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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Clinical Science

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-Naive Subjects

Sanne, Ian*; Piliero, Peter†; Squires, Kathleen‡; Thiry, Alexandra§; Schnittman, Steven§; AI424-007 Clinical Trial Group

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Author Information

*Department of Infectious Diseases and Clinical Microbiology, University of Witwatersrand, Johannesburg, South Africa; †Division of Clinical Pharmacology, Albany Medical College, Albany, New York, U.S.A.; ‡Rand Schrader Clinic, Los Angeles County and University of Southern California Medical Center, Los Angeles, California, U.S.A.; and §Bristol-Myers Squibb Research Institute, Wallingford, Connecticut, U.S.A.

This study was funded by unrestricted educational grants from Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough, and Triangle Pharmaceuticals; by clinical trials projects from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, Triangle, Ketyx, Arones, and Pharma Natura; by a consulting agreement with Triangle Pharmaceuticals; and by the World AIDS Foundation.

Address correspondence and reprint requests to Ian Sanne, WHC Infectious Diseases Clinical Trials Unit, 27 Eton Road, Parktown, Johannesburg, South Africa 2193; e-mail: ian_sanne@witshealth.co.za

Manuscript received July 23, 2002; accepted October 22, 2002.

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Abstract

Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (−2.57 to −2.33 log10 copies/mL), the proportion of subjects with HIV RNA <400 copies/mL (56%–64%) and <50 copies/mL (28%–42%), and mean increases in CD4 cell count (185–221 cells/mm3) were comparable across treatment groups. Diarrhea was two to three times more common in the nelfinavir group (61% of subjects) than in the atazanavir groups (23%–30% of subjects, p < .0001 versus nelfinavir), and jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) (p < .03 for all atazanavir regimens vs. nelfinavir). Mean percent change from baseline in fasting low-density lipoprotein (LDL) cholesterol was significantly less in the atazanavir groups (−7% to 4%) than in the nelfinavir group (31%) (p < .0001). In conclusion, once-daily atazanavir is a potent, safe, and well tolerated PI that rapidly and durably suppresses HIV RNA and durably increases CD4 cell count in antiretroviral-naive subjects. Through 48 weeks, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglycerides. In comparison, nelfinavir was associated with prompt, marked, and sustained elevations in these parameters of a magnitude that suggests they are clinically relevant.

Protease inhibitors (PIs), when combined with nucleoside analogue reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), have proved highly effective in reducing HIV-1 replication and improving clinical outcomes (1–4). Effective use of currently available PIs, however, is often limited by complex dosing regimens and drug-related toxicities. Antiviral regimens require strict adherence to multiple daily dosing schedules, carry a high pill burden (5–7), often necessitate specific food restrictions, and induce severe metabolic toxicities. One potential metabolic toxicity (8–11), elevated lipid levels (8,12–14), may increase a patient's risk of cardiovascular events and potentially complicates treatment. The collective impact of these factors reduces patients' motivation and willingness to adhere to therapy. Poor adherence and the consequent lower and variable drug levels can lead to the emergence of drug-resistant variants of HIV-1 (15–17). Failure of a highly active antiretroviral therapy (HAART) regimen, regardless of its cause, is often followed by extensive cross-resistance, which limits future drug options (18).

Atazanavir is a selective azapeptide inhibitor of the HIV-1 protease characterized by certain pharmacokinetic and resistance features that may attenuate treatment-limiting complications associated with current PI therapy (19,20). First, the pharmacokinetic profile of atazanavir permits once-daily dosing (21–25). The trough plasma concentration (Cmin) of atazanavir at steady state following an oral dose of ≥400 mg (taken with a light snack or meal) remains above the concentration required to inhibit 50% of HIV-1 replication (EC50) for >36 hours (24). Second, the resistance profile of atazanavir is distinct. In vitro studies demonstrate that HIV-1 isolates resistant to one or two PIs retain sensitivity to atazanavir (26). Third, the inhibitory quotient (IQ) of atazanavir is 10.2 to 25.5, among the highest of current PIs (26), without requiring pharmacologic boosting (27). (IQ, an index for determining the potency of a compound, is calculated as the compound's Cmin divided by its EC50 [Cmin / EC50]). Finally, atazanavir is associated with a lower degree of dyslipidemia (28), a significant problem associated with therapy with other PIs (29–31).

