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1.  Protease Inhibitor Levels in Hair Samples Strongly Predict Virologic Responses to HIV Treatment 
AIDS (London, England)  2009;23(4):471-478.
Objective
Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. Currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months and may provide a novel method for predicting therapeutic responses.
Design/methods
The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly-prescribed protease inhibitors (PIs) - lopinavir (LPV) and atazanavir (ATV) - in small hair samples. We examined the association between hair PI levels and initial virologic responses to therapy in multivariate logistic regression models.
Results
ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new PI-based regimen. For participants initiating LPV/RTV, the odds ratio (OR) for virologic suppression was 39.8 (95%CI 2.8–564) for those with LPV hair levels in the top tertile (>1.9ng/mg) compared to the bottom (≤0.41ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4, and prior PI experience. For women starting ATV, the adjusted OR for virologic success was 7.7 (95%CI 2.0-29.7) for those with hair concentrations in the top tertile (>3.4ng/mg) compared to the lowest (≤1.2ng/mg).
Conclusions
PI levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This noninvasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.
doi:10.1097/QAD.0b013e328325a4a9
PMCID: PMC2654235  PMID: 19165084
Hair levels; therapeutic drug monitoring; antiretroviral exposure; virologic response; protease inhibitors; atazanavir; lopinavir; WIHS cohort
2.  Atazanavir Pharmacokinetics With and Without Tenofovir during Pregnancy 
Background
Plasma concentrations of several protease inhibitors are decreased during pregnancy. Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.
Design
IMPAACT 1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included two cohorts receiving atazanavir/ritonavir 300mg/100mg once daily during the third trimester through 6-12 weeks postpartum either with or without tenofovir.
Methods
Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase HPLC with a detection limit of 0.13 mcg/mL. Pharmacokinetic targets were the estimated 10th percentile atazanavir AUC (29.4 mcg*hr/mL) in non-pregnant historical controls taking the standard dose (mean AUC=57 mcg*hr/mL) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs. Infant bilirubin concentrations were measured at 24-48 hours and 4-6 days after birth.
Results
Atazanavir pharmacokinetic data were available for 38 women (18 without tenofovir, 20 with tenofovir. Median atazanavir AUC was reduced during the third trimester compared to postpartum for subjects not receiving tenofovir (41.9 vs 57.9 mcg*hr/mL, p=.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg*hr/mL, p=.04). During the third trimester, AUC was below the target in 33% (6/18) of women not receiving tenofovir and 55% (11/20) of women receiving tenofovir. Trough concentration was below the target in 6% (1/18) of women not receiving tenofovir and 15% (3/20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29 paired samples was 0.18 (0 - 0.45). No excessive infant bilirubin concentrations were observed.
Conclusions
Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400mg/100mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults, especially for pregnant women who are antiretroviral-experienced and/or who are also receiving tenofovir.
doi:10.1097/QAI.0b013e31820fd093
PMCID: PMC3125419  PMID: 21283017
atazanavir; tenofovir; pharmacokinetics; pregnancy; HIV; mother to child transmission
3.  Atazanavir: its role in HIV treatment 
Azatanavir is a protease inhibitor (PI) approved for the treatment of HIV-1 infection. Atazanavir is a substrate and inhibitor of cytochrome P450 isozyme 3A and an inhibitor and inducer of P-glycoprotein. It has similar virologic efficacy as efavirenz and ritonavir-boosted lopinavir in antiretroviral-naive individuals. Its impact on lipids is less than other PIs and it is suitable for those in whom hyperlipidemia is undesirable. Ritonavir boosting of atazanavir enhances the bioavailability of atazanavir but may result in some elevation of lipids and is recommended for treatment-experienced patients and those receiving efavirenz or tenofovir. Ritonavir-boosted atazanavir has similar antiviral activity as ritonavir-boosted lopinavir in both antiretroviral therapy-naive and -experienced patients. Atazanavir causes unconjugated bilirubinemia in over 40% of patients but results in less than 2% discontinuations. Atazanavir is licensed for once-daily use and atazanavir/ritonavir competes with lopinavir/ritonavir as the most commonly prescribed PI.
doi:10.1586/14787210.6.6.785
PMCID: PMC3805961  PMID: 19053892
atazanavir; hyperbilirubinemia; lipid profile; protease inhibitor; ritonavir
4.  A single centre cohort experience with a new once daily antiretroviral drug 
Postgraduate Medical Journal  2006;82(967):343-346.
Background
Atazanavir, an azadipeptide protease inhibitor (PI) with once daily dosing, a lack of insulin resistance, lipid increase, and gastrointestinal toxicities, is approved in combination with other antiretrovirals for the treatment of patients infected with HIV. Unboosted atazanavir is also used in highly active antiretroviral therapy (HAART) naive patients.
Methods
The study prospectively followed up an established cohort of patients who received atazanavir, and for whom one year of follow up data were available.
Results
It was found that use of atazanavir in intent to treat and on treatment analyses, maintained and led to virological suppression and increases in CD4 count in both PI naive and experienced patients. Virological failure occurred in 7% of patients and the main toxicity was hyperbilirubinaemia, which led to treatment withdrawal in 2%. Its efficacy and safety profile was similar to that seen in previous randomised studies investigating its use.
Conclusions
These data should provide reassurance for clinicians wishing to introduce a new antiretroviral into an established cohort.
doi:10.1136/pmj.2006.044867
PMCID: PMC2563794  PMID: 16679474
HIV; AIDS; compliance; atazanavir; lipid
5.  Correlations between atazanavir Ctrough and hyperbilirubinemia: a case report 
Introduction
Hyperbilirubinemia is a common side effect of the antiretroviral agent atazanavir but is generally reversible upon discontinuation of treatment. We used therapeutic drug monitoring to investigate the occurrence of hyperbilirubinemia in a 49-year-old Hispanic man infected with HIV, following an overdose of ritonavir in ritonavir-boosted atazanavir therapy.
Case presentation
A 49-year-old Hispanic man with HIV who had received several highly active antiretroviral therapy regimens over a number of years including atazanavir-containing regimens, was diagnosed with hyperbilirubinemia. An inappropriate doubling of ritonavir boosting resulted in a high atazanavir Ctrough and an initial rise in bilirubin plasma levels. Bilirubin levels later decreased, probably as a consequence of enzyme induction, while atazanavir plasma concentrations remained elevated.
Conclusion
This article describes an occurrence of hyperbilirubinemia in a man infected with HIV and supports the importance of therapeutic drug monitoring in investigations of hyperbilirubinemia among patients receiving antiretroviral agents. That the patient tolerated exceptionally high atazanavir levels further strengthens the tolerability profile of this drug.
doi:10.1186/1752-1947-3-9307
PMCID: PMC2803830  PMID: 20062736
6.  Atazanavir–bilirubin interaction: a pharmacokinetic–pharmacodynamic model 
Purpose
The aim of this work was to analyze the atazanavir–bilirubin relationship, using a new mathematical approach to pharmacokinetic–pharmacodynamic models, for competitive drug interactions based on Michaelis–Menten equations.
Patients and methods
Because atazanavir induces an increase of plasma bilirubin levels, in a concentration-dependent manner, we developed a mathematical model, based on increments of atazanavir and bilirubin concentrations at steady state, in HIV infected (HIV+) patients, and plotted the corresponding nomogram for detecting suboptimal atazanavir exposure.
Results
By applying the obtained model, the results indicate that an absolute value or an increment of bilirubin at steady state below 3.8 μmol/L, are predictive of suboptimal atazanavir exposure and therapeutic failure.
Conclusion
We have successfully implemented a new mathematical approach to pharmacokinetic–pharmacodynamic model for atazanavir–bilirubin interaction. As a result, we found that bilirubin plasma levels constitute a good marker of exposure to atazanavir and of viral suppression.
doi:10.2147/CPAA.S48377
PMCID: PMC3792011  PMID: 24106429
atazanavir; bilirubin; HIV/AIDS; pharmacodynamics; pharmacokinetics
7.  Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients 
Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h−1; P = 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter−1; P = 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.
doi:10.1128/AAC.01822-12
PMCID: PMC3535925  PMID: 23147727
8.  External Validation of the Bilirubin–Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients 
The AAPS Journal  2012;15(2):308-315.
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.
doi:10.1208/s12248-012-9440-8
PMCID: PMC3618856  PMID: 23224752
atazanavir; bilirubin; nomogram
9.  External Validation of the Bilirubin–Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients 
The AAPS journal  2012;15(2):308-315.
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.
doi:10.1208/s12248-012-9440-8
PMCID: PMC3618856  PMID: 23224752
atazanavir; bilirubin; nomogram
10.  Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients 
Aim
To study population pharmacokinetics and pharmacogenetics of ritonavir boosted atazanavir using exactly recorded drug intake time by MEMS.
Methods
The ANRS134–COPHAR 3 trial was conducted in 35 HIV-infected treatment-naïve patients. Atazanavir (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg) were supplied in bottles with a MEMS cap to be taken once daily during 6 months. Six concentrations measurements were collected at week 4, then trough levels bimonthly. A model integrating atazanavir and ritonavir pharmacokinetics and pharmacogenetics was developed using non-linear mixed effects.
Results
Use of exact dosing history data halved unexplained variability in atazanavir clearance. Ritonavir-atazanavir interaction model suggested that optimal boosting effect is achievable by lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 42% increased oral CL.
Conclusion
We provide evidence that variability in atazanavir pharmacokinetics is defined by adherence, CYP3A5 genotype and ritonavir exposure.
doi:10.1038/clpt.2012.137
PMCID: PMC3939416  PMID: 23033116
Adenine; analogs & derivatives; therapeutic use; Adult; Aged; Alleles; Cytochrome P-450 CYP3A; genetics; Deoxycytidine; analogs & derivatives; therapeutic use; Drug Interactions; Drug Therapy, Combination; Female; Genotype; HIV Infections; drug therapy; HIV Protease Inhibitors; pharmacokinetics; pharmacology; therapeutic use; Humans; Male; Medication Adherence; Middle Aged; Models, Biological; Nonlinear Dynamics; Oligopeptides; pharmacokinetics; therapeutic use; Organophosphonates; therapeutic use; Pharmacogenetics; Pyridines; pharmacokinetics; therapeutic use; Ritonavir; pharmacology; therapeutic use; Young Adult; Atazanavir; Adherence; Pharmacogenetics; Population pharmacokinetics
11.  Effect of Concomitantly Administered Rifampin on the Pharmacokinetics and Safety of Atazanavir Administered Twice Daily▿ † 
The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C12 h) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C12 h values for atazanavir were 44 ng/ml (range, <25 to187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.
doi:10.1128/AAC.00341-07
PMCID: PMC2043180  PMID: 17576825
12.  Are we conSTRucting the best treatment regimens for all patients with HIV infection? 
The British HIV Association (BHIVA) 2012 guidelines for the treatment of HIV recommend patients start combination antiretroviral therapy (ART) containing tenofovir and emtricitabine as the nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone. BHIVA third agent preferred choices comprise efavirenz, boosted atazanavir, boosted darunavir and raltegravir, and the guidelines further state that ‘fixed dose combinations (FDC) of drugs can increase adherence’ [1]. Atripla is currently the only available single-tablet regimen (STR) for the treatment of HIV which contains a combination of BHIVA preferred first-line antiretrovirals (tenofovir, emtricitabine and efavirenz). In addition, studies have shown that Atripla can improve adherence, treatment satisfaction and outcomes for patients infected with HIV [2]. A retrospective case note review was conducted for all HIV-positive patients attending a UK HIV centre and receiving ART. The purpose was to ascertain the proportion of patients receiving BHIVA preferred ART in its simplest dosing format (in this case Atripla) and to investigate whether there were clinically or virologically appropriate reasons why patients not on Atripla were prescribed more complex drug regimens. The total number of patients receiving ART at the time of review was 142, of which 47 (33%) were currently taking Atripla. Of the remaining 95 patients, 30 (32%) had taken Atripla or some of its components in the past and been changed from this for valid clinical or virological reasons. In addition, there were a further 34 cases (36%) where Atripla had never been offered to the patient for appropriate reasons and documentation of 8 instances in which Atripla had been declined by the patient. There remained, however, 28 cases (29%) where there was no documentation of Atripla having been considered or offered, and no apparent contraindications to the STR or its components. This included 4 patients with an elevated cardiovascular risk, all of whom were taking an abacavir-containing ART regimen at the time of review. Despite extensive professional guidance on preferred ART regimens and evidence to suggest that STR can increase adherence and patient satisfaction there remain patients in clinical care taking more complex drug regimens with no clear indication for this. We would encourage physicians to identify such patients and to discuss with them their treatment options in the light of advances in ART combination preparations.
