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Rapid CD4+ Cell Decrease After Transient cART Initiated During Primary HIV Infection (ANRS PRIMO and SEROCO Cohorts)

Seng, Remonie MD*†‡; Goujard, Cécile MD, PhD§‖; Desquilbet, Loïc PhD*†‡; Sinet, Martine MD†‖; Rouzioux, Christine MD, PhD¶#; Deveau, Christiane MD*†‡; Boufassa, Faroudy MD*†‡; Delfraissy, Jean-François MD, PhD§‖; Meyer, Laurence MD, PhD*†‡; Venet, Alain MD†‖and the ANRS PRIMO and SEROCO Study Groups

JAIDS Journal of Acquired Immune Deficiency Syndromes: November 2008 - Volume 49 - Issue 3 - p 251-258
doi: 10.1097/QAI.0b013e318189a739
Clinical Science
Free

Objective: To modelize the rate of CD4+ cell count decline and its determinants after cessation of combination antiretroviral therapy (cART) started during primary HIV infection (PHI) and compare it with never-treated patients.

Methods: Kinetics of CD4+ counts were analyzed on the square root scale by using a mixed-effects model in 170 patients who received cART during PHI from the Primary Infection (PRIMO) cohort and 123 never-treated patients from the Seroconverters (SEROCO) cohort.

Results: After cART interruption in the PRIMO cohort, the CD4+ cell count fell rapidly during the first 5 months and more slowly thereafter. The timing of treatment initiation had no influence on the rate of CD4+ cell decline. In contrast, a larger increase in CD4+ cell counts during cART was associated with a steeper decline and a larger loss of CD4+ cells after treatment interruption. The mean CD4+ cell loss 3 years postinterruption was 383 cells per microliter. In the SEROCO cohort, the CD4+ T-cell decline was less steep (3-year CD4+ loss 239 cells/μL). As a result, the mean CD4+ cell counts were similar (416 cells/μL) 3 years after cART interruption (PRIMO) or after infection (SEROCO).

Conclusions: These data question the benefit of a limited course of cART even when initiated within 3 months after PHI diagnosis.

From the *INSERM U822, Le Kremlin-Bicêtre, France; †Faculté de Médecine Paris-Sud, Univ Paris-Sud, Le Kremlin-Bicêtre, France; ‡AP-HP, Hôpital Bicêtre, Service de Santé Publique, Le Kremlin-Bicêtre, France; §AP-HP, Département de Médecine Interne, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; ‖INSERM U802, Le Kremlin-Bicêtre, France; ¶AP-HP, Laboratoire de Virologie, Hôpital Necker, Paris, France; and #Laboratory EA 3620, Univ René Descartes Paris V, Paris, France.

Received for publication November 27, 2007; accepted July 17, 2008.

Supported by Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Paris, France (ANRS CO-06 and ANRS CO-02).

Part of the data was presented at 14th Conference on Retroviruses and Opportunistic Infections, February 25-28, 2007, Los Angeles, CA. Abstract 347.

The authors have no commercial or other associations that might pose a conflict of interest in this study or for this publication.

Correspondence to: Alain Venet, INSERM U802, Faculté de Médecine Paris-Sud, Univ Paris-Sud, 63 rue Gabriel Péri, F-94276 Le Kremlin-Bicêtre, France (e-mail: alain.venet@u-psud.fr).

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INTRODUCTION

It has been postulated that an early initiation of combination antiretroviral therapy (cART) during primary HIV infection (PHI) could reduce the initial spread of the virus, the size of the viral reservoir, attenuate the deleterious general immune activation, and preserve HIV-specific CD4+ T-cell responses.1-9 Initiation of cART during PHI has thus been widely used, but a significant number of patients only undergo a limited course of cART.10 In contrast to observations made in patients who were treated in the chronic stage of infection,11-15 little information is available on the dynamics of CD4+ T-cell levels after cART withdrawal when the therapy is initiated very early during infection. Determining the rate of decline in CD4+ T-cell counts after cART interruption is however of peculiar interest because it will directly determine the timing of treatment resumption. In PHI, 2 controlled clinical trials are currently ongoing to investigate the effect of a limited course of cART initiated early during infection. A few observational studies have been performed during PHI to address the question of the dynamics of CD4+ T-cell decline after cART withdrawal.16-18 These studies reported conflicting results, and none of these have thoroughly evaluated the impact of baseline virological and immunological parameters and that of the treatment characteristics on the CD4+ decline rate.

