HIV and ageing

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 [2▪]. 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 [3▪]. 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 [5▪,6▪]. 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 [7▪] 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 [9▪] 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: ▪ of special interest ▪▪ of outstanding interest