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 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)

Abstract

To investigate the current status of non-AIDS-defining malignancies among HIV-infected patients in Japan, a survey was conducted among Japanese HIV core hospitals. In 2016, 47 HIV patients were diagnosed with malignancies, a decrease from the 52 patients noted in the preceding year. In HIV patients, the malignancy with the highest cumulative incidence was lung cancer, followed by gastric cancer, colorectal cancer, liver cancer, leukemia, and anal tumors; head and neck tumors and throat tumors were also common. The cumulative lung cancer incidence was found to have been decreasing since 2010. The incidence of colorectal cancer substantially increased in 2013; however, it decreased in 2016. Analysis of CD4 expression at the time of tumor onset showed more cases with lower levels of CD4 expression, whereas some cases showed high CD4 expression, demonstrating a substantially different distribution compared to that at the time of diagnosis for opportunistic complications. The median and mode of the ages at tumor onset were 50-59 and 60-69 years, respectively. Regarding time to tumor onset, about 75% of HIV patients were diagnosed with a malignancy more than 1 year after HIV diagnosis. The post-treatment completion and partial remission rate was 55%. Our data suggest that the long-term follow-up of HIV-positive patients should include regular malignancy monitoring and patient education for smoking cessation to minimize lung cancer risk.

A.Objective

The early introduction of anti-retroviral therapy (ART) and accumulating daily management procedures has made longer-term health management an important component of care for HIV carriers. However, since the high incidence of malignancy in this population was first reported, the study group on opportunistic infections of the Ministry of Health, Labour and Welfare (MHLW) has monitored the trend of non-AIDS-defining malignancies in HIV patients. This data showed an increased incidence for non-AIDS-defining malignancies among HIV carriers and a discrepancy in the incidence of monitored tumors between HIV carriers and the general Japanese population, which stimulated research activities on leukemia and other malignancies in the HIV patient population. Since this data is currently the only source to inform the nationwide trend of malignancies in this population, we designed the 2017 study to monitor non-AIDS-defining malignancies diagnosed in 2016 and the trend of HIV-associated opportunistic infections.

B.Methods

In Japan, HIV infection is preferentially treated in HIV/AIDS core hospitals. Therefore, in the current study, we sent questionnaires to these hospitals consisting of an epidemiological survey of HIV-associated opportunistic complications and malignancy (PDFAppendix 3 [in Japanese]). As the data between 1995 and 2006 were accumulated through previous studies, we have collected data since 2007. Additionally, in the year of this study, we requested the hospitals to submit information about the malignancy cases diagnosed in 2016.

To maximize the response recovery rate, questionnaire items were designed to be simple and the number of questions was minimized to limit physician review of patient medical records. However, this compromised the level of detail for characterizing each malignancy. We provided a return sheet for hospitals that encountered no malignancy cases. The recouped data were converted to a database using Microsoft Access for summarization. To avoid double entries from the same hospital in different years or from referring and referral hospitals, patient data with identical information—including year of birth, diagnosis, year of onset and region of the reporting hospital—were considered overlapping data and integrated into one patient sample. Diseases challenging to differentiate from AIDS-defining diseases—such as non-Hodgkin's lymphoma, brain lymphoma, cervical cancer, and Kaposi's sarcoma—a benign tumor data were also excluded from the analysis. The obtained data were compared with the updated cancer statistics data in Japan (2013) available on the website of the Center for Cancer Control and Information Services at the National Cancer Center to compare the malignancy prevalence between the general population and HIV carriers. This study was conducted in compliance with the Ethical Guidelines for Medical Research in Humans (partially revised on December 22, 2017) and with approval by the ethics committee at Nagasaki University Graduate School of Biomedical Sciences. Considerations were made to prevent the data analysis center from collecting patients’ personal information by omitting questions about personal information on the questionnaire form and instructing respondents not to write down their patient IDs or other personal data on the form and to meet the requirements to accept data requests from other hospitals as specified in the ethical guidelines for epidemiological studies. The collected data—which were anonymized but still contained information about HIV carriers—were handled and maintained in a controlled laboratory environment where only the study investigators had access to the data.

