Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.

OBJECTIVES: The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients. METHODS: All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions. RESULTS: A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/µL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/µL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay 'on track' (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise. CONCLUSIONS: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

Influence of control selection in nested case-control studies: the example of exposure to antiretroviral treatment (ART) and the risk of myocardial infarction (MI) in the French Hospital Database on HIV (FHDH-ANRS CO4).

PURPOSE: Soon after availability of protease inhibitors (PIs), a duration-related effect relationship between PI and myocardial infarction (MI) was shown. New antiretroviral treatments (ARTs) have allowed more individualized regimens. To study their influence established risk factors of MI and additional therapeutic options such as lipid-lowering drugs will have to be taken into account. A nested case-control is an interesting alternative raising the choice of controls. With the previous full cohort analysis as reference, we investigated the influence of control selection in nested case-control studies sampled in this cohort by testing nine sampling scenarios. METHODS: During the period 1996-1999, 49 MI occurred among male patients exposed to PI and followed-up in the French Hospital Database on HIV (FHDH-ANRS CO4). For each case, controls were selected using incidence-density sampling. The influence of additional matching criteria was tested. Random sampling and analysis was repeated 100 times with varying control-case ratios. RESULTS: When controls were randomly selected among patients of the same age who were free of MI at the date MI was diagnosed in the case, we observed a duration-related effect relationship between PI and MI in agreement with the results of the full cohort analysis. The use of four controls per case was sufficient. Estimates obtained with simple sampling were more precise than those obtained when controls were also matched for year of enrollment, initial CD4 cell count and HIV transmission group. CONCLUSION: To study ARTs as MI risk factors, nested case-control using incidence-density sampling without additional matching is one appropriate option.

Causes of the first AIDS-defining illness and subsequent survival before and after the advent of combined antiretroviral therapy.

OBJECTIVES: To analyse the impact of combined antiretroviral treatment (cART) on survival with AIDS, according to the nature of the first AIDS-defining clinical illness (ADI); to examine trends in AIDS-defining causes (ADC) and non-AIDS-defining causes (non-ADC) of death. METHODS: From the French Hospital Database on HIV, we studied trends in the nature of the first ADI and subsequent survival in France during three calendar periods: the pre-cART period (1993-1995; 8027 patients), the early cART period (1998-2000; 3504 patients) and the late cART period (2001-2003; 2936 patients). RESULTS: The three most frequent initial ADIs were Pneumocystis carinii (jirovecii) pneumonia (PCP) (15.6%), oesophageal candidiasis (14.3%) and Kaposi's sarcoma (13.9%) in the pre-cART period. In the late cART period, the most frequent ADIs were tuberculosis (22.7%), PCP (19.1%) and oesophageal candidiasis (16.2%). The risk of death after a first ADI fell significantly after the arrival of cART. Lower declines were observed for progressive multifocal leukoencephalopathy, lymphoma and Mycobacterium avium complex infection. After an ADI, the 3-year risk of death from an ADC fell fivefold between the pre-cART and late cART periods (39%vs. 8%), and fell twofold for non-ADCs (17%vs. 9%). CONCLUSIONS: The relative frequencies of initial ADI have changed since the advent of cART. Tuberculosis is now the most frequent initial ADI in France; this is probably the result of the increasing proportion of migrants from sub-Saharan Africa. After a first ADI, cART has a major impact on ADCs and a smaller impact on deaths from other causes. The risk of death from AIDS and from other causes is now similar.

Influence of gender and HIV transmission group on initial highly active antiretroviral therapy prescription and treatment response.

BACKGROUND: The literature contains conflicting findings on the influence of gender and HIV transmission group on the initial prescription of highly active antiretroviral therapy (HAART) and its biological and clinical efficacy. METHODS: We conducted a cohort study involving 62 French hospitals. We used Cox proportional hazards models to examine whether gender and HIV transmission group influenced the timing of elective HAART initiation, and the clinical and biological response to treatment. RESULTS: We studied 5735 patients enrolled between January 1997 and December 2001 who did not start HAART or develop a stage C HIV-related event during the first 3 months after inclusion. In multivariate analysis, no gender differences were found in the interval between enrollment in the database and HAART initiation, but this interval was shorter in homosexual patients than in other transmission groups; CD4 cell counts at treatment initiation were also higher in the homosexual group. The immunovirological response to treatment did not differ according to gender, but was better in homosexual patients than in patients in other categories. Injecting drug users had the weakest immunovirological responses. Clinical outcome was not related to gender or to HIV transmission group. CONCLUSIONS: The interval between diagnosis of HIV-1 infection and elective HAART initiation was not influenced by gender. However, homosexual patients had higher CD4 cell counts than other patients at treatment initiation, and also had better immunovirological responses.

