Definition of Advanced Age in HIV Infection: Looking for an Age Cut-Off

Abstract

The age of 50 has been considered as a cut-off to discriminate older subjects within HIV-infected people according to the Centers for Disease Control and Prevention (CDC). However, the International AIDS Society (IAS) mentions 60 years of age and the Department of Health and Human Services (DHHS) makes no consideration. We aimed to establish an age cut-off that could differentiate response to highly active antiretroviral therapy (HAART) and, therefore, help to define advanced age in HIV-infected patients. CoRIS is an open, prospective, multicenter cohort of HIV adults naive to HAART at entry (January 2004 to October 2009). Survival, immunological response (IR) (CD4 increase of more than 100 cell/ml), and virological response (VR) (HIV RNA less than 50 copies/ml) were compared among 5-year age intervals at start of HAART using Cox proportional hazards models, stratified by hospital and adjusted for potential confounders. Among 5514 patients, 2726 began HAART. During follow-up, 2164 (79.4%) patients experienced an IR, 1686 (61.8%) a VR, and 54 (1.9%) died. Compared with patients aged <25 years at start of HAART, those aged 50–54, 55–59, 60–64, 65–59, and 70 or older were 32% (aHR: 0.68, 95% CI: 0.52–0.87), 29% (aHR: 0.71, 95% CI: 0.53–0.96), 34% (aHR: 0.66, 95% CI: 0.46–0.95), 39% (aHR: 0.61, 95% CI: 0.37–1.00), and 43% (aHR: 0.57, 95% CI: 0.31–1.04) less likely to experience an IR. The VR was similar across all age groups. Finally, patients aged 50–59 showed a 3-fold increase (aHR: 3.58; 95% CI: 1.07–11.99) in their risk of death compared to those aged <30 years. In HIV infection, patients aged ≥50 years have a poorer immunological response to HAART and a poorer survival. This age could be used to define medically advanced age in HIV-infected people.

Introduction

Aging is a physiological fact that affects all living things. This process is accelerated in HIV-infected patients^1
–3 and, although highly active antiretroviral therapy (HAART) has slowed this process, it is uncertain as to whether this can be fully restored.

Even though most epidemiological studies in the general population do not consider patients ≥50 years as “elderly,” in the case of HIV infection the Centers for Disease Control and Prevention (CDC) has done so arguing that they are a special population.⁴ Based on this arbitrary age cut-off it is generally accepted that HIV-infected patients who start HAART after this age will have a poorer immunological response^{5

–15} and a better virological response.^{5,8,9,15

–19} compared with younger patients. Other studies have found mixed results.

The increasing awareness of the potential implications for health outcomes of the aging process of HIV-infected subjects has also led to the inclusion of age as a key variable for deciding when to initiate HAART in different guidelines. However, there is no consensus on what is the best age cut-off. The European AIDS Clinical Society (EACS) recommended it in patients >50 years,²⁰ the Spanish GESIDA in those >55 years,²¹ and the International AIDS Society (IAS) in >60 years.²² More recently the Department of Health and Human Services (DHHS) recommend it in patients >50 years.²³

The clinical relevance of this problem encouraged us to carry out the present study in a large prospective, hospital-based multicenter cohort of HAART-naive HIV subjects in Spain from 2004 to 2009. Our aim was to study the impact of the age at HAART initiation as a predictor of the immunological response and virological response as well as survival.

Materials and Methods

CoRIS is an open, prospective, multicenter cohort of HIV-positive subjects, over 13 years of age, who initiated care for the first time at the recruiting centers after January 1, 2004 and were naive for antiretrovirals at entry. CoRIS is linked to a BioBank.²⁴ Approval has been obtained from all Hospitals Ethics Committees and all patients have signed an informed consent.²⁵

CoRIS is a joint activity of the Research Network of Excellence (AIDS research network, RIS) that incorporates basic scientists, immunologists, virologists, clinicians, epidemiologists, and statisticians. A total of 27 hospitals from 13 of the 17 Autonomous Regions of the country participate in CoRIS. Cohort members are followed according to each hospital clinical routine, usually every 3–6 months. Internal quality controls are performed twice annually and 10% of data are externally audited every year.

