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 (HIV) Infection in Japan:
Analyses of 2021 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)

Abstract

Since 1995, we have been investigating the trends of opportunistic complications associated with human immunodeficiency virus (HIV) infection. In this study, we analyzed the cases encountered in 2021 and compared the results with those of previously analyzed cases. A questionnaire form was sent to 378 HIV core hospitals across Japan, and responses were obtained from 196 hospitals (response rate: 51.8%). A total of 262 patients and a total of 353 episodes of associated opportunistic complications 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, 315 patients were newly diagnosed with AIDS in 2021 (compared to 345 patients in the previous year). Although the number of new patients reported annually had been 400 or more since 2006, it has been decreasing since 2018. The estimated capture rate of patients in the present study was 81.2%. The largest proportion of patients developed opportunistic complications within 3 months of being diagnosed with HIV infection (including patients who were diagnosed with opportunistic complications before being diagnosed with HIV infection), which was similar to the trend observed in previous years. Furthermore, the largest proportion of patients were not receiving anti-HIV therapy at the time of the onset of complications. Among patients who had been undergoing treatment for 6 months or more, the cumulative incidence rates of complications were 19.4% for cytomegalovirus infection, 12.7% for pneumocystis pneumonia (PCP), 10.9% for candidiasis, 10.4% for non-Hodgkin’s lymphoma, 8.9% 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 2021 was PCP (45.9%), followed by candidiasis (16.4%) and cytomegalovirus infection (11.9%), as observed in the previous few years. The incidence of the other complications varied slightly as follows: non-Hodgkin’s lymphoma (5.7%), active tuberculosis (4.5%), Kaposi’s sarcoma (3.4%), HIV encephalopathy (0.8%), and progressive multifocal leukoencephalopathy (0.8%). Although the overall mortality rate in 2010 was 10.2%, it fell to record lows of 3.6% in 2017 and 3.7% in 2018. The mortality rates in 2019, 2020, and 2021 were 4.8%, 9.2%, and 4.5%, respectively. The cumulative disease-specific mortality rates for malignancies and central nervous system diseases remained high.

The time from diagnosis of opportunistic complications to initiation of anti-retroviral therapy (ART) tended to decrease each year from 2010 to 2013 for all major infections except for tuberculosis. However, since 2014, the proportion of patients who start ART 15 days or more after the diagnosis of opportunistic infections has been increasing. When the association between the time to ART initiation and outcomes was analyzed, the overall mortality rate was significantly higher among patients who started ART within 14 days of being diagnosed with opportunistic complications than those who started ART 15 days or more of being diagnosed with opportunistic complications. 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 initiated in the early stages of infection with human immunodeficiency virus (HIV), further efforts are still needed to improve the prognosis of HIV infection. In Japan, the numbers of newly reported HIV-positive patients and patients with acquired immunodeficiency syndrome (AIDS) had peaked in recent years; however, the numbers 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 identified after the onset of opportunistic complications. As the mortality rate after the onset of AIDS is approximately 10%, early detection of HIV infection is an important prognostic factor. Additionally, the timing of ART initiation after the start of treatment of opportunistic complications should be carefully determined for each complication in consideration of immune reconstitution inflammatory syndrome. However, the Department of Health and Human Services guidelines and the ACTGA5614 study results suggest that ART should be introduced soon after the onset of opportunistic infections. Thus, it is important to continuously monitor the trends regarding opportunistic complications in Japan to better understand the underlying issues. The present study aimed to continue the survey of nationwide trends of opportunistic complications, which had been started by Study Group Kimura, and to analyze the latest trends in opportunistic complications in light of the previous data.

B．Methods

Under the current circumstances, most patients diagnosed with HIV infection in Japan are referred to HIV core hospitals. Thus, the present study included 378 hospitals designated as HIV core hospitals across Japan as of 2021. The questionnaire form (Appendix 1 [in Japanese]) was mailed to all the target hospitals, and they were requested to complete and return the form. The survey period was from January to December 2021; the hospitals were requested to describe the cases of AIDS-defining diseases diagnosed during this period after final confirmation of the diagnosis.

To improve the response rate and reduce the burden on the treating physicians, the questionnaire item was designed to be as simple as possible, so that the questionnaire could be completed without a detailed review of medical records, and kept to the minimum number necessary. Although this approach has the drawback of reducing the volume of information collected, it was used because the present study focused on the objective of elucidating the trends in opportunistic infections, and individual complications were not investigated in detail. To further improve the response rate, we sent a written request for a response to hospitals that had not returned the questionnaire form by the set deadline. Thereafter, all the data collected were compiled together with the previous data into a database created using Microsoft Access 2010. This database was refined to be dedicated to the present study—specifically, menu and entry pages were created, and queries were developed to facilitate the 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 measures were taken to not collect any personal information at the participating hospitals—the questionnaire form was designed to not contain items that required information regarding patient initials, patient numbers, or any other data that could be used to identify individual patients. The study protocol was reviewed and approved by the ethics committee of Nagasaki University Graduate School of Biomedical Sciences. The data collected in the questionnaire survey did not contain personal information. However, as they pertained to clinical data on HIV infection, they were handled with due care and maintained in a controlled laboratory environment where only the study investigators could handle them.

C．Results

The questionnaire form was sent to 378 HIV core hospitals across Japan, and responses were obtained from 196 hospitals (response rate: 51.8%). A total of 262 patients and a total of 353 episodes of opportunistic complications were reported. The incidence of opportunistic complications in Japan 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, 315 patients were newly diagnosed with AIDS in 2021 (compared to 345 patients in the previous year). Although the number of new patients reported annually had been 400 or more since 2006, it has been decreasing since 2018. In addition, the estimated capture rate of patients in the present study was 81.2%.   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 at human immunodeficiency virus [HIV] core hospitals across Japan)

As for the time from the initial diagnosis of HIV infection to the onset of opportunistic complications, patients who develop the complications within 3 months of being diagnosed with HIV infection (including patients diagnosed with the complications before the diagnosis of HIV infection) have accounted for the majority of patients with these complications since 1998, when ART was widely adopted. These patients may include those directly diagnosed with AIDS (Figure 2). The response option of “not having sought medical attention for a long time” has been included since 2002.

Figure 2. Time from HIV infection diagnosis to the onset of opportunistic complications

As for the use of anti-HIV therapy at the time of onset of opportunistic complications, the largest proportion of patients were not receiving anti-HIV therapy at the time of onset (86%) (Figure 3). The separate response options of “untreated” and “treatment discontinued” have been included since 2002.

Figure 3. Use of anti-HIV therapy at the onset of opportunistic complications

According to the cross-tabulation of the data accumulated since 2002 regarding the time from the diagnosis of HIV infection to the onset of opportunistic complications and the duration of anti-HIV therapy (Figure 4), most patients who developed opportunistic complications within 3 months of being diagnosed with HIV infection and those who had not sought medical attention for a long time had been untreated or had discontinued treatment. Moreover, 55% of patients who developed opportunistic complications 1 year or more after the diagnosis of HIV infection had been untreated or had discontinued treatment. In particular, a large proportion of patients who developed opportunistic complications more than 1 year after the diagnosis of HIV infection (27%) had discontinued treatment; on the contrary, 2.0% of these patients had received ART for 6 months or more. When only the 2021 data were considered (Figure 5), the proportion of untreated patients was larger among patients who developed opportunistic complications within 3 months of being diagnosed with HIV infection but smaller among patients who developed the complications within 1 year. Among patients who had been treated for 6 months or more, the cumulative incidence rates of opportunistic complications were 19.4% for cytomegalovirus infection, 12.7% for pneumocystis pneumonia (PCP), 10.9% for candidiasis, 10.4% for non-Hodgkin’s lymphoma, 8.9% 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 use of anti-HIV therapy


Figure 5. Association between the time from the diagnosis of HIV infection to the onset of opportunistic complications and the use of anti-HIV therapy (2020)


Figure 6. Cumulative incidence of opportunistic complications in patients treated with anti-HIV therapy for 6 months or more

To assess whether opportunistic infections were associated with underlying severe persistent immunodeficiency, we examined whether the same patients 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 42.5% (74/174) of all HV-positive patients. The proportion of such patients has gradually decreased thereafter and has recently ranged between 20% and 29%. In 2021, the proportion of such patients was reported as 25.5% (67/262).


Figure 7. Proportion of patients who developed multiple opportunistic complications within 1 year

Figure 8 shows the cumulative incidence rates of specific opportunistic infections. The most common AIDS-defining disease was PCP (39.5%), followed by cytomegalovirus infection (13.4%), candidiasis (13.2%), active tuberculosis (6.9%), Kaposi’s sarcoma (4.5%), and nontuberculous mycobacteriosis (3.8%) in descending order. Figure 9 shows the corresponding incidence rates in 2021 alone. In terms of overall incidence rates, the most common AIDS-defining disease in 2021 was also PCP (45.9%), followed by candidiasis (16.4%) and cytomegalovirus infection (11.9%), as observed in the previous few years. The incidence rates of the other diseases were as follows: non-Hodgkin’s lymphoma (5.7%), active tuberculosis (4.5%), nontuberculous mycobacteriosis (3.4%), Kaposi’s sarcoma (3.4%), cryptococcosis (1.7%), toxoplasmosis (0.8%), progressive multifocal leukoencephalopathy (0.8%), and HIV encephalopathy (0.8%). The annual changes in the incidence of opportunistic complications were also examined. With regard to 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, began decreasing again in 2017, and then remained constant for the next 3 years. With regard to malignancies (Figure 12: absolute number of cases, Figure 13: relative frequency), both the absolute number of cases and relative frequency have been fluctuating but generally decreasing, except for those for non-Hodgkin’s lymphoma and primary brain lymphoma, which have remained constant. Data regarding the incidence of other opportunistic complications are presented in Figures 14–17 (Figure 14 and 16: absolute number of cases, Figure 15 and 17: relative frequency). While these incidences have fluctuated, the overall incidence of all complications has remained constant.


Figure 8. Cumulative incidence rates of acquired immunodeficiency syndrome (AIDS)-defining diseases from 1995 to 2020


Figure 9. Incidence rates of AIDS-defining diseases in 2020


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 in patients with opportunistic complications, which had decreased substantially to 3.6% in 2017 and was 4.8% in 2019, 9.2% in 2020, and 4.5% in 2021. The changes in the annual mortality rates for the four major infections (Figure 19), showed that rate for all infections had decreased but has recently remained constant. The mortality rate for cytomegalovirus infection decreased initially but leveled off in 2005. Subsequently, it remained at approximately 10% since 2010 but had been substantially decreasing since 2016 before increasing again since 2019. As for other infections, despite the small number of cases, the mortality rate for cryptococcosis has fluctuated but generally decreased. Since 2014, it remained at approximately 20% before exceeding 30% in 2019 and then decreasing since 2020 (Figure 20). Figures 21 and 22 show the changes in the mortality rates for other opportunistic complications; due to the small number of cases in each year, the rates widely vary. In addition, the cumulative disease-specific mortality rates (Figure 23) are characteristically high for malignancies (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 (among patients aged 13 years or younger), recurrent pneumonia, and cryptococcosis.


Figure 18. Proportion of patients who died from opportunistic complications and mortality rates among symptomatic AIDS patients


Figure 19. Changes in the mortality rates of four major infections


Figure 20. Changes in the mortality rates of other infections


Figure 21. Changes in the mortality rates of 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 between the diagnosis of opportunistic complications and ART initiation. Among patients with infections, ART tended to be initiated 15–30 days or more after the diagnosis of opportunistic complications. This interval was longer than the time to ART initiation among patients with malignancies or non-infectious encephalopathy. In particular, more than 50% of patients with active tuberculosis started ART more than 2 months after being diagnosed. A large proportion of patients with central nervous system diseases, such as progressive multifocal leukoencephalopathy and primary brain lymphoma, started ART within 14–30 days after being diagnosed, and thus, the time to ART initiation tended to be short in this group of patients (Figure 24); however, the number of cases of patients with central nervous system diseases was low. When the longitudinal trend in the time to ART initiation since 2010 was analyzed, the time tended to decrease each year until 2013 for all four major infections (i.e., cytomegalovirus infection, PCP, candidiasis, and active tuberculosis), except for active tuberculosis. However, the proportion of patients who started ART between 15 and 31 days after being diagnosed with these infections has increased since 2014 (Figure 25). No characteristic trend was observed with regard to the time from the diagnosis of other opportunistic complications to ART initiation from 2010 to 2021 (Figures 26-28).


Figure 24. Time from the diagnosis of opportunistic complications to 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 initiation and all complication outcomes. The mortality rate among patients who started ART within 14 days of being diagnosed with complications was significantly higher than that among patients who started ART 15 days or more after being diagnosed (11.39% vs. 2.80%, P<0.01). When the cutoff was set at 30 days, the mortality rate among patients who started ART within 30 days after being diagnosed was also significantly higher than that among patients who started ART 31 days or more after the diagnosis (5.97% vs. 2.45%, P<0.01). Next, we examined the association between the time to ART initiation and each opportunistic complication outcomes. With regard to PCP, the mortality rate was significantly higher among patients who started ART within 14 days of being diagnosed than those who started ART 15 days or more of being diagnosed (7.11% vs. 1.52%, P<0.01). When the cutoff of 30 days was applied, the mortality rate among patients who started ART within 30 days after being diagnosed was also significantly higher than that among 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: 12.04% vs. 5.06%, 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 all the personnel at the participating HIV core hospitals has made it possible to conduct the present study every year. We would like to express our deepest gratitude to them for their cooperation despite the yearly increasing burden of their duties. The hospitals that participated in this 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 and analyzed the incidence and distribution of opportunistic complications, as well as the associated longitudinal changes. The incidence rate of new HIV infections and the number of patients newly diagnosed with AIDS have been gradually decreasing globally in the past few years. In Japan, the corresponding values appear to have slightly decreased after continuously increasing for a few years. The present study also revealed that PCP is an important first-onset opportunistic complication and that early ART initiation may not always improve prognosis.

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