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 the incidence of malignancies (non–acquired immunodeficiency syndrome [AIDS]-defining malignancies) in patients infected with human immunodeficiency virus (HIV)
-Analysis of cases in 2020 -
| 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
To elucidate the current status of non-acquired immunodeficiency syndrome (AIDS)-defining malignancies in patients infected with human immunodeficiency virus (HIV), 378 HIV core hospitals in Japan were included in a questionnaire survey. Responses were received from 143 hospitals (response rate: 37.8%). In 2021, 60 patients were diagnosed with malignancies; this number was comparable to that in the previous year (69 patients in 2020). Based on the cumulative incidence rates, the most common malignancy was lung cancer, followed by colorectal cancer, gastric cancer, liver cancer, other hematologic tumors, anal tumors, head and neck tumors, other urologic tumors, and leukemia in descending order. Although the distribution of CD4 cell counts at the time of onset of malignancy showed that more patients had low CD4 cell counts, the distribution gradient of the counts was small, and some patients with high CD4 cell counts had also developed malignancies; moreover, the distribution of CD4 cell counts differed greatly from those at the time of the diagnosis of opportunistic complications. The most common age at the time of onset of malignancy was between 60 and 69 years. Approximately 75% of patients developed malignancy 1 year or more after being diagnosed with HIV infection. The post-treatment complete/partial remission rate was 62%. These findings suggest that long-term follow-up of HIV-positive patients should include regular monitoring, considering the risk of development of malignancies in general, and patient education on smoking cessation, considering the relatively high risk of lung cancer. Additionally, the noticeable increase in the incidence of colorectal cancer over time indicates the need for increasing appropriate screening for this condition.
A．Objective
Based on the accumulated data on early initiation of anti-retroviral therapy (ART) and daily management procedures for the treatment of human immunodeficiency virus (HIV) infection, long-term health management, including in cases of malignancies, has been recognized as an important issue. The study group investigating opportunistic infections, funded by the Health and Labour Sciences Research Grant of the Japanese Ministry of Health, Labour and Welfare, has monitored the trends associated with the development of non-acquired immunodeficiency syndrome (AIDS)-defining malignancies since it was reported that the incidence rates of malignancies in HIV-positive patients were high. The study group reported that the incidence rates of non-AIDS-defining malignancies among HIV-positive patients were also relatively high and that the reported incidence rates of malignancies among these patients differed from the corresponding rates in the general Japanese population. These findings have prompted several studies on these malignancies, including leukemia. As the data accumulated on the development of malignancies by this group is the only source for information on the corresponding nationwide trends in Japan, we continued this study to investigate the rates of non-AIDS-defining malignancies in 2021, as well as the trends associated with the development of opportunistic infections complicating HIV infection.
B．Methods
As HIV infection is preferentially treated at HIV/AIDS core hospitals in Japan, the present study was conducted by sending a questionnaire form to these hospitals and requesting them to complete and return it. The questionnaire form for the present study on malignancies (
Appendix 2) was enclosed along with the questionnaire form for an epidemiological study on HIV-associated opportunistic complications that was sent to these HIV core hospitals. As preceding studies had accumulated the data regarding malignancies for the period from 1995 to 2006, our study group collected the data that had been accumulated by these study groups since 2007 and requested the hospitals to report the cases of malignancies diagnosed in 2021.
The present study primarily aimed to elucidate the current status of the development of malignancies through cooperation with as many hospitals as possible. The questionnaire items were designed to be simple and kept to the minimum number necessary. To improve the response rate of the survey, the questionnaire items were limited to those that could be answered without a detailed review of the medical records of each patient; however, this approach slightly compromised our ability to elucidate the details regarding each malignancy. To further improve the response rate, we enclosed a return sheet with the questionnaire form and requested hospitals without any relevant cases to report the lack of data using these sheets. The collected data were entered and compiled into a database created using Microsoft Access. To exclude duplicate cases reported by the same hospital across years and by other referring and referred hospitals, cases with identical data for the year of birth, disease name, year of onset, reporting hospital region, etc., were regarded as duplicate cases and unified. Cases of non-Hodgkin’s lymphoma, brain lymphoma, cervical cancer, and Kaposi’s sarcoma, which are difficult to differentiate from AIDS-defining malignancies, were excluded from the aggregated data. Data on benign tumors reported by some hospitals were also excluded. The collected data were compared with the latest cancer statistics data in Japan (2014) available on the website of the Center for Cancer Control and Information Services at the National Cancer Center of Japan to compare the prevalence between HIV-positive patients and the general Japanese population. The present study was reviewed and approved by the ethics committee of Nagasaki University Graduate School of Biomedical Sciences as required by the Ethical Guidelines for Medical and Biological Research Involving Human Subjects (partially revised on December 22, 2017). The questionnaire survey was designed to meet the requirements for requests for the provision of data from other institutions to be accepted, as specified in the ethical guidelines for epidemiological studies. For example, to prevent the data analysis center from collecting personal information on patients, none of the questionnaire items asked for any personal information were included, and all hospitals were instructed not to provide any personal information, including patient identification numbers or codes, on the forms. Nonetheless, although the collected data were anonymized, they contained information on HIV-positive patients and were therefore handled with due care and analyzed in a controlled laboratory environment where only the study investigators could handle them.