This report describes the results of a clinical trial (AI424-007) conducted to compare the safety, tolerability, and antiretroviral efficacy of three doses of atazanavir with nelfinavir when given as monotherapy and then in combination with didanosine (ddI) and stavudine (d4T). An interim analysis of this trial has been presented previously (23).

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METHODS

Study Design

Trial AI424-007 was a multinational, 48-week, 2-stage, randomized, blind (by atazanavir dose) trial conducted in 39 clinical and research centers. The primary objective of the study was to compare the safety, tolerability, and antiretroviral efficacy of atazanavir administered once daily in one of three doses (200, 400, or 500 mg) with nelfinavir (750 mg) administered three times daily. Eligible subjects were randomized to receive one of the four treatment regimens in a 1:1:1:1 ratio. Randomization was stratified by both screening plasma HIV RNA level (<30,000 copies/mL, ≥30,000 copies/mL) and investigative site based on a permuted block design. The study was divided into two stages. Stage 1, a pilot study, evaluated safety and preliminary antiviral activity. Enrollment in Stage 2 began after all Stage 1 subjects had received 4 weeks of therapy and antiretroviral efficacy and safety had been evaluated. An additional objective was to determine the optimal dose of atazanavir for evaluation in phase 3 clinical trials.

Both atazanavir and nelfinavir were administered as monotherapy for 2 weeks, after which once-daily ddI (400 mg in subjects weighing ≥60 kg or 250 mg in subjects weighing <60 kg) and twice-daily d4T (40 mg in subjects weighing ≥60 kg or 30 mg in subjects weighing <60 kg) were added to the treatment regimens for the remaining 46 weeks. The original formulation of ddI was used in the study because it was the only registrational formulation at the time of initiation of the trial. Enrollment in the study was staged such that 80 subjects (approximately 20 per arm) were targeted for enrollment into Stage 1. Enrollment was then halted until Stage 1 subjects completed their week 4 visit; at that time, an assessment of safety and antiviral activity was conducted. Following this assessment, enrollment was reopened, and 300 additional subjects were targeted for accrual into Stage 2. Atazanavir was administered once daily on an empty stomach or with a light meal in Stage 1 and with a meal in Stage 2.

This study was carried out in accordance with U.S. Food and Drug Administration (FDA) Guidelines for Good Clinical Practice and the Declaration of Helsinki. Before enrollment, all trial participants provided written and signed informed consent. Regional ethics committee approval was obtained for each participating study site.

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Study Subjects

Subjects eligible for study enrollment were HIV-1–infected adult men and women ≥18 years of age. Subjects were required to have HIV RNA levels between 5000 and 750,000 copies/mL (Stage 1) or ≥2000 copies/mL (Stage 2), and CD4 cell counts ≥100 cells/mm3 (≥75 cells/mm3 in Stage 2 subjects with no previous AIDS-defining diagnoses) measured during the 14 days prior to randomization. Subjects were ineligible for enrollment if they had received previous antiretroviral therapy (defined as more than 4 weeks of nucleoside therapy and/or more than 1 week of NNRTI or PI therapy). Women of childbearing potential had to have negative serum or urine pregnancy test results within 72 hours of the start of treatment and were required to use effective barrier contraception throughout the study period. If the patient had a newly diagnosed HIV-1–related opportunistic infection that required acute therapy at the time of screening, he or she was excluded. Laboratory values measured within 14 days of the start of treatment were required to meet the following criteria: serum creatinine ≤1.5 times the upper limit of normal (ULN), total serum lipase ≤1.4 times the ULN, liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyltransferase [GGT]) <3 times the ULN, and total bilirubin <1.5 times the ULN.

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Management of Patients with Adverse Events or Intolerance

Toxicities were graded on a scale of 1 to 4 according to the modified WHO criteria; dose modification was permitted if toxicities were encountered. Subjects were allowed to withdraw from the study for any of the following reasons: major, serious, and unexpected or life-threatening toxicity; pregnancy; need for a medication prohibited by the protocol; increase in viral load from a previously confirmed undetectable level to a detectable level of HIV RNA; and personal request.

Subjects demonstrating intolerance to d4T during the study were permitted to substitute zidovudine; subjects demonstrating intolerance to ddI were permitted to substitute lamivudine. Subjects in the atazanavir 400- and 500-mg groups with grade 4 isolated hyperbilirubinemia (bilirubin 5–10 times the ULN) were allowed dose reductions to 200 and 400 mg, respectively; those in the 200-mg group were discontinued from the study.

