Early Virologic Rebound in a Pilot Trial of Ritonavir-Boosted Atazanavir as Maintenance Monotherapy

Olle Karlström, MD; Filip Josephson, MD; Anders Sönnerborg, MD, PhD

Disclosures

J Acquir Immune Defic Syndr. 2007;44(4):417-422. 

In This Article

Abstract and Introduction

Abstract

Objective: To investigate the feasibility of ritonavir-boosted atazanavir monotherapy in HIV-1-infected patients with stable antiretroviral therapy (ART).
Design: Single-armed single-center pilot trial.
Methods: Adult HIV-1-infected patients, without protease inhibitor (PI) experience, were eligible if they had maintained a viral load <20 copies/mL for a minimum of 12 months on conventional ART. The trial regimen was atazanavir/ritonavir at a dose of 300/100 mg once daily. The atazanavir dose could be adjusted if plasma concentrations showed a low exposure. The study was intended to recruit 30 patients to be followed over 72 weeks. If 5 cases of virologic failure occurred during this period, the study was to be terminated.
Results: The study was terminated according to protocol when 15 of the planned 30 patients had been recruited, because 5 cases of virologic failure had occurred. In patients failing therapy, viral rebound was seen at weeks 12 through 16. Plasma atazanavir concentrations were not associated with the outcome. The median serum bilirubin concentration was significantly lower in the patients failing therapy, however. No PI resistance was found in samples from patients failing therapy.
Conclusions: Ritonavir-boosted atazanavir as maintenance monotherapy in HIV-1 infection might not be as potent as conventional ART. Serum bilirubin should be further studied as a biomarker of adequate atazanavir exposure.

Introduction

Presently, the recommended initial therapy for HIV-1 infection consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) combined with 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) or 1 protease inhibitor (PI). Important long-term adverse effects include lipoatrophy, fat accumulation, and the metabolic syndrome, with component drugs often acting in synergy. Thus, it would be of great value if treatment could be simplified using as few drugs as possible, with these preferably being those with the least long-term toxicity.

The drug combinations are characterized by a high antiretroviral potency and a high genetic barrier to drug resistance. Both of these features are crucial for treatment success. It is notable that these qualities seem to be present in ritonavir-boosted PIs in the absence of other antiretroviral drugs. For instance, the short-term potency of ritonavir-boosted lopinavir was not significantly different when combined with 2 NRTIs.[1a] Furthermore, loss of virologic efficacy requires several mutations in the HIV-1 genome. Indeed, no development of PI mutations has been found in clinical trials of previously untreated patients when using boosted PIs along with 2 NRTIs.[1,2] Thus, successful long-term monotherapy with a boosted PI might be possible.

When PIs are used without ritonavir boosting, drug exposures are significantly lower. In this situation, the resistance barrier is confined to a single key mutation. This could be a reason why early trials exploring maintenance therapy using 1 PI or 1 PI plus 1 NRTI were disappointing, with a high frequency of virologic rebound.[3,4,5] Several recently reported pilot trials exploring maintenance monotherapy with ritonavir-boosted indinavir,[6] lopinavir,[7,8,9] and, just recently, atazanavir[10,11] have shown more promising results, with a lower frequency of viral rebound. Our pilot trial of maintenance monotherapy was conducted using boosted atazanavir because it has the most favorable metabolic profile[12] among the approved boosted PIs and is easily administrated once daily. The trial included carefully selected patients previously naive to PI therapy, who had maintained virologic suppression for a minimum of 1 year.

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