Increasing numbers of older people with HIV are under treatment and care, which is due to both the availability of effective highly active antiretroviral therapy (HAART) and increasing numbers of new transmissions and diagnoses in older adults.
Mortality due to AIDS-related malignancies and infections has fallen dramatically in treated patients, but overall mortality remains higher than in the general population [1], and life expectancy is shorter [2â–ª]. Mortality due to non-AIDS events (including non-AIDS defining cancers, pancreatitis, liver disease, serious cardiovascular events and end-stage kidney disease) is now more common than mortality resulting from AIDS-related events [3â–ª]. These diseases are associated with old age in the general population, and because relatively few people living with HIV can be considered old, this has led to speculation that normal ageing is accelerated [4].
WHY MIGHT HIV/HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ACCELERATE THE AGEING PROCESS?
There are many theories, but mechanisms underlying the ageing process are not fully understood. Untreated HIV has been associated with changes in the immune system that are similar to those observed in the elderly [5â–ª,6â–ª]. The extent to which antiretroviral therapy reverses these changes is not yet known. Conversely, individual drugs could contribute to premature ageing; thymidine analogues have been associated with mitochondrial dysfunction [7â–ª] and telomere shortening [8]. Both HIV and ageing have been associated with elevated markers of inflammation and coagulation. These markers remain elevated in patients on HAART [9â–ª] and have been associated with all-cause mortality in patients with HIV [10]. However, there are many potential confounders including behaviour (e.g. smoking, alcohol consumption, recreational drug use) and coinfections (e.g. cytomegalovirus, hepatitis C virus).
In order to support a theory of premature ageing, Martin and Volberding [11] suggest the following criteria should be fulfilled:
- HIV should affect conditions that are associated with ageing in the general population.
- There should be evidence of a greater incidence of age-related conditions among HIV-positive than HIV-negative people.
- The rate of these conditions should be greater among young HIV-infected patients than among uninfected patients of similar age.
We do not believe that the current data for the majority of comorbidites is sufficient to meet all of these criteria.
Researchers at the Modena University metabolic clinic recently reported a higher prevalence of age-related morbidity (cardiovascular disease, hypertension, renal failure, bone fracture, and diabetes mellitus) in HIV-positive individuals, that these morbidities occurred at an earlier age, and that polypathology was more frequent than in HIV-negative controls [12▪▪]. However, although the control group was matched for age, sex, and ethnicity, it was taken from an online database and, therefore, ascertainment of disease would have been different from that of the HIV-positive group who were intensively studied. This issue – of difficulties with adequate control groups – is seen throughout much of the literature purporting that HIV results in premature ageing.
We chose four examples of age-related diseases to demonstrate that recent evidence may be lacking to fully support the hypothesis of premature ageing.
CARDIOVASCULAR DISEASE
A massive study of over a million patients, reporting on acute myocardial infarction (AMI) recorded on a US healthcare system database [13], found increased rates of AMI (relative risk = 1.75; 95% confidence interval = 1.51–2.02) in HIV-positive patients compared with a general population control group. Although the authors were able to adjust for age, sex, race, hypertension, diabetes, and dyslipidaemia, they were not able to control for HIV clinical variables, smoking, coinfections and comorbidities, recreational drug use, or other behavioural risk factors for AMI that are known to be prevalent among people with HIV [14▪,15,16]. A cross-sectional study showed that HIV confers an independent risk of carotid artery intima-media thickness (CIMT) after adjustment for age, sex, ethnicity, and traditional risk factors [17]; however, prospective data linking CIMT to cardiovascular disease outcomes among people with HIV is currently lacking.
