No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database

Objective

To assess the potential association of selected antiretrovirals (ARVs), including efavirenz, with suicidality.

Design

Retrospective analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS), by performing a Multi-Item Gamma Poisson Shrinker (MGPS) disproportionality analysis.

Methods

MGPS disproportionality analysis, a technique to identify associations between drugs and adverse events, was performed using cumulative data from the FAERS database collected up to August 2012. This method yields an Empirical Bayesian Geometric Mean score and corresponding 90% confidence interval (EB05, EB95). EB05 scores ≥2 were pre-defined as a signal for a potential drug-event association. The FAERS database includes spontaneous adverse-event reports from consumers and healthcare professionals. All FAERS reports of suicidality (including suicidal ideation, suicide attempt and completed suicide or a composite of these) in patients taking efavirenz (as single agent or in fixed-dose combination), atazanavir, darunavir, etravirine, nevirapine and raltegravir were identified. A number of parallel analyses were performed to assess the validity of the methodology: fluoxetine and sertraline, antidepressants with a known association with suicidality, and raltegravir, an ARV with rhabdomyolysis and myopathy listed as “uncommon” events in the US-prescribing information.

Results

A total of 29,856 adverse event reports were identified among patients receiving efavirenz, atazanavir, darunavir, etravirine, nevirapine and raltegravir, of which 457 were reports of suicidality events. EB05 scores observed for the composite suicidality term for efavirenz (EB05=0.796), and other ARVs (EB05=0.279–0.368), were below the pre-defined threshold. Fluoxetine and sertraline gave EB05 scores for suicidality >2. Raltegravir gave EB05 scores >2 for myopathy and rhabdomyolysis.

Conclusions

The pre-determined threshold for signals for suicidality, including suicidal ideation, suicide attempt, completed suicide and a composite suicidality endpoint, was not exceeded for efavirenz and other ARVs in this analysis. Efavirenz has been associated with suicidality in clinical trials. Further studies that adjust for confounding factors are needed to better understand any potential association with ARVs and suicidality.     

The relation between efavirenz versus nevirapine and virologic failure in Johannesburg,South Africa

Introduction

Previous research has raised concerns that patients given nevirapine (NVP)-based regimens experience more virologic failure than patients given efavirenz (EFV)-based regimens. We investigated this hypothesis in a cohort of HIV-positive patients at a large HIV treatment clinic in South Africa.

Methods

All antiretroviral therapy (ART)-naïve non-pregnant patients, ≥18 years old, without tuberculosis, who initiated treatment with either NVP or EFV from April 2004 to August 2011 at the Themba Lethu Clinic in Johannesburg, South Africa, were included. Log-binomial regression and modified Poisson regression were used to estimate risk ratios (RR) with 95% confidence intervals (CI) for predictors of virologic failure, virologic suppression, and loss to follow-up (LTF), whereas a Cox proportional hazards model was used to estimate the risk of death, all within one year.

Results

Of 12,840 included patients, 62.0% were female and the median baseline CD4 count was 98 cells/mm³ (36–169). Of these patients, 93.2% initiated an EFV-based regimen. After adjusting for baseline characteristics, no difference in death (adjusted Hazards Ratio (aHR): 0.92; 95% CI: 0.68–1.25), LTF (adjusted Risk Ratio (aRR): 1.00; 95% CI: 0.79–1.25), nor suppression (aRR: 0.98; 95% CI: 0.95–1.00) at one year was found between regimens. Among patients with ≥1 viral load ≥4 months after ART initiation, 4% (n=350) experienced virologic failure within 12 months of initiation. Patients initiating NVP-based regimens were 60% more likely to fail than patients initiating EFV-based regimens (aRR: 1.58; 95% CI: 1.13–2.22).

Conclusions

In this cohort, patients initiating NVP-based regimens experienced more virologic failure than patients initiating EFV-based regimens. Future guidelines should consider the implications of different efficacy profiles when making recommendations for which drugs to prioritize.     