[Flecainide controlled-release for prevention of atrial fibrillation relapse]. / Acétate de flécaïnide a libération prolongée et prévention des récidives de fibrillation auriculaire: etude pharmaco-epidémiologique EPIFLEC dans une cohorte de 1 294 patients.

UNLABELLED: Flecainide acetate instant release (LI) has been prescribed for years in the prevention of atrial fibrillation (AF) relapse after sinus rate conversion. A new controlled-release (LP) formulation of flecainide was recently introduced. The objectives of this observational study were to evaluate the benefit/risk ratio of LI or LP flecainide treatment for prevention of AF relapse. METHODS: EPIFLEC study was an open, prospective, observational study conducted by 151 cardiologists who had prescribed either flecainide LI (group 1) to 838 patients or flecainide LP (group 2) to 214 patients or flecainide LI before LP (group 3) to 242 patients. In these patients, AF was either paroxystic (35%) or persistant (65%). Concomitant pathologies were observed in 80% of these patients (mean age 68 years) with a high incidence (50%) of hypertension. The mean duration of treatment was 6.9 +/- 6.7 months in group 1 (LI), 6.2 +/- 3.1 months in group 2 (LP) and 12.7 +/- 5.4 months in group 3 (LI-LP). RESULTS: mean daily dosages of flecainide were similar among the 3 groups. Antithrombotic drugs were prescribed in 74% (group 1) to 83% (group 2) of the patients and another antiarrhythmic drug was associated to flecainide among 12 to 21% of the patients. AF relapse was observed in 171 patients in group 1 (LI), 38 patients in group 2 (LP) and 39 patients in group 3 (LI-LP). The incidence of AF relapse was compared in groups 1 and 2 at 10 months of follow-up and AF relapse probability was not significantly different between flecainide LI and LP :26 +/- 2% and 23 +/- 4% respectively (OR = 0.99, CI 95%:0.69-1.4; p = 0.96). A multivariate analysis showed that previous multiples episodes of AF, electrical shock rate conversion and history of flutter and hypertension were independent predictors of AF relapse. Among 11 deaths observed during follow-up, only 2 were cardiovascular. The most frequent non lethal cardiovascular adverse events were arrhythmias or cardiac conduction disorders and were limited to less than 5% of the patients. Only 5 supraventricular transient pro arrhythmias episodes were recorded. CONCLUSION: this pharmaco-epidemiological study in private practice confirms that flecainide is able to prevent AF relapse in 75% of patients at 10 months and that the tolerance of the treatment is acceptable in these patients.

Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study(CIBIS II).

AIMS: Whether all patients with congestive heart failure (CHF) need to reach the target dose of beta-blocker to obtain a benefit in terms of survival remains uncertain. METHODS AND RESULTS: We classified by tertile the 2647 patients enrolled in CIBIS II according to the last tolerated dose: low dose (LD: 1.25, 2.5 or 3.75mg/day, n=434), moderate dose (MD: 5 or 7.5mg/day, n=328) and high dose (HD: 10mg/day, n=565) of bisoprolol or placebo (LD=234, MD=278 and HD=808). In both groups, patients tolerating only low doses were significantly older with more severe New York Heart Association (NYHA) functional class and higher frequency of co-morbidities. Treatment withdrawal was associated with a significant increase of mortality in the bisoprolol group (relative hazard (RH)=2.13, 95% confidence interval (CI)=1.43-3.17, p=0.0002). After adjustment, all-cause mortality was significantly reduced in the bisoprolol group compared to placebo regardless of the dose level considered: LD (RH=0.66, 95% CI=0.48-0.92), MD (RH=0.33, 95% CI=0.21-0.51) or HD (RH=0.59, 95% CI=0.40-0.89). CONCLUSIONS: Bisoprolol reduces mortality in CHF patients at all tolerated dose levels and its withdrawal increases the risk of mortality. Efforts should be made to maintain bisoprolol therapy based on the individual patient's tolerability.

