The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing ≥48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4+ cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (−16%), fasting low-density lipoprotein cholesterol (−21%), and fasting triglycerides (−28%) (P < 0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.
From *Somerset Hospital, Capetown, South Africa; †Chulalongkorn University, Bangkok, Thailand; ‡Fundación Huésped, Buenos Aires, Argentina; §Federal AIDS Center, Moscow, Russia; ‖Service des Maladies Infectieuses et Tropicales, Hôpital Tennon, Paris, France; ¶Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; #HIV Comprehensive Care Center, North Broward Hospital District, Ft. Lauderdale, FL; **Northwestern University, Chicago, IL; and ††Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT.
Received for publication October 24, 2003; accepted March 4, 2004.
This study was funded by Bristol-Myers Squibb.
Reprints: Michael Giordano, Pharmaceutical Research Institute, Bristol-Myers Squibb Company; 5 Research Parkway, Wallingford, CT 06492 (e-mail: Michael.Giordano@bms.com).
Introduction of highly active antiretroviral therapy (HAART) has led to a significant reduction in morbidity and mortality in patients with advanced HIV infection. Much of the impact of HAART on HIV infection and its progression to AIDS has been the result of the wide acceptance of HAART regimens. 1,2 The achievement of longer life spans with HAART has transformed HIV from a deadly disease to an incurable but chronic illness. Consequently, clinicians must consider not only the long-term effectiveness but the long-term safety and tolerability of the component parts of antiretroviral therapy.
Protease inhibitor (PI) therapy has been most strongly associated with a syndrome characterized by dyslipidemia, peripheral lipodystrophy, and insulin resistance. 3–5 Evidence suggests that the development of hypercholesterolemia and hypertriglyceridemia in patients with HIV has health implications similar to, if not greater than, those associated with the presence of these same lipid abnormalities in the general population 6–10 and has prompted the issuance of guidelines for the management of dyslipidemia in this patient population. 11,12 Thus, dyslipidemia adds a new and previously unanticipated health risk to the use of antiretroviral therapy.
Atazanavir is an azapeptide PI with a low pill burden and a pharmacokinetic profile supporting once-daily dosing. 13 Clinically, atazanavir produces rapid and durable HIV RNA suppression and durable increases in CD4+ cell count. 14–16 Atazanavir may be a viable alternative to other PIs for long-term HIV treatment because of its benign effects on lipid levels. Therapy with atazanavir does not result in clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. 14–16
This report describes the efficacy and safety of a median cumulative 108 weeks of extended atazanavir therapy in treatment-naive patients during a qualifying study, BMS AI424-008, 15 and during a rollover into BMS AI424-044. It also evaluates the effects of a switch from nelfinavir to atazanavir on viral load, CD4+ cell count, and PI-associated dyslipidemia.
BMS AI424-008 was a randomized, active-controlled, blinded (by atazanavir dose) trial in treatment-naive HIV-infected patients that has been described previously. 15 Briefly, in BMS AI424-008, eligible patients were randomized in a 2:2:1 ratio to treatment with atazanavir, 400 mg, once daily; atazanavir, 600 mg, once daily; or nelfinavir, 1250 mg, twice daily plus lamivudine (150 mg twice daily) and weight-dependent doses of stavudine twice daily (30 mg and 40 mg for patients <60 kg and ≥60 kg, respectively). Patients completing at least 48 weeks in BMS AI424-008 were eligible for entry into the open-label, rollover/switch study, BMS AI424-044. BMS AI424-044 entry criteria required HIV RNA levels below 10,000 copies/mL at the most recent available measurement taken on completion of BMS AI424-008. 15 Patients were excluded from BMS AI424-044 if they were expected to require treatment with myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic, or cytotoxic agents. A history of pancreatitis, proven or suspected acute hepatitis within 30 days, or chronic hepatitis with liver function test results at least 3 times above the upper limit of normal (ULN) were additional criteria for exclusion, as were hemophilia or other clinical conditions that might impair adherence or make the patient unsuitable for participation in the study.
Study Assignment and Treatment
Patients originally assigned to receive atazanavir in BMS AI424-008 received the same drug regimen, including nucleosides, in BMS AI424-044. After the database from BMS AI424-008 had been locked and analyzed, the atazanavir dose level was unblinded in BMS AI424-044 and atazanavir was administered in an open-label fashion. Patients originally assigned to receive nelfinavir plus nucleosides in BMS AI424-008 were switched to open-label atazanavir, 400 mg, plus the same nucleosides in BMS AI424-044 (nelfinavir-to-atazanavir 400-mg treatment group).
Assessments and Monitoring
Patients were evaluated by history and physical examination for vital signs and symptoms of adverse events and HIV-related adverse events on completion of BMS AI424-008 (designated as BMS AI424-044 entry), weeks 4 and 12, and every 12 weeks thereafter. Laboratory studies included fasting chemistry (including lipids), hematology, urinalysis, and plasma HIV RNA levels and CD4+ counts.
HIV RNA levels were measured at entry into BMS AI424-044 and every 12 weeks thereafter using the Roche AMPLICOR HIV-1 MONITOR ultrasensitive methodology (Roche Diagnostics, Branchburg, NJ), version 1.0 or 1.5 (accuracy range: 50–75,000 copies/mL). To measure HIV RNA, plasma was collected in Vacutainer PPT Plasma Preparation Tubes (PPT tubes; Becton Dickinson and Company, Franklin Lakes, NJ) provided by the study. HIV RNA levels greater than 75,000 copies/mL were reflexively measured using the Roche AMPLICOR HIV-1 MONITOR standard methodology (accuracy range: 400–750,000 copies/mL).
Statistical analyses of safety and efficacy data were conducted through 24 weeks of atazanavir therapy in BMS AI424-044. All efficacy analyses were exploratory and used the evaluable efficacy data set, which included treated patients with HIV RNA or CD4 measurements at entry into BMS AI424-044. Response rates at scheduled weeks for analysis were summarized based on virologic response–observed cases (VR-OC) analysis, presented for the limit of quantification (LOQ) of 400 copies/mL, the lower limit of detectability for the Roche AMPLICOR HIV-1 MONITOR standard methodology, and for the LOQ of 50 copies/mL, the lower limit of the Roche AMPLICOR HIV-1 MONITOR ultrasensitive methodology. VR-OC analysis classified subjects who remained on treatment as responders according to a single HIV RNA measurement below the LOQ that was taken closest to the scheduled visit and within a predefined visit window. The denominator was based on all subjects on treatment at the time of the analysis-week visit. The change from entry into BMS AI424-044 in CD4+ cell counts using observed values summarized the longitudinal analysis of immunologic response. Mean changes from entry into BMS AI424-044 were plotted at each scheduled visit.
The primary lipid analysis compared the percent change from entry into BMS AI424-044 to week 12 in TC concentrations in patients who were switched from nelfinavir plus stavudine and lamivudine to atazanavir, 400 mg, plus stavudine and lamivudine. The analysis used the evaluable safety data set, which included treated patients with lipid measurements at entry into BMS AI424-044. To assess whether the week 12 mean percent changes in lipids from entry were significantly less than 0, the comparison used a 95% confidence interval (CI) and P value based on the t-distribution. Durability of the effect on all lipid parameters for all treatment cohorts was summarized similarly. Use of lipid-lowering agents was not prohibited by the protocol. Lipid measurements obtained after the start of lipid-lowering therapy were censored (not included in the lipid analyses). The frequencies of adverse events, serious adverse events, deaths, laboratory abnormalities, and therapy discontinuations because of adverse events were tabulated by treatment group.
In general, patient characteristics on entry into BMS AI424-044 were comparable between the treatment groups (Table 1). Median HIV RNA level at entry into BMS AI424-044 was 1.73 log10 copies/mL; 75% of the patients had HIV RNA levels <400 copies/mL. Median CD4+ cell count at entry was 495 cells/mm3. Consistent with the differential effects of atazanavir and nelfinavir on lipid levels, lipid-lowering agents were used by 1% of the patients in each of the atazanavir treatment groups and by 10% of the patients in the nelfinavir group before entry. The median cumulative time on therapy was approximately 108 weeks (>72 weeks in BMS AI424-008 and >36 weeks in BMS AI424-044). Treatment discontinuations are shown in Table 2.
Virologic and Immunologic Outcome
After 24 weeks of atazanavir treatment in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL (Fig. 1). The proportion of patients with HIV RNA levels <50 copies/mL was also comparable across treatment groups at week 24 (atazanavir, 400 mg, 60%; atazanavir, 600 mg, 56%; and nelfinavir-to-atazanavir, 400 mg, 60%). When the cumulative treatment response for the 2 studies was assessed, the results showed either stability of or an increase in the proportion of patients with HIV RNA levels <400 copies/mL and <50 copies/mL at median cumulative week 108 compared with values at week 48 of BMS AI424-008 (Table 3). 15 Mean increases in CD4+ cell counts at week 24 were comparable across treatment groups: atazanavir, 400 mg, 44 cells/mm3; atazanavir, 600 mg, 43 cells/mm3; and nelfinavir-to-atazanavir, 400 mg, 29 cells/mm3.
Alterations in Lipid Profiles
In BMS AI424-044, patients who were treated with atazanavir during BMS AI424-008 and had median levels of TC, fasting LDL-C, and fasting TG in BMS AI424-044 showed minimal fluctuation compared with the levels observed at baseline in BMS AI424-008 (Fig. 2). 15 In contrast, patients switched from nelfinavir to atazanavir, 400 mg, on entry into BMS AI424-044 showed reductions in TC, fasting LDL-C, and fasting TG levels and showed increases in HDL-C by the time of the interim 12-week analysis in BMS AI424-044 (see Fig. 2). The mean percent changes in these parameters from the time of BMS AI424-044 entry to week 12 were statistically significant: TC, −16% (P < 0.0001); fasting LDL-C, −21% (P < 0.0001); fasting TG, −28% (P < 0.0001); and HDL-C, +5% (P < 0.05). At week 24, statistically significant differences were maintained for TC, fasting LDL-C, and fasting TG; specifically, the mean percent changes from entry to week 24 were −16% for TC, −20% for fasting LDL-C, and −25% for fasting TG. At week 24, the mean percent change for HDL-C remained at +5% but was no longer statistically significant.
Lipid Changes Related to National Cholesterol Education Program Target Guidelines
At BMS AI424-008 baseline, most of the patients who ultimately entered BMS AI424-044 had TC and fasting LDL-C levels within the desirable (<200 mg/dL) or optimal (<130 mg/dL) ranges as defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines (Fig. 3). 17 At entry into BMS AI424-044, most of the patients in the 2 atazanavir treatment groups continued to have TC and fasting LDL-C levels within the desirable or optimal ranges; however, most of the nelfinavir-to-atazanavir 400-mg patients had values that exceeded these levels (52% with TC ≥200 mg/dL and 55% with fasting LDL-C ≥130 mg/dL;Fig. 3). By week 12, the proportion of patients with TC and fasting LDL-C levels within desirable and optimal ranges, respectively, had increased in the nelfinavir-to-atazanavir 400-mg treatment group to a level that was generally comparable among all treatment groups. At week 24, the proportion of patients with TC <200 mg/dL was 67%, 64%, and 66% for the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir 400-mg groups, respectively; the proportion with fasting LDL-C levels below 130 mg/dL was 77%, 66%, and 70% for these respective groups.
Adverse Events and Laboratory Abnormalities
No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups (Table 4). Grade 3 or 4 and serious adverse events were infrequent, occurring with a comparable incidence among treatment groups. The most frequent laboratory abnormality in BMS AI424-044 was elevated total bilirubin (see Table 4), predominantly of the indirect and unconjugated type. The incidence of grade 3 (2.6–5 times ULN) or grade 4 (>5 times ULN) elevations in total bilirubin was higher for patients who continued on atazanavir (atazanavir, 400 mg, 26%; atazanavir, 600 mg, 44%) than for patients who were switched from nelfinavir to atazanavir, 400 mg (13%). Grade 4 elevations in total bilirubin were transient and occurred in only 5 patients (atazanavir, 400 mg, 1 patient [1%]; atazanavir, 600 mg, 4 patients [3%]). Three of these patients, all in the atazanavir 600-mg treatment group, had grade 4 elevations and underwent a reduction in dose in accordance with the protocol. Grade 3 or 4 elevations in aminotransferases were infrequent and were reported in 2% or less of treated patients. No patients had concurrent grade 3 or 4 elevations in total bilirubin and aminotransferases during treatment in BMS AI424-044.
Analysis of the cumulative safety profile of BMS AI424-008 and BMS AI424-044 demonstrated a comparable incidence of overall adverse events between the atazanavir 400-mg (93%) and the atazanavir 600-mg (95%) treatment groups. In general, the long-term safety profile of atazanavir was consistent with that observed in BMS AI424-008 alone. Jaundice was reported more frequently in the atazanavir 600-mg treatment group than in the atazanavir 400-mg group (22% vs. 13%). The incidence of scleral icterus and scleral jaundice, however, was comparable between the 2 atazanavir treatment groups (10% and <1%, respectively, in the atazanavir 400-mg group, and 13% and <1%, respectively, in the atazanavir 600-mg group).
Atazanavir is a PI that can be dosed once daily and shows potent antiviral activity without inducing clinically relevant increases in TC, fasting LDL-C, or fasting TG levels. 14–16 In BMS AI424-044, efficacy assessments demonstrated that extended use of atazanavir in treatment-naive patients resulted in sustained virologic suppression over a median treatment time of approximately 108 weeks and in continued increases in CD4+ cell count. Patients switched to atazanavir from nelfinavir showed increased viral suppression and CD4+ cell counts to levels comparable to those observed in the original atazanavir treatment groups of BMS AI424-008, 15 suggesting that virologically suppressed nelfinavir-treated patients can switch to atazanavir without loss of antiviral efficacy.
In BMS AI424-008, treatment with nelfinavir resulted in sustained mean percent increases of 23% to 50% from baseline in TC, fasting LDL-C, and fasting TG, whereas patients treated with atazanavir had no clinically relevant alterations in lipid parameters (increase of 5% to 8%). 15 In BMS AI424-044, patients who continued atazanavir treatment from BMS AI424-008 did not experience any clinically relevant changes in lipid levels over the long term. In addition, virologically suppressed nelfinavir-treated patients experienced statistically significant improvements in TC, fasting LDL-C, and fasting TG, approaching antiretroviral pretreatment levels as early as 12 weeks after beginning atazanavir treatment on entry into BMS AI424-044. The percentage of patients with desirable TC levels or optimal range fasting LDL-C levels, as defined by the NCEP Adult Treatment Panel III guidelines, also increased by 24 weeks after the switch from nelfinavir to atazanavir. These levels were comparable to those observed in the patients treated with atazanavir throughout BMS AI424-008 and BMS AI424-044. 15
A number of potential mechanisms have been proposed to explain PI-provoked dyslipidemia. PIs have been implicated in the suppression of adipogenesis and increased lipolysis, 18 stimulation of hepatic lipid synthesis, 19,20 reduced TG storage and increased levels of circulating TG, 21–23 and suppression of proteasome-induced degradation of apolipoprotein B in hepatocytes. 24 The reasons why dyslipidemia is not seen on atazanavir treatment are not yet clear. In vitro, however, atazanavir does not induce TG synthesis in HepG2 cells as strongly as ritonavir or nelfinavir. 25,26 In addition, atazanavir exhibits less interference than indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir in in vitro models of lipogenesis and proteasome function. 26
In the present study, long-term treatment with atazanavir was generally safe and tolerable. The extended duration of atazanavir therapy was not associated with new safety issues in patients who gained substantial additional atazanavir exposure or those whose new exposure to atazanavir began with the switch from nelfinavir. Atazanavir is a competitive inhibitor of the uridine diphosphate-glucuronosyl transferase 1A1 enzyme, and as such, it can lead to elevations in unconjugated bilirubin in a significant number of patients. 27,28 Consistently, elevated total bilirubin was the most common laboratory abnormality in the present study. These elevations were asymptomatic, reversible, and not associated with hepatotoxicity.
Atazanavir is a potent, safe, and effective PI for the long-term treatment of HIV. Patients who are virologically suppressed on nelfinavir can maintain their virologic and immunologic improvement when switched to atazanavir. Once-daily atazanavir treatment provides an alternative option to PI-sparing regimens and may preclude the need to introduce the use of lipid-lowering agents to control PI-induced dyslipidemia in a significant proportion of patients.
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Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
atazanavir; dyslipidemia; HIV infection; nelfinavir; protease inhibitor