Therefore, we studied the kinetics of the CD4+ T-cell counts after interruption of cART initiated during PHI in the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) PRIMO cohort. We evaluated the influence of parameters observed at PHI diagnosis (CD4+ T-cell counts, plasma HIV RNA, and cell-associated HIV DNA) or linked to the treatment (timing of therapy after infection, duration of treatment, and increase of CD4+ T cells on cART) on the CD4+ decline rate. In addition, we compared the decline after cART withdrawal with that observed during the natural history after infection in the ANRS SEROCO cohort.

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METHODS

Study Populations

ANRS PRIMO is an ongoing French multicenter cohort created in 1996. Patients are eligible for enrollment if they are diagnosed during PHI, as defined by (1) an incomplete Western blot (no anti-p68 or anti-p34), (2) detectable plasma HIV RNA (or p24 antigenemia) associated with a negative or weakly reactive enzyme-linked immunosorbent assay (ELISA) result, or (3) an interval of less than 6 months between authenticated negative and positive ELISA tests. Until 2000, most patients (83%) were treated early after HIV infection, and many of them (76%) had treatment interruptions for a variety of reasons.10 For this study, we analyzed the CD4+ T-cell count decline in the 170 individuals who started cART within 3 months after PHI diagnosis, who had a virological response (defined as HIV RNA <500 copies/mL within 6 months on cART), who interrupted cART for at least 3 months, and who had at least 2 CD4+ T-cell counts during the interruption.

The French ANRS SEROCO cohort enrolled 1551 HIV-infected patients starting in 1988. As described elsewhere,19 431 patients had a known date of infection. Of these 431 patients, 123 were selected for the current study if they would have been enrolled in the PRIMO cohort had this cohort been implemented at that time, using the PRIMO inclusion criteria detailed above. Moreover, they had to be enrolled before the arrival of cART and to have at least 2 CD4+ cell count measurements during the follow-up. Among these 123 individuals, 43 have received zidovudine only, and given the transient effect of zidovudine monotherapy on the CD4+ T-cell count,20 values obtained within 6 months after the outset of monotherapy were excluded from this analysis (6.7% of the 719 measurements). Only 3 other patients have received a bitherapy of nucleoside analogs, and their data were censored at the time of therapy.

In both cohorts, the date of infection was estimated as the date of symptom onset minus 15 days, the date of the incomplete Western blot minus 1 month, or the midpoint between a negative and a positive ELISA. The interval between the estimated date of infection and enrollment could not exceed 6 months.

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Laboratory Methods

In the PRIMO cohort, clinical data and biological samples were collected at inclusion, then at 1, 3, and 6 months, and every 6 months thereafter. In the SEROCO cohort, samples and data were collected at inclusion and then every 6 months. The CD4+ T-cell count was determined at each visit by flow cytometry. HIV RNA levels were routinely measured in plasma in the PRIMO cohort and in frozen serum in SEROCO.21 As previously described,19,22 a value of 0.28 log10 copies per milliliter was added to serum HIV RNA values above the detection limit to make them comparable to plasma HIV RNA values. HIV DNA levels in stored peripheral blood mononuclear cells (PBMC) were quantified by a central laboratory using a real-time polymerase chain reaction method with a quantification threshold of 70 copies per 106 PBMC.23,24

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Statistical Analysis

The CD4+ T-cell decline over time in the PRIMO cohort was modeled from the time of treatment interruption to either treatment resumption or the end of follow-up. In the SEROCO cohort, the data were modeled from the estimated date of HIV infection to either January 1996 or the initiation of bitherapy. Data obtained after more than 3 years of follow-up were not considered, as they could have been biased by the selection of slow progressors who were more likely to remain off therapy for long periods.

