New protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

AuthorLascar, Monica
PositionLEADING ARTICLE - Drug overview

INTRODUCTION

In spite of major progress in the field of antiretroviral drug development, there continues to be a need for more potent and better-tolerated antiretroviral treatments and in particular, therapies that are effective for the increasing pool of treatment-experienced patients.

This review focuses on the new protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) that are currently available for clinicians to prescribe and explores their potential niche in antiretroviral treatment choices. Drugs that are still in development and are inaccessible outside clinical trials are not discussed, nor are new formulations of well-established agents.

NEW PROTEASE INHIBITORS

Darunavir (TMC114, DRV) and tipranavir (TPV) are important new ritonavir-boosted protease inhibitors, with efficacy in patients who have had prior treatment failure with this class and whose viruses exhibit extensive resistance-conferring mutations in the protease gene. There are no head-to-head comparisons between these two new drugs, but the existing data can help guide the prescriber when deciding between them. The nuances of the mutation patterns that impair the efficacy of one more than the other can help identify which may perform better for individual patients. Tolerability and the potential for drug-drug interactions are also important considerations when choosing between these two agents.

Concerns regarding toxicity and drug-drug interactions make ritonavir-boosted tipranavir (TPV/r) an unlikely first choice for treatment-experienced patients whose resistance profiles indicate that they may respond to ritonavir-boosted darunavir (DRV/r). In addition to its efficacy when dosed at 600/100 mg twice daily in patients with protease-inhibitor resistance, DRV/r 800/100 mg once daily has also performed well head-to-head against ritonavir-boosted lopinavir (LPV/r) in naive patients, and competes favourably with the existing repertoire of first-line boosted PIs. Tipranavir is not recommended for treatment-naive patients who may choose from a range of more tolerable and less toxic regimens.

DARUNAVIR

Darunavir has a strong binding affinity for the HIV-1 protease and has been shown to be effective in vitro against wild type and multi-drug-resistant strains ofHIV [1-3]. The clinical efficacy of darunavir was first demonstrated in highly treatment-experienced patients with previous triple-class exposure and advanced HIV disease (POWER trials; [4]). The potential clinical use of darunavir was then explored in less treatment-experienced patients who were lopinavir-naive (TITAN), followed by ongoing trials in treatment-naive patients (ARTEMIS).

EFFICACY IN SALVAGE

The POWER trials [4] demonstrated the efficacy and safety of darunavir with low-dose ritonavir at week 48 in highly treatment-experienced patients. After 24-week dose-finding phases and primary efficacy analyses, patients were randomised to receive DRV/r 600/100 mg twice daily, and patients receiving investigator-chosen control protease inhibitors continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background therapy (OBT). The use of enfuvirtide was permitted as part of the OBT, but not of tipranavir, another new and potent PI with good activity in the setting of multiple PI mutations [5]. Patients were assessed at week 48 in an intent-to-treat (ITT) analysis. The results for those who discontinued earlier were considered to be treatment failures for virological response (in a time to loss of virological response algorithm [TLOVR]). At week 48, 67 of 110 (61%) DRV/r patients compared with 18 of 120 (15%) control PI patients achieved a viral load drop of at least 1 [log.sub.10] copies/ml (primary end-point), with a highly significant difference in response rates (46%; 95% confidence interval [CI] 35-57%; P

EFFICACY IN TREATMENT-EXPERIENCED PATIENTS

The efficacy and safety of DRV/r was further assessed in lopinavir-naive treatment-experienced patients (TITAN), where the main aim of the study was to show non-inferiority of DRV/r 600/100 mg twice daily compared with LPV/r 400/100 mg twice daily in terms of virological response. Both agents were given in addition to an OBT. In contrast to the POWER trials, where DRV/r already seemed superior to LPV/r, the patients selected here were less treatment-experienced and the use of enfuvirtide was not permitted, aiming to reduce selection bias and focus on the intrinsic antiviral efficacy of darunavir compared to lopinavir. Results from TITAN showed that more patients in the DRV/r arm compared to the LPV/r arm achieved HIV-RNA

EFFICACY IN NAIVE PATIENTS

In ARTEMIS, DRV/r is being assessed as a single-dose agent 800/100 mg in treatment-naive patients against LPV/r in addition to the fixed-dose combination Truvada (tenofovir/emtricitabine) in both arms. Preliminary data analysis (ITT-TLOVR algorithm) at week 48 [8] showed that 84% of patients in the DRV/r arm achieved a viral load

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