To determine the impact of highly active antiretroviral therapy (HAART) on the viro-immunological response of older HIV-positive patients, we prospectively selected 58 older cases and 116 younger controls. The CD4 T-cell count at baseline was lower in cases, whereas the HIV viral load was similar in both groups. Cases were more frequently affected by co-morbid conditions. Under HAART, a significant increase in CD4 T-cell numbers was observed in both groups, but there was no statistical difference regarding the response to HAART.
Most of the known epidemiological features of older HIV-infected patients were determined before the introduction of highly active antiretroviral therapy (HAART) in 1996 [1–5]. Since then a less beneficial effect of HAART on the immunological outcome in older compared with younger patients has been reported [6–8]. In fact, both the intensity [6,7] and the rapidity  of the immunological response appeared to be reduced in older patients, with few exceptions . Interestingly, older age did not seem to affect the long-term virological outcome of HAART-treated patients significantly [6,9,10].
The aim of this study was to determine using a prospective case–control study the impact of HAART on the virological and immunological response in a cohort of older HIV-positive patients, when confounding variables such as adherence to therapy, side-effects and non-HIV-related co-morbidities were evaluated.
All patients presenting with a first HIV-positive test from January 1997 to December 2000, admitted to our in- and outpatient care unit, were considered.
Older (≥ 50 years) and younger (20–35 years) patients who were given HAART regularly and with a follow-up of at least 6 months were included as cases and controls, respectively (ratio 1 : 2). The control group was matched by sex, year of HIV diagnosis and the presence of AIDS-defining conditions. A patient was considered regularly HAART-treated if he or she was under HAART for at least 3 months.
Three outcomes were considered: immunological success; virological success; and viro-immunological success, defined as a CD4 T-lymphocyte count greater than 200 cells/mm3 and an HIV viral load less than 50 copies/ml, both conditions together, respectively, at the end of the follow-up.
In order to evaluate the significance of non-HIV-related co-morbid conditions, we used a modified version of the Charlson co-morbidity index .
Fifty-eight older patients (cases) were compared with 116 younger individuals (controls). Cases had a median age of 57.5 ± 5.5 years and controls 30.9 ± 3.6 years. Seventy-six per cent of subjects in both groups were men and 48% were in stage C of HIV infection. The mean of CD4 T cells was significantly lower in cases (108 ± 111 versus 187 ± 199 cells/mm3; P = 0.005), whereas the mean of the HIV viral load log was similar in the two groups (4.97 ± 0.78 versus 4.88 ± 0.86 copies/ml; P = NS).
Cases had more co-morbid conditions than controls (44.8 versus 15.5%; P < 0.0001). One-third suffered from cardiovascular diseases, a rare condition among controls. Cases also had a higher mean Charlson index compared with controls (0.55 ± 0.98 versus 0.16 ± 0.5; P < 0.0001).
No statistically significant difference between cases and controls was observed in the type, number and duration of HAART regimens. The first-line antiretroviral therapy included protease inhibitors in more than 80% of cases and controls. Patients who required a second-line therapy received a cocktail including protease inhibitors in 43 versus 53% (P = NS) and non-nucleoside reverse transcriptase inhibitors in 57 versus 47% (P = NS) of cases and controls, respectively. A high level of adherence to HAART was observed in both groups (98 versus 93%; P = NS). The more frequent adverse reactions were dyslipidemia, digestive intolerance and lipodystrophy (P = NS).
Comparing the mean baseline with the end of follow-up values, a statistically significant increase in CD4 T-cell numbers was observed. There was a progressive linear enhancement at any individual time of the follow-up (Table 1).
Immunological success was observed in 69% of the cases and 79% of the controls (P = NS). The following variables were significantly associated with immunological success at univariate analysis: Centers for Disease Control and Prevention (CDC) stage A (P = 0.01), low Charlson index (P = 0.01), CD4 T-cell count at the beginning and at 6, 12, 18, 24, 30 and 36 months of HAART (P < 0.01), months to achieve CD4 T-cell count greater than 200 cells/mm3 (P = 0.001), enhancement of CD4 T-cell count in the first 6 months (P = 0.0003), HIV viraemia at 30 months (P = 0.003).
A statistically significant reduction in the HIV viral load was observed in both cases and controls when comparing baseline with the end of the follow-up values. In particular, the means of the HIV-RNA viral load log decreased from 4.97 ± 0.78 to 1.7 ± 0.1 copies/ml in cases (P < 0.0001) and from 4.88 ± 0.86 to 1.97 ± 0.67 copies/ml in controls (P < 0.0001).
Virological success was observed in 79% of cases and 72% of controls (P = NS). The following variables were significantly associated with virological success at univariate analysis: CDC stage A (P = 0.02), high adherence to HAART (P = 0.01), dyslipidemia as an adverse effect of HAART (P = 0.01), HIV viral load at 6 (P = 0.004) and 24 months (P = 0.02).
