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Case Report

CSIRO PUBLISHING

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Sexual Health, 2009, 6, 83–86

Rapidly ageing HIV epidemic among men who have sex with men in Australia John M. Murray A,B,C, Ann M. McDonald B and Matthew G. Law B A

School of Mathematics and Statistics, University of New South Wales, Sydney, NSW 2052, Australia. National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Level 2, 376 Victoria Street, Sydney, NSW 2010, Australia. C Corresponding author. Email: [email protected] B

Abstract. Background: Antiretroviral therapy has increased survival for individuals living with HIV and has led to an ageing of this population in developed countries. To date the rate of ageing has been unquantified, giving rise to uncertainty in the treatment emphasis and burden in this population. Methods: A mathematical model was used in conjunction with HIV/AIDS data from the Australian National HIV/AIDS Registry to estimate numbers and ages of Australian men who have sex with men (MSM) living with HIV infection from 1980 to 2005. Results: The average age of HIV-infected Australian MSM is estimated to exceed 44 years of age by the year 2010 and has increased by 1 year of age for each two calendar years since the mid-1980s. HIV-infected MSM over 60 years of age have been increasing in number by 12% per year since 1995. A consequence of successful therapy with subsequent ageing of those infected has meant that from 2001 estimated deaths from other causes exceed AIDS deaths in Australia. Conclusions: In summary, our analyses indicate an increasing and rapidly ageing population living with HIV in Australia. This will inevitably lead to more serious nonAIDS conditions in ageing patients living with HIV, and to increased treatment complexity. Additional keywords: HIV/AIDS, antiretroviral therapy, mortality.

Introduction Death from AIDS has devastated many communities in both developed and resource-poor countries since the HIV/AIDS epidemic commenced in the 1980s. The availability of combination antiretroviral therapy (cART), however, has differentiated the outcomes of HIV infection between these countries.1 Since the mid 1990s, cART has lengthened the median lifespan for those infected with HIV in countries where antiretroviral treatment is widely available.2,3 One of the consequences of extensive cART usage in developed countries has been that the number of HIV-infected individuals has increased as new infections occur, but also as those previously infected survive.4 Although most of those infected with HIV in the early to mid 1980s did not survive due to the unavailability of successful cART, some individuals survive to this day. There is an increasingly larger group of older individuals affected by HIV in developed nations.5 7 It is therefore not surprising that age-effects may have an impact on the health of individuals living with HIV.8 With the success of cART in reducing the number of deaths following AIDS, we may expect at some time that HIV/AIDS-related deaths would eventually be less than that from other causes. Moreover the interaction between HIV, cART, and age-related diseases may be expected to play a greater part in the future, although the size of this impact is currently unknown in Australia and in many developed countries.  CSIRO 2009

In Australia, 85% of new HIV diagnoses are in men who have had sex with men (MSM), and as such, largely reflect the epidemic in this country.9 We investigated the dynamics of this cohort from 1980 until the end of 2005, tracking the ages of individuals and therefore the age profile of the HIV epidemic in Australia. We also compared the number of AIDS deaths over time to the expected number of deaths from other causes. Methods HIV diagnoses for MSM in Australia were obtained from the Australian National HIV/AIDS Registry for cases where the exposure category was ‘Male Homosexual Contact’, ‘Male Homosexual Contact and Injecting Drug Use’, and male ‘Other/Undetermined’. Notifications reported as ‘other/ undetermined’ were included in these analyses for several reasons. First, the majority of all HIV/AIDS notifications reported as ‘other/undetermined’ are in men. Second, particularly for AIDS diagnoses, there has been a recent increase in men reported to be exposed to HIV as ‘other/undetermined’ with an almost exactly commensurate decrease in men with reported exposure as male homosexual contact. Third, most of HIV and AIDS notifications in men in Australia are through male homosexual sex (at least 80%). For these reasons, on balance, we prefer to include HIV/AIDS notifications as ‘other/ undetermined’ in analyses of all cases through MSM. This is a consistent approach taken, and in particular makes the analyses presented here consistent with recent HIV modelling.10 10.1071/SH08063

1448-5028/09/010083

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These diagnoses were tracked numerically over time, assuming ageing of individuals so that they progressed over 5 year age-groups from 15 to 60 years of age and above. Numbers of deaths following AIDS among homosexual men were obtained from the National HIV/AIDS Registry. The number of MSM living with HIV was then estimated from the diagnoses progressing with age, minus individuals in each group dying following AIDS, and also subject to natural mortality rates for males in each age group obtained from the Australian Bureau of Statistics.11 Given the possible increased mortality rates of individuals living with HIV through non-AIDS events, we also carried out calculations using double the natural mortality rates. This provided an estimate of the number of homosexual men living with diagnosed HIV infection from 1980 to the end of 2005. Comparison of the trend in ages of those living with HIV compared with those newly diagnosed was carried out with a Student’s t-test on the difference in the linear regression slopes.12