Evaluation of an immunoassay for determination of plasma efavirenz concentrations in resource-limited settings

Introduction

Therapeutic drug monitoring (TDM) may improve antiretroviral efficacy through adjustment of individual drug administration. This could result in reduced toxicity, prevent drug resistance, and aid management of drug–drug interactions. However, most measurement methods are too costly to be implemented in resource-limited settings. This study evaluated a commercially available immunoassay for measurement of plasma efavirenz.

Methods

The immunoassay-based method was applied to measure efavirenz using a readily available Humastar 80 chemistry analyzer. We compared plasma efavirenz concentrations measured by the immunoassay with liquid chromatography tandem mass spectrometry (LC-MS/MS) (reference method) in 315 plasma samples collected from HIV patients on treatment. Concentrations were categorized as suboptimal<1 µg/ml, normal 1–4 µg/ml or high>4 µg/ml. Agreement between results of the methods was assessed via Bland-Altman plot and κ statistic values.

Results

The median Interquartile range (IQR) efavirenz concentration was 2.8 (1.9; 4.5) µg/ml measured by the LC–MS/MS method and 2.5 (1.8; 3.9) µg/ml by the immunoassay and the results were well correlated (ρ=0.94). The limits of agreement assessed by Bland–Altman plots were −2.54; 1.70 µg/ml. Although immunoassay underestimated high concentrations, it had good agreement for classification into low, normal or high concentrations (K=0.74).

Conclusions

The immunoassay is a feasible alternative to determine efavirenz in areas with limited resources. The assay provides a reasonable approximation of efavirenz concentration in the majority of samples with a tendency to underestimate high concentrations. Agreement between tests evaluated in this study was clinically satisfactory for identification of low, normal and high efavirenz concentrations.     

Comparing the efficacy of efavirenz and boosted lopinavir using viremia copy-years

Introduction

HIV-1 plasma viral load during treatment can be highly variable. Thus, there is the need to find a measure of cumulative viremia that can be used to assess both the short- and long-term efficacy of highly active antiretroviral therapy (HAART). Here, we validate a measure of cumulative viremia to evaluate HAART efficacy.

Methods

We accessed HAART efficacy using data from a randomized clinical trial conducted in Mexico. We compared the proportion of individuals achieving a viral load <50 and <400 copies/mL at week 48, against the cumulative plasma viral load, estimated as the area under the plasma viral load curve (AUVLC). High AUVLC indicates high cumulative viremia.

Results and discussion

There was a strong and significant association between the proportion of individuals achieving a viral load <50 and <400 copies/mL at week 48, with individuals suppressed having significant lower cumulative viremia. The median area was 7513 (25th–75th percentile [Q1–Q3] 6634−8180) if viral load <50 copies/mL and 7679 (Q1–Q3 6899−9373) if viral load ≥50 copies/mL (p-value 0.0284). When the analysis was stratified by study arm, individuals on efavirenz had lower cumulative viremia than those on boosted lopinavir.

Conclusions

Our findings suggest that cumulative viremia should be explored further as a tool to simultaneously evaluate the individual and public health efficacy of HAART. This is particularly relevant to the implementation and evaluation of the Treatment 2.0 strategy recently proposed by UNAIDS and the WHO, as a means to maximize the individual and public health benefit of HAART.     

基因多态性与利福平对依非韦伦的疗效影响

依非韦伦（efavirenz）是中国HIV-1感染者广泛使用的一线抗HIV-1治疗药物。该药的临床标准用量来源于以白种人为主的临床试验,考虑到人种的差异、病理生理及合并用药的不同等对依非韦伦药物动力学的影响,标准剂量的依非韦伦并不适合所有的患者。本文综述依非韦伦血药浓度与其不良反应和疗效的相关性,依非韦伦相关代谢酶的基因多态性、利福平对其血药浓度的影响,并总结了有关中国HIV-1感染者使用依非韦伦的相关研究等,希望为临床及科研工作者提供参考。     

Efavirenz concentrations in HIV-infected patients with and without viral hepatitis

AIMS

Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included.

METHODS

A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period.

RESULTS

No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 ± 1.91 mg l^–1) vs. co-infected individuals (2.37 ± 0.37 mg l^–1).

