Atazanavir Plasma Concentrations Research Articles

Concomitant Use of Cotrimoxazole and Atazanavir in HIV-infected Patients: A Therapeutic Drug Monitoring and Pharmacovigilance Based Dual Approach.

Cotrimoxazole is the main antibiotic used in primary prophylaxis for opportunistic infections in advanced HIV infection. This drug can inhibit one of the metabolic pathways of atazanavir (ATV), such as the cytochromes P450 (CYP) 2C8/2C9 and could interfere with its safety and efficacy. We studied the drug-drug interaction (DDI) between cotrimoxazole and ATV by using therapeutic drug monitoring (TDM) and pharmacovigilance (PV) approaches. We compared a group of patients treated with cotrimoxazole and receiving an ATV-based regimen to controls. This historical cohort analysis used data from Dat'AIDS in HIV-infected patients who had at least two lowest plasma concentrations (C-trough) of ATV during their outpatient follow-up. Likewise, we used the international pharmacovigilance data from VigiBase to evaluate the notifications of hyperbilirubinemia reported with ATV. In the TDM analysis, the two groups of patients (treated with cotrimoxazole and controls) were almost homogeneous concerning the main baseline features. After at least six months of ATVbased regimen, there was no significant difference in the safety threshold of the ATV C-trough [with an adjusted odds ratio (aOR) of 1.4 (95% CI: 0.5 - 4.4)] compared to controls. We observed similar results with the efficacy thresholds of ATV C-trough. Regarding the PV analysis, there was no difference in hyperbilirubinemia occurring with ATV when cotrimoxazole was concomitant, with an adjusted reporting odds ratio (aROR) of 0.9 (95% CI: 0.6 to 1.2). This study showed a relevant concomitant use between Cotrimoxazole and ATV based on TDM and PV approaches.

Influence of CYP3A5 and SLCO1B1 polymorphisms on atazanavir/r concentrations in Thai HIV-infected patients.

Aim: To evaluate the influence of genetic polymorphisms on plasma trough concentrations of atazanavir (ATV) and ritonavir (RTV). Patients & methods: The concentration-to-dose ratios were compared between different genotype groups of CYP3A5, ABCB1, SLCO1B1and NR1I2 in 490 patients. Multiple regression analysis was used to examine the association between genetic and clinical factors and log-transformed concentration-to-dose ratio of ATV and RTV. Results: Higher concentrations of ATV and RTV were significantly associated with CYP3A5 6986 GG and SLCO1B1 521 TC or CC. Female patients had significantly higher ATV plasma concentration than male patients. Conclusion: Genetic polymorphisms and gender are factors affecting the variability of ATV and RTV concentrations in the Thai population. Thus, genetic testing is worth considering when atazanavir + low dose ritonaviris prescribed.

Atazanavir intracellular concentrations remain stable during pregnancy in HIV-infected patients.

Atazanavir (300 mg) boosted by ritonavir (100 mg) is the preferred third drug in pregnancy. However, there is still discordance on atazanavir dose increase during the third trimester. To evaluate plasma and intracellular atazanavir and ritonavir concentrations in HIV-infected women during pregnancy and after delivery. This was an observational study. HIV-infected pregnant patients treated with atazanavir/ritonavir plus either tenofovir/emtricitabine or abacavir/lamivudine had been prospectively enrolled after having signed a written informed consent form. Plasma and intracellular atazanavir and ritonavir Ctrough (24 ± 3 h after drug intake) were measured at each visit during the first, second and third trimesters and post-partum using validated HPLC-MS and HPLC-photodiode array methods (with direct evaluation of cellular volume). Data are described as median (IQR) and compared through non-parametric tests. Twenty-five patients were enrolled; at baseline, the median age was 32 years (27-35). All patients had plasma HIV RNA <50 copies/mL; the median CD4+ count was 736 cells/mm3 (542-779). Atazanavir plasma concentrations were 441 ng/mL (261-1557), 710 ng/mL (338-1085), 556 ng/mL (334-1022) and 837 ng/mL (608-1757) during the first, second and third trimesters and post-partum, respectively; intracellular concentrations were 743 ng/mL (610-1928), 808 ng/mL (569-1620), 756 ng/mL (384-1074) and 706 ng/mL (467-2688), respectively. Atazanavir intracellular/plasma ratios were 1.32 (0.98-2.77), 1.34 (1.13-1.88), 1.38 (0.61-2.63) and 1.07 (0.56-2.69), respectively. Atazanavir intracellular concentrations and intracellular/plasma ratios showed non-significant changes over time (P > 0.05). This is the first demonstration that intracellular atazanavir exposure remains unchanged during pregnancy supporting the standard 300/100 mg atazanavir/ritonavir dosing throughout pregnancy.

Treatment response to unboosted atazanavir in combination with tenofovir disoproxil fumarate and lamivudine in human immunodeficiency virus-1-infected patients who have achieved virological suppression: A therapeutic drug monitoring and pharmacogenetic study

Treatment response to switch regimens containing unboosted atazanavir and tenofovir disoproxil fumarate (TDF)/lamivudine guided by therapeutic drug monitoring in human immunodeficiency virus-infected patients is rarely investigated. Consecutive patients with plasma human immunodeficiency virus RNA load<200copies/mL switching to unboosted atazanavir plus zidovudine-lamivudine (coformulated), abacavir-lamivudine (coformulated), or TDF/lamivudine>3months were included for determinations of treatment response, plasma atazanavir concentrations, and single-nucleotide polymorphisms of MDR1, PXR, and UGT1A1 genes from 2010 to 2014. Treatment failure was defined as either discontinuation of atazanavir for any reason or plasma viral load ≥200copies/mL within 96weeks. During the study period, 128 patients switched to unboosted atazanavir with TDF/lamivudine (TDF group) and 186 patients switched to unboosted atazanavir with two other nucleoside reverse-transcriptase inhibitors (non-TDF group). There were no statistically significant differences in the distributions of single-nucleotide polymorphisms of MDR1 (2677 and 3435), PXR genotypes (63396), and UGT1A1*28 between the two groups. Recommended plasma atazanavir concentrations were achieved in 83.5% and 64.9% of the TDF group and non-TDF group, respectively (p<0.01). After a median follow-up duration of 96.0weeks, treatment failure occurred in 19 (14.9%) and 34 (18.3%) patients in the TDF group and non-TDF group, respectively (p=0.60). Low-level viremia (40-200 copies/mL) before switch (adjusted hazard ratio, 2.12; 95% confidence interval, 1.12-4.01) and without therapeutic drug monitoring (adjusted hazard ratio, 2.08; 95% confidence interval, 1.16-3.73) were risk factors for treatment failure. Switch to unboosted atazanavir with TDF/lamivudine achieves a similar treatment response to that with two other nucleoside reverse-transcriptase inhibitors in patients achieving virological suppression with the guidance of therapeutic drug monitoring.

Cholelithiasis and Nephrolithiasis in HIV-Positive Patients in the Era of Combination Antiretroviral Therapy.

ObjectivesThis study aimed to describe the epidemiology and risk factors of cholelithiasis and nephrolithiasis among HIV-positive patients in the era of combination antiretroviral therapy.MethodsWe retrospectively reviewed the medical records of HIV-positive patients who underwent routine abdominal sonography for chronic viral hepatitis, fatty liver, or elevated aminotransferases between January 2004 and January 2015. Therapeutic drug monitoring of plasma concentrations of atazanavir was performed and genetic polymorphisms, including UDP-glucuronosyltransferase (UGT) 1A1*28 and multidrug resistance gene 1 (MDR1) G2677T/A, were determined in a subgroup of patients who received ritonavir-boosted or unboosted atazanavir-containing combination antiretroviral therapy. Information on demographics, clinical characteristics, and laboratory testing were collected and analyzed.ResultsDuring the 11-year study period, 910 patients who underwent routine abdominal sonography were included for analysis. The patients were mostly male (96.9%) with a mean age of 42.2 years and mean body-mass index of 22.9 kg/m2 and 85.8% being on antiretroviral therapy. The anchor antiretroviral agents included non-nucleoside reverse-transcriptase inhibitors (49.3%), unboosted atazanavir (34.4%), ritonavir-boosted lopinavir (20.4%), and ritonavir-boosted atazanavir (5.5%). The overall prevalence of cholelithiasis and nephrolithiasis was 12.5% and 8.2%, respectively. Among 680 antiretroviral-experienced patients with both baseline and follow-up sonography, the crude incidence of cholelithiasis and nephrolithiasis was 4.3% and 3.7%, respectively. In multivariate analysis, the independent factors associated with incident cholelithiasis were exposure to ritonavir-boosted atazanavir for >2 years (adjusted odds ratio [AOR], 6.29; 95% confidence interval [CI], 1.12–35.16) and older age (AOR, 1.04; 95% CI, 1.00–1.09). The positive association between duration of exposure to ritonavir-boosted atazanavir and incident cholelithiasis was also found (AOR, per 1-year exposure, 1.49; 95% CI, 1.05–2.10). The associated factors with incident nephrolithiasis were hyperlipidemia (AOR, 3.97; 95% CI, 1.32–11.93), hepatitis B or C coinfection (AOR, 3.41; 95% CI, 1.09–10.62), and exposure to abacavir (AOR, 12.01; 95% CI, 1.54–93.54). Of 180 patients who underwent therapeutic drug monitoring of plasma atazanavir concentrations and pharmacogenetic investigations, we found that the atazanavir concentrations and UGT 1A1*28 and MDR1 G2677T/A polymorphisms were not statistically significantly associated with incident cholelithiasis and nephrolithiasis.ConclusionsIn HIV-positive patients in the era of combination antiretroviral therapy, a high prevalence of cholelithiasis and nephrolithiasis was observed, and exposure to ritonavir-boosted atazanavir for >2 years was associated with incident cholelithiasis.

Herb–drug interaction between an anti-HIV Chinese herbal SH formula and atazanavir in vitro and in vivo

Ethnopharmacological relevanceWith the prevalent use of highly active antiretroviral therapy (HAART) for AIDS patients since 1996, the mortality of HIV/AIDS patients has been remarkably decreased. With long-term use of HAART, drug resistance and side effects of antiretrovirals have been frequently reported, which not only reduce the efficacy, but also decreases the tolerance of patients. Traditional herbal medicine has become more popular among HIV/AIDS patients as adjuvant therapy to reduce these adverse effects of HAART. SH formula is a Chinese herbal formula consisting of five traditional Chinese herbs including Morus alba L., Glycyrrhiza glabra L., Artemisia capillaris Thumb., Astragalus membranaceus Bge., and Carthamus tinctorius L. SH formula is clinically used for HIV treatment in Thailand. However, the possible pharmacokinetic interactions between these Chinese herbs and antiretroviral drugs have not been well documented. The aim of this study was to investigate the potential herb-drug interaction between SH herbal Chinese formula and the antiretroviral drug atazanavir (ATV). Materials and methodsThe combination effect of SH formula and ATV on HIV protease was studied in HIV-1 protease inhibition assay in vitro. The inhibition of SH formula on rat CYP3A2 was assessed by detecting the formation of 1′–OH midazolam from midazolam in rat liver microsomes in vitro. The in vivo pharmacokinetic interaction between SH formula and ATV was investigated by measuring time-dependent plasma concentrations of ATV in male Sprague–Dawley rats with liquid chromatography–mass spectrometry. ResultsThrough the in vitro HIV-1 protease inhibition assay, combination of SH formula (41.7–166.7μg/ml) and ATV (16.7–33.3ng/ml) showed additive inhibition on HIV-1 protease activity than SH formula or ATV used alone. In vitro incubation assay indicated that SH formula showed a weak inhibition (IC50=231.2µg/ml; Ki=98.2µg/ml) on CYP3A2 activity in rat liver microsomes. In vivo pharmacokinetic study demonstrated that SH formula did not affect the metabolism of ATV in rats. ConclusionsOur study demonstrated for the first time that there is no metabolism-based herb-drug interaction between SH formula and ATV in rats, but this combination enhances the inhibition potentials against HIV protease activity. This observation may support the combinational use of anti-HIV treatment in human.

Low-Dose Ritonavir-Boosted Atazanavir (200/100 mg) Maintained a High Virological Efficacy Up To 4 Years in Treatment-Experienced HIV-1 Infected Adults: A Prospective Cohort Study from Asia

Background: HIV requires lifelong treatment so ARV dose optimization is important for long-term efficacy and safety. Previously, low-dose atazanavir (ATV)/ritonavir(r) plus 2 NRTIs in HIV-infected Thai patients provided adequate plasma ATV concentrations and reduced risk of hyperbilirubinemia. However, long-term efficacy and safety data is limited. Methods: 127 HIV-infected adults on ATV/r200/100mg plus 2 NRTIs were prospectively followed in Thailand. CD4 cell counts, HIV-RNA, and safety parameters were performed every 6 months. Estimated glomerular filtration rate (eGFR) was calculated by chronic kidney disease epidemiology (CKD-EPI). ATV plasma concentrations (ATV Ctrough) were assessed. Results: Median body weight was 60 kg and 50% were females. Previous regimens were mainly standard dose ATV/r (54%) and lopinavir/r (29%). 93% of them were on tenofovir and 9.4% had HIV-RNA > 50 copies/mL at the time when lower dose of ATV/r was initiated. The median duration of lower dose ATV/r was 154 (IQR 65-271) weeks and 50.4% had been followed for more than 3 years. HIV-RNA 0.15 mg/L. Conclusions: Long-term use of ATV/r 200 mg/100 mg based-HAART as a maintenance therapy for patients who are sensitive to PI was efficacious and well-tolerated. Use of low-dose ATV/r could benefit resource limited settings because it will reduce toxicity, increase accessibility and save costs.

Potential association between rosuvastatin use and high atazanavir trough concentrations in ritonavir-treated HIV-infected patients.

Emerging evidence shows that standard atazanavir (ATV) dosages are associated with considerable interindividual variability in plasma drug concentrations. Given the potential impact of ATV exposure on clinical outcome, in this retrospective study we sought to assess demographic and clinical factors influencing ATV plasma concentrations in a large cohort of HIV-infected patients. HIV-infected patients treated with ATV for at least 3 months and with at least one assessment of ATV trough concentrations were enrolled. Blood trough samples were collected from all patients immediately before the next drug intake. Plasma ATV and ritonavir concentrations were quantified by a validated chromatographic method coupled with tandem mass spectrometric detection. Univariate and multivariate regression analyses were performed using ATV plasma concentrations as the dependent variable, with demographic and clinical characteristics as the independent ones. A total of 273 HIV-infected adult patients were included in the present study. Factors significantly associated with increased ATV concentrations by univariate analysis were ATV dosage, number of concomitant drugs, ritonavir or statin use. However, with multivariate regression analysis, the only factors independently and significantly associated with ATV concentrations were ritonavir use (r=0.291, P<0.0001) and concomitant rosuvastatin therapy (r=0.315, P<0.0001). We found that patients on ATV/ritonavir given rosuvastatin concomitantly have ATV concentrations that exceed the upper therapeutic threshold of 800 ng/ml known to be associated with a high risk of experiencing ATV-related side effects. In agreement with previous findings we confirmed the lack of association between other demographic and clinical characteristics such as age, gender, body weight and ATV exposure.

Evaluation of Boosted and Unboosted Atazanavir Plasma Concentration in HIV Infected Patients

The aim of the study was to identify variables that can influence atazanavir plasma concentration. We retrospectively analysed atazanavir trough concentration of HIV infected patients who performed therapeutic drug monitoring between October 2007 and July 2011. Qualitative variables were compared with X(2) test while continuous ones with Mann-Whitney and Student's t-test. A linear regression model was used to investigate factors influencing atazanavir plasma concentration. Therefore, we analysed the impact of cirrhosis on atazanavir pharmacokinetic variability. 255 plasma samples from 179 patients were analysed. At the univariate analysis female gender (+144.4 ng/mL; p=0.05) and tenofovir (+196.8 ng/mL; p=0.002) were associated with higher atazanavir concentrations. The multivariate model confirmed these two variables (+164.6 ng/mL; p=0.02 and +150.4 ng/mL; p=0.01) as independently associated with higher atazanavir trough concentration. The analysis of cirrhotic population showed an influence of tenofovir (-255.9 ng/mL; p=0.01), increased AST (+95.3 ng/mL; p=0.09), ALT (+67.9 ng/mL; p=0.07) and creatinine (+517.2 ng/mL; p=0.04). The multivariate model confirm that tenofovir was associated with lower atazanavir trough concentration (-284.1 ng/mL; p=0.005) while AST values significantly increased atazanavir concentrations (+114.5 ng/mL; p=0.03). Atazanavir is a safe and manageable drug. Our results suggest that female patients tend to have higher atazanavir plasma concentration, while the effect of tenofovir needs to be better clarified.

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Plasma and Intracellular Antiretroviral Concentrations in HIV-Infected Patients under Short Cycles of Antiretroviral Therapy.

Study of plasma and intracellular concentrations of atazanavir, lopinavir, nevirapine, and efavirenz was conducted on 48 patients under short cycles of antiretroviral therapy. Intracellular concentrations (IC) were still measurable for all drugs after 85 h or 110 h drug intake despite the absence of drug in plasma for atazanavir and lopinavir. A linear relationship between plasma and intracellular efavirenz was observed. Further studies to fully understand the impact of IC in the intermittent antiviral treatment are required.

Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients

Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC(0-24) 71.2 vs. 53.1 mg·h/liter, C(max) 8.5 vs. 5.5 mg/liter, and C(trough) 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV C(trough) levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.

Related factors to atazanavir plasma levels in a cohort of HIV positive individuals with undetectable viral load

ObjectiveTo evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). DesignCross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. MethodsPatients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200cells/mm3, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. Results and discussionOverall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p=0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r=0.32 and r=0.33 respectively; p<0.05 in both cases). No statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. ConclusionIn summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. Prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p=0.068).

External Validation of the Bilirubin–Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients

Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95–100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.

Coadministration of tenofovir decreased atazanavir plasma concentration after unilateral nephrectomy

We report a case in which the atazanavir (ATV) concentration in the plasma decreased after unilateral nephrectomy in a patient receiving tenofovir (TDF). The patient was a 39-year-old man diagnosed with human immunodeficiency virus type 1 infection and was being treated with TDF/emtricitabine, ATV, and ritonavir. Before nephrectomy, ATV and TDF plasma trough concentrations were 810 and 65ng/ml, respectively. At this time, estimated glomerular filtration rate (eGFR) was 111ml/min/1.73m(2). Approximately 5months after starting antiretroviral therapy (ART), the patient underwent nephrectomy. Plasma concentrations were remeasured 18weeks after the operation, and the TDF concentration had increased to 109ng/ml, whereas the ATV concentration decreased to 290ng/ml. His eGFR decreased to 50ml/min/1.73m(2) at the time of the second measurement. The decreased ATV plasma concentration suggested that interactions between ATV and TDF were exacerbated by an increase in TDF plasma concentration caused by renal dysfunction. This case report suggests that it is important to monitor the ATV plasma concentration to ensure that it is no less than the target trough concentration when renal function decline is observed in patients receiving ART including ATV and TDF.

A Randomized Study of Pharmacokinetics, Efficacy, and Safety of 2 Raltegravir Plus Atazanavir Strategies in ART-Treated Adults

New antiretroviral drug classes provide opportunities to explore novel regimens. HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up. Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable. In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents.

To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300 mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1 L h(-1) (70 kg)(-1), respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32-50 kg. To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg.

Therapeutic Monitoring and Variability of Atazanavir in HIV-Infected Patients, With and Without HCV Coinfection, Receiving Boosted or Unboosted Regimens

Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 μg/mL, based on the proposed therapeutic range (0.15-0.85 μg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis. In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 μg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) μg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) μg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) μg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) μg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) μg/mL, and there was a significant difference when compared with HIV patients without coinfection. Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.

HIV-Infected Adolescents: Relationship Between Atazanavir Plasma Levels and Bilirubin Concentrations

The use of atazanavir (ATV) in adolescents infected with human immunodeficiency virus was analyzed in this study. ATV morning plasma concentrations were determined during regular visits to the outpatient department. Results showed that bilirubin levels were higher among patients with higher ATV plasma concentrations (p = .018). Monitoring plasma levels of ATV could avoid toxicity in these patients.