Does enfuvirtide increase the risk of bacterial pneumonia in patients receiving combination antiretroviral therapy?

Transcription

1 J Antimicrob Chemother 2010; 65: doi: /jac/dkp402 Advance publication 10 November 2009 Does enfuvirtide increase the risk of bacterial pneumonia in patients receiving combination antiretroviral therapy? I. Kousignian 1,2 *, O. Launay 3, C. Mayaud 4, C. Rabaud 5, D. Costagliola 1,2,6 and S. Abgrall 1,2,7 on behalf of the FHDH-ANRS CO4 1 INSERM U 943, Paris, F France; 2 UPMC Université Paris 06, UMR_S 943, Paris, F France; 3 Assistance Publique-Hôpitaux de Paris (APH-HP), Hôpital Cochin, Pôle de Médecine, Paris, F France; 4 Service de Pneumologie et Réanimation respiratoire, Hôpital Tenon, Paris, F France; 5 CHU de Nancy, Service de maladies infectieuses et tropicales, Hôpitaux de Brabois, Vandoeuvre, F France; 6 AP-HP, Groupe hospitalier Pitié-Salpétrière, Service des maladies infectieuses et tropicales, Paris, F France; 7 AP-HP, Hôpital Avicenne, Service de maladies infectieuses et tropicales, Bobigny, F France *Corresponding author. Present address: Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire Santé Publique et Environnement-EA 4064, 4 avenue de l Observatoire, Paris, France. Tel: þ ; Fax: þ ; isabelle.kousignian@parisdescartes.fr Members are listed in the Acknowledgements section. Received 30 June 2009; returned 3 August 2009; revised 11 October 2009; accepted 13 October 2009 Background: Pooled analysis of the TORO comparative clinical trial data sets showed a significantly higher incidence rate (IR) of bacterial pneumonia (BP) among patients treated with enfuvirtide-containing combination antiretroviral therapy (ENF-cART) than in those treated with other cart regimens. Objectives: To examine the possible impact of ENF-cART on the risk of BP. Methods: From the French Hospital Database on HIV, we selected two groups of patients among cart-treated patients who were prescribed a new cart regimen during the period , when their CD4 counts were,350 cells/mm 3. The ENF-cART and cart groups consisted of 1220 and 9374 patients, respectively. Poisson regression models were used to quantify the relationship between ENF-cART therapy and the risk of BP. Results: At baseline the median CD4 counts were 100 and 211 cells/mm 3 and the median plasma viral load (pvl) values were and 2702 copies/ml in the ENF-cARTand cart groups, respectively. The respective BP IRs were 0.65 [95% confidence interval (CI) ] and 0.31 (95% CI ) cases per 100 person-years. After adjustment for age, the HIV transmission group, the time period, co-trimoxazole prophylaxis, and stratified CD4 cell counts and pvl values, we found that the BP risk ratio was not increased by enfuvirtide treatment (relative rate 1.39; 95% CI ). In contrast, lower CD4 cell counts and higher pvl values were significantly associated with a higher risk of BP. Conclusions: ENF-cART is not associated with a significantly higher risk of BP than other cart regimens, although the value of the adjusted risk and the upper limit of the CI do not allow us to exclude a small increased risk. Keywords: HIV, cart, cohort study Introduction Highly effective combination antiretroviral therapy (cart) has transformed the outlook of HIV-infected patients. 1,2 However, viral suppression is sometimes incomplete, necessitating a switch to more effective antiretroviral combinations. 3 As the number of HIV-1-infected patients exposed to several antiretroviral combinations has grown, the management of multidrug resistance and long-term toxicity has become a major challenge. 4 7 Enfuvirtide (or T-20) is the first of a novel class of antiretrovirals known as HIV fusion inhibitors. 8,9 14 Its efficacy and safety, when combined with an optimized background antiretroviral regimen, were mainly shown in two international randomized trials named TORO1 15 and TORO2. 13,15,16 However, a safety analysis of pooled data showed a significantly higher incidence of pneumonia in the enfuvirtide group than in the control group both at week 24 [4.9 versus 0.6 cases per 100 person-years (PYs), P¼0.02] and at week 48 (6.7 versus 0.6 per 100 PYs). 15,17 # The Author Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 138

