Intention-to-treat vs. on-treatment analyses of clinical trial data: experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group.

Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.

Survival after AIDS-defining events in patients with < 200 lymphocytes CD4+ x 10(6)/L who are toxoplasmosis antibody positive. ANRS 005/ACTG 154 Trial Group.

The objective of this study was to assess whether patients with CD4+ cell counts <200 x 10(6)/L have a decreased survival after the occurrence of any AIDS-defining event; 187 patients from the placebo arm of a clinical trial of toxoplasmosis prophylaxis (ANRS005-ACTG154) were included. For this analysis, patients were HIV infected without any AIDS-defining event, had a CD4+ lymphocyte count < 200 x 10(6)/L, had a positive serology for Toxoplasma gondii, and had no severe liver, renal, or hematologic abnormalities. We used proportional hazards regression to study the relationships between baseline variables. AIDS-defining events as time-dependent variables, and survival. The risk of dying was increased by 1.9 for a 10-year increase in age and by 1.3 when CD4+ decreased by 50 x 10(6)/L; after the occurrence of a pneumocystosis, a cytomegalovirus infection, or a toxoplasmosis, the risk of dying was multiplied, respectively, by 10.9 (3.0-40.2), 10.0 (2.8-35.4), and 10.0 (4.5-22.2). None of the other AIDS-defining events was associated with an increased risk of dying, but the power to detect such an association was limited. We conclude that the occurrence of pneumocystosis, cytomegalovirus infection, or toxoplasmosis; age; and CD4+ cell count are important determinants of survival for HIV1-infected patients with CD4+ counts < 200 x 10(6)/L who are toxoplasmosis antibody positive.

Progression of human immunodeficiency virus infection in patients with tuberculosis disease. A cohort study in Bordeaux, France, 1988-1994. The Groupe d'Epidémiologie Clinique du Sida en Aquitaine (GECSA).

To assess the role of Mycobacterium tuberculosis disease in human immunodeficiency virus (HIV) infection, the authors compared survival of tuberculosis patients and controls matched on year of HIV diagnosis and CD4+ lymphocyte count. Patients were selected in the Aquitaine Cohort, which follows, since 1985, all patients infected with HIV, aged more than 13 years, in five hospitals. Time of inclusion of controls was the date of diagnosis of tuberculosis for the corresponding tuberculosis patient. Patients who had received primary prophylaxis against mycobacteria other than tuberculosis were excluded. As of June 30, 1994, 104 tuberculosis patients and 620 controls were selected; they were similar, except for history of intravenous drug use (tuberculosis patients, 51%, vs. controls, 31%) and AIDS-defining opportunistic infection (40 vs. 29%). Survival was shorter in tuberculosis patients than in controls (risk ratio 1.5, 95% confidence interval 1.2-2.1) even after controlling for differences at entry. The risk of AIDS-defining opportunistic infection or a decrease to fewer than 50 CD4+ cells/mm3 was slightly but not statistically greater in tuberculosis patients than in controls. Tuberculosis disease affected survival but not occurrence of subsequent opportunistic infections or rate of CD4+ count decline. Tuberculosis may be a marker of advanced HIV and may accelerate its course of infection.

[Pneumocystis carinii pneumonia in AIDS: retrospective analysis of 80 documented cases (1985-1993)]. / La pneumocystose pulmonaire au cours du sida: analyse rétrospective de 80 cas documentés (1985-1993).

Eighty initial episodes of HIV-associated Pneumocystis carinii pneumonia (PCP) diagnosed at Bordeaux hospital between 1985 and 1993 are reported (57 were men and 23 women). PCP revealed HIV infection in 29 patients (36%). Others cases were patients with poor medical follow up (10%), with a CD4+ lymphocyte count above 200/mm3 at last follow-up (9%), non compliant with PCP prophylaxis (9%), or using aerolized pentamidine (AP+) (20%). The main clinical symptoms were fever (90%), dyspnea (68%), non productive (63%) and productive (17%) cough. Radiographic infiltrates were purely interstitial (59%), acinar and interstitial (25%), purely acinar (5%) and absent (11%). Thirty-eight percent of AP+ had upper lobe preferential involvement and 13% a pleural effusion. In all cases, Pneumocystis carinii was detected in bronchoalveolar lavage. Extrapulmonary localizations of pneumocystosis were noticed (eye, liver, spleen, ascitis) in two AP+. Mean CD4+ count was 54/mm3 in patients not having received aerolized pentamidine (AP-) and 22/mm3 in AP+. P24 antigenemia was positive in 53% (AP-) and 88% (AP+). PaO2 LDH and albuminemia were similar in both groups. Antimicrobial therapy (Cotrimoxazole in 91% of the cases) was combined with corticosteroids in 45% and mechanic ventilation in 19%. After 30 days of follow-up, 17 deaths were observed (21%) and 14 attributed to PCP: mortality was worse in AP+ (31%) than in AP- (19%). The main conclusions of our study are the followings: HIV related PCP is still in 1995 frequent and severe; atypical features should not rule out diagnosis; preventive measures are neither sufficient nor efficient. PCP remains in 1995 a priority in HIV related public health and therapeutical research.

Prospective cohort study of the effect of pregnancy on the progression of human immunodeficiency virus infection. The Groupe d'Epidémiologie Clinique Du SIDA en Aquitaine.

