In the scenarios considered above, the risk of death for a person with a given AIDS condition was assumed to be the same, regardless of whether the AIDS event occurred at diagnosis or under follow-up. We performed a sensitivity analysis to estimate the life expectancy if in the low diagnosis rate scenario, we instead assumed a three-fold raised risk of AIDS-related deaths occurring at HIV diagnosis (on the basis that delays in diagnosis can lead to more serious disease). This resulted in a life expectancy of 68.0 years (Table 1). In other sensitivity analyses, we altered the rate of ART interruption under the assumption of a high diagnosis rate. Increasing the rate by 10-fold in those with low tendency to adhere (compared with 1.5-fold in the initial model) resulted in a life expectancy of 73.8 years, whereas reducing the rate of interruption to zero (regardless of adherence level) resulted in a life expectancy of 76.5 years. Assuming a high diagnosis rate, we also altered the probability of initiation of ART. We assessed the effect of both a higher rate and lower rate of uptake than what we speculate is being observed; however, both scenarios did not impact much on predicted life expectancy (Table 1).
In order to attempt to fully quantify the uncertainty associated with our life expectancy estimate, we investigated the effect of plausible variations in parameter values. A total of 10 000 runs of the model were made, each time sampling at random, values for a number of different key parameters in order to generate the distribution of life expectancy in the multivariable sensitivity analysis. The median life expectancy from this analysis was 73.8 years and the 95% uncertainty bounds were 68.0 and 77.3 years. Further details are given in the Supplementary Material (http://links.lww.com/QAD/A193).
It was projected that a relatively high proportion (41%) will at some point in their lifetime develop an AIDS condition. This arises largely due to the fact that in our model, there is a small risk of AIDS occurring even at higher CD4 cell counts and because of our assumption that a high proportion of people will interrupt ART at least once. There are also rapid consequences in terms of viral load increase and CD4 cell count depletion in our model. Estimated life expectancy increased by 1.5 years when it was assumed that no treatment interruptions occurred. Our rates of interruption were based on observed proportions of ART-experienced people on ART .
In the initial model, we assumed a high rate of diagnosis, consistent with that currently observed in data on MSM in the UK . When we instead assumed a much lower rate of diagnosis (such that the CD4 cell count at diagnosis was 140 cells/μl instead of 432 cells/μl), this increased the death rate within 10 years from diagnosis, but the effect on life expectancy after this period was more modest. This is due to the durable effects of ART, even in those who start ART when their CD4 cell count is low [32,33]. However, late diagnoses can and should be prevented by increased access and uptake of HIV testing. Figure 1 emphasizes the importance of early diagnosis and the substantial difference it makes to the death rates, especially in the first 20 years after infection. Furthermore, under the assumption of a low diagnosis rate, we estimated that 42% would present with AIDS at diagnosis (Table 2). Late diagnoses not only reduce the life expectancy of the HIV-positive person but also impact on the probability of onward transmission because treatment, which reduces infectivity, is also delayed.
We did not assume an increased risk of death associated with the use of any specific antiretrovirals. Despite evidence that some drugs lead to an increased risk of myocardial infarction and possible impairment of liver and kidney functions [21,34–38], we assumed that the direct effect of antiretrovirals on mortality would be minimal, as drugs with severe adverse effects would probably not be used from 2010 due to the considerable choice of drugs available. However, we did assume a lifelong 1.5-fold increased risk of non-AIDS deaths compared with the general population, due to presence of HIV infection per se. Bearing in mind that most people are predicted to have viral suppression and high CD4 cell counts for most of their lives, this may well be a pessimistic assumption, resulting in underestimation of life expectancy.
As our model takes into account the predicted durability of ART (using estimates of virologic failure and resistance emergence rates [32,39–41]), our approach to estimating life expectancy differs from that employed in analyses of cohort studies which have been based on the assumption that current death rates will remain unchanged [4,6,7]. The fact that risks appear to decrease as the CD4 cell count is increased with more durable viral load suppression means that such an assumption is also likely to be pessimistic . Another key difference with some previous assessments is that we started on the basis of a person being infected with HIV in 2010, rather than a person with HIV presenting for healthcare in 2010.
