Nevirapine or efavirenz for tuberculosis and HIV coinfected patients: exposure and virological failure relationship*

Abstract

ObjectivesWe describe nevirapine and efavirenz exposure on and off tuberculosis treatment and consequences for virological efficacy and tolerance in patients included in the ANRS 12146/12214-CARINEMO trial.MethodsParticipants were randomly selected to receive either nevirapine at 200 mg twice daily (n = 256) or efavirenz at 600 mg daily (n = 270), both combined with two nucleoside analogues. Blood samples were drawn 12 h after nevirapine or efavirenz administration, while on tuberculosis treatment and after tuberculosis treatment discontinuation. In 62 participants, samples taken 12 h after drug administration were drawn weekly for the first month of ART. Sixteen participants participated in an extensive pharmacokinetic study of nevirapine. Concentrations were compared with the therapeutic ranges of 3000–8000 ng/mL for nevirapine and 1000–4000 ng/mL for efavirenz.ResultsNevirapine concentrations at the end of the first week of treatment (on antituberculosis drugs) did not differ from concentrations off tuberculosis treatment, but declined thereafter. Concentrations at steady-state were 4111 ng/mL at week 12 versus 6095 ng/mL at week 48 (P < 0.0001). Nevirapine concentrations <3000 ng/mL were found to be a risk factor for virological failure. Efavirenz concentrations were higher on than off tuberculosis treatment (2700 versus 2450 ng/mL, P < 0.0001).ConclusionsThe omission of the 2 week lead-in dose of nevirapine prevented low concentrations at treatment initiation but did not prevent the risk of virological failure. Results support the WHO recommendation to use efavirenz at 600 mg daily in patients on rifampicin-based antituberculosis therapy.

Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review

“…Of the 14 studies conducted among adult patients that reported EFV concentrations on and off RH, 10 were in Africa and four in Asia. Notably, among the 10 adult studies conducted in Africa, six reported higher EFV concentration during RH coadministration compared to the off‐RH period, although the difference is highly variable, ranging from 3.7% to 33.3% across studies and countries . The remaining four adult African studies reported a lower EFV concentration while on RH, still with a difference that is highly variable, ranging from –16.3 to –33.3% .…”

“…Of the total 119 records retrieved, 22 records were included in the analysis (Figure 1). Of these, 20 studies had data on at least mean or median EFV C 12 (n = 16) or predose C min (n = 6) measured either in the morning (n = 4) or evening (n = 2) during RH coadministration [17,35,38,[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65], while one study only reported body weight-specific EFV C 12 data during RH coadministration [66] and one reported only proportions of patients with subtherapeutic EFV concentrations [67]. Table 1 shows characteristics of the 22 included studies.…”

“…In addition, many of these studies also showed an increase in EFV concentrations during RH coadministration. Notably, the two studies that enrolled >200 patients reported a very small difference (~4%) in median EFV C 12 with vs . without RH coadministration.…”

The pregnane X receptor in tuberculosis therapeutics

“…Nevirapine is metabolized by both CYP3A4 and CYP2B6 [87]. Nevirapine plasma concentration declined when co-administered with RIF [88, 89]. Efavirenz is metabolized mainly by CYP2B6, an enzyme that is upregulated by PXR [55, 90, 91].…”

“…Efavirenz is metabolized mainly by CYP2B6, an enzyme that is upregulated by PXR [55, 90, 91]. However, the data are inconsistent with a clinically significant effect of RIF on efavirenz metabolism [89, 92]. …”