Time to initiation of antiretroviral therapy in HIV-infected patients diagnosed with an opportunistic disease: a cohort study

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1 DOI: /hiv ORIGINAL RESEARCH Time to initiation of antiretroviral therapy in HIV-infected patients diagnosed with an opportunistic disease: a cohort study L Deconinck, 1,2,5 Y Yazdanpanah, 2,3 RJ Gilson, 1,4, H Melliez, 5 N Viget, 5 V Joly 3 and CA Sabin 1 1 UCL Research Department of Infection and Population Health, University College London, London, UK, 2 Decision Sciences in Infectious Disease: Prevention, Control, and Care, IAME, UMR 1137, Paris Diderot University, Sorbonne Paris Cité, Paris, France, 3 Department of Infectious Diseases, Bichat-Claude Bernard Hospital, Paris, France, 4 The Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK and 5 Department of Infectious Diseases, Lille School of Medicine, Tourcoing Hospital, Tourcoing, France Objectives The aim of the study was to identify factors associated with the time between opportunistic disease (OD) diagnosis and antiretroviral therapy (ART) initiation in HIV-infected patients presenting for care with an OD, and to evaluate the outcomes associated with any delay. Methods A multicentre cohort study was undertaken in London, Paris and Lille/Tourcoing. The medical records of patients diagnosed from 2002 to 2012 were reviewed. Results A total of 437 patients were enrolled in the study: 70% were male, the median age was 40 years, 42% were from sub-saharan Africa, 68% were heterosexual, the median CD4 count was 40 cells/μl, and the most common ODs were Pneumocystis pneumonia (37%), tuberculosis (24%), toxoplasmosis (12%) and Kaposi s sarcoma (11%). Of these patients, 400 (92%) started ART within 24 weeks after HIV diagnosis, with a median time from OD diagnosis to ART initiation of 30 [interquartile range (IQR) 16 58] days. Patients diagnosed between 2009 and 2012 had a shorter time to ART initiation than those diagnosed in earlier years [hazard ratio (HR) 2.07; 95% confidence interval (CI) ]. Factors associated with a longer time to ART initiation were a CD4 count 200 cells/μl (HR 0.30; 95% CI ), tuberculosis (HR 0.40; 95% CI ) and diagnosis in London (HR 0.62; 95% CI ). Patients initiating deferred ART (by 30 days) exhibited no difference in disease progression or immunovirological response compared with patients who had shorter times to ART initiation. Patients in the deferred group were less likely to have ART modifications (HR 0.69; 95% CI ) and had shorter in-patient stays (mean 14.2 days shorter; 95% CI days) than patients in the group whose ART was not deferred. Conclusions The time between OD diagnosis and ART initiation remains heterogeneous and relatively long, particularly in individuals with a high CD4 count or tuberculosis or those diagnosed in London. Deferring ART was associated with fewer ART modifications and shorter in-patient stays. Keywords: AIDS-related opportunistic infections, antiretroviral therapy, HIV, time to treatment Accepted 13 August 2014 Correspondence: Dr Laurène Deconinck, U 738 ATIP/Avenir Inserm Team, Université Paris 7, Faculté de Médecine Site Bichat, 16 rue Henri Huchard, Paris, France. Tel: (33) ; fax: (33) ; laurene.deconinck@yahoo.fr 219

2 220 L Deconinck et al. Introduction Across Europe, approximately 30% of HIV-infected patients present for care with advanced HIV disease [1,2]. These patients have a poor prognosis with a higher mortality, more AIDS- and non-aids-related events, a weaker immune response to antiretroviral therapy (ART), and more ART-related adverse events than those diagnosed earlier [3,4]. A crucial issue is the optimal time to initiate ART in HIV-infected patients diagnosed with an opportunistic disease (OD). ART is often delayed in these patients in order to prevent drug interactions, drug intolerance as a result of overlapping toxicities and the occurrence of immune reconstitution inflammatory syndrome (IRIS) [5]. Nevertheless, recent trials have provided evidence to support the earlier introduction of ART in patients with an OD [6 9]. Thus, guidelines now advise that ART should be started at an early stage among individuals with ODs, with the exception of cryptococcosis and tuberculous meningitis [10,11]. As early is not clearly defined, however, medical practices remain heterogeneous. The main objective of this study was to identify factors associated with the time between OD diagnosis and ART initiation in HIV-infected patients presenting for care with an OD. A secondary objective was to determine the outcomes associated with the time to ART initiation in terms of immunovirological response, disease progression (mortality and AIDS and non-aids progression), ART modifications and in-patient stays. Methods Study design and setting A multicentre cohort study was undertaken in three HIV reference centres in France and the UK: Bichat-Claude Bernard University Hospital in Paris; Dron Regional Hospital in Tourcoing; and the Mortimer Market Centre (MMC) in London. The study targeted all patients who entered care with an OD at the time of HIV diagnosis from 2002 to Participants Eligible participants were aged > 18 years; had been diagnosed with HIV-1 infection at one of the participating centres between 1 June 2002 and 31 May 2012; and had a diagnosis of a stage C AIDS-defining event [12] within 45 days of HIV diagnosis. As this was a study of service delivery and all data were pseudonymized, ethics committee approval was not required. In the French centres, the patients were