C．Results
In 2021, 60 cases of malignancy were reported, and the cumulative number of reported cases increased to 922. Based on the annual number of reported cases (Figure 1), the incidence of non-AIDS-defining malignancies substantially increased to eight cases in 2000 and has thereafter been increasing each year. Subsequently, the incidence kept fluctuating but has leveled off at approximately 40–50 cases since 2010. The highest incidence was recorded in 2017, after which it slightly decreased again and has fluctuated between 60 and 70 cases since 2018.
Due to the considerable influence of year-to-year fluctuations, we calculated the mean incidence rate of malignancies per year and the prevalence per 100,000 persons for the 2-year period from 2020 to 2021. As the present study was a questionnaire survey, the capture rate was calculated by comparing the number of cases of opportunistic infections reported in the simultaneously conducted survey and the number of AIDS cases reported by the AIDS Surveillance Committee (81.2%). Based on the assumption that the current number of surviving HIV-positive patients was approximately 32,000, the prevalence per 100,000 persons was calculated as 248.1. The age-adjusted prevalence calculated based on the model population in 1985 was 426.34 per 100,000 persons, which was 0.90 times the cancer (including cancer in situ) prevalence of 471.5 in the Japanese population in 2014 (based on the survey conducted in 2019-2020).
Figure 1. Annual number of patients diagnosed with non–AIDS-defining malignancies
Figure 2 shows the cumulative number of reported cases of malignancy. The most common malignancy was lung cancer (cumulative number of cases, 131). Liver cancer had been the most common malignancy until 2009; however, its incidence has decreased thereafter. On the contrary, the incidence of lung cancer increased to 11 cases in 2010, when it emerged as the most common malignancy. Although its incidence has been decreasing since then, lung cancer has remained the most common malignancy in terms of cumulative incidence. The second most common malignancy is colorectal cancer, and the third most common malignancy is gastric cancer, followed by liver cancer, hematologic tumors, anal tumors, head and neck tumors, other urologic tumors, leukemia, and pharyngolaryngeal tumors (in decreasing order of incidence). In 2021 alone, there were 12 cases of colorectal cancer, seven of lung cancer, four of head and neck cancer, two of gastric cancer, three of anal tumors, four of liver cancer, and two of pharyngolaryngeal cancer (Figure 3). According to the data on changes in the annual incidence of the eight major malignancies (Figure 3), there has been a particularly prominent increasing trend in the incidence of cases of colorectal cancer since 2009, despite year-to-year fluctuations. The incidence of liver cancer peaked at six cases in 2006 and has decreased thereafter, fluctuating between one and four cases for the next few years before increasing to 11 cases in 2017, after which the incidence has decreased again. With regard to the changes in the annual incidence of malignancies based on infection route (Figure 4), homosexual transmission of HIV was the most commonly reported infection route. Regarding the characteristics of malignancies by infection route (Figure 5), notably, liver cancer cases accounted for approximately 50% of the cases of iatrogenic infection (mainly infection caused by blood coagulation factor products in patients with hemophilia). Among patients infected through homosexual transmission, the incidence of lung, colorectal, gastric, anal, and head and neck cancers was characteristically high. The incidence of lung cancer was high regardless of the infection route. According to the distribution of peripheral CD4 cell counts at the time of onset of malignancy (Figure 6), most patients had low CD4 cell counts. However, the distribution gradient among patients with malignancies was smaller than that among patients with opportunistic infections (Figure 7). The distribution among patients who developed malignancies in 2021 showed a similar trend.
Figure 2. Number of patients diagnosed with AIDS-defining malignancies by malignancy type
Figure 3. Annual changes in the incidence of major malignancies
Figure 4. Annual incidence of malignancies by infection route
Figure 5. Incidence of malignancies by infection route
Figure 6. Distribution of CD4 cell counts at the onset of malignancies
Figure 7. Distribution of CD4 cell counts at the time of diagnosis of opportunistic complications
Figure 8 shows the distributions of CD4 cell counts by major malignancy types. The counts varied widely regardless of malignancy type, and no particular trend was noted for any specific malignancy. The most common age at the time of onset of malignancy (Figure 9) was 60–69 years. Some older HIV-positive patients also developed malignancies, as evidenced by the reported incidence rate of 2.1% in the small population of HIV-positive patients in their 80s. Compared with the age at the onset of opportunistic infections, which appears to be close to the age at the time of detection of HIV infection, the distribution of age at the time of onset of malignancy was more skewed toward the older than the younger age groups. Based on the age distribution according to HIV infection routes (Figure 10), patients with iatrogenic infection tended to develop malignancies at younger ages than those infected through heterosexual or homosexual transmission. In addition, based on the age distribution by malignancy type (Figure 11), testicular tumors tended to develop at younger ages. As for the time to the onset of malignancy (Figure 12), more than 80% of all HIV-positive patients developed malignancies 1 year or more after being diagnosed with HIV infection. This time to onset was in contrast to the time to onset of opportunistic infections, as they developed within 3 months in more than 80% of HIV-positive patients (including in cases of simultaneous detection). This finding indicates that these malignancies can develop after patients are diagnosed as being infected with HIV and have been followed-up for some time. As for the outcomes of HIV-positive patients with malignancies (Figure 13), 62% of them achieved complete/partial remission. Based on mortality rate by malignancy type (Figure 14) the mortality rate was the highest for pancreatic cancer, which is inherently associated with a poor prognosis, followed by leukemia, lung cancer, liver cancer, esophageal cancer, and pharyngolaryngeal cancer.