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Study Assessments

Subjects were evaluated at screening; baseline; weeks 2, 4, 8, 12, and 16; and every 8 weeks thereafter. Efficacy assessments included plasma HIV RNA levels and CD4 cell counts. Additional visits were permitted as required. Plasma HIV RNA levels were determined in Stage 1 by the AMPLICOR HIV-1 Monitor assay and in Stage 2 by the AMPLICOR HIV-1 Monitor Ultrasensitive assay (versions 1.0 and 1.5; Roche Molecular Systems; Branchburg, NJ, U.S.A.), with limits of quantification of 400 and 50 copies/mL, respectively, on samples shipped at ambient temperature. Version 1.0 of the assays was used on all samples from North America, and version 1.5 of the assays was used in Africa, Europe, and South America. CD4 cell counts were determined by validated three-color flow cytometry.

Safety was assessed through medical history, physical examination, clinical laboratory testing, and the reporting of adverse events, grouped using a modified version of the FDA Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART).

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Statistical Analyses

Separate efficacy data sets were created for all randomized subjects in Stage 1 and all randomized subjects in Stage 2. For both stages, monotherapy efficacy analyses were based on subjects who completed the 2-week monotherapy phase of treatment. The safety analyses were based on combined data from all treated subjects in both stages who received at least one dose of PI therapy. HIV RNA values outside the upper (or lower) limit of quantification were assigned a value of one more (or less) than the limit.

Efficacy analyses were stratified according to HIV RNA level (<30,000 copies/mL, ≥30,000 copies/mL). The target sample size of 80 subjects (20 per regimen group) in Stage 1 was not based on statistical considerations. The Stage 2 target sample size of 300 treated subjects was allocated equally across each of the three atazanavir treatment regimens and the nelfinavir regimen (i.e., 75 subjects per regimen). This sample size provided at least 95% power to demonstrate that the antiretroviral activity of any dose of atazanavir was similar to that of nelfinavir. Antiviral activity was assessed by the time-averaged difference (TAD) in the change from baseline in HIV RNA levels (expressed in log10 copies/mL) over 48 weeks of therapy between each atazanavir treatment group and the nelfinavir group. A 0.5-log10 similarity level was based on an upper 98.3% confidence limit to preserve the overall two-sided alpha level of 0.05 adjusted for three primary comparisons.

A secondary analysis of the difference in the proportion of Stage 2 subjects with plasma HIV RNA <400 and <50 copies/mL at 48 weeks was performed using a difference in proportions based on normal approximations. The virologic response for randomized subjects classified subjects who remained on treatment as responders according to a single HIV RNA measurement <400 or <50 copies/mL closest to the scheduled visit and within a predefined visit window. The denominator was based on randomized subjects. Subjects with HIV RNA >400 or >50 copies/mL and subjects who discontinued prior to their scheduled visit were considered failures in this analysis (intent-to-treat noncompleter = failure [ITT NC = F]). Subjects who remained on treatment and did not have a week 48 measurement were classified as responders only if their previous and subsequent measurements were <400 or <50 copies/mL. The denominators for the on-treatment analysis included only subjects who remained on treatment.

Changes from baseline in CD4 cell counts were compared using the TAD through 48 weeks. Lipid concentrations were compared using mean percentage changes from baseline at 48 weeks based on t distributions. Discrete variables (e.g., adverse events) were compared using the Fisher exact test.

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RESULTS

Study Subjects

A total of 420 HIV-infected subjects were randomized, 98 subjects in Stage 1 (92 of whom were treated) and an additional 322 subjects in Stage 2 (318 of whom were treated). Table 1 shows the subject disposition at 48 weeks for all randomized subjects. Ten randomized subjects (2 in the atazanavir 200-mg group, 2 in the atazanavir 400-mg group, 3 in the atazanavir 500-mg group, and 3 in the nelfinavir group) were not treated. Discontinuation rates were comparable across all treatment groups; 64 subjects (15%) discontinued treatment before week 48.

Table 1
Table 1
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Table 2 summarizes the baseline characteristics for all randomized subjects. The total randomized study population was 64% male and 36% female, and the mean age was 35 years. Mean (SEM) HIV RNA at baseline was 4.73 (0.03) log10 copies/mL, and mean CD4 cell count was 348 cells/mm3 (9 cells/mm3). In general, baseline characteristics were comparable across treatment groups and stages. Mean time on therapy was also comparable across the four treatment regimens (58, 60, and 61 weeks for 200, 400, and 500 mg of atazanavir, respectively, and 60 weeks for nelfinavir).

