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
Non-AIDS-defining malignancies
associated with HIV infection
- 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)

Abstract

To elucidate the current status of non-acquired immunodeficiency syndrome (AIDS)-defining malignancies in patients infected with human immunodeficiency virus (HIV), a questionnaire survey was conducted in HIV core hospitals. In 2017, malignancies were diagnosed in 96 patients. This number was larger than that in the previous year (47 patients in 2016). Based on the cumulative data up to the time of the survey, lung cancer was the most common, followed by gastric cancer, colorectal cancer, liver cancer, anal tumors, and leukemia in the descending order. The incidence rates of head and neck tumors and throat tumors were also high. Although the incidence rate of lung cancer had been decreasing since 2010, it increased again in 2017. Likewise, the incidence rate of colorectal cancer decreased in 2016 but increased again in 2017. Although more patients had low CD4 cell counts at the onset of malignancies, the distribution of CD4 cell counts was relatively even. There were even patients with high CD4 cell counts who developed malignancies. This greatly differed from the distribution of CD4 cell counts at the time of diagnosis of opportunistic complications. The most common age at the onset of malignancies was 60 to 69 years. Malignancies occurred at 1 year or more after the diagnosis of HIV infection in approximately 3/4 of the patients. The post-treatment complete/partial remission rate was 55%. The present study suggests that the long-term follow-up of HIV-positive patients should include regular monitoring with consideration for the development of malignancies and patient education for smoking cessation with consideration for the risk of lung cancer.

A.Objective

For the treatment of infection with human immunodeficiency virus (HIV), longer-term health management has been recognized as an important issue, based on the accumulated data on early initiation of anti-retroviral therapy (ART) and daily management procedures. As part of this issue, the development of malignancies is considered as a problem. Since the incidence rates of malignancies were reported to be high in HIV-positive patients, the study group on opportunistic infections of the Ministry of Health, Labour and Welfare has also monitored the trend of the development of non-acquired immunodeficiency syndrome (AIDS)-defining malignancies. The study group found a slightly higher incidence rate of non-AIDS-defining malignancies in HIV-positive patients and a discrepancy in the incidence rates of monitored malignancies between HIV-positive patients and the general Japanese population. These findings have prompted research activities on leukemia and other malignancies. Because the data accumulated on the development of malignancies by the present study are the only source that informs the nationwide trend of the development, we designed the 2018 study to investigate non-AIDS-defining malignancies occurring in 2017, in addition to the trend of the development of opportunistic infections complicating HIV infection.

B.Methods

Because HIV infection is preferentially treated in HIV/AIDS core hospitals in Japan, the present study was conducted by sending questionnaire forms to these hospitals and requesting them to complete the forms. The questionnaire form for monitoring of malignancies (PDFAppendix 2 [in Japanese])was enclosed with the questionnaire form used in the epidemiological study on HIV-associated opportunistic complications and sent to HIV core hospitals to request responses. The data between 1995 and 2006 had been accumulated through previous studies. Therefore, we have collected data since 2007. For the present study, we requested the hospitals to report cases of malignancies diagnosed in 2017.

In the present study, the primary objective was to elucidate the current status of the development of malignancies through cooperation of as many hospitals as possible. The questionnaire items were designed to be as simple as possible and kept to the minimum necessary, so that the questionnaire could be completed without detailed review of medical records of each patient. Attention was paid to improve the recovery rate of the questionnaires. Consequently, this approach slightly compromised the ability to elucidate the details of each malignancy. The return sheets were enclosed with the questionnaire forms. To determine the accurate recovery rate, we requested hospitals without any relevant cases to report the lack of data by using these sheets. The collected data were compiled in a database using Microsoft Access. In this process, to exclude duplicate cases spanning across years reported by the same hospital and duplicate cases reported by referring and referral hospitals, cases containing identical data on the year of birth, disease name, year of onset, region of the reporting hospital, 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 diseases, were excluded from the aggregated data. In addition, data on benign tumors reported by some hospitals were also excluded. The collected data were compared with the latest cancer statistics data in Japan (2013) 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 the general population and HIV-positive patients. The present study was conducted in compliance with the Ethical Guidelines for Medical Research in Humans (partially revised on December 22, 2017), and the ethics committee of Nagasaki University Graduate School of Biomedical Sciences reviewed and approved the study. To meet the requirements to accept data requests from other institutions as specified in the ethical guidelines for epidemiological studies, the following considerations were made: To prevent the data analysis center from collecting personal information on patients, questions about personal information were omitted from the questionnaires, and the hospitals were instructed not to provide personal information including patient identification on the questionnaire forms. Although the collected data were anonymized, they contain information on HIV-positive patients. Thus, the data were handled with due care and analyzed in a controlled laboratory environment where only the study investigators could handle them.