The kinetics of CD4+ T-cell counts were analyzed on the square root scale by using a mixed-effects model to take into account the correlation between measurements in the same subjects. As the decline in the CD4+ cell count was not linear in either PRIMO or SEROCO, it was modeled as a piecewise linear function. Different time points of slope changes were tested and chosen with the profile likelihood method. This modelization was performed either with all data points available or with only the scheduled measurements performed every 6 months and gave similar results. The square root transformation of CD4+ cell counts was used to fulfill the model assumption.

In the PRIMO cohort, a 3-slope model best described the CD4+ T-cell count decline during cART interruption. We tested the effect of baseline parameters on the slopes of the CD4+ T-cell decline after cART interruption by testing interaction terms between each slope and the studied parameters. In the SEROCO cohort, a 2-slope model best described the CD4+ T-cell count decline during the first 3 years after HIV infection (without treatment). Both the PRIMO and SEROCO models included both fixed and random effects for the intercept and the first slope, which were therefore allowed to vary between subjects.

Statistical analysis was carried out with SAS version 9.1 (SAS Institute, Cary, NC). The PROC MIXED procedure was used for linear mixed-effects models.

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RESULTS

Characteristics of PRIMO Subjects

We included in this analysis 170 subjects who started cART during the primary phase of HIV infection and who then interrupted cART for at least 3 months after at least 6 months of effective therapy. The characteristics of these subjects are summarized in Table 1. Their baseline characteristics were as expected for a cohort of subjects with primary infection.19,25-27 The median HIV RNA level at inclusion was 5.3 log10 copies per milliliter, and the median CD4+ cell count was 489 cells per microliter. The median interval between the estimated date of infection and cART initiation was 38 days. Thirty-eight patients (22%) were diagnosed before seroconversion (<2 Western blot bands) and were treated within 2 weeks of diagnosis. These patients are referred to below as being in acute stage PHI. The others were considered to be in early stage. Most patients (87%) started with a protease inhibitor-containing regimen. The median duration of cART was 19 months, during which the median CD4+ T-cell count rose to 769 cells per microliter.

TABLE 1

TABLE 1

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CD4+ T-Cell Decline After cART Interruption

During cART interruption (median duration 21 months; interquartile range, 12-36), a total of 1149 CD4+ T-cell measurements were available (median of 6 measurements per subject). The CD4+ T-cell count decline during cART interruption was best described by a 3-slope model (Fig. 1). A strong decline, of −0.47 √cells per μL/month on the square root scale, was observed during the first 5 months, followed by slower declines of −0.23 √cells per μL/month from 5 to 17 months and −0.14 √cells per μL/month thereafter. This corresponded to a fall in the CD4+ cell count from an estimated mean value of 799 cells per microliter [95% confidence interval (CI): 751 to 855] at the time of cART interruption to 590 cells per microliter (552 to 629) at 1 year after the interruption, 490 cells per microliter (453 to 531) at 2 years, and 416 cells per microliter (376 to 464) at 3 years.

FIGURE 1

FIGURE 1

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Influence of Baseline Parameters on the CD4+ T-Cell Decline After cART Interruption

Baseline parameters were categorized on the basis of usual clinical thresholds. Figure 2 shows the slopes of the CD4+ cell decline according to the pretreatment CD4+ T-cell count (≤500 or >500 cells/μL), the HIV RNA level (≤5.0 or >5.0 log10 copies/mL), and the cellular HIV DNA level (≤3.4 or >3.4 log10 copies/106 PBMC). Table 2 shows the mean annual CD4+ T-cell loss according to these parameters. None of these slopes were significantly influenced by any of the baseline parameters. On the other hand, these parameters influenced the estimated CD4+ T-cell counts 36 months after cART interruption (last column, Table 2); consequently, lower CD4+ T-cell counts and higher viral loads at inclusion were associated with lower CD4+ T-cell counts during cART interruption. In contrast, the baseline HIV DNA level had no significant influence on the CD4+ T-cell count at 36 months.

