The primary phase of HIV infection (PHI) is a period associated with intense viral replication. Early treatment reduces the duration of exposure to high-level viremia. Guidelines for treatment initiation during PHI have evolved over time. In France, in clinical practice, treatment used to be started in all patients presenting during PHI , until specific guidelines issued in 2002 recommended treatment initiation only in case of symptomatic primary infection or a low CD4+ cell count . Moreover, in the early era of combination antiretroviral therapy (cART), because of concerns regarding toxicity, PHI treatment was recommended for 18–24 months only. Treatment interruption has not been recommended since 2008. More recently, as in the USA, a continuous treatment has been recommended at diagnosis, regardless of the stage of HIV infection, since 2013 [3,4]. Apart from the framework of clinical trials or of past recommendations, treatment interruptions can still occur nowadays, because of patient decisions, suboptimal adherence or irregular follow-up. In the vast majority of cases, viremia rapidly rebounds after discontinuation of cART [5–12].
The impact of cumulative exposure to HIV viremia is a growing focus of attention. Estimates of lifelong exposure to HIV viremia must take into account both the degree of viremia and the duration of each viremic episode since HIV infection, and relevant methods were proposed a few years ago [13,14]. In the pre-cART era, cumulative HIV viremia among untreated patients was reported to influence the risk of AIDS and death, independently of the time since infection, age, race, the CD4+ cell count and viral load . In patients on cART, high cumulative HIV viremia was found to be predictive of the risk of developing AIDS-related lymphoma  and all-cause mortality [15,16]. In young adults infected perinatally with HIV, with currently controlled viral replication, the main factor associated with current total cellular HIV-DNA load was cumulative viremia over the previous 5 years . The only study to evaluate the impact of cumulative HIV viremia on CD4+ cell count gain in treated patients showed no significant relationship . However, in this study, only exposure to cumulative HIV viremia from cART initiation was analysed and not the lifelong cumulative viremia.
To what extent the sum of past exposure to the virus since HIV infection affects immunological recovery on treatment in terms of the CD4+ cell count and the CD4+/CD8+ ratio has rarely been explored. Low CD4+/CD8+ ratio has been shown in recent studies to be associated with immune activation and higher morbidity, more specifically non-AIDS related events [19,20]. The increase in CD4+/CD8+ ratio is therefore to be considered along with the CD4+ cell count gain in the optimal response to treatment.
It is not known whether cumulative exposure to viremia is more deleterious for long-term immune recovery when treatment initiated during PHI is discontinued or when treatment is deferred.
Using data from the French ANRS Primo Cohort, a large cohort of patients followed since primary HIV infection, we analysed the influence of cumulative HIV viremia since HIV infection on current immunological status, according to the timing of cART initiation.
Materials and methods
The ANRS PRIMO cohort
The ANRS PRIMO cohort (CO06) is an ongoing prospective cohort created in 1996. Patients are enrolled during primary HIV infection, defined by an incomplete western blot, or detectable p24 antigenemia/plasma viral load with a negative or weakly reactive ELISA, or an interval of 6 months or less between a negative and positive ELISA test.
CD4+ cell count, CD8+ cell count and plasma viral load data are recorded along with clinical characteristics, first at enrolment and then during follow-up visits (M1, M3, M6 and subsequently every 6 months). Data are regularly monitored, and all clinical AIDS events are authentified.
Among the 586 patients who started cART (at least three drugs) during PHI (within 3 months after HIV infection), we selected the 244 patients who had had at least one treatment interruption (>15 days), whatever the reason, and who were back on treatment before the last follow-up visit (Fig. 1). This group represents patients with lifelong viremia mostly accumulated after treatment interruption. Among the 248 patients in whom treatment was deferred for at least 12 months after infection, we selected the 218 patients who pursued treatment with no interruptions greater than 15 days and still were on treatment at the last follow-up visit. This group represents patients with lifelong viremia mostly accumulated between HIV infection and treatment initiation at the chronic stage.
For purposes of comparison with a group with very low cumulative viremia exposure, we also analysed current CD4+ and CD4+/CD8+ ratio in the 265 patients who initiated treatment during PHI and did not interrupt treatment (early/continuous group).
Cumulative HIV viremia was calculated according to Zoufaly et al., by summing over the whole period the products of the log viral load and the time interval extending to the previous measurement; this time interval was set to a maximum of 180 days when the previous viral load measurement was more distant. For the first viral load measured at enrolment during primary infection, the time interval was extended to the estimated date of HIV infection. Only viral load measurements recorded at the protocol visits, hence at identical scheduled time intervals for all the patients, were used in the calculation. The detection limit of HIV-RNA quantification assays evolved over time. Over the whole study period, the highest detection limit was 400 copies/ml, and we therefore included only viral load values above this threshold; all the protocol viral load measurements were considered, whether the patient was on or off cART. We performed a sensitivity analysis considering a threshold of 50 copies/ml instead of 400 copies/ml, wherein all values undetectable at a threshold of more than 50 copies/ml were considered as undetectable at a threshold of 50 copies/ml.
The outcome measure was immunological status at the last cohort follow-up visit on treatment, referred to below as ‘current’ status. We analysed the current CD4+ cell count and the current CD4+/CD8+ ratio as continuous variables, and the following binary outcomes, considered to reflect an optimal treatment response: CD4+ cell count more than 500 cells/μl and a CD4+/CD8+ ratio more than 1.