selected from the medical database Nadis [13] using the International Classification of Diseases, 10th revision (ICD-10) coding system. At the MMC, patients were selected through data submitted to the UK Collaborative HIV Cohort Study [14]. These databases contain routinely collected information on all HIV-positive individuals who have attended any of the collaborating centres in France and the UK. Data collection took place from December 2012 to March 2013 and was performed by the same investigator in all centres. A standardized questionnaire was used to review the patient s electronic medical record and when necessary nonelectronic records. For the analysis, follow-up of patients started on the date of HIV diagnosis and ended at ART initiation. Follow-up of patients who did not start ART was censored at 24 weeks after HIV diagnosis. The patients who started ART within 24 weeks after HIV diagnosis were then followed until 24 weeks after ART initiation. Patient follow-up was censored at death, or at date of last visit for those lost to follow-up (LFU). Statistical analysis Kaplan Meier analysis was performed to determine the median time between OD diagnosis and ART initiation. When several ODs occurred in a single patient, only the first OD diagnosed was considered in this analysis. When ART was introduced before OD diagnosis, the time between ART and OD diagnosis was set to 0 days. Factors associated with the time between OD diagnosis and ART initiation were first identified using an unadjusted Cox proportional hazards regression model. In order to create mutually exclusive groups for the initial OD in patients who presented with multiple ODs, the primary OD was defined for each patient as the one that was the most likely to lead to a deferral of ART initiation [by decreasing order of likelihood: tuberculosis (TB), toxoplasmosis, Pneumocystis pneumonia (PCP), Kaposi s sarcoma (KS) and other OD]. Any variables that remained associated with the time to ART (P < 0.2) after adjustment for the type of OD were considered for inclusion in the fully adjusted Cox model, with the final covariates selected using a backwards stepwise approach (P < 0.05). Patients who started ART were then classified into one of two groups: immediate initiation of ART (< 30 days after OD diagnosis) or deferred initiation of ART ( 30 days after OD diagnosis). The threshold of 30 days was used to permit comparisons with other published studies. Logistic regression was performed to evaluate the impact of the time to ART on the odds of having an undetectable ( 50 HIV-1 RNA copies/ml) viral load at 24 weeks after ART initiation. Linear regression was performed to evaluate the

3 Determinants and impact of time to ART 221 impact of the time to ART on the CD4 count increase seen between ART initiation and 24 weeks after ART initiation and on the total duration of any in-patient stays within the first 24 weeks after ART initiation. Cox models were used to evaluate the impact on: time to death, time to a new AIDS event, time to IRIS (according to the Shelburne et al. definition [15]), time to a non-aids-related event (cardiovascular, renal, hepatic or non-hiv-related cancer) or serious biological adverse events (grade 3 or 4 [16]), time to any clinical event (death, AIDS-related event/iris or non- AIDS-related/adverse event), and time to ART modification, where these occurred within the first 24 weeks after ART initiation. In order to avoid misclassifying any preexisting conditions diagnosed after ART initiation as new events, we only considered events that were diagnosed more than 45 days after HIV diagnosis. Sensitivity analysis was performed taking into account all events diagnosed after ART initiation regardless of their time after HIV diagnosis. Potential confounders were defined as factors that (1) had previously been identified as significantly associated with the time to ART in our study (P < 0.05 in the multivariable model) and (2) were associated with the outcome considered in the univariate analysis (P < 0.2). Multivariable analyses were developed using a backwards stepwise approach to select the final covariates for each model (P < 0.05). All analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, NC). Results Participants Overall, 651 patients were screened, of whom 437 were included in the cohort (Fig. 1): 206 (47.1%) from Bichat, 132 (30.2%) from MMC and 99 (22.7%) from Tourcoing. Of these, 11 patients (2.5%) died and four patients (0.9%) were LFU before ART initiation. Baseline characteristics Patient characteristics at the time of HIV diagnosis are presented in Table 1, both overall and stratified by centre. The patients were mainly male (307; 70.3%), with a median age of 40 years [interquartile range (IQR) years]. 651 patients screened 119 note consultations 214 patients excluded : 81 no stage C disease 59 initial care elsewhere a 24 time between HIV and OD diagnosis >45 days 28 HIV previously diagnosed 12 OD after HIV diagnosis b 4 age <18 years 6 no information available 437 patients included 11 dead pre-art 4 lost to follow-up pre-art 422 patients at 24 weeks after HIV diagnosis 22 not starting ART 400 starting ART 11 dead 13 lost to follow-up 376 patients at 24 weeks after ART initiation Fig. 1 Flow diagram of patients enrolled in the cohort. a First consultation/in-patient stay not at Bichat, Tourcoing, Mortimer Market Centre or University College Hospital. b No opportunistic disease symptoms at the time of HIV diagnosis. ART, antiretroviral therapy; OD, opportunistic disease.

