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AIDS:
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Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy

Jouan, Marca; Savès, Mariannef; Tubiana, Rolanda; Carcelain, Guislaineb; Cassoux, Nathaliec; Aubron-Olivier, Camillea; Fillet, Anne-Maried; Nciri, Maryemf; Sénéchal, Brigitted; Chêne, Genevièvef; Tural, Christinag; Lasry, Stéphanee; Autran, Brigitteb; Katlama, Christine*; for the RESTIMOP study team

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From the Departments of aInfectious Diseases, bImmunology, cOphthalmology and dVirology , Hôpital Pitié-Salpêtrière and the eHôpital Pasteur, Paris, fINSERM U330, Université Victor Segalen, Bordeaux 2, France and the gHôpital German Trias i Pujol Badalona, Spain. *See Appendix for the study members of RESTIMOP.

Received: 28 July 2000;

revised: 13 September 2000; accepted: 12 October 2000.

Sponsorship: Supported by a grant from the Agence Nationale de Recherches sur le SIDA (ANRS 078).

Requests for reprints to Dr C. Katlama, Department of Infectious Diseases, Hôpital Pitié-Salpêtrière, 47-83 Bld de l'Hôpital, 75013 Paris, France.

Note: The work in this paper has been presented in part at the Sixth Conference on Human Retroviruses and Related infections, Chicago, 1999 [abstract 456].

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Abstract

Objective: To study the safety of discontinuing cytomegalovirus (CMV) maintenance therapy among patients with cured CMV retinitis receiving highly active antiretroviral therapy (HAART).

Methods: Patients with a history of CMV retinitis who were receiving anti-CMV maintenance therapy and who had a CD4 cell count > 75 × 106 cells/l and a plasma HIV RNA level < 30 000 copies/ml while on HAART were included in a multicentre prospective study. Maintenance therapy for CMV retinitis was discontinued at enrolment and all the patients were monitored for 48 weeks by ophthalmological examinations and by determination of CMV markers, CD4 cell counts and plasma HIV RNA levels. T helper-1 anti-CMV responses were assessed in a subgroup of patients. The primary study endpoint was recurrence of CMV disease.

Results: At entry, the 48 assessable patients had been taking HAART for a median of 18 months. The median CD4 cell count was 239 × 106 cells/l and the median HIV RNA load was 213 copies/ml. Over the 48 weeks, 2 of the 48 patients had a recurrence of CMV disease. The cumulative probability of CMV retinitis relapse was 2.2% at week 48 (95% confidence interval, 0.4–11.3) and that of all forms of CMV disease 4.2%. CMV blood markers remained negative throughout follow-up. The proportion of patients with CMV-specific CD4 T cell reactivity was 46% at baseline and 64% at week 48.

Conclusions: CMV retinitis maintenance therapy may be safely discontinued in patients with CD4 cell counts above 75 × 106 cells/l who have been taking HAART for at least 18 months.

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Introduction

Cytomegalovirus (CMV) retinitis is a sight-threatening complication of severe immunodeficiency caused by HIV infection [1–3]. In the absence of maintenance therapy, CMV retinitis progresses within 3 to 4 weeks after the end of induction treatment [4,5], compared with a median of 3–4 months when maintenance therapy is prescribed [6–8]. Chronic systemic maintenance therapy markedly affects these patients’ quality of life, because of the need for daily infusions, the adverse drug effects and catheter-related infections.

Since the introduction of highly active antiretroviral therapy (HAART) in 1996, the incidence of opportunistic infections, including CMV infection, has fallen considerably in HIV-infected patients [9–13]. In particular, HAART is associated with a reduction in CMV replication and clearance of CMV viraemia [14–16].

The immune restoration observed among patients on HAART includes an increase in the absolute CD4 cell count, initially through an increase in memory T cells, and then by renewed production of naive CD4 T cells [17]. If HIV replication is suppressed long enough by HAART, in addition to the quantitative increase in CD4 cells, proliferative responses against recall environmental antigens such as CMV and tuberculin can be restored even in patients with persistent severe immunodeficiency [17,18] or prior retinitis [19]. This raised questions as to the need to continue CMV maintenance therapy in patients with cured CMV retinitis whose immune status had improved.

This prospective study assesses the safety of discontinuing maintenance therapy in patients with cured CMV retinitis who were receiving an effective HAART regimen.

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Methods

Study design and patients

This prospective, multicentre, single-arm study was designed to assess whether the quantitative immune restoration observed during effective HAART was sufficient to prevent recurrence of CMV disease after discontinuation of maintenance therapy.

Patients were recruited from 18 sites in France, Italy, Belgium and Spain. They were considered eligible if they had a history of healed CMV retinitis, were receiving CMV maintenance therapy (systemic or local injections) and had negative pp65 antigenaemia or negative CMV viraemia, had a CD4 cell count of > 75 × 106 cells/l and had a plasma HIV RNA load < 30 000 copies/ml for at least the 3 last months, after receiving a protease inhibitor-containing antiretroviral regimen. Patients with a CMV retinitis scar near the optic nerve or the macula, and patients receiving ganciclovir implants, were ineligible.

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Endpoints and follow-up

The primary outcome measure was the recurrence of CMV disease during the 48-week follow-up period.

Reactivation of CMV retinitis was defined as the occurrence of yellowish-white retinal oedema associated with haemorrhages on the scar border, or the onset of any new retinal lesions. All extraocular sites of CMV disease had to be histologically confirmed. All clinical events were validated by an expert committee.

Secondary outcomes included quantitative plasma CMV leukocyte DNA and CMV-specific T cell proliferation.

Patients were seen every 2 weeks during the 48 weeks of follow-up and underwent a physical assessment and a complete opthalmological examination (visual acuity using the Snellen chart, slit-lamp biomicroscopy and dilated indirect funduscopy). Fundus photographs were taken at baseline and every 3 months. Retinal fluorescein angiography was performed at week 48. Ophthalmological data were reviewed by a committee of ophthalmologists.

Laboratory monitoring included monthly measurements of the CD4 cell count and CMV blood culture or pp65 antigenaemia (which depended on the local virology laboratory); for each patient the same assay was performed throughout the study. Plasma HIV RNA was measured every 3 months using a standard reverse transcriptase polymerase chain reaction (RT-PCR) assay.

CMV PCR was performed on polymorphonuclear leukocytes in the same virology laboratory, at enrolment then every 3 months and if CMV disease recurred; 150 000 polymorphonuclear leukocytes were used to amplify the CMV major immediate-early gene (20 Demmler). CMV PCR was performed with the HS ELOSA CMV kit (Lambdatech, Namur, Belgium), which has a detection limit of 10 copies.

A lymphocyte proliferation assay (LPA) was performed in a single laboratory on samples from a subgroup of 26 patients from centres in Paris. Fresh peripheral blood mononuclear cells (PBMC) were tested as previously described [17,18] against cytomegalovirus (Behring, Marburg, Germany) and tuberculin antigens (Statens Serum Institut, Denmark) at enrolment, and at weeks 12, 24, 36 and 48. Results were expressed as mean c.p.m. A stimulation index was calculated as previously described [17,18]. Positive antigen-specific responses were defined as > 3000 cpm and a stimulation index > 3 in vitro. Interferon γ production levels were measured with an enzyme-linked immunosorbent assay (Diaclone, Besançon, France) on day 2 culture supernatants of PBMC stimulated with the CMV antigen. Interferon-γ levels in medium controls were consistently < 50 pg/ml, and this value was subtracted from the sample values. A response was considered positive if it was > 50 pg/ml.

Clinical investigators were advised to reintroduce anti-CMV therapy in the following situations: any progression of CMV disease; positive CMV viraemia or pp65 antigenaemia in two consecutive samples; fall in the CD4 cell count to < 50 × 106 cells/l; increase in plasma HIV RNA load to > 100 000 copies/ml; discontinuation of antiretroviral therapy for more than 1 month; and failure to attend two consecutive visits.

The study was approved by the Pitié-Salpêtrière Ethics Committee for French centres and local ethics committees in Belgium, Spain and Italy. Written informed consent was obtained from all the patients.

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Statistical analysis

The sample size (n = 54) was calculated to ensure that the incidence of relapse would not exceed 25% at 3 months (upper limit of the 95% confidence interval) with a power of 80% and a type I error of 5% (Fleming's single-stage procedure, one-sided test). Follow-up was to be extended to 48 weeks if the number of CMV clinical events did not reach seven at 3 months.

Follow-up data were available until week 48 for all the patients and were censored at that time. The time to the first relapse of CMV retinitis or other CMV disease was calculated as the interval between the date of enrolment and the date of the CMV event or week 48. The CMV event-free probability curve throughout the trial was plotted using the Kaplan–Meier product-limit method. SAS software (6.11, SAS Institute, Cary, North Carolina, USA) was used for statistical analysis.

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Results

Characteristics of the patients

A total of 53 patients were enrolled in the study between May 1997 and July 1998; of these 53 patients only 48 were assessable. Five patients did not fulfil the inclusion criteria, for the following reasons: absence of visible cured retinitis in two patients, retinal detachment in one patient and plasma HIV RNA > 30 000 copies/ml in two patients. All the patients enrolled in the study completed the 48-week follow-up period.

Baseline characteristics of the 48 study participants are shown in Table 1. At enrolment, the median CD4 cell count was 239 × 106 cells/l (range, 83–889), and 75% of patients had plasma HIV RNA values < 500 copies/ml. The median duration of HAART prior to enrolment was 18 months. The median interval between the last episode of CMV retinitis and enrolment was 17 months (Table 2). The median CD4 cell count, at the time of CMV retinitis, was 14 × 106 cells/l and 44% of patients had had at least two episodes of CMV retinitis. The retinitis was unilateral in 35 patients (73%) and bilateral in 13 patients (27%). At enrolment, all but one of the patients were receiving systemic maintenance therapy for CMV retinitis [foscarnet or ganciclovir intravenous infusion in 24 patients (50%); oral ganciclovir in 23 patients (48%)]. The remaining patient was receiving only intravitreal ganciclovir injections (Table 2).

Table 1
Table 1
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Table 2
Table 2
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Incidence of CMV disease

Over the 48 weeks following discontinuation of maintenance therapy, 2 of the 48 patients developed recurrent CMV disease. The cumulative probability of any CMV disease site was 4.2% [95% confidence interval (CI) 1.2–14.1], and the cumulative probability of recurrent CMV retinitis was 2.2% (95% CI, 0.4–11.3).

One patient had a recurrence of CMV retinitis (confirmed by funduscopy and angiography) 11 weeks after discontinuing intravenous ganciclovir. The CD4 cell counts were 302 and 352 × 106 cells/l, respectively and the plasma HIV RNA values were 4.1 and 4.3 log10 copies/ml, respectively, at baseline and at the time of CMV retinitis relapse.

The second patient developed CMV-related peripheral neuropathy 5 weeks after withdrawal of CMV maintenance therapy. Clinical manifestations included paraesthesias, pain and gait disorders. From baseline to the onset of the neuropathy, the plasma HIV RNA levels remained stable at 2.3 log10 copies/ml and the CD4 cell counts were 140 and 106 × 106 cells/l, respectively. Antiretroviral therapy in this patient consisted of stavudine, lamivudine and indinavir, for 10 months. No CMV inclusions were detected in neuromuscular biopsy specimens. Because of the clinical severity, stavudine was discontinued and ganciclovir was resumed; the patient gradually improved after a few weeks.

CMV blood culture, pp65 antigenaemia and CMV DNA assays were negative in both patients at CMV disease recurrence.

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Course of HIV infection

The median CD4 cell count increased significantly during follow-up, from 239 × 106 cells/l at baseline to 347 × 106 cells/l at week 48 (P < 10−4) (Table 3).

Table 3
Table 3
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The median plasma HIV RNA load did not change significantly from baseline (median 2.3 log10 copies/ml; range, 2.1–4.7) to week 48 (2.3 log10 copies/ml; range, 2.1–4.5) (P = 0.11). Three-quarters of patients had HIV RNA values below 500 copies/ml at week 48.

None of the 48 patients had to resume secondary CMV prophylaxis, as defined in the protocol, because of a fall in the CD4 cell count or an increase in plasma HIV RNA. None of the 46 patients who remained free of CMV disease experienced any major HIV-related clinical event.

Two patients died during follow-up, one from acute leukaemia and one from lymphoma.

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CMV-specific immune responses

CMV-specific responses, measured in the LPA, showed CD4 T cell reactivity in 12 of the 26 patients (46%) tested at baseline, 12 of the 22 patients (55%) tested at week 24, and 14 of the 22 patients (64%) tested at week 48 (Fig. 1) (P = 0.29). Of the 24 patients tested who did not develop recurrent CMV disease, five were never CMV LPA-positive during the 48 weeks of follow-up; 8 of the 13 patients with an initially negative response became positive during follow-up, while 1 of the 11 patients with an initially positive response became repeatedly negative. A significant T cell production of interferon-γ after stimulation with CMV antigens (median 247 pg/ml; range, 30–687) was detected in 44% (11/25) of patients at week 48. Two of the five LPA-negative patients had significant T cell interferon-γ production. Overall, only 3 of the 24 patients had no anti-CMV T cell reactivity at any time during the 48 weeks of follow-up; 16 of the 22 listed patients (73%) had anti-CMV T cell reactivity at the end of study.

Fig. 1
Fig. 1
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The patient in whom CMV retinitis relapsed at week 11 had strong specific T cell proliferation to CMV antigens at enrolment (6266 c.p.m.; stimulation index 27) and had lost this reactivity at the time of the clinical CMV relapse (96 c.p.m.; stimulation index 1). The patient who developed CMV neuropathy at week 6 had no proliferative response to CMV at baseline.

Similar percentages of lymphocyte reactivity to tuberculin were observed, with tuberculin-specific proliferative response in 37, 46 and 65% of patients at baseline, week 24 and week 48, respectively.

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Ophthalmological follow-up

Among the 61 eyes evaluated at baseline in these 48 patients, visual acuity was impaired in 23/61 eyes, with a score of less than 20/32 on the Snellen chart. Over the 48-week follow-up period, visual acuity remained stable in 38 of the 57 assessable eyes (46 patients), deteriorated by more than one line on the Snellen chart in 14 eyes and improved in five eyes.

At enrolment, immune recovery vitreitis was present in 24/59 assessable eyes (41%) in 47 patients. At week 48, it remained stable in eight eyes, had deteriorated in four and improved in six. Immune recovery vitreitis appeared in nine eyes during follow-up. The prevalence of cystoid macular oedema assessed on retinal fluoroscein angiography at week 48 was 67% (29/43) (95% CI, 51–81). No association was found between the presence of immune recovery vitreitis and LPA positivity: 11 of the 14 patients with a sustained anti-CMV Th1 response had immune recovery vitreitis compared with three of the five patients with a consistently negative anti-CMV Th1 response (P = 0.57).

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Discussion

In this prospective study designed to investigate the safety of discontinuation of therapy for CMV, the overall recurrence rate of CMV disease was 4.2% and that of CMV retinitis 2.2% during a 48-week period after discontinuation of CMV maintenance therapy in 48 patients with CD4 cell counts > 75 × 106 cells/l while on HAART.

Two patients developed recurrent CMV disease. In one patient, funduscopy showed a minimal progression of peripheral retinitis 11 weeks after stopping maintenance therapy. The episode responded favourably to anti-CMV therapy.

The second patient developed peripheral neuropathy, which the expert committee considered to be potentially related to CMV despite the absence of CMV inclusions and antigens in cerebrospinal fluid and neuromuscular biopsy specimens. This patient was taking a stavudine-containing HAART regimen, which is known to induce peripheral neuropathy, and the patient had had a prior episode of neuropathy while on this drug. However, the sudden onset of paraesthesia, the presence of acute axonal lesions on neuromuscular biopsy and the rapid recovery on specific therapy were considered to favour a diagnosis of CMV-related neuropathy.

Whereas a minimal CD4 cell count of 75 × 106 cells/l was required to enter the study, the median count at baseline, i.e. when maintenance therapy was discontinued, was 239 × 106 cells/l (range, 83–899). The discrepancy might be explained by the fact that at the time of the enrolment in the study, between May 1997 and July 1998, most patients with a history of CMV retinitis had received protease inhibitors and had been on a HAART regimen for a median of 18 months, with a substantial increase in the CD4 cell count. The study population is, therefore, fairly representative of candidates for discontinuation of secondary CMV prophylaxis during HAART. However, some of the study investigators may have been reluctant to discontinue CMV maintenance therapy in patients with CD4 cell counts below 150 × 106 cells/l.

One limitation of our study is that it was not comparative or randomized. However, to demonstrate equivalence between discontinuing and pursuing maintenance therapy, we would have had to include a much larger number of patients, given the small number of clinical events on HAART. Furthermore, the frequent adverse effects of CMV maintenance therapy would probably have made it difficult to maintain secondary CMV prophylaxis in the control group over such a long follow-up period. Such a study would be even more difficult to set up at present.

The epidemiology of clinical CMV infection and the course of CMV disease were extensively studied in the pre-HAART era. CMV retinitis usually occurs when the CD4 cell count falls to < 50 × 106 cells/l [1,2,20]. For patients with CD4 cell counts < 100 × 106 cells/l, the reported probability of CMV disease at 2 years was 21%, compared with 1% among patients with higher counts [1]. In randomized studies, the median time to retinitis progression ranged from 3 to 4 months in the maintenance arm and 3 to 6 weeks in the absence of maintenance therapy [4–7,21]. Longer remission of CMV retinitis has been observed with intravitreal ganciclovir implants [22]. However, this approach fails to prevent progression to the other eye or to other organs. Therefore, it is reasonable to postulate that, in the absence of immune restoration, the recurrence rate of CMV retinitis after discontinuation of secondary prophylaxis would have been nearly 100% after 3 months. The fact that we observed only two cases of recurrent CMV disease in these 48 patients over 48 weeks of follow-up is clearly related to the impact of the immune restoration associated with HAART in this setting.

Several observational cohort studies have shown a sharp fall in the incidence of CMV infection since the introduction of HAART [23–24]. In the PREDIVIR study [10], the incidence of CMV disease in patients with CD4 lymphocyte counts < 100 × 106 cells/l fell from 20 to only 3.5 per patient-year.

The reduced incidence of most major opportunistic infections is thought to be essentially a consequence of the immune restoration facilitated by the sustained inhibition of viral replication, as reflected by the restoration of CMV-specific CD4 T cell responses 3–6 months after initiation of efficient antiretroviral therapy [17–19].

Our study was the first to investigate prospectively the clinical consequences of discontinuing secondary CMV prophylaxis in parallel with measurements of CMV-specific helper immune response. A median of 18 months following HAART initiation, 46% of the 26 patients tested had anti-CMV T cell proliferative capacity; this proportion tended to increase during follow-up, as 64% of tested patients had positive proliferative responses after 48 weeks.

The production of interferon-γ by CMV-specific T cells assesses the Th1 profile of this reactivity, as previously shown [10]. Such Th1 response should help the restoration of a potent effector response against CMV mediated by parallel cytotoxic T lymphocytes. Studies performed in parallel confirmed that high frequencies of CD8 cells specific for CMV were detectable in these patients (G. Carcelain et al., personal communication).

Interestingly, the two CMV-related clinical events occurred in patients who had no immune reactivity against CMV antigens at onset. Because of the small number of clinical events, we cannot determine whether immunological non-reactivity to CMV antigens is predictive of CMV disease progression.

Our results suggest that HAART, by quantitatively and qualitatively restoring immune status [median CD4 cells 14 × 106 cells/l at the time of CMV retinitis and 239 × 106 cells/l at the discontinuation of maintenance therapy (with a minimal value of 83 × 106 cells/l)] confers clinical protection from recurrent CMV disease.

Overall, the impact of HAART on plasma HIV RNA load remained stable over the 48 weeks of follow-up, suggesting that HAART rarely fails in highly motivated patients, with excellent initial control of HIV replication.

Immune recovery vitreitis was first described in patients with inactive CMV retinitis who had an increase in the CD4 cell count in response to HAART [25,26]. As reported by other authors, we found a high frequency of immune recovery vitreitis (41%) in these patients. Interestingly, while Karavellas et al. reported a median time of 43 weeks after starting HAART to the onset of immune recovery vitreitis [range 35–47 weeks], seven of our patients who were free of immune recovery vitreitis at enrolment developed it after 28–90 weeks of HAART. This suggests that patients with a history of CMV retinitis should receive regular and prolonged ophthalmological monitoring after starting HAART.

Despite close monitoring throughout follow-up, including measurement of highly sensitive CMV markers such as quantitative pp65 antigenaemia every month [27,28] and CMV DNA screening by PCR in blood leukocytes every 3 months, both of which are predictors of CMV disease progression [29], we found no signs of CMV reactivation in any of the patients. The absence of CMV replication in leukocytes at baseline was probably a result of the specific maintenance therapy, but thereafter it was probably a consequence of the immune restoration conferred by HAART; this has been supported by a patient in whom immune restoration was able to control persistent CMV replication in the absence of specific CMV therapy [30].

The discontinuation of prophylaxis against opportunistic infections in HIV-infected patients showing an improvement in immune status during HAART has mainly been studied for primary Pneumocystis carinii pneumonia [31–33] and, more recently, for primary Mycobacterium avium complex disease [34] Regarding the issue of discontinuing CMV maintenance therapy, our data are in keeping with previous series of 7–15 patients with median CD4 cell counts ranging from 180 to 300 × 106 cells/l in which no progression of CMV retinitis occurred over follow-up periods ranging from 6 to 72 months [35–39] The possibility of withdrawing CMV maintenance therapy in patients with a history of extraretinal CMV disease has not been examined.

In conclusion, this study shows that it is safe to stop maintenance therapy for CMV retinitis in patients who respond to HAART with an increase in the CD4 cell count to at least 75 × 106 cells/l. These results should be applicable to routine practice. Withdrawal of CMV maintenance therapy in this setting should lead to a major improvement in these patients’ quality of life, together with a significant cost saving. Discontinuation of maintenance therapy for CMV retinitis in patients with immune restoration while taking HAART has recently been incorporated into the USPHS/IDSA guidelines for the Prevention of Opportunistic Infections in the United States [40] and into French guidelines on the management of HIV-infected patients [41].

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Acknowledgments

We would like to thank the study participants, the investigators of RESTIMOP and David Young for help in manuscript preparation.

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Appendix

Scientific Committee: M. Jouan, R. Tubiana, C. Katlama, G. Chêne, X. Mengual, S. Matheron, T. May, D. Salmon, N. Cassoux (OPH), B. Autran (Immunologie), A.-M. Fillet (Virologie). Clinical and ophthalmological committee: I. Badelon, I. Cochereau, D. Salmon. Investigators: M. Bonmarchand, M. A. Valantin, F. Bricaire (Hôpital de la Pitié-Salpêtrière, Paris, France); L. Ruiz, B. Clotet (Germans Trias y Pujol, Badalona, Spain); L. Aït-Igil, P. Point, N. Kerbouche (Hôpital Pasteur, Paris, France); A. Govoni, C. Mussini, D. Palmieri (Policlinico di Modena, Italy); M. Gérard, G. Zissis, L. Caspers-Velu (CHU Saint-Pierre, Bruxelles, Belgium); C. Longuet, S. Matheron, I. Cochereau (Hôpital Bichat-Claude Bernard, Paris, France); D. Ponscarme, J. M. Molina, C. Scieux (Hôpital Saint-Louis, Paris, France); M. Karmochkine, G. Raguin (Hôpital de la Croix St-Simon, Paris, France); M. Six, C. Bazin, S. Miocque (CHU de Caen, France); V. Leclerc, H. Moussallati (Hôpital de Mantes la Jolie, France); C. Ceppi, J. Cottalorda (Hôpital L'Archet, Nice, France); P. Clevenbergh, F. Imbert, J. M. Legay (Hôpital L'Archet, Nice, France); P. Chevojon, M. Chaneac (Centre hospitalier de Corbeil, France); H. Masson, S. Abada (CHG de Poissy, France); P. de Truchis, C. Perronne (Hôpital Raymond Poincarré, Garches, France); F. Jeanblanc (Hôpital E. Herriot, Lyon, France); C. Burty, A. Le Faou (Hôpital de Brabois, Nancy, France); P. Palmer, P. Lebon (Hôpital Saint-Vincent de Paul, Paris, France); E. Angelini, G. Chêne, M. Nciri, S. Pérusat, V. Rondé-Ousteau, M. Savès (INSERM U330, Bordeaux, France). Cited Here...

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