A LOOK INTO THE GREY ZONE: AGEING WITH HIV

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Ageing with HIV, can be both a celebration and a concern. A celebration because effective HIV treatments have given life-years back to all people on effective treatment; but a concern since people are now moving into older age with HIV and experiencing age-related health conditions. In Australia, there are approximately 6000-7000 people living with HIV aged over 55 years.  In the US, it has been reported that 50% are over 50 yo, 20-25% are over 60, and soon 50% will be over 60 years old.

But ageing (living longer term with HIV) and being ‘old’ are two different things.  Is being 55 truly old, or even 45?  What is important is as you age (get older) with HIV is how do you stay holistically healthy and well.  Could a person who is 70, be healthier than a person who is 50?…The answer is a fairly obvious YES!..however…

There are multitude of contributing factors and many ‘domains’ (or health conditions) of ageing impact to consider, including the contribution of HIV to the ageing process. Much of the present research is attempting to unravel whether HIV is linked (or causative) to accelerated ageing (i.e. getting age-related comorbidities at an earlier age than individuals without HIV) – OR – accentuated ageing (i.e. more severe or more of age-related comorbidities at the same age as individuals without HIV). Frailty (including falls), bone health, heart health, body organ health (kidneys, liver), cognition (brain ageing), cancers and other co-morbidities, all come into play.

This article touches on some of the aspects and provides a brief overview.

Age Acceleration or Accentuation

It has been generally accepted that there is a 10 year shift in ‘premature’ (earlier) ageing among HIV-positive people, such that HIV-positive people are ageing 10 years faster than those without HIV1.  However, accelerated ageing is contentiously debated, while improvements in treatment and care indicate most people can expect to have near-normal expectancy falling short about 6 years of those without HIV2.  However, these are estimates – we need to get there first, while a closer examination of the mortality rate is warranted in association with ageing conditions.  Whatever the real rate of ageing or mortality, for each individual this is highly dependent upon a whole gamut of other co-factors, such as diet (including gut health), lifestyle (including smoking, alcohol, substance use), family genetics, gender, treatment histories, coinfections (which cause cancers), etc., such that one could forseeably live well to a ripe old normal age with HIV with all these things considered and managed as best as possible.

According to the US Veterans Aging Cohort Study Virtual Cohort (VACS) prospective sub-study conducted between 2003 to 20113 – which assessed the incidence of heart attack (myocardial infarction), end stage renal (kidney) disease and non-AIDS cancers – the rate of these age-associated events occurred at similar ages than those without HIV; although the likelihood of these 3 outcomes was higher among HIV-positive people. The research suggests, HIV is a risk factor that accentuates these outcomes, not accelerate when they occur. However, their findings did not capture the length of time that people were living with HIV (time since diagnosis) so it was unable to assess difference in living longer term with HIV – it assessed age with age-related conditions. In reporting the findings, Keri Althoff said “Many HIV-infected adults feel older than their age” so “this is not the whole story”…More research is needed comparing traditional ageing risk factors (such as smoking cessation, high blood pressure or blood fats, etc.) to determine if they are of a greater magnitude impact than HIV itself or HIV treatment as a risk factor upon accentuated ageing.

A Danish study4 conducted between 1995 and 2014 (nearly 20 years) – which studied heart attack, stroke, virus-associated cancers, smoking-associated cancer, other cancers, neurocognitive problems, kidney dysfunction, liver dysfunction, osteoporotic bone fractures – also found that while HIV-positive people were more likely to have severe forms (and be at much high risk) of age-related diseases than HIV-negative people, these did not occur at a different age than people without HIV (once again suggesting the case against accelerated earlier ageing that those without HIV).  Also, overall, relatively small proportions of HIV-positive people had severe forms of these conditions (although expert review commentary on this study suggested this might be because “HIV-positive patients most at risk for [severe age-related diseases] do not survive to older age”). It was also unclear which traditional risk factors such as smoking, alcohol & substance use, or Hep B or Hep C coinfections may have contributed the greatest to the increased incidence of the age-related conditions studied.

The field of HIV and ageing research is an evolving one as never before have people began to grow old – or more precisely grow elderly – living long term with HIV. More definitive research is needed, including a closer look at the correlation between traditional ageing risk factors, and differences in age at diagnosis vs. time since diagnosis (years living with HIV) vs. current (chronological) age, and how these factors together may lead to advancing ‘biological’ age. For now, the facts may belong to HIV-positive people and their experience/s and realities about ageing progression living with HIV.

A bit about ageing frailty

Ageing results in functional decline of daily living and can lead to frailty. Frailty is difficult to define as a precise condition, so it’s termed a ‘geriatric syndrome’.  It is characterised by LS Fried et al as a pattern of weight loss, strength loss (including grip strength), endurance loss, slowed walking speed, a decline (or difficulty) in daily living activities, sensory loss (hearing and sight), neurocognitive impairment – for which HIV-positive people over the age of 50 (in some studies) are at increased risk at an earlier age than those without HIV. [Wing 20162].