Impact of highly active antiretroviral therapy on the incidence of visceral leishmaniasis in a French cohort of patients infected with human immunodeficiency virus.

The incidence of human immunodeficiency virus (HIV)-Leishmania coinfections in France was estimated on the basis of the French Hospital Database on HIV, and risk factors for the occurrence of visceral leishmaniasis (VL) were analyzed by a multivariate Cox model. VL was diagnosed in 165 of 55,626 HIV-infected patients followed since 1992. The incidence of VL decreased from 11.6+/-1.2 per 10,000 persons-years before 1996 to 6.3+/-0.7 per 10,000 persons-years after 1996, the year when highly active antiretroviral therapy (HAART) was initiated in France. The relative hazard (RH) for development of VL was higher in (1) intravenous drug users versus other transmission groups (RH=1.56; 95% CI, 1.13-2.15), (2) patients living in southern France versus those living in northern France (RH=3.36; 95% CI, 2.44-4.61), and (3) patients who had a CD4 cell count of /=3 drugs versus those who did not (RH=0.41; 95% CI, 0.26-0.65). We found a significant decrease in the incidence of HIV-Leishmania coinfections after 1996, associated with the introduction of HAART in France.

[Efficacy and tolerance of propafenone after correction of atrial fibrillation: PEPS pharmaco-epidemiologic study]. / Efficacité et tolérance de la propafénone après régularisation de la fibrillation auriculaire: étude pharmaco-épidémiologique PEPS.

The PEPS study had the objective of documenting the acceptability and efficacy of propafenone in 1366 treated patients, after correction of chronic or paroxysmal AF, and followed up over one year. All the cases were validated by quality controls performed by the 196 participating cardiologists. All the events during follow up were validated by a committee of independent experts. The patients, aged 67 +/- 11 years, were in sinus rhythm on inclusion. Propafenone was prescribed at the initial dose of 600 mg/day in 65% of patients. The proportion of patients without relapse of AF was 64 +/- 1% at 12 months. After adjustment, the significant predictors of AF relapse were male sex, previous history of chronic AF and prescription of associated drugs. Neither patient age nor propafenone dose significantly influenced AF relapse. Seven deaths (0.5%) occurred during the study of which 3 were of unknown cause. A pro-arrhythmic effect was observed in 8 patients (0.59%) of which 6 had underlying heart disease. The overall frequency of pro-arrhythmic effects, including the 3 deaths of unknown cause, was therefore 0.81%. Tolerance of treatment with propafenone after correction of AF is therefore satisfactory and the frequency of pro-arrhythmic effects is less than 1%. The efficacy of the treatment for the maintenance of sinus rhythm is in accordance with previously published results.

Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II).

BACKGROUND: Whether female sex is associated with a better prognosis in patients with congestive heart failure (CHF) remains uncertain. The Cardiac Insufficiency Bisoprolol Study (CIBIS) II showed that bisoprolol reduced all-cause mortality and morbidity rates in CHF patients treated with diuretics and ACE inhibitors. We examined whether survival was different in men (n=2132) and women (n=515) enrolled in CIBIS II. METHODS AND RESULTS: Women differed from men with regard to age, NYHA functional classification, primary cause of CHF, and risk factors such as left bundle-branch block. After adjustment for baseline differences, the probability of all-cause mortality was significantly reduced by 36% in women compared with that in men (hazard ratio 0.64, 95% CI 0.47 to 0.86, P:=0.003). Women also had a 39% reduction in cardiovascular deaths (hazard ratio 0.64, 95% CI 0.45 to 0.91, P:=0.01) and a 70% reduction in deaths from pump failure (hazard ratio 0.30, 95% CI 0.13 to 0.70, P:=0.005) compared with men. Kaplan-Meier survival analysis revealed a significant reduction in all-cause mortality among women treated with bisoprolol compared with men (6% versus 12% P:=0.01) but not among women treated with placebo (13% versus 18%, P:=0.10). However, this sex/ss-blocker effect was not significant in multivariate analysis. CONCLUSIONS: These results indicate that regardless of ss-blocker treatment and baseline clinical profile, female sex is a significant independent predictor of survival in patients with CHF.

