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 2016 -

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 384 HIV core hospitals across Japan to collect information on patients diagnosed with any of the 23 AIDS-defining diseases between January 1, 2016, and December 31, 2016. The data obtained were combined with corresponding data from previous surveys conducted between 1995 and 2015 for analysis.
C. Results… Response recovery status in 2017;
cases diagnosed in 2016 (as of February 10).

Questionnaire sent to: 385 hospitals
Response received from: 144 hospitals (recovery rate: 37.4%)
Cases encountered in: 79 hospitals (case encounter rate: 37.4%)
No. of affected patients: 332
Total no. of episodes: 419 

Abstract

This study investigates the trend of opportunistic complications for HIV-infected patients since 1995 in Japan. In the study in this year, we collected information on HIV patients diagnosed with opportunistic complications in 2016 and combined it with previous data for analysis. We sent a questionnaire to 385 HIV core hospitals across Japan and received responses from 144 (recovery rate: 37.4%). Of the responding hospitals, 79 (54.9%) had encountered relevant cases. A total of 332 patients and 419 episodes were encountered, reflecting a continuously decreasing trend since 2012. The AIDS Surveillance Committee of the Ministry of Health, Labour and Welfare reported that the number of HIV/AIDS patients declined between 2013 and 2015, but again increased to 437 in 2016 from 428 in 2015. The case capture rate of the present study was estimated to be 76.0%. As in previous years, the largest proportion of opportunistic complications was detected within 3 months after HIV diagnosis, including those observed before HIV diagnosis. Moreover, most HIV patients were not receiving anti-HIV therapy at the time of opportunistic complication onset. Common diseases reported in HIV patients treated for more than 6 months were cytomegalovirus infection (20.0%), pneumocystis pneumonia (13.2%), candidiasis (11.3%), atypical mycobacterial infection (8.7%), non-Hodgkin's lymphoma (8.3%), active tuberculosis (7.6%), and Kaposi's sarcoma (5.8%).

Consistent with data from the last several years, in 2016, pneumocystis pneumonia showed the overall highest cumulative incidence (50.2%), followed by candidiasis (14.1%), cytomegalovirus infection (10.5%), non-Hodgkin's lymphoma (4.3%), Kaposi's sarcoma (3.8%), active tuberculosis (3.3%), and progressive multifocal leukoencephalopathy (3.3%). The overall mortality rate was 10.2% in 2010 and decreased to 3.8% in 2016—the lowest value ever noted. However, the cumulative disease-specific mortality rates for malignancy and central nervous system (CNC) disease remained high in HIV patients.

The interval from the diagnosis of opportunistic complications to the introduction of anti-retroviral therapy (ART) for major infections, except for tuberculosis, increasingly shortened between 2010 and 2013; in contrast, from 2014 onward, an increasing proportion of HIV patients started ART more than 15 days after the diagnosis of opportunistic infections.

Analysis of time to ART introduction and patient outcome showed a significantly higher overall mortality in HIV patients who started ART between 0 and 14 days after the diagnosis of opportunistic complications. The same trend was also observed for pneumocystis pneumonia and cytomegalovirus infection.

A.Objective

With anti-retroviral therapy (ART) utilization increasing and implementation occurring earlier in treatment, growing efforts are being made to improve the prognosis of HIV infection. The numbers of newly reported HIV/AIDS cases have reached a plateau. The AIDS Surveillance Committee of the Ministry of Health, Labour and Welfare (MHLW) has reported that about 30% of all HIV/AIDS cases are diagnosed during the manifestation of opportunistic complications. The mortality rate for symptomatic AIDS patients is about 10%, suggesting the importance of early detection of HIV infection as a prognostic determinant. The timing of ART initiation during the treatment course of opportunistic complications should be determined carefully to avoid immune reconstitution syndrome. The DHHS guidelines and the findings from the ACTGA5614 study recommend starting ART immediately after the manifestation of an opportunistic infection. Therefore, understanding the trend of opportunistic infections in HIV patients in Japan is critical, and continuous surveillance is needed to characterize the trend of opportunistic complications. In this study, we analyzed the collected data along with previous data to characterize the current trend of opportunistic complications in Japan, utilizing the nationwide trend survey of opportunistic complications from the Kimura group.

