committee of the Japanese Ministry of Health, Labour and Welfare, 291 patients were newly diagnosed with AIDS in 2023 (compared with 252 patients in the previous year). Although the annual number of new patients has been 400 or more since 2006, this number has decreased since 2018. The estimated capture rate in the present study was 79.0%. Figure 1 shows the changes in the annual numbers of reported cases.
Figure 1. Changes in the number of reported cases of opportunistic complications (based on a questionnaire administered to human immunodeficiency virus [HIV] core hospitals across Japan)
Regarding the time from initial diagnosis of HIV infection to the onset of opportunistic complications, patients who developed such complications within 3 months after being diagnosed with HIV (including those diagnosed with opportunistic complications before the diagnosis of HIV infection) accounted for the majority since 1998, when the administration of ART was widely adopted. These patients may have included those directly diagnosed with AIDS (Figure 2). The option of no hospital visits for a long time after diagnosis was added in 2002.
Figure 2. Time from the diagnosis of HIV infection to the onset of opportunistic complications
The largest proportion of patients were not undergoing anti-HIV therapy at the onset of opportunistic complications (87%; Figure 3). Since 2002, we have requested that participating hospitals distinguish in the questionnaire which patients were untreated and which had discontinued treatment.
Figure 3. Administration of anti-HIV therapy at the onset of opportunistic complications
According to the cross-tabulation of data accumulated since 2002 on the time from the HIV diagnosis to the onset of opportunistic complications and the duration of anti-HIV therapy (Figure 4), most patients who developed opportunistic complications within 3 months after HIV diagnosis and those who had not visited the hospital for a long time after diagnosis were clearly untreated or had discontinued treatment. Of the patients, 57% who developed opportunistic complications 1 year or more after being diagnosed with HIV infection were untreated or had discontinued treatment. Particularly, a large proportion (29%) of patients who developed opportunistic complications more than 1 year after being diagnosed with HIV infection had discontinued treatment; 41.0% of these patients had received ART for 6 months or more. When only the 2023 data were considered (Figure 5), the proportion of untreated patients among patients who developed opportunistic complications within 3 months after HIV diagnosis was substantially larger, whereas the proportion among patients who developed opportunistic complications within 1 year was smaller. In patients who had been treated for 6 months or more, the cumulative incidences of opportunistic complications, in descending order, were 19.2% for cytomegalovirus infection, 12.4% for Pneumocystis pneumonia (PCP), 11.0% for non-Hodgkin’s lymphoma, 10.8% for candidiasis, 9.0% for nontuberculous mycobacteriosis, 7.7% for active tuberculosis infection, and 5.8% for Kaposi’s sarcoma (Figure 6).
Figure 4. Association between the time from the diagnosis of HIV infection to the onset of opportunistic complications and the administration of anti-HIV therapy
Figure 5. Association between the time from the diagnosis of HIV infection to the onset of opportunistic complications and the administration of anti-HIV therapy (2022)
Figure 6. Cumulative incidence rates of opportunistic complications in patients treated with anti-HIV therapy for 6 months or more
To determine whether the onset of opportunistic infections occurring in a given year indicates persistent severe immunodeficiency, we examined whether a single patient developed multiple opportunistic complications during a single year (Figure 7). In 1995, patients who were suspected to have persistent immunodeficiency and who developed multiple opportunistic infections during a single year accounted for 38.1% (74/194) of all patients. The percentage of such patients gradually decreased thereafter and has recently remained between 20% and 29%. In 2023, this percentage was 29.9% (75/251).
