Efavirenz 600 mg exposure appears sufficient with high-dose daily rifapentine
19 June 2019. Related: Conference reports, PK and drug interactions, TB coinfection, PK Workshop 20th 2019.
Polly Clayden, HIV i-Base
Preliminary pharmacokinetic (PK) data support starting efavirenz (EFV)-based ART during TB treatment with high-dose daily rifapentine (RPT). These findings were presented at the 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs.
The Tuberculosis Trials Consortium Study 31 (S31)/AIDS Clinical Trials Group Study A5349 is a phase 3 trial comparing two short-course TB treatment regimens including high dose daily RPT to standard TB treatment.
RPT is a CYP inducer and EFV is a CYP substrate, so there is a potential risk of decreased EFV exposure with co-administration. A secondary objective and sub study of S31/A5349 was to look at the effect of RPT on EFV PK in treatment-naive participants starting EFV-based ART while receiving RPT-based TB treatment.
This sub study included participants starting EFV-based (600mg) ART within the first 9 weeks of TB treatment, randomised to one of two regimens containing daily RPT (1200mg), isoniazid (H), pyrazinamide and either ethambutol or moxifloxacin.
Data were presented for 28 evaluable participants: 25% women, 96% black/African, median age 36 years and mean baseline CD4 count 252 cells/mm3.
Median EFV concentrations approximately 4 and 8 weeks after starting EFV were: 2.76 (IQR 2.12 to 4.67) mg/L and 2.86 (IQR 2.19 to 4.88) mg/L respectively. EFV concentrations at week 22 (after TB treatment completed) were: 2.86 (IQR 1.93-4.21) mg/L.
The protocol specified that at least 80% of participants must have EFV concentrations >1 mg/L at both time points during TB treatment in order to continue enrolment.
The percentage of participants with EFV concentrations >1 mg/L at 4 and 8 weeks after starting EFV were: 25/28 (89%) and 26/28 (93%). At week 22 19/21 (90%) of participants had EFV concentrations >1mg/L.
Median EFV CL/F were: 7.28 (IQR 5.47 to 10.08) and 8.3 (IQR 6.17 to 10.66) L/hr during and post RPT/H respectively.
The GMR of during to post RPT/H EFV CL/F was 0.89 (90% CI 0.64 to 1.23). Median baseline viral load (n=25) was 81,003 copies/mL; 20/23 (87%) participants had undetectable viral load at week 22.
These data provide preliminary support for initiating EFV-containing ART during co-administration of daily high-dose RPT for TB treatment.
This presentation included a summary of ongoing investigations and knowledge gaps in the use of RPT DDI with ART. See Table 1.
Table 1. Gaps in RPT DDI pharmacology
| LTBI | Compatible ART | DDI trial status | Results expected | Knowledge gaps |
| 3HP | EFV RAL 400 mg BID DTG |
3HP w/ TAF in HV (Yoda) enrolling | Final 2020 | 3HP + TAF in HIV+ |
| 1HP | EFV | ACTG A5372 | Initial PK 2020 | DTG (what dose?) TAF |
| TB treatment | Compatible ART | DDI trial status | Results expected | Knowledge gaps |
| RPT x 17 weeks (S31) | EFV | S31/A5349 | Final PK results late 2019 | DTG TAF |
Key: DDI drug drug interaction; DTG, dolutegravir; EFV, efavirenz; LTBI, latent TB infection; PK, pharmacokinetics; RAL, raltegravir; RPT, rifapentine; TAF, tenofovir alafenamide; 1HP, one month isoniazid/rifapentine; 3HP, three month isoniazid/rifapentine.
Adapted from Swindells and Dooley
Reference
Podany A et al. Efavirenz pharmacokinetics in HIV/TB coinfected persons initiating ART while receiving high dose rifapentine. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. 14–16 May 2019, Noordwijk, the Netherlands. Oral abstract 1.
http://regist2.virology-education.com/presentations/2019/20AntiviralPK/07_Podany.pdf (PDF slides)