Overview of cancer incidence and mortality among people living with HIV/AIDS in British Columbia, Canada: Implications for HAART use and NADM development

The advent of combination triple antiretroviral therapy (ART), later referred to as highly active ART (HAART), was found to result in superior patient outcomes and sustained HIV suppression [1, 2]. Reports of remarkable improvements in patient survival and morbidity with the expanded use of the HAART regimen soon followed, ushering in a new era in which HIV/AIDS became viewed as a chronic manageable disease [3‐6]. The longevity experienced by people living with HIV/AIDS (PLWHA) in the modern HAART era has resulted in increasing vulnerability to age-related diseases and new health challenges [7, 8]. The decline in the incidence of AIDS defining malignancies (ADMs) (Kaposi’s sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer) has been accompanied by a dramatic increase in the incidence of non-AIDS defining malignancies (NADMs) [9‐11]. However, the incidence of NADMs amongst PLWHA does not appear to be attributable to age alone, as PLWHA have an increased risk of malignancy compared to age-matched cohorts in the general population. While behavioural differences between HIV-positive and HIV-negative populations must be noted, studies controlling for smoking status found PLWHA to remain at increased risk for lung cancer development when compared to the general population [12, 13]. Furthermore, as well as an increased risk of viral co-infection (such as Hepatitis viruses, Human Papillomaviruses, and the Epstein-Barr virus) [14‐18] and incidence of cancers attributable to these tumor-associated oncogenic viruses, PLWHA also have a higher incidence of cancer types that have no known viral etiology, notably lung cancer [19]. Finally, cancer-related outcomes may vary by HIV serostatus as NADM related mortality is observably higher compared to the general population [20]. Thus, fundamental characteristics reflective of the immune and health status of PLWHA represent important factors that may mediate the differential cancer risk observed in the HIV/AIDS population.

This is amongst the first Canadian studies reporting on NADMs in PLWHA. It also represents one of only a few contemporary reports evaluating cancer risk during the late-HAART era. Our study is uniquely poised because antiretroviral medications are centrally administered and are free of charge in British Columbia, Canada, resulting in a comprehensive population based database of all individuals receiving antiretroviral therapy in the province. Thus, our study captured detailed drug information and reduces confounding bias related to access to care. The objective of this study was to determine the incidence, clinical correlates, and survival outcomes of NADMs amongst PLWHA in British Columbia, Canada, during the HAART era.

The demographic and clinical characteristics of HIV/AIDS patients in the study population are summarized in Table 1. The cohort consisted of 4918 men and women. The median follow-up time was 64 months (Interquartile range (IQR): 32 to 112 months). Study participants were more likely to be men, younger than 50 years, and have a nadir CD4 level lower than 200 cells/mm3. The majority of the study HIV/AIDS population did not have an ADM at the start of the study period upon initiation of antiretroviral therapy. All patients in the study cohort received antiretroviral drug therapy, with the majority of these individuals receiving HAART (combination triple-therapy), and only a few patients receiving non-HAART therapy (mono- or dual-antiretroviral therapy).

This is amongst the first study to report on NADM incidence in a Canadian PLWHA population. The study specifically focused on PLWHA that were receiving treatment during the current HAART era. Outcomes were based on linked, single-payer administrative data from the Bristish Columbia Cancer Registry (BCCR) and the Drug Treatment Program (DTP), which provides a comprehensive analysis of province-wide antiretroviral use and cancer incidence in British Columbia, Canada.

Within our study, 2.95% (145 of 4918) of patients developed a NADM, which represents a significantly higher risk when compared to individuals without HIV/AIDS in the general population (SIR 2.05, CI: 1.73 to 2.41). The types of NADMs most commonly diagnosed in our study population were generally consistent with other reports of HIV/AIDS populations [21‐24]. The increased incidence of lung cancer that we observed in our study population has also been reported by other groups in PLWHA during both the pre-HAART and post-HAART eras [25‐28]. Our study also found a significantly increased incidence of anal cancer in PLWHA when compared to the general population, particularly for males aged 20 to 39 years (SIR 64.55, C.I. 20.98 to 150.66) and aged 40 to 59 years (SIR 8.39, C.I. 5.19 to 12.82). This is a higher incidence than observations made by other groups in which the SIR for development of anal cancer ranged from 6.8 to 10.3 [29, 30]. An increase in lung and anal cancer incidence is known to be associated with shared risk factors, such as increased incidence of smoking in PLWHA [27, 31].

