Background
In high-income settings, HIV infection has become a chronic manageable condition [
1]. Overall, HIV/AIDS associated morbidity and mortality has decreased to unprecedented levels, largely due to the widespread use of combination antiretroviral therapy (ART) [
2]. People living with HIV/AIDS (PLW-HIV) now have life expectancies comparable to those observed in the general population, although variability between sub-groups remain [
3]. Despite successful treatment-mediated viral suppression, premature morbidity and mortality due to non-AIDS related infectious and non-infectious comorbidities are increasingly prevalent, raising new challenges for healthcare providers and health systems [
4].
Globally, the hepatitis C virus (HCV) has become one of the most prevalent co-infection among PLW-HIV [
5]. Indeed, HCV mortality has surpassed that of all other reportable infectious diseases together, including AIDS and tuberculosis, in the United States [
6]. According to a recent meta-analysis, the prevalence of both HIV and HCV is the highest (82%) among people who inject drugs (PWID) [
5]. In Canada, similar to the United States, 20% to 30% of PLW-HIV are also living with HCV, while the prevalence of both viruses among PWID ranges between 50% and 90% [
7‐
9]. In addition, the presence of both viruses has been shown to increase the risk for clinical progression of HIV as well as premature mortality (despite ART), and accelerated progression of HCV-associated liver diseases [
10,
11].
Enhanced immunosenescence, resulting from HIV infection via persistent inflammatory activity and immune activation, is associated with increased morbidity and mortality [
12,
13]. It is becoming increasingly evident that HCV infection also contributes to systemic immunosenescence [
14‐
16]. Of note, HCV-related disease burden is not restricted to the liver; it extends to several conditions (immune-mediated or activated by chronic inflammation) impacting extrahepatic organs/tissues [
17]. Additionally, life-style factors, socio-economic constraints, and inadequate engagement in care tend to exacerbate other comorbid conditions, further complicating clinical outcomes among some subgroups of PLW-HIV, particularly those co-infected with HCV [
18,
19].
To date, a large number of people living with HIV and HCV (PLW-HIV/HCV) have no or limited access to HCV treatment. However, very recently, the healthcare landscape in British Columbia (BC), Canada, has been rapidly transforming with the advent of highly efficacious and tolerated HCV direct-acting antiviral therapies, resulting in a steady increase in the number of individuals accessing this life-saving therapy [
20,
21]. Still, there are barriers for accessing healthcare services and programs for those afflicted by these diseases that need to be identified, particularly among those who are marginalized and vulnerable in the population [
20].
Thus, the main objective of this study was to characterize the trends in healthcare-related visits (HRV) of PLW-HIV and PLW-HIV/HCV, in BC. Additionally, we aimed at identifying modifiable risk factors, associated with the highest HRV rates over time that could be targeted as potential means to minimize the disease burden of this population and on the healthcare system.
Discussion
This population-based cohort study adds to the growing body of evidence indicating that PLW-HIV/HCV incur significantly greater HRV rates relative to those only living with HIV [
42‐
44]. It is worth noting that although PLW-HIV/HCV experienced an 18% higher rate relative to PLW-HIV, we observed a decrease in HRV rates over time among both groups, even after controlling for several confounders including disease severity and the cohort effect. Apart from HCV infection, the excess in HRV rates among PLW-HIV/HCV were at least partially attributable to the fact that these individuals had a history of injection drug use, presented later for HIV treatment, had sub-optimal adherence to ART and had higher prevalence of comorbidities.
To understand the reason behind the decreasing rates over time, the reader should be aware that the study period encompasses three phases of BC’s response to HIV/AIDS: the harm reduction and health service scale-up phase (2000–2005); the early Treatment as Prevention phase (2006–2009); and the STOP HIV/AIDS phase (2010-present), during which BC’s HIV therapeutic guidelines recommended ART treatment for all adults with HIV infection, regardless CD4 count [
45,
46]. Throughout these phases, various HIV care initiatives have been implemented and may have attenuated the healthcare-related utilization of this population. Namely, the evolving deployment of biomedical and health service interventions (e.g., the development of improved antiretroviral drugs, substance use treatment, and medication adherence support) and structural interventions (e.g., legal and policy), which have been comprehensive described elsewhere [
45].