Antiretroviral-naive patients starting HAART from January 1, 2004 to October 31, 2009 (administrative censoring date) were considered for inclusion. We excluded patients who did not have at least one CD4 cell count and viral load measurements in the 6 months prior to HAART initiation and at least two CD4 cell count and viral load measurements following the start of HAART.

Immunological response was defined as an increase of at least 100 cells/ml in CD4 cell count from pre-HAART levels confirmed in two consecutive measurements. Virological response was defined as two consecutive viral loads <50 copies/ml.¹⁴ The clinical endpoint considered was death from any cause.

Statistical analyses

For each individual, follow-up began on the date of starting HAART and ended on the date of last recorded CD4 cell count or viral load measurement for time to immunological and virological response analyses, respectively, or the date of last contact for time to death analyses.

Age at HAART was initially divided into the following age intervals: <25, 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, and 70 years or older. However, 10-year age groups were considered for time to death analyses due to the small number of deaths.

The impact of age on the time to immunological response, virological response, and death from any cause was assessed using Cox proportional hazard models. All models were stratified by hospital, and adjusted for sex, transmission category, educational level, country of origin, pre-HAART CD4 cell count and viral load, pre-HAART AIDS diagnosis, year of HAART initiation, and hepatitis C virus (HCV).

All analyses were performed using Stata 11.

Results

Among 5514 patients included in CoRIS, 3523 (64%) started HAART between January 1, 2004 and October 31, 2009. Of those, 282 (8%) had no viral load and CD4 cell count in the 6 months prior to start of HAART and 515 (15%) did not have a minimum of two measurements of viral load and CD4 cell count following HAART initiation. The sociodemographic and clinical characteristics of 2726 patients included are shown in Table 1.

Table 1.

Sociodemographic and Clinical Characteristics of 2726 Patients Included

Median age at start of HAART [years (IQR)]	38 (31–44)
Age at start of HAART [n (%)]
<25	171 (6.3)
25–29	386 (14.2)
30–34	536 (19.7)
35–39	524 (19.2)
40–44	478 (17.5)
45–49	275 (10.1)
50–54	167 (6.1)
55–59	97 (3.6)
60–64	49 (1.8)
65–69	28 (1.0)
>70	15 (0.6)
Sex [n (%)]
Men	2101 (77.1)
Women	625 (22.9)
Educational level [n (%)]
No studies	176 (6.5)
Primary school	884 (32.4)
Secondary school	783 (28.7)
University studies	432 (15.9)
Unknown	451 (16.5)
Country of origin [n (%)]
Europe (mainly Spain)	1908 (70.0)
Latin America	463 (17.0)
Sub-Saharan Africa	172 (6.3)
Other/unknown	183 (6.7)
Transmission category [n (%)]
MSM	1155 (42.4)
Heterosexual	1071 (39.3)
IDU	384 (14.1)
Other/unknown	116 (4.2)
Median CD4 cell count at start of HAART [cells/mm³ (IQR)]	211 (83–307)
CD4 cell count at start of HAART (cells/mm³) [n (%)]
<200	1264 (46.4)
200–350	1026 (37.6)
>350	436 (16)
Median VL at start of HAART [copies/ml (IQR)]	85,000 (22,964–226,725)
VL at start of HAART (copies/ml) [n (%)]
<100,000	1568 (57.5)
≥100,000	1158 (42.5)
AIDS diagnosis at start of HAART [n (%)]
No	2110 (77.4)
Yes	616 (22.6)
Year of HAART Initiation [n (%)]
2004–2005	786 (28.8)
2006–2007	1060 (38.9)
2008–2009	880 (32.3)
Hepatitis C virus coinfection [n (%)]
No	1963 (72.0)
Yes	459 (16.8)
Unknown	304 (11.2)

IQR, interquartile range; IDU, injecting drug user; MSM, men who have sex men; VL, viral load.

During the follow-up, 2164 (79.4%) patients experienced an immunological response. The chance of experiencing an immunological response decreased as age increased (Fig. 1a). Compared with patients aged less than 25 years at start of HAART, those aged 50–54, 55–59, 60–64, 65–59, and 70 or older were 32% (aHR: 0.68, 95% CI: 0.52–0.87), 29% (aHR: 0.71, 95% CI: 0.53–0.96), 34% (aHR: 0.66, 95% CI: 0.46–0.95), 39% (aHR: 0.61, 95% CI: 0.37–1.00), and 43% (aHR: 0.57, 95% CI: 0.31–1.04) less likely to experience an immunological response. The chance of experiencing an immunological response was also associated with having acquired HIV infection through homosexual/bisexual intercourse, higher educational level, European origin, lower pre-HAART CD4 cell counts, higher pre-HAART viral load, AIDS diagnosis at start of HAART, later years of starting HAART, and no HCV coinfection (data not shown).