Table 2
Table 2
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Antiretroviral and Immunologic Efficacy
Monotherapy

In total, 87 subjects in Stage 1 and 272 subjects in Stage 2 had HIV RNA measurements at baseline and week 2 and were evaluable for monotherapy efficacy. In Stage 1 subjects, decreases from baseline in HIV RNA levels at week 2 were comparable across all dose regimens. In Stage 2, decreases in HIV RNA at week 2 in atazanavir-treated subjects were dose dependent (Table 3), with the largest decrease seen in the atazanavir 500-mg group. All atazanavir doses were similar in efficacy to nelfinavir.

Table 3
Table 3
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Combination Therapy

Figure 1A shows the change in mean HIV RNA levels from baseline through 48 weeks for Stage 2 subjects. Mean [SEM] log10 changes from baseline in HIV RNA were comparable across the atazanavir 200-, 400-, and 500-mg groups and the nelfinavir group at 24 weeks (−2.50 [0.1], −2.31 [0.12], −2.56 [0.13], and −2.39 [0.11] log10 copies/mL, respectively) and again at 48 weeks (−2.57 [0.09], −2.42 [0.11], −2.53 [0.13], and −2.33 [0.12] log10 copies/mL, respectively). The cutoff for the limit of quantification constrains the measurement of the actual decline in viral load. These changes in HIV RNA were durable for the 48 weeks of the trial and comparable across both stages.

Fig. 1
Fig. 1
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Treatment responses over time for the ITT NC = F analysis are shown in Figure 1B. After 48 weeks of treatment, the proportions of Stage 2 subjects with HIV RNA <400 and <50 copies/mL were comparable in the atazanavir and nelfinavir treatment groups. Specifically, HIV RNA levels <400 copies/mL were attained in 61% (51/83), 64% (50/78), and 59% (47/79), respectively, of subjects in the atazanavir 200-, 400-, and 500-mg groups and in 56% (46/82) of subjects in the nelfinavir group. Similarly, HIV RNA levels <50 copies/mL were attained in 28% (23/83), 36% (28/78), and 42% (33/79) of subjects in the atazanavir 200-, 400-, and 500-mg groups, respectively, and in 39% (32/82) of the subjects in the nelfinavir group. In the on-treatment analysis, the proportions of subjects achieving HIV RNA levels <400 copies/mL at 48 weeks were 74% (51/69), 76% (50/66), 73% (47/64), and 70% (46/66), respectively, for the four treatment groups, whereas the proportions of subjects achieving HIV RNA levels <50 copies/mL at 48 weeks were 33% (23/69), 42% (28/66), 52% (33/64), and 48% (32/66), respectively, for the four treatment groups.

CD4 cell counts increased through 48 weeks in all treatment groups. Mean (SEM) changes from baseline in CD4 cell count were 220 (22), 221 (25), and 208 (30) cells/mm3, respectively, in the atazanavir 200-, 400-, and 500-mg groups and 185 (17) cells/mm3 in the nelfinavir group at 48 weeks of treatment (Fig. 1C).

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Safety

Adverse events reported with a frequency of ≥20% in any treatment group are shown in Table 4. With few exceptions, adverse events were generally grade 1 to 2 in severity, and the rates of grade 3 to 4 adverse events were comparable across regimens. The number and type of adverse events occurring during treatment with any of the doses of atazanavir were generally comparable to the adverse events seen with nelfinavir treatment. Diarrhea occurred at a higher frequency in nelfinavir-treated subjects (61%) than in atazanavir-treated subjects (23%–30%) (p < .0001). Jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) (p < .03 for all atazanavir regimens versus nelfinavir). Scleral icterus occurred only with atazanavir treatment (2%, 6%, and 5% for the 200-, 400- and 500-mg groups, respectively). Subjects treated with 400 mg of atazanavir reported a higher frequency of nausea (35%) than subjects treated with nelfinavir (17%) (p = .01).