2 Bacterial pneumonia and enfuvirtide-containing cart JAC The aim of this study was to examine the possible influence of enfuvirtide-containing cart (ENF-cART) on the risk of bacterial pneumonia (BP) in patients included in the French Hospital Database on HIV (FHDH-ANRS CO4). Materials and methods Study population The database The FHDH clinical epidemiological network is a large prospective cohort involving 62 French hospitals belonging to 29 HIV/AIDS treatment and information centres (CISIH). 18,19 FHDH inclusion criteria are HIV-1 or HIV-2 infection, and signed written informed consent. Trained research assistants prospectively collect clinical, biological and therapeutic data from medical records by using specialized software (DMI2, property of the French Ministry of Health). A follow-up form is completed at each visit or hospital admission for an HIV-related clinical event or a new treatment prescription, or at least every 6 months. The FHDH was approved by the French data protection authority (Commission Nationale de l Informatique et des Libertés, CNIL). Patients We selected HIV-1-infected patients from the FHDH 18,19 who were aged at least 15 years and who were followed between 1 January 2001 (when enfuvirtide became available in France) and 31 December 2006 (last update of the FHDH). In this period, patients were eligible if they had taken cart for at least 6 months before enrolment in the study, if they were then switched to a new cart regimen while their CD4 count was,350 cells/mm 3 and if they had at least two subsequent follow-up visits and no previous history of BP. CART was defined as a combination of three or more antiretroviral drugs, or two ritonavir-boosted protease inhibitors (PIs), or one ritonavir-boosted PI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI). To study the impact of ENF-cART on the risk of BP, we divided the selected population into patients switching to a new cart regimen that included enfuvirtide (ENF-cART group) and patients switching to a new cart regimen without enfuvirtide (cart group). Statistical analysis Follow-up data Baseline was defined as the date of the cart switch. Follow-up data were censored at the date of enfuvirtide interruption in the ENF-cART group and at the date of cart interruption or addition of enfuvirtide in the cart group, or at the date of death, or 31 December Moreover, beyond these specified conditions, patients could change their cart without being censored. The CD4 cell counts and plasma viral load (pvl) were analysed as time-updated values from baseline to the end of follow-up. We used linear interpolation to fill in missing CD4 counts and pvl values between two registered values. For patients whose follow-up was ongoing, the last recorded CD4 count and pvl values were carried forward by 2 months. Other missing values were categorized as missing data. Patients were still considered to be on ENF-cART or cart 15 days after the last registered follow-up visit. Event definition Diagnosis of BP was based on information provided by physicians in each hospital. All diagnoses of BP, both definite (new X-ray evidence not present earlier with bacteriological documentation) and presumptive (new symptoms, signs or X-ray evidence not present earlier and no diagnosis of Pneumocystis jirovecii pneumonia or Mycobacterium disease), were considered for the study. 20,21 First BP, occurring at least 15 days after the baseline point, was considered for the analysis. Statistical methods The BP incidence rates (IRs) in each group were calculated by dividing the number of patients who had BP during the entire follow-up period by the number of PYs at risk in the same group, both overall and within different CD4 cell count strata and pvl strata. Poisson regression models were used to quantify the relationship between ENF-cART therapy and the incidence of BP. The following potential factors were considered: sex, age, the HIV transmission group, sub-saharan origin, the time period, the CD4 cell count and pvl strata, AIDS status 19 and co-trimoxazole