HIV, Aging and the CTN

Aging affects all organ systems and diseases related to aging include cardiovascular disease, kidney impairment, osteoporosis, cancer, and neurocognitive disorders. Some studies show that conditions such as osteoporosis and frailty occur about 5–10 years earlier in people with HIV compared to the general population. Other research shows that conditions such as cardiovascular disease and kidney and liver impairment are made more severe. The processes behind this are incompletely understood and accelerated or accentuated aging is not seen in every person with HIV. Studies suggest that circumstances related to behavioural risk — such as smoking and poor diet — may be more common in persons with HIV, along with a greater prevalence of depression. Overall exposure to antiretrovirals, especially older, more toxic drugs, as well as the degree of immune depletion before treatment initiation are also likely to affect aging dynamics.

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 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 including cytomegalovirus (CMV). 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 decline 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 with HIV are cancer; diabetes; cardiovascular, liver, and kidney disease; and co-infections such as hepatitis C, hepatitis B and syphilis. In the early days of the epidemic, AIDS-defining illnesses, such as Kaposi’s sarcoma, were a result of HIV infection. Now that people with HIV are living longer, healthier lives, the link between HIV and some comorbidities is less clear. Instead, comorbidities such as diabetes, high blood pressure, and neurocognitive disorders may occur more often due to aging. 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 such as housing, social support, and food security can also contribute to comorbid conditions.

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 272-2) is underway as a prospective, observational study funded by a team grant on HIV and healthy living by CIHR. This study has recruited over 1,000 HIV+ and HIV- participants. By following participants for up to 12 years, this study 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.

Recognizing that gender is a major determinant of aging, in 2019, the Canadian HIV and Aging Cohort was expanded to increase recruitment of women. Its objectives were also broadened to include determinants of frailty and the impact of diet and gender on aging with HIV, as well as new immune pathways that could affect aging. You can read more about this cohort study in this blog post.

Beginning in 2019 following a team grant from CIHR, CTN 314 is the first geriatric cohort of people living with HIV in Canada, and focuses on people over 65 years of age. With strong participation from community, CTN 314 aims to understand the physical, mental, cognitive, and social aspects of health and how they interact to affect wellbeing.

On the other end of the age spectrum, CTN 281 focuses on children and youth who acquired HIV at or around the time of birth and the impact of early versus late initiation of antiretroviral therapy. Outcomes of interest in the study include the HIV viral reservoirs and biomarkers linked to aging and immune exhaustion. This study continues to yield important knowledge on the impact of aging with HIV from a very young age.

The Canadian Observational Cohort (CANOC) Collaboration (CTN 242) is a national partnership of nine cohorts across Canada. This collaborative cohort, which concluded at the end of 2022, followed more than 10,000 people 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 have accessed 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 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 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) 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 difference. Results from CTN 277, a study in women living with HIV, showed that almost two-thirds of the study participants had higher 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 50 peer-reviewed publications since the study’s launch.

In 2022, a collaboration between the CHIWOS and CARMA cohorts was launched (The British Columbia CARMA–CHIWOS Collaboration [BCC3]; CTN 335). This study aims to use a collaborative approach to understand how biological, clinical, and social factors interact to support healthy aging in women living with HIV. The CTN 335 team have developed YouTube videos describing exactly what participants can expect.

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.

In a substudy of CTN 272, participants undergo detailed cardiovascular imaging with CT scans to describe in details the quantity and the type of atherosclerosis present in their coronary arteries. This study demonstrated that cardiovascular disease presents in a different way in people living with HIV compared with HIV-negative people. Leveraging CTN 272’s biobank, and partnering with immunovirologists from the CTN’s Vaccines and Immunotherapies (VIT) Core, distinct immune pathways have been identified that are associated with increased atherosclerosis in people living with HIV, and may one day lead to new treatment targets.