Over the same period the number of individuals 60 years and older increased by an average 12% per year. The percentage of MSM 40 years and older has shown a dramatic change, increasing from 21% to 22% in 1985 to 57–61% in 2005. The estimated average age of the MSM population living with HIV has increased from 33 years of age in 1985 to between 42 and 43 years of age by 2005 (Fig. 2a). Average age has increased at a roughly linear rate of 1 year increase in average age of those living with HIV with every two calendar years. With this rate of increase the average age of HIV-infected MSM in Australia will be over 44 by 2010. New HIV diagnoses have increased in age along with the infected population but at a slower rate (P < 0.0001). The introduction of protease inhibitors and the availability of cART in 1996,13 led to a dramatic decrease in deaths following AIDS (Fig. 2b). The combination of an increased lifespan for MSM living with HIV and the subsequent ageing of this population have both contributed to a decreasing impact of AIDS deaths to mortality in this group. From at least 2001, estimated deaths from other causes have exceeded AIDS deaths in Australia (Fig. 2b).

Results The estimated number of HIV-positive MSM increased quickly in the 1980s, plateauing during the first half of the 1990s at ~8600 before undergoing a second expansion from 1995 as the introduction of protease inhibitors increased survival (Fig. 1a).13 In 2005 there were between 10 500 and 12 154 MSM living with diagnosed HIV infection in Australia, according to our model and assuming that AIDS-unrelated mortality ranged from double natural mortality to the same as natural mortality respectively. The number of new HIV diagnoses has continually exceeded AIDS deaths and estimates of deaths from other causes, resulting in the expansion of numbers of HIVinfected MSM over the course of the epidemic. In 2005 numbers of deaths from any causes ranged between 27% and 42% of numbers of new HIV diagnoses among homosexual men in that year, dependent on the assumed level of AIDS-unrelated mortality. The estimated age distribution of HIV-positive MSM has changed significantly over the course of the epidemic (Fig. 1b). In 1995 12–14% of the HIV-positive MSM population was over 50, whereas it had increased to 23–28% by the end of 2005.

Discussion The average age of MSM living with HIV in Australia has increased over the course of the epidemic (Fig. 2a), and it is expected to continue to increase given improved survival associated with cART. For individuals living with HIV in Denmark, median survival was estimated to have increased during the period 2000 to 2005 to 32.5 years.2 This increased survival is also reflected in the dramatic drop in AIDS deaths in Australia (Fig. 2b). Consequently an increasing focus of HIV management is to accommodate issues associated with ageing in a population of individuals living with HIV.8 In the Strategies for Management of Antiretroviral Therapy (SMART) trial non-AIDS-defining malignancies were more common than AIDS-defining malignancies; non-AIDS defining malignancies were also the most common cause of death, and risk increased with age.14 Older age was also associated with increased risk of asymptomatic myocardial ischaemia in HIVinfected adults.15 (b)

(a)

Age

100 60+

12 000

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50−54 45−49 40−44

50

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4000 25

25−29 20−24 15−19

0 1985

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Year

2000

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1995

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2005

Year

Fig. 1. (a) Numbers and (b) percentages of HIV-positive men who have sex with men (MSM) in 5-year adult agegroups in Australia from 1985 to 2005 assuming natural mortality rates in addition to AIDS deaths.

Ageing HIV epidemic in Australia

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44

700

(b)

(a) 600

42

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85

38 36

400 300 200

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0 1985

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Fig. 2. (a) Average ages of HIV-positive men who have sex with men (MSM) under the assumption of non-AIDS-associated mortality equivalent to that for uninfected men of the same ages11 (circles), and where twice this rate was assumed (diamonds); also displayed are average ages of MSM newly diagnosed with HIV infection (squares). (b) Annual deaths following AIDS (squares) and estimated deaths from other causes are shown for both scenarios of non-AIDS associated mortality (natural mortality, circles; double mortality diamonds).

The introduction of cART in 1996 dramatically reduced the death rate associated with HIV, and in our analyses has reduced the AIDS-related death rate below those attributed to other causes (Fig. 2b). These findings are consistent with 40% of deaths between 1999 and 2004 registered in the Australian HIV Observational Database (AHOD) being attributed to an AIDSrelated event, with 52% of deaths being AIDS-unrelated.16 We have modelled the expansion of the MSM population living with HIV under the assumptions of natural mortality rates, or double this, in addition to AIDS deaths to determine a likely range of values. Under the assumption of natural mortality rates, 41% of deaths are estimated to be directly related to AIDS, reproducing the observations of percentage deaths attributable to an AIDS event seen in AHOD.16 Assuming double natural mortality rates decreases this to 27% of deaths attributable to AIDS. These results suggest that using natural mortality rates may more closely determine the numbers and age distributions of this population. Moreover apart from a higher incidence of deaths related to infectious diseases such as hepatitis B and C viruses, non-AIDS death rates in people living with HIV in France were similar to those in the general population.17 In addition, as a result of our assumptions on rates of non-AIDS mortality, our estimates for proportions of MSM living with HIV who are 40 years of age and above (61%), 50 and above (28%), and 60 and above (8%), are similar to estimates of proportions of people living with HIV in the USA (64%, 25%, and 6%, respectively).18 The expansion of an older group of people living with HIV through both new infections and ageing of younger infected individuals implies increasing complexity of treatment for the population living with HIV infection. Older individuals living with HIV exhibit slower and more limited immunological responses to antiretroviral therapy,19 despite better adherence to therapy.20 Several studies have suggested an increased risk of several serious non-AIDS events and moderate immunodeficiency, non-AIDS defining malignancies and liver failure.14,16,21,22 There is also an increased risk of diabetes and cardiovascular disease with increasing duration of antiretroviral