LOW BONE MINERAL DENSITY AND FRACTURE RISK
Low bone mineral density (BMD) and osteoporosis are more frequent among treated HIV-positive people than in the general population [18] and have been associated with traditional risk factors, HIV and HAART. The main clinical concern regarding reduced BMD is an increased risk of fragility fractures. Although a further large US study from the same healthcare system as above identified a greater prevalence of fragility fractures across age groups in people with HIV compared with the general population, there was insufficient information to enable appropriate adjustment for many of the known risk factors such as smoking, alcohol, low BMI, socioeconomic status, or medications [19]. The significance of appropriate adjustment was illustrated by Womack et al.[20▪▪], who initially reported increased fracture incidence among men with HIV compared with age, ethnicity and site-matched HIV-negative controls, but this increased risk was attenuated after controlling for other risk factors for fracture and became nonsignificant when BMI was included in the analysis.
COGNITIVE IMPAIRMENT
The incidence of AIDS dementia has been dramatically reduced since the advent of HAART; however, data from recent studies suggest that mild cognitive impairment still occurs in a significant proportion of people with treated HIV [21▪▪,22▪] and is more prevalent among people with HIV than people who are HIV negative [23▪]. However, conclusions are limited by a lack of comparative data from HIV negative populations matched for age, gender, ethnicity, comorbid illness and substance use. Furthermore, a recent study of asymptomatic individuals on effective HAART [24▪] suggested a much lower prevalence (19%) than the previous estimates of 47–69% [21▪▪,22▪,23▪]. The clinical significance of asymptomatic impairment for the development of dementia is not yet known, although many authors, including Mothobi and Brew in this issue (pp. 4–9), recommend screening in this population.
CANCER
Many reports have suggested an earlier age at diagnosis of non-AIDS-related cancers since the introduction of HAART [25,26]. However, after correcting for bias due to the differences in underlying age distribution between AIDS and general populations, the US HIV/AIDS Cancer Match Study [27▪▪] showed that most of these suggested age differences disappeared. Those that remained significant (anus, lung, and Hodgkin's lymphoma) may all have been associated with smoking or coinfections, and, therefore, the control population may not be well matched. Furthermore, it is possible that enhanced screening within the HIV-positive groups, for example, routine anal pap smears, may have contributed to an earlier diagnosis among people with HIV.
CONCLUSION
Although undoubtedly there are higher rates of comorbidities in the HIV-infected population, there are a number of possible explanations for this as well as the possibility that HIV or HAART causes premature ageing. Further research is needed to explore the mechanisms by which HIV/HAART may contribute to age-related diseases, the contribution of other important and potentially modifiable risk factors including smoking, alcohol and drug use, and the role of comorbid disease. The impact of behavioural and pharmacological interventions on the incidence of disease is yet to be prospectively explored. Prospective studies with long follow-up and appropriate controls to examine the incidence and risk factors for age-related conditions, together with advances in research into the biology of HIV and normal ageing, will further our understanding.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- â–ª of special interest
- ▪▪ of outstanding interest
REFERENCES
1. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/ mm
3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46:72–77.
May M, Gompels M, Delpech V,
et al. Impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK collaborative HIV cohort (UK CHIC) study. BMJ 2011; 343:d6016.
Showed increases in life expectancy in people with HIV, but that life expectancy still falls short of that of the general population.
Mocroft A, Reiss P, Gasiorowski J, et al. EuroSIDA Study GroupSerious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr 2010; 55:262–270.
Showed non-AIDS events were common in the HAART era and associated with older age.
4. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009; 338:a3172.
Rickabaugh TM, Kilpatrick RD, Hultin LE,
et al. The dual impact of HIV-1 infection and aging on naive CD4
+ T-Cells: additive and distinct patterns of impairment. PLoS ONE 2011; 6:e16459.
Found lower numbers of, and shorter telomeres within, naive CD4+ T-cell subsets in young HIV positive adults compared to age-matched HIV negative controls.
Appay V, Fastenackels S, Katlama C, et al. Old age and anticytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 2011; 25:1813–1822.
Found HIV amplified the effect of age on naive T-cell levels. Older age and strong responses to cytomegalovirus independently impacted on CD4 T-cell counts and recovery with HAART.
