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Continuous versus intermittent treatment strategies during primary HIV-1 infection

the randomized ANRS INTERPRIM Trial

Goujard, Cécilea,b; Emilie, Dominiquec,*; Roussillon, Carolined,e; Godot, Véroniquec; Rouzioux, Christinef; Venet, Alaing; Colin, Célined,e; Pialoux, Gillesh; Girard, Pierre-Mariei; Boilet, Valéried,e; Chaix, Marie-Lauref; Galanaud, Pierrec; Chene, Genevièved,e,j for the ANRS-112 INTERPRIM Study Group

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doi: 10.1097/QAD.0b013e32835844d9
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Abstract

Introduction

The optimal management of primary HIV-infection (PHI) remains controversial. Early immunological and virological events can predict subsequent rate of progression and the impact of initiating antiretroviral treatment (ART) at this stage is debated [1–6]. Until recently, proofs of evidence were lacking to recommend the rapid initiation of ART in patients diagnosed during PHI [7–9]. Two trials recently showed a benefit in favor of immediate ART for 9 months, that is, the ACTG A5217 study, or 12 months, that is, the Short Pulse AntiRetroviral Therapy at HIV SeroConversion (SPARTAC) study [10,11].

Among available strategies in PHI, the benefit of sequential ART to reinforce HIV-specific immune responses remains unknown as no randomized study has assessed its potential efficacy [12,13]. Interferon (IFN)-α could represent a good candidate in immune therapeutic strategies, as it shows both antiviral and immunostimulating properties [14–16]. As a matter of fact, IFN directly inhibits several stages of the HIV replication cycle. It also stimulates various components of the immune response involved in the control of HIV such as antigen presentation and differentiation of antigen-specific B and T lymphocytes. In addition, IFN display antiviral activity in ART-naive patients [17]. These observations supported evaluations of IFN in PHI. We then chose to administrate IFN to limit early viral replication and its dissemination in the reservoir and to augment HIV-specific immune responses in the presence of HIV-antigens, first at the time of PHI and second during treatment interruptions when viral rebound generally occurs.

Here, the ANRS-112 INTERPRIM trial compared the virological efficacy and the safety of two sequential ART regimens associated or not with pegylated interferon alpha-2b (peg-IFN), with a continuous ART regimen, 6 months after ART interruption, among patients diagnosed during PHI. We hypothesized that the addition of IFN would result in improved HIV-specific responses induced by sequential ART interruptions and consequently, in enhanced and sustained control of viral replication after treatment interruption.

Patients and method

Patient selection

Patients were recruited from May 2002 to May 2004 in this multicenter randomized open study if they were diagnosed with an ongoing primary HIV-1 infection, defined by a detectable plasma HIV-RNA and a negative or incomplete Western-blot (≤3 bands). Acute infection was defined as a negative or indeterminate Western-blot (Centers for Disease Control/Association of State and Territorial Public Health Laboratory Directors criteria) [9]. The date of infection was estimated as the date of symptom onset minus 15 days. Patients with coinfection by hepatitis B or C virus, with a history of auto-immune or blood disease, or with any contra-indication to IFN were not included. The study was approved by the Bicêtre Ethics Committee and all the participants gave their written informed consent.

Therapeutic interventions

Patients were randomly allocated (1 : 1 : 1 ratio) to three parallel groups: in the ‘cART’ group, patients received cART; in the ART with sequential treatment interruption (ART-STI) group, patients received ART during 36 weeks followed by three interruptions of 4 weeks at week 36, 48 and 60; in the ‘ART-STI-IFN’ group, ART was identical to the ART-STI group, with addition of peg-IFN during the first 14 weeks and each ART interruption for 4 weeks, starting 2 weeks after interruption (at week 38, 50 and 62). ART was withdrawn on week 72 and patients were monitored up to week 96 (Fig. 1).

Fig. 1
Fig. 1:
Trial design.ANRS 112 INTERPRIM trial.

The choice of ART was left to the investigator's discretion: it combined two nucleoside reverse transcriptase inhibitors (NRTIs) with a protease inhibitor (PI) or a nonnucleosidic reverse transcriptase inhibitor (NNRTI). Peg-IFN (Viraferonpeg) was administrated subcutaneously (1 μg/kg per week; supplied by Schering–Plough, Paris, France). Peg-IFN dosage was decreased (0.5 μg/kg per week) if a grade 3 event occurred and was stopped if the event persisted or if a grade 4 event occurred.