4 222 L Deconinck et al. Table 1 Baseline sociodemographic, clinical and biological characteristics of patients, overall and stratified by centre Centre Total Bichat MMC Tourcoing Number (% of total cohort) 437 (100) 206 (47.1) 132 (30.2) 99 (22.7) Sociodemographic characteristics Male sex [n (%)] 307 (70.3) 136 (66.0) 96 (72.7) 75 (75.8) Age (years) [median (IQR)] 40 (34 48) 40 (33 51) 39 (34 45) 42 (36 48) Country of origin [n (%)] Sub-Saharan Africa 183 (41.9) 112 (54.4) 49 (37.1) 22 (22.2) France and the UK 166 (38.0) 39 (18.9) 56 (42.4) 71 (71.7) Other country of origin 87 (19.9) 54 (26.2) 27 (20.5) 6 (6.1) Unknown 1 (0.2) 1 (0.5) 0 (0.0) 0 (0.0) Risk group [n (%)] Heterosexual 297 (68.0) 168 (81.6) 70 (53.0) 59 (59.6) MSM/bisexual 126 (28.8) 34 (16.5) 60 (45.5) 32 (32.3) Other risk group* 8 (1.8) 4 (1.9) 2 (1.5) 2 (2.0) Unknown 6 (1.4) 0 (0.0) 0 (0.0) 6 (6.1) Year of first access to care [n (%)] (41.4) 89 (43.2) 59 (44.7) 33 (33.3) (30.0) 62 (30.1) 46 (34.8) 23 (23.2) (28.6) 55 (26.7) 27 (20.5) 43 (43.5) Initial in-patient stay [n (%)] (n = 435) 355 (81.2) 176 (85.4) 102 (77.3) 77 (77.8) Initial ICU stay [n (%)] (n = 435) 79 (18.1) 53 (25.7) 9 (6.8) 17 (17.2) Comorbidities HBV coinfection (HBsAg) [n (%)] (n = 434) 25 (5.7) 16 (7.8) 8 (6.1) 1 (1.0) HCV coinfection (HCV antibodies) [n (%)] (n = 431) 8 (1.8) 5 (2.4) 3 (2.3) 0 (0.0) Clinical and biological characteristics at diagnosis CD4 T-cell count (cells/μl) [median (IQR)] (n = 436) 40 (12 111) 30 (11 97) 50 (20 130) 39 (11 100) < 50 cells/μl [n (%)] 244 (55.8) 127 (61.7) 61 (46.2) 56 (56.6) cells/μl [n (%)] 142 (32.5) 54 (26.2) 52 (39.4) 36 (36.4) cells/μl [n (%)] 35 (8.0) 17 (8.3) 12 (9.1) 6 (6.1) 350 cells/μl [n (%)] 15 (3.4) 7 (3.4) 7 (5.3) 1 (1.0) HIV RNA (log 10 copies/ml) [median (IQR)] (n = 433) 5.4 ( ) 5.5 ( ) 5.3 ( ) 5.5 ( ) > 5 log 10 copies/ml [n (%)] 305 (69.8) 150 (72.8) 81 (61.4) 74 (74.7) Number of ODs per patient [n (%)] (78.3) 171 (83.0) 111 (84.1) 60 (60.6) 2 70 (16.0) 25 (12.1) 17 (12.9) 28 (28.3) 3 25 (5.7) 10 (4.9) 4 (3.0) 11 (11.1) OD at diagnosis [n (%)] PCP 161 (36.8) 57 (27.7) 64 (48.5) 40 (40.4) Tuberculosis 107 (24.5) 70 (34.0) 18 (13.6) 19 (19.2) Toxoplasmosis 52 (11.9) 35 (17.0) 4 (3.0) 13 (13.1) Kaposi s sarcoma 48 (11.0) 14 (6.8) 25 (18.9) 9 (9.1) Candidiasis 42 (9.6) 15 (7.3) 10 (7.6) 17 (17.2) HIV encephalopathy/wasting syndrome 39 (8.9) 11 (5.3) 9 (6.8) 19 (19.2) CMV infection 33 (7.6) 17 (8.3) 4 (3.0) 12 (12.1) Cryptococcosis 24 (5.5) 14 (6.8) 6 (4.5) 4 (4.0) Other OD 54 (12.4) 20 (9.7) 17 (12.9) 17 (17.2) Time from OD to HIV diagnosis (days) [median (IQR)] 1 ( 7 0) 2 ( 8 0) 0 ( 5 2) 3 ( 12 0) CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAg, HBV surface antigen; IQR, interquartile range; MMC, Mortimer Market Centre; MSM, men who have sex with men; ICU, intensive care unit; OD, opportunistic disease; PCP, Pneumocystis pneumonia. *Injecting drug use, five (1.1%); blood products, two (0.5%); mother-to-child transmission, one (0.2%). Three individuals had four ODs (0.7%). Lymphoma, 15 (3.4%); cryptosporidiosis, 13 (3%); herpes simplex virus infections, six (1.4%); histoplasmosis, six (1.4%); progressive multifocal leukoencephalopathy, five (1.1%); mycobacteriosis, four (0.9%); isosporiasis, three (0.7%); recurrent Salmonella septicaemia, one (0.2%); invasive cervical cancer, one (0.2%). They were mostly from sub-saharan Africa (183; 41.9%), France (110; 25.2%) and the UK (56; 12.8%). The main routes of HIV acquisition were heterosexual transmission (297; 68%) and homo/bisexual transmission (126; 28.8%). The median CD4 count at HIV diagnosis was 40 cells/μl (IQR cells/μl); the median HIV viral load was 5.4 log 10 copies/ml (IQR log 10 copies/ml). The proportion of patients hospitalized at the time of diagnosis did not differ significantly between MMC and the French hospitals (77.9% versus 83.2%, respectively; P = 0.22), but the dura-

5 Determinants and impact of time to ART 223 tion of the first hospitalization was significantly shorter at MMC than in the French hospitals median 15 (IQR 11 25) versus 27 (19 42) days, respectively; P < 0.01). Three hundred and forty-two patients (78.3%) presented with a single OD, and 95 (21.7%) presented with multiple ODs. The first OD was diagnosed at a median of 1 day (IQR 0 7 days) after HIV diagnosis. The most frequent ODs at presentation were PCP (161; 36.8%), TB (107; 24.5%), cerebral toxoplasmosis (52; 11.9%), and KS (48; 11%). Time to ART initiation Overall, 400 patients (91.5%) started ART within 24 weeks after HIV diagnosis. The median time between OD diagnosis and ART initiation was 30 days (IQR days). ART was introduced before OD diagnosis in 16 patients, who presented mainly with TB (six cases) and lymphoma (four cases). The proportion of individuals starting ART while an in-patient was significantly higher