treatment.23,24 All of these serious non-AIDS conditions, malignancies, liver failure, diabetes and cardiovascular disease, are chronic conditions that are known to increase with ageing. As the population of those living with HIV ages, it seems almost certain that the risk of these serious non-AIDS conditions will increase as a result of sustained moderate immunodeficiency or lengthy cumulative exposure to antiretroviral drugs. To reduce the risk of these serious non-AIDS conditions in ageing, people living with HIV will require careful monitoring of risk factors on a regular basis, and appropriate risk reduction treatments such as lipid or blood pressure lowering medications, anti-diabetic treatment, hepatitis C virus antiviral treatment in co-infected patients, and smoking cessation support, ideally without compromising the patient’s antiretroviral therapy and immune status. Our calculations required estimates of non-AIDS-associated mortality and application of these estimates to predict likely numbers of MSM living with HIV. Modelling MSM in this context had the advantage of being a group where the corresponding uninfected cohort would exhibit mortality not different to the general population, unlike individuals exposed through injecting drug use. However, individuals exposed through heterosexual contact would be expected to exhibit a similar trend in terms of non-AIDS associated mortality exceeding AIDS deaths. Moreover, given that MSM compose the majority of those living with HIV in Australia, the trends exhibited in this group reflect the entire HIV/AIDS epidemic in Australia. In summary, our analyses indicate an increasing and rapidly ageing population living with HIV in Australia. This will inevitably lead to more serious non-AIDS conditions in ageing patients living with HIV, and to increased treatment complexity. Conflicts of interest None declared.

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Acknowledgement

13 National Centre in HIV Epidemiology and Clinical Research. HIV/ AIDS, Hepatitis C and Sexually Transmissible Infections in Australia Annual Surveillance Report 1999. Sydney: National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales; 1999. 14 Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS 2007; 21: 1957–63. doi: 10.1097/ QAD.0b013e3282ed6338 15 Carr A, Grund B, Neuhaus J, El-Sadr WM, Grandits G, Gibert C, et al. Asymptomatic myocardial ischaemia in HIV-infected adults. AIDS 2008; 22: 257–67. 16 Petoumenos K, Law MG. Risk factors and causes of death in the Australian HIV Observational Database. Sex Health 2006; 3: 103–12. doi: 10.1071/SH05045 17 Lewden C, Salmon D, Morlat P, Bevilacqua S, Jougla E, Bonnet F, et al. Causes of death among human immunodeficiency virus (HIV)infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol 2005; 34: 121–30. doi: 10.1093/ije/dyh307 18 Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report, 2005. Volume 17, Rev ed. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2007. 19 Manfredi R, Calza L, Cocchi D, Chiodo F. Antiretroviral treatment and advanced age: epidemiologic, laboratory, and clinical features in the elderly. J Acquir Immune Defic Syndr 2003; 33: 112–4. 20 Hinkin CH, Hardy DJ, Mason KI, Castellon SA, Durvasula RS, Lam MN, et al. Medication adherence in HIV-infected adults: effect of patient age, cognitive status, and substance abuse. AIDS 2004; 18(Suppl 1), S19–25. doi: 10.1097/00002030-20040100100004 21 Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006; 166: 1632–41. doi: 10.1001/archinte.166.15.1632 22 Monforte A, Abrams D, Pradier C, Weber R, Reiss P, Bonnet F, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008; 22: 2143–53. doi: 10.1097/QAD.0b013e3283112b77 23 Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356: 1723–35. doi: 10.1056/NEJMoa062744 24 Friis-Moller N, Weber R, Reiss P, Thiebaut R, Kirk O, d’Arminio Monforte A, et al. Cardiovascular disease risk factors in HIV patients – association with antiretroviral therapy. Results from the DAD study. AIDS 2003; 17: 1179–93. doi: 10.1097/00002030-200305230-00010

We thank B. Donovan and D. Wilson for valuable comments. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales. Its work is overseen by the Ministerial Advisory Committee on AIDS, Sexual Health and Hepatitis. The NCHECR Surveillance Program is a collaborating unit of the Australian Institute of Health and Welfare.

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Manuscript received 12 August 2008, accepted 15 January 2009

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