A case-control study of virological and immunological effects of highly active antiretroviral therapy in HIV-infected patients with advanced age.

Abstract

The mean age at first diagnosis of HIV infection is progressively increasing worldwide [1–5] (with 1–2% of cases of HIV infection occurring in persons aged 65 years or older) [1,4], but very limited data have been available until now about the efficacy of highly active antiretroviral therapy (HAART) according to the patients' age [6–11]. The virological and immunological response to a first-line HAART containing two nucleoside analogues and a potent protease inhibitor evaluated in 21 consecutive patients 55 years of age or older, was retrospectively compared with that of 84 individuals randomly selected from nearly 450 patients aged 35 years or less who had started a similar HAART regimen since 1997, in a case–control study including a 12 month follow-up. Ultrasensitive assays were used for quantitative viral load measurement: the branched DNA method and the nucleic acid sequence-based assay, with minimum detectable levels of 50 and 40 copies/ml, respectively. The adherence to HAART was checked by monthly visits, including direct distribution of antiretroviral compounds, and drug accountability. The two patient groups were comparable with regard to sex, number of individuals naive to antiretroviral agents, duration of previous anti-HIV therapy in experienced patients, expected potency of selected HAART regimen (containing either indinavir, ritonavir, or nelfinavir), levels of compliance with administered compounds, drug-related adverse events (mild to moderate in severity, and never affecting the continuation of HAART), as well as the baseline mean plasma viral load and mean CD4 lymphocyte count (Table 1).Table 1: Outcome of first-line highly active antiretroviral therapy in 21 consecutive HIV-infected patients aged 55 years or older, compared with that of 84 control subjects aged 35 years or less. Compared with patients aged 35 years or less, those aged 55 years or older showed a greater prevalence of sexually transmitted disease, a more frequent diagnosis of AIDS, a significantly reduced decrease of viraemia at the sixth month of follow-up, although a similar virological response was attained in both patient groups after 12 months (−1.8 and −1.9 log10, respectively), with a comparable number of patients reaching complete viral suppression. On the other hand, the immunological response was significantly less favourable in older compared with younger patients, after 6 and especially 12 months of follow-up, and individuals with a modest CD4 cell count gain were significantly more frequent in the older as opposed to the younger group. Before the HAART era, the elderly were known to have a more severe HIV disease evolution and a shorter survival rate [12–21] : in 1995, older age was related linearly to an increased probability of death, and a relative risk of progression to AIDS or death of 2% per year of age was estimated [15]. Patients' age showed a marked influence on the progression to stage C disease [17], proved independently related to the decline of CD4 cell count in untreated patients [19], and recently showed a correlation with plasma viraemia [22]. The inability of older individuals to replace impaired immune defences is expected to play a key pathogenic role [16,18]. However, a recent study [5] identified access to antiretroviral therapy as the only predictor of survival in a cohort of 86 patients aged 50 years or older. Recently, some large literature series that evaluated predictors of HAART outcome [6,9–11], failed to identify age as a relevant variable: the latter study [11] even excluded age as a determinant for naive T cell repopulation, independently from virological outcome. No difference [7], or a slightly increased risk [8] of clinical failure of HAART, were detected in an Italian setting, in patients aged over versus those aged less than 35 and 34 years, respectively [7,8]. In our experience, older age does not seem to affect significantly the long-term virological outcome of HIV disease initially treated with HAART (despite an apparently less rapid drop of plasma viral load levels), but the immunological response (as assessed by the profile of recovery of the peripheral CD4 cell count), appears to be significantly blunted among patients aged 55 years or over (independently from a series of clinical and therapeutic variables). A limited residual function of the thymus and other lymphoid tissues [23,24], and a consequently reduced potential for immune reconstitution [22,25] (which appears somewhat related to a recovery of thymic output) [22,23,26,27] may play an important role, although the central position of the thymus in immune restoration after HAART is actively discussed [22,26]. An aggressive therapeutic approach is therefore warranted for older patients with HIV disease, with special attention paid to the administration of potent antiretroviral compounds, and the continuation of appropriate primary or secondary chemoprophylactic regimens for opportunistic infections (when indicated), waiting for the availability of novel immunotherapeutic strategies, which would possibly ensure a more rapid and effective recovery of the immune defences, when advanced age is of concern. Roberto Manfredi Francesco Chiodo