prophylaxis. For multivariate Poisson regression analysis we first used bivariate analyses to identify potential confounders that changed the enfuvirtide-related relative rate (RR) of BP by 10%, with adjustment for the relevant variables. Statistical analyses were performed with the SAS software package version 9.1 (SAS Institute). Results Patients characteristics During the period , 1220 and 9374 patients, respectively, were selected for the ENF-cART and cart groups. Follow-up totalled 1531 and PYs, respectively. During this period, the yearly median number of medical appointments was similar in the two study groups, between 6 and 8 for the ENF-cART group and between 3 and 11 for the cart groups. The median durations between the first two visits were 28 days [interquartile range (IQR) 14 53] and 56 days (IQR 28 99) in the ENF-cART and cart groups, respectively. The first two visits thus were within the first year of inclusion in the study. In the ENF-cART group the baseline median CD4 count was 100 cells/mm 3 (IQR ), 55.2% of patients had already had an AIDS-defining event and 10.2% of patients had pvl values,500 copies/ml (Table 1). The median duration of prior cart was 86 (IQR 70 99) months, the median number of previously taken antiretroviral drugs was 12 (IQR 9 13) and 788 patients (64.6%) had previously received at least one NRTI, one PI and one NNRTI. Follow-up totalled 557 PYs in the,100 CD4 cells/mm 3 stratum, 749 PYs in the cells/mm 3 stratum, 206 PYs in the 350 cells/mm 3 stratum and 19 PYs in the missing values stratum. Follow-up totalled 578 PYs in the,500 copies/ml stratum, 445 PYs in the copies/ml stratum and 480 PYs in the copies/ml stratum. In the cart group, the baseline median CD4 count was 211 cells/mm 3 (IQR ), 37.7% of the patients had already had AIDS-defining events and 38.5% of patients had pvl values,500 copies/ml (Table 1). The median duration of prior cart was 59 (IQR 41 72) months, the median number of previously taken antiretroviral drugs was 6 (IQR 4 8) and 2116 patients (22.6%) had previously received at least one NRTI, one PI and one NNRTI. Follow-up totalled 3531 PYs in the,100 CD4 cells/mm 3 stratum, PYs in the cells/mm 3 stratum, 7604 PYs in the 350 cells/mm 3 stratum and 560 PYs in the missing values stratum. Follow-up totalled PYs in the,500 copies/ml 139

3 140 Table 1. Demographic and clinical characteristics of the ENF-cART and cart groups at study entry and at the date of the first episodes of BP Kousignian et al. At baseline At the date of BP ENF-cART group (n¼1220) cart group (n¼9374) ENF-cART group (n¼10) cart group (n¼82) Male sex, n (%) 1012 (83.0%) 6797 (72.5%) 8 (80.0%) 61 (74.4%) Median age, years (IQR) 43 (39 49) 42 (37 48) 43 (36 47) 42 (37 47) HIV transmission group, n (%) homo/bisexual 575 (47.2%) 2869 (30.6%) 3 (30.0%) 23 (28.0%) heterosexual 366 (30.0%) 3515 (37.5%) 4 (40.0%) 21 (25.7%) intravenous drug user 165 (13.5%) 2099 (22.4%) 2 (20.0%) 27 (32.9%) other/unknown 114 (9.3%) 891 (9.5%) 1 (10.0%) 11 (13.4%) Time period, n (%) (31.2%) 7338 (78.3%) 4 (40.0%) 37 (45.1%) (68.8%) 2036 (21.7%) 6 (60.0%) 45 (54.9%) History of AIDS-defining events, n (%) 673 (55.2%) 3535 (37.7%) 9 (90.0%) 52 (63.4%) Median CD4 cell count, cells/mm 3 (IQR) 100 (31 196) 211 ( ) 12 (9 168) 130 (33 225) Number (%) of patients with CD4 counts (cells/mm 3 ) missing values 0 (0.0%) 0 (0.0%) 0 (0.0%) 5 (6.1%), (50.1%) 1765 (18.8%) 7 (70.0%) 34 (41.5%) (49.9%) 7609 (81.2%) 2 (20.0%) 35 (42.6%) (0.0%) 0 (0.0%) 1 (10.0%) 8 (9.8%) Median pvl, copies/ml (IQR) ( ) 2702 (, ) (, ) ( ) Number (%) of patients with pvl (copies/ml) missing values 4 (0.3%) 63 (0.7%) 2 (20.0%) 5 (6.1%), (10.2%) 3609 (38.5%) 3 (30.0%) 22 (26.8%) (35.6%) 3647 (38.9%) 0 (0.0%) 25 (30.5%) (53.9%) 2055 (21.9%) 5 (50.0%) 30 (36.6%) Number (%) of patients with co-trimoxazole prophylaxis 655 (53.7%) 4402 (47.0%) 6 (60.0%) 49 (59.8%) Median follow-up after baseline, months (IQR) 10 (4 20) 34 (19 48) 6 (2 16) 18 (7 28) IQR, interquartile range; ENF, enfuvirtide; cart, combination antiretroviral treatment; ENF-cART, enfuvirtide-containing cart; BP, bacterial pneumonia; pvl, plasma viral load.