Figure 8. Distribution of CD4 cell counts at the onset of malignancies by malignancy type
Figure 9. Age distribution at the onset of malignancies
Figure 10. Age distribution at the onset of malignancies by infection route
Figure 11. Age distribution at the onset of malignancies by malignancy type
Figure 12. Time from the diagnosis of HIV infection to the onset of malignancies
Figure 13. Outcomes of malignancies
Figure 14. Mortality rates by malignancy type
D．Discussion
ART introduction has allowed HIV-positive patients to remain in a stable condition for long periods of time; consequently, the development of malignancies among HIV-positive patients has emerged as an issue that requires appropriate management. The present study was initiated with the aim of addressing this issue. Its results showed that the incidence of non-AIDS-defining malignancies among HIV-positive patients is increasing each year in Japan. Previous studies have already shown that the prevalence of malignancies among HIV-positive patients tends to be higher than that among the general Japanese population. The present study revealed that, when comparing the age-adjusted prevalence rates in 2020 to 2021 based on the model population in 1985, the prevalence among HIV-positive patients was 0.90 times that in the general Japanese population (0.9 times that in the 2019–2020 study). Given that data for some AIDS-defining malignancies, namely malignant lymphoma, cervical cancer, and Kaposi’s sarcoma, were excluded from the aggregated data in the present study, the actual incidence rates of malignancies may be even higher. However, because the effects of HIV infection become evident after some time post-infection, monitoring long-term changes seems necessary. The distribution of malignancies among HIV-positive patients differed clearly from that among the general Japanese population. Lung cancer, liver cancer, leukemia, head and neck cancer, pharyngolaryngeal tumors, anal cancer, and testicular tumors were characteristically common in HIV-positive patients. Liver cancer has been suggested to be affected by concomitant hepatitis C and B virus infection and anal cancer with human papillomavirus infection. In contrast, there is no known association between lung cancer and viral infections. Notably, the prevalence of leukemia is particularly high in Japan; this includes all subtypes of leukemia, namely the myeloid, lymphatic, acute, and chronic subtypes, and there are no characteristic differences among their prevalence rates. The annual incidence of the eight major malignancies indicated that there has been a sharp increase in the incidence of lung cancer in the past few years. Despite the lack of definitive data in this regard, HIV-positive patients could be more likely to be predisposed to factors for developing lung cancer, such as smoking, than others. Thus, the promotion of smoking cessation in HIV-positive patients will presumably be an important issue in the future. Furthermore, the incidence of colorectal cancer is also increasing, and future trends in this context could also be important. On the contrary, liver cancer, which is presumably caused by co-infection with hepatitis C virus transmitted through blood products, had been the most common malignancy until 2009, but its incidence has decreased thereafter; nevertheless, it would still be considered necessary to monitor the future trends in the incidence of liver cancer. Based on the distribution of CD4 cell counts at the time of onset of malignancy, the incidence of malignancies was higher among patients with lower CD4 cell counts. However, the distribution gradient was small, and the onset of malignancies was not as strongly associated with CD4 cell counts as the onset of opportunistic infections. Furthermore, malignancies mainly developed in patients who were in their 40s or older and were mostly detected after HIV-positive patients had been treated for 1 year or more. This finding suggests that the risk of developing malignancies is not greatly reduced even if the treatment for HIV infection improves CD4 cell counts.
As HIV-positive patients continue to be treated for long periods, they are also more likely to develop malignancies. In the future, HIV-positive patients undergoing treatment, including control with anti-viral therapy and monitoring of metabolic complications, may need to undergo regular screening for early detection of malignancies more frequently than middle-aged and older adults of the general population who undergo outpatient screening.
E．Conclusion
We investigated and characterized the incidence of various malignancies among HIV-positive patients. In addition to the originally high incidence of lung cancer, the incidence of colorectal cancer has been rapidly increasing in recent years; thus, the factors underlying this increase need to be analyzed.