in the French hospitals than in MMC (47.7% versus 16.8%, respectively; p < 0.01). Two hundred and sixty-three patients (65.8%) started ART while still receiving OD treatment, 789 patients (22.3%) started ART after all OD treatments were completed, and 40 patients (10%) did not receive any OD treatment (20 with HIV encephalopathy/wasting syndrome, 16 with KS, three with progressive multifocal leucoencephalopathy, and one with isosporiasis). The first ART regimen was protease inhibitor (PI)-based in 268 cases (67%), nonnucleoside reverse transcriptase inhibitor (NNRTI)-based in 113 cases (28.3%), and other regimens [nucleoside reverse transcriptase inhibitor (NRTI)-based, PI monotherapy or raltegravir] in 18 cases (4.5%) (one was unknown), with similar distributions over time. Twenty-two patients did not start ART within 24 weeks after HIV diagnosis (14 with TB, three with oesophageal candidiasis, two with PCP, one with mycobacteriosis, one with toxoplasmosis, and one with TB and HIV encephalopathy). Determinants of time to ART initiation In the fully adjusted multivariable analysis (Table 2), factors remaining significantly associated with a longer time to ART initiation (p < 0.05) were a CD4 count 200 cells/μl versus cells/μl [median 98 versus 26 days, respectively; hazard ratio (HR) 0.30; 95% confidence interval (CI) ], a diagnosis of TB versus PCP (median 64 versus 26 days, respectively; HR 0.40; 95% CI ) and diagnosis at MMC versus Bichat (median 39 versus 31 days, respectively; HR 0.62; 95% CI ). Those diagnosed in versus had a significantly shorter time to ART initiation (median 18 versus 39 days, respectively; HR 2.07; 95% CI ). There was a trend towards a shorter time to ART initiation in patients with KS versus PCP (median 31 versus 26 days, respectively; HR 1.41; 95% CI ), and towards a longer time to ART initiation in those with toxoplasmosis versus PCP (median 32 versus 26 days, respectively; HR 0.71; 95% CI ) (Kaplan Meier plots of the univariate analyses are shown in Supporting information Fig. S1). Impact of time to ART initiation The main outcomes within 24 weeks after ART initiation are described in Table 3, overall and stratified by time to ART initiation (baseline characteristics of both groups are reported in Supporting information Table S1). Among the 400 patients who started ART, 207 (51.7%) started < 30 days after OD diagnosis, while 193 (48.3%) started 30 days after OD diagnosis. The median time from OD diagnosis to ART initiation was 15 days (IQR 7 21 days) in the immediate group and 52 days (IQR days) in the deferred group. Patients in the immediate group were more likely than those in the deferred group to have a period of overlap between the OD treatment and ART (73.9% versus 57%, respectively; p < 0.01), and to start ART as in-patients (66.2% versus 15.6%, respectively; p < 0.01). The CD4 count at ART initiation was higher in the deferred group than in the immediate group (median 42 versus 31 cells/μl, respectively; p < 0.01). Patients in the immediate group were more likely than those in the deferred group to start a PI-based regimen (74.4% versus 59.1%, respectively), whereas patients in the deferred group more often started an NNRTI-based regimen than those in the immediate group (36.8% versus 20.3%, respectively) (p < 0.01). Among these 400 patients, 13 (3.3%) were LFU. Of the remaining patients, 240 (60%) had an undetectable HIV viral load at 24 weeks and the median CD4 count increase since ART initiation was 130 cells/μl (IQR cells/ μl). Eleven patients (2.8%) died, with eight deaths (2%) occurring more than 45 days after HIV diagnosis. Seventysix patients (19%) experienced a new AIDS-related event, with 55 (13.8%) of these events occurring more than 45 days after HIV diagnosis; 33 (8.3%) of these events were secondary to IRIS, 19 (4.8%) of which occurred more than 45 days after HIV diagnosis. Eighty-five patients (21.3%) experienced a non-aids-related or adverse event, with 63 events (15.8%) occurring more than 45 days after HIV diagnosis. These events were mostly haematological (36 cases), including 22 cases of neutropenia. Overall, 142 patients (35.5%) experienced any clinical event, with 105 events (26.3%) occurring more than 45 days after HIV diagnosis. In addition, 126 patients (31.5%) required a

6 224 L Deconinck et al. Table 2 Results from unadjusted and adjusted Cox regression analyses of the factors associated with the time to initiation of antiretroviral therapy (ART) following opportunistic disease (OD) diagnosis Time between OD diagnosis and ART initiation (n = 437) Median (IQR) Unadjusted Adjusted HR (95% CI) P HR (95% CI) P Sociodemographic characteristics Sex Male 29 (14 52) 1 Female 36 (20 79) 0.73 ( ) <0.01 Age < 30 years 33 (20 67) 0.87 ( ) years 30 (14 56) 1 50 years 32 (17 57) 1.03 ( ) 0.81 Place of birth France/UK 26 (14 43) 1 Sub-Saharan Africa 33 (17 79) 0.61 ( ) <0.01 Other place of birth 34 (17 64) 0.63 ( ) <0.01 Risk group MSM/bisexual 30 (16 50) 1 Heterosexual 31 (16 64) 0.78 ( ) 0.03 Other risk group 18 (13-/) 0.95 ( ) 0.91 Year of first access to care (11 33) 1.78 ( ) < ( ) < (23 61) (17 70) 0.97 ( ) ( ) 0.08 Centre Bichat 31 (17 56) 1 1 MMC 39 (21 74) 0.84 ( ) ( ) <0.01 Tourcoing 21 (10 39) 1.38 ( ) ( ) 0.78 Initial in-patient stay No 31 (15 59) 1 Yes 30 (16 57) 1.03 ( ) 0.83 Initial ICU stay No 31 (15 61) 1 Yes 26 (17 47) 1.35 ( ) 0.02 Comorbidities HBV coinfection No 30 (15 57) 1 Yes 30 (17 57) 1.06 ( ) 0.78 HCV coinfection No 30 (16 57) 1 Yes 17 (8 90) 1.08 ( ) 0.83 Clinical and biological characteristics CD4 T-cell count < 50 cells/μl 28 (15 48) 1.10 ( ) ( ) cells/μl 26 (13 52) cells/μl 98 (52-/) 0.30 ( ) < ( ) <0.01 HIV RNA 5 log 10 copies/ml 38 (14 90) 1 > 5 log 10 copies/ml 30 (16 52) 1.51 ( ) <0.01 Number of ODs 1 32 (15 60) 1 > 1 25 (16 48) 1.26 ( ) 0.06 Type of OD PCP 26 (17 48) 1 1 Tuberculosis 64 (26 109) 0.41 ( ) < ( ) <0.01 Kaposi s sarcoma 31 (6 40) 1.18 ( ) ( ) 0.08 Toxoplasmosis 32 (19 56) 0.79 ( ) ( ) 0.05 Other OD 20 (6 43) 0.98 ( ) ( ) 0.77 IQR, interquartile range; HBV, hepatitis B virus; HCV, hepatitis C virus; OD, opportunistic disease; HR, hazard ratio; CI, confidence interval; MSM, men who have sex with men; MMC, Mortimer Market Centre; ICU, intensive care unit; PCP, Pneumocystis pneumonia.

7 Determinants and impact of time to ART 225 Table 3 Outcomes at 24 weeks after antiretroviral therapy (ART) initiation, overall and stratified by time from opportunistic disease (OD) diagnosis to ART initiation Time from OD diagnosis to ART initiation Total (n = 400) Immediate group <30 days (n =207) Deferred group 30 days (n = 193) P Immunovirological response CD4 count (cells/μl) [median (IQR)] (n = 376) 188 ( ) 178 ( ) 197 ( ) 0.02 CD4 increase (cells/μl) [median (IQR)] (n = 375) 130 (75 196) 131 (72 193) 129 (79 203) 0.63 HIV RNA undetectable ( 50 copies/ml) [n (%)] (n = 375) 240 (60.0) 124 (59.9) 116 (60.1) 0.75 Death [n (%)] (n = 387) 8 (2.0) 4 (1.9) 4 (2.1) 1.00 New AIDS-related event [n (%)] (n = 388) 55 (13.8) 25 (12.1) 30 (15.5) 0.38 Type of new AIDS-related event [n (%)] (n = 62) Tuberculosis 13 (21.0) 5 (17.9) 8 (23.6) CMV infection 10 (16.1) 6 (21.4) 4 (11.8) Kaposi s sarcoma 8 (12.9) 2 (7.1) 6 (17.6) Toxoplasmosis 7 (11.3) 1 (3.6) 6 (17.6) Other OD* 24 (38.7) 14 (50.0) 10 (29.4) IRIS [n (%)] (n = 388) 19 (4.8) 7 (3.4) 12 (3.1) 0.24 Paradoxical IRIS [n (%)] 15 (78.9) 4 (57.1) 11 (91.7) Unmasking IRIS [n (%)] 4 (21.1) 3 (42.9) 1 (8.3) Non-AIDS-related event [n (%)] (n = 387) 63 (15.8) 31 (15.0) 32 (16.6) 0.78 Type of non-aids-related event [n (%)] (n = 80) Haematological 36 (45.0) 18 (41.9) 18 (48.7) Hepatic 18 (22.5) 11 (25.6) 7 (18.9) Renal 13 (16.3) 6 (14.0) 7 (18.9) Cardiovascular 9 (11.2) 4 (9.3) 5 (13.5) Neoplasia 2 (2.5) 2 (4.6) 0 (0.0) Pancreatic 2 (2.5) 2 (4.6) 0 (0.0) Any event (death, AIDS-related event or non-aids-related event) [n (%)] (n = 388) 105 (26.3) 51 (24.6) 54 (28.0) 0.57 ART modification [n (%)] (n = 387) 126 (31.5) 71 (34.3) 55 (28.5) 0.19 Reason for ART modification [n (%)] (n = 334) Adverse event 201 (60.1) 135 (61.9) 66 (56.9) Interaction 21 (6.3) 12 (5.5) 9 (7.8) Noncompliance 21 (6.3) 13 (6.0) 8 (6.9) Failure 20 (6.0) 10 (4.6) 10 (8.6) IRIS 15 (4.5) 7 (3.2) 8 (6.9) Simplification/end of treatment 14 (4.2) 12 (5.5) 2 (1.7) Other reason 27 (8.1) 24 (11.0) 3 (2.6) Missing 15 (4.5) 5 (2.3) 10 (8.6) New in-patient stay [n (%)] (n = 387) 143 (35.8) 92 (44.4) 51 (26.4) <0.01 Total duration (days) [median (IQR)] (n = 387) 7 (0 21) 14 (4 30) 0 (0 11) <0.01 Reason for in-patient stay [n (%)] (n = 193) Initial OD 50 (25.9) 43 (34.7) 7 (10.2) New AIDS-related event (including IRIS) 44 (22.8) 28 (22.6) 16 (23.2) Non-AIDS-related event (including adverse event) 33 (17.1) 16 (12.9) 17 (24.6) Other 66 (34.2) 37 (29.8) 29 (42.0) OD, opportunistic disease; ART, antiretroviral therapy; IQR, interquartile range; CMV, cytomegalovirus; PCP, Pneumocystis pneumonia; PML, progressive multifocal leukoencephalopathy; IRIS, immune reconstitution inflammatory syndrome. *Mycobacteriosis, four; recurrent bacterial pneumonia, three; cervix neoplasia, three; cryptococcosis disseminated, two; lymphoma, two; oesophageal candidiasis, two; herpes simplex virus infection, one; recurrent Salmonella septicaemia, one; cryptosporidiosis, one; HIV encephalopathy, one; isosporiasis, one; histoplasmosis, one; PCP, one; PML, one. ART modifications secondary to laboratory results including resistance genotype, impaired renal/hepatic function or any event not attribuitable to ART, clinician s decision or patient s request. modification of at least one drug of the first ART regimen, and 143 patients (35.8%) needed at least one new hospital admission, with a median in-patient stay of 7 days (IQR 0 21 days). In multivariable analyses (Table 4), there was no significant association between deferred or immediate initiation of ART and any of the immunovirological outcomes. No significant association was found between the time to ART initiation and progression to death, a new AIDSrelated event, IRIS, a non-aids-related/adverse event, or any clinical event. However, patients in the deferred group were less likely than those in the immediate group to require a new hospital admission (HR 0.50; 95% CI ), and