4 Bacterial pneumonia and enfuvirtide-containing cart JAC Table 2. RRs (95% CI) of BP in univariate and bivariate (RR of bacterial pneumonia associated with enfuvirtide exposure) regression models Univariate analyses Bivariate analyses ENF-cART ENF-cART 2.09 ( ) (P¼0.0280) Sex male 1 female 1.17 ( ) (P¼0.0516) ENF-cARTþsex 2.03 ( ) (P¼0.0924) Age, years 50 1, ( ) (P¼0.0287) ENF-cARTþage 2.10 ( ) (P,0.0001) Intravenous drug user 1.66 ( ) (P¼0.0239) ENF-cARTþintravenous drug user 2.21 ( ) (P,0.0001) Sub-Saharan origin 0.97 ( ) (P¼0.0587) ENF-cARTþsub-Saharan origin 2.06 ( ) (P¼0.0709) Time period ( ) (P¼0.0504) ENF-cARTþtime period 2.32 ( ) (P¼0.0547) a Previous AIDS, (, to,0.0001) (P,0.0001) ENF-cARTþprevious AIDS 2.21 ( ) (P¼0.0801) CD4 cell count stratum, ( ) (P,0.0001) ( ) (P,0.0001) missing values 0.86 ( ) (P¼0.7550) ENF-cARTþCD4 cell count stratum 1.33 ( ) (P¼0.2865) a pvl stratum, ( ) (P¼0.0012) ( ) (P,0.0001) ENF-cARTþpVL stratum 1.46 ( ) (P¼0.6056) a Co-trimoxazole prophylaxis 0.67 ( ) (P¼0.0508) ENF-cARTþco-trimoxazole prophylaxis 2.04 ( ) (P,0.0001) RR, relative rate; ENF, enfuvirtide; cart, combination antiretroviral treatment; ENF-cART, enfuvirtide-containing cart; pvl, plasma viral load; BP, bacterial pneumonia. a Variables modifying the BP RR associated with ENF-cART by 10%. 141

5 Kousignian et al. Table 3. RRs (95% CI) of BP in multivariate Poisson regression models stratum, 6150 PYs in the copies/ml stratum and 3371 PYs in the copies/ml stratum. Comparative IRs of BP ENF-related RRs of BP ENF-cART 1.39 ( ) (P¼0.5433) Age, years 50 1, ( ) (P¼0.5303) Intravenous drug user 1.50 ( ) (P¼0.1763) Time period ( ) (P¼0.3736) CD4 cell count stratum, ( ) (P¼0.0175) ( ) (P¼0.0248) missing values 0.72 ( ) (P¼0.7541) pvl stratum, ( ) (P¼0.1727) ( ) (P¼0.0308) Co-trimoxazole prophylaxis 1.25 ( ) (P¼0.4848) RR, relative rate; ENF, enfuvirtide; cart, combination antiretroviral treatment; ENF-cART: enfuvirtide-containing cart; pvl, plasma viral load; BP, bacterial pneumonia. During the study period, 10 patients on ENF-cART {IR 0.65/100 PYs [95% confidence interval (CI) ]} and 82 patients on cart [IR 0.31/100 PYs (95% CI )] developed a first episode of BP (Table 1). Table 2 shows the RR of BP associated with enfuvirtide treatment alone and with enfuvirtide treatment associated with each studied covariate. In univariate analysis the RR for BP was twice as high among patients on ENF-cART as among patients on cart (RR 2.09; 95% CI ). All the studied covariates were associated with the risk of BP in univariate analyses. After separate adjustment for each covariate, however, only the time period, the CD4 cell count and pvl modified the relationship between enfuvirtide exposure and BP by 10%. After adjustment, the RR of BP associated with enfuvirtide treatment was not statistically significant (RR 1.39; 95% CI ) (Table 3). Only a lower CD4 cell count and a higher pvl value were independently associated with an increased risk of BP. The adjusted BP IRs were 0.61/100 PYs (95% CI ) and 0.44/100 PYs (95% CI ) in the ENF-cART and cart groups, respectively. Similar results were obtained when the analysis was restricted to patients having received at least one PI, one NRTI and one NNRTI before baseline [IRs 0.66/100 PYs (95% CI ) and 0.33/100 PY (95% CI ) in the ENF-cART and cart groups, respectively; adjusted RR 1.92 ( ), P¼0.3572]. Discussion During the period , among 1220 and 9374 patients who started a new cart regimen with and without enfuvirtide, respectively, when their CD4 counts were,350 cells/mm 3, the respective IRs of BP were 0.65/100 PYs (95% CI ) and 0.31/100 PYs (95% CI ). After adjustment for age, HIV transmission group, time period, CD4 cell count, pvl and co-trimoxazole prophylaxis, enfuvirtide