FIG. 1.

Crude and adjusted hazard ratios of the impact of age on time to (a) immunological response, (b) virological response, and (c) death from start of highly active antiretroviral therapy (HAART).

There were significant differences in the median pre-HAART CD4 cell count according to age at start of HAART (p<0.001), with the highest CD4 cell count in patients aged less than 25 years and declining thereafter. In all age groups, the median CD4 cell count increased rapidly in the first 6 months after HAART initiation to follow a more gradual increase thereafter (Fig. 2).

FIG. 2.

Median CD4 cell count over time according to age group.

During the follow-up, 1686 (61.8%) patients experienced a virological response, with those aged less than 25 years at HAART initiation showing the greatest chance of response. Among patients aged 25 years or older, the chance of experiencing a virological response was similar across age groups (Fig. 1b).

Other predictors of achieving a virological response were European origin, lower pre-HAART CD4 cell counts, higher pre-HAART viral load, earlier years of starting HAART, and no coinfection with HCV (data not shown).

A total of 54 (1.9%) patients died. Of all patients for whom information on the cause of death was available, 75% died of non-AIDS-related causes. No significant differences in the risk of death were found between patients aged 30–39 (aHR: 1.36; 95% CI: 0.43–4.34) or 40–49 (aHR: 1.27; 95% CI: 0.38–4.21) and those aged less than 30 years. However, patients aged 50–59 showed a 3-fold increase (aHR: 3.58; 95% CI: 1.07–11.99) in their risk of death compared to those aged less than 30 years (Fig. 1c). Other predictors of mortality were male sex, lower educational level, AIDS diagnosis at start of HAART, and HCV coinfection.

Discussion

In this large cohort of HIV-infected patients with recent initiation of antiretroviral treatment, we have found that an age of 50 years or more clearly impacts the immunological response and the survival of HIV-infected patients after starting HAART with no effect on the virological response. Our results may have clinical importance. It gives support to current recommendations of initiating antiretroviral therapy after a given age irrespective of other criteria, and establishes the cut-off at which this recommendation should be considered.

As far as immune status is concerned, the determinants of recovery are not entirely clear and seem to depend on both host and virus (HIV).²⁶ In relation to the host most studies suggest that the immune response to HAART decreases with age.^{5

–15} These results are also observed in our study showing a worse immunological recovery in patients aged 50 years or over. However, this has not been observed by other authors.^{16,18,19,27

–33} Perhaps the higher prevalence of delayed HIV described in older patients may contribute to their poorer immune response.^{30,32,34

–38} In this sense, we found a late diagnosis of HIV infection in 53.3% of the patients >50 years vs. 21.5% in those <30 years (p<0.001).³⁹ Similar findings were reported by Smith et al., with almost half of patients ≥50 years being late presenters compared to 33% of younger adults (p<0.001).³⁸ We have shown that the immunological response is lower in patients ≥50 years and is not modified by other variables.

In our study, 61.8% of patients experienced a virological response during the follow-up. Many authors have found no differences in virological control according to age,^{7,10,12,27

–32,40} and, moreover, some have found a better virological response in older patients.^{5,8,9,15

–19} In our case the virological response was similar across all age groups but improved significantly in patients over 60 years. The best virological control in elderly patients has been associated with better adherence to antiretroviral therapy (ART),^{18,28,41
–43} despite the fact that many of them take other treatments (e.g., antihypertensives, antidiabetics). For some authors the best virologic control during the first year of ART in patients ≥50 years was entirely explained by better adherence,¹⁸ while others have observed that this better virological control persists regardless of the degree of adherence, the treatment regimen, and the stage of the CDC.⁹ In our study the impact of age on virological response is similar in all the groups and is not modified by other variables, as shown in our analysis.

