SECONDARY OBJECTIVES:

Transcription

1 Study No.: Title: Retrospective study using the NADIS database of the reasons for discontinuing the Abacavir-Lamivudine combination in HIV-infected patients treated by an antiretroviral regimen Rationale: More than 25 years after the detection of the first cases of AIDS in France and 10 years after the introduction of antiretroviral multi-therapies, the prevalence of HIV infection is estimated to be between 106,000 and 138,000 cases in France (possible range from 88,000 to 185,000) and is increasing by 3,500 cases per year [1,2]. All the available scientific studies on patient management by abacavir and lamivudine have concerned the immediate tolerability of the molecules and the risks of delayed hypersensitivity to abacavir. Few medium- and long-term data are available except for clinical trial results [3]. There is little information about the safety profile of patients receiving this treatment for several months or even several years. The study reported here is a retrospective analysis of the reasons for discontinuing medium- or long-term treatment with the abacavir-lamivudine combination by HIV-infected patients, using the medical files of a historical cohort of patients collected in the NADIS database. Phase: observational Study Period: 1 January 2004 to 31 May 2008 Study Design: This was a retrospective analysis of a historical cohort of HIV-infected patients followed-up using the NADIS database during the period from 1 January 2004 to 31 May Patient inclusion criteria were as follows: - HIV-1 infected patient aged 18 or over, - Abacavir-naive patient, - Patient initiating treatment by a fixed or free-dose abacavir-lamivudine combination for the first time between 1 January 2004 and 31 December 2007, within the framework of antiretroviral therapy and whatever the treatment line, Patient whose file is or was followed up using the NADIS database since initiation of treatment by the abacavir-lamivudine combination, whether or not the patient was still in the file active (list of patients seen at least once during the reference period) at the point date. Patients who had already received an antiretroviral regimen including abacavir for one week or more and patients for whom no information was recorded about the reason for discontinuing treatment by the fixed or free-dose abacavir-lamivudine combination were excluded from the study. Patients whose medical record had major inconsistencies (pre-treated patients with no viral load for less than 6 months and treatment-naive patients with an undetectable viral load) were also excluded. Centres: 7 centres were retained: Marseilles, Nantes, Nice, Lille, Paris (Pitié Salpêtrière/ Pasteur Necker), Toulouse and Fort de France. Indication: Treatment: Abacavir + lamivudine Objectives: PRIMARY OBJECTIVES: - To describe the reasons for discontinuing treatment with the abacavir-lamivudine combination by the retrospective study of HIV-infected patients receiving an antiretroviral regimen including this combination and followed-up in the NADIS database. SECONDARY OBJECTIVES: 1

2 - To describe, during time, discontinuations of the abacavir-lamivudine combination due to intolerance and/or virologic failure in these patients by the Kaplan Meier method. - To describe, during time, the clinical and laboratory events occurring in patients treated by antiretroviral therapy including the abacavir-lamivudine combination. - To evaluate the efficacy at 1, 3, 6 months and then every 6 months, of treatment by an antiretroviral regimen including the abacavir-lamivudine combination in terms of reduction in viral load and CD4 cell gain, according to the Yeni report guidelines. - To estimate the proportion of patients with a change of at least one severity score in their lipid, renal, hepatic and glycaemic laboratory parameters during treatment by an antiretroviral regimen including the abacavir and lamivudine combination. - To describe the resistance mutations acquired after virologic failure of an antiretroviral regimen including the abacavir-lamivudine combination. Primary Outcome : reasons for discontinuing treatment with the abacavir-lamivudine combination Secondary Outcome : cardiovascular clinical events and evolution in the immunologic/virologic parameters Statistical Methods: Descriptive statistical analyses Statistical analysis of the data was performed using SAS software (version 9.1, SAS Institute, North Carolina USA). The descriptive analysis of qualitative variables concerned the sample size and the incidence of each modality (percentage column except where otherwise mentioned). Analysis of quantitative variables comprised the mean, standard deviation, confidence intervals as well as the median and extreme values. For the immunologic-virologic values, the percentiles (P5, P25, P75, P95) were added. Survival analysis The probability of the occurrence of discontinuation of the abacavir + lamivudine combination was estimated by the Kaplan-Meier method [3]. The event of interest of this analysis was discontinuation of the abacavir + lamivudine combination The survival function S(t) corresponds to the probability that the event of interest does not occur before date t. This function was represented graphically by a survival curve. The patients' participation time, given in number of months, was defined using the following parameters: - Date of origin (DO) is the start date for patient monitoring which was the date of initiation of abacavir-lamivudine treatment. It is limited on the left by 1 January 2004 and on the right by 31 December The event date (ED) is the date of onset of the event of interest - Date of last contact (DLC) is the latest date at which the last news concerning the patient is available, corresponding to the date of the last contact recorded in the database. - The point date (PD) is the date when follow-up of the cohort was stopped. This date was set on 31 May The participation time for each subject (TP) was: The time between the date of origin and the date of the event if the studied event occurred before the point date. The time between the date of origin and the date of last contact if this occurred before the point date. If the date of last contact was after (or the same as) the point date, the patient was censored on the right and the participation time was the time between the date of origin and the point date. As 2

3 in the study synopsis..add definitions of the populations included in the CTR summary for the assessment of efficacy and safety if not included in the synopsis stats section. Make it clear if the populations for efficacy and safety are not the same. Study Population: A B Number of Subjects: 1814 None Planned, N 1814 None Randomised, N None None Completed, n (%) 1704 None Total Number Subjects Withdrawn, N (%) None None Withdrawn due to Adverse Events n (%) None None Withdrawn due to Lack of Efficacy n (%) None None Withdrawn for other reasons n (%) None None Demographics A B N (ITT) 1704 None Females: Males 31% female and 69% None male Mean Age, years (SD) 44 (10) None Race, n (%) Not collected None Results: Patient characteristics 5,102 patients, consulting a physician at one of the seven participating centres, received at least one prescription of the abacavir-lamivudine combination before 1 January Among these patients, 1,704 complied with the study eligibility criteria with a heterogeneous distribution among the seven centres. More than 90% of the 3,288 ineligible patients had started taking the combination before January 2004 or were not ABC-naive on initiation of ABC/3TC. Patient profiles varied slightly among the different centres, in particular in terms of the proportion of antiretroviral-naive patients and HCV or HBV co-infected patients. The average age of patients was 44 years. Most patients were men (69%). The mean duration of HIV infection was 9 years (5.1 years for treatment-naive patients, 9.6 years for pre-treated patients with an undetectable VL on initiation and 11.1 for those with a detectable VL). 24% were coinfected with HBV and/or HCV including ¾ with hepatitis C. Nearly 30% of patients were at the AIDS stage on initiation of abacavir-lamivudine treatment. 407 patients (24%) were naive of all antiretroviral (ARV) medication and 1,297 had already received ARV drugs: 696 of them (41%) had an undetectable VL and 601 a detectable VL (35%) on initiation of the combination. Treatment-naive patients had a mean viral load of 4.7 log 10 cp/ml, pre-treated patients with a detectable VL at initiation had a VL of 3.8 log 10 cp/ml and pre-treated patients with an undetectable VL on initiation, a VL of 1.7 log 10 cp/ml. 54% of pre-treated patients had an undetectable viral load and 46% a detectable viral load. The mean CD4 count was 399 cells/mm 3. This count was lower for treatment-naive patients (239 CD4/mm 3 ). It was greater than 500 CD4/mm 3 for pre-treated patients with an undetectable VL (533) and 331 CD4/mm 3 for pretreated patients with a detectable VL. In terms of therapeutic management, 79% of patients received a fixed-dose abacavir-lamivudine combination at the start of treatment: 57% Kivexa and 22% Trizivir and 21% a free-dose abacavir-lamivudine: 19% Ziagen -Epivir and 2% Ziagen -Combivir. Most patients (89%) received tritherapy and 8% quadritherapy. 46%, 21 %, 19 % and 3 % of the treated patients were receiving 2NRTI+1bPI, 3NRTI, 2NRTI+NNRTI and 2NRTI+1PI regimens respectively. Pre-treated patients had received on average 4 lines of antiretroviral drugs before the first initiation of the abacavir-lamivudine combination. 93% had already received lamivudine (3TC). All 1,704 patients were exposed to the abacavir-lamivudine combination for 2,636 patient-years 3

4 Number of patients Reasons for treatment discontinuation Thirty-three percent (565) of the 1,704 patients, who started treatment by abacavir and lamivudine, stopped it during the study period. Patients who discontinued treatment had received the combination for a mean time of 9.4 months (standard deviation=10.6 months). Fourteen percent (234) of patients who started the abacavir-lamivudine combination stopped it for intolerance, 7% on their own decision (115), 7% for immunologic/virological failure (114), 2% for another reason (32) and 1.6% died (27). Among the 565 patients who stopped the combination, 26% (148) continued abacavir in the next treatment line. Among the patients without abacavir in the treatment line after discontinuing the combination, 12% (48) started taking it again after an interruption of 4 days or more. The most frequent reason for discontinuing the combination for intolerance was a hypersensitivity reaction (29%). Two of the 69 patients who stopped abacavir treatment because of an HSR subsequently started taking it again. The proportion of discontinuations for intolerance was similar whether the discontinued regimen included a PI or not. Patient's death 5% Adjustment 5% Other reason 6% Noncompliance 2,5% Simplification 2,5% Reason for stopping the line with ABC/ 3TC Intolerance 41% Patient's decision 18% Immunologicvirologic failure 20% Reasons for stopping the line including ABC/ 3TC for intolerance Length of treatment with the combination The theoretical median time to discontinuation of the abacavir-lamivudine treatment according to the Kaplan Meier method was 51.7 months with a 95% confidence interval of [ ND]. 4