Table 4
Table 4
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A total of 28 subjects (7%) discontinued treatment due to adverse events. The proportion of patients who discontinued treatment was comparable across treatment groups: 5 subjects (5%) in the atazanavir 200-mg group, 6 (6%) in the atazanavir 400-mg group, 10 (9%) in the atazanavir 500-mg group, and 7 (7%) in the nelfinavir group. Discontinuations due to hyperbilirubinemia occurred in 3 atazanavir subjects (1 in the 200-mg group and 2 in the 500-mg group) and were thought to be drug related. Discontinuations due to lipodystrophy occurred in 2 atazanavir subjects (1 each in the 200- and 400-mg groups) and in 1 nelfinavir subject, whereas discontinuations due to lactic acidosis occurred in 2 atazanavir subjects (1 each in the 200- and 400-mg groups).

There were five deaths reported during the study. Two deaths occurred in patients receiving 200 mg of atazanavir (one from a gunshot wound and the other from complications of HIV disease, possibly from Kaposi sarcoma with multiorgan failure), two in patients receiving 500 mg of atazanavir (one from sepsis and lactic acidosis and the other from lactic acidosis), and one in a patient receiving nelfinavir (from lactic acidosis).

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Clinical Laboratory Evaluation

Grade 3 to 4 laboratory abnormalities are shown in Table 5. Bilirubin elevations were reversible and predominantly of the indirect or unconjugated form. There was no correlation between grade 3 to 4 elevations in hepatic transaminase levels, a marker of hepatotoxicity, and grade 3 to 4 elevations in total and indirect bilirubin. Grade 3 to 4 abnormalities for AST and ALT were observed more frequently in atazanavir-treated subjects (4%–14%) than in nelfinavir-treated subjects (4%–6%). Seventeen subjects treated with atazanavir (2%–10% across regimens) had worst on-study grade 3 to 4 transaminitis with worst on-study grade 3 to 4 bilirubinemia. Of these 17 atazanavir-treated subjects, 10 had these elevations concurrently (i.e., on the same day).

Table 5
Table 5
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Ten subjects developed lactic acidosis syndrome (2.6% [8/310]) on atazanavir for 22.6 cases per 1000 patient-years and 2 developed lactic acidosis syndrome on nelfinavir (2.0% [2/100]) for 17.5 cases per 1000 patient-years. Three of the 10 subjects died (2 on atazanavir and 1 on nelfinavir). The overall rate by gender was 8 of 150 (5.3%) in women and 2 of 270 (0.7%) in men. Two subjects had a confirmatory diagnosis of hepatic steatosis. Lactic acidosis syndrome is commonly associated with NRTIs, and the risk factors identified in this study were female gender, obesity or overweight, and pregnancy. These have been previously identified as risk factors for lactic acidosis syndrome for NRTIs.

Through 48 weeks of treatment, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting low-density lipoprotein (LDL) cholesterol, or fasting triglycerides as assessed by mean percent changes from baseline (Table 6). In contrast, at 48 weeks, the increase from baseline in these lipid parameters was significantly greater in the nelfinavir treatment group than in the atazanavir treatment groups (p < .001, all comparisons of 400 mg of atazanavir to nelfinavir). Nelfinavir was associated with prompt, marked, sustained, and clinically relevant increases in each of these parameters (see Table 6). Changes in high-density lipoprotein (HDL) cholesterol were comparable across the four treatment groups.

Table 6
Table 6
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At baseline, total cholesterol levels as categorized by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) (32) were comparable across treatment groups. Baseline total cholesterol levels at desirable levels (<200 mg/dL) were observed in 82% to 87% of subjects. A higher proportion of nelfinavir-treated subjects had at least borderline high concentrations (≥200 mg/dL) after 24 and 48 weeks of treatment (52%–59% of nelfinavir patients vs. 16%–30% of atazanavir patients), however. In contrast, the proportion of atazanavir-treated subjects with total cholesterol levels in the desirable range at 24 and 48 weeks (71%–84%) was comparable to the proportion that had these levels at baseline (85%–87%).

The incidence of grade 1 to 4 lipodystrophy was infrequent (4%, 9%, 2%, and 3% in the atazanavir 200-, 400-, and 500-mg groups and the nelfinavir group, respectively;p not significant at the .05 level in atazanavir 400-mg group compared with nelfinavir group). Although there is currently no case definition for lipodystrophy, the majority of cases were reported as grade 1 to 2.

Of the 235 subjects who were tested at baseline, 58 (25%) were positive for either hepatitis B or hepatitis C, and 4 (2%) were positive for both. Grade 3 to 4 transaminitis was higher in subjects who were positive for hepatitis B or hepatitis C compared with those who were negative for both parameters but were comparable across treatment regimens. On atazanavir treatment, grade 3 to 4 transaminitis occurred in 20% to 40% of subjects who were positive for hepatitis B or hepatitis C compared with 2% to 12% of subjects who were not positive for hepatitis B or hepatitis C. On nelfinavir treatment, in the same hepatitis B or hepatitis C populations, respectively, grade 3 to 4 transaminitis occurred in 23% and 2% of subjects. Occurrence of grade 3 to 4 bilirubinemia was comparable for subjects who were positive or negative for hepatitis B or hepatitis C.

Lactic acidosis did not develop more commonly in subjects who were positive for hepatitis B or hepatitis C. Of the 10 subjects with lactic acidosis, 1 in the atazanavir 400-mg group was positive for hepatitis B or hepatitis C. Five subjects were negative for both hepatitis B and hepatitis C, 1 in the atazanavir 400-mg group, 2 in the atazanavir 500-mg group, and 2 in the nelfinavir group. The other 4 subjects with lactic acidosis were not tested at baseline.

As a result of these findings and to optimize both safety and antiviral efficacy, the 400-mg dose of once-daily atazanavir was chosen for further evaluation in phase 3 clinical trials.

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DISCUSSION

The results of this trial in antiretroviral-naive subjects demonstrate the safety, tolerability, and antiretroviral efficacy of atazanavir administered once daily at doses of 200, 400, and 500 mg compared with 750 mg of nelfinavir administered three times daily. The primary objective, similar antiretroviral activity, was shown after 2 weeks of monotherapy for each dose of atazanavir and, again, after an additional 46 weeks of triple combination therapy using ddI and d4T. A prompt decline in HIV RNA of about 1.4 log10 copies/mL occurred in all monotherapy arms. In the combination therapy phase, similar HIV RNA reductions of about 2.5 log10 copies/mL were reached by 16 weeks and were durably sustained through 48 weeks with all treatment regimens.

The proportion of subjects with HIV RNA levels <400 and <50 copies/mL was comparable across all dosing regimens of atazanavir and nelfinavir. Both atazanavir and nelfinavir produced positive effects on immune reconstitution as assessed by CD4 cell count increases. CD4 cell counts increased continually over 48 weeks in all treatment groups, reaching a mean increase exceeding 150 cells/mm3 by the end of treatment (Fig. 2).

Fig. 2
Fig. 2
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As part of a three-drug regimen, atazanavir was well tolerated at all doses, and its safety as assessed by clinical and laboratory adverse events was comparable to that of nelfinavir. Diarrhea, a well-known side effect of nelfinavir, reduces quality of life in patients treated for HIV infection (33,34); in this study, the incidence of diarrhea associated with atazanavir was significantly lower than that occurring with nelfinavir (p < .0001). The observation that subjects treated with atazanavir may experience a higher frequency of nausea compared with nelfinavir has not been repeated in a larger phase 2 evaluation (R. L. Murphy et al., The Feinberg Medical School, Northwestern University, Chicago, IL, U.S.A., manuscript in preparation, 2002).

Reversible asymptomatic elevations of unconjugated bilirubin (indirect type) were observed only in the atazanavir treatment groups and occurred in a dose-related manner; however, elevated bilirubin was not associated with hepatotoxicity as assessed by grade 3 to 4 elevations of ALT and AST. In the presence of elevated bilirubin, measurement of serum aminotransferases increases the sensitivity of detecting the presence or absence of liver damage. In acute hepatocellular necrosis caused by drug-induced hepatitis, elevated bilirubin levels are accompanied by a significant elevation in levels of ALT and AST (35). These elevations did not occur with atazanavir treatment. Preclinical data support the hypothesis that atazanavir-associated elevations in bilirubin may be attributed to inhibition of uridine diphosphate glucuronosyltransferase (UDP-GT) 1A1 (36). This mechanism is similar to that described for the reversible elevations in bilirubin associated with Gilbert syndrome, which are of little clinical significance (37), and it is also the apparent mechanism for the reversible elevations in bilirubin that occur with indinavir treatment (38).