Figure 7. Proportion of patients who developed multiple opportunistic complications within 1 year
Figure 8 shows the cumulative incidences of opportunistic infections. The most common AIDS-defining disease was PCP (39.5%), followed in descending order by cytomegalovirus infection (13.3%), candidiasis (13.3%), active tuberculosis (6.6%), Kaposi’s sarcoma (4.6%), non-Hodgkin’s lymphoma (4.1%), and nontuberculous mycobacteriosis (3.8%). Figure 9 shows the corresponding incidences in 2023 alone. In terms of the incidences of all reported diseases, and similar to the observations of the previous few years, the most common AIDS-defining disease in 2023 was PCP (40.3%), followed by candidiasis (13.3%) and cytomegalovirus infection (12.7%). The subsequent order of other diseases varied as follows: non-Hodgkin’s lymphoma (6.1%), Kaposi’s sarcoma (4.6%), nontuberculous mycobacteriosis (3.7%), progressive multifocal leukoencephalopathy (3.7%), HIV encephalopathy (3.2%), active tuberculosis (2.3%), HIV wasting syndrome (1.7%), cryptococcosis (1.7%), herpes simplex infection (1.4%), primary brain lymphoma (1.4%), cryptosporidiosis (1.4%), and toxoplasmosis (1.2%). We examined annual changes in the incidence of opportunistic complications: As for major infections (Figure 10: absolute number of cases, Figure 11: relative frequency), the absolute number of PCP cases peaked in 2011 and has since decreased. The relative frequency of PCP increased between 2013 and 2016; it then decreased in 2017 and remained constant for the next 3 years. In 2023, the absolute number of PCP decreased, but the relative frequency again increased. Although the incidences of all malignancies (Figure 12: absolute number of cases, Figure 13: relative frequency), have fluctuated, those of non-Hodgkin’s lymphoma and Kaposi’s sarcoma decreased over time. The incidences of other opportunistic complications are shown in Figures 14 to 17 (Figure 14 and 16: absolute number of cases, Figure 15 and 17: relative frequency). Except for small fluctuations, the incidence of all complications has remained constant.
Figure 8. Cumulative incidence rates of acquired immunodeficiency syndrome (AIDS)-defining diseases from 1995 to 2022
Figure 9. Incidence rates of AIDS-defining diseases in 2022
Figure 10. Changes in the number of cases of common opportunistic complications
Figure 11. Changes in the relative frequency of common opportunistic complications
Figure 12. Changes in the number of cases of opportunistic malignancies
Figure 13. Changes in the relative frequency of opportunistic malignancies
Figure 14. Changes in the number of cases of opportunistic complications (1)
Figure 15. Changes in the relative frequency of opportunistic complications (1)
Figure 16. Changes in the number of cases of opportunistic complications (2)
Figure 17. Changes in the relative frequency of opportunistic complications (2)
Figure 18 shows the mortality rate of patients with opportunistic complications, which substantially decreased to 3.6% in 2017. The mortality rates were 4.8% in 2019, 9.2% in 2020, 4.5% in 2021, 5.6% in 2022, and 5.5% in 2023. The annual mortality rates for the four major infections (Figure 19), showed that the mortality rates for all infections decreased but have recently remained constant. The mortality rate for cytomegalovirus infection decreased initially but leveled off in 2005, subsequently remaining at approximately 10% from 2010 but substantially decreasing in 2016. Although the mortality rate of cytomegalovirus infection had been increasing again since 2019, it decreased in 2023. The rate of active tuberculosis has increased for the past 2 years, but decreased in 2023. Despite the small number of cases, the mortality rate for cryptococcosis has fluctuated and generally decreased. The rates have fluctuated at approximately 20% since 2014, although it exceeded 30% in 2019. However, it has been decreasing since 2020 (Figure 20). Figures 21 and 22 show changes in the mortality rates for other opportunistic complications. Owing to the small number of cases reported each year, the rates varied widely. Furthermore, the cumulative disease-specific mortality rates (Figure 23) were typically high for malignancies (e.g., non-Hodgkin’s lymphoma and primary brain lymphoma) and central nervous system-related diseases (e.g., progressive multifocal leukoencephalopathy, HIV encephalopathy, and cryptococcosis). The mortality rates were high for histoplasmosis, suppurative bacterial infections (age ≤13 years), recurrent pneumonia, and cryptococcosis.
Figure 18. Proportion of patients who died from opportunistic complications: Mortality rates among symptomatic patients with AIDS
Figure 19. Changes in the mortality rates for four major infections
Figure 20. Changes in the mortality rates for other infections
Figure 21. Changes in the mortality rates for opportunistic malignancies
Figure 22. Changes in the mortality rates of other opportunistic complications
Figure 23. Disease-specific cumulative mortality rates
In 2010, we began investigating the time from diagnosis of opportunistic complications to initiation of ART. In patients with infections, ART tended to be introduced 15 to 30 days, or more, after the opportunistic complication was diagnosed. This interval was longer than the time to initiating ART in patients with malignancies or noninfectious encephalopathies. Specifically, more than half the patients with active tuberculosis started ART more than 2 months after diagnosis. Despite the small number of cases, a large proportion of patients with central nervous system diseases, such as progressive multifocal leukoencephalopathy and primary brain lymphoma, started ART within 14 to 30 days after diagnosis. The time to ART initiation tended to be short in these patients (Figure 24). When the longitudinal trend in the time to initiation of ART from 2010 was analyzed, the time tended to decrease year on year until 2013 for three of the four major infections, that is, cytomegalovirus infection, PCP, and candidiasis, but not for tuberculosis. However, the proportion of patients who started ART 15 days or more and 31 days or more after diagnosis of infection typically increased from 2014 (Figure 25). Figures 26 to 28 show the comparisons of the time from diagnosis of other opportunistic complications to ART initiation from 2010 to 2022. No characteristic trend was observed.
Figure 24. Time from the diagnosis of opportunistic complications to anti-retrovirus therapy (ART) introduction (since 2010)
Figure 25. Comparison of the time from the diagnosis of opportunistic complications to ART introduction (2010–2020) (1)
Figure 26. Comparison of the time from the diagnosis of opportunistic complications to ART introduction (2010–2020) (2)
Figure 27. Comparison of the time from the diagnosis of opportunistic complications to ART introduction (2010–2020) (3)
Figure 28. Comparison of the time from the diagnosis of opportunistic complications to ART introduction (2010–2020) (4)
Table 1 shows the association between the time to initiation of ART and outcomes for all complications. The mortality rate was significantly higher in patients who started ART within 14 days after being diagnosed with complications than in those who started ART 15 days or more after being diagnosed (11.41% vs. 2.69%; P<0.01). When a cutoff was set at 30 days, the mortality rate was significantly higher in patients who started ART within 30 days after diagnosis than in those who started ART 31 days or more after diagnosis (5.94% vs 2.45%; P\<0.01). After analyzing each opportunistic complication, we found that the mortality rate for PCP was significantly higher in patients who started ART within 14 days after diagnosis (6.67% vs 1.41%; P<0.01). When a cutoff of 30 days was applied, the mortality rate was significantly higher in patients who started ART within 30 days after diagnosis than in those who started ART 31 days or more after diagnosis (Table 2). A similar trend was observed for cytomegalovirus infection (15-day cutoff: 11.45% vs 5.02%; P<0.01; Table 3).
Table 1. Association between the time to ART introduction and outcomes (since 2010)
Table 2. Association between the time to ART introduction and outcomes (since 2010)
Table 3. Association between the time to ART introduction and outcomes (since 2010)
D．Acknowledgments
The cooperation of the personnel involved at the participating HIV core hospitals has made it possible to continue this study every year. Therefore, we would like to express our deepest gratitude to them for their cooperation in the survey despite the increasing burden of their duties every year. The hospitals that participated in this study in the current fiscal year are listed in Appendix 3 [in Japanese].
E．Conclusion
We continued the nationwide survey of opportunistic complications associated with HIV at core HIV hospitals across Japan. In the present study, we analyzed the incidences and distributions, as well as longitudinal changes, of opportunistic complications. Recently, across the globe, the incidence of new HIV infections and the number of patients newly diagnosed with AIDS have been gradually decreasing. In Japan, the corresponding values appear to have slightly decreased after they had continuously increased. The present study revealed that PCP is an important first-onset opportunistic complication and that early initiation of ART may only sometimes improve the prognosis.
