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Summary 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. [ABSTRACT FROM AUTHOR]

Abstract: We herein report the 5α-reductase inhibitors, antiviral and anti-tumor activities of some synthesized heterocyclic cyanopyridone and cyanothiopyridone derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds, except 3b, were interestingly less toxic than the reference drug (Prednisolone®). Seventeen heterocyclic derivatives containing a cyanopyridone or cyanothiopyridone rings fused to a steroidal moiety were synthesized and screened for their 5α-reductase inhibitors, antiviral and anti-tumor activities comparable to that of Anastrozole, Bicalutamide, Efavirenz, Capravirine, Ribavirin, Oseltamivir and Amantadine as the reference drugs. Some of the compounds exhibited better 5α-reductase inhibitors, antiviral and anti-tumor activities than the reference drugs. The detailed 5α-reductase inhibitors, antiviral and anti-tumor activities of the synthesized compounds were reported. [Copyright &y& Elsevier]

Abstract: A simple and rapid isocratic, high performance liquid chromatography (HPLC) assay employing solid phase extraction (SPE) for the simultaneous determination of the anti HIV drug, efavirenz, the anti-tuberculosis drug, rifampicin and the desacetyl metabolite of rifampicin in plasma from HIV/tuberculosis infected patients has been developed. Using a Zorbax SB-Phenyl reverse-phase analytical column with UV detection, good separation and detection of the drugs was attained within a 10min run time. Intra- and inter-assay precision RSD values were found to be less than 15% at the concentrations examined (0.1–20μg/mL). The LOQ was found to be 0.1μg/mL for each agent and the assay was found to generate a linear response up to 20μg/mL. This low cost assay can accurately detect efavirenz and rifampicin concentrations within a clinically relevant concentration range using standard chromatography equipment, making it particularly applicable to resource-limited settings. [Copyright &y& Elsevier]

Abstract: Efavirenz is commonly used as part of the highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) type 1. The effects of chronic administration of efavirenz on the kidney of adult Wistar rats were investigated. The rats were divided into two groups, those given efavirenz (treatment) and those given water (control), both for 30 days. The animals were sacrificed by cervical dislocation on Day 31 of the experiment and kidneys were dissected, weighed and quickly fixed in 10% formalin for histological analysis. The findings indicate that there was a significant (p < 0.05) decrease in weight and increase in relative weight of treated right and left kidneys compared to the control group. Kidneys in the treated group showed disruption of the cytoarchitecture of the renal cortical structure, diffuse glomerulonephritis with some cell congestion, and dilation of Bowman’s space compared to the control group. Chronic efavirenz administration may therefore have an adverse effect on the kidney function of adult Wistar rats. Further studies to corroborate these observations should be carried out. [Copyright &y& Elsevier]

Abstract: Objectives: To assess the budget impact of the government use licenses policy, a form of compulsory licensing used by the government, on seven patented drugs, namely, efavirenz, lopinavir/ritonavir combination, clopidogrel, letrozole, docetaxel, erlotinib, and imatinib, in Thailand between 2006 and 2008. Methods: By using government''s perspective, budget impact was estimated within a 5-year period after the introduction of the policy. The number of patients who need treatment with each drug and the costs of treatments by both original and generic versions were obtained from Thai government agencies. Probabilistic sensitivity analysis was used to determine the impact of uncertainty surrounding parameters such as the numbers of patients and the health-care costs. Results: The study indicated that the use of generic drugs under the policy could save the government budget approximately $370 million over 5 years. It was also found that each drug had a different effect on budget saving depending on the number of patients treated, the difference in drug costs between original and generic drugs, and the lag time from the introduction of the policy to the availability of the generic drugs on the market. Conclusion: The study showed that the introduction of the government use licenses policy in Thailand would provide significant benefits for the study timeframe; however, there are several issues that should be taken into account when the government use licenses policy is adopted. [Copyright &y& Elsevier]