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
A Nationwide Survey on Opportunistic
Complications of HIV Infection in Japan
- A questionnaire administered among
HIV core hospitals across Japan in 2017 -

Investigators: Koichi Izumikawa (Department of Infectious Diseases, Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences)
Research coordinator: Kei Kawano (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

The present study has been investigating the trend of opportunistic complications associated with infection with human immunodeficiency virus (HIV) since 1995. In this fiscal year, cases detected in 2016 were investigated and analyzed together with those collected in the previous surveys. The questionnaire forms were sent to 383 HIV core hospitals across Japan, and responses were obtained from 203 hospitals (recovery rate: 53.0%). Of these hospitals, 78 (38.4%) had encountered relevant cases. There were a total of 320 patients with 391 episodes in total. The incidence of opportunistic complications has been decreasing since 2012. According to the report by the Acquired Immunodeficiency Syndrome (AIDS) Surveillance Committee of the Ministry of Health, Labour and Welfare, the number of AIDS patients in 2017 was 413 (437 in the previous year). The annual number of new patients has been 400 or more since 2006. In addition, the case capture rate of the present study appeared to be 76.1%. As in previous years, the largest proportion of patients with opportunistic complications occurred within 3 months after the diagnosis of HIV infection (including those with opportunistic complications diagnosed prior to the diagnosis of HIV infection). Meanwhile, the largest proportion of patients were not receiving anti-HIV therapy at the onset of the complications. In patients treated for 6 months or longer, the cumulative incidence rates were 19.9% for cytomegalovirus infection, 13.1% for pneumocystis pneumonia (PCP), 11.1% for candidiasis, 8.8% for non-Hodgkin's lymphoma, 8.7% for atypical mycobacterial infection, 7.7% for active tuberculosis, and 5.9% for Kaposi's sarcoma in the descending order.

As in the previous few years, the highest overall incidence rate in 2017 was observed for PCP (45.9%), followed by candidiasis (13.7%) and cytomegalovirus infection (9.8%). After this, the order of other complications slightly varied as follows: non-Hodgkin's lymphoma (5.4%), Kaposi's sarcoma (4.9%), active tuberculosis (3.6%), and progressive multifocal leukoencephalopathy (2.3%). Although the overall mortality rate was 10.2% in 2010, it fell to the record low of 3.6% in 2017. The cumulative disease-specific mortality rates remain high for malignancies and central nervous system disease. The time from the diagnosis of opportunistic complications to the introduction of anti-retroviral therapy (ART) for major infections, except for tuberculosis, shortened each year between 2010 and 2013. However, the proportion of patients starting ART at 15 days or more after the diagnosis of opportunistic infections has been increasing since 2014.

When the association between the time to ART introduction and outcomes was analyzed, the overall mortality rate was significantly higher in patients starting ART at the time of or within 14 days after the diagnosis of opportunistic complications. The same trend was also observed for PCP and cytomegalovirus infection.

A.Objective

While anti-retroviral therapy (ART) has been widely adopted and tended to be initiated in the early stages of infection with human immunodeficiency virus (HIV), efforts have been made to improve the prognosis of HIV infection. In Japan, the numbers of newly reported HIV-positive patients and patients with acquired immunodeficiency syndrome (AIDS) have recently reached a plateau and remained constant. According to the AIDS surveillance data from the Ministry of Health, Labour and Welfare, 30% of HIV infection/AIDS cases are detected after the onset of opportunistic complications. Because the mortality rate after the onset of AIDS is approximately 10%, how early to detect HIV infection is an important prognostic factor. In addition, when to initiate ART after the start of treatment for opportunistic complications should be carefully determined for each complication with consideration of immune reconstitution syndrome. However, according to the Department of Health and Human Services (DHHS) guidelines and the ACTGA5614 study, ART should be initiated soon after the onset of opportunistic infections. Thus, understanding the trend of opportunistic infections 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 to analyze the latest trend of opportunistic complications along with the previous data.

B.Methods

Under the current circumstances regarding the treatment of HIV infection in Japan, most patients diagnosed with HIV infection are referred to HIV core hospitals. Thus, the present study included 383 HIV core hospitals (designated as core hospitals in 2017) across Japan. The questionnaire forms (PDFAppendix 1 [in Japanese]) were sent to the target hospitals by mail, and the hospitals were requested to complete and return the forms. The surveyed period was from January to December 2017. The hospitals were requested to describe the cases of AIDS-defining diseases diagnosed during this period after confirming the final diagnosis.