At week 36, ART was stopped in patients of the ART-STI and ART-STI-IFN groups with an HIV-RNA less than 400 copies/ml at week 32 and the second and third interruptions were then systematically performed. If HIV-RNA was more than 400 copies/ml at week 32, the first interruption was postponed until the next control of HIV-RNA occurred at week 44 or week 56. From week 72 to 96, ART was to be permanently interrupted in all three groups.

Patient follow-up

For the sake of clarity, the three periods considered will be denoted: week 0–36, 36–72 and 72–96. The patients had a physical examination and routine laboratory tests at the time of screening (i.e. week –1) then at treatment initiation (week 0) and at week 2, 4, 8, 12, 16, 24, 32, 36, 48, 60 and 72. Supplementary visits were performed during STIs (week 38, 40, 52 and 64). Then, patients were evaluated at week 74, 76, 80, 84, 92 and 96 during the phase off treatment. Clinical and laboratory events related to either HIV, or ART, or peg-IFN were validated by an expert committee.

HIV-RNA and CD4+ T-cell count measurements were performed locally. Additional measurements of HIV-RNA and total cell-associated HIV-DNA were performed in a central laboratory at week 0, 12, 24, 32, 48, 64, 92 and 96. HIV-DNA was assessed by using the real time PCR ANRS-assay [detection limit, 70 copies/106 peripheral blood mononuclear cells (PBMC)] [18].

An extended follow-up of 5 years after the end of the study was approved by the Steering Committee. Data (HIV-RNA levels, CD4+ and CD8+ T-cell counts, changes in ART, clinical or biological events) were collected every 6 months up to 5 years.

Primary and secondary outcomes measures

The primary endpoint with respect to efficacy was the mean HIV-RNA level (centralized measures) in the absence of ART at week 92 and 96. Secondary outcomes included HIV-related events and tolerance, CD4+ T-cell counts, HIV-RNA and HIV-DNA kinetics and proportion of patients with HIV-RNA less than 50 copies/ml at week 96.

T-lymphocyte functions

CD4+ T responses to p24 HIV antigen were tested by both proliferation and IFNγ-release assays [19]. Proliferative responses were also assessed to recall antigens (tuberculin-PPD, cytomegalovirus, Candida and tetanus toxoid) [20]. Patients were considered as responsive to an antigen when the corresponding stimulation index was above three. A score reflecting the number of responding antigens was determined.

IFNγ secretion by virus-specific CD8+ T cells was quantified using the enzyme-linked immunospot (Elispot) assay [21]. Responses were considered positive if the mean of spot forming cells (SFCs) was greater than twice the mean of the negative control wells, and greater than 100 SFCs/106 PBMCs after subtracting the SFCs in the negative control wells. For each patient, the total HIV-specific CD8+ T-cell response corresponds to the sum of the SFC obtained for the 18 different pools.

Sample size and statistical analyses

Thirty patients were required in each group to have a power of at least 80% of detecting a difference of 0.7 log10 copies/ml for the average HIV-RNA level at week 92 and 96 between two groups (two-sided 5% level), with an anticipated loss of follow-up of 5%. The primary analysis was based on the intention-to-treat principle and involved all patients who were randomly assigned to the three groups, including observed data of all patients, who started the assigned strategy, regardless of whether it was prematurely discontinued or not. Intergroup differences were assessed by using the Wilcoxon test for continuous variables and the chi-square or Fisher exact test for categorical variables. Multivariate analysis of lower HIV-RNA levels and higher CD4+ T-cell counts at week 96 was performed by stepwise logistic regression entering into the model the parameters associated with lower HIV-RNA levels or higher CD4+ T-cell counts with a P value less than 0.25. All statistical analyses were carried out with 9.1.3 service pack 2 version of SAS (SAS Institute Inc., Cary, North Carolina, USA).

Results

Study population

Ninety-one patients were randomized: 30 in the cART group, 31 in the ART-STI group and 30 in the ART-STI-IFN group. Two patients withdrew their participation into the study before treatment initiation and were excluded from the analysis, hence 89 patients were analyzed (Fig. 2). Median time between screening (week-1) and treatment initiation (week 0) was 6 days.

