If efavirenz is coadministered with rifampicin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg/day may be considered. Coadministration of rifampicin (600 mg once daily) and efavirenz (600 mg once daily) decreased efavirenz AUC, Cmax and Cmin by 26%, 20% and 32%, respectively. When taken with rifampicin in patients weighing 50 kg or greater, increasing efavirenz daily dose to 800 mg may provide exposure similar to a daily dose of 600 mg when taken without rifampicin. The clinical effect of this dose adjustment has not been adequately evaluated. Individual tolerability and virological response should be considered when making the dose adjustment. No dosage adjustment is necessary for rifampicin.

If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg once daily is recommended. Coadministration of rifampicin (600 mg) with efavirenz (600 mg) in 12 subjects caused a 20% decrease in efavirenz Cmax, a 26% decrease in AUC, and a 32% decrease in Cmin.

The effect of a higher dose of rifampicin (35 mg/kg) on the pharmacokinetics of dolutegravir or efavirenz was evaluated in coinfected HIV/TB adults. Newly-diagnosed TB patients were randomized to either a standard (10 mg/kg) or a higher (35 mg/kg) dose of rifampicin. Antiretroviral treatment naïve patients were assigned to dolutegravir or efavirenz based regimens. Patients on dolutegravir or efavirenz based regimens at enrolment were maintained on the same regimen, however, dolutegravir was adjusted from once daily to twice daily dosing. Pharmacokinetic sampling was performed 6 weeks post TB treatment initiation with sampling for dolutegravir 12 hours (Ctrough) after the last dose and a mid-dose sampling for efavirenz. Overall, 149 participants were enrolled in the study. Geometric mean (95% CI) dolutegravir trough concentration for patients on higher dose rifampicin was lower than for those receiving standard dose rifampicin: 0.46 (0.31-0.67) mg/L versus 0.80 (0.56-1.14) mg/L, with a GMR of 0.57 (0.34-0.97). Using a threshold of 0.3 mg/L, a higher proportion of participants on higher dose rifampicin failed to attain the target dolutegravir through concentration compared to those on standard dose (39% vs 7%), P = 0.014. Using a lower target threshold of 0.064 mg/L, the difference in target attainment between higher and standard dose rifampicin was not statistically significant (4.4% vs 3.6%), P = 0.999. No patients with dolutegravir concentrations below either target thresholds had a detectable HIV viral load at week 24. The geometric mean for efavirenz mid-dose concentrations for patients on higher dose rifampicin was 37% lower than those receiving the standard dose: 2.94 (95% CI, 1.98-4.36) mg/L vs 4.64 (3.31-6.50) mg/L, with a GMR of 0.63 (0.38-1.07), P = 0.083. The proportion of patients who failed to attain the target mid-dose efavirenz concentrations of 1 mg/L was not significantly different between the 2 groups. No patients below the target had a detectable HIV viral load at week 24. Grade 3-4 adverse effects were similar in the high vs standard dose rifampicin arms. Sputum conversion at week 8 was higher in high dose versus standard dose arms. In conclusion, compared to the standard dose, a three-fold dose increase for rifampicin reduced plasma exposure of dolutegravir and efavirenz without loss of virological control of HIV.

This systematic review analysed 22 studies of efavirenz and rifampicin-isoniazid coadministration in patients from high TB/HIV burden countries. Rifampicin induces CYP2B6 (the enzyme responsible for the majority of efavirenz metabolism) and the product labels for efavirenz recommends an increase in efavirenz dosing from 600 mg to 800 mg once a day, when coadministered with rifampicin to patients weighing 50 kg or more. However, the WHO recommends maintaining the 600 mg once a day dose in high HIV burden countries due to an increased risk of CNS toxicity with increased efavirenz concentrations. This meta-analysis found that efavirenz C12 or Cmin was within the therapeutic range (1000-4000 ng/ml) when the 600 mg daily dose was coadministered with rifampicin-isoniazid. Only in one study (in children) were efavirenz concentrations subtherapeutic and this is likely to be driven by adherence, CYP2B6 polymorphism or low EFV dosing in children. The results of this systematic review support efavirenz dosing of 600 mg once daily with rifampicin-isoniazid administration in coinfected African and Asian patients.

Efavirenz pharmacokinetics were determined in HIV-infected patients without TB receiving EFV (400 mg once daily, with FTC/TDF) and rifampicin-isoniazid at baseline (n=26) and after 4 weeks (n=22) and 12 weeks (n=17) of treatment. Coadministration with rifampicin-isoniazid was associated with limited changes in efavirenz exposure (decreases of 16%, 25% and 16% for Cmax, C24 and AUC at week 12) and concentrations were maintained within the range measured in the ENCORE-1 study irrespective of CYP2B6 genotype. All patients had viral loads below 50 copies/ml at baseline and this was maintained throughout this study. These results suggest that efavirenz can be administered at 400 mg once daily with rifampicin, but these results should be confirmed in HIV/TB-coinfected patients.

Efavirenz pharmacokinetics were evaluated in Ugandan HIV/TB co-infected patients receiving high-dose rifampicin (20 mg/kg) as part of their standard TB treatment with efavirenz 600 mg once daily (n=31) or 800 mg once daily (n=33) and compared to values obtained in patients receiving rifampicin (10 mg/kg) with efavirenz 600 mg once daily (n=33). No relationship could be evidenced between viral load decline and efavirenz concentrations. Despite a trend to lower efavirenz concentrations when rifampicin dosing was doubled, concentrations remained in the therapeutic window and there was no sign of decreased tolerance.

Coadministration of rifampicin-based TB treatment (rifampicin 450 mg in patients <50 kg or 600 mg in patients >50 kg, once daily; with isoniazid, pyrazinamide and ethambutol) and efavirenz/tenofovir-DF/emtricitabine (600/245/200 mg, once daily) was studied in 21 TB-HIV coinfected patients in a crossover study. Coadministration increased efavirenz AUC, Cmax and Cmin by 8%, 2% and 11%, respectively; tenofovir AUC and Cmin increased by 13% and 9% respectively, while Cmax decreased by 2%; emtricitabine AUC and Cmin increased by 5% and 26% respectively, while Cmax decreased by 3%. Bioequivalence for the TB drugs was suggested for Cmax when administered with and without efavirenz/tenofovir/emtricitabine (coadministration decreased rifampicin by 14%, decreased isoniazid by 5%, increased pyrazinamide by 14% and had no effect on ethambutol). The combination was tolerated well by Tanzanian TB–HIV-coinfected patients. The authors conclude that coadministration of the standard first-line TB treatment regimen with efavirenz, tenofovir and emtricitabine does not alter pharmacokinetic parameters.