We should also note that both groups of individuals were linked to HIV care and receiving treatment. Most likely, if people only living with HCV were included in this analysis, we would see that these trends, in this same period, did not decrease given that, in BC, most of these individuals are not fully engaged into care. In addition, given the recent approval for use of safer, more tolerable and efficacious interferon-free direct acting antivirals-based HCV therapy, going forward, these trends will likely change, particularly for specialist-related visits as they will be the ones mainly prescribing these medications and following these individuals. Thus, there is a need for continued monitoring and evaluation of HRV among PLW-HIV/HCV, especially since in 2017, the BC Ministry of Health has announced a province-wide expansion of HCV treatment to all of those living with HCV starting in March 2018 [
21].
The persisting disparity in HRV rates observed among PLW-HIV and PLW-HIV/HCV clearly indicates that there is a critical need for interventions that may attenuate the risk of requiring higher resource use for care among those living with both viruses. Additionally, any successful strategy to attenuate the utilization of PLW-HIV/HCV will require significant levels of treatment uptake and adherence, especially among PWID (including PLW-HIV/HCV). Our data also suggest that addressing the underlying substance use disorder may be beneficial in this regard. Furthermore, doing so would also contribute to preventing HCV reinfection, which would greatly enhance the individual and societal impact of interferon-free direct acting antivirals-based HCV therapy [
47‐
49]. On that note, several clinical models have proved to be successful in this regard by combining services aimed to address viral hepatitis and HIV, substance use detoxification, opioid substitution, and primary care in low threshold environment, coupled with comprehensive and integrated multidisciplinary teams of health care professionals including treaters, nurses, substance use and behavioral health service providers, as well as other social support services [
48]. In 2016, the BC Centre for Excellence in HIV/AIDS launched a province-wide monitoring and evaluation strategy, which will address the health needs of those living with or at risk of HCV infection, including those also living with HIV [
50,
51]. The key aims of this program include the normalization of HCV testing, especially among those at higher risk; support to facilitate access to HCV and substance use treatment; extensive deployment of harm reduction strategies; and strengthening of educational programs to treat and care for this population.
The implications of HIV/HCV co-infection in the context of a rapidly expanding population of aging PLW-HIV are important, particularly at a time when meeting health demands in BC, and in other high-resource settings, is becoming exceedingly challenging amid fiscal constraints [
52]. As PLW-HIV live longer and non-AIDS-related comorbidities continue to rise, the impact of HIV/HCV co-infection will be increasingly relevant, both from a clinical perspective and a health systems perspective. Chronic HCV infection among PLW-HIV may have contributed to the exacerbation of progressive immunosenescence, and it may be associated with premature morbidity and mortality manifested by the development of multiple comorbidities (as observed in this study) [
16,
53], further contributing to increased financial strain on healthcare systems.
The findings of the present study should be interpreted in light of several limitations. First, HIV/HCV co-infection status was assigned based on ever having recorded a positive HCV antibody test or detected HCV RNA. Thus, it is unknown whether these individuals had active HCV infection during the study period. Second, several factors such as rates of spontaneous viral clearance, HCV treatment and re-infection (among those successfully treated) were unknown for this cohort, thus limiting our ability to identify and adjust for these factors in the model. Third, therapy for opioid dependence was not considered, but may have impacted HRV among PLW-HIV/HCV with active injection drug use. Fourth, although healthcare administrative data are an important source of information for evidence-based clinical and policy decision-making as well as medical research, we should note that these data are susceptible to inaccurate or incomplete coding, potentially leading to missing or misclassified HRV in both groups. Finally, while this study examined HRV exclusively, there are other forms of healthcare utilization not accounted for in these analyses (e.g., addiction support services).
Conclusions
In conclusion, in this retrospective study, we found that although HRV rates have been decreasing steadily over time, PLW-HIV/HCV consistently maintained higher HVR rates relative to PLW-HIV. Our results highlight several modifiable risk factors (i.e., late presentation for ART, injection drug use, sub-optimal ART adherence and comorbidities) that could be targeted as potential means to minimize the disease burden of this population and on the healthcare system.
Acknowledgements
We would like to thank our patients, and the physicians, nurses, social workers and volunteers who support them.