5 Survival curve modelling ABC+3TC discontinuations according to reasons Probability Duration of participation (in months) Patients at risk : At initiation At 3 months At 6 months At 1 year At 2 years At 3 years At 4 year Continuation rates of theabc+3tc combination Rates at 3 months Rates at 6 months Rates at 1 year Rates at 2 years Rates at 3 years Rates at 4 years All patients 86,7% 81,8% 75,7% 66,9% 58,2 52,1% Description of patients presenting cardiovascular events 4,0% 3,5% Proportion of patients presenting at least one cardiovascular event according to patient treatment history 3,0% 2,5% 2,0% 1,5% 1,0% 0,5% 0,0% Treatment-naive patients (N=407) Pre-treated patients (N=1297) Total (N=1704) Major cardiovascular event Myocardial infarction Minor cardiovascular event Cardiovascular event (broad definition) 5

6 A cardiovascular event (according to the broad WHO MONICA definition) occurred in 58 patients (i.e. 3.4%) during abacavir and lamivudine treatment. This represents an incidence rate of cardiovascular events (broad definition) of 23 patients per 1000 person-years of treatment by this combination (TI= ). A major event occurred in 21 patients (1.2%) including 12 patients (less than 1%) with nonfatal myocardial infarction (2 treatment-naive patients and 10 pre-treated patients). One death related to a cardiovascular event (myocardial infarction) was recorded for the whole cohort. The occurrence of major cardiovascular events during abacavir and lamivudine treatment had an incidence rate of 8 patients per 1000 person-years (TI= ) and the occurrence of myocardial infarction (fatal or not), an incidence rate of 5 patients per 1000 person-years (TI= ). Most of the patients presenting a cardiovascular event during abacavir and lamivudine treatment were men with an average age of fifty years. Nearly one patient out of four had hepatitis. Fifteen patients (26%) had already had a cardiovascular event before initiation of the combination. On average the cardiovascular event occurred 16.9 months after initiation of treatment. The average age of the 13 patients who had a myocardial infarction was 44 years and 15% (2 patients) were ARV-naive before initiation of ABC/3TC. Two had a detectable viral load before the occurrence of the cardiovascular event. The ABC/3TC combination had been taken for a mean duration of 16.4 months (+/-9.8) before the occurrence of the event. Virologic success (undetectable viral load) and immunologic success (CD4 count>500/mm 3 in patients treated by ABC/3TC Change in the proportion of patients with an 100% undetectable VL after 90% initiation of abacavir and lamivudine treatment 80% 70% 60% 50% 40% 30% 20% 10% 0% At 6 months (N=175/354/287) At 1 year (N=196/463/354) At 2 years (N=105/274/210) At 3 years (N=53/110/83) Naive patients Pretreated patients with undetectable VL Pretreated patients with detectable VL The proportion of patients with an undetectable viral load during treatment increased with time: 6 months after initiation of a treatment regimen including the ABC-3TC combination nearly four patients out of five had an undetectable viral load: 74% in treatment-naive patients, 91% in pretreated patients with an undetectable VL and 70% in pre-treated patients with a detectable VL. At 6 months, 45% of treated patients had a CD4 count > 500 /mm3. This proportion was lower for treatment-naive patients (27% at 6 months and 40% at 2 years). The median CD4 cell gain since initiation of treatment was 136 for treatment-naive patients at 6 months and 177 at 12 months. 6

7 CD4 gain in cells/mm3 Gain média n de CD4 /mm Change in median CD4 cell gain since initiation of abacavir and lamivudine treatment Naive patients Pretreated patients with undetectable VL Pretreated patients with detectable VL Total 0 M6 (N=154/365/298) M12 (N=170/462/354) M24 (N=92/276/208) M36 (N=44/108/82) A B Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n(%) Not collected - Database None List specific AEs according to guidance above Not collected - Database None Not collected - Database None Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] A B Subjects with non-fatal SAEs, n (%) Not collected - Database None n (%) [related] n (%) [related] Not collected - Database None Subjects with fatal SAEs, n (%) Not collected - Database None n (%) [related] n (%) [related] Not collected - Database None Conclusion: The study showed that only one-third of patients who initiated the ABC-3TC combination over the period discontinued this combination during the study period. Continuation of treatment was favourable with a theoretical median treatment continuation of 4 years according to the Kaplan Meier method. At three years, 58% of patients were still receiving the ABC-3TC combination. Fourteen per cent of patients who started this combination discontinued it due to intolerance to the treatment regimen. In nearly 30% of cases, these were premature discontinuations due to hypersensitivity reactions, occurring in 4% of all patients who started treatment with ABC/3TC. After this first trimester, discontinuations for intolerance occurred less frequently, showing the safety of the combination. The description of the occurrence of cardiovascular events, with all the limitations associated with the methodology of this study which was not initially designed to meet this objective, reported an incidence of myocardial infarction of 5 cases per 1000 person-years and that no cardiovascular events occurred during the 6 months after initiation of a treatment by ABC/3TC. 7