Along with the increased incidence in lung and anal cancers, we also observed that the majority of NADMs were represented by other cancer types, including cancers of the head and neck, liver, rectum, prostate, kidney and lymphatic system. These observations have important implications on screening and treatment protocols for PLWHA. Screening interventions for a variety of cancer types have been proven to be beneficial in the general population, and studies have been encouraging for adoption of specific cancer screening practices for PLWHA [28]. The increased incidence of other cancer types, not just lung and anal cancers, suggests that physician awareness and cancer screening are especially important for PLWHA.

To further address the observed increase in NADMs diagnosed in PLWHA, our study analyzed the association between NADM development, HAART utilization, and host clinical characteristics. Previous studies have hypothesized that HAART utilization is indirectly associated with decreased cancer incidence due to improvement of host immune surveillance and clearance of tumor cells [32]. HAART utilization is also associated with increased survival, which results in a more prolonged time interval for the development of NADMs. Furthermore, in recent years, cancer incidence may also be influenced by intensified screening practices and greater physician awareness of the HIV/AIDS population.

Our current study found that individuals undergoing treatment in the late-HAART era (2000 and later) did not have a significantly decreased incidence of NADM when compared to individuals that began therapy during the early-HAART era (prior to 2000). However, this may be due to the fact that many individuals would have changed treatment regimens during the later HAART era and as such, cannot be simply categorized by the date of initiation. However our work does suggest that although NADM incidence is increased when compared with the general population, the use of more effective and efficient HAART therapy is protective against the development of NADMs in PLWHA through immune reconstitution, and this is also supported by previous research [33‐37]. This observation underscores the importance of early initiation of effective antiretroviral treatment, and implies that NADM incidence may be associated with immunological correlates in the HIV/AIDS population.

To further understand the mechanism by which HAART protects against NADM development, our present study found that a nadir CD4 level > 200 cells/mm³ was also protective against NADM development. Previous research has suggested that a higher percentage time with undetectable HIV RNA was protective against the development of NADMs, highlighting the importance of the host immune system in HIV clearance and NADM development [38]. Therefore, our observed association between CD4 levels and NADM development further supports the concept that HAART utilization may be protective due to its immune-restorative properties. These findings support early initiation of effective HAART therapy in order to maintain high CD4 levels. Furthermore, although the mechanisms that underlie the effects of HAART on the development of NADM in PLWHA are currently poorly understood, our observations suggest the importance of host immunological factors.

Previous studies have also suggested an association between HAART utilization and NADM incidence. In a study by Burgi et al. reporting on a cohort of 4144 HIV-positive individuals treated at military clinics in the United States between 1988 and 2003, the use of HAART was significantly associated with lower rates of NADMs [39]. Furthermore, studies from Australia and Europe have also reported higher CD4 levels and HAART utilization as being protective against NADM development [40, 41]. These reports are consistent with our observation and further suggest that the on-going immune-restorative effects of HAART may be beneficial in reducing the risk of NADM in PLWHA.

In our current study, we also observed that the development of a NADM not only resulted in a significantly reduced survival in PLWHA when compared to PLWHA without a cancer diagnosis, but also a post-cancer survival probability similar to individuals diagnosed with ADMs. The similarity in these survival outcomes suggests similarities in host reactions to all types of malignancies, which could be due to the specific immune factors required to clear the cancer cells. This would suggest that regardless of whether a cancer diagnosed in PLWHA is an ADM or NADM, protection against its development is impacted by adequate immune function, and therefore importantly mediated by HAART therapy.

The current study had several limitations, many of which are a consequence of its retrospective design. Evaluation of the number of NADMs and ADMs is highly dependent upon the accurate reporting of cancer in the provincial database. Furthermore, attempts to evaluate the impact of HAART on NADM diagnosis, represented by the absence or presence of HAART as well as the start date of antiretroviral treatment, are also potentially confounded by the changes that occurred in treatments over time. Moreover, there is considerable heterogeneity across NADM, and over time, and it can be difficult to infer direct clinical benefits of HAART uptake from epidemiological trends, although we suggest that overall we see a positive association between higher CD4 cell counts and cancer incidence. Conversely, there are notable differences between individuals receiving HAART therapy compared to individuals receiving mono−/dual- antiretroviral treatment, as we have controlled for duration of HIV infection but are unable to control for varying effects of therapeutic changes over time. Furthermore, age and CD4 level were included in the multivariate modeling as an objective measure of the health status of the study population.

The current study provides a contemporary overview of cancer risk in a large population of PLWHA during the HAART era. Currently, NADMs are an important cause of morbidity in PLWHA. Utilization of HAART and its associated improved immune-restoration may be beneficial for these individuals. Unquestionably, the development of more effective cancer screening and prevention practices, that are not limited to anal and lung cancers, will be important in the future. Further study of cancer epidemiology in PLWHA is important and will lead to the development of strategies that improve outcomes for this unique population.