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According to most currently accepted guidelines, antiretroviral therapy is not recommended in patients with a viral load of less than 5000 copies/ml and CD4 T lymphocytes greater than 500 × 106/l 1. The objectives of the present study were to analyse the natural history of these patients and to assess the virological and immunological predictive factors of progression. This would allow us to determine which group of patients has a higher probability of progression and, consequently, would benefit from a closer follow-up. From October 1994 to September 1999, 100 consecutive asymptomatic antiretroviral-naive HIV-1-infected patients with a CD4 lymphocyte count greater than 500 × 106/l and a viral load of less than 5000 copies/ml (determined twice with an interval of at least 3 months) attending a previously scheduled medical visit as outpatients in one university hospital were enrolled and followed up to February 2000. Eighty-three of these 100 patients belonged to the same cohort already reported with a shorter follow-up 2. None of them had suffered from symptomatic primary infection within 6 months before enrolment. Medical visits occurred at least every 6 months and included CD4/CD8 T cell counts and plasma viral load, using the Roche Amplicor HIV Monitor assay (Roche Molecular Systems, Alameda, CA, USA). Samples below the detection limits of the test were retested using the method reported by Schockmel et al. 3. At baseline, patients were offered a tonsillar biopsy viral load was determined using the NucliSens HIV-1 RNA QT Assay (Organon Teknika, Turnhout, Belgium) as described elsewhere [4] and an immunological study (including CD4 and CD8-naive and memory cells, CD8+ CD38+ and CD8+CD28+ T cells, and proliferative responses to mitogens, and specific antigens, including HIV-1 antigens). The expression of co-receptors (CCR5 and CXCR4) were measured both in CD4 and CD8 T cells in a subset of patients (n = 32). Subpopulations of T cells were determined by three-colour flow cytometry. Lymphocyte proliferation assays were performed as described elsewhere 4. Progression was defined as a sustained increase (at least two consecutive determinations separated by 3 months) in viral load greater than 30 000 copies/ml or an increase in viral load greater than 5000 copies/ml plus a drop in CD4 T cells to less than 500 × 106/l, as these are the criteria for recommended antiretroviral therapy according to recently published guidelines 1. A substudy was performed to detect progression markers in the subgroup]# of patients with a baseline viral load of less than 200 copies/ml. In this substudy, progression was defined as a sustained increase of viral load greater than 200 copies/ml (at least two consecutive determinations separated by 3 months). The influence of virological and immunological variables in the progression of HIV-1 disease was studied with a survival analysis and the groups compared with the log-rank test. Because discriminant analysis is more robust in the setting of small datasets and the levels of co-receptors were performed only in a subset of 32 patients, we performed discriminant analysis to determine which variables could identify patients at high risk of progression. The variables utilized were those with significance in the univariate analysis. The median time of follow-up of the patients was 24 months (range 6–60). The mean age was 33 years (SE 2). Of the 100 patients, 50 were men (50%). The risk factors for HIV-1 infection were drug addiction in 37 cases (37%), male homosexuality in 57 cases (57%) and heterosexual transmission in six cases (6%). The median known duration of HIV-1 infection was 54 months (range 6–132). Nineteen patients (19%) had suffered from symptomatic primary infection, but never within 6 months before enrolment. None of the 100 patients were lost to follow-up. No deaths or AIDS-defining clinical events occurred in the cohort during the follow-up. Overall, 24 out of 100 patients (24%) fulfilled the criteria for progression. The variables that predicted progression in the univariate analysis were the baseline viral load (mean ± SE 2.77 ± 0.05 in the non-progressor group versus 3.24 ± 0.08 in the progressor group;P = 0.0001), the level of CD8+CD38+ T cells (52 ± 3 versus 71 ± 3 non-progressor versus progressor group, respectively;P = 0.003), and the percentage of CD4 and CD8 T cells HIV-1 expressing entry co-receptors (CD4+CXCR4+ 32 ± 6 versus 66 ± 8, P = 0.007; CD8+CXCR4+ 25 ± 5 versus 52 ± 9, P = 0.01; CD4+CCR5+ 4 ± 1 versus 8 ± 3, P = 0.05; CD8+CCR5+ 3 ± 1 versus 10 ± 3, P = 0.006; non-progressor versus progressor group in all the comparisons, respectively) (see Table 1). A model incorporating three variables (baseline viral load, expression of CD4+CCR5+ and CD8+CCR5+ in T cells) correctly identified 94% of patients with and without progression (see Table 1). Proliferative responses or memory/naive T cells baseline levels were not predictors of progression. Neither sex, age, hepatitis C virus co-infection, past history of symptomatic HIV-1 infection, duration of HIV-1 infection nor the risk group were associated with a higher risk of progression.Table 1: Risk of progression of a cohort of 100 patients with baseline viral load below 5000 copies/ml and CD4 T cell counts above 500 × 106/l. Among the 37 patients with baseline viral loads of less than 200 copies/ml, 20 (54%) had a sustained increase of plasma viral load above detectable levels. Those who during the follow-up remained below 200 copies/ml (n = 17) had a significantly higher probability of presenting baseline viral load of less than 5 copies/ml (14 out of 17 versus three out of 20 in the progressor group), tonsillar tissue viral load below detectable levels (six out of six versus one out of six in the progressor group, tonsillar biopsies were available in 12 out of 37 patients), higher levels of CD8+CD28+ T cells (mean ± SE 78 ± 8 versus 55 ± 6 in the progressor group, P = 0.04), lower levels of CD8+CD38+T cells (mean ± SE 39 ± 7 versus 55 ± 4, P = 0.05), and a lower percentage of CD4 and CD8 T cells expressing HIV-1 entry co-receptors. As has been observed in other cohorts 5,6, we observed evidence of virological progression (24% progressed to a stage at which antiretroviral therapy may be recommended) in our cohort of chronically infected asymptomatic patients with a viral load of less than 5000 copies/ml and CD4 cell count greater than 500 × 106 cells/l followed for a median of 2 years. There are many currently available laboratory markers that can help predict the clinical course of HIV-1 infection 7–12 in a broad HIV-1-infected population. We have found in our cohort of early stage patients that a high viral load or CD8+CD38+ T cells is a marker of progression. We did not observe that CD4 T cell counts in these patients with high levels of CD4 T lymphocytes predict progression. However, we did find that the expression of HIV-1 entry co-receptors CCR5 both in CD4 and CD8 T cells were also independent markers of progression. The relevance of the expression of HIV-1 entry co-receptors as predictors of progression could be explained because the expression of these co-receptors may be a marker of immune system activation, as are CD8+CD38+ T cells 13,14. An alternative explanation may be that those patients who progress had a higher expression of HIV-1 entry co-receptors, which could facilitate the entry of HIV-1 into the cells and the expansion of the infection, and therefore progression. In fact, both hypotheses could be complementary, and could explain the relevance of the levels of HIV-1 entry co-receptors in the evolution of HIV-1 disease and, therefore, their importance as therapeutic targets, at least in these early stages. These markers could also help to differentiate in antiretroviral-naive patients with a plasma viral load of less than 200 copies/ml, those patients who are true long-term non-progressors from those patients with a good prognosis, but with a higher risk of progression. The high percentage of patients with virological progression and, consequently, the need to consider antiretroviral therapy, over short periods of time suggest that even patients in these early stages of disease should be strictly followed. Felipe Garciaa Montserrat Planab Alex Sorianoa Carmen Vidalc Mireia Arnedoc Cristina Gilc Anna Crucetaa Tomas Pumarolac Teresa Gallartb Jose M. Miroa Jose M. Gatella
García et al. (Mon,) studied this question.