Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all

Abstract

Importance of the field: HIV/tuberculosis (TB) co-infection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy during TB treatment is associated with substantial survival benefit but drug-drug interactions complicate NNRTI dosing.

Areas covered in this review: We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. PubMed database was searched from 1966 to July 2009 using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed.

What the reader will gain: A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies were controlled for genetic factors and there were limited data on children.

Take home message: There were insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that the standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug-gene interactions.

Figure 1

Disposition of cytochrome P450 substrates such the protease inhibitors (PIs) or the nonnucleoside reverse transcriptase inhibitors (NNRTIs) and potential influence of induction or inhibition of enzymes or transporters on systemic drug exposure. *Rifampin is a potent inducer and the NNRTIs and PIs are themselves inducers and/or inhibitors of CYP enzymes or P-glycoprotein transporter. Modulation of these systems may cause altered metabolism and drug concentrations when inducers and/or inhibitors are used concurrently with enzyme substrates.

Figure 2

Efavirenz concentration-time profile in three healthy volunteers in the absence (close circles) and presence of rifampin (open circles). The effect of rifampin co-administration varied from a reduction in efavirenz area under the curve by 100% (A) to an intermediate of a reduction by 42% (B) to an increase by 56% (C).

Figure 3

Nevirapine Cmax (A), Cmin (B) and AUC (C) in 13 patients with HIV and tuberculosis in the absence and presence of rifampicin. Nevirapine and rifampicin were administered at standard dosage and patients were in steady state. Rifampicin co-administration caused a mean reduction in Cmax by 42%, Cmin by 53% and AUC by 46%.