To assess the influence of cumulative HIV viremia on each of these outcomes, four different multivariate analyses were performed with cumulative viremia as the independent variable, categorized by its tertiles. To better characterize the dose–relationship between cumulative HIV viremia and current immunological status, cumulative viremia was also entered in an alternative multivariate model as a function of the restricted cubic spline with three knots (located at the fifth, 50th and 95th percentiles) . The influence of cumulative HIV viremia on the current CD4+ cell count and CD4+/CD8+ ratio was examined using linear regression models. Its impact on the probability of an optimal treatment response (CD4+ cell count >500 cells/μl or CD4+/CD8+ >1) was examined with logistic regression models. In all models, we chose to adjust for baseline immunological parameters (CD4+ cell count or CD4+/CD8+ ratio) at PHI diagnosis and not at cART initiation, as the latter might lie in the causal pathway between cumulative HIV viremia and outcome. The other adjustment variables were sex, age at cART initiation and the cumulative treatment duration, or the duration since last resumption.
Statistical analyses used SAS software version 9.3 (SAS Institute Inc., Cary, North Carolina, USA).
Characteristics of the patients and long-term therapeutic response
The analysis included patients who were on treatment at the last follow-up visit, of whom 244 received early/intermittent treatment, 218 received deferred/continuous treatment and 265 received early/continuous treatment (Fig. 1). In the first group, cART was started a median of 38 days after HIV infection, at a median CD4+ cell count of 471 cells/μl (Table 1). These patients’ median follow-up after cART initiation was 9.5 years. The first treatment interruption occurred after a median of 14.6 months of treatment, at a median CD4+ cell count of 681 cells/μl and a median CD4+/CD8+ ratio of 0.97. They had one (52.5%) or several (47.5%) treatment interruptions. The median cumulative duration of the interruptions was 2.5 years, and the median CD4+ cell count at the last treatment resumption was 355 cells/μl. At the last follow-up visit, the median CD4+ cell count was 645 cells/μl, after a median of 4.8 years of continuous treatment since the last resumption; a median of 72.8% of the time since HIV infection had been spent on treatment. The CD4+ cell count at the last cohort follow-up visit was more than 500 cells/μl in 75% of patients; the CD4+/CD8+ ratio was more than 1 in only 36.1% of patients, 96% of whom had CD4+ cell count more than 500 cells/μl.
Compared with the patients who started treatment during PHI, the 218 patients in whom treatment was deferred had significantly higher CD4+ cell counts and lower plasma viral loads at PHI diagnosis (P < 0.0001), and were also less likely to have had a symptomatic PHI (82.1 vs. 90.2%, P = 0.01). They started treatment a median of 30.2 months after HIV infection. Their median CD4+ cell count at cART initiation was 336 cells/μl overall, but gradually increased during the study period, from 259 cells/μl in 2002–2003 to 379 cells/μl in 2010–2011, along with the evolution of French guidelines . At the last follow-up visit, the median CD4+ cell count was 654 cells/μl, a median of 6.1 years after HIV infection and after a median of 3.0 years of continuous treatment; 54% of the time since HIV infection had been spent on treatment. The CD4+ cell count at the last follow-up visit was more than 500 cells/μl in 76.2% of patients and the CD4+/CD8+ ratio was more than 1 in only 39.8% of patients
Current plasma HIV-RNA was less than 50 copies/ml in 85.1% of patients in the early/intermittent treatment group and 84.3% in the deferred/continuous group, P = 0.8, and the current treatment regimen was similar in the two groups. Twelve patients (4.9%) in the early/intermittent group and 11 patients (5.1%) in the deferred/continuous group experienced an AIDS-defining event during follow-up. In the early/intermittent group, the first AIDS event occurred a median of 56.2 months [interquartile range (IQR) 30.8–64.6] after treatment initiation, either during or after a treatment interruption, except for one patient who developed a cutaneous Kaposi disease early after infection (3.4 months). The events were tuberculosis (n = 2), Kaposi's disease (n = 5), pneumocystis pneumonia (n = 3), lymphoma (n = 1) and toxoplasmosis (n = 1). In the deferred/continuous group, eight events occurred before cART initiation and three after a median of 13.3 months on cART. The events were Kaposi's disease (n = 3), pneumonia (n = 1) pneumocystis pneumonia (n = 2), lymphoma (n = 3), cytomegalovirus retinitis (n = 1) and cryptosporidiosis (n = 1). The median CD4+ cell counts at the time of these events were 345 cells/μl (IQR 205–414) in the early/intermittent group and 283 (IQR 173–462) in the deferred/continuous group.
Influence of cumulative HIV viremia on current immunological status
The median cumulative HIV viremia to which patients had been exposed since HIV infection was 9.9 years*log10 copies/ml in the early/intermittent treatment group, in which the median cumulative time off treatment was 2.7 years. Cumulative HIV viremia was similar in the deferred/continuous treatment group (median: 9.5 years*log10 copies/ml), who started treatment a median of 2.4 years after HIV infection. Cumulative HIV viremia correlated negatively with the percentage of the time since infection spent on treatment (Spearman rank correlation r = −0.71, P < 0.0001, and r = −0.58, P < 0.0001 in the early and deferred treatment groups, respectively).
The current CD4+ cell count at the last follow-up visit was not significantly associated with cumulative HIV viremia in either treatment group (Table 2). Current CD4+ cell count was positively associated with both the CD4+ cell count at PHI diagnosis and with the cumulative duration of treatment in both groups, and also with younger age at cART initiation in the deferred treatment group only. The lack of association between the current CD4+ cell count and cumulative HIV viremia persisted after controlling for the duration of the latest treatment period rather than for the total duration of treatment. Similar results were obtained when the CD4+ cell count outcome was more than 500 or more than 800 cells/μl.