C.Results

In 2017, 96 malignancy cases were reported, and the cumulative number of reported cases increased to 625. According to the annual number of reported cases (Figure 1), the incidence of non-AIDS-defining malignancies substantially increased to 8 cases in 2000 and then tended to increase each year afterward. While the incidence fluctuated, there were 52 cases in 2015 and 47 cases in 2016. Although the incidence remained constant for the previous few years, the largest number of cases was reported in 2017.

Because of the great influence of year-to-year fluctuations, we calculated the mean number of malignancy cases per year and the prevalence per 100,000 people from the data covering a 2-year period from 2016 to 2017. Because the present study was a questionnaire survey, the case capture rate was calculated by comparing the number of concurrently reported cases of opportunistic infections and the number of AIDS cases reported by the AIDS Surveillance Committee (76.1%). On the assumption that the current number of surviving HIV-positive patients was approximately 27,800, the prevalence per 100,000 people was calculated to be 356.9. The age-adjusted prevalence, calculated based on the model population in 1985, was 538.68 per 100,000 people. This was 1.51 times as high as the cancer prevalence (including carcinoma in situ) of 354.6 in the Japanese in 2014.


Figure 1. Annual number of cases of non-AIDS-defining malignancies

The cumulative number of reported cases of malignancies is shown in Figure 2. The most frequent malignancy is lung cancer, which had been reported in a cumulative number of 96 cases. Liver cancer had been the most frequent malignancy until 2009, but its incidence decreased thereafter. On the other hand, lung cancer showed an increase to 11 cases and was ranked in the first place in 2010. Although reported cases have been decreasing since then, lung cancer has remained the most frequent malignancy in terms of the cumulative number. The second most frequent malignancy is gastric cancer and colorectal cancer, followed by liver cancer. The malignancies that followed after this in the descending order are anal tumors, leukemia, head and neck cancer, and throat tumors. In 2017 alone, there were 10 cases of lung cancer, 12 cases of colorectal cancer, 11 cases of liver cancer, 7 cases of gastric cancer, 7 cases of anal tumors, 3 cases of head and neck cancer, and 1 case of throat tumor (Figure 3). The chart showing changes in the annual incidence of the 8 major malignancies (Figure 3) displays a particularly noticeable sharp increase in colorectal cancer cases since 2009 . The incidence of liver cancer peaked at 6 cases in 2006 and decreased thereafter. Although the annual incidence had remained between 1 to 4 cases for the previous few years, it increased to 11 cases in 2017. Based on changes in the annual incidence of malignancies by HIV infection route (Figure 4), homosexual transmission of HIV was associated with the highest incidence of malignancies. Regarding the characteristics of malignancies by HIV infection route (Figure 5), liver cancer cases remarkably accounted for approximately 50% of the cases of iatrogenic infection (mainly infection in patients with hemophilia caused by blood coagulation factor products). In patients with homosexual transmission of HIV, the incidence of lung cancer, colorectal cancer, gastric cancer, anal cancer, and head and neck cancer was characteristically high. The incidence of lung cancer was high regardless of infection routes. According to the distribution of peripheral CD4 cell counts at the onset of malignancies (Figure 6), there were more patients as the CD4 cell count was lower. However, the differences in the number of patients with malignancies were smaller than those in the number of patients with opportunistic infections (Figure 7). The same trend of the distribution of peripheral CD4 cell counts was observed in patients who developed malignancies in 2017.


