Efficacy and safety in clinical practice of a rilpivirine,tenofovir and emtricitabine single-tablet regimen in virologically suppressed HIV-positive patients on stable antiretroviral therapy

Introduction

Switching to a rilpivirine, tenofovir and emtricitabine (RTE) single-tablet regimen (STR) has been evaluated in a limited number of virologically suppressed patients. The aim of this study was to describe clinical outcomes in HIV-positive patients switched from a suppressive antiretroviral regimen to RTE STR in routine clinical practice.

Methods

In this retrospective study of antiretroviral-treated patients with <50 copies of HIV RNA/mL switched to RTE STR, virological failure (VF) was defined as two consecutive measurements of ≥50 copies/mL or a single measurement of ≥50 copies/mL followed by any change in treatment. Treatment failure (TF) was defined as VF or discontinuation of the STR for any reason. Univariate mixed-linear models were used to identify differences in laboratory parameters over time.

Results and discussion

The analysis involved 307 patients (83% males) with a median age of 45.8 years (interquartile range (IQR 39.3–50.9), who were followed up for a median of 7.4 months (IQR 4.6–10.9). VF occurred in three patients (1%) switched from a protease inhibitor (PI)-based regimen, after a median of 2.6 months (IQR 1.6–3.0), and TF in 34 patients (11%) after a median of three months (IQR 1.4–5.8), 24 of whom (71%) were receiving a PI-based regimen at baseline. Overall, there was a slight but statistically significant improvement in the mean monthly change from baseline in CD4+ cell counts (p=0.027), the CD4+/CD8+ ratio (p=0.0001), and Hb (p=0.024), alanine amino transferase (ALT) (p=0.009), total bilirubin (p<0.0001), indirect bilirubin (p<0.0001), total cholesterol (p<0.0001) and triglyceride (p<0.0001) levels. There was also a slight but statistically significant increase in serum creatinine (p=0.0004), aspartate amino transferase (AST) (p=0.001) and liver fibrosis index (FIB-4) (p=0.002), and a decrease in eGFR_creat (p<0.0001) and high-density lipoprotein (HDL) cholesterol (p<0.0001) values. The study limitations include its retrospective design, the relatively short follow-up, and the absence of data concerning the severity of clinical adverse events; however, it does provide new information concerning the laboratory changes that occur in patients switching from PI-based or PI-sparing regimens to RTE STR.

Conclusions

The study findings confirm the efficacy and safety in clinical practice of switching to RTE STR in virologically suppressed patients receiving other antiretrovirals.     

Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose

Aims

To determine pharmacokinetic and pharmacogenomic correlates of efavirenz central nervous system (CNS) side effects following a single dose.

Methods

Thirty-four healthy HIV-negative African Americans were administered a 600 mg dose of efavirenz. Blood samples for pharmacokinetics were drawn serially from 0 to 12 h post-dose. Neuropsychometric testing with drowsiness visual analogue scale, grooved pegboard and letter digit substitution tests was done the day prior to dosing and at 1, 2, 3, 4 and 6 h post-dose. Subjective CNS symptoms were assessed at 6 h post-dose. Composite CYP2B6 516/983 genotype was determined.

Results

Pharmacokinetic indices reflecting increased plasma efavirenz exposure were associated with slower non-dominant hand grooved pegboard task completion (C_max, P_{1 h} = 0.01, P_{2 h} = 0.05, P_{3 h} = 0.03, P_{4 h} = 0.01; AUC, P_{1 h} = 0.04; clearance P_{1 h} = 0.05, P_{2 h} = 0.02, P_{6 h} = 0.01). In a repeated measures model analysis that adjusted timing of neuropsychometric testing for timing of peak drug concentration, clearance (P < 0.001), AUC(0.312 h) (P = 0.001) and C_max (P = 0.008) were associated with non-dominant grooved pegboard test performance. CYP2B6 genotype trended to correlate with non-dominant hand grooved pegboard at 4 and 6 h (P = 0.07 and 0.06). Decreased drowsiness at 6 h was associated with higher C_max (P = 0.02).

Conclusions

Following a single dose of efavirenz, an association between pharmacokinetics and neuropsychometric performance was discernable. A weaker association between genotype and neurocognitive test performance is likely mediated by effect of genotype on plasma clearance. Strategies that lower C_max during initial dosing may decrease CNS side effects.     

Efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all?

ATRIPLA? (Bristol-Myers Squibb and Gilead Sciences) is a complete regimen in a single, fixed-dose combination tablet that contains: efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg. Current treatment guidelines recommend this triple combination for initial therapy because of its excellent potency, tolerability and favorable safety profile. Individually, these agents have long half-lifes that allow for once-daily dosing and may provide a pharmacologic bridge for the occasional missed dose. Although several options for once-daily regimens are available, comparative clinical trials are still in progress. This article reviews relevant efficacy and safety data of efavirenz, emtricitabine and tenofovir disoproxil fumarate, compared with other once-daily agents or certain common alternate drugs presently used as initial therapy in treatment-naive patients.     

Neuronal toxicity of efavirenz: a systematic review

Introduction: Efavirenz commonly causes early neuropsychiatric side effects, but tolerance develops in most patients. There is emerging evidence that efavirenz use may damage neurons, which could result in impaired neurocognitive performance.

Areas covered: The authors conducted a systematic review using the PubMed database, references cited by other articles and conference web sites to determine if there is evidence that efavirenz may contribute to cognitive impairment by damaging nerve cells.

Expert opinion: There is weak clinical evidence suggesting that efavirenz use may worsen neurocognitive impairment or be associated with less improvement in neurocognitive impairment than other antiretrovirals. Efavirenz, especially its major metabolite 8-hydroxy-efavirenz, is toxic in neuron cultures at concentrations found in the cerebrospinal fluid. Extensive metabolizers of efavirenz may therefore be more likely to develop efavirenz toxicity by forming more 8-hydroxy-efavirenz. Several potential mechanisms exist to explain the observed efavirenz neurotoxicity, including altered calcium hemostasis, decreases in brain creatine kinase, mitochondrial damage, increases in brain proinflammatory cytokines and involvement of the cannabinoid system. There is a need for large randomized controlled trials to determine if the neuronal toxicity induced by efavirenz results in clinically significant neurological impairment.