doi:10.7448/IAS.15.6.18095
PMCID: PMC3512522
13.  Adherence Profiles and Therapeutic Responses of Treatment-Naive HIV-Infected Patients Starting Boosted Atazanavir-Based Therapy in the ANRS 134-COPHAR 3 Trial 
The adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self-completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (±3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10 per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS-defined adherence for correct dosing (−0.68% per 4-week period, P < 0.03) and timing compliance (−1.60% per 4-week period, P < 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.)
doi:10.1128/AAC.02605-12
PMCID: PMC3632895  PMID: 23459496
14.  Factors influencing lopinavir and atazanavir plasma concentration 
Background
The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration.
Methods
Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake.
Results
Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54).
Conclusions
This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.
doi:10.1093/jac/dkp408
PMCID: PMC2793688  PMID: 19897506
pharmacokinetics; rifabutin; drug interactions
15.  Cost-effectiveness Analysis of UGT1A1 Genetic Testing to Inform Antiretroviral Prescribing in HIV Disease 
Antiviral therapy  2012;18(3):399-408.
Background
Homozygosity for UGT1A1*28/*28 (Gilbert’s variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals.
Methods
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually.
Results
Initiating atazanavir-based ART at CD4 <500/µl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinemia by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario.
Conclusions
Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
doi:10.3851/IMP2500
PMCID: PMC3744167  PMID: 23264445
16.  An Investigation of the Possible Interaction between the Use of Vitamin C and Highly Active Anti-Retroviral Therapy (HAART) Adherence and Effectiveness in Treated HIV+ Women 
Objectives
Our goal in this study was to examine how Vitamin C interacts with antiretroviral therapy in individuals with HIV. We specifically evaluated how Vitamin C impacts highly active antiretroviral therapy (HAART) adherence and HAART effectiveness as adjudicated by HIV viral loads and CD4 cell counts. Women served as their own controls, comparing periods of Vitamin C usage with periods of non-usage.
Design
An intra-individual, cross-sectional comparative study ‘nested’ in the WIHS observational cohort study
Subjects
Women in the Women’s Interagency HIV Study (WIHS).
Outcome Measures
Adherence, CD4 count and Viral load.
Results
Our study population was drawn from 2,813 HIV+ participants who contributed 44,588 visits in WIHS from October, 1994 to April, 2009. Among them, there were 1,122 Vitamin C users with 4,954 total visits where use was reported. In the multivariate model adjusting for age, education, race, income, drug use, Vitamin C use order and depression score, there was a 44% increase in the odds of >=95% HAART adherence among participants during their period of Vitamin C use compared to when they were not using Vitamin C (OR=1.44; 95% CI=1.1–1.9; P-value=0.0179). There was an association with Vitamin C usage and CD4 counts on viral loads.
Conclusion
Vitamin C usage appears to be associated with improved adherence. Future Vitamin C studies should target specific HAART drugs, and prospective clinical outcomes.
doi:10.1016/j.ctim.2012.03.001
PMCID: PMC3351689  PMID: 22579434
17.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Objective
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
Methods
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Results
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Conclusion
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
doi:10.1097/QAD.0b013e32834fa121
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
18.  Short-term Garlic Supplementation and Highly Active Antiretroviral Treatment Adherence, CD4+ Cell Counts, and Human Immunodeficiency Virus Viral Load 
Context
Human immunodeficiency virus (HIV)–infected individuals frequently have consumed garlic, a popular complementary supplement. Researchers rarely have studied garlic’s association with antiretroviral therapies, however, even though that association is very relevant clinically.
Objective
To examine associations of supplemental use of garlic with highly active antiretroviral treatment (HAART) adherence level and HAART effectiveness (HIV viral load and CD4+ cell counts) in HIV-infected women.
Design
The research team carried out a self-controlled, longitudinal study nested within the Women’s Interagency HIV Study (WIHS). The team used a paired study design that allowed participants to serve as their own controls. The team first identified all of the study’s visits in which the participant self-reported the use of a garlic supplement since her last visit (index visit). Then for each index visit, the team identified a matching visit (a control visit) using the following criteria: (a) the visit must be one for the same participant in which that participant reported no garlic supplementation; (b) the visit must immediately precede the index visit (less than 1 year apart); and (c) at the time of the control visit, the participant must have been using antiretroviral therapy identical to that used at the time of the index visit.
Participants
Participants were persons using garlic supplementation who already were participants in the WIHS.
Outcome Measures
The research team used a logistic regression model to examine the association between garlic supplementation and HAART adherence level. The team used a mixed linear model to examine the association of garlic supplementation with HIV viral load and CD4+ cell counts.
Results
From October 1994 to April 2009, 390 HIV-infected women in the WIHS made 1112 visits at which they reported using garlic supplements. Seventy-seven HIV-infected women using HAART met the research team’s selection criteria and contributed 99 pairs of visits for the study. Among the women who used garlic supplements, 22% were 50 years and older; 58% were black and non-Hispanic; and 23% had less than a high-school education. Neither use of garlic supplementation nor reasons for using garlic supplements were significantly associated with the HAART adherence level, HIV viral load, or CD4+ cell counts; however, “use garlic as needed,” a potential marker of a disease state, was significantly associated with higher viral load (P = .0003).
Conclusion
Short-term garlic supplementation did not impact HAART adherence level, HIV viral load, and CD4+ cell counts.
PMCID: PMC3376904  PMID: 22516847
19.  Pharmacologic Boosting of Atazanavir in Maintenance HIV-1 Therapy: The COREYA Propensity-Score Adjusted Study 
PLoS ONE  2012;7(11):e49289.
Background
Among HIV-1 infected patients who achieved virologic suppression, the use of atazanavir without pharmacologic boosting is debated. We evaluated the efficacy and tolerance of maintenance therapy with unboosted atazanavir in clinical practice.
Methods and Results
This multicenter retrospective cohort study evaluated the efficacy of switching HIV-1-infected patients controlled on triple therapy to unboosted (ATV0, n = 98) versus ritonavir-boosted atazanavir (ATV/r, n = 254) +2 nucleos(t)ide reverse transcriptase inhibitors. The primary endpoint was time to virologic failure (VF, >200 copies/mL). ATV groups were compared controlling for potential confounding bias by inverse probability weighted Cox analysis and propensity-score matching. Overall and adjusted VF rates were similar for both strategies. Both strategies improved dyslipidemia and creatininemia, with less jaundice in the ATV0 group.
Conclusion
In previously well-suppressed patients, within an observational cohort setting, ATV0–based triple-therapy appeared as effective as ATV/r- based triple-therapy to maintain virologic suppression, even if co-administered with TDF, but was better tolerated.
doi:10.1371/journal.pone.0049289
PMCID: PMC3494679  PMID: 23152890
20.  Effects of Minocycline and Valproic Acid Coadministration on Atazanavir Plasma Concentrations in Human Immunodeficiency Virus-Infected Adults Receiving Atazanavir-Ritonavir▿  
Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [± standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24), the plasma concentration 24 h after the dose (Cmin), and the maximum concentration during the dosing interval (Cmax) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC0-24, Cmin, and Cmax with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.
doi:10.1128/AAC.00194-08
PMCID: PMC2533492  PMID: 18573930
21.  Effects of the H2-Receptor Antagonist Famotidine on the Pharmacokinetics of Atazanavir-Ritonavir With or Without Tenofovir in HIV-Infected Patients 
AIDS Patient Care and STDs  2011;25(9):509-515.