Overall mortality of patients with HIV infection has decreased significantly in the era of HAART.^44,45 This has been due in particular to the decrease in deaths related to AIDS events while the proportion of deaths related to non-AIDS events (cardiovascular, liver, and tumors) has increased.^44,46,47 In our series 2% of the patients died. Among patients in whom a cause of death was identified (85%), 24% died of an AIDS event (63.6% noninfectious) and 76% of an event not related to AIDS (76.4% of noninfectious cause). These results differ from those found by other authors who noted that the main causes of death in the period from 1996 to 2004 were AIDS events (49.6%), and within them those related to infectious processes (46.2%).⁴⁷ The difference may be explained by the more recent initiation of our cohort, which included patients who started therapy after 2004.

Mortality is higher among older patients,^{16,18,19,30,46,48,49} which has also been observed in patients between 50 and 59 years in our study. This association is not seen in those aged more than 60 years probably due to the small sample size of this group. Gutiérrez et al.⁵⁰ observed that the greater progression to AIDS events or death among older people persists after adjusting for CD4 lymphocyte count in patients on HAART and a sustained virological response. The increased mortality in older patients may be related to age as a predictor of disease progression, diagnostic delay,^{30,32,34

–38} the presence of comorbidities,^{17,18,29,30,51} or the presence of AIDS or not AIDS,^17,52,53 among others. Other authors have not found an association between mortality and age.^19,44,54

We must recognize some limitations in our study. One of the limitations common to all cohort studies is that they may not be representative of all HIV-infected patients. However, this cohort includes patients from all over Spain with a broad spectrum of patient characteristics and antiretroviral regimens. Also their number is high, limiting the bias of other studies with a smaller sample size. Similarly our cohort is subjected to quality controls limiting errors related to the collection of information. The results should therefore be applicable to many individuals with HIV-1 infection beginning HAART in Spain and elsewhere. In summary, our result indicates that being 50 years of age or older is one of the variables that determines the immunological response and survival of patients with HIV infection. Further studies addressing the when to start question for different age cut-offs using causal methods are warranted.

Footnotes

Acknowledgments

This study would not have been possible without the collaboration of all the patients, medical and nursery staff, and data managers who have taken part in the project. The RIS Cohort (CoRIS) is funded by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RIS RD06/006). Dr. José R. Blanco is a recipient of an INT 11/68 Intensification Research Grant (13SNS) from the Instituto de Salud Carlos III, Madrid, Spain. Members of the CoRIS Group are: Berenguer J, del Amo J, García F, Gutiérrez F, Labargo P, Moreno S, Muñoz MA, Caro-Murillo AM, Vegas PS, Pérez-Cachafiero S, Sebastián VH, Ferreras BA, Alvarez D, Monge S, Jarrin I, Trastoy M, Muñoz-Fernández MA, García-Merino I, Rico CG, de la Fuente JG, Almudena GT, Sogorb JP, de Lucas EM, Bañuls SR, Martínez VB, Oncina LG, Pastor CG, Tamarit IP, Toledo PA, Sirvent JL, Fortúnez PR, Valls MR, Socas Mdel M, Lirola AM, Hernández MI, Díaz-Flores F, Soriano V, Labarga P, Barreiro P, Castañares C, Rivas P, Ruiz A, Blanco F, García P, de Diego M, Asensi V, Valle E, Cartón JA, Miró JM, López-Dieguez M, Manzardo C, Zamora L, Pérez I, García MT, Ligero C, Blanco JL, García-Alcaide F, Martinez E, Mallolas J, Gatell JM, Rubio R, Pulido F, Fiorante S, Llenas J, Rodríguez V, Matarranz M, Iribarren JA, Arrizabalaga J, Aramburu MJ, Camino X, Rodríguez-Arrondo F, von Wichmann MA, Tomé LP, Goenaga MA, Bustinduy MJ, Galparsoro HA, Gutiérrez F, Masiá M, Ramos JM, Padilla S, Navarro A, Montolio F, Peral Y, García CR, Clotet B, Tural C, Ruiz L, Miranda C, Muga R, Tor J, Sanvisens A, Berenguer J, de Quirós JC, Miralles P, Ochaíta JC, Conde MS, Cuellar IG, Schacke MR, Oretga BP, Vidaurreta PG, Vidal F, Peraire J, Viladés C, Veloso S, Vargas M, López-Dupla M, Olona M, Sirvent JJ, Aguilar A, Soriano A, Aldeguer JL, Juliá MB, Rodrigo JL, Salavert M, Montero M, Calabuig E, Cuéllar S, García JG, de la Serna IB, de Rivera JM, Rillo MM, Lopez JR, Ramírez ML, Pareja JF, Arribas B, Castro JM, Vargas FX, Valero IP, de los Santos I, Sanz JS, Rodríguez J, Aparacio AS, Cepeda CS, Oteo JA, Blanco JR, Ibarra V, Metola L, Sanz M, Pérez-Martinez L, Moraza JP, Dalmau D, Manzanera AJ, Llobell MC, Puig DI, Ibáñez L, Montañez QJ, Valls MX, Martinez-Lacasa J, Velli P, Font R, Boneta JS, Uriz J, Castiello J, Reparaz J, Arraiza MJ, Irigoyen C, Mozas D, Segura F, Amengual MJ, Penelo E, Navarro G, Sala M, Cervantes M, Pineda V, Moreno S, Casado JL, Dronda F, Moreno A, Elías MJ, López D, Gutiérrez C, Hernández B, Pumares M, Marti P, Sánchez AC, Morell EB, Pérez AM, García FG, Quero JH, Monje AP, Medina LM, Ruiz JP, Guerrero Jdel R, Martin CR, López TP, Montiel JC, Raposo P, González C, Antela A, Prieto A, Losada E, Riera M, Murillas J, Peñaranda M, Leyes M, Ribas MA, Campins A, Villalonga C, Pineda JA, Sánchez ER, de León FL, Macías J, del Valle J, Gómez-Mateos J, Mata R, González JS, Solero MM, Ramos IV, Muñoz RP, Viciana P, Leal M, López-Cortés LF, Trastoy M.

