HIV and Aging

Due to the success of modern antiretroviral therapy (ART) and an increase in the average age of new HIV diagnoses, the population of Canadians living with HIV is aging. In fact, over 50% of Canadians living with HIV are now over the age of 50. Aging in itself is a complex and poorly understood process, which is experienced differently among people. As with any chronic condition, the interaction between HIV and aging increases this complexity and presents a unique set of challenges to people aging with HIV, health care providers, researchers, and advocates.

The Canadian AIDS Society in partnership with Realize, formerly the Canadian Working Group on HIV and Rehabilitation (CWGHR), describe the following groups for discussion of HIV and aging:

  1. Canadians who have known they were HIV-positive for many years, and who are now over 50 years of age;
  2. Canadians over 50 who have recently been infected and diagnosed with HIV;
  3. Canadians over 50 receiving a late diagnosis, but who were infected years before; and,
  4. Canadians over 50 who are at risk of HIV.

The CTN's Role

Throughout the years, the CTN has been involved in research to understand, prevent, and reduce health complications related to HIV. This research has changed accordingly to remain current with the field and reflect evolving research priorities and changing demographics.

The CTN is organized into Core Research Teams, a structure that fosters concentrated discussion and development of novel clinical trials and research initiatives. The Clinical Care and Management (CCM) Core conducts the majority of the Network’s research related to HIV and aging. The CCM Core conducts clinical research aimed at creating evidence-based knowledge that optimizes engagement in the HIV Cascade of Care in Canada and is co-led by Drs. Jason Brophy and Madeleine Durand.

Drs. Jason Brophy and Madeleine Durand

What We Know About HIV and Aging

The interaction between HIV and the aging process is complex and is often complicated by the occurrence of other diseases and health challenges. Much of what we know about this area comes from observational studies that follow large groups of people living with HIV.

HIV and Aging: Core Concepts

Diseases related to aging include cardiovascular disease, kidney impairment, osteoporosis, and neurocognitive disorders. Some studies show that some comorbidities such as osteoporosis and frailty occur earlier in people living with HIV compared to the general population by about 5 to 10 years. Other research shows that some conditions such as cardiovascular disease, and kidney and liver impairment are accentuated. The process behind this is unclear and is not seen in every person living with HIV. Other studies suggest that we see more comorbidities related to behavioural risk (such as smoking and poor diet) along with a greater prevalence of depression.

What is known about aging with HIV is that the immune system remains activated, even when viral suppression is maintained, resulting in a state of chronic inflammation often referred to as “inflammaging”. This persistent, low-level inflammation is thought to occur for a number of reasons including, but not limited to: replication of HIV that remains hidden in viral reservoirs, impairment of and direct damage to the gastrointestinal tract (known as leaky gut or microbial translocation), and co-infection with other viruses. The overall consequence of chronic inflammation is the decline in the function, replication, and health of the body’s immune cells (T-cells). A similar deterioration in T-cells is seen throughout the normal process of aging. For more information about chronic inflammation and immune activation see this short blog post or the Body for a more in-depth overview.

When another disease occurs alongside a primary disease, HIV in this case, the secondary disease is referred to as a comorbidity. Comorbidities may be caused by the primary disease or occur independently. Examples of comorbidities in people living with HIV are cancer; diabetes; cardiovascular, liver, and kidney disease; and co-infections like hepatitis C and syphilis. In the early days of the epidemic, AIDS-defining illnesses, such as Kaposi’s sarcoma, were a result of HIV. Now that people with HIV are living longer, healthier lives, the causality between HIV and some comorbidities is less clear. Understanding and separating out the effect of HIV, ART, and age on these comorbidities is difficult. Behavioural factors­—such as diet and physical activity—and social factors like housing and food security can also contribute to comorbid conditions.

Observing HIV+ Aging: Cohort Studies

Because of gaps in our understanding of aging with HIV, there is much to be learned from simply observing people living with HIV who are receiving regular care over time. Currently, the Canadian HIV and Aging Cohort (CTN 272) is underway as a prospective, observational study. This study has recruited over 1,000 HIV+ and HIV- participants. By following participants for between 5 and 8 years, CTN 272 will compare the rates of cardiovascular events (such as heart attack, stroke, and angina or chest pain) between those living with and without HIV. Secondarily, researchers hope to compare rates of diabetes, kidney failure, and decreased bone health as well as the mechanisms and characteristics of these diseases in both groups.

The Canadian Observational Cohort (CANOC) Collaboration (CTN 242) is a national partnership of nine cohorts across Canada. This collaborative cohort follows more than 10,000 people living with HIV who are accessing ART. Almost 50% of HIV+ Canadians who accessed treatment since 2000 are included under the CANOC umbrella. A variety of different studies and projects access the CANOC cohort. Investigating comorbidities, aging-associated changes, and HIV care and management within the cohort is helping inform clinical and research priorities.

Analyses and publications from CANOC have been instrumental in the current understanding of Canadians aging with HIV. A recent collaboration between CANOC and cohorts in the UK, Europe, and the US, looked at the effect of HIV subtype on long-term outcomes. Another analysis looked for differences in clinical outcomes in people living with HIV and HCV with and without a history of injection drug use. CANOC also participated in another large cohort collaboration to understand the rates of, and factors related to, end-stage kidney disease in North American adults living with HIV.

Another cohort in which the CTN is involved is the Cellular Aging and HIV Comorbidities in Women and Children (CARMA) Cohort. This cohort is a large, federally funded study that is looking at a wide range of risk factors associated with health problems in HIV+ women as well as children exposed to ART during development. A sub-study of this cohort, the CARMA-ENDO study (CTN 277) is compared the prevalence of endocrine, metabolic, and reproductive complications between women living with and without HIV. These complications increase with age and may be more common in HIV-positive people. By collecting markers of accelerated cellular aging—telomere length and alterations in mitochondrial DNA—CTN 277 researchers are looking for possible explanations for this discrepancy. Results from CTN 277, a study in women living with HIV, showed that almost two-thirds of the study participants had elevated levels of blood lipids, like cholesterol. The authors highlighted the importance of addressing this metabolic risk factor, as well as smoking, in order to prevent long-term consequences to cardiovascular health. More about HIV and cardiovascular health is available below.

The Canadian HIV Women’s Sexual and Reproductive Health Cohort Study (CHIWOS; CTN 262) is a large, community-based prospective cohort study supported by the CTN. The broad aim of this study is to look at the distribution, use, and factors related to women-centered HIV services and how these services affect health outcomes in Canadian women living with HIV. In relation to HIV and aging, the CHIWOS group is researching the relationship between premature ovarian failure and menopause and HIV, among other projects. The CHIWOS team has published over 30 peer-reviewed publications since the study’s launch. The team is now working to implement a women-centered HIV care model in the Atlantic provinces and are assessing readiness and feasibility in the pilot study CTNPT 040.

One of the CTN’s newer studies, CTN 314, is a five-year longitudinal cohort study that aims to improve knowledge of the complexities of HIV and aging, with a focus on understanding the physical, mental, cognitive, and social aspects of health and how they interact to affect wellbeing and healthy aging.

HIV, Aging and Comorbidity Research

Beyond purely observational research, the CTN has supported a wide range of studies that aim to understand how specific treatments, interventions, and conditions affect the different aspects of HIV and aging.

Cardiovascular Health: From Then to Now

In the early days of the epidemic, the CTN was involved in optimizing effective ART medications and secondary treatments to address the side effects of these drugs. At that time, cardiovascular health was significantly impacted by ART with increases in cholesterol and triglycerides (a type of fat) in the blood and progression of atherosclerosis (hardening of the arteries). CTN 157 looked at the impact of two medications (L-carnitine and fenofibrate) on lowering blood triglycerides and a sub-study looked at the effect of these two approaches on fasting blood cholesterol, C-peptide (residue in the formation of insulin), and insulin levels. CTN 178 tested the effect of rosiglitazone (Avandia®) in an attempt to reduce atherosclerosis in people taking ART. Although the effects of the study treatment in both CTN 157 and 178 were not found to be statistically significant, both studies showed a promising trend toward improving cardiovascular health. Another study, CTN 175, used nevirapine to lower cholesterol levels in people taking protease inhibitor-containing ART, however, the study was closed early due to low enrolment.

Chronic immune activation and inflammation continue to impact cardiovascular health making it an ongoing focus of research. The Niaspan Study (CTNPT 006) looked at the effect of extended-release niacin (vitamin B3) on immune activation with a secondary goal of assessing changes in cholesterol, triglycerides, and neurocognitive scores. Although not directly related to cardiovascular health, the CTN’s Vaccines and Immunotherapies (VIT) Core continues to research interventions to reduce viral reservoirs, inflammation, and immune activation.

The REPRIEVE trial (A5332, CTN 293 – Randomized Trial to Prevent Vascular Events in HIV) is the first large-scale multinational Phase IV study to test a strategy for heart disease prevention in people living with HIV. The study will enroll 6,500 participants in the US, Canada, and Thailand over the course of six years. The study is seeking to determine whether people living with HIV should be prescribed statins as a preventive measure, even if they don’t qualify for statins under current guidelines.

For more information on HIV and cardiovascular disease, see this article from CATIE.

Bone Health

In the early 2000s, the CTN took part in the large, international Strategies for Management of ART (SMART) study (CTN 190). The SMART study included over 300 sites in 33 countries; the CTN was charged with managing the 10 Canadian sites. At the time, available ART drugs were more toxic and caused significant side effects. The primary purpose of the study was to compare the effectiveness of taking ART only when needed (episodic use) versus continual ART use. As we know today, people whose ART use is interrupted or sporadic are more likely to experience adverse clinical outcomes than people who adhere strictly to their regimen. Because of this finding, the study was ended early and participants were encouraged to use ART continually; data from this study has been used in over 30 research publications. Of particular interest to the area of HIV and aging was the finding from a SMART sub-study that continuous ART decreased bone mineral density (BMD) compared to intermittent ART.

BMD loss occurs with increasing age, making osteoporosis (bone fragility) one of the most common diseases related to aging. Osteoporosis and BMD loss is more common and more severe in people living with HIV which may increase BMD loss directly through its immune and inflammatory effects. Some ART drugs can also contribute to an increased rate of BMD loss. Since the SMART study, the CTN has initiated two pilot trials to study bone health and HIV.

CTNPT 001, CTN’s first pilot trial, compared bone characteristics between people living with HIV with and without a history of bone fracture. This small study suggests there may be a difference in bone structure, health, and function between these two groups and explored new techniques that could be useful in assessing bone health.

CTNPT 021, the BATARI pilot trial, looked at the effect of a bone anti-resorptive therapy (alendronate with vitamin D) to prevent BMD loss during the first year of initiating HIV treatment. The first year of ART is when the majority of BMD loss occurs and the BATARI pilot trial hopes to aid in the design of a larger clinical trial. As a pilot study, the findings from this study will help inform the development of a larger trial, and show good feasibility, acceptability, adherence, and tolerability of alendronate with vitamin D in people living with HIV.

The rate of BMD loss may also be affected by the type of ART a person takes. CTN 299 is looking at the effectiveness and safety of switching from tenofovir disoproxil fumarate (TDF), a drug known to increase BMD loss, to tenofovir alafenamide (TAF) among peri-menopausal HIV-positive women. The study will also analyze if the effectiveness of switching is impacted by menopause, a phase of life in which women experience a sharp drop in BMD.

Brain Health

Despite viral suppression, ART adherence, and proper clinical care, brain health may be impacted by HIV. Rates of cognitive impairment and mental health detriments are higher in HIV+ people over the age of 50 than in HIV- people. Brain function may be negatively affected by viral replication, inflammation, the toxic effects of ART, other comorbidities, and by depression, stress, and substance use.

Brain Health Now! (CTN 273) was implemented with the broad objective of identifying, understanding, and optimizing brain health in people living with HIV. CTN 273 has nearly 1,000 participants and is helping researchers refine the way brain health is measured, its determinants, and how it manifests in people over the age of 35. This study is also extremely useful in identifying eligible participants for sub-studies to test new interventions. One such sub-study is CTNPT 026, a pilot study of 80 participants that is assessing the response to an 8-week cognitive training program and the most effective way to measure cognitive changes using magnetic resonance imaging (MRI). For more information about Brain Health Now and associated studies please visit the study website.

A sub-study of the Brain Health Now study is looking at the effect of a computer-based treatment program to improve sleep and cognitive function in people living with HIV who experience insomnia. The digital therapy program used in CTN 290 covers the behavioural, mental, and educational aspects of sleep problems. This study is an example of the lifestyle and behavioural intervention studies supported by the CTN, discussed below.

CTNPT 005 tested the utility of a computerized neurocognitive assessment tool in comparison to standard neuropsychological testing. For health care workers, this tool requires minimal training and can be used by participants regardless of their language capabilities. CTNPT 015 investigated the usefulness of personalizing ART based on sampling of participants’ cerebrospinal fluid via lumbar puncture. Unfortunately, this study was ended early as the test was found to be ineffective. Discussed above, a secondary objective of the Niaspan Study (CTNPT 006) was to measure the impact of vitamin B3 on neurocognitive scores.

CNTPT 029 is testing the feasibility and acceptability of cognitive remediation group therapy in older adults (≥40 years of age) living with HIV who have been diagnosed with HIV-associated neurocognitive disorder. The therapy includes tablet-based cognitive training and mindfulness-based stress reduction sessions. The results of this pilot study suggest that combining mindfulness and brain training activities may be preferential to standard group therapy sessions.

Impacts on cognitive ability aside, mental health in relation to living with HIV is complex. Stress levels, coping, physical health, and social factors all play important roles. Accordingly, CTN researchers and knowledge users are now turning to interventions and measures relating to lifestyle factors and behaviours.

Health and Lifestyle

Healthy behaviours like increasing physical activity, eating well, and substance-use moderation are recommended and encouraged for people of all ages. Because of an increased susceptibility to age-related conditions such as cardiovascular and metabolic disorders, people living with HIV can benefit significantly from lifestyle modification. CTN 288, LHIVE Healthy, is evaluating the effectiveness of a web-based intervention to support people living with HIV to adopt healthy behaviours. Using personalized virtual nurses, this study will support participants in all ages in one of three behaviour modifications: eating better, exercising more, or stopping smoking.

Smoking is a risk factor for cardiovascular disease and is very common among people living with HIV. The CTN supported a pilot trial (CTNPT 008) that looked at the effectiveness of a counselling program in combination with a nicotine patch to improve quitting rates. By looking at depression as a cause of smoking habits, this study highlighted the importance of addressing mental health as a barrier to smoking cessation and improving overall health. The larger follow-up study, funded by CIHR, unfortunately ended early due to issues with recruitment.

Adherence to an appropriate treatment regimen is the most important and impactful behaviour that someone living with HIV can do to achieve an undetectable viral load and maintain their health. With this in mind, the I-Score Study (CTN 283) is creating a patient-focused questionnaire to understand, from the point of view of a person living with HIV, the factors that affect their treatment adherence. A tailored approach, based on what individuals see as obstacles to following their treatment schedule and what they struggle with, can help to better orient patient-provider discussions of adherence and the modification of prescribed treatments to optimize them based on individual needs. A new pilot study, CTNPT 039, is implementing and assessing an electronic patient-reported outcome measure as a part of HIV care.

HIV and Aging Research Outside the CTN

Outside the CTN, Canadian researchers have contributed significantly to HIV and aging research and our understanding of HIV and the aging process. Researchers at Dalhousie University have collaborated several times with Italian researcher Dr. Giovanni Guaraldi, who is also co-principal investigator for CTN 299. This work has focused on defining and developing a frailty index specific to HIV. At the University of Toronto, Dr. Kelly O’Brien is using data from the HIV, Health, and Rehabilitation Survey (HHRS) to profile disabilities and comorbidities in HIV+ Canadians and their use of rehabilitation services. Dr. O’Brien is also implementing a CIHR-funded community-based exercise intervention study in HIV+ adults in partnership with the YMCA Toronto. During her at PhD at U of T, Dr. Hannah Kia analyzed interview data to understand the health care experiences of older gay men, half of which were living with HIV.

McMaster University is also involved in HIV and aging research. Dr. Patty Solomon is conducting a longitudinal of health in people aging with HIV. PhD candidate Charles Furlotte has written on approaches to successful aging in older adults and his thesis project is focusing on aging with HIV from the perspective of gay men in Toronto. At the Centre for Addiction and Mental Health in Toronto, Dr. Sergio Rueda has published extensively on HIV and quality of life, among other topics, and is currently building a framework to understand successful aging with HIV. The Ontario HIV Treatment Network (OHTN) has a significant body of work relating to HIV and dementia and other comorbidities. Finally, the Public Health Agency of Canada continues to compare the needs of people living with and without HIV in both home and long-term care settings.

The above examples are just a small selection of the research that is ongoing in Canada. There is a diverse group of scientists, knowledge users, and community members that are expanding our knowledge of HIV and aging, from lab-based studies to community and social program implementation.