[Mycobacterium avium complex disease in HIV seropositive patients: incidence and risk factors before and after the introduction of highly active antiretroviral treatments. Clinical Epidemiology Group of the Information and Care Center for Human Immunodeficiency]. / Mycobacterium avium complex chez les sujets séropositifs pour le VIH: incidence et facteurs de risque avant et après l'introduction des traitements antirétroviraux hautement actifs. Groupe d'épidémiologie clinique des centres d'information et de soins de l'immunodéficience humaine (CISIH).

The objective of this study was to determine the risk factors of the first occurrence of Mycobacterium avium complex disease (MAC) infection among human immunodeficiency virus (HIV)-infected subjects during two different time periods: before and after the introduction of protease inhibitor (respectively, period 1: 1 January 1992 to 31 December 1995, and period 2: 1 January 1996 to 30 June 1998). This study was performed using the French Hospital Database on HIV (FHDH). Subjects were included when their CD4+ cell count was less than 100/mm3. If they did not die or develop MAC within the first 6 months after the inclusion, their follow-up had to be longer than 6 months to be included. Cox's model was used to calculated the relative hazards (RH) of MAC occurrence according to the age and time-dependent variables, such as CD4+ below 50/mm3, previous occurrence of tuberculosis, cytomegalovirus (CMV) infection and other acquired immunodeficiency syndrome (AIDS)-defining disease, nature of antiretroviral treatment and MAC prophylaxis. Among the 14,779 subjects followed during period 1, 1,710 (11.6%) had a diagnosis of MAC infection during their follow-up (incidence: 8.4 +/- 0.2 for 100 persons per year), while only 453 (4.4%) among 10,239 subjects presented this infection during period 2 (2.8 +/- 0.1 for 100 persons per year). Rifabutin regular prescription was a protective factor of MAC occurrence during period 1 (RH = 0.51 95% confidence interval (CI) = [0.37-0.69]), whereas this protective effect was not observed during period 2 (RH = 1.05 CI = [0.63-1.67]). Thus, during the HAART period, the results that we present do not indicate an interest into continuing MAC prophylaxis.

Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity.

BACKGROUND: Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione-S-transferases (GST), of which two isozymes (GST M1 and GST T1) are polymorphically expressed. OBJECTIVE AND METHODS: To determine whether GST M1, GST T1, and the combined GST M1 and GST T1 null genotypes predict individual susceptibility to tacrine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine were genotyped. RESULTS: During the treatment period, 52 patients had elevated alanine aminotransferase (ALT) levels at least three times the upper limit of normal, whereas 89 patients had normal ALT values (< or = upper limit of normal). Both groups were comparable in demographic and clinical characteristics. Twenty-eight patients were found to be GST T1-negative (20%; with a 95% confidence interval [95% CI] from 13% to 27%), and 68 patients (48%; 95% CI from 40% to 57%) were GST M1-negative. The combined GST M1-T1 null genotype was observed in 18 patients (13%; 95% CI from 7% to 18%) of whom 13 had an elevated plasma ALT at least three times the upper limit of normal during the study period. Although the cumulative percentage of elevated plasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 nor GST T1 alone could predict individual susceptibility to tacrine hepatotoxicity. Multivariate Cox hazards model showed that the association of the GST M1-T1 null genotype was an independent risk factor of hepatotoxicity. CONCLUSIONS: The presence of combined alleles M1 and T1 deficiencies in glutathione-S-transferase genes increases the susceptibility to tacrine hepatotoxicity.

AIDS-related primary pulmonary lymphoma.

We describe 12 cases of AIDS-related primary pulmonary lymphoma occurring between 1986 and 1996 in a large French cohort of HIV-infected patients. Diagnostic criteria were: (1) histologically proven lymphomatous pulmonary involvement; (2) absence of mediastinal and/or hilar adenopathy on chest radiography; (3) absence of extrathoracic lymphoma extension. All patients were severely immunodeficient at the time of diagnosis. All but one patient presented with B and/or nonspecific respiratory symptoms. Chest radiography showed one or more marginated nodule(s) or large mass. CT scan showed a cavitary lesion in five patients. No lymph node enlargement or specific pleural effusion was detected. Transthoracic needle biopsies were performed in 10 patients and avoided open-lung biopsy for the diagnosis of lymphoma in five patients. All but one of the primary pulmonary lymphoma were high-grade B-cell non-Hodgkin's lymphomas. Using antilatent membrane protein-1 antibodies and an Epstein-Barr-Virus-encoded RNA transcript-specific probe, latent EBV infection of tumor cells was demonstrated in every case. All but one of the patients received chemotherapy. The median survival time was 4 mo, and no patient was still alive at the cut-off date for this analysis. Progessive pulmonary lymphoma was the main cause of death, but infections were also frequent.