Author Disclosure Statement

No competing financial interests exist.

References

Bhavan

, Kampalath

, Overton

. The aging of the HIV epidemic. Curr HIV/AIDS Rep, 2008; 5:150–158.

Effros

, Fletcher

, Gebo

, Halter

, Hazzard

, Horne

et al. Aging and infectious diseases: Workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis, 2008; 47:542–553.

Deeks

, Phillips

. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ, 2009; 338:288–292.

Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep, 1992; 41:1–19.

Knobel

, Guelar

, Valldecillo

, Carmona

, González

, López-Colomés

et al. Response to highly active antiretroviral therapy in HIV-1 infected patients aged 60 years or older after 24 months of follow up. AIDS, 2001; 15:1591–1593.

Viard

, Mocroft

, Chiesi

, Kirk

, Roge

, Panos

et al. Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: Evidence from the EuroSIDA study. J Infect Dis, 2001; 183:1290–1294.

Yamashita

, Phair

, Muñoz

, Margolick

, Detels

, O'Brien

et al. Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study. AIDS, 2001; 15:735–746.

Grabar

, Kousignian

, Sobel

, Le Bras

, Gasnault

, Enel

et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS, 2004; 18:2029–2038.

Goodkin

, Shapshak

, Asthana

, Zheng

, Concha

, Wilkie

et al. Older age and plasma viral load in HIV-1 infection. AIDS, 2004; 18,Suppl 1:S87–98.

10.

Kalayjian

, Spritzler

, Pu

, Landay

, Pollard

, Stocker

et al. Distinct mechanisms of T cell reconstitution can be identified by estimating thymic volume in adult HIV-1 disease. J Infect Dis, 2005; 192:1577–1587.

11.

Kaufmann

, Furrer

, Ledergerber

, Perrin

, Opravil

, Vernazza

et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis, 2005; 41:361–372.

12.

Manfredi

, Chiodo

. A case-control study of virological and immunological effects of highly active antiretroviral therapy in HIV-infected patients with advanced age. AIDS, 2000; 14:1475–1477.

13.

Baker

, Peng

, Rapkin

, Krason

, Reilly

, Cavert

et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases. J Acquir Immune Defic Syndr, 2008; 48:541–546.

14.

Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: variation by age. AIDS, 2008; 22:1463–1473.

15.

Nogueras

, Navarro

, Antón

, Sala

, Cervantes

, Amengual

et al. Epidemiological and clinical features, response to HAART, and survival in HIV-infected patients diagnosed at the age of 50 or more. BMC Infect Dis, 2006; 6:159.

16.