C.Results

In 2016, a total of 47 malignancy cases were reported, which increased the total number of reported cases to 527. When considering the annual incidence data (Fig. 1), the number of reported cases for non-AIDS-defining malignancies substantially increased to 8 in 2000, gradually increased thereafter, and reached 52 in 2012—the largest annual number recorded. The number of cases per year has remained almost stable with some fluctuations for the last few years—52 in 2015 and 47 in 2016.


Figure 1. Number of reported cases of non-AIDS-defining malignancies in each year

To minimize the 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 2-year data from 2013 and 2014. Since this was a questionnaire survey, the case capture rate was determined by comparing the number of cases of opportunistic infections reported concurrently and the number of AIDS cases reported by the AIDS Surveillance Committee (83.7%). Assuming that the current number of surviving HIV carriers is about 25,200, the prevalence per 100,000 people was calculated to be 215.7. The age-adjusted prevalence, calculated based on the model population in 1985, was 377.9 per 100,000 people. This is 0.91 times the prevalence of cancer (including carcinoma in situ) in the Japanese population for 2012 (414 cases).

The cumulative number of malignancy cases reported is shown in Fig. 2. The most frequent tumor type was lung cancer (86 cases). Liver cancer had been the most frequent until 2009 and decreased thereafter. By comparison, the number of reported cases of lung cancer increased to 11, which ranked in first place in 2010. Since then, lung cancer has remained the most prevalent disease by cumulative incidence though the number of incidences has declined annually. The second most prevalent malignancy was gastric cancer, followed by colorectal cancer, liver cancer, leukemia, anal tumors, head and neck tumors, and throat tumors. In 2016, there were 5 cases of lung cancer, 2 cases of gastric cancer, 6 cases of colorectal cancer, 3 cases of liver cancer, 1 case of leukemia, 1 case of anal tumor, 5 cases of head and neck tumor, and 3 cases of throat tumor (Fig. 3). The annual incidence chart for these 8 diseases (Fig. 3) shows a sharp increase in colorectal cancer from 2009 onward. Liver cancer reached a peak in 2006 (6 cases) and declined thereafter; the number has remained between 1 and 4 incidences for the last several years. The analysis of the annual incidence of malignancy and HIV infection route (Fig. 4) showed that homosexual transmission of HIV was associated with the highest incidence of malignancy. Analysis for malignancy type and HIV infection route (Fig. 5) showed that liver cancer accounted for about 60% of all malignancies associated with iatrogenic infection (mostly in hemophilia patients through blood coagulation factor products). Additionally, anal cancer, head and neck cancer, throat tumor, and testicular tumor were common in patients with homosexual transmission of HIV infection. Regardless of infection route, lung cancer and leukemia had high incidences in HIV patients. At the time of tumor onset, HIV patients had lower numbers of CD4-positive cells (Fig. 6), although the slope was more gradual than that for opportunistic infections (Fig. 7). The same trend in CD4-positive cells was observed for patients diagnosed with malignancies in 2016.


Figure 2. Number of reported cases of AIDS-defining malignancies, classified by disease


Figure 3. Annual change in the number of reported cases of major tumor types


Figure 4. Annual incidence of malignancies, classified by infection route


Figure 5. Incidence of malignancies, classified by infection route


Figure 6. Distribution of the number of CD4 cells at the time of tumor onset


Figure 7. Distribution of the number of CD4 cells at the time of diagnosis of opportunistic complications

Figure 8 shows the prevalence of CD4-positive cells among major malignancies, revealing that CD4-positive cells were widely distributed regardless of tumor type, with no biased distribution in particular tumor types. The median and mode ages at tumor onset were 50-59 and 60-69 years, respectively (Fig. 9). A higher incidence of malignancy was reported in older age groups, as evidenced by 10 cases reported in HIV patients aged 80 years and older, which is a minor age group for HIV carriers. Compared with the age at opportunistic infection onset, which appears near the age of HIV infection diagnosis, the distribution of tumor onset age was clearly shifted toward higher age groups. When analyzing the age distribution by HIV infection route (Fig. 10), it appeared that patients with iatrogenic HIV infection developed malignancy at younger ages compared to those with heterosexual or homosexual infection. Analyzing the age distribution by tumor type (Fig. 11) shows that testicular tumors tend to occur at younger ages in HIV patients. As for time to tumor onset (Fig. 12), more than 70% of HIV patients developed malignancies more than 1 year after HIV diagnosis, in contrast to opportunistic infections, which occurred within 3 months after diagnosis in more than 80% of HIV patients, including simultaneously diagnosed cases. This indicates that tumor onset occurs following HIV diagnosis. As for the outcome of HIV patients with tumors (Fig. 13), 55% achieved complete or partial remission. When considering the mortality by tumor type (Fig. 14), the highest mortality was observed for pancreatic cancer—generally associated with poor prognosis—followed by throat cancer, lung cancer, esophageal cancer, and leukemia.