Payne BA, Wilson IJ, Hateley CA,
et al. Mitochondrial aging is accelerated by antiretroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet 2011; 43:806–810.
Found HIV infected patients treated with NRTIs accumulated somatic mitochondrial DNA mutations, similar to those found much later in life due to normal ageing.
8. Strahl C, Blackburn EH. The effects of nucleoside analogs on telomerase and telomeres in Tetrahymena. Nucleic Acids Res 1994; 22:893–900.
Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–1795.
This study found higher levels of inflammation and coagulation biomarkers among people on HAART compared to general population controls.
10. Kuller LH, Tracy R, Belloso W, et al. INSIGHT SMART Study GroupInflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
11. Martin J, Volberding P. HIV and premature aging: a field still in its infancy. Ann Intern Med 2010; 153:477–479.
Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 2011; 53:1120–1126.
Large study reporting a higher prevalence of age-related comorbidities and polypathology in people with HIV compared to age, sex and ethnicity matched general population controls.
13. Triant VA, Lee H, Hadigan C, Grinspoon S. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab 2007; 92:2506–2512.
Freiberg MS, McGinnis KA, Kraemer K, et al. VACS Project TeamThe association between alcohol consumption and prevalent cardiovascular diseases among HIV-infected and HIV-uninfected men. J Acquir Immune Defic Syndr 2010; 53:247–253.
Found alcohol abuse and dependence were associated with cardiovascular disease among HIV-infected men.
15. Sabin CA, Worm SW. Conventional cardiovascular risk factors in HIV infection: how conventional are they? Curr Opin HIV AIDS 2008; 3:214–219.
16. Urbanus AT, van de Laar TJ, Stolte IG, et al. Hepatitis C virus infections among HIV infected men who have sex with men: an expanding epidemic. AIDS 2009; 23:F1–F7.
17. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 2009; 23:1841–1849.
18. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174.
19. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008; 93:3499–3504.
Womack JA, Goulet JL, Gibert C, et al. Veterans aging cohort study project team increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One 2011; 6:e17217.
This study showed an increased risk of fragility fracture associated with HIV which was attenuated after controlling for traditional risk factors including body mass index.
Heaton RK, Clifford DB, Franklin DR Jr, et al. CHARTER GroupHIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010; 75:2087–2096.
Showed that although HIV dementia was rare, mild forms of HIV-associated neurocognitive disorders remain common in the HAART era.
Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010; 24:1243–1250.
Found a high prevalence of HIV associated neurological disorder in patients on HAART with long-term undetectable viral load.
Heaton RK, Franklin DR, Ellis RJ, et al. CHARTER Group; HNRC GroupHIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 2011; 17:3–16.
Compared rates of neurocognitive impairment (NCI) in HIV + and HIV − groups in pre-HAART and HAART eras. Found significantly increased rates of NCI in asymptomatic individuals in HAART era.
Garvey L, Surendrakumar V, Winston A. Features of neurocognitive performance in over 100 neurologically asymptomatic HIV-infected adults receiving combination antiretroviral therapy (cART). In: Proceedings of the 17th Annual Conference of the British HIV Association; April 6–8 2011; Bournemouth, UK.
Found prevalence of HIV-associated neurological disorders of 19% among asymptomatic individuals on effective HAART.
25. Demopoulos BP, Vamvakas E, Ehrlich JE, Demopoulos R. Nonacquired immunodeficiency syndrome-defining malignancies in patients infected with human immunodeficiency virus. Arch Pathol Lab Med 2003; 127:589–592.
26. Crum-Cianflone NF, Hullsiek KH, Marconi VC, et al. Infectious Disease Clinical Research Program HIV Working GroupAnal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS 2010; 24:535–543.
Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Ann Intern Med 2010; 153:452–460.
After correcting for differences in age distributions between AIDS and general populations, this study found similar age at diagnosis of most cancers between the groups.
