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 2022 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 383 HIV core hospitals across Japan to collect information on patients diagnosed with any of the 23 AIDS-defining diseases between January 1, 2017, and December 31, 2017. The data obtained were combined with corresponding data from previous surveys conducted between 1995 and 2016 for analysis. |
| C. Results… | Response recovery status in 2017; cases diagnosed in 2016 (as of February 10). Questionnaire sent to: 383 hospitals Response received from: 203 hospitals (recovery rate: 53.0%) Cases encountered in: 78 hospitals (case encounter rate: 38.4%) No. of affected patients: 320 Total no. of episodes: 413 |
Abstract
Since 1995, we have been investigating the trend of opportunistic complications associated with human immunodeficiency virus (HIV) infection. In this fiscal year, we investigated cases encountered in 2022 and analyzed them together with previously investigated cases. We sent a questionnaire to 378 HIV core hospitals across Japan and received responses from 201 hospitals (response rate: 53.1%). A total of 281 patients and 395 episodes were reported. The incidence of opportunistic complications has been decreasing since 2012. According to the report by the Acquired Immunodeficiency Syndrome (AIDS) Surveillance Committee of the Japanese Ministry of Health, Labour and Welfare, 252 patients were newly diagnosed with AIDS in 2022 (315 patients in the previous year). 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 77.6%. The largest proportion of patients developed opportunistic complications within 3 months after the diagnosis of HIV infection (including patients diagnosed with opportunistic complications before the diagnosis of HIV infection), as seen in previous years. Similarly, the largest proportion of patients were not receiving anti-HIV therapy at the onset of complications. In patients who had been treated for 6 months or more, the cumulative incidence rates of complications were 19.4% for cytomegalovirus infection, 12.5% for pneumocystis pneumonia (PCP), 10.9% for candidiasis, 10.5% for non-Hodgkin’s lymphoma, 9.1% for nontuberculous mycobacteriosis, 7.7% for active tuberculosis, and 5.8% for Kaposi’s sarcoma, in descending order.
In terms of overall incidence rates, the most common complication in 2022 was PCP (38.2%), followed by candidiasis (16.5%) and cytomegalovirus infection (11.9%), as seen in the previous few years. The subsequent order of other complications slightly varied as follows: Kaposi’s sarcoma (6.6%), non-Hodgkin's lymphoma (6.1%), nontuberculous mycobacteriosis (4.1%), HIV encephalopathy (3.8%), active tuberculosis (3.0%), primary brain lymphoma (2.5%), and progressive multifocal leukoencephalopathy (2.3%). Although the overall mortality rate was 10.2% in 2010, it fell to record lows of 3.6% in 2017 and 3.7% in 2018. The mortality rates were 4.8% in 2019, 9.2% in 2020, 4.5% in 2021, and 5.6% in 2022. The cumulative disease-specific mortality rates remained high for malignancies and central nervous system diseases.
The time from the diagnosis of opportunistic complications to the introduction of anti-retroviral therapy (ART) tended to decrease each year from 2010 to around 2013 for major infections, except for tuberculosis. However, since 2014, the proportion of patients who start ART at 15 days or more after the diagnosis of opportunistic infections has been increasing.
When the association between the time to ART introduction and outcomes was analyzed, the overall mortality rate was significantly higher in patients who started ART within 14 days after the diagnosis of opportunistic complications than in those who started at 15 days or more after the diagnosis. A similar trend was observed for PCP and cytomegalovirus infection.
A．Objective
While anti-retroviral therapy (ART) has been widely adopted and tends to be started in the early stages of human immunodeficiency virus (HIV) infection, efforts have been made to improve the prognosis of HIV infection. In Japan, the numbers of newly reported patients with HIV and patients with acquired immunodeficiency syndrome (AIDS) peaked in recent years but have been decreasing since 2016. According to the AIDS surveillance data from the Japanese Ministry of Health, Labour and Welfare, 30% of patients with HIV infection/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%. In addition, the time to introduce ART after the start of treatment of opportunistic complications should be carefully determined for each complication, in consideration of immune reconstitution syndrome. However, based on the Department of Health and Human Services guidelines and the ACTGA5614 study, ART should be introduced soon after the onset of opportunistic infections. Thus, understanding the trend in opportunistic complications in Japan is important. Under these circumstances, the trend of opportunistic complications needs to be continuously investigated. The present study aimed to continue the nationwide trend survey of opportunistic complications, which had been conducted by Study Group Kimura, and analyze the latest trend in opportunistic complications together with previous data.
B．Methods
Under the current circumstances regarding the treatment of HIV infection in Japan, the majority of patients diagnosed with HIV infection are referred to HIV core hospitals. Thus, the present study included 378 HIV core hospitals (designated as core hospitals in 2022) across Japan. The questionnaire forms (
Appendix 1 [in Japanese]) were mailed to the target hospitals, and we requested that they complete and return them. The survey period was from January to December 2022. We requested that the hospitals describe the cases of AIDS-defining diseases diagnosed during this period after confirming the final diagnosis.
The questionnaire items were designed to be as simple as possible and kept to the minimum to enhance the response rate and reduce the burden on treating physicians. The questionnaire could be completed without a detailed review of the medical records. Although this approach has the undesirable effect of limiting the volume of information collected, we used it because the present study focused on elucidating the exact trend in opportunistic infections. Therefore, we did not investigate individual complications in detail. To improve the response rate, we sent a written request for a response to hospitals that had not returned the questionnaire forms by the set deadline. The collected data were entered and compiled together with the previous data into the database constructed with Microsoft Access 2010. The database was refined to be software dedicated to the present study. Specifically, the menu and entry pages were created, and queries were developed to facilitate necessary compilation.
The present study was conducted in compliance with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects (partially revised on December 22, 2017). Special considerations were made not to collect personal information from the participating hospitals. Therefore, the questionnaire forms were designed not to contain initials, patient numbers, or any other data that could identify individual patients. 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, they were handled with due care and maintained in a controlled laboratory environment where only the study investigators could access them because they were clinical data on HIV infection.
C．Results
We sent a questionnaire to 378 HIV core hospitals across Japan and received responses from 201 hospitals (response rate: 53.1%). A total of 281 patients and 395 episodes were reported. The incidence of opportunistic complications has been decreasing since 2012. According to a report by the AIDS Surveillance Committee of the Japanese Ministry of Health, Labour and Welfare, 252 patients were newly diagnosed with AIDS in 2022 (315 patients in the previous year). 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 77.6%. Figure 1 shows the changes in the annual number of cases reported at HIV core hospitals in Japan.
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 these complications within 3 months after the HIV diagnosis (including patients diagnosed with opportunistic complications before the diagnosis of HIV infection) have accounted for the majority since 1998, when ART was widely adopted. These patients may include those directly diagnosed with AIDS (Figure 2). The option of “not having sought medical attention for a long time after diagnosis” has been added since 2002.
Figure 2. Time from the diagnosis of HIV infection to the onset of opportunistic complications
As for the administration of anti-HIV therapy at the onset of opportunistic complications, the largest proportion of patients were not receiving anti-HIV therapy at the onset (87%) (Figure 3). The separate response options of “untreated” and “treatment discontinued” have been added since 2002.
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 HIV diagnosis to the onset of opportunistic complications and the duration of anti-HIV therapy (Figure 4), the majority of patients who developed opportunistic complications within 3 months after HIV diagnosis and those who had not sought medical attention for a long time had obviously been untreated or discontinued treatment. Moreover, 56% of patients who developed opportunistic complications 1 year or more after the diagnosis of HIV infection had been untreated or discontinued treatment. In particular, a large proportion of patients who developed opportunistic complications more than 1 year after the diagnosis of HIV infection (28%) had discontinued treatment. However, 41.0% of these patients had received ART for 6 months or more. When only the 2022 data were considered (Figure 5), the proportion of untreated patients was significantly larger among patients who developed opportunistic complications within 3 months after HIV diagnosis than among patients who developed opportunistic complications within 1 year. In patients who had been treated for 6 months or more, the cumulative incidence rates of opportunistic complications were 19.4% for cytomegalovirus infection, 12.5% for pneumocystis pneumonia (PCP), 10.9% for candidiasis, 10.5% for non-Hodgkin’s lymphoma, 9.1% for nontuberculous mycobacteriosis, 7.7% for active tuberculosis, and 5.8% for Kaposi’s sarcoma, in descending order (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 opportunistic infections were associated with underlying severe persistent immunodeficiency, we examined whether a single patient developed multiple opportunistic complications during a single year (Figure 7). In 1995, patients who were suspected to be persistently immunodeficient and 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 hovered between 20% and 29%. In 2022, it was 30.6% (86/281).
Figure 7. Proportion of patients who developed multiple opportunistic complications within 1 year
Figure 8 shows the cumulative incidence rates of opportunistic infections. The most common AIDS-defining disease was PCP (39.4%), followed by cytomegalovirus infection (13.3%), candidiasis (13.3%), active tuberculosis (6.8%), Kaposi’s sarcoma (4.6%), non-Hodgkin’s lymphoma (4.0%), and nontuberculous mycobacteriosis (3.8%), in descending order. Figure 9 shows the corresponding incidence rates in 2022 alone. In terms of overall incidence rates, the most common AIDS-defining disease in 2022 was also PCP (38.2%), followed by candidiasis (16.5%) and cytomegalovirus infection (11.9%), as seen in the previous few years. The subsequent order of other diseases varied as follows: Kaposi’s sarcoma (6.6%), non-Hodgkin's lymphoma (6.1%), active tuberculosis (4.1%), nontuberculous mycobacteriosis (4.1%), HIV encephalopathy (3.8%), active tuberculosis (3.0%), primary brain lymphoma (2.5%), progressive multifocal leukoencephalopathy (2.3%), toxoplasmosis (1.8%), HIV wasting syndrome (1.3%), and cryptococcosis (1.3%). 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 decreased thereafter. The relative frequency increased between 2013 and 2016 before it turned to decrease in 2017 and remained constant for the next 3 years. In 2022, the frequency decreased again. Although the incidence of all malignancies (Figure 12: absolute number of cases, Figure 13: relative frequency), has been fluctuating, that of non-Hodgkin’s lymphoma and Kaposi’s sarcoma decreased over time but increased in 2022. The incidence of other opportunistic complications is shown in Figures 14–17 (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, and 5.6% in 2022. The changes in the annual mortality rates for 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, it hovered at approximately 10% since 2010 and has been substantially decreasing since 2016. The mortality rate has been increasing again since 2019. For active tuberculosis, the rate has been increasing for the past 2 years. As for other infections, despite the small number of cases, the mortality rate for cryptococcosis has fluctuated and generally decreased. The fluctuations have been at approximately 20% since 2014. However, the rate exceeded 30% in 2019 but has been decreasing since 2020 (Figure 20). Figures 21 and 22 show changes in the mortality rates of other opportunistic complications. Owing to the small number of cases each year, the rates widely vary. In addition, the cumulative disease-specific mortality rates (Figure 23) are characteristically 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). As for infections, the mortality rates are high for histoplasmosis, suppurative bacterial infections (age 13 or younger), 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 started investigating the time from the diagnosis of opportunistic complications to ART introduction. In patients with infections, ART tended to be introduced 15 to 30 days or more after the diagnosis of opportunistic complications. This interval was longer than the time of ART introduction in patients with malignancies or non-infectious encephalopathy. In particular, more than half of patients with active tuberculosis started ART more than 2 months after the 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 the diagnosis. The time to ART introduction tended to be short in these patients (Figure 24). When the longitudinal trend in the time to ART introduction since 2010 was analyzed, the time tended to decrease each year until 2013 for major infections (i.e., cytomegalovirus infection, PCP, candidiasis, and active tuberculosis) except for tuberculosis. However, the proportion of patients who started ART 15 days or more and 31 days or more after the diagnosis of these infections has characteristically increased since 2014 (Figure 25). Figures 26 to 28 show the comparison of the time from the diagnosis of other opportunistic complications to ART introduction 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 ART introduction and outcomes for all complications. The mortality rate was significantly higher in patients who started ART within 14 days after the diagnosis of complications than in patients who started ART at 15 days or more after the diagnosis (11.57% vs. 2.72%, P<0.01). When the cutoff was set at 30 days, the mortality rate was significantly higher in patients who started ART within 30 days after the diagnosis than in patients who started ART at 31 days or more after the diagnosis (5.99% vs. 2.48%, P<0.01). Next, we examined the association between the time to ART introduction and outcomes for each opportunistic complication. As for PCP, the mortality rate was significantly higher in patients who started ART within 14 days after the diagnosis (7.09% vs. 1.44%, P<0.01). When the cutoff of 30 days was applied, the mortality rate was significantly higher in patients who started ART within 30 days after the diagnosis than in patients who started ART at 31 days or more after the diagnosis (Table 2). A similar trend was observed for cytomegalovirus infection (15-day cutoff: 12.61% vs. 5.13%, 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 personnel involved at the participating HIV core hospitals has made it possible to continue the present study every year. Therefore, we would like to express our deepest gratitude to them for their cooperation in the survey despite the yearly increasing burden of their duties. The hospitals that participated in the present study in this fiscal year are listed in Appendix 3 [in Japanese].
E．Conclusion
We continued the nationwide survey of opportunistic complications associated with HIV at HIV core hospitals across Japan. In the present study, the incidence and distribution of opportunistic complications, as well as the longitudinal changes, were analyzed. In the past few years, the incidence rate of new HIV infection and the number of patients newly diagnosed with AIDS have been gradually decreasing in the world. In Japan, the corresponding values appear to be slightly decreasing after they had continuously increased. The present study revealed that PCP is an important first-onset opportunistic complication and that early ART introduction may not always improve the prognosis.