was no longer significantly associated with the risk of BP. In contrast, the risk of BP correlated negatively with CD4 cell count and positively with pvl. HIV infection is associated with a 5- to 25-fold increase in the risk of BP and invasive pneumococcal disease, despite a decrease in the incidence of invasive pneumococcal disease since the beginning of the cart era in Other reported risk factors are age, cigarette smoking, injection drug use, a low CD4 cell count and a high pvl value; in contrast, co-trimoxazole prophylaxis and cart are protective. Although we found that adjusted BP risk ratio was not significantly increased by enfuvirtide treatment (RR 1.39; 95% CI ), the estimated risk was higher than 1.00 and we cannot exclude a small increased risk. In the TORO study, the crude relative risks of BP associated with enfuvirtide were 8.17 at week 24 and at week 48. Our study including 1220 patients in the ENF-cART group and 9374 patients in the cart group, with 10 and 82 events, respectively, had a power of 90% to show an RR of BP of at least 2.5 and a power of 95% to show an RR of at least 4 between the ENF-cART group and cart group. 25 Nevertheless, despite having enough power, we did not show such risks. As the upper limit of the CI is 4.13, our results are compatible with a small increase of the real risk, but much smaller than previously seen in the TORO study. Some relevant information is lacking in the FHDH. For example, pneumococcal vaccination status is not recorded, but the 23-valent polysaccharide vaccine has been recommended for HIV-infected patients with a CD4 count,500 cells/mm 3 only since 2006 in France. 26 Smoking status is not recorded either, but smoking is not known to influence enfuvirtide prescription. The overall incidence of BP may be underestimated in the FHDH database, as some cases may have been managed solely on an outpatient basis. However, the frequency of such events is likely to have been the same in the two groups studied here, especially as the yearly number of medical appointments was the same during the study period. The large number of patients included in the FHDH allows us to investigate rare events. Different follow-up could explain a different crude percentage of BP events between TORO and our study but not different IRs for which estimation takes into account duration of follow-up on enfuvirtide. However, enfuvirtide was mostly prescribed late in the period and patients frequently 142

6 Bacterial pneumonia and enfuvirtide-containing cart JAC switched their ENF-cART to a cart without enfuvirtide after immune recovery, both explaining the shorter follow-up duration in the ENF-cART group than in the cart group and than in the TORO study. As estimation of the IRs takes into account the different follow-up durations in the study groups, this should not have over- or underestimated the incidence of BP in our study. The incidence of pneumonia observed in the TORO studies was similar to that reported during the early cart era. 17 We excluded cases of pneumonia occurring during the first 15 days of the switch regimen, in order to avoid any influence of the previous antiretroviral regimen on the frequency of BP (even though the results were similar when these cases were included in the analysis; data not shown). In the TORO studies it may be noteworthy that 9 of the 45 cases of pneumonia observed among patients allocated to the enfuvirtide group occurred during the first month of treatment. The incidence of BP in the ENF-cART group of our study was much lower than that observed in the enfuvirtide arms of the TORO studies, but it was very similar to that observed in the control group of the TORO studies. The patients included in the TORO studies had lower baseline CD4 cell counts, more frequent previous AIDS-defining events, higher baseline viral replication and a longer follow-up, and this may explain the different IRs observed between the enfuvirtide-treated patients in our study and in the TORO trials. 