Estimating duration of HIV infection with CD4 cell count and HIV-1 RNA at presentation (2001)

Most HIV-positive individuals still seek medical care a long time after acquiring HIV infection, the ‘long-term non-presenters', as defined by Samet et al. [1]. Defining the characteristics of such individuals is crucial for targeting intervention strategies more effectively. However, estimating the duration of HIV infection at the patients’ first presentation is still a controversial matter. A lower CD4 cell count at the time of the first HIV-positive test or first presentation to medical care is commonly considered to be an indicator of longer duration of HIV infection [2,3]. Recently, Samet et al. [1] used the CD4 cell count at presentation to provide an estimate of the previous duration of HIV infection in 203 HIV-infected individuals from two urban hospitals in the United States. The authors, using data from the MACS cohort study [4], considered a weighted average CD4 cell decline of 60 cells/μl per year of HIV infection. Assuming an initial CD4 cell count of 800 cells/μl at the time of infection, they estimated a mean duration of infection of 8.1 years, before the first presentation to primary care. To verify the reliability of estimating the duration of HIV infection using data collected at first presentation, we used data from patients enrolled in the Italian Cohort Naive Antiretrovirals (ICONA) study [5], between March 1997 and December 2000. We included in the analysis 161 patients who had their first HIV-positive test within 6 months before presentation, completed a self-administered questionnaire [6], had an initial CD4 cell count less than 800 cells/μl, and a documented or self-reported date of previously negative HIV test, as resulting from the clinical charts. By using the date of the last negative HIV test, we computed the maximum estimate of duration of HIV infection, which was then compared with estimates obtained using different approaches. Out of the 160 individuals included in the analysis, 73% were men, mean age 33 years, the mean CD4 cell count at presentation was 372 cells/μl and median plasma viral load was 21 470 copies/ml. As shown in Table 1, their mean time since the last HIV-negative test (date of first available CD4 cell count after the positive HIV test − date of last negative HIV test) was 3.48 years. Using the approach proposed by Samet et al. [1] (method 1 in Table 1), the estimated mean time since infection was 7.01 years. As a further step, as the MACS data provided different estimates of the CD4 cell slopes according to HIV-1-RNA levels [5], we also performed the calculations by using different rates of CD4 cell decline according to HIV-1-RNA levels at enrolment. This adjustment did not substantially modify the estimate (method 2 in Table 1). Finally, given that women proved to have lower HIV-1-RNA levels compared with men at a similar clinical stage [7,8], we also calculated the time since infection, by doubling the viral load for women before applying MACS-derived slopes for different HIV-1-RNA categories (method 3 in Table 1). The estimates were also unchanged (6.75 years) using this last approach.Table 1: Time since last negative HIV test and estimated duration of HIV infection among 160 HIV-infected patients enrolled in the Italian Cohort Naive Antiretrovirals study. With all three approaches used, the estimated duration of infection was substantially longer than the time elapsed since the last negative test, except for patients with higher CD4 cell counts (> 400 cells/μl). It is worth noting that the time since the last negative test is probably an over-estimate of the time since infection, particularly for patients who had their last negative HIV test a long time before their first positive test. A major limitation of our analysis is that, for most patients, the date of the last negative test was self-reported, with possible recall biases. However, the mean time since the last negative test was similar when we used the date reported in the self-administered questionnaire, instead of that reported in the clinical charts. The time since infection is clearly a major determinant of the CD4 cell count, although other factors play a role in determining the rate of CD4 cell decline over time, such as age, virological features and host genetic characteristics [9,10]. This may explain the difficulty in estimating the time since infection using a single CD4 cell count determination, even when HIV-1-RNA levels are taken into account. Lower initial CD4 cell counts at the time of the first positive test or at presentation can be a useful marker of the delay in seeking testing or medical care. However, our data suggest that a great deal of caution is required (especially for patients with CD4 cell counts lower than 400/μl) in providing a direct estimation of the time since infection using non-validated models that are based on a single determination of laboratory parameters. Members of the Italian Cohort Naive Antiretrovirals (ICONA) BEHEPI Study Group Ancona: M. Montroni, G. Scalise, A. Costantini, M.S. Del Prete. Aviano: U. Tirelli, G. Nasti. Bari: G. Pastore, M.L. Perulli. Bergamo: F. Suter. Bologna: F. Chiodo, F.M. Gritti, V. Colangeli, C. Fiorini, L. Guerra. Brescia: G. Carosi, G.P. Cadeo, F. Castelli, C. Minardi, D. Vangi. Busto Arsizio: G. Rizzardini, G. Migliorino. Cagliari: P.E. Manconi, P. Piano. Catanzaro: T. Ferraro, A. Scerbo. Chieti: E. Pizzigallo, F. Ricci. Cremona: G. Carnevale, D. Galloni. Ferrara: F. Ghinelli, L. Sighinolfi. Firenze: F. Leoncini, F. Mazzotta, S. Ambu, S. LoCaputo. Galatina (LE): P. Grima, P. Tundo. Genova: G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo. Grosseto: M. Toti, S. Chigiotti. Latina: F. Soscia, L. Tacconi. Lecco: A. Orani, G. Castaldo. Lucca: A. Scasso, A. Vincenti. Mantova: A. Scalzini, F. Alessi. Milano: M. Moroni, A. Lazzarin, A. Cargnel, G.M. Vigevani, L. Caggese, S. Melzi, F. Delfanti, B. Carini, S. Merli, C. Pastecchia, C. Moioli. Modena: R. Esposito, C. Mussini. Napoli: N. Abrescia, A. Chirianni, C. Izzo, M. Piazza, M. De Marco, V. Montesarchio, E. Manzillo, S. Nappa. Pavia: G. Filice, L. Minoli, F.A. Patruno Savino, R. Maserati. Perugia: S. Pauluzzi, F. Baldelli. Piacenza: F. Alberici, M. Sisti. Pisa: F. Menichetti, A. Smorfa. Potenza: C. De Stefano, A. La Gala. Ravenna: T. Zauli, G. Ballardini. Reggio Emilia: L. Bonazzi, M.A. Ursitti. Rimini: M. Arlotti, P. Ortolani. Roma: L. Ortona, A. Antinori, G. Antonucci, S. D'Elia, P. Narciso, N. Petrosillo, V. Vullo, A. De Luca, L. Del Forno, M. Zaccarelli, P. De Longis, M. Ciardi, G. D'Offizi, P. Noto, M. Lichtner, Sassari: M.S. Mura, M. Mannazzu. Torino: P. Caramello, A. Sinicco, M.L. Soranzo, L. Gennero, M. Sciandra, B. Salassa. Venezia: E. Raise, S. Pasquinucci. Verbania: A. Poggio, G. Bottari. Taranto: F. Resta, A. Chimienti. Enrico Girardia Claudio Aricib Michele Ferraraa Diego Ripamontib Maria Stella Aloisia Anna Alessandrinic Alfredo Scalzinid Antonella d'Arminio Monfortee Diego Serrainoa Giuseppe Ippolitoa for the ICONA Behavioural Epidemiology Study