Persistent transient myocardial ischemia despite beta-adrenergic blockade predicts a higher risk of adverse cardiac events in patients with coronary artery disease.

OBJECTIVES: We evaluated the prevalence and prognostic significance of transient myocardial ischemia despite beta-adrenergic blockade in patients with coronary artery disease. BACKGROUND: Persistence of transient ischemia despite therapy may correspond to a subset of high risk patients with coronary disease. The impact of beta-blocker withdrawal in these patients remains unknown. METHODS: Patients (n = 313) with documented coronary artery disease and beta-blocker therapy, with (group I, n = 84) or without (group II, n = 229) transient ischemia on ambulatory electrocardiographic monitoring, were followed up during 21 +/- 9 months for cardiac events (death, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass surgery and worsening angina). Occurrence of events was compared by log-rank test. RESULTS: The number of coronary stenoses did not differ significantly between groups I and II. Beta-blocker therapy was discontinued more frequently during follow-up in group II (25% vs. 14% in group I, p = 0.04). Cumulative percentage of death or myocardial infarction, or both, tended to be higher in group I a 30 months (17% vs. 5% in group II, p = 0.09). Coronary angioplasty and bypass surgery were significantly more frequent in group I (p = 0.01 and 0.0008, respectively). Transient ischemia was associated with a higher cumulative probability of adverse events (p = 0.004). The number of coronary stenoses, presence of transient ischemia and beta-blocker withdrawal were the only significant prognostic factors of cardiac events in the Cox model. In group I patients, the relative hazard of cardiac events was increased threefold when beta-blocker therapy was interrupted. CONCLUSIONS: These data suggest that 1) the occurrence of transient ischemia despite beta-blocker therapy identifies a subset of high risk patients with coronary artery disease, and 2) the interruption of beta-blocker therapy increases the risk of adverse cardiac events.

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators.

The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy. Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes. However, the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronary artery disease, a positive exercise test within 6 months before entry and background beta-blocker therapy, were screened. Inclusion criteria (> or = 4 episodes of transient ST segment depression of > or = 1.0 mm and/or > or = 20 min of ischaemia) were demonstrated in a 48 h ECG during the placebo run-in period in 84 (25%) of the patients. Eighty-nine percent of the ischaemic episodes were silent. The eligible patients were then randomized in a 2-week, double-blind, parallel group study comparing placebo to amlodipine 10 mg daily added to the beta-blocker. The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests. Compared to placebo, amlodipine did not significantly reduce either the frequency (3.7 +/- 4.3 vs 4 +/- 4.8 episodes in the amlodipine group) or the duration of ambulatory ischaemia (mean duration: 43.9 +/- 57.1 vs 39.6 +/- 65.7 min, total duration 3.1 +/- 6.7 vs 2.8 +/- 6.1 h). Exercise-induced ST segment depression tended to decrease with amlodipine (58% vs 73% in the placebo group) and the ischaemia-free workload capacity was increased (+1.7 stage vs 0.7 stage in the placebo group, P = 0.08). These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti-ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy.

Conditions of validation and use of the screening method for vaccine efficacy evaluation.

If PV is the proportion of the target population vaccinated and PCV the proportion of cases in the same population who have been previously vaccinated, vaccine efficacy can be computed as (PV-PCV)/[PV(1-PCV)]. In the screening method, this formula is currently applied to sample values. The objective of this paper is to provide the corresponding statistical tools. Taylor series expansion has been used to derive the bias, variance and confidence interval of the estimate. The bias may be very high when vaccine efficacies are low. It is below 1% for vaccine efficacies higher than 80%. Monte Carlo simulations were used to assess the departure from normality of the estimate. The number of subjects required by the method for given precisions are presented.