Our projected life expectancy after entry into healthcare (median 41.5 years) is much longer than the value of 24.2 years generated from the model used by Schackman et al.  and values generated by many others [42–45]. It is also higher than those calculated from both cohort data and surveillance data in recent years; Lohse et al.  calculated median survival to be 38.9 years among patients with HIV from age 25 years without hepatitis co-infection in the Danish HIV Cohort Study, whereas Harrison et al.  estimated an average 22.5 years of survival after diagnosis in 2005 using surveillance data in the USA. It is likely that this difference in life expectancy is partially due to the fact that data emerging from treated patient cohorts in recent years have shown still increasing prevalence of viral load suppression in treated patients and continuing very low rates of virologic failure in patients with viral suppression and increased regimen stability [13,14,46,47]. Walensky et al.  observed an increasing trend in life expectancy with growing numbers of antiretrovirals and increasing potency and tolerability. The higher life expectancy estimated by our model could also be explained by the fact that patients are assumed to start ART with combination therapy and because we also assumed that they are neither co-infected with hepatitis, nor do they inject drugs. In fact, it has been estimated recently that asymptomatic treatment-naive patients have near-normal life expectancy, based on their current death rates . Our life-expectancy estimate is also somewhat higher than that found in a study by the Antiretroviral Therapy Cohort Collaboration  which estimated that survival for a person aged 20 years initiating combination ART was 49.4 years, although the life expectancy of 69.4 years is within our uncertainty bounds of (68.0, 77.3).
There are several limitations that should be considered. The main limitations relate to those inherent in modelling a process and then using that model to predict many years into the future. Our model has been shown to encapsulate the main features of HIV progression and the effect of ART, as they are currently understood fairly closely (see reference [13,17] and Supplementary Material, http://links.lww.com/QAD/A193). However, any model is at best an approximation to the truth and the effects of any model misspecification could be amplified due to the extremely long simulation period. We also make several assumptions in the model in order to make these projections. We assume that testing and treatment guidelines and the current standard of care will remain as they are now and we do not incorporate changes which may happen in the future. We assume that all-cause death rates will remain fixed at 2009 levels, instead of assuming that the current downward trend will continue . We also assume that adherence to ART will remain stable over time and not decline. There is some recent evidence that this is the case for over 10 years , but only time will tell whether this is the case for the 40–50 years that will be required by many. In addition as discussed above, we take no account of any increased risk of death associated with some antiretroviral drugs. With currently available drugs, such risks are likely to be small, but in the future as more data on the long-term effects of drugs become available, it will be possible to refine and update our model, incorporating new drugs and resistance mutations. We did not estimate life expectancy for females which would require using death rates amongst females in the UK. However, as a large proportion of HIV-positive females living in the UK are not originally from the country (whereas a large proportion of MSM are), it is uncertain whether those rates apply. Finally, our estimates at this stage do not apply to people with hepatitis co-infection.
In summary, based on continuing low rates of virologic failure in treated patients, predicted life expectancy in people with HIV is high in settings with access to multiple antiretroviral drugs. Delays in diagnosis pose the greatest risk of excess mortality for people with HIV. Despite recent progress in the testing, treatment and care of HIV infected patients, there is still room for improvement such that life expectancy reaches the same as that of the non-infected population.
The authors acknowledge the use of the University College London Legion High Performance Computing facility, and associated services, in the completion of this work.
F.N. and A.N.P. were involved in model programming. A.N.P. and J.D.L. helped develop the original model. F.N. drafted the manuscript. All authors were involved in the conception of the article, interpretation of results, critical revisions of the paper and approved the final version.
There are no conflicts of interest.
1. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection
. N Engl J Med
2. Lima VD, Harrigan R, Bangsberg DR, Hogg RS, Gross R, Yip B, et al. The combined effect of modern highly active antiretroviral therapy regimens and adherence on mortality over time
. J Acquir Immune Defic Syndr
3. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection
4. Lohse N, Hansen ABE, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, et al. Survival of persons with and without HIV infection in Denmark, 1995–2005
. Ann Intern Med
5. 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
6. Hogg R, Lima V, Sterne JAC, Grabar S, Battegay M, Bonarek M, et al. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies
7. van Sighem A, Gras L, Reiss P, Brinkman K, de Wolf F. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals
8. May MT, Sterne JAC, Costagliola D, Sabin CA, Phillips AN, Justice AC, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis
9. Sterne JAC, Hernan MA, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study
10. Staszewski S, Miller V, Sabin C, Schlecht C, Gute P, Stamm S, et al. Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy
11. Chadborn TR, Delpech VC, Sabin CA, Sinka K, Evans BG. The late diagnosis and consequent short-term mortality of HIV-infected heterosexuals (England and Wales)
12. Schackman BR, Gebo KA, Walensky RP, Losina E, Muccio T, Sax PE, et al. The lifetime cost of current human immunodeficiency virus care in the United States
. Med Care
13. Bansi L, Sabin C, Delpech V, Hill T, Fisher M, Walsh J, et al. Trends over calendar time in antiretroviral treatment success and failure in HIV clinic populations
. HIV Med
14. Lampe FC, Smith CJ, Madge S, Loes SKD, Tyrer M, Sabin CA, 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
15. Lampe FC, Gatell JM, Staszewski S, Johnson MA, Pradier C, Gill MJ, et al. Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002
. Arch Intern Med
16. Gill VS, Lima VD, Zhang W, Wynhoven B, Yip B, Hogg RS, et al. Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection
. Clin Infect Dis
17. 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
18. Health Protection Agency, CD4 Surveillance Scheme, Centre for Infections.
Survey results to the end of 2009. http://http://www.hpa.org.uk
/web/HPAweb&HPAwebStandard/HPAweb_C/1203064758366. [Accessed 6 June 2011]
19. Kuller LH, Ockene JK, Meilahn E, Wentworth DN, Svendsen KH, Neaton JD. Cigarette-smoking and mortality
. Prev Med
20. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity
21. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS
22. Frisch M, Biggar RJ, Engels EA, Goedert JJ. for the AIDS-Cancer Match Registry Study GroupAssociation of cancer with AIDS-related immunosuppression in adults
23. Herida M, Mary-Krause M, Kaphan R, Cadranel J, Poizot-Martin I, Rabaud C, 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
24. Maggi P, Quirino T, Ricci E, De Socio GVL, Gadaleta A, Ingrassia F, et al. Cardiovascular risk assessment in antiretroviral-naive HIV patients
. AIDS Patient Care STDS
25. Francisci D, Giannini S, Baldelli F, Leone M, Belfiori B, Guglielmini G, et al. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction
26. Lewden C, Chene G, Morlat P, Raffi F, Dupon M, Dellamonica 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
27. Lodwick RK, Sabin CA, Porter K, Ledergerber B, van Sighem A, Cozzi-Lepri A, et al. Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per μL in Europe and North America: a pooled cohort observational study
28. Office of National Statistics. Mortality statistics: deaths registered in 2009. http://http://www.statistics.gov.uk
/downloads/theme_health/dr2009/dr-09.pdf. [Accessed 6 June 2011]
29. Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease
. Arch Intern Med
30. Bronnum-Hansen H, Juel K. Abstention from smoking extends life and compresses morbidity: a population based study of health expectancy among smokers and never smokers in Denmark
. Tob Control
31. Phillips AN, Leen C, Wilson A, Anderson J, Dunn D, Schwenk A, et al. Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study
32. Phillips AN, Staszewski S, Weber R, Kirk O, Francioli P, Miller V, et al. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load
33. Re MC, Ramazzotti E, Manfredi R, Furlini G, Vignoli M, Maldini C, et al. Viral load trend in HIV-1 seropositive patients with different CD4 cell counts before starting HAART
. J Clin Virol
34. Friis-Moller N, Sabin CA, Weber R, Monforte AD, El-Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction
. N Engl J Med
35. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D : A : D study: a multicohort collaboration. Lancet
36. Kovari H, Ledergerber B, Peter U, Flepp M, Jost J, Schmid P, et al. Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case–control study
. Clin Infect Dis
37. Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects
. J Infect Dis
38. Kirk O, Mocroft A, Reiss P, De Wit S, Sedlacek D, Beniowski M et al. Chronic kidney disease and exposure to ART in a large cohort with long-term follow-up: the EUROSIDA study
[#107LB]. In: Proceedings of the 17th Conference on Retroviruses and Opportunistic Infections
; 16–19 February 2010; San Francisco, CA, USA.
39. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study
40. The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS
41. The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long-Term probability of detecting drug-resistant HIV in treatment-naive patients initiating combination antiretroviral therapy. Clin Infect Dis
42. Paltiel AD, Weinstein MC, Kimmel AD, Seage GR, Losina E, Zhang H, et al. Expanded screening for HIV in the United States: an analysis of cost-effectiveness
. N Engl J Med
43. King JT, Justice AC, Roberts MS, Chang CCH. Long-term HIV/AIDS survival estimation in the highly active antiretroviral therapy era
. Med Decis Making
44. Braithwaite RS, Justice AC, Chang CCH, Fusco JS, Raffanti SR, Wong JB, et al. Estimating the proportion of patients infected with HIV who will die of comorbid diseases
. Am J Med
45. Fang CT, Chang YY, Hsu HM, Twu SJ, Chen KT, Lin CC, et al. Life expectancy of patients with newly-diagnosed HIV infection in the era of highly active antiretroviral therapy
46. Lodwick RK, Smith CJ, Youle M, Lampe FC, Tyrer M, Bhagani S, et al. Stability of antiretroviral regimens in patients with viral suppression
47. Mocroft A, Ruiz L, Reiss P, Ledergerber B, Katlama C, Lazzarin A, et al. Virological rebound after suppression on highly active antiretroviral therapy
48. Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. The survival benefits of AIDS treatment in the United States
. J Infect Dis
49. Cambiano V, Lampe FC, Rodger AJ, Smith CJ, Geretti AM, Lodwick RK, et al. Long-term trends in adherence to antiretroviral therapy from start of HAART