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A theoretical concern exists that atazanavir (ATV) use during pregnancy may exacerbate physiologic neonatal hyperbilirubinemia. The aim of this substudy was to evaluate patterns of neonatal bilirubin following ATV/ritonavir (RTV) treatment of pregnant mothers and clinical and pharmacogenetic factors that may correlate. The design involved a subanalysis of study AI424182, a multicenter, open-label, prospective, single-arm Phase I study. The study had two treatment arms: (1) ATV/RTV 300/100 mg once daily or (2) ATV/RTV 400/100 mg once daily, both in combination with zidovudine/lamivudine 300/150 mg twice daily. Total bilirubin was assessed at baseline, each visit, and delivery day for mothers and on days 1 (delivery day), 3, 5, and 7 and weeks 2 and 6 for neonates. Blood samples were obtained for UGT1A1 genotyping and ATV cord blood concentration. Bilirubin elevation of any grade occurred in 14/40 neonates (35%). All Grade 3 to 4 bilirubin abnormalities (n=7) occurred after day 14. The pattern of neonatal bilirubin levels reported was consistent with neonatal physiologic elevations of bilirubin. Little correlation was observed between either maternal bilirubin levels over the last 4 weeks of pregnancy (including delivery) or ATV cord concentration and neonatal bilirubin. There was a significant association between UGT1A1 genotype and bilirubin grade in the maternal population (p=0.0006) but not neonates (p=0.49). Neither neonatal UGT1A1 genotype nor cord blood ATV concentration is a good predictor of neonatal hyperbilirubinemia. ATV/RTV treatment of mothers does not appear to exacerbate neonatal physiologic hyperbilirubinemia.

Study Objective: To investigate the pharmacokinetic and pharmacodynamic relationships of the human immunodeficiency virus (HIV)-protease inhibitor atazanavir (ATV) in the presence and absence of the pharmacokinetic booster ritonavir, utilizing ATV plasma trough concentrations (Ctrough ) and clinical biomarkers of antiviral efficacy and safety over 48 weeks., Design: Randomized, open-label, multicenter, study designed to compare the efficacy and safety of ATV 300 mg plus ritonavir 100 mg (ATV300/r) with that of ATV 400 mg (ATV400)., Setting: Thirty clinic sites across 10 countries in Africa, Europe, North America, and South America., Patients: Patients who were HIV-positive and treatment-naïve., Interventions: Randomized to once-daily ATV400 (105 patients) or ATV300/r (95 patients) plus lamivudine and extended-release stavudine., Measurements and Main Results: The Ctrough approximately 24 hours after the prior unobserved dose was measured through week 48. Composite Ctrough (i.e., the geometric mean of all trough concentrations over the 48 weeks), population inhibitory quotient ([IQ], i.e., Ctrough divided population estimated protein binding adjusted effective concentration at 90% [EC90 , 14 ng/ml]), composite population IQ (i.e., ATV composite trough divided by population estimated protein binding adjusted EC90 ), HIV RNA, CD4 cell counts, and metabolic and safety parameters were also assessed. For ATV400 and ATV300/r, respectively, geometric mean composite Ctrough (CV%) were 127 (106) ng/ml and 670 (63) ng/ml, geometric mean composite population IQ were 9 and 48, and composite Ctrough values of HIV EC90 or more were achieved in 98% and 100% of patients. High ATV Ctrough was associated with low HIV RNA at week 48; however, 88% of patients had HIV RNA less than 400 copies/ml in the lowest composite Ctrough quartile. There was no clear relationship between ATV Ctrough and changes in CD4 cell count. Increases in total bilirubin or jaundice were associated with higher Ctrough . Modest increases in triglycerides and cholesterol were associated with the addition of ritonavir., Conclusion: ATV-containing regimens with or without ritonavir achieved ATV exposures that provide robust antiretroviral efficacy and acceptable tolerability in treatment-naïve patients., (© 2013 Pharmacotherapy Publications, Inc.)

CASTLE was a randomized 96-week study that demonstrated that atazanavir/ritonavir (ATV/r) was noninferior to lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-infected patients. Analyses were carried out among patients who received ATV/r in the CASTLE study to better understand the clinical significance of unconjugated hyperbilirubinemia associated with administration of boosted ATV. Hyperbilirubinemia was defined as total bilirubin (conjugated and unconjugated) elevation greater than 2.5 times the upper limit of normal (grade 3-4). Patients in the ATV/r arm were assessed based on the presence or absence of hyperbilirubinemia through week 96. Analyses included number of confirmed virologic responders (CVR; HIV RNA<50 copies per milliliter), impact of hyperbilirubinemia on symptoms, elevations in liver enzymes, patient quality of life, and medication adherence. Through 96 weeks in the CASTLE study, 44% of patients who received ATV/r had hyperbilirubinemia at any time point, and between 12.5% and 21.6% had hyperbilirubinemia at any single study visit. At 96 weeks, 74% of patients overall and 84% and 69% of patients with and without hyperbilirubinemia, respectively, achieved CVR. Symptoms of jaundice or scleral icterus occurred in 5% of patients overall and in 11% with hyperbilirubinemia and 0% without hyperbilirubinemia. Four percent of patients with and 3% of patients without hyperbilirubinemia had grade 3-4 elevations in liver transaminases. Less than 1% of patients discontinued treatment due to hyperbilirubinemia. There were no differences in quality of life or adherence between patients with or without hyperbilirubinemia. In the CASTLE study, hyperbilirubinemia observed in the ATV/r group did not negatively impact clinical outcomes in HIV-infected patients.

Background: Nucleoside and ritonavir (RTV) toxicities have led to increased interest in nucleoside reverse transcriptase inhibitors (NRTIs) and RTV-sparing antiretroviral regimens. SPARTAN was a multicenter, randomized, open-label, noncomparative pilot study evaluating the efficacy, safety, and resistance profile of an investigational NRTI- and RTV-sparing regimen (experimental atazanavir [ATV] dose 300 mg bid + raltegravir [RAL] 400 mg bid [ATV+RAL]). The reference regimen consisted of ATV 300 mg/RTV 100 mg qd + tenofovir (TDF) 300 mg/emtricitabine (FTC) 200 mg qd (ATV/r+TDF/FTC)., Methods: Treatment-naïve HIV-infected patients with HIV-RNA ≥5,000 copies/mL were randomized 2:1 to receive twice-daily ATV+RAL (n=63) or once-daily ATV/r+TDF/FTC (n=31). Efficacy at 24 weeks was determined by confirmed virologic response (CVR; HIV-RNA <50 copies/mL) with noncom-pleters counted as failures based on all treated subjects., Results: The proportion of patients with CVR HIV RNA <50 copies/mL at week 24 was 74.6% (47/63) in the ATV+RAL arm and 63.3% (19/30) in the ATV/r+TDF/FTC arm. Systemic exposure to ATV in the ATV+RAL regimen was higher than historically observed with ATV/r+TDF/ FTC. Incidence of Grade 4 hyperbilirubinemia was higher on ATV+RAL (20.6%; 13/63) than on ATV/r+TDF/FTC (0%). The criteria for resistance testing (virologic failure [VF]: HIV-RNA ≥400 copies/mL) was met in 6/63 patients on ATV+RAL, and 1/30 on ATV/r+TDF/FTC; 4 VFs on ATV+RAL developed RAL resistance., Conclusions: ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.

Objectives: To characterize the pharmacokinetics and inhibitory quotient (IQ) of atazanavir/ritonavir- and lopinavir/ritonavir-based regimens in HIV-infected, treatment-naive patients., Methods: The CASTLE Study was a 96 week randomized study comparing 300 mg of atazanavir once daily with 400 mg of lopinavir twice daily, each with low-dose ritonavir (100 mg) plus tenofovir disoproxil fumarate/emtricitabine in HIV-infected, treatment-naive patients. A subset of patients participated in an intensive pharmacokinetic evaluation of the atazanavir regimen (n = 18) and the lopinavir regimen (n = 21) at week 4. (ClinicalTrials.gov NCT00272779), Results: Atazanavir geometric mean (CV%) C(max), C(min) and AUC over the dosing interval were 2897 (46) ng/mL, 526 (57) ng/mL and 28 605 (46) ng · h/mL, respectively, and for lopinavir they were 10 655 (51) ng/mL, 5944 (68) ng/mL and 90 946 (59) ng · h/mL, respectively. The baseline protein binding-adjusted 90% effective concentration (PBA-EC(90)) was 16 (44) ng/mL for atazanavir and 173 (44) ng/mL for lopinavir. The median IQ (min, max), calculated as the ratio of C(min) to individual baseline PBA-EC(90), was 35 (4, 77) for atazanavir and 34 (11, 129) for lopinavir. The C(max) for ritonavir was 46% higher, while AUC(0-24) and C(min) were 16% and 72% lower in the atazanavir regimen compared with the lopinavir regimen. Tenofovir exposures were similar with both treatments., Conclusions: Atazanavir (300 mg once daily) and lopinavir (400 mg twice daily), each with low-dose ritonavir, achieved similar IQs in HIV-infected, treatment-naive patients. These results are supportive of the main clinical finding of the CASTLE Study, that the atazanavir/ritonavir-based regimen is non-inferior in antiviral efficacy to the lopinavir/ritonavir-based regimen in antiretroviral-naive subjects.

Objective: There are limited antiretroviral options for use in the treatment of HIV infection during pregnancy. The purpose of this study was to assess the safety, efficacy and appropriate dosing regimen for ritonavir (RTV)-boosted atazanavir in HIV-1-infected pregnant women., Methods: In this nonrandomized, open-label study, HIV-infected pregnant women were dosed with either 300/100 mg (n=20) or 400/100 mg (n=21) atazanavir/RTV once-daily (qd) in combination with zidovudine (300 mg) and lamivudine (150 mg) twice daily in the third trimester. Pharmacokinetic parameters [maximum observed plasma concentration (C(max) ), trough observed plasma concentration 24 hour post dose (C(min) ) and area under concentration-time curve in one dosing interval (AUC(τ) )] were determined and compared with historical values (300/100 mg atazanavir/RTV) for HIV-infected nonpregnant adults (n=23)., Results: At or before delivery, all mothers achieved HIV RNA <50 HIV-1 RNA copies/mL and all infants were HIV DNA negative at 6 months of age. The third trimester AUC(τ) for atazanavir/RTV 300/100 mg was 21% lower than historical data, but the C(min) values were comparable. The C(min) value for atazanavir/RTV 400/100 mg was 39% higher than the C(min) for atazanavir/RTV 300/100 mg in historical controls, but the AUC(τ) values were comparable. Twice as many patients in the 400/100 mg group (62%) had an increase in total bilirubin (>2.5 times the upper limit of normal) as in the 300/100 mg group (30%). Atazanavir (ATV) was well tolerated with no unanticipated adverse events., Conclusions: In this study, use of atazanavir/RTV 300/100 mg qd produced C(min) comparable to historical data in nonpregnant HIV-infected adults. When used in combination with zidovudine/lamivudine, it suppressed HIV RNA in all mothers and prevented mother-to-child transmission of HIV-1 infection. During pregnancy, the pharmacokinetics, safety and efficacy demonstrated that a dose adjustment is not required for ATV., (© 2011 British HIV Association.)

Objectives: To examine whether the overall results of the CASTLE study pertain to both genders, we analysed the efficacy and safety of atazanavir/ritonavir and lopinavir/ritonavir in 277 female and 606 male patients in the open-label, multinational trial over 96 weeks. The trial is registered with ClinicalTrials.gov, number NCT00272779., Methods: Treatment-naive patients aged ≥ 18 years with HIV-1 RNA ≥ 5000 copies/mL were randomized to receive either atazanavir/ritonavir 300/100 mg once daily or lopinavir/ritonavir 400/100 mg twice daily, with fixed-dose tenofovir/emtricitabine 300/200 mg once daily., Results: At week 96, confirmed virological response rates (HIV RNA <50 copies/mL; intent-to-treat analysis) were higher in women and men receiving atazanavir/ritonavir than those receiving lopinavir/ritonavir and lower in women than men in both treatment arms (67% of women and 77% of men on atazanavir/ritonavir and 63% of women and 71% of men on lopinavir/ritonavir). These differences were not observed in the on-treatment analysis. Mean change in CD4 cell count from baseline to week 96 was 265 cells/mm(3) for women and 269 cells/mm(3) for men on atazanavir/ritonavir and 298 cells/mm(3) for women and 286 cells/mm(3) for men on lopinavir/ritonavir. Discontinuation rates were higher in women than men in each treatment arm (22% of women and 15% of men on atazanavir/ritonavir and 29% of women and 18% of men on lopinavir/ritonavir). In women and men, grade 2-4 nausea and diarrhoea were more frequent in the lopinavir/ritonavir group; jaundice and hyperbilirubinaemia occurred more frequently in the atazanavir/ritonavir group., Conclusions: Once-daily atazanavir/ritonavir is an effective and well-tolerated therapeutic option for women and men with HIV-1 infection. The sex-based differences in response may be due to higher discontinuation rates in women.

Background: Once-daily atazanavir/ritonavir demonstrated similar antiviral efficacy to twice-daily lopinavir/ritonavir over 48 weeks, with less gastrointestinal disturbance and a better lipid profile, in treatment-naive patients., Methods: International, multicenter, open-label, 96-week noninferiority randomized trial of atazanavir/ritonavir 300/100 mg once daily vs lopinavir/ritonavir 400/100 mg twice daily, each in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily, in antiretroviral-naive, HIV-1-infected patients. The primary end point was the proportion of patients with HIV RNA <50 copies/mL at 48 weeks. Results through 96 weeks are reported., Results: Of 883 patients enrolled, 440 were randomized to atazanavir/ritonavir and 443 to lopinavir/ritonavir. At week 96, more patients receiving atazanavir/ritonavir achieved HIV RNA <50 copies/mL (74% vs 68%, P < 0.05) in the intent-to-treat analysis. On both regimens, 7% of subjects were virologic failures by 96 weeks. Bilirubin-associated disorders were greater in patients taking atazanavir/ritonavir. Treatment-related gastrointestinal adverse events were greater in patients taking lopinavir/ritonavir. Mean changes from baseline in fasting total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides at week 96 were significantly higher with lopinavir/ritonavir (P < 0.0001)., Conclusions: Noninferiority of atazanavir/ritonavir to lopinavir/ritonavir was confirmed at 96 weeks. Atazanavir/ritonavir had a better lipid profile and fewer gastrointestinal adverse events than lopinavir/ritonavir.

This study assesses virologic response, safety, tolerability, and changes in health-related quality of life (HRQoL) in antiretroviral (ARV)-naive patients treated with 2 atazanavir (ATV)-based regimens over 96 weeks. Treatment-naive adult patients (n = 200) were randomized to receive either ATV 300 mg with ritonavir (RTV) 100 mg (ATV300/r, n = 95) or ATV 400 mg (ATV400; n = 105). At week 96, 75% of ATV300/r-treated and 70% of ATV400-treated patients achieved viral loads <400 copies/mL (difference estimate [95% confidence interval, CI] = 5.1 [-7.1 to 17.2]). Five and 20 patients, respectively, experienced virologic failure. Adverse event-related discontinuations occurred among 8% receiving ATV300/r and 3% receiving ATV400. Plasma lipid elevations were generally low. Both regimens were well tolerated and associated with sustained improvements in HRQoL. These findings demonstrate long-term efficacy, tolerability, and safety of both ATV300/r and ATV400 in ARV-naive patients through 96 weeks with improvements in HRQoL.

Objective: The primary objective was to compare the change in fasting low-density lipoprotein (LDL) cholesterol from baseline to week 12 between patients receiving an atazanavir-containing regimen and those receiving comparator protease inhibitor (PI) regimens., Design: AI424-067 was a 48-week, open-label, randomized, prospective study of 246 patients on PI-based regimens with hyperlipidemia [fasting LDL cholesterol >130 mg/dL (>3.4 mmol/L)] and with HIV RNA <50 copies per milliliter. Patients were randomized to switch to atazanavir (400 mg once daily) on day 1 (immediate switch) or maintain current PI regimen for the first 24 weeks, then switch to atazanavir (delayed switch)., Methods: Plasma lipid levels were compared with baseline values at weeks 12, 24, and 48. Safety, viral load, and CD4 profiles were also evaluated., Results: At week 12, the mean percent changes in LDL cholesterol from baseline for the immediate-switch and delayed-switch groups were -15% and +1%, respectively (P < 0.0001). Favorable LDL cholesterol levels in the immediate-switch group were sustained through week 48. Both groups maintained comparable virologic control. Switching to atazanavir did not produce a significant change in safety or tolerability., Conclusions: A switch-either immediate or delayed-from a boosted or unboosted PI to unboosted atazanavir in patients with hyperlipidemia was associated with improvements in plasma lipid parameters without loss of virological suppression.

This 96-week, open-label, randomized study assessed changes in body composition in treatment-naive patients infected with human immunodeficiency virus type 1 who were treated with either atazanavir or ritonavir-boosted atazanavir, in combination with stavudine and lamivudine. Both treatment groups had similar increases in trunk fat, but patients treated with ritonavir-boosted atazanavir had a significantly lower incidence of lipoatrophy.

Background: Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients., Methods: In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779., Findings: At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1.7%, 95% CI -3.8 to 7.1). Mean increases from baseline in CD4 cell count were similar (203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2-4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2-4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3-4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one (<1%) of 431 patients on lopinavir/ritonavir., Interpretation: In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia.

Background: Atazanavir (ATV), the first once-daily protease inhibitor approved for the treatment of HIV-1 infection, is recommended for use in antiretroviral (ARV) treatment-naive and -experienced patients. Study AI424-089 was a prospective, randomized, open-label, 96-week study comparing 2 ATV-based treatment regimens in ARV-naive HIV-infected patients., Methods: Adults with HIV RNA levels > or =2000 copies/mL were randomized (1:1) to once-daily ATV at a dose of 300 mg with ritonavir at a dose of 100 mg (ATV300/RTV) or ATV at a dose of 400 mg (ATV400); both regimens included lamivudine and an investigational extended-release formulation of stavudine. The primary endpoint for this noninferiority study was the proportion of patients (response rate) with an HIV RNA load <400 copies/mL at week 48., Results: Response rates at week 48 were 86% and 85% on the ATV300/RTV and ATV400 regimens, respectively (difference estimate [95% confidence interval] = 1.5 [-8.2 to 11.1]). There were 3 and 10 patients with virologic failure in the ATV300/RTV and ATV400 groups, respectively. One patient (ATV400) developed phenotypic resistance to ATV associated with an I50L substitution. Adverse event-related discontinuations were 8% among ATV300/RTV-treated patients and <1% among ATV400-treated patients. Plasma lipid elevations were low with both regimens. Both regimens were well tolerated., Conclusions: These findings demonstrate the safety and efficacy of the ATV300/RTV regimen and confirm the safety and efficacy of ATV400 in an ARV-naive patient population.