Viro-immunological success was observed in 64% of cases and 62% of controls (P = NS). The following variables were significantly associated with viro-immunological success at univariate analysis: CDC stage A (P = 0.007), high adherence to HAART (P = 0.02), dyslipidemia as an adverse effect of HAART (P = 0.006), CD4 T-cell numbers at baseline and at 6, 12, 18, 24, 30 and 36 months of HAART (P < 0.01), enhancement of CD4 T-cell count in the first 6 months (P = 0.001), HIV viral load at 6 (P = 0.04) and 30 months (P = 0.01).
Multivariate analysis showed that, after adjustment for sex and Charlson index, there was no statistically significant difference between cases and controls for immunological, virological and viro-immunological success (P = NS). Similar results were obtained when HIV- and HAART-related variables were added to the model (Table 2).
The benefits of antiretroviral therapy in HIV-positive older patients have not been up to now completely elucidated. In fact, clinical trials often exclude older patients because of multiple medical problems or co-existing non-HIV-related therapeutic regimens .
Since HAART became available, few reports have regarded its effects in older HIV-positive patients. A poor immunological response under HAART was observed [6,7], possibly caused by the depressed thymic function of older patients [6–8]. Only one report showed a similar virological and immunological outcome in older HIV-positive patients compared with younger individuals .
Our study confirms this preliminary observation and clearly demonstrates that older patients under HAART experienced a successful immunological response comparable to that of younger individuals. In fact, our older patients, starting HAART with a lower level of CD4 T cells, obtained a significant increment in their CD4 T-cell count, with the same rapidity, intensity and persistence in time as observed in younger patients. Previous observations have reported that high adherence to HAART allowed HIV-positive patients to achieve successful response [13,14]. Our findings indicate that this goal could be achieved independently of age. In fact, a substantial output of CD4 T cells can be maintained into late adulthood, thus contributing to HAART-related immune recovery in older HIV-positive patients [15–17].
It is of note that no differences were observed in virological response as indicated by viral load reduction in older patients compared with younger patients. This result is in line with previous reports [6,9], including a large study that indicated that older age decreased the risk of having a viral load greater than 1000 copies/ml in HIV-positive patients under HAART .
Univariate analysis showed an association of low Charlson index with immunological success. However, considering that the Charlson index was higher in older patients, none of the models of multivariate analysis indicated an association between co-morbidity and virological or immunological response. Interestingly, cardiovascular disease and diabetes were the more frequent co-morbidities in our older population. In view of the recent reports of premature atherosclerosis in younger HAART-treated patients [18,19], an important increase in coronary events in older HIV-positive patients under HAART could occur in the forthcoming years.
In conclusion, an early diagnosis of HIV infection in older patients is mandatory because the use of HAART allows them to achieve the same viro-immunological response as younger individuals.
The authors are indebted to Dr Rita Grillo (Department of Microbiology, Catholic University, Rome) for her support in identifying patients for inclusion in the study.
1.Ferro S, Salit IE. HIV infection in patients over 55 years of age
. J Acquir Immune Defic Syndr
2.Phillips AN, Lee CA, Elford J, Webster A, Janossy G, Timms A, et al
. More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts
. J Acquir Immune Defic Syndr
3.Ship JA, Wolff A, Selik RM. Epidemiology of acquired immune deficiency syndrome in persons aged 50 years or older
. J Acquir Immune Defic Syndr
4.Tumbarello M, Tacconelli E, Cauda R, Ortona L. Age as a prognostic factor in AIDS
5.Centers for Disease Control and Prevention. AIDS among persons aged ≥ 50 years – United States, 1991–1996
6.Manfredi R, Chiodo F. A case control study of virological and immunological effects of highly active antiretroviral therapy in HIV-infected patients with advanced age
7.Goetz MB, Boscardin WJ, Wiley D, Alkasspooles S. Decreased recovery of CD4 lymphocytes in older HIV-infected patients beginning highly active antiretroviral therapy
8.Viard JP, Mocroft A, Chiesi A, Kirk O, Roge B, Panos G, 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
9.Knobel H, Guelar A, Valldecillo G, Carmona A, González A, López-Colomés JL, et al
. Response to highly active antiretroviral therapy in HIV-infected patients aged 60 years or older after 24 months follow-up
10.Paredes R, Mocroft A, Kirk O, Lazzarin A, Barton SE, van Lunzen J, et al
. Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe
. Arch Intern Med
11.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis
12.Chiao EY, Ries KM, Sande MA. AIDS and the elderly. Clin Infect Dis
13.Paterson DL, Swindells S, Mohr J, Brester M., Vergis EN, Squier C, et al
. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med
14.Cingolani A, Antinori A, Rizzo MG, Murri R, Ammassari A, Baldini F, et al
. Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study. AIDS
15.Renaud M, Katlama C, Mallet A, Calvez V, Carcelain G, Tubiana R, et al
. Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen. AIDS
16.Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al
. Changes in thymic function with age and during the treatment of HIV infection. Nature
17.Carcelain G, Debré P, Autran B. Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy
. Curr Opin Immunol
18.Laurence J. Vascular complications associated with use of HIV protease inhibitors. Lancet
19.Henry K, Melroe H, Huebsch J, Hermundson J, Levine C, Swensen L, Daley J. Severe premature coronary artery disease with protease inhibitors. Lancet