Lactic acidosis developed in 10 subjects and contributed to three deaths in this study. Lactic acidosis is frequently reported in patents receiving HAART and is typically associated with the nucleoside component of the regimen (39). In the current study, reports of lactic acidosis were comparable across all treatment regimens and were associated with previously described risk factors, including obesity and female gender (40). Appropriate vigilance for early symptoms of lactic acidosis is important in preventing morbidity and mortality.

AI424-007 was the first phase 2 study of a PI with a low pill burden consisting of two capsules administered once daily. The simplicity of this dosing regimen allows for easier administration and is expected to encourage adherence and improve virologic outcomes. Based on studies in other diseases, a low incidence of side effects and better tolerability are expected to increase adherence and patients' willingness to remain on the regimen (41). In anti-HIV therapy, better adherence can lead to more durable suppression of viral load and may delay the emergence of drug-resistant HIV variants (6,42,43). Treatment with atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, and fasting triglyceride concentrations as assessed by mean percent changes from baseline. After 48 weeks, the nelfinavir treatment group showed significantly greater increases for these lipid parameters than the atazanavir treatment groups, in which decreases or only small increases were noted (p < .001 in all comparisons of 400 mg of atazanavir). Treatment with current PIs in antiretroviral-naive patients results in dyslipidemia that is prompt, marked, and sustained and is of a magnitude that suggests the lipid increases are clinically relevant (29,31). Thus, the absence of a negative effect on lipid profiles suggests that atazanavir may be associated with a reduction in the risk of cardiovascular events linked to dyslipidemia in this population. Prolonged elevations in total cholesterol, LDL cholesterol, and triglyceride levels have been implicated in the development of cardiovascular disease and lipodystrophy (8–11,31,44,45). Current guidelines (32) recommend that PI-related dyslipidemia be managed according to the NECP ATP III criteria (46). In this study, atazanavir-treated subjects who had desirable total cholesterol at baseline maintained desirable levels through 24 and 48 weeks in contrast to nelfinavir-treated subjects.

Managing the elevations in lipid levels that result from PI use can add complexity to an already complex HAART regimen (47). The potential cardiovascular risks associated with elevated total cholesterol, LDL cholesterol, and triglyceride levels are of sufficient concern that they were factored into the recent decision to recommend delaying the initiation of HAART (48). A PI treatment option for HIV-1 infection that is not associated with adverse changes in these lipid parameters could foster timely initiation of HAART, lessening the concern for potential long-term cardiovascular risk associated with PI treatment.

In summary, once-daily treatment with atazanavir as part of a HAART regimen was safe and well tolerated. Atazanavir rapidly and durably suppressed HIV RNA and durably increased CD4 cell count. Its efficacy was similar to that of nelfinavir administered three times daily in antiretroviral-naive patients for 48 weeks. The most frequently reported clinical adverse events were diarrhea (which occurred significantly more frequently with nelfinavir than with atazanavir), nausea, and infection. Dose-related reversible elevation of unconjugated bilirubin occurred only with atazanavir. Because treatment with atazanavir is not associated with adverse changes in lipid parameters, incorporating atazanavir into a HAART regimen may lead to a reduced risk of cardiovascular events linked with dyslipidemia in this population. The favorable lipid characteristics of atazanavir and once-daily dosing may facilitate adherence to the HAART regimen, contributing to successful long-term viral suppression in antiretroviral-naive HIV patients.

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Acknowledgments:

The authors are grateful to the many persons with HIV-1 infection who volunteered for this study.

The following members of the Protocol 007 Study Group participated in subject recruitment, enrollment, and medical management as well as in data collection: Jonathan Angel, Francisco Attunes, Marek Beniowski, David Brand, Bonaventura Clotet, Jorge Corral, Robin Dretler, Fernando Dronda, George Drusano, José M. Gatell, Jonathan Gill, Frank-Detlef Goebel, Scott Hammer, Andrzej Horban, Harold Kessler, Joep Lange, Adriano Lazzarin, Michael Lederman, Sergio Lupo, Kamal Mansinho, F. Mazzotta, Donna Mildvan, Jane Ellen Mobley, Giuseppe Pastore, Dolores Peterson, Andreas Plettenberg, Daniel Podzamczer, Richard Pollard, William Powderly, Robert Schooley, Kathleen Squires, Shlomo Staszewski, Melanie Thompson, Joseph Timpone, and M.E. Van Der Ende.

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Keywords:

Atazanavir; Protease inhibitor; Dyslipidemia; HAART; Nelfinavir

© 2003 Lippincott Williams & Wilkins, Inc.

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