15,17 Nevertheless, the BP IRs in our study were similar to those observed in other recent cohort studies involving patients with similar baseline immunovirological and treatment status. 22,27 Studies performed early during the cart era ( ) gave higher IRs, 23,28 but the risk of BP has fallen in recent years, related to longer duration of efficient viral suppression on cart. 24 The arrival of less toxic antiretroviral drugs in recent years may have improved treatment adherence and, thus, patients immune status. The main finding of this study is that patients starting an ENF-cART regimen were more immunosuppressed than patients starting other cart regimens, with lower CD4 cell counts, more previous AIDS-defining events and higher viral replication. ENF-cART was associated with a higher frequency of BP in univariate analysis, but this difference disappeared in multivariate analysis with stratified CD4 cell counts and pvl values. In conclusion, this study the largest observational cohort study of this issue showed no significant difference in the incidence of BP between patients receiving cart with and without enfuvirtide, after adjustment for potential confounding factors. As the upper limit of the CI is 4.13, our results are compatible with a small increase of the real risk, but much smaller than previously seen in the TORO study. Acknowledgements This work has been presented in part at the Twelfth International Workshop on HIV Observational Databases, Malaga, Spain, 2008 (Abstract 12C1125) and at the Seventeenth International AIDS Conference, Mexico City, 2008 (Poster THPE0195). We are grateful to all participants and research assistants of the FHDH. Clinical Epidemiology Group of the FHDH Scientific committee: S. Abgrall, F. Barin, M. Bentata, E. Billaud, F. Boué, C. Burty, A. Cabié, D. Costagliola, L. Cotte, P. De Truchis, X. Duval, C. Duvivier, P. Enel, L. Fredouille-Heripret, J. Gasnault, C. Gaud, J. Gilquin, S. Grabar, C. Katlama, M. A. Khuong, J. M. Lang, A. S. Lascaux, O. Launay, A. Mahamat, M. Mary-Krause, S. Matheron, J. L. Meynard, J. Pavie, G. Pialoux, F. Pilorgé, I. Poizot-Martin, C. Pradier, J. Reynes, E. Rouveix, A. Simon, P. Tattevin, H. Tissot-Dupont, J. P. Viard, N. Viget. DMI2 coordinating centre: French Ministry of Health (Valérie Salomon), Technical Hospitalization Information Agency, ATIH (N. Jacquemet). Statistical analysis centre: INSERM U943 (S. Abgrall, D. Costagliola, S. Grabar, M. Guiguet, E. Lanoy, L. Lièvre, M. Mary-Krause, H. Selinger-Leneman), INSERM Transfert (J. M. Lacombe, V. Potard). COREVIH: Paris area: Corevih Ile de France Centre (GH Pitié-Salpétrière: F. Bricaire, S. Herson, C. Katlama, A. Simon; Hôpital Saint-Antoine: N. Desplanque, P. M. Girard, J. L. Meynard, M. C. Meyohas, O. Picard; Hôpital Tenon: J. Cadranel, C. Mayaud, G. Pialoux), Corevih Ile de France Est (Hôpital Saint-Louis: J. P. Clauvel, J. M. Decazes, L. Gerard, J. M. Molina; GH Lariboisière-Fernand Widal: M. Diemer, P. Sellier; Hôpital Avicenne: M. Bentata, P. Honoré; Hôpital Jean Verdier: V. Jeantils, S. Tassi; Hôpital Delafontaine: D. Mechali, B. Taverne), Corevih Ile de France Nord (Hôpital Bichat-Claude Bernard: E. Bouvet, B. Crickx, J. L. Ecobichon, S. Matheron, C. Picard-Dahan, P. Yeni), Corevih Ile de France Ouest (Hôpital Ambroise Paré: H. Berthé, C. Dupont; Hôpital Louis Mourier: C. Chandemerle, E. Mortier; Hôpital Raymond Poincaré: P. de Truchis), Corevih Ile de France Sud (Hôpital Européen Georges Pompidou: D. Tisne-Dessus, L. Weiss; GH