Perez

, Moore

. Greater effect of highly active antiretroviral therapy on survival in people aged>or=50 years compared with younger people in an urban observational cohort. Clin Infect Dis, 2003; 36:212–218.

17.

Vallecillo

, Knobel

, Guelar

, Saballs

. Evolución de una cohorte de pacientes mayores de 60 años infectados por el VIH tratados con tratamiento antirretroviral de gran actividad. Enferm Infecc Microbiol Clin, 2005; 23:390–391.

18.

Silverberg

, Leyden

, Horberg

, DeLorenze

, Klein

, Quesenberry

Jr . Older age and the response to and tolerability of antiretroviral therapy. Arch Intern Med, 2007; 167:684–691.

19.

Navarro

, Nogueras

, Segura

, Casabona

, Miró

, Murillas

et al. HIV-1 infected patients older than 50 years. PISCIS cohort study. J Infect, 2008; 57:64–71.

20.

Clinical management and treatment of HIV infected adults in Europe. http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf. 2010 December 11.

21.

Documento de consenso del Grupo de Estudio de Sida/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (Actualización enero de 2012). http://www.gesida-seimc.org/pcientifica/fuentes/DcyRc/gesidadcyrc2012-Documentoconsenso-TAR-adulto-verordenador.pdf. 2012 May 18.

22.

Thompson

, Aberg

, Cahn

, Montaner

, Rizzardini

, Telenti

et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA, 2010; 304:321–333.

23.

Guidelines for the use of antiretroviral agents in HIV-1-infected adults, adolescents—March 27, 2012. http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. 2012 May 18.

24.

Garcia-Merino

, de Las

, Jimenez

, Gallego

, Gomez

, Prieto

et al. The Spanish HIV BioBank: A model of cooperative HIV research. Retrovirology, 2009; 6:27.

25.

Caro-Murillo

, Castilla

, Pérez-Hoyos

, Miró

, Podzamczer

, Rubio

et al. Cohorte RIS de pacientes con infección por VIH sin tratamiento antirretroviral previo (CoRIS): Metodología y primeros resultados. Enferm Infecc Microbiol Clin, 2007; 25:23–31.

26.

Battegay

, Nuesch

, Hirschel

, Kaufmann

. Immunological recovery and antiretroviral therapy in HIV-1 infection. Lancet Infect Dis, 2006; 6:280–287.

27.

Grimes

, Otiniano

, Rodriguez-Barradas

, Lai

. Clinical experience with human immunodeficiency virus-infected older patients in the era of effective antiretroviral therapy. Clin Infect Dis, 2002; 34:1530–1533.

28.

Manfredi

, Calza

, Cocchi

, Chiodo

. Antiretroviral treatment and advanced age: Epidemiologic, laboratory, and clinical features in the elderly. J Acquir Immune Defic Syndr, 2003; 33:112–114.

29.

Tumbarello

, Rabagliati

, de Gaetano

, Bertagnolio

, Tamburrini

, Tacconelli

et al. Older HIV-positive patients in the era of highly active antiretroviral therapy: changing of a scenario. AIDS, 2003; 17:128–131.

30.

Tumbarello

, Rabagliati

, de Gaetano

, Bertagnolio

, Montuori

, Tamburrini

et al. Older age does not influence CD4 cell recovery in HIV-1 infected patients receiving highly active antiretroviral therapy. BMC Infect Dis, 2004; 4:46.

31.

Orlando

, Meraviglia

, Cordier

, Meroni

, Landonio

, Giorgi

et al. Antiretroviral treatment and age-related comorbidities in a cohort of older HIV-infected patients. HIV Med, 2006; 7:549–557.

32.

Cuzin

, Delpierre

, Gerard

, Massip

, Marchou

. Immunologic and clinical responses to highly active antiretroviral therapy in patients with HIV infection aged >50 years. Clin Infect Dis, 2007; 45:654–657.

33.

Brañas

, Berenguer

, Sánchez-Conde

, López-Bernaldo de Quirós

, Miralles

, Cosín

et al. The eldest of older adult living with HIV: response and adherence to highly active antiretroviral therapy. Am J Med, 2008; 121:820–824.

34.

Stall

, Catania

. AIDS risk behaviors among late middle-aged and elderly Americans: The national AIDS behavioral surveys. Arch Intern Med, 1994; 154:57–63.

35.

Antón

, Sala

, Mallolas

, Navarro

, Cervantes

, Gatell

et al. Estudio de una serie clínica de pacientes infectados por el VIH mayores de 50 años. Enferm Infecc Microbiol Clin, 2005; 23:145–148.

36.

Orchi

, Balzano

, Scognamiglio

, Navarra

, De Carli

, Elia

et al. Ageing with HIV: Newly diagnosed older adults in Italy. Aids Care, 2008; 20:419–425.

37.

Caro-Murillo

, Gil

, Navarro

, Leal

, Blanco

. CoRIS: La infección por VIH en diferentes grupos de edad: potenciales implicaciones para la prevención. Cohorte CoRIS, España, 2004–2008. Med Clin (Barc), 2010; 134:521–527.

38.

Smith

, Delpech

, Brown

, Rice

. HIV transmission and high rates of late diagnoses among adults aged 50 years and over. AIDS, 2010; 24:2109–2115.

39.

Caro-Murillo

, Gil Luciano

, Navarro Rubio

, Leal Noval

, Blanco Ramos

. Infección por el virus de la inmunodeficiencia humana en diferentes grupos de edad: implicaciones potenciales para la prevención. Cohorte CoRIS, España, 2004–2008. Med Clin (Barc), 2010; 134:521–527.

40.

Greenbaum

, Wilson

, Keruly

, Moore

, Gebo

. Effect of age and HAART regimen on clinical response in an urban cohort of HIV-infected individuals. AIDS, 2008; 22:2331–2339.

41.

Carrieri

, Leport

, Protopescu

, Cassuto

, Bouvet

, Peyramond

et al. Factors associated with nonadherence to highly active antiretroviral therapy. A 5-year follow-up analysis with correction for the bias induced by missing data in the treatment maintenance phase. J Acquir Immune Defic Syndr, 2006; 41:477–485.

42.

Barclay

, Hinkin

, Castellon

, Mason

, Reinhard

, Marion

et al. Age-associated predictors of medication adherence in HIV-positive adults: health beliefs, self-efficacy, and neurocognitive status. Health Psychol, 2007; 26:40–49.

43.

Zaragoza-Macias

, Cosco

, Nguyen

, Del Rio

, Lennox

. Predictors of success with highly active antiretroviral therapy in an antiretroviral-naive urban population. AIDS Res Hum Retroviruses, 2010; 26:133–138.

44.

Palella

FJJ

, Baker

, Moorman

, Chmiel

, Wood

, Brooks

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.

45.

Bhaskaran

, Hamouda

, Sannes

, Boufassa

, Johnson

, Lambert

et al. Changes in the risk of death after HIV seroconversion compared with mortality in the general population. JAMA, 2008; 300:51–59.

46.

Monforte

, Abrams

, Pradier

, Weber

, Reiss

, Bonnet

et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS, 2008; 22:2143–2153.

47.

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.

48.

Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: A collaborative re-analysis. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Concerted Action on SeroConversion to AIDS and Death in Europe. Lancet, 2000; 355:1131–1137.

49.

Egger

, May

, Chêne

, Phillips

, Ledergerber

, Dabis

et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet, 2002; 360:119–129.

50.

Gutiérrez

, Padilla

, Masiá

, Iribarren

, Moreno

, Viciana

et al. Clinical outcome of HIV-infected patients with sustained virologic response to antiretroviral therapy: Long-term follow-up of a multicenter cohort. PLOS One, 2008; 1:e89.

51.

Shah

, McGowan

, Smith

, Blum

, Klein

. Comorbid conditions, treatment, and health maintenance in older persons with human immunodeficiency virus infection in New York City. Clin Infect Dis, 2002; 35:1238–1243.

52.

Braithwaite

, Justice

A.C.

, Chang

CCH

, Fusco

, Raffanti

, Wong

et al. Estimating the proportion of patients infected with HIV who will die of comorbid diseases. Am J Med, 2005; 118:890–898.

53.

Gutiérrez

, Padilla

, Masiá

, Iribarren

, Moreno

, Viciana

et al. Patients' characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy. Curr HIV Res, 2008; 6:100–107.

54.

Garcia

, de Lazzari

, Plana

, Castro

, Mestre

, Nomdedeu

et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr, 2004; 36:702–713.