Special Feature

Atazanavir: Have We Finally Arrived at Once-Daily Dosing for HIV?

By John O’Brien, PharmD, HIV Pharmacy Specialist, Positive PACE Clinic, Santa Clara Valley Medical Center, and Carol A. Kemper, MD, FACP

Introduction

Atazanavir (Reyetaz®), an azapeptide class of protease inhibitors, was approved by the US FDA for use in HIV infection on June 20, 2003. Atazanavir (ATV) has a unique pharmacokinetic profile allowing for once-daily dosing, which is optimized when taken with food.

Clinical Trials Data

Several clinical trials, in both antiretroviral (ARV)-naïve and -experienced patients, comparing combinations of 2 nucleoside reverse transcriptase inhibitors (nRTIs) with either ATV or another protease inhibitor, have been completed, some of which are available for review only in abstract form. In a randomized, dose-blinded clinical trial in which 420 treatment-naïve patients were enrolled, Sanne and colleagues evaluated combinations of d4T, ddI, and various dosages of ATV (either 200, 400, or 500 mg daily) vs nelfinavir (NLF) 750 mg t.i.d.1 The average CD4 count and viral load for the 4 treatment groups were similar at entry to study (about 350 and 4.7 log10 viral copies/mL, respectively). In the intent-to-treat analysis, 36% of patients receiving ATV 400 mg daily and 39% of those receiving NLF were undetectable (HIV viral load < 50 copies/mL) at 48 weeks of therapy. CD4 count increases were similar for the 2 groups (220 cells/mm3 and 185 cells/mm3 for the ATV 400 mg and NLF groups, respectively). Patients receiving ATV had significantly less diarrhea (20%) compared with those receiving NLF (60%) (P < .0001). Jaundice occurred in 6% of patients receiving ATV 400 mg daily, compared with none of the patients receiving NLF (P < .03). Mean fasting LDL decreased 4% in patients receiving ATV, while LDL increased 30% in patients receiving NLV.

In a second double-blind clinical trial, treatment-naïve patients with CD4 counts > 100 cells/mm3 were randomly assigned to receive d4T/3TC plus either ATV 400 mg or 600 mg daily, or NLF 1250 mg b.i.d. for 48 weeks.2 Baseline CD4 and viral loads were similar for both ATV arms and NLF (baseline CD4, ~270 cells/mm3). In the intent-to-treat analysis following 48 weeks of therapy, 31%, 36%, and 38% of patients receiving ATV 400 mg, ATV 600 mg, or NLF, respectively, had viral loads < 50. Baseline HIV viral loads decreased 2.51, 2.58, and 2.31, respectively (P < .05, comparing all 3 groups). Increases in CD4 cell counts were similar.

Haas and colleagues assessed the response of 85 treatment-experienced patients who were randomized to receive 2 nRTIs plus either ATV 400 mg daily or 600 mg once daily, saquinavir (SAQ) 1200 mg once daily, or ritonavir 400 mg/SAQ 400 mg twice daily.3 At baseline the groups were well matched, with a similar mean CD4 cell count (~330 cells/mm3), although slightly more than half of the patients receiving ATV 400 mg daily had viral loads > 30,000 copies/mL, compared with 22% of patients receiving RTV/SAQ. Following 48 weeks of therapy, the reduction in HIV viral load was similar for patients receiving either dose of ATV or RTV/SAQ, and CD4 counts increased 109, 55, and 149 cells, respectively (P values not reported).

In a fourth study, 358 protease-inhibitor-experienced patients were randomly assigned to receive tenofovir plus one other nRTI plus either ATV 300 mg/RTV 100 mg daily, ATV/SAQ once daily, or lopinavir/ritonavir (LPV/r). The groups were well balanced at entry to study, with an average CD4 count of ~300 cells/mm3. In the intent-to-treat analysis, 39%, 23%, and 42% of patients receiving either ATV/RTV, ATV/SAQ, or LPV/r, respectively, were undetectable (< 50 particles/mL) at 24 weeks of therapy.