Figure 2. Number of reported cases of 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 the diagnosis of opportunistic complications

Figure 8 shows the distribution of CD4 cells by major malignancies. Regardless of malignancy types, CD4 cells were widely distributed, and there was no uneven distribution of CD4 cells to particular malignancies. The most common age at the onset of malignancies (Figure 9) was 60-69 years. The incidence of malignancies was high in older HIV-positive patients, as evidenced by 12 cases reported even in the small population of HIV-positive patients in their 80s. Compared with the age at the onset of opportunistic infection, which appears to be close to the age at the time of detection of HIV infection, the age at the onset of malignancies was apparently shifted to higher age groups. Based on the age distributions by HIV infection route (Figure 10), patients with iatrogenic infection tended to develop malignancies at younger ages than those with heterosexual or homosexual transmission of HIV. In addition, based on the age distributions by malignancy type (Figure 11), testicular tumors tended to develop at younger ages. As for the time to the onset of malignancies (Figure 12), more than 70% of all HIV-positive patients developed malignancies at 1 year or more after the diagnosis of HIV infection, which contrasted with the time to the onset of opportunistic infections. More than 80% developed opportunistic infections within 3 months (including simultaneously detected cases). This revealed that malignancies develop some time after the diagnosis of HIV infection. As for the outcomes of HIV-positive patients with malignancies (Figure 13), 55% of them achieved complete/partial remission. Among malignancy types, the highest mortality rate (Figure 14)was observed for pancreatic cancer, which is inherently associated with poor prognosis, followed by lung cancer, throat cancer, esophageal cancer, and leukemia.


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 by infection route at the onset of malignancies


Figure 11. Age distribution by malignancy type at the onset of malignancies


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

The ART introduction has allowed HIV-positive patients to remain in a stable condition for a long time; consequently, the development of malignancies among them has become an issue. The present study was initiated to address this issue. It revealed that the incidence of non-AIDS-defining malignancies in HIV-positive patients has been increasing yearly also in Japan. According to preceding studies, the prevalence of malignancies in HIV-positive patients tended to be higher than that in the Japanese general population. The present study also revealed that the age-adjusted prevalence of malignancies in HIV-positive patients in 2016 through 2017 was 1.51 times as high as the corresponding prevalence calculated based on the model population in 1985. Given that some AIDS-defining diseases, 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. Meanwhile, because the effects of HIV infection become evident after some time has passed after HIV infection, long-term monitoring may be necessary. The distribution of malignancies observed in HIV-positive patients was clearly different from that in the general Japanese population and was characterized by higher incidences of lung cancer, liver cancer, leukemia, head and neck cancer, throat tumors, anal cancer, and testicular tumors. Liver cancer has been suggested to be affected by concomitant hepatitis C and B, and anal cancer has been suggested to be associated with human papillomavirus. In contrast, no association has been demonstrated between lung cancer and viral infection. Particularly, a high prevalence of leukemia is characteristic in Japan. All subtypes of leukemia, including myeloid, lymphoid, acute, and chronic types, have been observed, and there are no differences in characteristics among them. The annual incidence of 8 major malignancies shows that a sharp increase in the incidence of lung cancer has been noticeable for the previous few years. Despite the lack of definitive data, HIV-positive patients may be highly likely to be predisposed to factors for developing lung cancer, such as smoking. Thus, promotion of smoking cessation in HIV-positive patients presumably becomes an important issue in the future. Furthermore, the incidence of colorectal cancer has been increasing, and the future trend seems to be an important issue. On the other hand, liver cancer, which was presumably related to the co-infection with hepatitis C virus transmitted through blood products, had been the most frequent malignancy until 2009, but its incidence decreased afterwards. It also seems that the future trend of the incidence of liver cancer should be monitored. Although the incidence of malignancies was higher in patients with a lower CD4 cell count at the onset of malignancies, the distribution of CD4 cell counts was relatively even. The onset of malignancies was not as strongly associated with CD4 cell counts as the onset of opportunistic infections. As for age at the onset of malignancies, malignancies developed mainly in HIV-positive patients 40 years of age and older. In addition, malignancies were mostly detected at 1 year or more after the diagnosis of HIV infection. Even if the treatment of HIV infection reduces CD4 cell counts, the risk of developing malignancies will not be reduced substantially. As treatment is prolonged, HIV-positive patients will develop malignancies. In the future treatment of HIV infection, which includes control of anti-viral therapy and monitoring for metabolic complications, regular screening for early detection of malignancies may be required at a greater extent than in routine outpatient care for middle-aged and older individuals.

E.Conclusion

We investigated and characterized the incidence of malignancies in 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. The factors for this increase need to be analyzed.