One of greatest concerns about frailty is the risk of falls. Balance and walking are affected by reduced muscle tone and weight loss. Falls can result in fractures and thus a significant worsening of frailty.  Already with a back drop of bone mineral density loss – which can occur from low body weight, vitamin D deficiency, excessive alcohol, smoking , as well as Protease Inhibitor- and tenofovir-based HIV treatment regimens – the risk of fractures among the ageing HIV population is of concern [Wing 20162]. Preventing frailty in older age may be hard to do completely, but preventing falls through muscle conditioning strength training exercise (such as aqua-classes,  swimming, gentle weight bearing exercise, etc) is worthy of some consideration.  Quitting smoking and reducing alcohol consumption will also help. If you have been living with HIV for while and are experiencing any of the above signs of frailty, then a good discussion about them with your doctor may be warranted.

The Brain, Cognition and Diet

It is understood that inflammation (immune activation) from ongoing HIV infection may contribute significantly to the ageing process.  This is most evident in the gut (where HIV replicates) and the brain (where HIV treatments don’t reach as well as in blood).

Advancing age can be associated with cognitive decline, as the brain also ages. This can cause issues related to concentration, memory recall and movement, which slow during the ageing process. The precise mechanisms that affect cognition (and mental states such as mood, anxiety and depression) are complex but are increasingly linked to inflammation5 and immune activation in the gut6,7,8.

About 2/3rds of all HIV replication occurs in the gut (within lymph tissue lining the entire length of the intestinal tract).  The gut contains hundreds of microorganisms involved in digestion, collectively called the gut ‘microbiome’.  HIV alters the diversity of good bacteria in the gut, placing the gut microbiome out of order – a term called ‘gut dysbiosis’. Unhealthy organisms ‘leak’ out of the gut into the bloodstream and so travel to the brain, a condition called ‘leaky gut’ causing ‘microbial translocation’.

Although HIV has a deleterious effect on the gut microbiome (in ways that are only just beginning to be understood), following a healthy diet (www.eatforhealth.gov.au) and including pre-biotics, pro-biotics, and high fibre foods may be the keys to restoring the gut immunity and keeping your brain ‘firing’ how you expect it to.

Pre-biotics are the types of fibrous foods that can reach your large intestine (where much of our gut bacteria exists) and tend to ferment into complex sugars in your bowel giving probiotics (good gut bacteria that you eat or take supplements of) capacity to grow and develop by ‘feeding’ on these fermentable fibres. These foods contain fibrous material that is not affected by digestion to reach the lower bowel. Prebiotic foods include garlic, onions, cabbage, leeks, asparagus, beans and legumes, barley and oats. Diet can be complex so it’s a good idea to consult a dietician about beneficial pre-biotic foods, but a good healthy diet containing high fibre (which slows the bowel down) gives a better environment for probiotic ‘good’ gut bacteria to develop and help the absorption of nutrients.  Fermented foods such as yogurt, sauerkraut, kimchi (cabbage), pickles are examples of probiotic foods as they contain live bacteria that helps populate good bacteria in the gut.  A good probiotic supplement can also help, but prebiotics in the diet are key.  There is no sense taking a probiotic supplement with a bad diet.  Saturated fats (usually from animal sources) and simple sugars in the diet should be avoided as they weaken the gut microbiome.  A good place to start learning about high fibre and high probiotic diets is in the following guide by Monash University, who are also instrumental in creating the FODMAPS diet (for which there is app you can also download):  www.med.monash.edu.au/cecs/gastro/prebiotic/

A recent study9 among 20 HIV-positive people taking cART and a probiotic supplement consisting of Streptococcus, Bifidobacteria, and Lactobacillus twice daily for 48 weeks found a reduction in immune activation (inflammatory) markers, along with a moderate increase in CD4+ T cell count, suggesting “that long-term probiotics consumption may reduce some of the HIV inflammatory markers, potentially improving the chronic inflammation associated with chronic disease and ART treatment in HIV-positive individuals.” The study authors conclude that “Supplementing cART with probiotics in HIV-infected individuals may improve GI tract immunity and there by mitigate inflammatory sequelae, ultimately improving prognosis.”

These things on their own are unlikely to combat additional issues that cause inflammation such as excessive alcohol, so easing up on alcohol to 2 standard drinks per day (with days without alcohol) will also likely help combat ageing as well…Adequate water intake (2 litres a day) is also important for the gut.

The other great contributor to brain function (and feelings of wellbeing and mental focus) is exercise.  If you are unaccustomed to exercise seek someone who can provide you a graded or modified exercise plan, this will account for your personal circumstances, interest, and physical abilities or limitations.  You can also start out slowly by taking a daily walk. Exercise increases appetite, and hopefully that means healthy food choices, as lack of sustained food energy and an unhealthy gut will lower exercise interest and potential.

