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Antiviral Therapy 14:451 457 Short communication CD4 + T-cell percentage is an independent predictor of clinical progression in AIDS-free antiretroviral-naive patients with CD4 + T-cell counts >200 cells/mm 3 Marguerite Guiguet 1,2 *, Eric Kendjo 1,2, Guislaine Carcelain 3, Sophie Abgrall 4, Murielle Mary-Krause 1,2, Pierre Tattevin 5, Yazdan Yazdanpanah 6, Dominique Costagliola 1,2 and Xavier Duval 7 on behalf of the FHDH-ANRS CO4 Epidemiology Group 1 NSERM U943, Paris, France 2 Université Pierre et Marie Curie-Paris 6, UMR S943, Paris, France 3 AP-HP Hôpital Pitié-Salpétrière, Paris, France 4 AP-HP, Hôpital Avicenne, Bobigny, France 5 CHU Pontchaillou, Rennes, France 6 CHU Tourcoing, Tourcoing, France 7 APHP, Hôpital Bichat, Paris, France *Corresponding author: E-mail: mguiguet@ccde.chups.jussieu.fr A list of all participating members of the FHDH-ANRS CO4 Epidemiology Group can be found in the Additional file Background: The aim of this study was to evaluate the clinical prognostic value of the CD4 + T-cell percentage (%CD4), the CD4 + /CD8 + T-cell ratio or the CD8 + T-cell count, in addition to the CD4 + T-cell count and viral load (VL) in antiretroviral-naive HIV- infected patients with CD4 + T-cell counts >200 cells/ mm 3. Methods: Antiretroviral-naive patients (n=9,740) who were AIDS-free and had a CD4 + T-cell count >200 cells/ mm 3 at their first visit after January 1997 were followed-up until treatment initiation or clinical progression (mean follow- up 17 months and 13,660 person-years). Poisson regression was used for statistical analyses. Results: Progression to AIDS-defining events (ADEs), serious ADEs and death occurred in 228 patients (crude rate 1.69 per 100 person-years), 105 patients (0.77 per 100 person-years) and 67 patients (0.49 per 100 personyears), respectively. Regarding progression to ADE, the data fit was improved when the model also included the %CD4 (Akaike s information criteria [AIC] 2,049) and, to a lesser extent, the CD4 + /CD8 + T-cell ratio (AIC 2,053), in addition to CD4 + T-cell count and VL (AIC 2,056). After adjustment for VL and baseline characteristics, patients with CD4 + T-cell counts of 350 500 cells/mm 3 and %CD4<15% had an estimated incidence of ADE of 3 per 100 person-years, similar to that in patients with CD4 + T-cell counts of 200 350 cells/mm 3 and %CD4>15%. The %CD4 was also significantly associated with the risk of serious ADE. By contrast, %CD4, CD4 + /CD8 + T-cell ratio or CD8 + T-cell count had no additional prognostic value for the risk of death. Conclusions: In antiretroviral-naive HIV-infected patients with CD4 + T-cell counts >200 cells/mm 3, the %CD4 was predictive of the risk of clinical progression independently of CD4 + T-cell count and VL. Introduction Before treatment initiation, the CD4 + T-cell count and viral load (VL) are strong predictors of the risk of HIV disease progression [1,2]. Updated guidelines now recommend treatment for asymptomatic patients who have CD4 + T-cell counts <350 cells/mm 3 [3,4]. However, the risk of AIDS is far from negligible among patients with CD4 + T-cell counts >350 cells/mm 3 [5]. In addition, results of the SMART study indicate that the risk of serious non-aids events is high among untreated patients with high CD4 + T-cell counts [6]. The need for therapy in asymptomatic patients with higher CD4 + T-cell counts is controversial [7], and additional biological markers predictive of clinical progression would therefore be useful. Here, we focussed on patients with CD4 + T-cell counts >200 cells/mm 3 as previous studies have shown a benefit of initiating 2009 International Medical Press 1359-6535 (print) 2040-2058 (online) 451