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 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 with HIV. The study aimed to enroll 6,500 participants in the US, Canada, and Thailand over the course of six years. The study is seeking to determine whether people with HIV should be prescribed statins as a preventive measure, even if they don’t qualify for statins under current guidelines.

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. The virus may increase BMD loss directly through its immune and inflammatory effects. Risk factors for osteoporosis (e.g., low body weight and smoking) may also be more common in persons with HIV. 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.

CTNPT 043 leverages data and samples from CTN 272 to study the endocannabinoid system in people living with HIV and HIV-negative controls, to see if levels of endocannabinoids are associated to presence of cardiovascular disease. The endocannabinoid system is a key player in the maintenance and functionality of heart and blood vessels.

The rate of BMD loss may also be affected by the type of ART a person takes. CTN 299 looked 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 also analyzed if the effectiveness of switching is impacted by menopause, a phase of life in which women experience a sharp drop in BMD. Results suggest that women taking TDF may have lower BMD than those on TAF, but that switching to TAF may help restore bone health.

Frailty is a state of general exhaustion of the body associated with aging, resulting in a diminished ability to cope with stressors, and increased risk for adverse health events. The exact causes of frailty, and whether they are distinct in people living with HIV, are unknown. CTN 272 and CTN 314 measure frailty prospectively in their participants. Coupled with the availability of biosamples, researchers hope that this information will help to identify specific pathways that can lead to increased risk of frailty.

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 had 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 was CTNPT 026, a pilot study of 80 participants that assessed the most effective way to measure cognitive changes using neuroimaging. The research team found that electroencephalogram (EEG) imaging while completing tasks could be a good indicator of cognitive ability in people with normal to mild cognitive impairment. The findings also showed that the severity of HIV infection (lowest CD4 count) is related to brain function and cognitive ability.

A sub-study of the Brain Health Now study looked at the effect of a computer-based treatment program to improve sleep and cognitive function in people with HIV who experience insomnia. The digital therapy program used in CTN 290 covered the behavioural, mental, and educational aspects of sleep problems. Results for this study are pending. CTN 290 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 supplementation on neurocognitive scores.

CTNPT 029 tested 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 included 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.

Both HIV itself as well as the antiretrovirals used to treat HIV can have negative effects on the organs of the body, including the liver and the kidneys. Healthy functioning of these organs is important to healthy aging, making research into these areas an important priority. Older ART formulations were particularly hard on the kidneys. An early CTN pilot trial, CTNPT 007, demonstrated the potential side effects of ART options available at the time and improved the ability of clinicians and people living with HIV to make informed choices about which regimen to use.

We know that people aging with HIV have higher rates of age-related diseases. One such disease is advanced chronic kidney disease. CTN 326 is developing a risk assessment tool to understand which individuals are at highest risk of developing advanced chronic kidney disease. One of the main culprits for this kidney risk it thought to be non-alcoholic fatty liver disease, the most frequent disease in persons aging with HIV in Canada. CTNPT 035 is a pilot study looking for clues about what might cause this disease, including vitamin D deficiency, which is frequent in patients with HIV, with or without non-alcoholic fatty liver disease. Vitamin D deficiency appears to be an independent risk factor for advanced chronic kidney disease, and can also increase risk of osteoporosis and poor bone health. Together, these two studies aim to provide much needed answers about how HIV affects healthy aging.

The long-term impacts of HIV and antiretroviral therapy during fetal development and childhood are not yet understood, but preliminary results from the CARMA-ENDO study (CTN 277) suggested possible reduced ovarian reserve which could suggest a risk of reduced fertility potential earlier than expected in the course of typical aging. The FIND+ Study (CTNPT 046) is a pilot study assessing fertility potential and fertility intentions for female and male youth living with HIV since childhood, aiming to assess whether this is a concern and determine the need and methods for future fertility studies in this important population.

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 pilot study, CTNPT 039, is implementing and assessing an electronic patient-reported outcome measure as a part of HIV care.