Fig. 2
Fig. 2:
Trial profile.ANRS 112 INTERPRIM trial.

Baseline characteristics are indicated in Table 1. Overall, 91% were men, with a median age of 34 years, 72% of them were infected through homosexual contacts. All patients except three presented with symptoms and 44% were acute seroconverters. At enrolment, CD4+ T and CD8+ T-cell counts were highly variable, with a median CD4+ T and CD8+ T-cell counts of 382 and 939 cells/μl, respectively. Median HIV-RNA and HIV-DNA levels were 5.7 log10 copies/ml and 3.5 log10 copies/106 PBMCs. ART was initiated within a median time of 38 days from infection. The majority of patients (84%) initiated a combination of two NRTIs and one PI boosted or not with ritonavir.

Table 1
Table 1:
Baseline characteristics of patients at screening (week –1) and treatment initiation (week 0). ANRS 112 INTERPRIM trial.

Two patients were lost to follow-up, one from the cART group at week 36 and one from the ART-STI-IFN group at week 16. Deviations to treatment strategy were reported in five patients, who did not interrupt their treatment at week 72, one each from the cART and the ART-STI groups, three from the ART-STI-IFN group. Five other patients spontaneously interrupted their ART before week72, three in the cART group and two in the ART-STI-IFN group. Treatment resumption occurred in four patients before the end of the interruption period: two patients in the cART group for HIV-RNA more than 100 000 copies/ml and two patients in the ART-STI group for CD4+ cell count less than 350 cells/μl. Finally, 81 patients enrolled in the study having interrupted ART at week 72 were still followed at week 92, and were available for the analysis of the primary study end-point.

Virological outcome during treatment and after interruption

HIV-RNA rapidly declined upon treatment initiation (Fig. 3a). During period week 0–36, there was no difference in viral load between patients treated with ART alone, and those receiving ART and peg-IFN. Eighty-seven percent of patients achieved undetectable HIV-RNA levels (<50 copies/ml) at week 32. HIV-RNA rebounded in the ART-STI and ART-STI-IFN groups upon each ART interruption, viral rebounds being lower in the ART-STI-IFN group than in the ART-STI group (P = 0.0002, P = 0.006 and P = 0.04, for the first, second and third interruptions, respectively). Viral rebounds were also lower during the second and third interruptions compared with the first interruption in the two groups (P = 0.02 and P = 0.001).

Fig. 3
Fig. 3:
Evolution of immuno-virological characteristics from week 0 to 96.ANRS 112 INTERPRIM trial. (a) Median HIV-RNA (log10 copies/ml) evolution. (b) Median CD4+ T-cell count (per μl) evolution. (c) Median ratio CD4+/CD8+ evolution. (d) Total cellular HIV-DNA median evolution.

However, median HIV-RNA levels 6 months after the last interruption did not differ between groups: 4.3 log10 copies/ml (IQR, 3.7–4.6) in the cART group, 3.9 log10 copies/ml (3.2–4.6) in the ART-STI group and 3.9 log10 copies/ml (3.2–4.4) in the ART-STI-IFN group. The median delay between the final ART interruption and the first HIV-RNA more than 400 copies/ml did not differ between groups. Four patients maintained undetectable HIV-RNA levels at week 96, one from the ART-STI group and three from the ART-STI-IFN group. Therefore, unless HIV rebounds were lower during successive treatment interruptions in the ART-STI groups, none of the strategies induced a significant benefit on the viral set-point at the end of the trial compared to continuous ART.

Evolution of CD4+ T-cell counts

The increase of CD4+ T cells was rapid in the two groups treated with ART alone (Fig. 3b). Recovery of CD4+ T cells was delayed and partial in the ART-STI-IFN group, with a median gain of 71 cells/μl (IQR, −31 to 233) at week 12, versus 181 cells/μl (76–245) in the cART group and 270 cells/μl (−3 to 366) in the ART-STI group (P = 0.02). CD4+ T-cell counts did not differ any more from week 24–96 between the three groups. At week 72, median increase in CD4+ T cells since treatment initiation was 216 cells/μl (IQR, 62–361) for the whole population, with a higher median CD4+/CD8+ ratio in the cART group compared with the ART-STI and ART-STI-IFN groups (1.2, 0.9 and 0.8, respectively; P = 0.05) (Fig. 3c).

CD4+ T cells declined after treatment interruption (median change from week 72–96, −92 cells/μl (IQR, −267 to 12) but remained higher than at ART initiation (P = 0.005). At week 96, CD4+ T-cell counts were similar between groups, with 553 cells/μl (IQR, 459–663), 585 cells/μl (454–853) and 559 cells/μl (523–836), respectively. Median CD4+/CD8+ ratios also declined to similar levels between groups at week 96. Nine patients experienced CD4+ T-cell counts less than 350 per μl upon final ART interruption.

Evolution of cellular HIV-DNA levels

HIV-DNA levels decreased in the three treatment groups upon treatment initiation, from a median level of 3.5 log10 copies/106 PBMCs (IQR, 3.2–3.8) to 2.4 log10 copies/106 PBMCs (1.9–2.8) at week 72 before treatment interruption (Fig. 3d). Although the level of HIV-RNA was lower during interruptions in the ART-STI-IFN group, it did not result in different HIV-DNA levels at week 72 between arms [median, 2.4 log10 copies/106 PBMCs (IQR, 1.9–2.8), 2.3 (1.9–2.7) and 2.4 (2.0–2.8) in the cART, the ART-STI and the ART-STI-IFN arms, respectively). Then, HIV-DNA level increased similarly upon final ART interruption, with a median value at week 96 of 2.9 log10 copies/106 PBMCs (IQR, 2.5–3.2), 2.6 (2.2–3.1) and 2.6 (2.4–2.8) in the cART, ART-STI and ART-STI-IFN groups, respectively.

CD4+ T-lymphocyte functions

At treatment initiation, the three groups did not differ for p24-induced CD4+ T proliferative response, with a mean stimulation index of 3.7 (CI50, 2.7–4.7), 4.0 (3.1–4.9) and 9.1 (3.0–15.3) in the cART, ART-STI and ART-STI-IFN groups, respectively. Following treatment initiation, proliferative responses to p24 antigen rapidly increased in the three groups and remained stable up to week 72 (Fig. 4a). They tended to decline after treatment interruption. The fraction of cells releasing IFN-γ following p24 stimulation was high at treatment initiation, and abruptly declined in the three groups following ART initiation (Fig. 4b). This fraction remained stable up to week 96. Proliferative responses to recall antigens were also analyzed. The number of antigens to which patients responded increased after ART initiation, and stabilized up to week 96 (Fig. 4c). Groups did not differ at any moment from week 0 to 96 for either proliferation or IFN-γ production in response to p24 or responses to recall antigens.

Fig. 4
Fig. 4:
T-lymphocyte functions.ANRS 112 INTERPRIM Trial. T-lymphocyte functions were monitored during the follow-up to week 96. (a) T-lymphocyte proliferation in response to p24 antigen (mean stimulation index). (b) Release of IFNγ in response to p24 antigen [mean number of spot-forming cells/106 peripheral blood mononuclear cells (PBMC)]. (c) Proliferative response to four recall antigens (mean score). (d) Release of IFNγ in response to HIV peptides (mean number of spot-forming cells/106 PBMC).

HIV-specific CD8+ responses

Frequencies of HIV-specific CD8+ T cells declined until week 32 in cART and ART-STI groups, although a slight increase was first observed in the ART-STI-IFN group at week 12. However, no differences were observed within the groups at week 32. At week 72, frequencies continued to decrease in cART group whereas the levels reached at week 32 were maintained in ART-STI groups, without any differences, however, between groups (Fig. 4d).

Safety and HIV-related events

The most frequent adverse events in the whole population were gastro-intestinal events (diarrhea, 38%; nausea, 21%; vomiting, 9%; abdominal pains, 7%). Peg-IFN administration resulted in more frequent adverse events, although most of them were not severe (asthenia, 41%; influenza-like syndrome, 38%; neutropenia, 17%; anemia, 10%). Overall, 21 patients (72%) received at least 20 out of the 23 planned peg-IFN injections in the ART-STI-IFN group. Thirteen serious adverse events were reported (two in the cART group, one in the ART-STI group and 10 in the ART-STI-IFN group), mainly gastro-intestinal, neuropsychiatric and laboratory disorders. All serious neuropsychiatric effects occurred in patients treated with peg-IFN (two suicide attempts, one depression and one generalized epilepsy).

Lipodystrophy abnormalities were infrequent upon week 72: 10 patients presented with abdominal hypertrophy (12%) and three, four and two patients with atrophy in the face, buttocks or legs, respectively (4, 5 and 2%). Abdominal hypertrophy improved in five patients after treatment interruption; facial or buttocks atrophy persisted in four cases whereas it improved in the others. Few HIV-related events were reported (one oral candidiasis, one herpes zoster and one esophageal candidiasis). No acute viral symptoms were observed during ART interruptions.

Predictive factors of virological outcome

The 38 patients who maintained HIV-RNA levels below 5000 copies/mL at week 96 were more likely to have lower levels of HIV-RNA (<5 log10 copies/ml) and HIV-DNA (<3.5 log copies/106 PBMC) at enrolment and of HIV-DNA (<2.4 log) at treatment interruption compared with others (Table 2). Proliferative and HIV-specific responses during the trial, CD4+ T-cell counts at treatment interruption were not associated with the viral set-point reached 6 months after treatment interruption.

Table 2
Table 2:
Factors associated with virological outcome at week 96.

Extended follow-up at 5 years

Sixty-five patients were enrolled in the long-term follow-up. They were followed for up to 54 months: 23 from the cART group, 23 from the ART-STI group and 19 from the ART-STI-IFN group. One patient from the ART-STI group died from septic shock. Two patients from the ART-STI-IFN group presented a Kaposi disease 16 and 37 months after treatment interruption, with respectively 315 and 415 CD4+ T cells/μl, whereas cART had been resumed. Finally, therapy resumption occurred in 48% of patients between week 96 and their last follow-up, with a similar frequency and median time (9.9 months) between groups. Two of the four patients with undetectable HIV-RNA at week 96 were followed, none maintained their viral control.

Discussion

This randomized trial is the first one to compare continuous or sequential treatment interruptions, with or without the administration of IFN, in the context of primary HIV infection. Overall virological efficacy was high, and CD4+ T-cell levels were preserved after treatment interruption. Treatment interruptions, whether associated or not with IFN, did not improve immune responses nor reinforce control of HIV replication in very early treated patients.

Several studies addressed the question of the impact of a temporary ART in acute or recent infection using different strategies of sequential or continuous ART, or of ART combined with vaccines or interleukin-2, with the objectives to augment HIV-immune responses and to improve the course of HIV infection after ART interruption [22–26]. Although some patients showed a lowering of the viral set point and beneficial effects on immunological outcome after ART discontinuation, these effects were not sustained in the majority of patients [27–32]. Finally, the impact of the treatment itself versus the weight of the immunological or virological status at the time of primary infection remain debated [23–28,33–35].

In the INTERPRIM trial, treatment efficacy was high as nearly 90% of patients were virological responders with a combined therapy containing a protease inhibitor for the majority of patients, close to results reported with once-daily NNRTI-based regimen [36]. We observed a higher CD4+/CD8+ T-cell ratio in the continuous ART group, compared with ART-STI groups. Nonetheless, CD4+ T cells and CD4+/CD8+ ratio fell after ART interruption and were similar between groups at the end of the study. Overall, antiviral treatments were associated with a substantial therapeutic effect, as median CD4+ T cell counts and CD4+/CD8+ ratio remained higher 6 months after ART interruption compared with their baseline values. Reseeding of the reservoir measured by total HIV-DNA occurred during the last interruption but its level did not return to values observed before ART. As already reported, few patients experienced a delayed viral rebound or even no rebound during the study period [35–36]. These encouraging results need to be confirmed in future research aiming at curing HIV.

In our study, 44% of patients maintained a viremia of less than 5000 copies/ml 6 months after treatment interruption, with a similar outcome whether antiretroviral therapy was sequentially interrupted or not and IFN was added or not. These results are close to those previously reported with other sequential ART strategies [12,13]. Factors found to be predictive of viral set-point after treatment interruption were HIV-RNA and HIV-DNA levels at enrolment, and HIV-DNA levels before treatment interruption reflecting treatment potency. These factors have been reported as associated with spontaneous or post-ART viral control in primary-infected patients in several studies, with discordant results for the predictive value of HIV-DNA levels on viral rebound in patients from the Swiss cohort [18,19,34,35–38].

The capacity of an early temporary ART to postpone the time when therapy needs to be resumed during chronic infection remains unknown. Actually, half of our patients resumed antiretroviral therapy during long-term follow-up, with no difference between treatment strategies. This immunological benefit has also recently be shown in the SPARTAC randomized trial comparing a transient treatment during 48 weeks to no treatment in recent seroconverters, although the actual delay may not have been longer than the time spent on treatment [11].

The ANRS 112 INTERPRIM study was based on a pilot study suggesting that IFN associated with ART could induce a rapid control of HIV replication and a high decay of the reservoir [39]. In the INTERPRIM randomized study, it is likely that direct antiviral effects of IFN contributed to limit HIV replication, accounting for lower HIV viremia in the ART-STI-IFN group at the end of each ART interruptions. This effect was detected even before re-administration of IFN, indicating that it might involve enhanced anti-HIV immune responses. In contrast, and on the contrary to untreated patients, we observed no additional impact of sequential IFN courses on immune T-lymphocyte responses assessed on ART [17]. We also showed that transient administration of IFN potentiates the emergence of anti-HIV antibodies in the first phase of the trial [40]. However, like in chronically treated patients, IFN effects on host-viral relationships were not translated into decreased HIV set-point or reservoir when ART was durably withdrawn [41]. It is possible that the design of our study, in which IFN was administrated during periods with active viral replication, could have masked its role as an adjunctive treatment to ARV in search for a HIV cure.

The question of discontinuation of ART initiated in primary-infected patients is less relevant whereas initiation of ART is proposed in less advanced HIV disease and ART is discussed as a universal approach to prevent HIV transmission. Transient ART, even intensified with immune therapies, did not result in substantial viral control after ART interruption even if the majority of patients achieved greater benefits in terms of CD4+ T-cell counts and cellular reservoir compared with patients treated at the chronic phase of infection. Otherwise, as long as we have no strategy capable of containing residual HIV replication after ART interruption or leading to HIV cure, current antiretroviral therapies might be prolonged from primary infection for life.

Acknowledgements

We thank all the patients who participated in the ANRS 112 INTERPRIM Study and their physicians from the INTERPRIM study group. We also thank Marc Pallardy for supporting the revision of the article.

Authors’ contributions: Study concept and design, study supervision: G.C., D.E., P.G., C.G.

Acquisition of data: V.B., C.C., C.R.

Laboratory coordination and determinations: M.C., D.E., P.G., V.G., A.V.

Events Review Committee: D.E., C.G., C.R.

Statistical analysis and interpretation of data: G.C., C.C., D.E., C.G., C.R.

Critical edition and revision of the article: G.C., C.C., P.G., P.G., C.G., G.P., C.R., C.R.

All authors have read and approved the final article.

Financial support: This study was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). Schering Plough provided Peg-interferon alpha-2b and a grant for immunological substudies.

This trial has been registered in the National Library of Medicine's registry. Its registration number is NCT 00196638.

ANRS 112 INTERPRIM study group: Investigator Site: Regional hospital, Angers: J.M. Chennebault, J. Loison, P. Fialaire, E. Pichard; Henri Duffaut hospital, Avignon: G. Lepeu, B. Slama; Saint Jacques hospital, Besançon: F. Chapoutot, F. Coquet, J.M. Estavoyer, A. Foltzer, B. Hoen; Saint Andre hospital, Bordeaux: J. Beylot, M. Bonarek, D. Lacoste, D. Malvy, P. Morlat; Antoine Béclère hospital (AP-HP), Clamart: F. Boué, A.M. Delavalle, D. Emilie, P. Galanaud, C. Pignon, F. Boué; Hôtel Dieu hospital, Clermont-Ferrand: O. Baud, J. Beytout, V. Chanet, S. Dydymski, C. Jacomet, H. Laurichesse; Compiegne hospital, Compiegne: D. Merrien, P. Veyssier; Henri Mondor hospital (AP-HP), Creteil: N. Brahimi, C. Jung, A.S. Lascaux, J.D. Lelièvre, P. Lesprit, Y. Levy, A. Sobel; Lagny hospital, Lagny sur Marne: F. David, E. Froguel, P. Lagarde; Bicêtre hospital (AP-HP), Le Kremlin Bicêtre: JF. Delfraissy, C. Goujard, F. Chaix, V. Schiffer, M. Mole; Edouard Herriot hospital, Lyon: F. Jeanblanc, J.J. Jourdain, J.M. Livrozet, D. Makhloufi, J.L. Touraine; Hôtel Dieu hospital, Lyon: C. Augustin-Normand, N. Benmakhlouf, C. Brochiet, P. Miailhes, S. Radenne, C. Trepo; Gui de Chauliac hospital, Montpellier: V. Baillat, F. Janbon, V. Le Moing, C. Merle de Boever, J. Reynes, M. Vidal; Hôtel Dieu hospital, Nantes: B. Bonnet, P. Lehoussine, F. Raffi, M. Sicot, E. Billaud; Lariboisière hospital (AP-HP), Paris: M. Bendenoun, C. Caulin, M. Diemer, M. Parrinello, A. Rami, P. Sellier; Necker hospital (AP-HP), Paris: C. Boitard, B. Dupont, R. Lahoulou, A. Maignan, J.P.Viard; Pitié Salpêtrière hospital (AP-HP), Paris: F. Bricaire, J. Ghosn, C. Katlama, M. Richard; Saint Antoine hospital (AP-HP), Paris: D. Berriot, D. Bollens, P.M. Girard, M. Sebire, P. Tangre; Saint Louis hospital (AP-HP), Paris: S. Fournier, C. Lascoux-Combe, J.M. Molina, P. Morel, C. Pintado, D. Ponscarme, D. Sereni, F.J. Timsit, M. Tourneur; Tenon hospital (AP-HP), Paris: C. Chakvetadze, W. Rozenbaum, L. Slama; Pontchaillou hospital, Rennes: C. Bouvier, L. Javaudin, C. Michelet, C. Peaucelle, F. Souala, P. Tattevin, R. Thomas; Charles Nicolle hospital, Rouen: F. Caron, Y. Debab, I. Gueit; Suresnes hospital: O. Bletry, C. Majerholc; Chalucet hospital, Toulon: S. Chadapaud, A. Lafeuillade, G. Hittiger, G. Philip, A. Rieu; Brabois hospital, Vandoeuvre les Nancy: L. Boyer, T. May, C. Rabaud, S. Wassoumbou.

Steering Committee: M. Burgard; M.L. Chaix; G. Chêne; M.J. Commoy; J.F. Delfraissy; D. Emilie; P. Galanaud; V. Godot; C. Goujard; B. Hoen; A. Lafeuillade; C. Lascoux-Combe; J.M. Livrozet; L. Meyer; C. Roussillon; C. Rouzioux; D. Sereni; A. Venet.

Data Safety Monitoring Board: V. Calvez; D. Costagliola; J.L. Pellegrin.

Events Review Committee: D.E.; R. Fior; C.G.; B. Hoen; J.M. Livrozet; A. Métro; C.R.; D. Séréni; J.P. Viard.

Clinical Trials Unit/INSERM U897, Bordeaux School of Public Health (ISPED), University Bordeaux Segalen: V.B., G.C., C.C., S. Martiren, C.R.

Conflicts of interest

G.C., D.E., C.R. and A.V. have received research support from the French Agency for Research on AIDS and Hepatitis (ANRS) for this study and other past and ongoing projects. D.E. Unit has received grants from Schering Plough for complementary biological studies. G.C. institution has received research grants from Boehringer Ingelheim, Bristol-Myers Squibb, Glaxo-Smithkline, Gilead, Janssen, Merck Sharp and Dohme, Roche, Tibotec and ViiV Healthcare. P.G. has received financial support (board membership, grants, lectures and educational presentations) from Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp and Dohme, Roche and ViiV Healthcare. C.G. has received financial support (consultancy, expertise and lectures) from Abbott, Gilead and Janssen. G.P. has received has received financial support (board membership, grants, lectures and educational presentations) from Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp and Dohme, Boeringher, Roche, Nephrotek, and ViiV Healthcare. The remaining authors have no conflict of interest to declare.

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Keywords:

antiretroviral treatment; HIV-1; interferon; primary infection; treatment interruption

© 2012 Lippincott Williams & Wilkins, Inc.