On the other hand, once-daily atazanavir 400 mg/d did not appear to perform as well as LPV/r in another study involving heavily pretreated patients failing their current protease inhibitor. Cohen and colleagues randomly assigned 300 patients failing their current PI, all of whom had baseline CD4 counts > 50 cells/mL, to receive either ATV 400 mg/d (unboosted) or LPV/r.5 At 24 weeks of therapy, 54% of patients receiving LPV/r vs 38% of those receiving ATV had undetectable viral loads (< 50 particles/mm3).

Pharmacokinetics

Atazanavir inhibits both cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1). The latter is responsible for bilirubin glucuronidation. Atazanavir, similar to other available protease inhibitors, has the potential to interact with substrates, inhibitors, or inducers of CYP3A4. Important drug interactions can therefore occur with many different drugs, especially those agents with a narrow therapeutic window, such as benzodiazepines (triazolam, alprazolam) and calcium channel blockers. Agents known to induce the CYP3A4 system (eg, nevirapine and efavirenz) markedly lower the blood levels of ATV. To offset this interaction, it is recommended to decrease the ATV to 300 mg and add RTV 100 mg daily, thereby increasing the minimum concentration (Cmin) and maintaining or decreasing the Cmax (the latter is believed to be more responsible for potential toxicity).

An interaction between ATV and tenofovir has also emerged. From a pharmacokinetic standpoint, this is difficult to envision: ATV is fully metabolized by the liver, and TDF is eliminated unchanged by the kidneys. Nonetheless, in 34 healthy controls, the Cmin of ATV was diminished by up to 48% (mean, 40%) in the presence of tenofovir.6 In patients with HIV infection, an about sevenfold increase in Cmin of ATV has been found when ATV 300 mg/d is boosted by RTV 100 mg/d. However, when tenofovir was added, the mean Cmin dropped 26%. Based on these results, ATV 300 mg should always be boosted with RTV 100 mg/d whenever tenofovir is also used in the regimen. The mechanism for this drug interaction is not fully elucidated, but could be some type of pharmacodynamic interaction on the level of P-glycoprotein or some other type of efflux transporter.

Side Effects

In contrast to other protease inhibitors, ATV is associated with fewer GI side effects, although this advantage might be diminished if the drug is boosted with RTV. Atazanavir has been shown to increase the QTc and PR intervals, usually at higher dosages than those used for most HIV regimens. This may have contributed to the death of a patient enrolled in the expanded-access study (which excluded subjects with a baseline QTc interval > 450 msec). This individual was receiving ATV plus delavirdine (a known CYP3A4 inhibitor), as well as verapamil (a substrate for CYP3A4, as well as a potent inhibitor of P-glycoprotein). It is prudent to obtain a baseline EKG in those with known or suspected cardiovascular disease. Furthermore, the clinician should avoid medications that may increase ATV drug levels or that have the potential to alter the QTc interval.

Summary

Adherence to ARV medications is an important consideration when structuring an antiretroviral regimen. Both clinicians and patients have been eagerly awaiting a once-daily regimen with as few pills as possible. Atazanavir is the first FDA-approved once-daily protease inhibitor. Moreover, it appears to be well tolerated, with fewer GI side effects than some of the other PIs, and may be very useful in patients with hyperlipidemia.

References

1. Sanne I, et al. Results of a phase 2 clinical trial at 48 weeks (AI424-007): A dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naïve subjects. J Acquir Immune Defic Syndr. 2003;32: 18-29.

2. Sanne I, et al. Atazanavir vs nelfinavir in combination with stavudine and lamivudine in treatment-naïve, HIV-infected patients: 48 week results. (Abstract) ICAAC, 2001.

3. Haas DW, et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: A randomized comparative pilot trial. AIDS. 2003;17:1339-1349.

4. Clotet B, et al. (Abstract) IAS, July 2003.

5. Cohen et al. Atazanavir vs lopinavir/ritonavir in patients with virologic failure to a protease inhibitor (Abstract). IAS, July 2003.