Conclusion

A considerable (and growing) body of research demonstrates that HIV is linked to increased ageing (in multiple domains), even when fully suppressed on HIV antiretroviral treatment. Ageing HIV-positive people are experiencing more age-related comorbidities at much higher rates and possibly at a younger age than people without HIV. This includes a range of conditions such as bone mineral density loss, frailty, heart disease, abnormal blood fats (lipids), cancers, kidney disease, brain and neurologic disorders, and coinfections.  “To date, it is well accepted that inflammation and immune dysfunction are the main inducers of these non-AIDS-associated age-related clinical manifestations” [Zilberman-Schapira et al.2016 7]  Multiple comorbidities (3 or more) and polypharmacy (7-12 treatment medications) are increasingly common especially in those older than 6510.

In our modern times the ‘shine’ may have been rubbed off a little since the elation in 1996 of life saving combination HIV treatments, since now several decades latter we are faced with a new set of complications in living well with the chronic HIV persistence over a lifetime and maintaining durability over that. However, many of the present studies are estimations which are limited in being able to predict how older HIV-positive people will truly fair in their senior years.  New research insights and new ways of combating HIV persistence are sorely needed. One thing is certain, a cure couldn’t come soon enough – but also it is hoped that future treatments may help overcome the burden of growing older with HIV and ageing comorbidities.

The issue highlights, more than ever before, that the adoption of healthy lifestyle pursuits (as best as one can) over a lifetime will have a positive impact on ageing outcomes. Additionally, the psychosocial aspects of maintaining a quality of life over a lifetime will also have an added bearing and dimension over the biological and clinical impacts of ageing with HIV, and greater community supports will be needed in this arena as well.  Increased community, and clinical, care of those ageing with HIV is now becoming paramount for those who long fought the journey to survive HIV, as well as for those with a bit of ‘mileage under their belt’ (longer time living with HIV).  The title of the most recent publication of HIV and ageing, by well known and regarded Italian researcher in HIV & ageing, Giovanni Guaraldi, says it all “Geriatric-HIV medicine is born11.

 

Further Reading:

References:
  1. Projecting CVD Risks in HIV-infected individuals in the US: competing risks and premature aging. Losine et.al. CROI 2013 (as cited in www.natap.org/2017/HIV/040417_01.htm Jules Levin - see sources).
  2. HIV and Aging. Edward J. Wing. International Journal of Infectious Diseases 53 (2016) 61-68. P62. doi: http://dx.doi.org/10.1016/j.ijid.2016.10.004. Open Access Licence: http://creativecommons.org/licences/by-nc-nd/4.0/
  3. Comparison of Risk and Age at Diagnosis of Myocardial Infarction, End-Stage Renal Disease, and Non-AIDS-Defining Cancer in HIV-Infected Versus Uninfected Adults. Keri N. Althoff et. al. Clin Infect Dis (2015) 60 (4): 627-638. DOI: https://doi.org/10.1093/cid/ciu869 (http://www.mdmag.com/medical-news/Age-related-Diseases-dont-Occur-Earlier-in-HIV-infected-Patients )
  4. Rasmussen LD, May MT, Kronborg G, et al. Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. Lancet HIV. 2015; in press. (http://www.catie.ca/en/catienews/2015-07-20/danish-study-raises-questions-about-accelerated-aging-hiv )
  5. The Dana Foundation. The Brain Inflamed. http://www.brainfacts.org/diseases-disorders/psychiatric-disorders/articles/2015/the-brain-inflamed/
  6. How Gut Microbiota Impacts HIV Disease. Bob Roehr. https://www.scientificamerican.com/article/how-gut-microbiota-impacts-hiv-disease/
  7. Impact of HIV on the human gut microbiota: Challenges and perspectives. Gregory Dubourgh. Human Microbiome Journal 2 (2016) pp 3-9. DOI http://dx.doi.org/10.1016/j.humic.2016.10.001 (http://www.humanmicrobiomejrnl.com/article/S2452-2317(16)30017-3/fulltext)
  8. The gut microbiome in human immunodeficiency virus infection. Gili Zilberman-Schapira, et. al. BMC Medicine 2016 14:83. DOI: 10.1186/s12916-016-0625-3 (https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0625-3) Open Access Licence: https://creativecommons.org/publicdomain/zero/1.0/
  9. d’Ettorre G, Ceccarelli G, Giustini N, Serafino S, Calantone N, De Girolamo G, et al. Probiotics Reduce Inflammation in Antiretroviral Treated, HIV-Infected Individuals: Results of the “Probio-HIV” Clinical Trial. PLoS One. Sep. 2015;10(9): e0137200 doi: 10.1371/journal.pone.0137200 (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137200)
  10. Chronic Health Conditions in Medicare Beneficiaries 65 years and older with HIV infection. AIDS July 2016. Elenore E Freidman.
  11. Geriatric-HIV medicine is born. Guaraldi G, Rockwood K. Clin Infect Dis. 2017 Apr 6. doi: 10.1093/cid/cix316. [Epub ahead of print]
Sources: