Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study.

BACKGROUND: The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks. METHODS: ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (≥16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50-500 cells per µL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (≤ or >100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above -10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS: Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90·0%) of 321 patients in the efavirenz 400 mg group and 280 (90·6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference -0·6, 95% CI -5·2 to 4·0; p=0·72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0·48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0·03). The number of patients who reported serious adverse events did not differ between the groups (p=0·20). INTERPRETATION: Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation. FUNDING: Bill & Melinda Gates Foundation, and UNSW Australia.

Eosinophil count in nasal mucosa is more suitable than the number of ICAM-1-positive nasal epithelial cells to evaluate the severity of house dust mite-sensitive allergic rhinitis: a clinical correlation study.

BACKGROUND: House dust mite (HDM)-sensitive allergic rhinitis is a perennial rhinitis with persistent nasal inflammation. Currently, there are no reliable parameters to monitor the severity of perennial allergic rhinitis. The purpose of this study was to evaluate correlations between clinical and laboratory parameters in patients with HDM-sensitive allergic rhinitis. METHODS: We measured nasal symptoms, did the Dermatophagoides pteronyssinus (Der P) skin prick test (SPT), evaluated the Der P allergen nasal challenge threshold, and laboratory parameters [(1) inflammatory cell count from nasal mucosal scraping specimens: eosinophils and neutrophils and (2) immunocytochemistry: ICAM-1 expression on nasal epithelial cells] in 20 cases of HDM-sensitive allergic rhinitis and performed correlation tests between all parameters. RESULTS: The wheal diameter induced by Der P SPT was significantly correlated with the Der P allergen nasal challenge threshold (p = 0.001). The number of eosinophils from nasal mucosal scrapping specimens was correlated with the ICAM-1 expression on nasal epithelial cells (p = 0.039), the number of neutrophils from nasal mucosal scrapping specimens (p = 0.001), and nasal stuffiness (p = 0.037) but did not correlate with total nasal symptom scores. CONCLUSION: Clinical symptoms of HDM-sensitive allergic rhinitis showed a poor correlation with inflammatory parameters. The eosinophil count in nasal mucosa is correlated with ICAM-1 expression and more suitable than ICAM-1 levels to evaluate the severity of HDM-sensitive allergic rhinitis. This study also supports the role of the SPT in the diagnosis of nasal allergy to HDM.

Pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in HIV-infected Thai patients.

OBJECTIVES: To describe the pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients. PATIENTS AND METHODS: Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either indinavir 800 mg every 8 h (n = 19) or indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS: The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for indinavir AUC, Cmax and Cmin were 20.9 (13.1-27.0) mg x h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg x h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an indinavir Cmin of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg x h/L were at increased risk of developing nephrotoxicity. CONCLUSIONS: Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population

Impact of particulate air pollutants on allergic diseases, allergic skin reactivity and lung function.

Elevated levels of particulate matter can exacerbate existing asthma and atopy, while evidence that it can promote the induction of atopy and asthma is limited. A cross sectional study was taken to compare the prevalence of eye, nose, ear and airway allergic symptoms, allergic skin sensitivity and lung function in 290 high school students with a history of high 24 hour average exposure to particulate matter less than 10 microm in diameter (PM10) = 170 microg/m3 versus low PM10 of 36 microg/m3 in central Bangkok. Multivariate analysis revealed an increased risk of eye and airway symptoms in groups exposed to higher PM10 levels (p = 0.003, and 0.05, respectively). Positive skin prick tests and a history of having a lawn at home were associated with nasal symptoms (p = 0.008 and 0.04, respectively). Mean FEF(25-75%) (forced expiratory flow that occurs during the middle 50% of the forced expiratory effort) was significantly lower in those who were exposed to higher PM10 levels (3.89 +/- 1 vs 4.42 +/- 0.9 l/sec, p < 0.001). A significant increase in days of school absence and medical expenses was associated with high PM10 exposure. It is concluded that chronic exposure to high PM 10 levels was significantly associated with increased prevalence of eye and airway symptoms and a decrement of FEF(25-75%) resulting in increase of school absence and medical expense.