About the necessity to manage events coded with MedDRA prior to statistical analysis: proposal of a strategy with application to a randomized clinical trial, ANRS 099 ALIZE.

BACKGROUND: Since 2003, the Medical Dictionary for Regulatory Activities (MedDRA) is the regulatory standard for safety report in clinical trials in the European Community. Yet, we found no published example of a practical experience for a scientifically oriented statistical analysis of events coded with MedDRA. We took advantage of a randomized trial in HIV-infected patients with MedDRA-coded events to explain the difficulties encountered during the events analysis and the strategy developed to report events consistently with trial-specific objectives. METHODS: MedDRA has a rich hierarchical structure, which allows the grouping of coded terms into 5 levels, the highest being "System Organ Class" (SOC). Each coded term may be related to several SOCs, among which one primary SOC is defined. We developed a new general 5-step strategy to select a SOC as trial primary SOC, consistently with trial-specific objectives for this analysis. We applied it to the ANRS 099 ALIZE trial, where all events were coded with MedDRA version 3.0. We compared the MedDRA and the ALIZE primary SOCs. RESULTS: In the ANRS 099 ALIZE trial, 355 patients were recruited, and 3,722 events were reported and documented, among which 35% had multiple SOCs (2 to 4). We applied the proposed 5-step strategy. Altogether, 23% of MedDRA primary SOCs were modified, mainly from MedDRA primary SOCs "Investigations" (69%) and "Ear and labyrinth disorders" (6%), for the ALIZE primary SOCs "Hepatobiliary disorders" (35%), "Musculoskeletal and connective tissue disorders" (21%), and "Gastrointestinal disorders" (15%). CONCLUSIONS: MedDRA largely enhanced in size and complexity with versioning and the development of Standardized MedDRA Queries. Yet, statisticians should not systematically rely on primary SOCs proposed by MedDRA to report events. A simple general 5-step strategy to re-classify events consistently with the trial-specific objectives might be useful in HIV trials as well as in other fields.

Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).

BACKGROUND: Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. METHODS: This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. RESULTS: After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. CONCLUSION: A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

Changes in the peripheral blood mtDNA levels in naive patients treated by different nucleoside reverse transcriptase inhibitor combinations and their association with subsequent lipodystrophy.

Nucleoside reverse transcriptase inhibitors (NRTIs) differ in the type and severity of adverse effects resulting from mitochondrial abnormalities. mtDNA in peripheral blood mononuclear cells (PBMCs) was measured during the first 12 months of different NRTIs combinations and its association with clinical lipodystrophy was estimated. Extended follow-up of a randomized trial, ALBI-ANRS 070, including antiretroviral naive patients was conducted. Total DNA was extracted from available cryopreserved PBMCs at baseline and months 6 and 12. Nuclear and mitochondrial genes were amplified using a real-time PCR assay. Clinical lipodystrophy was assessed 30 months after randomization using a standardized questionnaire. A logistic regression analysis assessed the value of mtDNA to predict lipodystrophy. Mean mtDNA level (copies/cell) significantly decreased from 5847 at baseline to 3176 at month 12 (p < 0.0001). In the zidovudine + lamivudine (ZDV + 3TC) arm (n = 37), the mean mtDNA was 6098, 6807, and 3725 copies/cell for baseline, month 6, and month 12, respectively. In the stavudine + didanosine (d4T + ddI) arm (n = 40), the mean values were 5616, 5731, and 2648 copies/cell, respectively. The proportion of patients in the lowest quartile of mtDNA (<1421 copies/cell) at month 12 was higher in 18 patients with lipodystrophy (44%) than in 28 without lipodystrophy (7%) (p = 0.008). At 12 months, a larger reduction of mtDNA from baseline was observed in those started on the d4T + ddI arm. Furthermore, a low mtDNA level at month 12 was associated with the subsequent development of lipodystrophy. This marker may be of value for the early prevention of lipodystrophy in treated HIV-infected patients.

Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099.

BACKGROUND: Efavirenz (EFV) is a highly active antiretroviral drug, use of which is associated with frequent (although transient) neurosensorial adverse reactions. Whether the use of EFV is associated with the risk of depression or suicide remains controversial. METHODS: ALIZE-ANRS (Agence Nationale de Recherches sur le SIDA et les Hepatites Virales) 099 was a 48-week randomized trial involving virologically suppressed, human immunodeficiency virus (HIV)-infected patients that compared the maintenance of a treatment regimen that contained protease inhibitors (177 subjects) with a switch to a once-daily combination of EFV, didanosine, and emtricitabine (178 subjects). We used the trial's adverse events reporting system and a self-administered Center for Epidemiologic Studies-Depression Scale questionnaire to assess depressive disorders. Determinants were studied using a multivariate proportional hazards model adjusted for antiretroviral treatment, sex, age, HIV risk factor, history of depression, hepatic disorder, alcohol abuse, and HIV-related or non-HIV-related events. RESULTS: Thirty cases of depressive disorder (26 cases of depression and 4 suicide attempts) occurred during treatment in 27 patients (12 patients [7%] and 15 patients [8%] in the protease inhibitor-based and EFV-based treatment arms, respectively; P = .56). In the proportional hazards model, only age (hazard ratio, 1.6 per 10 years younger; 95% confidence interval, 1.0-2.6) and a history of depressive disorder (hazard ratio, 5.0; 95% confidence interval, 2.1-12.0) were associated with a risk of depressive disorders. The proportion of depressive patients (24%), as determined on the basis of the Center for Epidemiologic Studies-Depression Scale data, was stable during the follow-up period, without difference between treatment groups. Patients with a history of depressive disorder were more frequently depressed (53%) than were those without such history (22%; P = .03). CONCLUSIONS: The frequency of depressive disorders was high in this population, but the disorders were not related to EFV treatment. Younger age and a history of depression are important determinants for depression and should be considered for early detection and case management.

Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial.

BACKGROUND: We assessed a once-daily combination to simplify therapy in patients infected with human immunodeficiency virus type 1 (HIV-1). METHODS: A total of 355 adults with plasma HIV-1 RNA levels <400 copies/mL were randomly assigned to either switch to once-daily emtricitabine, didanosine, and efavirenz (n=178) or maintain their protease inhibitor (PI)-based regimens (n=177). The primary end point was sustained suppression of plasma HIV-1 RNA levels to <400 copies/mL. RESULTS: At week 48, the proportion of patients meeting the end point was 87.6% in the PI group and 90.5% in the once-daily group, with a treatment difference of -2.9% (upper bound of the 1-tailed 95% confidence interval, 2.6%). The proportion of patients with HIV-1 RNA levels <50 copies/mL was higher in the once-daily group (87%) than in the PI group (79%) (P<.05). Resistance mutations to efavirenz and emtricitabine were detected in all patients in the once-daily group who experienced virologic failure while receiving study medication. The proportion of patients discontinuing study medication because of adverse events was similar between the once-daily group (9%) and the PI group (10%) (P=.8). CONCLUSIONS: Substituting a convenient once-daily combination of emtricitabine, didanosine, and efavirenz for a PI-based regimen was well tolerated and associated with sustained virologic suppression.

Analysis of undetectable HIV RNA using survival analysis: results must be interpreted carefully.

This methodological note exemplifies the drawbacks of conventional survival analysis for studying the determinants of the evolution of HIV RNA after the initiation of a HAART regimen in observational cohort studies. The potential for loss of information might yield differential misclassification biases and therefore unreliable results. Longitudinal models are better suited to analyze the repeated measures of a continuous outcome such as HIV RNA.

Is hepatitis C virus co-infection associated with survival in HIV-infected patients treated by combination antiretroviral therapy?

OBJECTIVE: To study whether hepatitis C virus (HCV) co-infection or the severe elevation of transaminases is associated with survival after the initiation of antiretroviral combination therapy. DESIGN: Prospective hospital-based cohort (Aquitaine Cohort). METHODS: HIV-infected adults started on an antiretroviral combination before 30 June 1999. HCV infection was defined as antibody detection or positive HCV RNA. Severe elevation of transaminases was defined as a value of aspartate or alanine aminotransferase (AST, ALT) above five times the upper limit of normal values. Survival was studied using a Cox model, including at least baseline HCV status and transaminases as a time-dependent covariate. RESULTS: Overall, 995 patients were analysed, including 576 HCV-positive individuals (58%). At baseline, HCV-positive patients were younger, more often injecting drug users and women, and had more frequently elevated transaminases. A shorter survival was associated with AIDS stage [hazard ratio (HR) versus non-AIDS 1.67; 95% confidence interval (CI) 1.03; 2.68], lower CD4 cell count (HR for 50 cells/mm3 lower 1.33; CI 1.17; 1.51), lower haemoglobin (HR for 1 g/dl lower 1.20; CI 1.07; 1.35), lower platelet count (HR for 10 000 cells/mm3 lower 1.04; CI 1.01; 1.07), and AST during follow-up (HR for > or = 200 IU/l 2.30; CI 1.32; 4.03). HCV co-infection (HR 1.20; CI 0.75; 1.92) was not statistically associated with survival. CONCLUSION: The occurrence of a severe elevation of transaminases was associated with poorer survival, although HCV was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments of antiretroviral treatments currently prescribed to optimize their use.

Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients.

The role of nucleoside analogues (NAs) in lipodystrophy (LD) syndrome in human immunodeficiency virus (HIV)-infected patients remains controversial. We studied the prevalence of LD in previously untreated patients randomized to receive different NA combinations (in the ALBI-ANRS 070 trial) for 6 months. At month 30 of follow-up, 37 (31%) of 120 patients had >/=1 morphologic change, and 21 (57%) of 37 had isolated peripheral lipoatrophy; corresponding values for the patients who received only NAs throughout follow-up were 20 (30%) of 66 and 14 (67%) of 21, respectively. In multivariate analysis, factors associated with presence of LD at month 30 were initial assignment to the group receiving stavudine and didanosine (odds ratio [OR], 6.7; P=.02), age (OR for being 10 years older, 3.6; P=.002), and HIV RNA level at month 30 (OR, 0.4; P=.007). No difference was observed in cholesterol and glucose levels as a function of any pattern of antiretroviral exposure. Exposure to stavudine and didanosine was associated with LD syndrome (predominantly lipoatrophy).