8 226 L Deconinck et al. Table 4 Association of deferred [ 30 days after opportunistic disease (OD) diagnosis] versus immediate (< 30 days after OD diagnosis) initiation of antiretroviral therapy (ART) with immunovirological response, disease progression, ART modifications and in-patient stays within 24 weeks after ART initiation Impact of deferred ( 30 days) versus immediate (< 30 days) initiation of ART (n = 400) On events > 45 days after HIV diagnosis On all events after HIV diagnosis Unadjusted Adjusted* Unadjusted Adjusted* Parameter P Parameter P Parameter P Parameter P Immunovirological response CD4 count increase from 5.2 ( ) ( ) 0.26 ART initiation (cells/μl) HIV RNA undetectable 0.92 ( ) ( ) 0.22 ( 50 copies/ml) Death 1.06 ( ) ( ) ( ) ( ) 0.24 New AIDS-related event 1.32 ( ) ( ) ( ) ( ) 0.13 IRIS 1.83 ( ) ( ) ( ) ( ) 0.03 Non-AIDS-related event 1.10 ( ) ( ) ( ) ( ) 0.03 Any event (death, AIDS-related event 1.18 ( ) ( ) ( ) < ( ) <0.01 or non-aids-related event) ART modification 0.76 ( ) ( ) 0.05 In-patient stay New in-patient stay 0.50 ( ) < ( ) <0.01 Number of in-patient stays 0.26 ( 0.42 to 0.10) < ( 0.41 to 0.09) <0.01 Total duration of in-patient stays (days) 12.8 ( 18.1 to 7.5) < ( 19.5 to 8.9) <0.01 IRIS, immune reconstitution inflammatory syndrome. *After adjustment for calendar period, centre, OD at baseline, and CD4 count. Odds ratio (95% confidence interval) for logistic regression models; hazard ratio (95% confidence interval) for Cox models; parameter (95% confidence interval) for linear regression models. experienced fewer new in-patient stays (mean 0.25 stays lower; 95% CI stays lower) and shorter in-patient stays (mean 14.2 days shorter; 95% CI days shorter) on average. They were also significantly less likely to have a modification of ART (HR 0.69; 95% CI ). When the impact of the time to ART initiation on all events after ART initiation (taking into account any events that occurred within the first 45 days after HIV diagnosis) was considered, significant associations were found between deferred initiation of ART and a lower risk of IRIS (HR 0.45; 95% CI ), of non-aids-related/ adverse events (HR 0.60; 95% CI ), and of progression to any clinical event (HR 0.63; 95% CI ). There was no significant impact on our findings regarding death or AIDS progression. Discussion Determinants of time to ART initiation In this study conducted in three clinical centres in France and the UK, the median time between OD diagnosis and ART initiation was 30 days; the factors found to be significantly associated with the time to ART initiation were the CD4 count, the type of OD, the centre and the period of care, results that are consistent with those previously reported in the literature [17]. Our finding of a shorter time to ART initiation in those diagnosed from 2009 onwards may be a consequence of the change in the guidelines concerning OD and HIV management, following in particular the results of the AIDS Clinical Trials Group (ACTG) A5164 study which were first presented at the Conference on Retroviruses and Opportunistic Infections in 2008 [6,18]. However, even in , the median time between OD diagnosis and ART initiation was 18 days; this delay remains longer than that recommended by both the French and British guidelines since 2008, which stipulate that ART is started within 2 weeks for most ODs [10,11,19]. The longer delay observed in MMC (UK) versus Bichat (France) may be explained by the fact that, at MMC, ART is usually introduced when individuals are out-patients and not while the patient is still hospitalized, the proportion of patients starting ART as in-patients being higher in the UK than in France. The delay may therefore be longer because of the time between discharge from the ward and the first appointment as an out-patient. NNRTI-based regimens were more often prescribed in patients starting ART later,