B.Methods

In Japan, after diagnosis, most HIV cases are referred to HIV core hospitals. This survey, therefore, included a total of 385 hospitals across Japan that had a HIV core hospital designation as of 2016. A questionnaire (PDFAppendix 1 [in Japanese]) was sent to participating hospitals by mail, and the hospitals were requested to complete and return this questionnaire. The questionnaire pertained to AIDS-defining diseases diagnosed between January and December 2016. Respondent hospitals were requested to complete the questionnaire after confirming the final diagnosis for each case.

In order to maximize the recovery rate and minimize the burden on treating physicians, questionnaire items were designed to be simple and the number of questions was kept at a minimum. Although this approach may reduce the volume of potential information collected, this study focused on the precise characterization of the trend of opportunistic infections and did not collect detailed information about individual diseases. To improve the recovery rate, a written request for a response was sent to those hospitals that did not return the form by the set deadline. The collected data, combined with previous data, were entered into a database constructed with Microsoft Access 2010 for summarization. The database was refined to fit the purpose of this study, with a newly created menu, entry pages, and queries to facilitate necessary calculations.

This study was conducted in compliance with the Ethical Guidelines for Medical Research in Humans (partially revised on December 22, 2017). Considerations were made to prevent the study sites from collecting patients’ personal information by ensuring that the questionnaire did not include personally identifiable data, such as initials and patient numbers. The study protocol was approved by the ethics committee of the Nagasaki University Graduate School of Biomedical Sciences. Although the data collected through the questionnaire did not contain personal information, there was clinical data on HIV infection. Thus, the data were handled with due care and maintained in a controlled laboratory environment where only the study investigators could access it.

C.Results

We sent a questionnaire to 385 HIV core hospitals across Japan and received responses from 144 (recovery rate: 37.4%; see PDFAppendix 2 [in Japanese]). Of these hospitals, 79 (37.4%) encountered patients with AIDS-defining diseases that manifested in 2016. The total numbers of patients and episodes encountered were 332 and 419, respectively, reflecting a continuously decreasing trend since 2012. The MHLW AIDS Surveillance Committee reported that the number of AIDS patients declined between 2013 and 2015; however, it again increased in 2016 (437 cases). The case capture rate of the present study was estimated to be 76.0%. The change in the annual number of cases reported is shown in Fig. 1.


Figure 1. Change in the number of reported cases of opportunistic complications over time
(based on a questionnaire administered among HIV core hospitals across Japan)

The analysis of the relationship between the time of the first diagnosis of HIV infection and the time to the onset of opportunistic complications showed that since 1998, when ART became popular, the largest proportion of opportunistic complications was observed in those diagnosed within 3 months after HIV diagnosis (including those diagnosed before HIV diagnosis). These cases may include patients directly diagnosed with AIDS without a prior diagnosis of HIV infection (Fig. 2) (the response option “not having sought medical attention for a long time” has been added since 2002).


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

Most (91.4%) patients were not receiving anti-HIV therapy at the onset of opportunistic complications, and this proportion has been increasing since 2014 (Fig. 3). (The response options “untreated” and “treatment discontinued” have been delineated since 2002).


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

Cross-tabulation of the cumulative data on the time from HIV diagnosis to the onset of opportunistic complications and the duration of anti-HIV therapy (Fig. 4) shows that most patients diagnosed within 3 months after HIV diagnosis and those not receiving medical attention for a long time were untreated or had treatment discontinued. Additionally, nearly 60% of patients with a symptom onset interval of more than 1 year after diagnosis were also untreated or had treatment discontinued. In particular, a large proportion (24.7%) of HIV patients with a time from diagnosis to symptom onset of >1 year had their treatment discontinued. In this patient subgroup, 41.9% continued ART for more than 6 months. When only 2016 data were considered (Fig. 5), the proportion of untreated HIV patients was clearly greater when symptoms appeared within 1 year after HIV diagnosis. Common diseases reported in HIV patients undergoing ART for more than 6 months were cytomegalovirus infection (20.0%), pneumocystis pneumonia (13.2%), candidiasis (11.3%), atypical mycobacterial infection (8.7%), non-Hodgkin's lymphoma (8.3%), active tuberculosis (7.6%), and Kaposi's sarcoma (5.8%; Fig. 6).


Figure 4. Relationship between time from HIV diagnosis to the onset of opportunistic
complications and the use of anti-HIV therapy


Figure 5. Relationship between time from HIV diagnosis to the onset of
opportunistic complications and the use of anti-HIV therapy (2016)


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

To determine whether the reported opportunistic infections were associated with severe persistent immunodeficiency, we examined the proportion of HIV patients who experienced multiple opportunistic complications within a single year (Fig. 7). In 1995, the proportion of HIV patients who experienced multiple opportunistic infections within a single year, and thus were suspected of having persistent immunodeficiency, was 41.6% (74/178) of all HIV patients. This proportion gradually declined to around 20-30% in recent years (22.9% [75/327] in 2016).


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

Figure 8 shows the cumulative incidence of different opportunistic infections. The most common AIDS-defining diseases were pneumocystis pneumonia (38.4%), cytomegalovirus infection (13.8%), candidiasis (12.7%), tuberculosis (7.5%), Kaposi’s sarcoma (4.6%), and atypical mycobacterial infection (4.0%). Figure 9 shows the corresponding incidence in 2016. As in the last several years, pneumocystis pneumonia showed the overall highest cumulative incidence (50.2%), followed by candidiasis (14.1%), cytomegalovirus infection (10.5%), non-Hodgkin's lymphoma (4.3%), Kaposi's sarcoma (3.8%), active tuberculosis (3.3%), and progressive multifocal leukoencephalopathy (3.3%). When changes in the annual disease incidence were considered—both in the absolute number of cases (Fig. 10) and the relative frequency (Fig. 11)—for major infectious diseases among HIV patients, the absolute number of pneumocystis pneumonia cases peaked in 2011 and declined thereafter. In contrast, the relative frequency has been increasing since 2013.


Figure 8. Cumulative incidence of AIDS-defining diseases between 1995 and 2016


Figure 9. Incidence of AIDS-defining diseases in 2016


Figure 10. Change in the number of reported cases of common opportunistic complications over time


Figure 11. Change in the relative frequency of common opportunistic complications over time

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 12. Change in the number of reported cases of opportunistic malignancies over time


Figure 13. Change in the relative frequency of opportunistic malignancies over time


Figure 14. Change in the number of reported cases of opportunistic complications over time (1)


Figure 15. Change in the relative frequency of opportunistic complications over time (1)


Figure 16. Change in the number of reported cases of opportunistic complications over time (2)


Figure 17. Change in the relative frequency of opportunistic complications over time (2)

Figure 18 shows mortality rates among HIV patients with opportunistic complications. The rate substantially decreased to 3.8% in 2016. The analysis of the change in the annual mortality rates for 4 major diseases (Fig. 19) in HIV patients shows that the mortality rates for all 4 diseases declined over time; the rate for pneumocystis pneumonia and tuberculosis became closer to that for candidiasis, which has remained at the lowest level. The mortality rate for cytomegalovirus infection initially declined, reached a plateau in 2005, and remained at around 10% from 2010 onward until 2016, wherein it showed a substantial decrease. Among other infections, the mortality rate for Cryptococcus infection declined over time, with some fluctuations including increases to above 20% in 2014 and 2016 (Fig. 20), although the sample size was small. Figures 21 and 22 show the mortality rates for other opportunistic complications, with relatively large variations due to the small sample size. In terms of cumulative disease-specific mortality (Fig. 23), the rates for malignancies (non-Hodgkin's lymphoma and primary brain lymphoma) and CNS-related diseases—such as progressive multifocal leukoencephalopathy, HIV encephalopathy, and Cryptococcosis—were characteristically high. Among infectious diseases, histoplasmosis, suppurative bacterial infections (age ≤13 years), recurrent pneumonia, and Cryptococcosis were associated with high mortality.


Figure 18. Proportion of patients who died from opportunistic complications


Figure 19. Change in the mortality rates for 4 major diseases over time


Figure 20. Change in the mortality rates for other infections over time


Figure 21. Change in the mortality rates for opportunistic malignancies over time


Figure 22. Change in the mortality rates for other opportunistic complications over time


Figure 23. Disease-specific cumulative mortality rates

In 2010, we started collecting information about the time from the diagnosis of opportunistic complications to the introduction of ART. For infectious diseases, ART tended to be introduced 15-30 days after malignancies and non-infectious encephalopathy were detected. In particular, for active tuberculosis, more than half of the patients started ART more than 2 months after HIV diagnosis. ART tended to be introduced earlier for CNS-related diseases—such as progressive multifocal leukoencephalopathy and primary brain lymphoma—with about 60% and 80-90% of the HIV patients starting the therapy within 14 and 30 days after diagnosis, respectively (Fig. 24). The analysis of data starting from 2010 showed that the time to ART introduction for the 4 major infectious diseases, except for tuberculosis, decreased year-by-year until 2013, although an increasing proportion of HIV patients started ART more than 15 or even 31 days after diagnosis from 2014 onward (Fig. 25).


Figure 24. Time to ART introduction after diagnosis of opportunistic complications (from 2010)


Figure 25. Time to ART introduction after diagnosis of opportunistic complications:
7-year comparison (2010 to 2016) (1)

Table 1 summarizes the relationship between time to ART introduction and outcomes for all complications in HIV patients. HIV patients who started ART between 0 and 14 days after the diagnosis of complications had a significantly higher mortality rate than those who started the therapy ≥15 days after diagnosis (14.19% vs. 3.36%, p<0.01). When the cutoff was set to 30 days, HIV patients who started ART within 30 days after diagnosis also had a significantly higher mortality rate than those who started ≥31 days after diagnosis (6.97% vs. 3.21%, p<0.01). Regarding disease-type, HIV patients who started ART between 0 and 14 days after the diagnosis of pneumocystis pneumonia had a significantly higher mortality rate than those who started it ≥15 days after diagnosis (8.73% vs. 1.85%, p<0.01), whereas no significant difference was observed when a cutoff of 30 days was applied (Table 2). The same trend was also observed for cytomegalovirus infection with a cutoff of 15 days (14.29% vs. 6.29%, p=0.098; Table 3). Figures 26 - 28 show the data for the time from diagnosis to ART introduction for other opportunistic complications between 2010 and 2014. No specific trend was noted for any disease.

Table 1. Relationship between time to ART introduction and outcomes (from 2010)

Table 2. Relationship between time to ART introduction and outcomes (from 2010)

Table 3. Relationship between time to ART introduction and outcomes (from 2010)


Figure 26. Time to ART introduction after diagnosis of opportunistic complications:
7-year comparison (2010 to 2016) (2)


Figure 27. Time to ART introduction after diagnosis of opportunistic complications:
7-year comparison (2010 to 2016) (3)


Figure 28. Time to ART introduction after diagnosis of opportunistic complications:
7-year comparison (2010 to 2016) (4)

D.Acknowledgments

The cooperation of all personnel involved at the participating HIV core hospitals has made it possible to continue this study every year. The authors would like to express their deepest gratitude to them for their support for the survey, which they provided while dealing with the increasing burden of duties. The hospitals that participated in the study in this year are listed in PDFAppendix 2 [in Japanese].

E.Conclusion

We analyzed HIV patient data from 1995 to 2016 to evaluate the change in the frequency and distribution of associated opportunistic complications at HIV core hospitals across Japan. Globally, the number of patients with newly diagnosed HIV infection or AIDS has been gradually decreasing in the past several years, whereas the corresponding number had been increasing in Japan, until recently, when a decrease was observed. The current data revealed the importance of pneumocystis pneumonia as a first-onset illness and that the early introduction of ART does not necessarily lead to an improved outcome for HIV patients in Japan.