Clinical Implications of Stopping Nevirapine-Based Antiretroviral Therapy: Relative Pharmocokinetics and Avoidance of Drug Resistance

NE Mackie; S Fidler; N Tamm; JR Clarke; D Back; JN Weber; GP Taylor

Disclosures

HIV Medicine. 2004;5(3) 

In This Article

Abstract and Introduction

Objective: To determine the pharmacokinetics of cessation of nevirapine (NVP) in order to design clinical protocols which will reduce the risk of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs).
Methods: In a case study, NNRTI genotypic resistance was demonstrated in a patient discontinuing therapy for toxicity. Subsequently, nine patients receiving NVP-containing antiretroviral regimens and stopping treatment were recruited. Patients were advised to continue the nucleoside analogue reverse transcriptase inhibitor (NRTI) backbone for 5 days following cessation of NVP. Plasma NVP concentrations were determined over 7-10 days after the last dose. HIV-1 reverse transcriptase genotyping was performed at viral load rebound (approximately day 21 following cessation) to detect mutations associated with reduced NNRTI sensitivity.
Results: The median predicted time for plasma NVP concentration to fall below the inhibitory concentration (IC)50 of wild-type virus was 168 h (range 108-264 h). De novo genotypic mutations conferring resistance to NRTIs or NNRTIs were not demonstrated following cessation of therapy.
Conclusions: The prolonged elimination half-life of NVP compared with NRTIs, which persists even after 20 weeks of therapy, raises concern over the development of NNRTI resistance if all three drugs are stopped together. Continuation of the NRTI backbone for a further 5 days, allowing the elimination of NVP, may avoid the development of drug resistance.

Highly active antiretroviral therapy (HAART) can durably suppress viral replication to below the current limits of detection (<50 HIV-1 RNA copies/mL plasma) with significant clinical benefit. Persistent HIV replication in the presence of HAART selects mutations within HIV pol that are associated with reduced susceptibility to therapy. These mutations can also reduce the efficacy of subsequent regimens as a result of cross-resistance, with obvious clinical implications. After stopping therapy, drug-resistant strains may become undetectable by current techniques as wild-type virus re-emerges as the dominant strain.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are frequently part of the currently recommended combinations for the treatment of HIV-1 infection. Two NNRTIs are licensed in the UK: nevirapine (NVP) and efavirenz (EFV). NNRTIs are characterized by similar pharmacokinetic parameters, including excellent oral absorption and a long half-life, and are extensively metabolized in the liver through cytochrome P450. NVP is also an inducer of the cytochrome P450 enzyme CYP3A (and CYP2B6), with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy. NVP concentrations of greater than 3000 ng/mL are recommended for sustained suppression of viral replication, although activity has been reported against wild-type virus at 10 ng/mL.[1]

The current NNRTIs have a low genetic barrier to the selection of resistance, and a single key mutation in the NNRTI-specific pocket site or in the surrounding domain poses a major therapeutic problem for this class. Resistant virus emerges rapidly and uniformly when NVP is administered as monotherapy, and so NVP should always be administered in combination with drugs from other classes.[2,3,4]

Treatment interruptions are not currently recommended as routine clinical practice. However, adverse events are common and may require cessation of therapy; patients may opt to take a 'drug holiday', and pregnant women may take therapy until delivery to reduce the risk of mother-to-child transmission of HIV. In addition, short-course treatment of primary HIV infection is under investigation.[5] Some guidelines[6] recommend that all therapy is discontinued simultaneously to reduce the risk of resistance, but this does not allow for the different clearance rates of the individual constituents of a combination. Although the efficacy and half-life of NVP are an advantage in combination therapy, these attributes also make NVP susceptible to the emergence of resistance. Indeed, resistance mutations have been observed following exposure to a single dose of NVP when administered to pregnant women[3] or even when added to other therapy.[4]

Few data are available on the management of cessation of NNRTI-based therapy in order to avoid a 'monotherapy' state and the potential evolution of drug-resistant variants. From the half-life of NVP, it can be estimated that NRTIs should be continued for 5-7 days following cessation of NVP in order to avoid this. We present a case report that demonstrates the problems that can result from cessation of all components of an NNRTI-containing HAART regimen at the same time and a pharmacokinetic study demonstrating the intersubject variability of NVP clearance in patients on established therapy. A protocol for stopping NNRTI-containing HAART to limit the development of drug resistance is proposed.

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