9 Determinants and impact of time to ART 227 probably because of the availability of the resistance test in this group and because this regimen is more commonly used in the UK. Concerning the association between a high CD4 count and a longer delay, this can be explained by the fact that the CD4 count is an important prognostic factor [20]. ART was started later in patients with TB, probably because guidelines for TB management advise to defer ART initiation in patients with meningitis or in those not too severely immunocompromised, and because of the risk of IRIS and the complexity of combining antituberculous drugs with antiretrovirals. Indeed, patients with mycobacterial infections were excluded from the ACTG A5164 study. Clinical trials focusing particularly on individuals with TB found a decrease in mortality and AIDS-related events when ART was started earlier in the case of severe immunosuppression, but these results are counterbalanced by an increased risk of IRIS and of severe adverse events, in particular in those with tuberculous meningitis [21 24]. As a result, guidelines for TB management have also changed towards an earlier initiation of ART, but in the most immunocompromised patients only, and otherwise still stipulate that ART should be deferred [10,19]. Thus, the time to ART initiation in patients with TB has also been reduced in recent years but remains longer than in patients with other ODs. The heterogeneity in the time to ART initiation in patients with other ODs reflects the lack of consensus concerning the best time to initiate ART in these patients and the evolution of guidelines over time. In our study, the time to ART initiation was longer in patients with toxoplasmosis, even though guidelines do not stipulate deferral of ART in this group. One possible explanation is that deferring ART is recommended in the case of central nervous system involvement for some ODs, such as TB or cryptococcosis, and clinicians may similarly prefer to defer ART in cerebral toxoplasmosis. ART is often introduced after several weeks of empirical treatment against toxoplasmosis when an improvement occurs. Patients with toxoplasmosis may also present with neurological disorders or with adverse events as a result of the OD treatment, both of which may lead to a deferral of ART initiation. Impact of time to ART initiation The significant association found between the time to ART initiation and ART modifications can be explained by the overlap period between the OD treatment and ART, which was more common in the immediate group. This overlap may have led to a greater number of drug drug interactions and adverse events caused by the cumulative toxicities of both treatments, two of the main reasons for changing ART. In addition, patients in the deferred group were less immunocompromised and may have experienced fewer adverse events as a result [25]. They also may have had more time to prepare to start ART and may have had better adherence to treatment. The shorter duration of in-patient stays after ART initiation in the deferred group may be attributable to the fact that these patients often started ART as out-patients. Patients in the deferred group may also have had a less severe disease, and they may have been less likely to require a further hospital admission. There was no significant impact of the time to ART initiation on the immunovirological response, a result that has already been described in previous studies [6,8]. The fact that we found no association between the time to ART initiation and mortality or AIDS progression is not consistent with the literature, in which a trend has been reported towards a better outcome when ART is started earlier [6,8,9]. Our result can be explained by reverse causality, as clinicians may start ART earlier in patients whom they estimate to be at high risk of dying or developing another OD. Insufficient power secondary to a low frequency and nonexhaustive collection of events might also be an issue. Finally, there was no impact of the time to ART initiation on non-aids-related/adverse events, IRIS or any clinical event in our main analysis. However, taking into account all events occurring after ART initiation, patients in the deferred group had a significantly lower risk of non- AIDS-related/adverse events, IRIS, and any event overall. A trend towards fewer adverse events and fewer cases of IRIS when ART was started later has already been reported in the literature, especially in patients with TB [21 24]. In our study, this result can be explained by the higher CD4 count at ART initiation in the deferred group. Furthermore, events occurring soon after HIV diagnosis were more probably related to pre-existing severe immunosuppression than to early ART initiation. Several limitations of our study should be acknowledged. Firstly, although all HIV-infected patients should have been registered in the databases, some patients who died soon in the intensive care unit (ICU) may have been missed. Exclusion of these patients may have had an impact on the association found between the time to ART initiation and disease progression, the number of events, especially the number of deaths, being relatively small. Secondly, the data collection was retrospective. Some events may therefore have been unreported in electronic medical records. In addition, events that happened before ART initiation have not been taken into account in the analyses. These events may have been more numerous in