Tarnier-Cochin: D. Salmon; Hôpital Saint-Joseph: I. Auperin, J. Gilquin; Hôpital Necker adultes: L. Roudière, J. P. Viard; Hôpital Antoine Béclère: F. Boué, R. Fior; Hôpital de Bicêtre: J. F. Delfraissy, C. Goujard; Hôpital Henri Mondor: C. Jung, Ph. Lesprit; Hôpital Paul Brousse: D. Vittecoq). Outside Paris area: Corevih Alsace (CHRU de Strasbourg: P. Fraisse, J. M. Lang, D. Rey; CH de Mulhouse: G. Beck-Wirth), Corevih de l Arc Alpin (CHU de Grenoble: J. P. Stahl, P. Lecercq), Corevih Auvergne-Loire (CHU de Clermont-Ferrand: F. Gourdon, H. Laurichesse; CHRU de Saint-Etienne: A. Fresard, F. Lucht); Corevih Basse-Normandie (CHRU de Caen: C. Bazin, R. Verdon), Corevih Bourgogne (CHRU de Dijon: P. Chavanet), Corevih Bretagne (CHU de Rennes: C. Arvieux, C. Michelet), Corevih Centre (CHRU de Tours: P. Choutet, A. Goudeau, M. F. Maître), Corevih Franche-Comté (CHRU de Besançon: B. Hoen; CH de Belfort: P. Eglinger, J. P. Faller); Corevih Haute-Normandie (CHRU de Rouen: F. Borsa-Lebas, F. Caron), Corevih Languedoc-Roussillon (CHU de Montpellier: J. Reynes; CHG de Nîmes: J. P. Daures), Corevih Lorraine (Nancy Hôpital de Brabois: T. May, C. Rabaud; CHRU de Reims: J. L. Berger, G. Rémy), Corevih de Midi- Pyrénées (Toulouse CHU Purpan: E. Arlet-Suau, L. Cuzin, P. Massip, M. F. Thiercelin Legrand; Toulouse Hôpital la Grave: G. Pontonnier; Toulouse CHU Rangueil), Corevih Nord-Pas de Calais (CH de Tourcoing: N. Viget, Y. Yasdanpanah), Corevih PACA Est (Nice Hôpital Archet 1: P. Dellamonica, C. Pradier, P. Pugliese; CHG Antibes-Juan les Pins: K. Aleksandrowicz, D. Quinsat), Corevih PACA Ouest (Marseille Hôpital de la Conception: I. Ravaux, H. Tissot-Dupont; Marseille Hôpital Nord: J. P. Delmont, J. Moreau; Marseille Institut Paoli Calmettes: J. A. Gastaut; Marseille Hôpital Sainte-Marguerite: I. Poizot-Martin, F. Retornaz, J. Soubeyrand; Marseille Centre pénitentiaire des Baumettes: A. Galinier, J. M. Ruiz; CHG d Aix-En-Provence: T. Allegre, P. A. Blanc; CH d Arles: D. Bonnet-Montchardon; CH d Avignon: G. Lepeu; CH de Digne Les Bains: P. Granet-Brunello; CH de Gap: J. P. Esterni, L. Pelissier; CH de Martigues: R. Cohen-Valensi, M. Nezri; CHI de Toulon: S. Chadapaud, A. Laffeuillade), Corevih Pays de la Loire (CHRU de Nantes: E. Billaud, F. Raffi), Corevih de la Vallée durhône (Lyon Hôpital de la Croix-Rousse: A. Boibieux, D. Peyramond; Lyon Hôpital Edouard Herriot: J. M. Livrozet, J. L. Touraine; Lyon Hôtel-Dieu: L. Cotte, C. Trepo). 143

7 Kousignian et al. Overseas: Corevih Guadeloupe (CHRU de Pointe-à-Pitre: M. Strobel; CH Saint-Martin: F. Bissuel), Corevih Guyane (CHG de Cayenne: R. Pradinaud, M. Sobesky), Corevih Martinique (CHRU de Fort-de-France: A. Cabié), Corevih de La Réunion (CHD Félix Guyon: C. Gaud, M. Contant). Funding Data have been generated as part of the analyses conducted on the ANRS CO4-FHDH, which is supported by Agence Nationale de la Recherche sur le SIDA (ANRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour la recherche médicale and the French Ministry of Health. Transparency declarations D. C. has received consultancy fees, grant support and support for conference attendance from pharmaceutical companies including Glaxo- SmithKline, Roche, Abbott, Gilead, Tibotec and Boehringer Ingelheim. Other authors: none to declare. References 1 Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: Murphy EL, Collier AC, Kalish LA et al. Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med 2001; 135: Deeks SG. Determinants of virological response to antiretroviral therapy: implications for long-term strategies. Clin Infect Dis 2000; 30 Suppl 2: S Rousseau MN, Vergne L, Montes B et al. Patterns of resistance mutations to antiretroviral drugs in extensively treated HIV-1-infected patients with failure of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 26: Erratum in: J Acquir Immune Defic Syndr 2001; 26: Race E, Dam E, Obry V et al. Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS 1999; 13: Van Vaerenbergh K, Van Laethem K, Albert J et al. Prevalence and characteristics of multinucleoside-resistant human immunodeficiency virus type 1 among European patients receiving combinations of nucleoside analogues. Antimicrob Agents Chemother 2000; 44: Yeni PG, Hammer SM, Carpenter CC et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2004; 292: Department of Health and Human Services. FDA Approves Fuzeon. 13 March Available at: ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm htm (October 2003, date last accessed). 9 Wild C, Greenwell T, Matthews T. A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res Hum Retroviruses 1993; 9: Cohen CJ, Dusek A, Green J et al. Long-term treatment with subcutaneous T-20, a fusion inhibitor, in HIV-infected patients: patient satisfaction and impact on activities of daily living. AIDS Patient Care STDS 2002; 16: Kilby JM, Lalezari JP, Eron JJ et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 2002; 18: Lalezari JP, Eron JJ, Carlson M et al. A phase II clinical study of the longterm safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 2003; 17: Lazzarin A, Clotet B, Cooper D et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: Wheeler DA, Lalezari J, Kilby M et al. Safety, tolerability and plasma pharmacokinetics of high-strength formulations of enfuvirtide (T-20) in treatment experienced HIV-1-infected patients. J Clin Virol 2004; 30: Lalezari JP, Henry K, O Hearn M et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348: Nelson M, Arastéh K, ClotetBet al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 2005; 40: Trottier B, Walmsley S, Reynes J et al. Safety of enfuvirtide in combination with an optimized background. J Acquir Immune Defic Syndr 2005; 40: French Hospital Database on HIV (FHDH). Available online at: (July 2007, date last accessed). 19 Tassie JM, Gasnault J, Bentata M et al. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV. AIDS 1999; 13: Centers for Disease Control and Prevention revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41: WHO. Manuel de la Classification Statistique Internationale des Maladies et des Problèmes de Santé Connexes, 10th révision. Geneva, Switzerland: WHO, Barry P, Zetola N, Keruly JC et al. Invasive pneumococcal disease in a cohort of HIV-infected adults: incidence and risk factors, AIDS 2006; 20: Kohli R, Lo Y, Homel P et al. Bacterial pneumonia, HIV therapy, and disease progression among HIV-infected women in the HIV Epidemiologic Research (HER) study. Clin Infect Dis 2006; 43: Sogaard OS, Lohse N, Gerstoft J et al. Hospitalization for pneumonia among individuals with and without HIV infection, : a Danish population-based, nationwide cohort study. Clin Infect Dis 2008; 47: Breslow NE, Day NE. Statistical Methods in Cancer Research: Volume II: The Design and Analysis of Cohort Studies. IARC Scientific Publications No. 82. Lyon, France: IARC, 1987; chapter 7, page Yéni P et le groupe d experts sur l infection par le VIH. Suivi de l adulte infecté par le VIH. In: Prise en Charge Médicale des Personnes Infectées par le VIH. Rapport Paris, France: Flammarion Médecine-Sciences, 2006; Le Moing V, Rabaud C, Journot V et al. Incidence and risk factors of bacterial pneumonia requiring hospitalization in HIV-infected patients started on a protease inhibitor-containing regimen. HIV Med 2006; 7: Sullivan JH, Moore RD, Keruly JC et al. Effect of antiretroviral therapy on the incidence of bacterial pneumonia in patients with advanced HIV infection. Am J Crit Care Med 2000; 162: