Discussion
The main findings of this study, comprising a Japanese cohort of 28 089 PLWH (male 91.9%) taking ART from 2009 to 2019, are as follows: the cumulative burden of vascular disease and AIDS-defining cancers increased with age, with the incidence of AIDS-defining cancers being 6.4% for non-Hodgkin lymphoma and 1.1% for bronchus or lung cancer. At the end of 2019, the total number of patients in Japan with HIV infection reported under the Infectious Diseases Control Law and people diagnosed with AIDS at the time of their initial report was 31 385 (male 95.1%). This is the first report of comorbidities and co-medications in a nationwide Japanese cohort.
Similar changes in the spectrum of the burden of chronic comorbidities were observed in PLWH, as in our previous study of fewer subjects, with chronic comorbidities common in HIV populations, and the cumulative burden of vascular disease and non-AIDS-defining cancer increasing with age. Recent population-based cohort studies in different countries have also reported greater numbers of comorbidities in older PLWH.[18–20] A study in Canada (2021) found an excess burden of age-associated comorbidities in PLWH, with a higher prevalence of comorbidities and earlier ages at diagnosis compared with HIV-negative individuals.[18] In France (2020), non-HIV-related comorbidities were more common among PLWH than among matched non-HIV controls.[19] In the BESIDE study in Germany (2020),[20] the prevalence of comorbidities and use of co-medications remained consistently high, increasing across age groups and highlighting the complexity of treating older PLWH. In Switzerland and the US, older PLWH, when compared with younger patients, were more likely to have diabetes mellitus, cardiovascular diseases, non-AIDS-defining malignancies, osteoporosis, liver diseases and chronic kidney disease.[2,3,21]
The cumulative incidence of the AIDS-defining cancer Kaposi sarcoma in a North American cohort study (2015) was 4.1%, and that of non-Hodgkin lymphoma was 4.0% by age 75 years.[22] The prevalence was much lower than that reported in a previous Japanese study of autopsied PLWH who had received ART from 1985 to 2012, being 37.9% and 15.2% for non-Hodgkin lymphoma and Kaposi sarcoma, respectively.[23] This discrepancy is probably attributed to the different study populations, particularly the fact that autopsied patients are usually examined in more detail because of greater acuity than in the PLWH study population. In addition, this study population represents PLWH in the current ART era, which is noted for improved immune function. It is possible that the incidence of non-Hodgkin lymphoma and Kaposi sarcoma in PLWH has decreased due to effective ART.[24]
In the present study, non-AIDS-defining cancers accounted for 50.5% of all malignancies, with approximately 30% of non-AIDS-defining cancers observed in patients aged ≥ 70 years compared with < 10% in patients aged < 40 years, confirming the previous finding by Ruzicka et al.[14,15] that non-AIDS-defining cancers were more frequent in PLWH aged ≥ 60 years. Increases in non-AIDS-defining cancers among the HIV population appear to be a consequence of ageing in the AIDS population.[24] Given these previous findings, the present results highlight the importance of non-AIDS-defining cancers among elderly PLWH as a result of their extended life spans.
A 2013 study by Holtzman et al.[25] reported that 32% of patients aged < 50 years and 54% of patients aged ≥ 50 years used five or more co-medications. In another study, 47.6% of PLWH aged ≥ 70 years used five or more co-medications.[14] The proportions on co-medications were smaller in the present study. Although the result of co-medication in PLWH in the present study showed that younger PLWH used fewer co-medications than older PLWH, the use of co-medications was common across all age groups. These results further support the view that the treatment strategies for HIV and comorbidities in PLWH could be complicated by drug–drug interactions.[20,26]
Limitations of This Study
The present study has several limitations. Cross-sectional design cannot infer causality, which limited the ability to draw a conclusion about a causal relationship. A more rigorous longitudinally designed study is needed to show causality between HIV infection and comorbidities and/or co-medications. Patients without records of ART were excluded, even though a certain proportion of PLWH do not receive ART. Homelessness is not a disease classification in Japan, and thus the prevalence of HIV in homeless people, and the effect of lack of housing on delays to HIV care or treatment were not examined in this study. Potential relationships between chronic comorbidities and CD4 count, HIV-RNA or ART duration could not be analysed due to a lack of sufficient detailed data regarding HIV infection status. Stigma against women and bisexual men in Japan may possibly lead to some under-reporting, but the proportion is likely to be minor as, according to a report by Iwamoto et al.,[27] 85.6% of the PLWH population in Japan has been diagnosed with HIV.
Despite these limitations, the critical strength of this study is that it is a cohort study using a national database that stores electronic claims for > 99.9% of hospitals in Japan. The NDBis a database in which Japanese insurance claims data and specific health check-up data are stored. It has been managed since 2009 by the Ministry of Health, Labour and Welfare, and has been widely used for public research since 2011. The NDB claims data include essentially every insured citizen in Japan. Japan's universal healthcare coverage system consists of national health insurance for most employees, the self-employed and unemployed individuals and a medical care system for the elderly in the latter stage of life, including individuals aged 75 and older and those aged 65 and older with certified disabilities. The NDB stores data for 99.9% of hospitals in Japan and is one of the largest databases in the world, recording more than 1.6 billion electronic claims annually. The database includes hospital identification codes, hospital types and comprehensive patient data, including admission and discharge status, diagnoses, drugs and procedures used. A recent review of studies using the database shows extensive study across various disease entities.[28,29] Therefore, we are confident that the present study provides a comprehensive sample of PLWH nationwide in Japan.
HIV Medicine. 2022;23(5):485-493. © 2022 Blackwell Publishing
