Mills and colleagues have investigated life expectancy and survival in people receiving ART in Uganda [27▪▪,32,33]. In one study, they found that life expectancy was 26.7 years at age 20, approaching the overall rate for all young adults in Uganda [27▪▪]. Similar to the observations seen in resource-rich settings, there was substantial variability in the life expectancy depending on the patient's age, sex, and CD4 count at baseline [27▪▪]. Most of these patients were treated with older regimens than those currently used in the USA and Western Europe.
Since the roll out of ART, adult life expectancy has increased in a South African population cohort, where 28% of adults are infected with HIV . In 2003, the expected age at death was 52 years, but by 2011, this figure was 61. In this study, Bor et al. also found that treatment costs were far outweighed by the economic value of gain in life expectancy.
Although developed primarily for cost-effectiveness analyses, the CEPAC model (a state-transition Monte Carlo simulation of HIV-infected individuals) has been used extensively to answer many research questions [17,18,29▪▪,35,36]. In one study, Sloan et al. [29▪▪] estimated the mean life expectancy for a simulated cohort with mean age of 38 years to be 26.5 years, assuming ART was initiated when CD4 counts fell below a threshold of 350 cells/μl. If patients presented earlier and ART was assumed to be initiated when CD4 counts fell below 500 cells/μl or if the HIV viral load was over 100 000 copies/ml, life expectancy increased slightly to 27.4 years.
Nakagawa and colleagues used their previously developed stochastic simulation model of HIV progression to project the life expectancy of men who have sex with men (MSM) in the UK [10,40,41]. The median life expectancy for MSM infected in 2010 at age 30 was estimated to be 45 years . This assumed that no one had hepatitis coinfection, 40% were lifelong smokers and the median CD4 count at diagnosis was 432 cells/μl. If the median CD4 count at diagnosis declined to 140 cells/μl, the median life expectancy dropped to 41.5 years. The authors suggest that their estimates of life expectancy are much higher than in most other studies because the model takes into account the long-term durable effects of therapy using current estimates of rates of virologic failure and resistance emergence and, therefore, over time the CD4 count increases and mortality rates decrease.
The major assumption made in all life expectancy calculations is that age-specific mortality rates estimated at a given point in time will apply throughout the individual's entire lifespan. This does not allow for potential improvements in mortality rates over time, which has been observed in both the HIV-infected population and the general population [42,43], and any estimates may therefore be an underestimation. Some studies  have taken into account that relative to HIV-negative populations, there is a late fall in survival because of increased mortality associated with several non-AIDS-related causes.
Methods to estimate life expectancy can be broadly split into two approaches: life table approach and use of mathematical models. Both approaches rely on data from cohort studies to either construct life tables or to inform the models, but there are some limitations inherently associated with the use of cohort studies. For example, patients followed up in cohort studies may have better HIV care and therefore better overall prognosis because of their participation in various research studies, although this is not always the case as in some cohorts data is collected as part of routine care. Under-ascertainment of deaths can also occur, which would lead to an overestimation of life expectancy.
The main limitation when using the life table approach is the under-ascertaining of death, combined with the lack of mortality data in older age groups, where the majority of the deaths occur in the comparator background population. Also unlike regression analyses, life tables do not adjust for covariates and therefore results need to be interpreted carefully.
One advantage of mathematical models is the ability to account for the long-term durability of ART and the subsequent decrease in mortality rates, which should ensure that life expectancy is not underestimated in people with HIV. However, it is important to note that mathematical models make many assumptions about the natural course of HIV progression as well as the effect of ART. Additionally, in the case of estimating life expectancy, considerable uncertainty is introduced by simulating very long periods of time.
A consequence of increased life expectancy is that the number of deaths from non-AIDS-related conditions now considerably exceeds the number of AIDS deaths in resource-rich settings . In particular, non-AIDS malignancies, cardiovascular disease, and hepatic disease (in those with hepatitis coinfection) are now amongst the leading causes of deaths [44,45]. HIV infection itself, as well as long-term use of ART, is also thought to increase the risk of non-AIDS-related diseases, probably, although to a lesser degree, even in people with viral suppression [45–51]. These data support the need for enhanced preventive measures more akin to those used in older people in the general population, such as screening programmes.
Another direct implication of increased life expectancy is that younger patients nowadays will expect to be on treatment for at least three or four decades. Results from the ongoing Strategic Timing of AntiRetroviral Treatment study, which is evaluating the risk/benefit of ART initiation in people with CD4 count greater than 500 cells/μl, compared with deferral to 350 cells/μl, could lead to patients being on treatment earlier . If ‘treatment as prevention’ strategies, such as ‘test-and-treat’ and preexposure prophylaxis (PrEP) regimens, are to be used widely, these could also add to the length of time people are on ART. A large proportion of the lifetime costs related to the care of HIV-infected patients is ascribed to antiretroviral drugs [29▪▪]. Therefore, further cost-effectiveness studies of different regimens need to be done  and it is vital for cheaper, generic drugs to be made available.
As a result of longer life expectancy, HIV will be more prevalent in older people. Ageing in HIV is not yet well studied as it is a relatively new occurrence ; however, the presence of HIV infection may accelerate ageing . The development of age-specific guidelines for HIV is now called for [56▪▪]. Other than guidance on HIV care and clinical management, the guidelines should provide recommendations on screening programmes and additional monitoring of biomarkers, especially for common comorbidities which occur more frequently with increasing age. Therefore, a more integrated approach to managing HIV-related and non-HIV-related diseases may be appropriate, such that people with HIV are seen in general practice and only referred to HIV specialist clinics when viral loads are unsuppressed. This could include lifestyle support, managing cardiovascular risk factors and other chronic diseases, as well as dealing with ART-associated complications such as drug–drug interactions.
As there is now sufficient evidence that the life expectancy of someone with HIV is nearly the same as that of an HIV-negative person, access to life insurance should be more widely available. The improved survival needs to be reflected in premium prices, particularly as survival often improves with age, which is unlike most other chronic diseases such as diabetes, because it takes several years of ART to restore CD4 counts to normal levels.
Many of the studies considered above have shown that life expectancy is longer in people who have a higher CD4 count at HIV diagnosis [10,28,29▪▪]. In the UK, approximately 50% of people are diagnosed late (defined as a CD4 count <350 cells/μl within 3 months of diagnosis)  and there is strong evidence that late diagnosis is associated with poorer prognosis including worse response to treatment and an increased risk for HIV-related morbidity and mortality [58–61]. Therefore, one way to further increase life expectancy of people with HIV is to improve HIV testing rates, particularly in high prevalence areas and perhaps in nontraditional settings. Early diagnosis of HIV will result in individuals starting ART in accordance with guideline recommendations and people being be in care and routinely monitored, both of which will improve life expectancy.
In general, it is recognized that HIV-positive people have an inferior profile of lifestyle risk factors compared to the general population [62–67]. Many of these risk factors, whether HIV-related or not, and which include smoking, alcohol abuse, and recreational drug use, are associated with an increased risk of death [46,62,68▪,69▪▪], and hence investment into support programmes may help to reduce the mortality rates more. The effect of hepatitis C coinfection on HIV is also important to consider, because HIV immunosuppression is associated with faster progression of liver disease in people with hepatitis C .
The risk factors for acquiring HIV are also associated with lower life expectancy . Studies comparing mortality rates in people with HIV and on ART to people without HIV have reported conflicting results [9,72▪,73], although there is some evidence of an increased death rate in individuals who are not yet on treatment because of high CD4 counts compared with the general population (with the exception of MSM with CD4 count >500 cells/μl) . Even if the life expectancy of an HIV-infected person were found to be equal to that of an HIV-negative person, the quality-adjusted life years would probably be less, mostly because of the potential harm resulting from long-term ART usage , but also because of the psychological aspects for some of carrying a lifelong virus, despite it being controlled at very low levels. More research is required on ways in which quality of life could be improved.
The life expectancy of someone living with HIV, especially if they are diagnosed before ART is indicated, is approaching that of HIV-negative individuals; however, it is still not equal (Table 2). Even if life expectancy were to improve further such that it did not differ by HIV status, quality-adjusted life years would almost certainly be less.
The improvement in life expectancy will mean that the number of people with HIV increases and there will be a shift in the age distribution. Further research into the impact of ageing on HIV-positive people will become crucial. Therefore, age-specific HIV treatment guidelines may need to be developed and introduced. Screening programmes and more comprehensive patient management are also required to address comorbidities and risk factors associated with HIV that increasingly occur as people age.
Modelling studies suggest that life expectancy could potentially rise further. Ways in which this could be possible include increased uptake of HIV testing, better antiretroviral regimens and treatment strategies and the adoption of healthier lifestyles by those living with HIV. In particular, earlier diagnosis and enrolment into care is one of the most important factors associated with better life expectancy.
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 100).
2. Cohen MH, French AL, Benning L, et al. Causes of death among women with human immunodeficiency virus infection in the era of combination antiretroviral therapy. Am J Med 2002; 113:91–98.
3. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–860.
4. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 2003; 362:22–29.
5. Mocroft A, Brettle R, Kirk O, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study. AIDS 2002; 16:1663–1671.
6. The Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 2010; 50:1387–1396.
7. Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol 2005; 42:799–805.
8. Bonnet F, Morlat P, Chene G, et al. Causes of death among HIV-infected patients in the era of highly active antiretroviral therapy, Bordeaux, France, 1998–1999. HIV Med 2002; 3:195–199.
9. Van Sighem A, Gras L, Reiss P, et al. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 2010; 24:1527–1535.
10. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS 2012; 26:335–343.
11. Porta M. A dictionary of epidemiology. 5th ed. New York, NY: Oxford University Press. 2008.
12. Chiang CL. The life table and its applications. Malabar (Florida): Robert E Krieger Publishing Company; 1984.
13. Anderson RM, Medley GF. Epidemiology of HIV infection and AIDS: incubation and infectious periods, survival and vertical transmission. AIDS 1988; 2:S57–S63.
14. Lifson AR, Hessol NA, Rutherford GW. Progression and clinical outcome of infection due to human immunodeficiency virus. Clin Infect Dis 1992; 14:966–972.
15. Collaborative Group on AIDS Incubation and HIV Survival and including the CASCADE EU Concerted Action. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Lancet 2000; 355:1131–1137.
16. Nicoll A, Gill ON. The global impact of HIV infection and disease. Commun Dis Public Health 1999; 2:85–95.
17. Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med 2001; 344:824–831.
18. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194:11–19.
19. Wood E, Low-Beer S, Bartholomew K, et al. Modern antiretroviral therapy improves life expectancy of gay and bisexual males in Vancouver's west end. Can J Public Health 2000; 91:125–128.
20. Lima VD, Hogg RS, Harrigan PR, et al. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS 2007; 21:685–692.
21. The Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372:293–299.
22. Lohse N, Hansen ABE, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146:87–95.
23. Phillips AN, Miller V, Sabin C, et al. Durability of HIV-1 viral suppression over 3.3 years with multidrug antiretroviral therapy in previously drug-naive individuals. AIDS 2001; 15:2379–2384.
24. Matthews GV, Sabin C, Mandalia S, et al. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 2002; 16:53–61.
25. Moore RD, Keruly JC. CD4+
cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 2007; 44:441–446.
26. Piroth L, Fournel I, Mahy S, et al. A decision tree to help determine the best timing and antiretroviral strategy in HIV-infected patients. Epidemiol Infect 2011; 139:1835–1844.
27▪▪. Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 2011; 155:209–216.
The first formal study of life expectancy in an African setting, which showed that HIV-infected people in Uganda with good access to combination therapy can expect an almost normal life expectancy.
28. Harrison KM, Song RG, Zhang XJ. Life expectancy after HIV diagnosis based on National HIV Surveillance data from 25 States, United States. J Acquir Immune Defic Syndr 2010; 53:124–130.
29▪▪. Sloan CE, Champenois K, Choisy P, et al. Newer drugs and earlier treatment: impact on lifetime cost of care for HIV-infected adults. AIDS 2012; 26:45–56.
This study showed that although annual costs of treating some with HIV has stayed roughly constant over the years, total lifetime costs have increased as a result of improved life expectancy, which in turn is a result of better and earlier initiation of treatment.
30▪▪. 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.
This study showed that although life expectancy of people with HIV in the UK has improved in the last decade, it is still 13 years shorter than that of the UK population.
31. Braithwaite RS, Roberts MS, Goetz MB, et al. Do benefits of earlier antiretroviral treatment initiation outweigh harms for individuals at risk for poor adherence? Clin Infect Dis 2009; 48:822–826.
32. Bakanda C, Birungi J, Mwesigwa R, et al. Association of aging and survival in a large HIV-infected cohort on antiretroviral therapy. AIDS 2011; 25:701–705.
33. Bakanda C, Birungi J, Mwesigwa R, et al. Survival of HIV-infected adolescents on antiretroviral therapy in Uganda: findings from a nationally representative cohort in Uganda. PLoS One 2011; 6:e19261.
34. Bor J, Herbst AJ, Newell ML, Barnighausen T. Dramatic increases in population life expectancy and the economic value of ART in rural South Africa. 19th International Conference on AIDS; 22nd–27th July 2012; Washington, DC; 2012. abstr. TULBE05.
35. Losina E, Schackman BR, Sadownik SN, et al. Racial and sex disparities in life expectancy losses among HIV-infected persons in the United States: impact of risk behavior, late initiation, and early discontinuation of antiretroviral therapy. Clin Infect Dis 2009; 49:1570–1578.
36. Walensky RP, Park JE, Wood R, et al. The cost-effectiveness of pre-exposure prophylaxis for HIV infection in South African women. Clin Infect Dis 2012; 54:1504–1513.
37. Braithwaite RS, Fiellin DA, Nucifora K, et al. Evaluating interventions to improve antiretroviral adherence: how much of an effect is required for favorable value? Value Health 2010; 13:535–542.
38. Roberts MS, Nucifora KA, Braithwaite RS. Using mechanistic models to simulate comparative effectiveness trials of therapy and to estimate long-term outcomes in HIV care. Med Care 2010; 48:S90–S95.
39. Braithwaite RS, Roberts MS, Chang CCH, et al. Influence of alternative thresholds for initiating HIV treatment on quality-adjusted life expectancy: a decision model. Ann Intern Med 2008; 148:178–185.
40. Bansi L, Sabin C, Delpech V, et al. Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations. HIV Med 2010; 11:432–438.
41. Phillips AN, Sabin C, Pillay D, Lundgren JD. HIV in the UK 1980–2006: reconstruction using a model of HIV infection and the effect of antiretroviral therapy. HIV Med 2007; 8:536–546.
42. Oeppen J, Vaupel JW. Broken limits to life expectancy. Science 2002; 296:1029–1031.
43. Leon DA. Trends in European life expectancy: a salutary view. Int J Epidemiol 2011; 40:271–277.
44. Lewden C, May T, Rosenthal E, et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: the ‘Mortalite 2000 and 2005’ surveys (ANRS EN19 and Mortavic). J Acquir Immune Defic Syndr 2008; 48:590–598.
45. Palella FJJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV Outpatient Study. J Acquir Immune Defic Syndr 2006; 43:27–34.
46. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009; 338:a3172.
47. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS 2008; 22:2409–2418.
48. Frisch M, Biggar RJ, Engels EA, Goedert JJ. for the AIDS-Cancer Match Registry Study GroupAssociation of cancer with AIDS-related immunosuppression in adults. JAMA 2001; 285:1736–1745.
49. Herida M, Mary-Krause M, Kaphan R, et al.
Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 2003; 21:3447–3453.
50. Maggi P, Quirino T, Ricci E, et al. Cardiovascular risk assessment in antiretroviral-naive HIV patients. AIDS Patient Care STDS 2009; 23:809–813.
51. Francisci D, Giannini S, Baldelli F, et al. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS 2009; 23:589–596.
52. Babiker AG, Emery S, Fatkenheuer G, et al.
Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. Clin Trials 2012; doi:10.1177/1740774512440342. [Epub ahead of print]
53. Beck EJ, Mandalia S, Youle M, et al. Treatment outcome and cost-effectiveness of different highly active antiretroviral therapy regimens in the UK (1996–2002). Int J STD AIDS 2008; 19:297–304.
54. Mills EJ, Barnighausen T, Negin J. HIV and aging – preparing for the challenges ahead. N Engl J Med 2012; 366:1270–1273.
55. Effros RB, Fletcher C, Gebo K, et al. Workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 2008; 47:542–553.
56▪▪. Oursler KK, Goulet JL, Crystal S, et al. Association of age and comorbidity with physical function in HIV-infected and uninfected patients: results from the Veterans Aging Cohort Study. AIDS Patient Care STDS 2011; 25:13–20.
This study investigated the effect of age-associated comorbidity on physical function and concluded on the basis of the results that age-related HIV care guidelines should be developed.
58. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008; 197:1133–1144.
59. Hughes MD, Ribaudo HR. The search for data on when to start treatment for HIV infection. J Infect Dis 2008; 197:1084–1086.
60. Stohr W, Dunn DT, Porter K, et al. CD4 cell count and initiation of antiretroviral therapy: trends in seven UK centres, 1997–2003. HIV Med 2007; 8:135–141.
61. Lucas SB, Curtis H, Johnson MA. National review of deaths among HIV-infected adults. Clin Med 2008; 8:250–252.
62. Lloyd-Smith E, Brodkin E, Wood E, et al. Impact of HAART and injection drug use on life expectancy of two HIV-positive cohorts in British Columbia. AIDS 2006; 20:445–450.
63. Friis-Møller N, Sabin CA, Weber R, et al.
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.
64. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3
on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46:72–77.
65. Duval X, Baron G, Garelik D, et al. Living with HIV, antiretroviral treatment experience and tobacco smoking: results from a multisite cross-sectional study. Antivir Ther 2008; 13:389–397.
66. Galvan FH, Bing EG, Fleishman JA, et al. The prevalence of alcohol consumption and heavy drinking among people with HIV in the United States: results from the HIV cost and services utilization study. J Stud Alcohol 2002; 63:179–186.
67. Lampe FC, Smith CJ, Madge S, et al. Success of clinical care for human immunodeficiency virus infection according to demographic group among sexually infected patients in a routine clinic population, 1999 to 2004. Arch Intern Med 2007; 167:692–700.
68▪. Murray M, Hogg RS, Lima VD, et al. The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis. HIV Med 2012; 13:89–97.
A cohort collaboration study determining that injecting drug users are disproportionately at higher risk of AIDS and death, mainly as a result of hepatitis, liver failure, and substance abuse.
69▪▪. Obel N, Omland LH, Kronborg G, et al. Impact of non-HIV and HIV risk factors on survival in HIV-infected patients on HAART: a population-based nationwide cohort study. PLoS One 2011; 6:e22698.
The study compared a population-based cohort of HIV-infected patients with a matched comparison cohort to determine that the increased risk of mortality in HIV-infected patients can be attributed to both HIV-associated and non-HIV-associated risk factors, which were identifiable prior to or in the initial period of ART.
70. Hernandez MD, Sherman KE. HIV/hepatitis C coinfection natural history and disease progression. Curr Opin HIV AIDS 2011; 6:478–482.
71. Beyrer C. HIV epidemiology update and transmission factors: risks and risk contexts – 16th International AIDS Conference epidemiology plenary. Clin Infect Dis 2007; 44:981–987.
72▪. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord; Lewden C, Bouteloup V, DeWit S, et al.
All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3
compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 2012; 41:433–445.
This large-scale cohort study consisting of over 80 000 people demonstrated that the majority of people with high CD4 cells counts, providing they are not injecting drug users, had similar mortality rates to the general population.
73. Rodger A, Lodwick R, Schechter M, et al.
Mortality in patients with well controlled HIV and high CD4 counts in the cART arms of the SMART and ESPIRIT randomized clinical trials compared to the general population. 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2012; Seattle. 2012. Poster #638.
74. Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per mu L in Europe and North America: a pooled cohort observational study. Lancet 2010; 376:340–345.
75. Gebo KA. HIV and aging – implications for patient management. Drugs Aging 2006; 23:897–913.