Metabolic complications of newer HIV drugs in older people
The lack of data is compounded by much of the research on natural ageing being based in high income countries, and control populations for health complications often being overrepresented by cisgender white men.
This is despite more than half of people living with HIV being older than 50 in many cohorts, including at the Royal Free Hospital in London, where for the last four years Dr Barber helped establish and run the Sage clinic to promote and support healthy ageing, with a focus on comorbidities and frailty.
Good metabolic health can be defined as covering five main goals: (i) having a good and stable appetite, (ii) minimal belly fat, (iii) normal blood sugar, (iv) normal blood pressure, and (v) having good enough muscle, bone and joints to be physically active. These targets are to achieve and maintain a good quality of life, rather than simply meeting good chemical and physiological markers.
Ideally, this is with minimal need for medications, but ART is clearly essential in people living with HIV and the newer ARVs from five drug classes include TAF, dolutegravir, bictegravir, doravirine, injectable cabotegravir-LA and rilpivirine-LA, ibalizumab and fostemsavir. Registrational studies for new drugs, however, generally include low numbers of people older than 50, unless they are specifically developed to overcome multidrug resistance.
Although weight gain has been an important new research focus since 2017, when the ADVANCE study reported significant associations with both dolutegravir and TAF, especially in Black women, few of these studies focus on older people. An Italian study in people older than 65 years old did not report weight gain after switching to dolutegravir, but this was in a largely male Caucasian cohort. 
Any discussion on weight changes in people living with HIV needs to relate to changes in the general population, where weight commonly increases during middle age and is linked to a wide range of health complications. These include cardiovascular disease and stroke, diabetes, NAFLD, some cancers, joint pains, general mortality, depression and lower quality of life. It is also associated with low self-image and stigma.
After the age of 60, weight starts to decrease, visceral abdominal fat increases and lean muscle declines (affecting the interpretation of BMI). But although the complications of high BMI are less pronounced (compared to when younger), excess weight still remains a concern, increasing pressure on the respiratory system and joints and increasing the risk of cancers, cardiovascular and liver diseases. In older people, low BMI and weight loss are associated with increased mortality.
Frailty is a critical issue in the management of older people. It is not just a measure of physical activity, strength and quality of life, but a diagnosis that is independently linked to mortality.
Two people with a similar chronological age, medical history, BMI and biomarkers can have very different levels of frailty based on lifestyle factors that achieve and maintain higher levels of activity.
Healthier lifestyle changes make it easier to have stronger responses to future complications.
HIV-related age and ART experience
The talk also introduced the importance of HIV-related age. Ageing with HIV will be very different for a man aged 70 who was diagnosed in 1994 compared to 2017.
Time of HIV diagnosis is important for experience of both HIV and treatment and can be split into the following four categories:
- Before 1996: before effective ART, longer time with detectable viral load, opportunistic infections, possible AIDS diagnosis, bereavement from partners and friends and being less financially prepared.
- 1996 to 2005: early ART was effective but had difficult side effects, sometimes permanently reducing quality of life, longer periods of viraemia, UK guidelines at one point had a CD4 threshold to start ART at 200 cells/mm3.
- 2005 to 2015: ART became better and easier, and was started earlier at CD4 350 cells/mm3.
- After 2015: ART has been routinely recommended after diagnosis at any CD4 count (although at least 40% of people are still diagnosed late after the CD4 count is <350 cells/mm3).
Duration of HIV and use of ART contributes to a complex pattern of factors that impact on metabolic health. These can make the underlying mechanisms and pathogenesis of ageing very different in people living with HIV. 
Both HIV and ART can cause or enhance:
- Genetic damage (epigenetic ageing, mitochondrial dysfunction, oxidative stress, telomere length).
- Cellular changes (senescence, altered autophagy, protein responses).
- Inflammation (detectable HIV, coinfections including CMV, inverted CD4:CD8 ratio).
- Biological changes (altered microbial balance, increased gut permeability, endocrine decline).
- Environmental (sexual history, smoking, use of drugs and alcohol, exercise and diet).
- Individual HIV drugs can have different side effects that affect metabolic health.
Older people living with HIV need to consider effects of long-term ART use, viral factors (reservoir and HIV proteins) and biological changes.
However, one review shows similar levels of viral suppression rates for people aged ≥ 50 years initiating ART compared to those under 50 (range: 85% to 100%) when using newer drugs as first-line ART. These studies include data for dolutegravir, bictegravir and TAF, but not so far for long-acting therapies.
Prescribing and polypharmacy
Several cohorts, including the AGEhIV cohort study, have reported that comorbidities (e.g. cardiovascular and renal disease) and polypharmacy increase with age. People aged >65 years report more comorbidities (40% report ≥2 non-HIV conditions) and polypharmacy (20% report taking ≥3 non-ART medications). 
The choice of ART needs to have the least potential for drug-drug interactions (DDIs). Drug handling changes with age, as hepatic and renal changes may alter ARV processing and clearance differently in older people.
Even though many people living with HIV report wanting to remain on the same therapy because they see it as effective, they might not understand that age-related changes in drug handling may make them more susceptible to side effects over time, especially with efavirenz. This should be considered alongside a review of comedications at every appointment.
There is an ethical imperative to evaluate ART and consider alternatives at least annually. This can involve switching from an “it’s working” mentality and considering better alternatives that often come with newer drugs. This review should focus on whether each current treatment is still the best option for each individual. Recent UK guidelines support routine use of integrase inhibitors rather than boosted protease inhibitors, that can have better tolerability, fewer DDIs and often overcome earlier drug resistance.
- Prescribe ART with least potential for DDIs.
- Counsel people about their drugs and blood results.
- Review ART for ageing people as co-medications will change.
- Consider impact of altered renal and hepatic function on drug handling and metabolism.
- Take accurate measurements of waist to hip ratio, blood pressure, BMI.
- Accurately record these results and monitor over time to look for unexpected changes.
- Motivate behavioural changes to increase exercise or modify diet to improve health.
This excellent talk stressed that ageing is a dynamic process and the importance of actively managing HIV in older age.
This involves recognising that people who are generally perceived as being stable on long-term ART, actually present new medical challenges as we age.
- Barber TJ. Older people. Metabolic consequences of new classes of ART. AIDS 2022, 29 July to 2 August 2022, Montreal.
- Guaraldi G et al. Dolutegravir is not associated with weight gain in antiretroviral therapy experienced geriatric patients living with HIV. AIDS. (01 May 2021). DOI: 10.1097/QAD.0000000000002853.
- Lagathu, C. et al. (2017) Basic science and pathogenesis of ageing with HIV: potential mechanisms and biomarkers. AIDS, 31:S105-S119; doi: 10.1097/QAD.0000000000001441.
- Schouten J, et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. CID 2014;59:1787–97.