Cytochrome 2B6 polymorphism and efavirenz-induced central nervous system symptoms : a substudy of the ANRS ALIZE trial.

OBJECTIVES: Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system (CNS) symptoms are limited. METHODS: We analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial. Kaplan-Meier methods and Cox regression analysis were used to investigate their association with efavirenz plasma levels and CNS events up to 48 months after switching. RESULTS: In total, 191 patients with a median age of 41 years, who were 87% male and 85% Caucasian, were enrolled in the study. Variant allelic frequencies were 0.49, 0.93, 0.59 and 0.63 for CYP2B6 516, CYP3A5 392, ABCB1 2677 and ABCB1 3435, respectively. The median efavirenz plasma concentration (MEPC) was 2.2 mg/L [interquartile range (IQR) 1.7-2.8 mg/L] and was significantly higher in patients with the deficient CYP2B6 516T. Overall, 242 CNS events were reported in 104 individuals (54%). No correlation was found between MEPC and CNS events. The occurrence of a first CNS event was lower in patients with the CYP2B6 516 G/G genotype vs. CYP2B6 516 T genotypes [50% (IQR: 40-60%) vs. 66% (IQR: 56-75%), respectively; P = 0.02]. In an adjusted Cox regression model, there was a tendency towards a higher risk of a first CNS event among carriers of the variant CYP2B6 516 T allele (relative risk 1.4 [95% CI, 0.99-2.1]; P?=?.06), compared with noncarriers. CONCLUSIONS: The deficient CYP2B6 516 T allele is associated with higher efavirenz plasma drug levels and more frequent CNS-related symptoms.

Results of the ALBI trial: a randomized comparison of stavudine/didanosine, zidovudine/lamivudine and alternating treatment in antiretroviral-naive patients.

In the ALBI trial, 151 antiretroviral-naive patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 10,000 to 100,000 copies/ml and CD4 cell counts > or = 200 cells/mm3 received 24 weeks of treatment with stavudine/didanosine (n=51), zidovudine/lamivudine (n=51) or stavudine/didanosine for 12 weeks followed by zidovudine/lamivudine (n=49). Baseline plasma HIV-1 RNA and CD4 cell counts were comparable in the treatment groups. The mean decrease in plasma HIV-1 RNA at 24 weeks in the stavudine/didanosine group (2.26 log10) was significantly greater than that in either the zidovudine/lamivudine group (1.26 log10) or the alternating treatment group (1.58 log10) (P<0.0001 for both). Proportions of patients with plasma HIV-1 RNA level <500 copies/ml (91% vs 42% and 60%) and <50 copies/ml (47% versus 4% and 9%) were significantly greater in the stavudine/didanosine group (P<0.001 for pairwise comparisons). Stavudine/didanosine was associated with a mean increase in CD4 cell count (124 cells/mm3) significantly greater than that in the zidovudine/lamivudine group (62 cells/mm3, P<0.01) and comparable to that in the alternating group (118 cells/mm3). All study regimens were well tolerated. These findings, indicating superiority of stavudine/didanosine over zidovudine/lamivudine in virological and immunological response over 24 weeks, suggest that the combination should be considered as a basis for highly active antiretroviral therapy.

Self-reported symptoms after initiation of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART.

PURPOSE: The purpose of our study was to assess short-term self-reported symptoms in patients who were started on two nucleoside reverse transcriptase inhibitors and one protease inhibitor (PI) in the multicenter APROCO cohort (N = 336) and to assess the influence of these symptoms on adherence. METHOD: Adherence and patient's reported symptoms were measured at 1 and 4 months (M) after initiation of highly active antiretroviral therapy (HAART) through self-administered questionnaires. RESULTS: Most patients reported at least one symptom (94.0% at M1; 88.0% at M4); fatigue and diarrhea were the most often reported symptoms. Respectively, 81.3% and 75.0% of patients were strictly adherent to HAART during the 4 days prior to M1 and M4 visits. After adjustment for younger age, history of antiretroviral treatment, unstable housing, poor social support, and alcohol consumption, patients who reported a high number of symptoms at M1 were more likely to be nonadherent at M4 (odds ratio per symptom = 1.13; 95% CI = 1.03-1.24). CONCLUSION: Patients reporting a high number of symptoms soon after HAART initiation are at higher risk of future nonadherence and could be targeted for interventions to achieve good levels of adherence and to improve treatment outcome.

[Improved left ventricular endocardial detection by a first generation contrast agent. Effect of dose]. / Amélioration de la détection de l'endocarde du ventricule gauche par un agent de contraste de première génération. Influence de la dose.

The study of global and segmental left ventricular function forms part of every echocardiographic examination. However, this is only possible when the endocardial borders are well identified. The authors report the results of a study with Albunex, a first generation contrast agent used by intravenous injection. The object of this study was to assess the efficacy of Albunex in improving left ventricular endocardial detection compared with standard transthoracic echocardiography (TTE) and the dose-effect relationship. Forty-one patients were included prospectively at two cardiological hospital centres between 1995 and 1997, before the development of second harmonic imaging. Two patients were excluded from the study. Each patient underwent transthoracic echocardiography in the fundamental mode with an apical four-chamber view. The following procedure was adopted: 1) standard examination, 2) low dose Albunex (0.1 mg/Kg) injected via a peripheral vein, 3) high dose Albunex (0.2 mg/Kg) injected via a peripheral vein, 4) low dose Albunex injected via a central vein, 5) high dose Albunex injected via a central vein. The analysis of results was performed by two independent observers and showed that Albunex improved endocardial detection (p < 0.005); this detection was significantly better with high doses of Albunex and with central vein injection (p < 0.005); the septal border was better visualised than the lateral wall endocardium (p < 0.005) but the improvement in endocardial detection was greater for the lateral wall (p < 0.005). No complications were observed during the procedure. The authors conclude that Albunex improves left ventricular endocardial detection. This benefit is mainly due to improved lateral wall detection, and increases with higher doses of the contrast agent.

Incidence and risk factors of bacterial pneumonia requiring hospitalization in HIV-infected patients started on a protease inhibitor-containing regimen.

OBJECTIVE: To describe the incidence and risk factors of bacterial pneumonia occurring in patients treated with antiretrovirals. METHODS: In the ongoing APROCO (Anti-proteases) cohort, 1281 patients at the initiation of a protease inhibitor (PI)-containing antiretroviral regimen were enrolled from 1997-1999. All events requiring hospitalization during follow up are recorded. Of these, bacterial pneumonia was defined as the occurrence of a new pulmonary infiltrate with fever and either evidence of a bacteriological cause (definite cases) or favourable outcome with antimicrobial therapy (presumptive cases). Risk factors of bacterial pneumonia were studied using survival analyses. RESULTS: During a median follow up of 43 months, 29 patients had at least one episode of bacterial pneumonia, giving an incidence of 0.8/100 patient years. The 11 definite cases were attributable to Streptococcus pneumoniae (n=9), Legionella pneumophila (n=1) and Haemophilus influenzae (n=1). In multivariate analysis, bacterial pneumonia was significantly more frequent in older patients, injecting drug users, patients having a CD4 cell count>500 cells/microL at baseline and patients who initiated PI therapy with nonboosted saquinavir. It was significantly less frequent in nonsmokers. The occurrence of bacterial pneumonia was also associated with lower self-reported adherence to antiretroviral therapy and to higher plasma HIV-1 RNA levels during follow-up. CONCLUSIONS: Bacterial pneumonia occurs rarely in patients treated with a PI-containing regimen and may be associated with virological failure.

Correction of anterior open bite deformity: a study of tongue function, speech changes, and stability.

Nine individuals with anterior open bite underwent tongue function and speech evaluation prior to treatment, postoperatively, and at three-month intervals for at least one year. Aberrant tongue function and speech improved in the absence of tongue or speech therapy during the postoperative period. Periodic clinical and cephalometric evaluation demonstrated generally good stability of treatment results for the period of study.

Predictive factors of occurrence of cytomegalovirus disease and impact on survival in the Aquitaine Cohort in France, 1985 to 1994. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine.

Our objectives were to determine the factors associated with the occurrence of a first episode of cytomegalovirus (CMV) disease in an HIV-infected population and to estimate the overall impact of CMV disease on survival. The study population consisted of the 3525 patients included in the Aquitaine Cohort between 1985 and December 31, 1993. Eligible patients (n = 1868) must have had at least one CD4+ lymphocyte count of <200 cells/mm3 during follow-up, which represents the baseline period. CMV disease manifestations were investigated using standardized definitions. A Cox proportional hazards regression analysis was used to determine the factors independently associated with the probability of developing a first episode of CMV infection and the probability of death. During follow-up, 111 patients presented with a first episode of CMV disease. Four factors were independently associated with the onset of CMV disease: older age at baseline (risk ratio [RR] = 1.03 by a 1-year increase; 95% confidence interval [CI] = 1.02-1.05), homosexuality (RR = 1.90; CI = 1.18-3.02), the progression to a CD4+ lymphocyte count <50/mm3 (RR = 10.58; CI = 5.58-20.05), and the occurrence of toxoplasmosis (RR = 3.00; CI = 1.97-4.57) or a neurologic disease (RR = 2.59; CI = 1.38-4.86) during follow-up. After other predictors were controlled for, CMV disease was associated with a high risk of death in the cohort (RR = 1.58; CI = 1.24-1.94). The development of prophylactic strategies for CMV disease for selected groups of HIV-infected patients must be a priority to improve their quality of life.

Viral load as a primary outcome in human immunodeficiency virus trials: a review of statistical analysis methods.

In Human Immunodeficiency Virus infection, several statistical methods are available to analyze viral load (HIV-1 RNA) used as a surrogate outcome in trials of antiretroviral treatments. We compared the most frequently used methods and applied them to one of these trials, where HIV-1 RNA was measured using two lower limits of detection. Methods were reviewed for different properties dealing with validity, interpretation, and handling. Compared to change of HIV-1 RNA at the end of follow-up or HIV-1 RNA area-under-the-curve during follow-up minus baseline, the most attractive methods appeared to be HIV-1 RNA undetectability, HIV-1 RNA reduction at the end of follow-up with censoring adjustment, and mixed linear model on HIV-1 RNA.

Modeling changes in CD4-positive T-lymphocyte counts after the start of highly active antiretroviral therapy and the relation with risk of opportunistic infections: the Aquitaine Cohort, 1996-1997.

After initiation of a treatment for human immunodeficiency virus type 1 infection containing a protease inhibitor, immune restoration associated with increases in CD4-positive (CD4+) T lymphocyte count may be delayed. In a sample of patients who had been prescribed protease inhibitors for the first time, the authors tested to see whether there was a minimal duration of CD4+ cell count increase before the increase had an impact on the occurrence of opportunistic infections. The evolution (difference between time t and baseline) of CD4+ cell count was modeled using a mixed effects linear model. Changes in CD4+ count estimated by this model were then included as time-dependent covariates in a proportional hazards model. Finally, the authors tested for the existence of a CD4+ change x time interaction. The authors used a sample of 553 French patients first prescribed protease inhibitors in 1996 and followed for a median of 16 months. During the first 120 days, there was no association between CD4+ change and the rate of opportunistic infections. After 120 days, each 50-cell/mm3 increase in CD4+ count was associated with a 60% (95% confidence interval: 45, 72) reduction in the incidence of opportunistic infections. These results, based on modeling of CD4+ cell response, at least indirectly reinforce the concept of a delayed but possible immune recovery with the use of protease inhibitors. The findings support the potential for interruption of certain types of prophylaxis against opportunistic infections under reasonable conditions of duration of antiretroviral therapy and sustained CD4+ cell response.

The dynamic of adherence to highly active antiretroviral therapy: results from the French National APROCO cohort.

OBJECTIVES: Our objective was to describe the evolution of adherence to highly active antiretroviral therapy (HAART) over a 20-month period and its relationship with virologic success. METHODS: Self-reported adherence, clinical, and virologic data were collected 4 (M4), 12 (M12), and 20 (M20) months after initiation of a protease inhibitor-containing regimen in the French APROCO cohort. At each visit, patients were classified as nonadherent, moderately, or highly adherent, and HIV plasma RNA was determined. RESULTS: Among the 762 patients who were regularly followed until M20, the 436 patients who answered to all questionnaires, including adherence measurement, were selected for the analysis. The proportion of highly adherent patients was 55.7%, 62.2%, and 60.3% at M4, M12, and M20, respectively. A total of 137 patients (31.4%) was "always," 225 (51.6%) "sometimes," and 74 (17.0%) "never" "highly adherent" during follow-up. After multiple adjustment for known baseline predictors, virologic success after 20 months of HAART was more likely achieved in patients who were always (odds ratio [OR] 95% confidence interval [CI], 3.02 [1.64-5.58]) or sometimes (OR [95% CI], 2.15 [1.24-3.74]) "highly adherent." CONCLUSION: Adherence behavior is a dynamic process. Continued adherence was associated with better response to therapy and should be encouraged to reduce the risk of virologic failure.

The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus.

A total of 151 previously untreated patients infected with human immunodeficiency virus type 1 (HIV-1) with CD4 cell counts >/=200/microL and plasma HIV-1 RNA levels of 10,000-100,000 copies/mL were randomly assigned to 24 weeks of open-labeled stavudine plus didanosine (group 1), zidovudine plus lamivudine (group 2), or stavudine plus didanosine followed by zidovudine plus lamivudine (group 3). The mean decrease in HIV-1 RNA level was greater in group 1 (2.26 log10 copies/mL) than in groups 2 (1.26 log10 copies/mL) or 3 (1.58 log10 copies/mL; P<.0001). The mean increase in CD4 cell counts was greater in groups 1 (124 cells/microL) and 3 (118 cells/microL) than in group 2 (62 cells/microL; P=.02). All regimens were generally well tolerated. The combination of stavudine plus didanosine reduced plasma HIV-1 RNA concentrations and increased CD4 cell counts more effectively than did the combination of zidovudine plus lamivudine or the regimen alternating both combinations.

Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients.

The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study.

Increases in CD3+CD4-CD8- T lymphocytes in AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection.

Human immunodeficiency virus type 1 (HIV-1)-infected persons frequently have increased numbers of T cells bearing the gamma delta T cell receptor for antigen (gamma delta TCR). HIV-1-seropositive patients with < 100 CD4+ cells/mm3 were selected and divided into 9 AIDS-defining illness groups. The percentages of CD4+, CD8+, or double-negative CD4-CD8- (DN) T cells (most of the latter expressing the gamma delta TCR) for 8 symptomatic groups were compared with those for a reference group of asymptomatic HIV-1-infected patients. DN T cells were increased only in patients with disseminated Mycobacterium avium-intracellulare complex (MAC) infection, toxoplasmosis, or Kaposi's sarcoma. Multivariate logistic regression analysis revealed that the percentage of DN T cells was a better predictor of MAC infection than was the percentage of CD4+T cells. The increased percentage of DN T cells might have important implications for the understanding of gamma delta T cell physiology and for the early diagnosis and management of MAC infections in AIDS patients.