TABLE 2

TABLE 2

FIGURE 2

FIGURE 2

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Influence of Treatment-Associated Parameters on the CD4+ T-Cell Decline After cART Interruption

We then examined the influence of treatment-associated parameters on the slopes of the CD4+ T-cell decline. The following parameters were considered: the timing of cART initiation, its duration, and its impact on the CD4+ T-cell count (assessed by the gain during cART and the count at cART interruption). Patients were categorized as acute or early stage PHI (see above), or were stratified according to parameter values close to the medians, as follows: cART duration ≤ or >19 months, CD4+ T-cell gain during cART ≤ or >250 cells per microliter, and CD4+ T-cell count at the time of cART interruption ≤ or >750 cells per microliter. Figure 2 represents the slopes of CD4+ T-cell decline according to these parameters, and Table 2 shows the mean annual CD4+ T-cell decline and the estimated CD4+ T-cell counts 36 months after cART interruption. The timing of cART initiation and its duration had very little influence on the slopes of the CD4+ T-cell decline. By contrast, a large CD4+ T-cell gain during cART (>250 cells/μL) was clearly associated with a steeper decline after cART withdrawal, particularly in the first year [P = 0.01 for the first slope (months 0-5); P = 0.04 for the second slope (months 5-17)]. The CD4+ T-cell count decline during the first year was 281 cells per microliter in patients who had a large CD4+ T-cell gain compared with 109 cells per microliter in the other patients. Consequently, the estimated mean CD4+ T-cell counts at M36 did not differ between patients who had gains of ≤ or >250 cells per microliter. A significant difference in the first slope was also observed according to the CD4+ T-cell count before cART interruption. However, although the patients with high CD4+ T-cell counts before cART interruption had a larger decline than other patients, they still had higher counts than the other patients 36 months after interruption (506 vs 304 cells/μL, P < 0.0001). In fact, the preinterruption CD4+ T-cell count is the consequence of both the initial count and the gain during cART. When we analyzed the results according to each of these parameters (Figs. 2A, F), the influence of the preinterruption count on the steepness of the CD4 slopes seemed linked to be the gain of CD4 during cART. Conversely, the influence of the preinterruption count on the estimated CD4 levels at M36 seemed to be linked more to the CD4 baseline count.

Together, these data suggested that the gain in CD4+ T cells (ie, the impact of treatment) was one of the main factors influencing the rate of decline in the CD4+ T-cell count: large increases during cART were rapidly lost after treatment interruption. These data prompted us to compare the rate of decline in these patients with that observed in never-treated patients belonging to the SEROCO cohort.

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Comparison of the CD4+ T-Cell Decline in Patients Who Interrupted cART and in Never-Treated Patients

A total of 671 CD4+ cell measurements in 123 patients enrolled in the SEROCO cohort were used to model the spontaneous CD4+ T-cell decline during the first 3 years of HIV infection (median 6 measurements per subject).

The median age at HIV infection was 27.5 years, and 28% of these subjects were women (Table 1). At enrollment, the median HIV RNA load was 4.50 log10 copies per milliliter (interquartile range, 3.85-4.97) and the median CD4+ T-cell count was 601 cells per microliter (479-772). After adjustment for sex, age, and the time since infection, by means of restricted quadratic spline regression with 2 knots,19 we found no difference in the baseline viral load, cellular HIV DNA, or CD4+ T-cell count between the 2 cohorts. This authorized us to compare the CD4+ cell kinetics in the 2 populations after systematically fixing the same age and sex distribution in the SEROCO model as in the treated PRIMO subjects. In the SEROCO model, the CD4+ T-cell count showed 2 slopes of decline. The decrease was −0.37 √cells per μL/month during the first 6 months and −0.10 √cells per μL/month thereafter (Fig. 3A). This corresponded to a fall from a mean of 655 cells per microliter (95% CI: 566 to 747) at the estimated date of HIV infection to 519 cells per microliter (95% CI: 484 to 553) at 1 year, 466 cells per microliter (95% CI: 429 to 501) at 2 years, and 416 cells per microliter (95% CI: 370 to 457) at 3 years. The slopes were less steep than in the patients who interrupted cART. Consequently, although the counts were higher at cART interruption in treated patients than at the time of HIV infection in never-treated patients (difference of 144 CD4+ T cells/μL), the difference between the 2 groups gradually diminished over time and, after 3 years without therapy, the mean counts were remarkably similar in the 2 cohorts: 416 cells per microliter (95% CI: 370 to 457) in never-treated patients and 416 cells per microliter (95% CI: 376 to 464) in the patients who had transiently received cART.

FIGURE 3

FIGURE 3

As current guidelines recommend treatment initiation in asymptomatic patients when the CD4+ T-cell count falls below 350 cells per microliter, we calculated the time taken to reach this level in never-treated and transiently treated patients, to determine whether short-term therapy had a sparing effect (Fig. 3B). Never-treated patients took an estimated 52 months to reach a CD4+ T-cell count of 350 cells per microliter. In the cART-treated patients, when the interval between infection and cART interruption was arbitrarily fixed at 18 months, the time taken to reach 350 CD4+ T cells per microliter was 66.6 months after HIV infection and 48.6 months after treatment interruption. When the interval between infection and cART interruption was set at 24 months, the time taken to reach 350 CD4+ T cells per microliter was 72.1 months in total and 48.1 months after cART interruption.

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DISCUSSION

Here we described the rate of CD4+ T-cell count decline and its determinants after a limited course of cART, initiated during the primary phase of HIV infection. We observed a sharp initial fall in the CD4+ T-cell count after interruption of early cART. The magnitude of this CD4+ T-cell loss was not associated with baseline parameters, or the timing of cART initiation (acute vs early), but was highly associated with the gain during treatment. A steeper decline in CD4+ T-cell count after interruption was also observed with higher CD4+ counts at the time of interruption. To our knowledge, this is the first analysis of the influence of these factors in patients who started cART during PHI.

Several studies of chronically infected patients have also shown a steep initial drop in the CD4+ T-cell count after treatment withdrawal.11-15 The main determinant of the CD4+ T-cell decline after cART interruption in these studies was the magnitude of the CD4+ T-cell gain during treatment,11,13,15,28 although an influence of baseline parameters on the slope has rarely been found.13

The reasons for the rapid loss of CD4+ T cells observed after treatment withdrawal are unclear. Viral rebound is frequent after cART withdrawal.29-31 This may induce a direct cytopathic effect or a systemic immune activation which is known to have a deleterious effect on CD4+ T-cell homeostasis.2,32 A redistribution of CD4+ T cells in lymph nodes or other sites of viral replication may also occur. These explanations are mutually compatible, but the rapid increase in the CD4+ T-cell count usually observed after cART reintroduction argues for redistribution from blood to tissues.33

Baseline CD4 counts and HIV RNA levels were not associated with the CD4 slope but were strongly related to the CD4 level after prolonged interruption. This has been described in treated patients with chronic infection,28,34,35 and we could observe these strong relations even when baseline parameters were measured during primary infection. This is consistent with previous reports on the influence of baseline parameters on virological level after a limited course of cART initiated during PHI.19,30

We compared the evolution of CD4+ T-cell counts in never-treated patients and in patients who interrupted cART after a transient therapy. This was a nonrandomized comparison. The occurrence of symptomatic primary infection is lower in the SEROCO cohort but it is likely to have been underreported as in many cohort studies of HIV seroconverters.36 However, it is noteworthy that no difference in baseline viral load, cellular HIV DNA, or CD4 cell counts was observed between the 2 study populations after adjustment for sex, age, and the time between infection and enrollment. Therefore, characteristics of patients from the SEROCO cohort more closely reflect those of treated patients from the PRIMO cohort than untreated patients from PRIMO who had less severe baseline parameters.

We also estimated in both groups the time taken to reach 350 CD4+ T cells per microliter, which is the current threshold recommended to resume therapy. Patients who initiated cART at primary infection took more time since infection to reach 350 CD4+ T cells per microliter than never-treated patients, but after taking into account the duration of treatment, they did not benefit from a longer time off therapy.

Three other observational studies have compared changes in the CD4+ T-cell count after interruption of cART initiated early after HIV infection with untreated patients.16-18 In the first one, no difference between the groups was observed at 1 year after infection, that is, 6 months after cART withdrawal.16 In the second study, with a longer treatment period and longer follow-up, the mean CD4+ T-cell count was higher in the treated group than in the untreated group, with a difference of 112-116 cells per microliter 6 months after interruption. This difference diminished with time but nonetheless persisted at the end of follow-up, at 18 months.17 Similarly, we found a difference of 113 cells per microliter in the mean CD4+ T-cell count between treated patients 6 months after cART withdrawal and never-treated patients. This difference also diminished with time, and a longer follow-up allowed us to observe that it vanished only after 36 months. The results of the third study are strikingly different as a marked difference in the CD4+ T-cell decline was observed after the sixth month off therapy between never-treated patients and patients treated for only 3 months.18 All these studies including ours are observational comparisons and therefore subject to biases including unmeasured confounding factors. A more definite answer to whether a limited course of cART, initiated during the primary phase of HIV infection, can delay subsequent disease progression will be brought from the ongoing randomized trials short pulse antiretroviral therapy at seroconversion (SPARTAC) MRC and AIDS clinical trials group (ACTG) 5217.

Altogether with our previous report that a limited course of cART did not significantly modify the viral set-point,19 our data on the CD4+ T-cell counts could question the utility of transient cART initiated shortly after infection compared with a deferred treatment. However, even if the CD4 decline after interruption of early cART was important (and highly related to the magnitude of the CD4 gain), it is important to underline that CD4 counts remained higher than CD4 counts observed in untreated patients until 36 months. This might be beneficial because treatment interruptions may be clinically deleterious in chronic infection (Strategies for Management of Antiretroviral Therapy [SMART], Trivacan),37,38 although this has not been reported in another study (Staccato)35 or in recently infected subjects.29-31 Finally, this study could not address the benefit of a transient treatment started during primary infection compared with a deferred treatment initiated at different levels of CD4 counts (such as >350 or 500 cells/μL). Moreover, neither a transient early cART nor a transient deferred cART may be optimal for all patients. We previously showed that patients with low CD4+ T-cell counts have a high risk of progression39 and would strongly benefit from an early treatment. Our data also lead to recommend not to interrupt therapy in particular in patients who have low CD4 counts during primary infection. Patient's characteristics during primary infection, and not treatment duration or therapeutic response, remain the most prominent factors which influence the outcome after treatment interruption. More active therapeutic strategies, or more prolonged ones,40 are needed to really impact the HIV infection prognosis.

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ACKNOWLEDGMENTS

We thank all the patients who are participating in the PRIMO and SEROCO cohorts, the physicians of the ANRS PRIMO (http://u822.kb.inserm.fr/COHAD/participantsPRIMO.htm) and SEROCO Network, Dr I. Iraqui, Dr Z. Nagy, Dr N. Saichi, Dr N. Balegroune, Dr Y. Zitoun, Dr S. Boucherit, Dr S. Hendou, Dr J. Surzyn for data monitoring, and David Young for editing the manuscript. The PRIMO Cohort Scientific Committee is composed of M. L. Chaix, M. J. Commoy, J.F.D., C.D., C.G., M. Harzic, L.M., I. Pellegrin, C.R., M.S., and A.V. The SEROCO Cohort Scientific Committee is composed of F.B., J.F.D., L.M., M. C. Meyohas, I. Poizot-Martin, C.R., D. Sereni, and J. L. Vilde.

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Keywords:

CD4+; HIV-1; primary infection; treatment interruption

© 2008 Lippincott Williams & Wilkins, Inc.