Abstract
Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H2-receptor antagonist, reduces exposures of atazanavir by 4–28% at doses of 20–40 mg twice daily. This study evaluated the effect of famotidine 20–40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26–63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (Cmin). In the presence of TDF, administration of famotidine 20–40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19–25%. However, all individual atazanavir Cmin values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC90) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H2-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H2-receptor antagonist with atazanavir/ritonavir.
doi:10.1089/apc.2011.0113
PMCID: PMC3157302  PMID: 21770762
22.  Association Between Living With Children and Adherence to Highly Active Antiretroviral Therapy in the Women’s Interagency HIV Study 
Pediatrics  2008;121(4):e787-e793.
OBJECTIVE
The purpose of this work was to evaluate whether living with children adversely affects adherence to highly active antiretroviral therapy in HIV-infected women.
PARTICIPANTS AND METHODS
We conducted a prospective cohort study between October 1998 and September 2005. The study outcome was ≥95% adherence to highly active antiretroviral therapy evaluated at 5832 semiannual visits among 1366 HIV-infected women in the Women’s Interagency HIV Study. The primary exposure defined at the visit immediately before outcome ascertainment was the number of children ≤18 years of age reported living in the household.
RESULTS
The percentage of women who reported ≥2 children in the household who also reported ≥95% adherence ranged from 68% to 75% compared with adherence when either 1 child or no children were reported. Each additional child reported living in the household was associated with a 6% decrease in the odds of ≥95% adherence.
CONCLUSION
The impact of living with a child on the ability to take medications by HIV-infected women has not been examined thoroughly. Our data suggest that adherence to highly active antiretroviral therapy is inversely associated with the number of children living in the household.
doi:10.1542/peds.2007-1586
PMCID: PMC2651400  PMID: 18381507
adherence; children; HAART; HIV
23.  Steady-State Pharmacokinetics of Tenofovir-Based Regimens in HIV-Infected Pediatric Patients▿ 
HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (Cmin) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and Cmin for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted.
doi:10.1128/AAC.01334-10
PMCID: PMC3165337  PMID: 21670182
24.  Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults 
Future virology  2011;6(2):157-177.
In the past 15 years, improvements in the management of HIV infection have dramatically reduced morbidity and mortality. Similarly, rapid advances in antiretroviral medications have resulted in the possibility of life-long therapy with simple and tolerable regimens. Protease inhibitors have been important medications in regimens of combination antiretroviral therapy for the treatment of HIV. One of the recommended and commonly used therapies in this class is once-daily-administered atazanavir, pharmacologically boosted with ritonavir (atazanavir/r). Clinical studies and practice have shown these drugs, in combination with other antiretroviral agents, to be potent, safe and easy to use in a variety of settings. Atazanavir/r has minimal short-term toxicity, including benign bilirubin elevation, and has less potential for long-term complications of hyperlipidemia and insulin resistance compared with other protease inhibitors. A high genetic barrier to resistance and a favorable resistance profile make it an excellent option for initial HIV treatment or as the first drug utilized in the protease inhibitors class. Atazanavir/r is also currently being studied in novel treatment strategies, including combinations with new classes of antiretrovirals to assess nucleoside reverse transcriptase inhibitor-sparing regimens. In this article we review atazanavir/r as a treatment for HIV infection and discuss the latest information on its pharmacology, efficacy and toxicity.
doi:10.2217/fvl.10.89
PMCID: PMC3127229  PMID: 21731578
antiretroviral therapy; atazanavir; HIV; protease inhibitor; ritonavir
25.  Long-Term Efficacy and Safety of Atazanavir/Ritonavir Treatment in a Real-Life Cohort of Treatment-Experienced Patients with HIV Type 1 Infection 
Abstract
Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV-experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV-experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA (<500 or ≥500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan–Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA <500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA ≥500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA <50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA ≥50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r-based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed.
doi:10.1089/aid.2012.0092
PMCID: PMC3698683  PMID: 23016535

Results 1-25 (635295)