In contrast, a significant association was found between cumulative HIV viremia and the current CD4+/CD8+ ratio (as a continuous variable), even after adjusting for total duration of treatment and other known predictive factors (sex, baseline CD4+/CD8+ ratio, age at cART initiation) (Table 2). We also considered the CD4+/CD8+ ratio as dichotomized according to 1, and looked for factors associated with achieving a CD4+/CD8+ ratio more than 1. In both groups, patients with high cumulative HIV viremia (>66th percentile) were less likely than patients with low cumulative HIV viremia (<33rd percentile) to normalize their CD4+/CD8+ ratio [adjusted odds ratio (OR) 0.34 (0.16–0.75), P = 0.008, and OR 0.30 (0.13–0.67], P = 0.004, respectively, after controlling for sex, age, the baseline CD4+/CD8+ ratio and the total treatment duration. Stratification for number of interruptions (1 vs. >1) in the early treatment group yielded similar results. Other independent predictors of a CD4+/CD8+ ratio more than 1 were the baseline CD4+/CD8+ ratio and the cumulative duration of treatment in both groups, and female sex in the deferred treatment group. Overall, 43.3% of patients with low cumulative viremia had achieved a CD4+/CD8+ more than 1 on cART, vs. 26.6% of patients with high cumulative viremia (P = 0.003).
Considering cumulative HIV viremia as a function of the restricted cubic spline rather than as a categorized variable yielded similar results. Sensitivity analysis considering a threshold of 50 copies/ml instead of 400 copies/ml also found similar results, although a relationship of borderline significance was found between higher cumulative viremia (>66th percentile vs. <33th percentile) and lower current CD4+ cell count (adjusted mean difference of CD4+ cell count −72.7 cells/μl, P = 0.06), only in the early/intermittent group.
Influence of the timing of combination antiretroviral therapy initiation on current immunological status
The role of the timing of cART initiation was studied. Overall, or when restricted to patients on suppressive cART (current viral load <50 copies/ml) (Table 3), we found no difference in the current CD4+ cell count between early and deferred treatment [crude mean difference in CD4+ cell count −4.8 cells/μl (95% confidence interval, 95% CI: −61.5 to 51.8), P
= 0.9], even after controlling for sex, age, the CD4+ cell count at PHI diagnosis and the cumulative duration of treatment. This result was not affected by further adjustment for cumulative HIV viremia [+5.3 (95% CI: −51.0 to 61.7), P
Conversely, the group of patients treated continuously since PHI (i.e. with very low exposure to cumulative viremia) had a significantly higher current CD4+ cell count (mean difference: >100 cells/μl CD4+ cell count) and CD4+/CD8+ ratio (mean difference: >0.26), than the early/intermittent and deferred treated patients (Table 3). They reached a median of 731 cells/μl CD4+ cell count after a median of 2.5 years of continuous treatment; the CD4+/CD8+ ratio was more than 1 in 64.1% of patients.
This is the first study to examine, in patients followed since primary HIV infection, the impact of cumulative HIV viremia since HIV infection on current immunological status, according to the timing of cART initiation. In neither the early/intermittent nor the deferred/continuous treatment group was cumulative HIV viremia a significant predictor of the CD4+ cell count reached after long-term treatment. In contrast, cumulative HIV viremia was an independent predictor of the current CD4+/CD8+ ratio in both groups.
One of the major strengths of our study is the long duration of patient follow-up, which started during PHI (median of 9 years for patients who received early/intermittent treatment and 6 years for patients who received deferred/continuous treatment), allowing us to analyse the impact of long-term exposure to HIV replication. One limitation is that viremic episodes occurring during short treatment interruptions might have been missed.
Consistently with previous studies [22–25], we found that the CD4+ cell count reached after long-term treatment was significantly associated with the total duration of treatment. As stated by Kulkarni et al. , we also found a significant association with the CD4+ cell count at PHI diagnosis, which is slightly different from the pretherapy CD4+ cell count, which has been extensively reported as a strong independent predictor [26–32]. The CD4+ cell count reached after long-term treatment was not associated with exposure to viremia more than 400 copies/ml cumulated since PHI, whether before starting deferred treatment or during interruptions of treatment started during PHI. This suggests that CD4+ cell recovery after several years of treatment is driven less by lifelong viremia than by the degree of CD4+ cell count depletion before starting ART, which may be influenced by genetic and/or immunologic factors.
We had hypothetized that prolonged exposure to HIV replication and the resulting immunological damage incurred when treatment is deferred would have a more detrimental impact than one or more viremic episodes during interruptions of early treatment. Indeed, a recent study of protocol-indicated ART discontinuation showed that the viremic rebound after discontinuing ART initiated during PHI was smaller than that observed after discontinuing ART initiated during the chronic phase of infection . However, this study did not investigate further impact on CD4+ cell counts, CD4+/CD8+ ratio or clinical outcome after treatment resumption. In our study, exposure to prolonged HIV replication before ART initiation did not have a worse impact than one or more episodes of viremia during interruption(s) of early treatment in terms of CD4+ cell count recovery. Indeed, we even found that cumulated exposure to viremia more than 50 copies/ml tended to be more deleterious for current CD4+ cell count in early/intermittent treatment than in deferred/continuous treatment, but the relationship was of borderline significance.
It is noteworthy that most of the patients who started treatment during PHI were virologically suppressed and had CD4+ cell counts above 500 cells/μl on current treatment resumption, despite one or several previous treatment interruptions. Nevertheless, despite a high percentage of time spent on treatment (75%) and a long duration of current treatment (almost a median of 5 years), only 36% of patients had attained a CD4+/CD8+ ratio more than 1. This contrasts with reported results for patients receiving continuous treatment since primary infection, in whom the median CD4+/CD8+ ratio raised up to above 1, here and in other studies [7,33]. A deleterious effect of serial interruptions of treatment initiated during PHI was also observed in the ANRS Interprim trial, in which a gradual decline in the CD4+/CD8+ ratio was observed after repeated short interruptions . We found that lifelong cumulative HIV viremia significantly influenced the current CD4+/CD8+ ratio in both the early/intermittent and deferred/continuous treatment groups, even after adjusting for the cumulative duration of treatment and the CD4+/CD8+ ratio at PHI diagnosis. This probably explains the discrepancy between the good long-term CD4+ cell count recovery and the far poorer CD4+/CD8+ recovery. This is a major result, as low CD4+/CD8+ ratios on cART are associated with inflammation/immune activation  and increased morbidity/mortality [19,20].
During the chronic phase of infection, it has been reported that immune reconstitution is generally poorer after treatment resumption than during first-line ART [35–37]. Here, we found that among patients with current viral suppression on cART, the current CD4+ cell count was similar in the early/intermittent and deferred/continuous treatment groups. However, this must not be interpreted as if interruptions of early treatment were not deleterious. Indeed, such interruptions are deleterious: 12 cases of AIDS-defining events occurred, most of them could have been probably avoided without these interruptions and the percentage of patients who reached a CD4+/CD8+ ratio greater than 1 was low. In contrast, patients treated continuously since PHI exhibited much higher CD4+ cell count and CD4+/CD8+ ratio. No AIDS-event occurred during the follow-up in this group.
It is noteworthy that current CD4+ cell count was not higher in the early/intermittent treatment than in the deferred/continuous group, given the longer duration of the current continuous treatment (4.8 compared with 3 years). This would support the hypothesis that cumulated exposure to viremia is more deleterious for CD4+ cell count recovery in early/intermittent treatment than in deferred/continuous treatment, although the negative association found between cumulative HIV viremia and current CD4+ cell count in the early/intermittent treatment group was of borderline significance. However, as in any observational study, there could be some confounding factors that could not be taken into account. We cannot exclude that the early treated patients were individuals with worse prognosis than those for whom the decision was to differ treatment initiation, although we tried to consider this by adjusting for baseline CD4+ cell count or baseline CD4+/CD8+ ratio.
HIV treatment guidelines have evolved during the last decade. Treatment interruption after early initiation of cART during primary infection has no longer been recommended. The CD4+ cell count threshold at which treatment initiation is recommended has gradually increased and the latest French guideline (2013) recommends treatment initiation for all patients at diagnosis, regardless of their CD4+ cell count. This has resulted in a higher proportion of patients being treated early after infection. Even if recent drugs are better tolerated, unscheduled treatment interruptions continue to occur, mainly because of suboptimal adherence or irregular follow-up. Our results underline the need to reinforce patient support during early treatment in order to maintain adherence to what is still a lifelong treatment.
We thank all the patients and physicians participating to the ANRS PRIMO cohort; M. Wehr, S. Clares Vera, A.S. Keita, L. Corvi, N. Ait Tahar, A. Essat, F. Boufassa, L. Tran, A. Persoz for monitoring and data management and D. Young for editing the manuscript.
The ANRS PRIMO is funded by the ANRS.
R.S., C.G., L.M wrote the manuscript. R.S. did the statistical analyses. L.M., C.G. conceived and designed the cohort. E.K., JM. M., C.R., P.M., L.P., M.S., S.O. did the critical revisions of the manuscript for important intellectual content.
Conflicts of interest
There are no conflicts of interest for this study. For activities outside the study, authors have received funding for research, grants, consultancy or presentation fees as detailed here. Board membership: C.G. (Gilead Sciences), P.M. (Gilead Sciences, ViiV Healthcare), J.M.M. (Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare), L.P. (Bristol-Myers Squibb, Gilead Sciences). Consultancy: L.P. ( Janssen, Merck, Roche, Schering-Plough, ViiV Healthcare). Grants/grants pending: J.M.M. (Gilead Sciences, Merck). Payment for lectures including service on speakers bureaus: J.M.M. (Gilead Sciences, Janssen, Merck), C.R. (Janssen, Merck). Travel/accommodations/meeting expenses unrelated to activities listed: L.P. (Gilead Sciences, ViiV Healthcare), C.R. (ViiV Healthcare).
The scientific committee is composed of F. Barin, M.L. Chaix, A. Cheret, S. Couffin-Cadiergues, J.F. Delfraissy, A. Essat, H. Fischer, C. Goujard, C. Lascoux-Combe, C. Lecuroux, L. Marchand, L. Meyer, C. Rouzioux, A. Saez-Cirion, R. Seng, A. Venet.
Members of the ANRS PRIMO are as follows:
Thierry ALLEGRE, Centre hospitalier général d’Aix en Provence, Service d’Hématologie
Jean-Michel LIVROZET, François JEANBLANC, Pierre CHIARELLO, Djamila MAKHLOUFI, Hôpital Edouard Herriot de Lyon, Immunologie Clinique
Christian TREPO, Dominique PEYRAMOND, Patrick MIAILHES, Joseph KOFFI, Valérie THOIRAIN, Corinne BROCHIER, Thomas BAUDRY, Sylvie PAILHES, Lyon La Croix Rousse, Services d’Hépato-Gastroentérologie et des Maladies Infectieuses
Alain LAFEUILLADE, Julie ALLEMAND, Edith DANIELLI, Gisèle PHILIP, Gilles HITTINGER, Assi ASSI, Alain RIEU, Véronique LAMBRY, Hôpital Font-Pré de Toulon, Médecine Interne, Hémato-Infectiologie
Jean-Gabriel FUZIBET, Jill-Patrice CASSUTO, Michèle QUARANTA, Hôpital L’Archet, Nice, Service de Médecine Interne
Pierre DELLAMONICA, Anne LEPLATOIS,; Alissa NAQVI,Pierre Marie ROGER, Pascal PUJLIESE; Jacques DURANT; Eric CUA; Matteo VASSALLO; Véronique MONDAIN -MITON, Hôpital de L’Archet, Nice, Maladies Infectieuses et Tropicales
Serge TEMPESTA, Centre Hospitalier d’Antibes, Service de Médecine Interne
Isabelle RAVAUX, Hôpital de la Conception de Marseille, Service des Maladies Infectieuses
Isabelle POIZOT MARTIN, Hôpital Sainte Marguerite de Marseille, Unité d’Hématologie
Hélène CHAMPAGNE, Centre Hospitalier de Valence, Maladies Infectieuses et Tropicales
Gilles PICHANCOURT, Centre Hospitalier Henri Duffaut d’Avignon, Service Hématologie Maladies Infectieuses
Philippe MORLAT, Fabrice BONNET, Isabelle LOUIS, Caroline ASLAN, Denis MALVY, Denis LACOSTE, Noëlle BERNARD, François PACCALIN, Mojgan BONAREK, Mojgan Marie-Anne VANDENHENDE, Jean DELAUN, Sabrina CALTADO, Hôpital Saint André de Bordeaux, Médecine Interne
Jean-Marie RAGNAUD, Michel DUPONT; Hervé DUTRONC, Frédéric DAUCHY, Charles CAZENAVE, Audrey, MERLET, Didier NEAU, Thierry PISTONE, Elodie BLANCHARD, Laetitia LACAZE-BUZ, Hôpital Pellegrin de Bordeaux, Maladies Infectieuses.
Jean-Luc PELLEGRIN, Isabelle RAYMOND, Jean-François VIALLARD, Estibaliz LAZARO, Carine GREIB, Gaetane WIRTH, Severin CHAIGNE DE LALANDE, Hôpital Haut Lévèque de Bordeaux, Médecine Interne et Maladies Infectieuses
Francis SAINT DIZIER, Daniel GARIPUY, Hôpital Joseph Ducuing de Toulouse, Médecine Interne
Martine OBADIA, Marie CHAUVEAU, Florence BALZARIN, Hôpital Purpan de Toulouse, SMIT-CISIH
Jacques REYNES, Vincent BAILLAT, Corinne MERLE, Vincent LEMOING, Nadine ATOUI, Alain MAKINSON, Jean Marc JACQUET, Christina PSOMAS, Antoine VILLADERO, Christine TRAMONI, Hôpital Guide Chauliac de Montpellier, Service des Maladies Infectieuses et Tropicales
Hugues AUMAITRE, Mathieu SAADA, Marie MEDUS, Martine MALET, Orélia EDEN, Ségolène NEUVILLE, Milagros FERREYRA, Hôpital Saint Jean de Perpignan, Service des Maladies Infectieuses
André CABIE, Sylvie ABEL, Sandrine PIERRE-FRANCOIS, Guillaume HURTREL, Patrick HOCHEDEZ, Guillaume AVENIN, Nicolas VIGNIER, Bernard LIAUTAUD, Christelle BARINGTHON, CHU Fort de France, Hôpital de Jour
Isabelle LAMAURY, CHU de Pointe à Pitre/ABYMES, Service de Dermatologie / Maladies Infectieuses
Geneviève BECK-WIRTH, Catherine MICHEL, Jean-Michel PETER, Charles BECK, Jean-Michel HALNA, Meryem BENOMAR, Hôpital Emile Muller de Mulhouse, Hématologie Clinique
Bruno HOEN ; Christine DROBACHEFF-THIEBAUT, Jean-François FAUCHER, Adeline FOLTZER, François PARCELIER, Catherine BOURDEAUX, Jean-Marie ESTAVOYER - Hôpital St Jacques de Besançon, Service des Maladies Infectieuses et de Dermatologie
Lionel PIROTH, Marielle BUISSON, Sandrine TREUVELOT, Hôpital du Bocage de Dijon, Service des Maladies Infectieuses
Thierry MAY, Laurence BOYER, Simone WASSOUMBOU, CHU de Vandoeuvre-lès-Nancy, Hôpital de Brabois, Service des Maladies Infectieuses et Tropicales
Masha MOHSENI ZADEH, Martin MARTINOT, Anaïs MOTHES, Anne PACHART, Hôpital Louis PASTEUR de Colmar, Service d’Immunologie Clinique
Benoît MARTHA, Centre Hospitalier William Morey de Chalon Sur Saône, Service de Médecine Interne
David REY, Maria PARTISANI, Christine CHENEAU, Michèle PRIESTER, Claudine BERNARD-HENRY, Erick DE MAUTORT, Patricia FISCHER, Service le Trait d’Union, Hôpitaux Universitaires de Strasbourg
Yazdan YAZDANPANAH, Thomas HULEUX, Faïza AJANA, Isabelle ALCARAZ, Christophe ALLIENNE, Véronique BACLET, Antoine CHERET, Xavier de la TRIBONNIERE, Hugues MELLIEZ, Agnès MEYBECK, Bertrand RIFF, Michel VALETTE, Nathalie VIGET, Emmanuelle AISSI, Centre Hospitalier DRON de Tourcoing, Service de Maladies Infectieuses
Dominique MERRIEN, Centre Hospitalier de Compiègne, Service de Médecine Interne
Georges DIAB, C H de la Haute Vallée de l’Oise de Noyon, Service de Médecine
Gilles Blaison, Mahsa Mohseni Zadeh, Martin Martinot and Anne Pachart, Hopital Pasteur, Colmar, France
François RAFFI, Bénédicte BONNET, Clotilde ALLAVENA, Jean-Philippe TALARMIN, Olivier MOUNOURY, Véronique RELIQIET, Eric BILLAUD, Cecile BRUNET, Sabelline BOUCHEZ, Nicolas FEUILLEBOIS, David BOUTOILLE, Hervé HUE, Delphine BROSSEAU, Hôtel-Dieu de Nantes, CISIH Médecine Interne
Faouzi SOUALA, Christian MICHELET, Pierre TATTEVIN, Cedric ARVIEUX, Matthieu REVEST, Helene LEROY, Jean-Marc CHAPPLAIN, Matthieu DUPONT, Fabien FILY, Maja RASJTAJACK, CHRU Pontchaillou de Rennes, Clinique des Maladies Infectieuses
Louis BERNARD, Frédéric BASTIDES, Pascale NAU, Hôpital Bretonneau de Tours, Service des maladies Infectieuses
Renaud VERDON, Arnaud DE LA BLANCHARDIERE, Vincent NOYON, Anne MARTIN, Philippe FERET, CH régional Côte de Nacre de Caen, Service de Maladies Infectieuses
Loïk GEFFRAY, Hôpital Robert Bisson de Lisieux, Service de Médecine Interne
Claude BEUSCART, Corinne DANIEL, Sylvie LE MOAL, Elizabeth DUHAMEL, Anne GATEL, Elisabeth PAPE, Centre Hospitalier La Beauchée de Saint-Brieuc, Médecine Interne et Maladies Infectieuses
Pascale FIALAIRE, Jean Marie CHENNEBAULT, Valérie RABIER, Pierre ABGUEGUEN, Sami REHAIEM, Centre Hospitalier Régional d’Angers, Service des Maladies Infectieuses
Odile LUYCX, Mathilde NIAULT, Philippe MOREAU, Centre Hospitalier Bretagne Sud de Lorient, Service d’Hématologie
Yves POINSIGNON, Anabèle DOS SANTOS,Virginie MOUTON- RIOUX, Centre Hospitalier Bretagne Atlantique de Vannes, Service de Medecine Interne et Maladies Infectieuses
Dominique HOULBERT, Sandrine ALVAREZ-HUVE, Frédérique BARBE, Sophie HARET, Centre Hospitalier d’Alençon, Médecine 2
Philippe PERRE,Sophie LEANTEZ-NAINVILLE, Jean-Luc ESNAULT, Thomas GUIMARD, Isabelle SUAUD, Centre Hospitalier Départemental de La Roche sur Yon, Service de Médecine
Jean-Jacques GIRARD, Véronique SIMONET, Hôpital de Lôches, Service de Médecine Interne
Yasmine DEBAB, CHU Charles Nicolle de Rouen, Maladies Infectieuses et Tropicales
Christine JACOMET, Florence GOURDON, Hacène TAS, Hôpital Gabriel-Montpied de Clermont Ferrand, Service des Maladies Infectieuses et Tropicales
Claire GENET, Hôpital DUPUYTREN de Limoges, Maladies Infectieuses et Tropicales
Bruno ABRAHAM, Centre Hospitalier de Brive, Departement de maladies Infectieuses
Alain REGNIER, Centre Hospitalier de Vichy, Service de Médecine Interne
Odile ANTONIOTTI, Centre Hospitalier de Montluçon, Dermatologie
Jean-Michel MOLINA, Samuel FERRET, Matthieu LAFAURIE, Nathalie COLIN DE VERDIERE, Diane PONSCARME, Nathalie DE CASTRO, Alexandre ASLAN, Willy ROZENBAUM, Jerome GOGUEL, Claire PINTADO, Suna BALKAN, Sebastien GALLIEN, François CLAVEL, Olivier TAULERA, Caroline GATEY, Valérie GARRAIT, Hôpital Saint Louis de Paris, Service des Maladies Infectieuses et Tropicales
Caroline LASCOUX-COMBE, Olivier TAULLERA, Claire PINTADO, Jeannine DELGADO, Hôpital Saint Louis de Paris, Service de Médecine Interne
Julie TIMSIT, Hôpital Saint Louis de Paris, Clinique MST
Laurence GERARD, Hôpital Saint Louis de Paris, Service d’Immunologie Clinique
Pierre-Marie GIRARD, Odile PICARD, Jürgen TREDUP, Diane BOLLENS, Nadia VALIN, Pauline CAMPA, Nelly DESPLANQUE Hôpital Saint Antoine de Paris, Service des Maladies Infectieuses et Tropicales
Patrick YENI, Bao PHUNG, Bilguissa DIALLO, Frédérique GUIROY, Nadia EL ALAMI TALBI, Golriz PAHALAVAN, Françoise LOUNI, G. Hospitalier Bichat-Claude Bernard de Paris, Service de Maladies Infectieuses et Tropicales
Catherine LEPORT, Corinne JADAND, G. Hospitalier Bichat-Claude Bernard de Paris, Service des Maladies Infectieuses et Tropicales
Gilles PIALOUX, Thomas LYAVANC, Laurence SLAMA, Valérie BERREBI, Hopital Tenon de Paris, Service des Maladies Infectieuses
Aurélie Durel, Agathe RAMI, Maguy PARRINELLO, Hôpital Lariboisière de Paris, Service de Médecine Interne A
Loïc GUILLEVIN, Dominique SALMON, Tassadit TAHI, Catherine CHAKVETADZE, Linda BELARBI, Odile LAUNAY, Benjamin SILBERMANN, Firouze BANI SADR, Marie-Pierre PIETRI, G. H. Cochin de Paris, Département de Médecine Interne
Anne SIMON, Manuela BONMARCHAND, Naouel AMIRAT, François PICHON, Jean-Luc VOURCH, Michele PAUCHARD, G. H. Pitié-Salpétrière de Paris, Service de Médecine Interne
Christine KATLAMA, Marc Antoine VALANTIN, Roland TUBIANA, Fabienne CABY, Luminita SCHNEIDER, Sophie SEANG, Hind STITOU, Saadia BEN ABDALLAH, G. H. Pitié-Salpétrière de Paris, Service des Maladies Infectieuses
Laurence WEISS, Martin BUISSON, Hôpital Européen Georges Pompidou de Paris, Service d’Immunologie Clinique
Jean-Paul VIARD, Jacques GILQUIN, Alain SOBEL, Blanka HADACEK, Nugyen THU-HUYN, Olivier ZAK-DIT-ZBAR, Agnes CROS - Hôtel Dieu de Paris, Centre de Diagnostic et Thérapeutique
Paul Henri CONSIGNY, Claudine DUVIVIER, Fatima TOUAM, Centre Médical de l’Institut Pasteur de Paris, Service des Maladies Infectieuses
Loïc BODARD, Isabelle SAURET, Sylvie GIBERT, Institut Mutualiste Montsouris de Paris, Département de Médecine Interne
Jean-François DELFRAISSY, Cécile GOUJARD, Jade GHOSN, Yann QUERTAINMONT, Martin DURACINSKY, Olivier SEGERAL, Arnaud BLANC, Delphine PERETTI, Valerie SEGUIN, Marie josée DULUCQ, Hôpital de Bicêtre, Médecine Interne
Yves LEVY, Anne Sophie LASCAUX, Jean Daniel LELIEVRE, Cécile DUMONT, Hôpital Henri Mondor de Créteil, Immunologie Clinique
François BOUE, Renato FIOR, Hôpital Antoine Béclère de Clamart, Médecine Interne et Immunologie Clinique
Pierre DE TRUCHIS, Huguette BERTHE, Hôpital Raymond Poincaré de Garches, Service des Maladies Infectieuses et Tropicales
Pierre CHEVOJON, Pierre CHEVOJON, Alain DEVIDAS, Olivier PATEY, Isabelle TURPAULT, Hôpital de Corbeil-Essonnes, Service Hématologie
Yvon LEMERCIER, Fabrice CHAIX, Isabelle TURPAULT, Centre Hospitalier Général de Longjumeau, Service de Médecine Interne
Olivier BOUCHAUD, François ROUGES, Sophie ABGRALL, Regine BARRUET, Frederic MECHAI, Patricia HONORE, Hôpital Avicenne de Bobigny, Maladies Infectieuses et Tropicales
Elisabeth ROUVEIX, Evelyne REIMANN, Hôpital Ambroise Paré de Boulogne, Médecine Interne
Audrey THERBY, Alix GREDER BELAN, Claire GODIN COLLET, Maria RUQUET, Hôpital du Chesnay, CH Andre Mignot du Chesnay, Maladies Infectieuses et Tropicales
Isabelle MAHE, Emmanuel MORTIER, Martine BLOCH, Anne-Marie SIMONPOLI, Véronique MANCERON, Isabelle CAHITTE, Ai-feng ZENG, Benedicte MONTOYA, Hôpital Louis Mourier de Colombes, Médecine Interne
David ZUCMAN, Catherine MAJERHOLC, Dominique BORNAREL, Hôpital Foch de Suresnes, Médecine Interne
Agnès ULUDAG, Justine GELLEN-DAUTREMER, Agnes. LEFORT, A.Tadlaoui, Hôpital Beaujon de Clichy, Médecine Interne
Vincent DANELUZZI, Juliette GERBE, Centre Hospitalier de Nanterre, Service de Médecine Interne
Gérôme STIRNMAN, Mélissa COUPARD, Hôpital Jean Verdier de Bondy, Service de Médecine Interne, Unité de Maladies Infectieuses
Olivier PATEY, BANTSIMBA Jonas, Sophie DELLLION, Pauline CARAUX PAZ, Benoit CAZENAVE, Laurent RICHIER, Centre Hospitalier Intercommunal de Villeneuve St Georges, Médecine Interne
Valérie GARRAIT, Isabelle DELACROIX, Brigitte ELHARRAR, Laurent RICHIER, Centre Hospitalier Intercommunal de Créteil, Médecine Interne, Hépato-Gastroentérologie
Daniel VITTECOQ, Lelia ESCAUT, Claudine BOLLIOT, Hôpital de Bicêtre, Service de Maladies Infectieuses et Tropicales
Annie LEPRETRE, Hôpital Simone Veil d’Eaubonne, Médecine 2, Consultation ESCALE
Philippe GENET, Juliette GERBE, Consultation d’Immuno/Hématologie d’Argenteuil
Véronique PERRONE, Centre Hospitalier François Quesnay de Mantes La Jolie, Service des Maladies Infectieuses
Jean-Luc BOUSSARD, Patricia CHARDON, Centre Hospitalier Marc Jacquet de Melun, Service de Médecine
Eric FROGUEL, Phlippe SIMON, Sylvie TASSIE, Hôpital de Lagny, Service de Médecine Interne
1. Krastinova E, Seng R, Yeni P, Viard JP, Vittecoq D, Lascoux-Combe C, et al. Is clinical practice concordant with the changes in guidelines for antiretroviral therapy initiation during primary and chronic HIV-1 infection? The ANRS PRIMO and COPANA cohorts
. PLoS One
2. SIDA. Rapport 2002: Prise en charge médicale des personnes infectées par le VIH. Recommandations du groupe d’experts. Sous la présidence du Pr Jean-François Delfraissy. [French Expert's recommendations for the management of people living with HIV/AIDS. 2002 Report] http://www.sante.gouv.fr/IMG/pdf/Sida_-_Rapport_2002.pdf
[accessed June 2014].
4. Hoen B, Bonnet F, Delaugerre C, Delobel P, Goujard C, L’Henaff M, et al. French 2013 guidelines for antiretroviral therapy of HIV-1 infection in adults
. J Int AIDS Soc
5. Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix ML, et al. Does transient HAART during primary HIV-1 infection lower the virological set-point?
6. Stohr W, Fidler S, McClure M, Weber J, Cooper D, Ramjee G, et al. Duration of HIV-1 viral suppression on cessation of antiretroviral therapy in primary infection correlates with time on therapy
. PLoS One
7. Goujard C, Emilie D, Roussillon C, Godot V, Rouzioux C, Venet A, et al. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial
8. Hogan CM, Degruttola V, Sun X, Fiscus SA, Del Rio C, Hare CB, et al. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals
. J Infect Dis
9. Grijsen ML, Steingrover R, Wit FW, Jurriaans S, Verbon A, Brinkman K, et al. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial
. PLoS Med
10. El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment
. N Engl J Med
11. Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, et al. Short-course antiretroviral therapy in primary HIV infection
. N Engl J Med
12. Hamlyn E, Ewings FM, Porter K, Cooper DA, Tambussi G, Schechter M, et al. Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection
. PLoS One
13. Zoufaly A, Stellbrink HJ, Heiden MA, Kollan C, Hoffmann C, van Lunzen J, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma
. J Infect Dis
14. Cole SR, Napravnik S, Mugavero MJ, Lau B, Eron JJ Jr, Saag MS. Copy-years viremia as a measure of cumulative human immunodeficiency virus viral burden
. Am J Epidemiol
15. Mugavero MJ, Napravnik S, Cole SR, Eron JJ, Lau B, Crane HM, et al. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy
. Clin Infect Dis
16. Wright ST, Hoy J, Mulhall B, O’Connor CC, Petoumenos K, Read T, et al. Determinants of viremia copy-years in people with HIV/AIDS after initiation of antiretroviral therapy
. J Acquir Immune Defic Syndr
17. Avettand-Fenoel V, Blanche S, Le Chenadec J, Scott-Algara D, Dollfus C, Viard JP, et al. Relationships between HIV disease history and blood HIV-1 DNA load in perinatally infected adolescents and young adults: the ANRS-EP38-IMMIP study
. J Infect Dis
18. Marconi VC, Grandits G, Okulicz JF, Wortmann G, Ganesan A, Crum-Cianflone N, et al. Cumulative viral load and virologic decay patterns after antiretroviral therapy in HIV-infected subjects influence CD4 recovery and AIDS
. PLoS One
19. Serrano-Villar S, Perez-Elias MJ, Dronda F, Casado JL, Moreno A, Royuela A, et al. Increased risk of serious non-AIDS-related events in HIV-infected subjects on antiretroviral therapy associated with a low CD4/CD8 ratio
. PLoS One
20. Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality
. PLoS Pathog
21. Desquilbet L, Mariotti F. Dose-response analyses using restricted cubic spline functions in public health research
. Stat Med
22. Mocroft A, Phillips AN, Gatell J, Ledergerber B, Fisher M, Clumeck N, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study
23. Egger S, Petoumenos K, Kamarulzaman A, Hoy J, Sungkanuparph S, Chuah J, et al. Long-term patterns in CD4 response are determined by an interaction between baseline CD4 cell count, viral load, and time: The Asia Pacific HIV Observational Database (APHOD)
. J Acquir Immune Defic Syndr
24. Hughes RA, Sterne JA, Walsh J, Bansi L, Gilson R, Orkin C, et al. Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study
. HIV Med
25. Wright ST, Petoumenos K, Boyd M, Carr A, Downing S, O’Connor CC, et al. Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience
. HIV Med
26. Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A, et al. CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study
. Arch Intern Med
27. Negredo E, Massanella M, Puig J, Perez-Alvarez N, Gallego-Escuredo JM, Villarroya J, et al. Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIV-infected patients: clinical implications
. Clin Infect Dis
28. Kulkarni H, Okulicz JF, Grandits G, Crum-Cianflone NF, Landrum ML, Hale B, et al. Early postseroconversion CD4 cell counts independently predict CD4 cell count recovery in HIV-1-postive subjects receiving antiretroviral therapy
. J Acquir Immune Defic Syndr
29. Lifson AR, Krantz EM, Eberly LE, Dolan MJ, Marconi VC, Weintrob AC, et al. Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort
. AIDS Res Ther
30. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression
. Clin Infect Dis
31. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment
. Clin Infect Dis
32. Li X, Margolick JB, Jamieson BD, Rinaldo CR, Phair JP, Jacobson LP. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy
. J Acquir Immune Defic Syndr
33. Chéret A, Nembot G, Mélard A, Lascoux C, Slama L, Miailhes P, et al. Pentatherapy during Primary HIV-1 infection: results of the OPTIPRIM-ANRS 147 randomised phase 3 study
. Lancet Inf Dis
2015; in press.
34. Serrano-Villar S, Gutierrez C, Vallejo A, Hernandez-Novoa B, Diaz L, Abad Fernandez M, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression
. J Infect
35. Touloumi G, Pantazis N, Stirnadel HA, Walker AS, Boufassa F, Vanhems P, et al. Rates and determinants of virologic and immunological response to HAART resumption after treatment interruption in HIV-1 clinical practice
. J Acquir Immune Defic Syndr
36. Mussini C, Touloumi G, Bakoyannis G, Sabin C, Castagna A, Sighinolfi L, et al. Magnitude and determinants of CD4 recovery after HAART resumption after 1 cycle of treatment interruption
. J Acquir Immune Defic Syndr
37. Kaufmann GR, Elzi L, Weber R, Furrer H, Giulieri S, Vernazza P, et al. Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death