OBJECTIVE: To study the prognostic role of pregnancy on the progression of human immunodeficiency virus (HIV) infection. METHODS: In a prospective cohort study at the Bordeaux University Hospital, France, 57 women who completed a pregnancy during the course of their HIV infection were compared with 114 HIV-infected women who never conceived. The two groups were matched on CD4 lymphocyte count (CD4), age, and year of HIV diagnosis. The main outcome measures were death, occurrence of a first AIDS-defining event, and drop of the CD4 below 200/mm3. RESULTS: The mean follow-up period in pregnant women was 61 months from HIV diagnosis (median CD4 at entry 455/mm3) and 54 months from beginning of pregnancy. Nonpregnant women were followed-up for 50 months since HIV diagnosis (median CD4 460/mm3). The proportion of asymptomatic women at entry in the study was 51 of 57 (90%) in pregnant and 87 of 114 (76%) in nonpregnant women. No significant difference was observed between the two groups with regard to the different end points studied, even after adjustment for other prognostic variables. Adjusted hazard ratios (pregnant/nonpregnant) were 0.92 for death (95% confidence interval [CI] 0.40-2.12), 1.02 for occurrence of a first AIDS-defining event (95% CI 0.48-2.18), and 1.20 for drop of the CD4 to less than 200/mm3 (95% CI 0.63-2.27). CONCLUSION: In a cohort of HIV-infected women with mild to moderate immunosuppression, pregnancy did not accelerate progression to AIDS or death.

[Factors associated with a 1-year development in the functional autonomy of elderly persons living at home]. / Facteurs associés à l'évolution à un an de l'autonomie fonctionnelle des personnes âgées vivant à leur domicile.

The purpose of the study was to examine the incidence and reversibility of disability among elderly people over one year follow-up and to determine the predictors of functional changes. The population used in this analysis consisted in 1850 subjects aged 65 and over included in the PAQUID cohort and visited again at one year follow-up. Disability was measured by Katz's scale (Activities of Daily Living or ADLs), Lawton's scale (Instrumental Activities of Daily Living or IADLs) and a mobility scale. The one year incidence of the dependency was 5.6% for ADLs, 10.8% for IADLs, and 3.3% for mobility. Being dependent at baseline was associated with an increased risk of one year mortality comprised between 3.3 and 5.3 according to the measurement scale. Recovery back to independence was frequent however, especially for ADLs (44.7%) and mobility (28.9%). Predictors of disability were: age in all scales, vision impairment and Mini Mental State Examination score for IADL and mobility scales, depressive symptomatology for ADLs, female sex and breathlessness for IADLs. Absence of cognitive impairment at baseline was associated with recovery to independence in all scales.

Self-reported memory complaints and memory performance in elderly French community residents: results of the PAQUID Research Program.

An epidemiological survey of self-reported memory complaints and memory performance [assessed with Benton's visual-retention test (BVRT) and the Wechsler paired-associates test (WPAT)] was undertaken in a community sample of 2,726 noninstitutionalized subjects aged 65 and over living in Gironde (southwestern France). A significant relationship was observed between the presence of self-reported memory problems and lower performance on the BVRT and the WPAT. However, beyond this relationship, there was significant discordance between the two evaluations, explained in part by the fact that the correlates of memory functioning were not related with similar strength to self reports and to actual performance. In general, females and subjects who scored above the depressive symptomatology threshold reported more problems, while lower performances were related to older age and low educational level. The discordance between self reports and actual performance may suggest anosognosia of mild memory deficits and could possibly be a predictor of future intellectual deterioration.

[Prevalence of dementia in Gironde (France)]. / Prévalence de la démence en Gironde (France).

The objective of the study is to estimate the prevalence of dementia using the data of the Paquid cohort. A sample of 3,149 subjects aged 65 years and older living at home or in institution was randomly chosen in Gironde (France). A questionnaire and psychometric tests were used to evaluate cognitive functioning and the presence of dementia was assessed through DSM III Diagnostic and Statistical Manual of mental disorders (ed. III) criteria. Hachinski scale and work group NINCDS-ADRDA criteria were applied to confirm the presence of dementia and identify Alzheimer's disease. Overall prevalence was estimated to 4.3%. No difference was found between men and women. The prevalence increased with age with nearly a doubling every 5 years of age. In institution, dementia frequency remained stable. The relative risk of a demented subject to be institutionalized with regard to a non demented subject decreased with age.

Motor disability in children in three birth cohorts.

A systematic registration was carried out in 1985-1986 and 1989 in 14 French 'departments' in order to assess whether the prevalence rates of different components of motor disability (MD) in three different birth cohorts (1972, 1976 and 1981) had changed at a time when the preterm birth rate and neonatal mortality were decreasing and there was evidence of changing perinatal practice. A total of 1355 MD were registered amongst resident children born in 1972, 1976 and 1981 with a prevalence of 3.34 per 1000. The prevalence of the MD types due to different causes did not differ significantly amongst the three birth cohorts with the exception of an excess of hereditary and degenerative disease of the central nervous system (CNS) among children born in 1981. The prevalence of cerebral palsy (CP) remained stable in the three birth cohorts: it was 1.30, 1.06 and 1.08 per 1000 respectively, for children born in 1972, 1976 and 1981. The prevalence of pre- or perinatal-origin of other motor disabilities (OMD) and of CNS malformations did not differ amongst the three birth cohorts. The method of registration is discussed and the results are related to those of the French perinatal surveys performed in 1972, 1976 and 1981, which showed a decrease in preterm birthrate, an increase in perinatal care and a decrease in the mortality rate of high-risk infants.