CONCLUSION

It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• HIV-1 co-infection with HBV/HCV is the most important factor determining efavirenz-induced liver toxicity. Higher efavirenz plasma concentrations have been reported in these patients facilitating concentration drug-related adverse effects.
• It is not known whether changes in efavirenz disposition are due to the hepatitis infection/inflammation or to liver failure. As a consequence, the guidelines for the application of therapeutic drug monitoring of efavirenz in HBV/HCV co-infected patients have not been established.

WHAT THIS STUDY ADDS

• The present study has shown that HBV/HCV infection in itself does not predispose to higher efavirenz plasma concentrations. In the absence of hepatic failure, the risk of efavirenz concentration-dependent toxicity is not increased.
• Thus, therapeutic drug monitoring indications in co-infected patients with hepatic function within the normal range should be the same as in HIV-1 mono-infected patients.

     

Nevirapine- versus efavirenz-based highly active antiretroviral therapy regimens in antiretroviral-naïve patients with advanced HIV infection

Objective

To compare virological and immunological responses to nevirapine (NVP)‐based and efavirenz (EFV)‐based highly active antiretroviral therapy (HAART) regimens in antiretroviral‐naïve patients with advanced HIV infection.

Methods

A retrospective observational cohort study was conducted on antiretroviral‐naïve HIV‐infected patients whose pretreatment CD4 cell counts were less than 100 cells/μL or whose viral loads were greater than 100 000 HIV‐1 RNA copies/mL.

Results

Baseline characteristics of patients in the NVP (n=24) and EFV (n=29) groups were not different. The proportion of patients with viral loads >100 000 copies/mL was higher in the EFV group. The probability of virological success estimated by the Kaplan‐Meier method showed that 3‐ and 6‐month success rates were 30.8% [95% confidence interval (CI): 16.7–52.2%] and 63.1% (95% CI: 44.7–81.3%) for the NVP group. The corresponding values were 41.2% (95% CI: 25.8–61.0%) and 62.9% (95% CI: 45.7–80.1%) for the EFV‐based group. The median success times of the two groups were about 4 and 3 months (P=0.678), respectively, for NVP and EFV. Cox's proportional hazard was used after adjusting for age, previous opportunistic infections (OIs), and viral load at baseline, and showed that patients who received the NVP‐based regimen had about 25% [hazard ratio (HR)=0.75, 95% CI: 0.37–1.51] less chance of virological success than patients who received the EFV‐based regimen (P=0.415). The median times to CD4≥100 cells/μL were 5.6 and 4.4 months for the NVP‐ and EFV‐based regimens, respectively (log‐rank test, P=0.144).

Conclusions

NVP‐ and EFV‐based HAART regimens as initial regimens in patients with advanced HIV infection are effective and comparable, in term of virological and immunological responses. However, further large‐scale randomized controlled clinical trials in this group of patients with advanced HIV infection are needed.

     

基于HPMCAS载体的依非韦伦固体分散体溶出模式研究

目的 以依非韦伦为原料药、不同规格（L、M、H）HPMCAS为载体，采用喷雾干燥法制备固体分散体并对其溶出模式进行初步探究。方法 通过X射线粉末衍射（XRPD）、扫描电子显微镜（SEM）对固体分散体理化性质进行制剂学表征；以动力溶解度为指标考察不同药载比、不同规格HPMCAS固体分散体的溶出情况；通过粒度分析仪和透射电子显微镜（TEM）、SEM探讨固体分散体溶出时的不同模式。结果 XRPD分析显示，固体分散体中药物以无定形的形态分散在HPMCAS中；SEM分析显示，L、M、H规格HPMCAS与依非韦伦形成的固体分散体均具有"萎缩葡萄干"形态；在pH 6.8磷酸缓冲盐溶液中溶出时，药载比1：6的固体分散体溶出好，药载比1：1.5的固体分散体溶出差且相同药载比时L规格HPMCAS的固体分散体溶出更快。结论 以不同规格HPMCAS为载体制备的依非韦伦固体分散体在pH 6.8磷酸缓冲盐溶液中溶出时，存在多种溶出模式。药载比1：6时，L、M规格HPMCAS的固体分散体以药物纳米颗粒的形式溶出；药载比1：1.5时，L、M规格HPMCAS的固体分散体存在类似溶蚀的溶出模式，药物从载体骨架中释放。