10 228 L Deconinck et al. the deferred group, the time between OD diagnosis and ART initiation being longer, leading to an underestimation of disease progression in this group. Thirdly, we did not collect any data on disease severity. As our study was observational and not a randomized trial, disease severity may not have been the same in our two groups, patients in the deferred group probably having less advanced disease than those in the immediate group, as suggested by the different CD4 counts in these two groups. This difference may be an important bias, causing worse outcomes in the immediate group, even after adjustment for other markers of severity, such as the CD4 count or initial ICU stay. Nevertheless, results were unchanged in the subgroups of patients with and without TB or with CD4 counts < 200 and 200 cells/μl. It is also possible that some other unknown confounders remained. Finally, the patients in our study may not be representative of the total cohort of patients attending each centre. In conclusion, the median time between OD diagnosis and ART initiation in our study was 30 days. Factors associated with this time were the calendar period, the CD4 count at the time of HIV diagnosis, the OD and the centre. Although this delay has been reduced in recent years, it remains longer than recommended. However, deferral of ART was associated with fewer ART modifications and shorter in-patient stays, without any association with early immunovirological response or disease progression. Further data and randomized clinical trials focusing on ODs other than PCP, TB or cryptococcosis are needed to guide clinicians on when to initiate ART in patients with an OD and to make recommendations more precise. Acknowledgements We would like to thank all the data managers, clinical research technicians, secretaries, biostatisticians and clinicians, and particularly Phillipe Choisy in Tourcoing, Sylvie Le Gac in Paris, and Nataliya Brima in London for their assistance with patient selection and data collection. Conflict of interest: LD received a grant from Lille School of Medicine for this work. The remaining authors have no conflicts of interest to declare. References 1 Johnson M, Sabin C, Girardi E. Definition and epidemiology of late presentation in Europe. Antivir Ther 2010; 15 (Suppl 1): Adler A, Mounier-Jack S, Coker RJ. Late diagnosis of HIV in Europe: definitional and public health challenges. AIDS Care 2009; 21: Lanoy E, Mary-Krause M, Tattevin P et al. Frequency, determinants and consequences of delayed access to care for HIV infection in France. Antivir Ther 2007; 12: Moreno S, Mocroft A, d Arminio Monforte A. Medical and societal consequences of late presentation. Antivir Ther 2010; 15 (Suppl 1): Battegay M, Fehr J, Flückiger U, Elzi L. Antiretroviral therapy of late presenters with advanced HIV disease. J Antimicrob Chemother 2008; 62: Zolopa AR, Andersen J, Komarow L et al. Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial. PLoS ONE [Internet]. 2009; 4: e5575. Available at pmc/articles/pmc / (accessed 4 December 2014). 7 Grant PM, Komarow L, Andersen J et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS ONE 2010; 5: e Manzardo C, Esteve A, Ortega N et al. Optimal timing for initiation of highly active antiretroviral therapy in treatment-naïve human immunodeficiency virus-1-infected individuals presenting with AIDS-defining diseases: the experience of the PISCIS Cohort. Clin Microbiol Infect 2012; 19: Miro JM, Manzardo C, Mussini C et al. Survival outcomes and effect of early vs. deferred cart among HIV-infected patients diagnosed at the time of an AIDS-defining event: a cohort analysis. PLoS ONE 2011; 6: e Prise en charge médicale des personnes infectées par le VIH, recommandations du groupe d experts, rapport 2013, Available at (accessed 4 December 2014). 11 Nelson M, Dockrell D, Edwards S et al. British HIV Association and British Infection Association guidelines for the treatment of opportunistic infection in HIVseropositive individuals HIV Med 2011; 12 (Suppl 2): From the Centers for Disease Control and Prevention revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. JAMA 1993; 269: Pugliese P, Cuzin L, Enel P et al. [NADIS 2000, development of an electronic medical record for patients infected by HIV, HBV and HCV]. Presse Méd 2003; 32: The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study. HIV Med 2004; 5: Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81:

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