To improve the recovery rate and reduce the burden on treating physicians, questionnaire items were designed to be as simple as possible and kept to the minimum necessary. The questionnaire could be completed without detailed review of medical records. Although this approach has a detrimental effect of reducing the volume of information collected, it was used in the present study, which focused on the objective of elucidating the exact trend of opportunistic infections. No detailed investigation of individual diseases was conducted. To improve the recovery rate, a written request for a response was sent 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 a 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 Research in Humans (partially revised on December 22, 2017). Special considerations were made not to collect personal information at the participating hospitals. In other words, the questionnaire forms did not contain any data that could identify individuals by linking data, such as initials and patient numbers. The study protocol was reviewed and approved by the ethics committee of Nagasaki University Graduate School of Biomedical Sciences. The data collected in the questionnaires did not contain personal information. However, because they were clinical data on HIV infection, the data were handled with due care and maintained in a controlled laboratory environment where only the study investigators could handle them.

C.Results

The questionnaire forms were sent to 383 HIV core hospitals across Japan, and responses were obtained from 203 hospitals (recovery rate: 53.0%) (PDFAppendix 3 [in Japanese]). Of these hospitals, 78 (38.4%) encountered patients with AIDS-defining diseases in 2017. There were a total of 320 patients with 391 episodes in total. The incidence of the diseases has been decreasing since 2012. According to the report by the AIDS Surveillance Committee of the Ministry of Health, Labour and Welfare, the number of AIDS patients in 2017 was 413 (437 in the previous year). The annual number of new patients has been 400 or more since 2006. In addition, the case capture rate of the present study appeared to be 76.1%. The changes in the annual number of reported cases are shown in Figure 1.


Figure 1. Changes in the number of reported cases of opportunistic complications (based on a questionnaire administered to HIV core hospitals across Japan)

As for the time from the first diagnosis of HIV infection to the onset of opportunistic complications, patients developing opportunistic complications within 3 months after the diagnosis of HIV infection (including those diagnosed with opportunistic complications before the diagnosis of HIV infection) have accounted for the majority of those with opportunistic 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 added since 2002.).


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

Regarding the use of anti-HIV therapy at the onset of opportunistic complications, the largest proportion of patients were not receiving the therapy at the onset (87.8%) (Figure 3). (The separate response options of “untreated” and “treatment discontinued” have been added 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 on 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 after the diagnosis of HIV infection and those who had not receive medical attention for a long time had obviously been untreated or discontinued treatment. However, even among patients who developed opportunistic complications at 1 year or more after the diagnosis of HIV infection, nearly 60% of them had been untreated or discontinued treatment. In particular, a large proportion of patients who developed opportunistic complications at more than 1 year after the diagnosis of HIV infection (24.9%) had discontinued treatment. On the other hand, 42.0% of these patients had continuously received ART for 6 months or longer. When only the 2017 data were considered (Figure 5), the proportion of untreated patients was obviously higher among patients who developed opportunistic complications within 3 months after the diagnosis of HIV infection but lower in patients who developed the complications within 1 year. In patients treated for 6 months or longer, the cumulative incidence rates were 19.9% for cytomegalovirus infection, 13.1% for pneumocystis pneumonia (PCP), 11.1% for candidiasis, 8.8% for non-Hodgkin's lymphoma, 8.7% for atypical mycobacterial infection, 7.7% for active tuberculosis, and 5.9% for Kaposi's sarcoma in the 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 (2017)


Figure 6. Cumulative incidence of diseases in patients treated with anti-HIV therapy for 6 months or longer

To determine whether opportunistic infections were caused in association 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 developed multiple opportunistic infections during a single year and were suspected of having persistent immunodeficiency accounted for 41.6% (74/178) of all patients. The proportion of such patients has gradually decreased afterward and has recently hovered around 20%. In 2017, it was 19.0% (61/320).


Figure 7. Proportion of patients who experienced multiple opportunistic complications within a single year

Figure 8 shows the cumulative incidence rates of opportunistic infections. The most frequent AIDS-defining disease was PCP (38.7%), followed by cytomegalovirus infection (13.6%), candidiasis (12.8%), active tuberculosis (7.3%), Kaposi's sarcoma (4.6%), and atypical mycobacterial infection (4.0%) in the descending order. Figure 9 shows the corresponding incidence rates in 2017 alone. As in the previous few years, the highest overall incidence rate in 2017 was observed for PCP (45.9%), followed by candidiasis (13.7%) and cytomegalovirus infection (9.8%). After this, the order of other AIDS-defining diseases varied as follows: non-Hodgkin's lymphoma (5.4%), Kaposi's sarcoma (4.9%), active tuberculosis (3.6%), atypical mycobacterial infection (3.6%), and progressive multifocal leukoencephalopathy (2.3%). When annual changes in the incidence of the diseases were examined for major infectious diseases (Figure 10: absolute number of cases, Figure 11: relative frequency), the incidence of PCP peaked in 2011. Although the absolute number of PCP cases has decreased since then, the relative frequency increased between 2013 and 2016. Then, it decreased again in 2017. As for malignancies (Figure 12: absolute number of cases, Figure 13: relative frequency), the incidence of all types has fluctuated but tended to decrease overall. The incidence of other diseases is shown in Figures 14 to 17 (Figure 14 and 16: absolute number of cases, Figure 15 and 17: relative frequency). While fluctuating, the incidence of all complications has remained constant.


Figure 8. Cumulative incidence rates of AIDS-defining diseases from 1995 to 2017


Figure 9. Incidence rates of AIDS-defining diseases in 2017


Figure 10. Changes in the number of cases of frequent opportunistic complications


Figure 11. Changes in the relative frequency of frequent opportunistic complications

Additionally,when changes in the annual disease incidence were considered—both in the absolute number of cases (Fig. 10) and the relative frequency (Fig. 11)— the number of pneumocystis pneumonia cases peaked in 2011 and declined year-by-year thereafter, although both the absolute number and relative frequency again increased in 2015.

The absolute number (Fig. 12) and relative frequency (Fig. 13) of malignancies fluctuated slightly, by generally decreased over time. As for other diseases, their absolute numbers (Figs. 14 and 16) and relative frequency (Figs. 15 and 17) remained almost constant. Figure 18 shows the mortality rate in patients with opportunistic complications. The rate substantially decreased to 3.6% in 2017. When changes in the annual mortality rates for 4 major diseases (Figure 19), the mortality rates for all diseases have decreased. In recent years, the rates for PCP and tuberculosis have become as low as the mortality rate for candidiasis, which has been the lowest rate among the diseases. The mortality rate for cytomegalovirus infection initially decreased but stopped decreasing in 2005. Subsequently, it hovered around 10% from 2010 onward. Since 2016, the rate has substantially been decreasing. As for other infections, despite the small number of patients, the mortality rate for Cryptococcus infection fluctuated but overall decreased. However, the rate exceeded 20% in 2014 and 2016. In 2017, it started decreasing again (Figure 20). Figures 21 and 22 show changes in the mortality rates for other opportunistic complications. Because of the small number of patients 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, such as progressive multifocal leukoencephalopathy, HIV encephalopathy and Cryptococcosis. Among infectious diseases, the mortality rates are high for histoplasmosis, suppurative bacterial infections (age of 13 or younger), recurrent pneumonia, and Cryptococcosis.


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. Proportion of patients who died from opportunistic complications


Figure 19. Changes in the mortality rates for 4 major diseases


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 for 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 infectious diseases, ART tended to be introduced 15 to 30 days or more after the diagnosis of opportunistic complication, which was longer than the time to ART introduction in patients with malignancies and non-infectious encephalopathy. Especially, more than half of patients with active tuberculosis started ART more than 2 months after the diagnosis. Despite the small sample size, patients with central nervous system-related diseases, such as progressive multifocal leukoencephalopathy and primary brain lymphoma, tended to start ART early. In many of them, ART was introduced within 14 or 30 days after the diagnosis (Figure 24). When the longitudinal trends of the time to ART introduction since 2010 was analyzed, the time tended to shorten each year until 2013 for 4 major infections diseases except for tuberculosis. However, the proportion of patients starting ART at least 15 or 31 days after the diagnosis has characteristically increased since 2014 (Figure 25).


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 (2010-2017) (1)

Table 1 shows the association between the time to ART introduction and outcomes for all complications. In patients who started ART at the time of or within 14 days after the diagnosis of complications, the mortality rate was significantly higher than in patients who started ART at 15 days or more after the diagnosis (12.98% vs. 3.22%, P<0.01). When the cutoff was set to 30 days, the mortality rate was also 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 (6.53% vs. 3.00%, P<0.01). According to specific diseases, among patients with PCP, the mortality rate was significantly higher in those who started ART at the time of or within 14 days after the diagnosis (8.16% vs. 1.66%, P<0.01). However, no significant difference was observed when the cutoff of 30 days was applied (Table 2). The same trend was also observed for cytomegalovirus infection (15-day cutoff: 14.00% vs. 5.84%, P=0.013) (Table 3). Figures 26 to 28 show the comparison of the time from the diagnosis of other opportunistic complications to ART introduction between 2010 and 2017. No characteristic trend was observed.

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)


Figure 26. Comparison of the time from the diagnosis of
opportunistic complications to ART introduction (2010-2017) (2)


Figure 27. Comparison of the time from the diagnosis of
opportunistic complications to ART introduction (2010-2017) (3)


Figure 28. Comparison of the time from the diagnosis of
opportunistic complications to ART introduction (2010-2017) (4)

D.Acknowledgments

The cooperation of all personnel involved at the participating HIV core hospitals has made it possible to continue the present study every year. 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 PDFAppendix 3 [in Japanese].

E.Conclusion

We continued the nationwide survey of opportunistic complications associated with HIV at HIV core hospitals. In the present study, the incidence and distribution of opportunistic complications, as well as the longitudinal changes, were analyzed. In the previous few years, the incidence rate of new HIV infection and the number of patients with newly diagnosed 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 the importance of PCP as a first-onset disease and the possibility that early ART introduction does not necessarily improve the prognosis.