M Guiguet et al. antiretroviral therapy above this threshold [8]. The aim was to determine the possible additional prognostic value of the CD4 + T-cell count divided by total lymphocyte count (CD4 + T-cell percentage [%CD4]), the CD4 + /CD8 + T-cell ratio or the CD8 + T-cell count for clinical progression in antiretroviral-naive AIDS-free patients with CD4 + T-cell counts >200 cells/mm 3, on the basis of the incidence rates of first AIDS-defining events (ADEs), serious ADEs and death. Methods The French Hospital Database on HIV (FHDH) is a large French prospective hospital cohort in which enrolment is ongoing [9]. Data from 40 centres in which CD8 + T-cell counts are recorded were analysed here. Patients were eligible if they were antiretroviral-naive, AIDSfree and had CD4 + T-cell counts >200 cells/mm 3 at their first visit after January 1997. The patients were monitored from this first visit until the first clinical event, death or last visit. Patients were censored when their CD4 + T-cell count decreased to <200 cells/mm 3 or when they started antiretroviral therapy. The following clinical events were studied: ADEs, serious ADEs (all ADEs except for recurrent bacterial pneumonia, oesophageal candidiasis, herpes simplex virus disease, and pulmonary and extrapulmonary tuberculosis) and death. All biological markers were studied as time-varying factors. Variables were updated at each follow-up and were categorized using the following cutoffs: CD4 + T-cell count (200 349, 350 499, 500 649 and 650 cells/ mm 3 ), VL (<4, 4 4.9 and >5 log 10 copies/ml); %CD4 (<15%, 15 19.9% and 20%), CD4 + /CD8 + T-cell ratio (<0.30 0.44 and >0.45) and CD8 + T-cell count (<400, 400 799 and >800 cells/mm 3 ). A Poisson regression model was fitted to evaluate independent contributions of the CD4 + T-cell count, VL, sex, age at the first visit (<50 and 50 years) and the HIV transmission group (injection drug users versus others) to the rate of progression. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated after adjusting for repeated observations for a given patient. Each additional marker (%CD4, CD4 + /CD8 + T-cell ratio and CD8 + T-cell count) was then introduced. As the different models were not nested, the contribution of each additional covariate was assessed using Akaike s information criterion (AIC), with the lowest AIC value indicating the best fit. Following the empiric rule proposed by Burnham and Anderson [10], we only considered additional covariates that reduced the AIC by 4 compared with the initial model. The risk of progression was estimated in each stratum of CD4 + T-cell counts and %CD4 values after adjusting for VL, sex, age and the HIV transmission group. As Poisson regression and Cox models gave similar results, we also assessed changes in model discrimination when additional marker was included to evaluate the prognostic value of the marker. The ability of Cox models to classify patients according to their risk of clinical progression was assessed by using the C-statistic developed for survival time data with timedependent covariates [11]. Results A total of 9,740 patients who were antiretroviral-naive, AIDS-free and had CD4 + T-cell counts >200 cells/mm 3 at their first visit after January 1997 were followed-up within the FHDH cohort until treatment initiation or clinical progression, yielding a mean of 17 months (±sd 21.5) and 13,660 person-years. Table 1 shows the patients baseline data. Median age was 35 years and 10% of patients were >50 years of age; 63% of patients were male and 11% were injection drug users. At enrolment, 68% of patients had CD4 + T-cell counts >350 cells/mm 3 and CD4 + T-cell counts were >350 cells/ mm 3 during 78% of the total person-years of follow-up. HIV RNA levels were >5 log 10 copies/ml in 17% of patients at baseline, and remained above this level during 10% of person-years of follow-up. At baseline, the %CD4 was <15% in 14% of patients, the CD4 + /CD8 + T-cell ratio was <0.30 in 22% of patients and 37% of patients had CD8 + T-cell counts <800 cells/mm 3. Progression to ADEs, serious ADEs and death occurred in 228 patients (crude rate 1.69 per 100 person- years), 105 patients (crude rate 0.77 per 100 person-years) and 67 patients (crude rate 0.49 per 100 person-years), respectively. The most frequent events were tuberculosis (n=89), Kaposi s sarcoma (n=34), non-hodgkin lymphoma (n=24), oesophageal candidiasis (n=19), recurrent bacterial pneumonia (n=17) and Pneumocystis jirovecii pneumonia (n=14). As expected, the CD4 + T-cell count and VL were strong predictors of clinical progression, and patients with high VL were 2 as likely to die (Table 2). Patients >50 years of age were at an increased risk of all three events, and men were more at risk than women of serious ADE and death. HIV infection by injection drug use was not associated with more rapid progression to ADE or serious ADE, but it was associated with an increased risk of death. Compared with the initial model of the rate of progression to ADE, which included CD4 + T-cell count, VL, sex, age and the HIV transmission group (AIC 2,056), the data fit was improved when the model also included the %CD4 (AIC 2,049), and to a far lesser extend the CD4 + /CD8 + T-cell ratio (AIC 2,053) or the CD8 + T-cell count (AIC 2,057). Discrimination was slightly improved when the %CD4 was included in the model for the prediction of clinical progression. The C-statistics for models of ADE were 0.714 (with CD4 + T-cell count, VL, sex, age and transmission group 452 2009 International Medical Press

CD4 + T-cell percentage predicts progression in ART-naive patients as predictors) and 0.734 (with CD4 + T-cell count, VL, sex, age, transmission group and %CD4 as predictors). Compared with patients with %CD4>20%, the risk of clinical progression was higher in patients with values in the range of 15 20% (RR 1.5, 95% CI 0.9 2.2), and patients with values <15% (RR 2.0; 95% CI 1.3 3.2). The %CD4 was also significantly associated with the risk of serious ADEs. The C-statistics for the two models of serious ADEs were 0.785 (with CD4 + T-cell count, VL, sex, age and transmission group as predictors) and 0.802 (with CD4 + T-cell count, VL, sex, age, transmission group and %CD4 as predictors). The %CD4, the CD4 + /CD8 + T-cell ratio, or the CD8 + T-cell count had no additional predictive value for the risk of death. The incidence rates of ADEs and serious ADEs were then estimated within each CD4 + T-cell count stratum according to %CD4, after adjustment for VL, sex, age and the HIV transmission group. As shown in Figure 1, patients with CD4 + T-cell counts between 350 and 500 cells/mm 3 and %CD4<15% had Table 1. Characteristics of AIDS-free antiretroviral-naive patients at study entry and during follow-up from 1997 to 2006 Characteristic Value (n=9,740) Follow-up, person-years (n=13,660) Male, n (%) 6,090 (63) Age 16 29 years, n (%) 2,729 (28) 30 39 years, n (%) 4,169 (43) 40 49 years, n (%) 1,864 (19) 50 years, n (%) 978 (10) Median age, years (IQR) 34 (29 41) Risk factor for transmission Men having sex with men, n (%) 2,725 (28) Injection drug use, n (%) 1,068 (11) Heterosexual contact, n (%) 4,761 (49) Other, n (%) 1,228 (12) CD4 + T-cell count 650 cells/mm 3, n (%) 1,801 (18) 3,176 (23) 500 649 cells/mm 3, n (%) 168 (19) 3,062 (44) 350 499 cells/mm 3, n (%) 2,930 (30) 4,341 (32) 200 349 cells/mm 3, n (%) 3,141 (32) 3,030 (22) Median CD4 + T-cell count, cells/mm 3 (IQR) 431 (316 584) 446 (337 591) a HIV RNA <4 log 10 copies/ml, n (%) 2,709 (28) 5,250 (38) 4 4.9 log 10 copies/ml, n (%) 4,003 (41) 5,493 (40) >5 log 10 copies/ml, n (%) 1,624 (17) 1,310 (10) Missing, n (%) 1,404 (14) 1,606 (12) Median HIV RNA, log 10 copies/ml (IQR) 4.3 (3.8 4.8) 4.2 (3.6 4.7) a CD4 + T-cell percentage 20%, n (%) 6,166 (63) 9,054 (66) 15 19.9%, n (%) 1,832 (19) 2,364 (17) <15%, n (%) 1,338 (14) 1,358 (10) Missing, n (%) 404 (4) 884 (7) Median CD4 + T-cell percentage (IQR) 23 (18 30) 24 (18 30) a CD4 + /CD8 + T-cell ratio >0.45, n (%) 5,200 (53) 7,519 (55) 0.30 0.44, n (%) 2,369 (24) 3,305 (24) <0.30, n (%) 2,154 (22) 2,305 (17) Missing, n (%) 17 (0.2) 531 (4) Median CD4 + /CD8 + T-cell ratio (IQR) 0.47 (0.32 0.68) 0.48 (0.33 0.68) a CD8 + T-cell count >800 cells/mm 3, n (%) 6,163 (63) 8,686 (63) 400 799 cells/mm 3, n (%) 3,165 (32) 4,054 (30) <400 cells/mm 3, n (%) 396 (4) 390 (3) Missing, n (%) 16 (0.2) 530 (4) Median CD8 + T-cell count, cells/mm 3 (IQR) 941 (677 1,309) 954 (692 1,323) a a Median of all measurements during follow-up. IQR, interquartile range. Antiviral Therapy 14.3 453

M Guiguet et al. an estimated ADE incidence of 3.5 per 100 personyears, similar to the incidence in patients with CD4 + T-cell counts 200 349 cells/mm 3 and %CD4>20%. The incidence was between 2 and 3 per 100 personyears in patients with CD4 + T-cell counts of 500 649 cells/mm 3 and %CD4<15%, and also in patients with CD4 + T-cell counts of 350 499 cells/mm 3 and %CD4 15 20%, whereas patients with CD4 + T-cell counts >650 cells/mm 3 and patients with CD4 + T-cell counts of 350 649 cells/mm 3 and %CD4>20%, had an estimated annual incidence of ADEs of <2 per 100 person-years. Similar trends were observed for serious ADEs. Several sensitivity analyses were conducted, after restricting the study population to patients with CD4 + T-cell counts of 200 349 cells/mm 3 or >350 cells/mm 3 as recent guidelines recommend treatment for asymptomatic patients with CD4 + T-cell counts below this threshold. We also pooled patients with CD4 + T-cell counts of 500 649 cells/mm 3 and >650 cells/mm 3 as patients with values >650 cells/mm 3 and %CD4<20% were uncommon (1.4% of person-years). The same model that included the %CD4 in addition to the CD4 + T-cell count and VL was selected for all analyses and similar levels of risk were observed across strata defined by the CD4 + T-cell count and %CD4 (data not shown). The results were also similar after excluding the 27 patients with CD4 + T-cell count >1,500 cells/ mm 3 or after censoring patients with intervals longer than 12 months between two visits. Discussion Among antiretroviral-naive AIDS-free patients with CD4 + T-cell counts >200 cells/mm 3, the %CD4 was associated with clinical progression to AIDS independently of the CD4 + T-cell count, VL, sex, age and the Table 2. Rate ratios based on Poisson regression models indicating the association between covariates and the risk of clinical progression in AIDS-free antiretroviral-naive patients with CD4 + T-cell count >200 cells/mm 3 Model ADE RR (95%CI) P-value Serious ADE RR (95%CI) P-value Death RR (95%CI) P-value Model 1 AIC 2,056 a 1,027 a 659 a CD4 + T-cell count 650 cells/mm 3 1.0 <0.0001 1.0 0.0001 1.0 0.01 500 649 cells/mm 3 1.47 (0.71 3.02) 1.27 (0.41 3.94) 0.38 (0.12 1.22) 350 499 cells/mm 3 2.13 (1.12 4.05) 2.30 (0.86 6.13) 1.20 (0.56 2.62) 200 349 cells/mm 3 5.04 (2.72 9.32) 5.25 (2.08 13.28) 1.48 (0.65 3.32) Viral load <4 log 10 copies/ml 1.0 <0.0001 1.0 <0.0001 1.0 0.04 4 4.9 log 10 copies/ml 1.65 (1.08 2.54) 1.77 (0.86 3.61) 0.79 (0.39 1.60) >5 log 10 copies/ml 4.59 (2.91 7.24) 6.64 (3.27 13.46) 2.40 (1.12 5.10) Age 50 years versus <50 years 2.05 (1.34 3.12) 0.008 2.33 (1.31 4.13) 0.03 8.43 (4.50 15.79) <0.0001 Male versus female 0.98 (0.70 1.38) 0.92 1.77 (0.99 3.15) 0.03 1.62 (0.82 3.17) 0.13 Injection drug use versus other groups 1.37 (0.88 2.15) 0.21 0.82 (0.37 1.82) 0.61 5.24 (2.73 10.05) 0.001 Model 2 b AIC 2,049 (-7) a 1,023 (-4) a 662 (3) a CD4 + T-cell percentage 20% 1.0 0.01 1.0 0.03 1.0 0.65 15-19.9% 1.46 (0.95 2.24) 1.65 (0.87 3.11) 1.65 (0.87 3.11) <15% 2.04 (1.31 3.20) 2.43 (1.27 4.65) 2.43 (1.27 4.65) Model 3 b AIC 2,053 (-3) a 1,028 (1) a 663 (4) a CD4 + /CD8 + T-cell ratio >0.45 1.0 0.05 1.0 0.26 1.0 0.82 0.30 0.44 1.15 (0.74 1.77) 1.23 (0.65 2.34) 0.95 (0.47 1.92) <0.30 1.68 (1.10 2.58) 1.66 (0.9 3.05) 0.69 (0.29 1.63) Model 4 b AIC 2,057 (1) a 1,029 (2) a 661 (2) a CD8 + T-cell count >800 cells/mm 3 1.0 0.28 1.0 0.30 1.0 0.53 400 799 cells/mm 3 0.78 (0.55 1.11) 0.67 (0.39 1.16) 1.08 (0.58 2.04) <400 cells/mm 3 1.24 (0.59 2.59) 1.08 (0.34 3.44) 2.15 (0.81 5.68) a Value is Akaike s information criteria (AIC) score (difference from Model 1). b Model adjusted for current CD4 + T-cell count, viral load, age, sex and HIV transmission group. ADE, AIDS-defining event; CI, confidence interval; RR, rate ratio. 454 2009 International Medical Press

CD4 + T-cell percentage predicts progression in ART-naive patients HIV transmission group. These results suggest that patients with CD4 + T-cell counts between 350 and 500 cell/mm 3 and %CD4<15% have the same risk of progression, before treatment initiation, as patients with CD4 + T-cell counts between 200 and 350 cells/ mm 3 and %CD4>20%. Guidelines for treatment initiation are currently based mainly on the absolute CD4 + T-cell count. Studies performed before and since the advent of antiretroviral drugs have shown that the CD4 + T-cell count, the %CD4 or the CD4 + /CD8 + T-cell ratio predict the risk of progression to AIDS [12 14]. In a study restricted to patients with CD4 + T-cell counts <350 cells/mm 3, the %CD4 had no supplementary predictive value to the absolute CD4 + T-cell count for progression to AIDS, after adjustment for VL [15]. A longitudinal study performed before the highly active antiretroviral therapy era showed that relatively high baseline CD8 + T-cell counts, which could reflect immunological hyperactivity, were associated with clinical progression, whereas the CD4 + /CD8 + T-cell ratio was less informative [16]. In patients starting antiretroviral therapy, a low %CD4 is consistently associated with disease progression [17 20]. In our study of clinical progression among antiretroviral-naive patients with CD4 + T-cell counts above 200 cells/mm 3, a model including the %CD4 was superior to a model including only the CD4 + T-cell count and VL. The %CD4 made a moderate supplementary contribution to risk prediction Figure 1. Estimated incidence rates of ADEs and serious ADEs A %CD4<15% %CD4 15 19.9% %CD4 20% 10.0 ADE rate per 100 person-years 7.5 5.0 2.5 B 0.0 5.5 200 349 350 499 500 649 650 CD4 + T-cell count, cells/mm 3 ADE rate per 100 person-years 2.5 0.0 200 349 350 499 500 649 650 CD4 + T-cell count, cells/mm 3 (A) AIDS-defining events (ADEs). (B) Serious ADEs. %CD4, CD4 + T-cell percentage. Antiviral Therapy 14.3 455

M Guiguet et al. in individual patients, but this simple marker is derived from the CD4 + T-cell count and the total lymphocyte count, both of which are routinely measured during follow-up of HIV-infected patients, and therefore has the advantage of being cost-free. Although biological values are expressed on a continuous scale, we categorized these variables with thresholds that are commonly used in clincial practice and are easier to manipulate. In HIV-infected patients, the CD4 + T-cell count shows within-patient variations that are far from negligible [21,22]. In addition, we performed sensitivity analyses using Cox models that included spline functions of continuous covariables [23]. Models with one knot provided optimal fit. The thresholds were 350 cells/mm 3 and 4 log 10 copies/ml for the CD4 + T-cell count and VL, respectively, in keeping with the results obtained using categorized biological values. On the basis of log-likelihood, both %CD4 and CD8 + T-cell count added prognostic information additionally to CD4 + T-cell and VL when using continuous versions of these predictors. A decreasing risk of clinical progression with increasing %CD4 was observed until the threshold of 20% was reached. The threshold was set at 400 cells/mm 3 for the CD8 + T-cell count, but the risk seemed roughly constant below or above the cutoff point with slopes not significantly different from zero. This study has certain limitations. First, we focused on ADEs, although it would also be interesting to study the predictive value of these additional markers for non-aids events associated with HIV-infection [6,24]. Second, patients were censored at treatment initiation and 62% of patients started treatment before progression to clinical AIDS. To avoid a prescription bias, we also included ADEs and deaths occurring during the first month of therapy, which accounted for 9% of all ADEs and deaths. Our results might not apply to children, pregnant women and patients with specific haematopoietic abnormalities. Information on hepatitis C virus infection and anti-hepatitis C virus therapy that are known to reduce the CD4 + T-cell count were not fully recorded, and we did not therefore analyse this risk factor. In conclusion, this study demonstrates the independent predictive value of %CD4 for the risk of progression to AIDS. This additional marker might assist with the decision on when to begin antiretroviral therapy. Acknowledgements The authors are grateful to all FHDH participants and research assistants, without whom this work would not have been possible. FHDH is supported by Agence Nationale de Recherches sur le SIDA (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM) and the French Ministry of Health. We thank David Young for his editing help. Disclosure statement The authors declare no competing interests. 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