Figure 8. Distribution of the number of CD4 cells at the time of tumor onset, classified by disease


Figure 9. Distribution of age at tumor onset


Figure 10. Distribution of age at tumor onset, classified by infection route


Figure 11. Distribution of age at tumor onset, classified by tumor type


Figure 12. Time from HIV diagnosis to tumor onset


Figure 13. Outcome of malignancies


Figure 14. Mortality rates by tumor type

D.Discussion

The introduction of ART has enabled stable long-term prognosis for HIV-positive patients, which has led to an increased incidence of malignancy among HIV patients. In Japan, evidence has also revealed a year-by-year increase in the incidence of non-AIDS-defining malignancies among HIV carriers. Consistent with previous finding that the tumor prevalence in HIV patients was higher than the general Japanese population, the present study also revealed that the mean age-adjusted tumor prevalence in HIV carriers in 2015-2016 was 1.31 times the corresponding prevalence in the general Japanese population. Given that some AIDS-defining diseases—including malignant lymphoma, cervical cancer, and Kaposi’s sarcoma—were excluded from the present analysis, it is possible that the actual incidence of malignancy in this population is even higher. Importantly, a longer-term follow-up is needed to evaluate the effect of HIV infection as it takes some time before the effects become evident. The distribution of reported malignancies in HIV patients was clearly different from the general Japanese population and characterized by higher frequencies of lung cancer, liver cancer, leukemia, head and neck cancer, throat tumor, anal tumor, and testicular tumor. While evidence has suggested associations between liver cancer and coexisting hepatitis C/B as well as between anal cancer and human papillomavirus, no association with viral infection has been demonstrated for lung cancer. The high prevalence of leukemia is especially specific to Japan; all subtypes of leukemia were observed, including myeloid, lymphoid, acute, and chronic. Analyzing the annual incidence of 8 major malignancies revealed a sharp increase in lung cancer during the last several years. Although no definitive data are available, it is possible that HIV carriers have more predisposing factors for lung cancer, such as smoking. Thus, smoking cessation should be promoted among HIV carriers. The prevalence of colorectal cancer has also been increasing in the HIV patient population and should, therefore, be monitored continuously. In contrast, the incidence of liver cancer—likely related to the co-infection of hepatitis C virus transmitted through blood products—has been decreasing after reaching a peak (6 cases) in 2006; still, since 4 cases were reported in 2015, there is a need for continuous monitoring of liver cancer in HIV patients. When considering the distribution of CD4-positive cells at the time of tumor onset, there were more cases with lower numbers of CD4-positive cells in HIV carriers than in the general Japanese population; however, the slope was gradual and the correlation between incidence and CD4 expression as observed for opportunistic infections was not strong. In terms of age, the largest proportion of patients were age 40 or older. Moreover, in most cases, malignancies were detected in HIV patients who were followed for more than 1 year after HIV diagnosis. These observations suggest that the reductions in CD4-positive cells related to HIV treatment do not substantially reduce the risk for malignancy development. Therefore, in clinical care for HIV carriers, in addition to controlling anti-viral therapy and patient monitoring for metabolic complications, regular screening aimed at the early detection of malignancies is recommended to a greater degree than in routine outpatient care for middle-aged and older individuals.

E.Conclusion

We investigated the incidence of malignancy and the associated cancer types among HIV carriers in Japan. In addition to the continuous high annual incidence of lung cancer, our data showed a rapid increase in colorectal cancer in recent years, suggesting the need for further analysis to determine the associated factors in HIV patients.