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David W Kimberlin, Edward P Acosta,
Mark N Prichard,
Pablo J Sánchez,
Krow Ampofo,
David Lang,
Negar Ashouri,
John A Vanchiere,
Mark J Abzug,
Nazha Abughali, [......],
Sunil K Sood,
Michael G Spigarelli,
John S Bradley,
Judy Lew,
Marian G Michaels,
Wen Wan,
Gretchen Cloud,
Penelope Jester,
Fred D Lakeman,
Richard J Whitley
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ABSTRACT: Background. Children under 2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children under 2 years of age is unknown.Methods. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants from birth to 2 years of age in an age-deescalation, adaptive design with a targeted systemic exposure.Results. From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0 through 8 months of age, although there was a greater degree of variability in infants under 3 months of age. In subjects 9 through 11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of ten subjects 12 through 23 months of age receiving the FDA-approved unit dose for this age group of 30 mg had oseltamivir carboxylate exposures below the target range. Virus from three subjects developed oseltamivir resistance during antiviral treatment.Conclusions. The appropriate twice-daily oral oseltamivir dose for infants birth through 8 months of age is 3.0 mg/kg, while the dose for infants 9 through 11 months is 3.5 mg/kg.
The Journal of Infectious Diseases 12/2012; · 6.41 Impact Factor
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Emily R Holzinger,
Benjamin Grady,
Marylyn D Ritchie,
Heather J Ribaudo, Edward P Acosta,
Gene D Morse,
Roy M Gulick,
Gregory K Robbins,
David B Clifford,
Eric S Daar,
Paul McLaren,
David W Haas
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ABSTRACT: OBJECTIVES: Prior candidate gene studies have associated CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics. MATERIALS AND METHODS: Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry. RESULTS: Among 856 individuals, CYP2B6 516G→T was associated with efavirenz estimated Cmin (P=8.5×10). After adjusting for CYP2B6 516G→T, CYP2B6 983T→C was associated (P=9.9×10). After adjusting for both CYP2B6 516G→T and 983T→C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4×10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5×10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms. CONCLUSION: Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization.
Pharmacogenetics and Genomics 10/2012; · 3.48 Impact Factor
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ABSTRACT: INTRODUCTION:: There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV-diphosphate (TFV-DP) concentrations. Our objectiveswere to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations. METHODS:: TFV-DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV-DP were quantified with validated LC/MS/MS methods. Data were pooled with other studies in HIV-infected adults (N = 55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model,partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation. RESULTS:: Apparent oral TFV clearance (CL/F) was significantly faster in patients <25 versus ≥25 years. The most significant covariate on CL/F and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations (EC50) was almost 2-fold lower in patients <25 versus ≥25 years. The estimated intracellular TFV-DP half-life for these groups was 70 and87 hours,respectively. CONCLUSIONS:: These data demonstrate children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age-related difference appears to arise from an increased sensitivity to formation ofTFV-DP.
AIDS (London, England) 10/2012; · 4.91 Impact Factor
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ABSTRACT: Durable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations (C(trough)) are correlated with response, but determination of target C(trough) values is hindered by a paucity of in vivo concentration-response data. In the absence of these data, in vitro susceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressive in vivo drug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations on in vitro drug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC(95)) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC(95) (PBIC(95)) values. PBIC(95) values were concordant with the minimum effective C(trough) values that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC(95) values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC(95) values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly when in vivo concentration-response relationships are lacking.
Antimicrobial Agents and Chemotherapy 09/2012; 56(11):5938-45. · 4.84 Impact Factor
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ABSTRACT: Paired plasma and intracellular samples were obtained from 12 HIV-infected adults taking raltegravir twice-daily (BID), and after switching to once daily (QD). With BID dosing, no plasma trough concentrations were below the IC95, in contrast to 33% for QD dosing. 50% of the QD group had intracellular trough concentrations below the IC95; 25% in the BID group. Lower plasma and intracellular concentrations may contribute to inferior virologic suppression rates observed with QD raltegravir dosing.
AIDS (London, England) 08/2012; · 4.91 Impact Factor
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ABSTRACT: PURPOSE: To evaluate the impact of enzyme-inducing antiepileptic drugs (EI-AEDs) on serum antiretroviral (ARV) levels in patients with HIV. METHODS: Data from the U.S. Military HIV Natural History Study were screened to identify participants taking ARVs with EI-AEDs and controls taking ARVs with non enzyme-inducing AEDs (NEI-AEDs). The proportion of serum ARV levels below the recommended minimum concentrations (C(min)) was compared between these groups. RESULTS: ARV levels were available for 10 individuals exposed to 16 intervals on combined ARVs/EI-AEDs (phenytoin and carbamazepine) and for 25 controls exposed to 30 overlap intervals on combined ARVs/NEI-AEDs. The percentage of overlap intervals with ≥1 ARV levels below C(min) was higher in the EI-AED group than in controls (37.5% vs. 23.3%; p=0.124). After excluding intervals associated with serum levels of EI-AEDs below the reference range (n=6), the proportion of intervals with ≥1 ARV level below C(min) was significantly greater among EI-AED recipients (60%) compared to controls (23.3%; p=0.008). CONCLUSIONS: ARV levels below C(min) were more common in participants receiving EI-AEDs, the difference being statistically significant for intervals associated with EI-AED levels within the reference range. These data suggest that, in agreement with current guidelines, EI-AEDs should be avoided in patients receiving ARV therapy.
Epilepsy research 07/2012; · 2.48 Impact Factor
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ABSTRACT: The biggest challenge facing highly antiretroviral-experienced patients and their caregivers is the diminishing number of
therapeutic options available that sustain activity despite increasing numbers of drug-resistance mutations. New options in
antiretroviral treatment have been introduced: two new members of traditional antiretroviral classes (darunavir and etravirine)
and two drugs with novel mechanisms of action (raltegravir and maraviroc). Each was approved for use in treatment-experienced
patients. A fifth drug—containing efavirenz, tenofovir, and emtricitabine (Atripla; Bristol-Myers Squibb, New York, NY, and
Gilead Sciences, Foster City, CA)—is a novel coformulation of existing drugs from two different classes, simplifying administration
with the intent of increasing adherence. Because successful management of HIV infection requires the simultaneous use of three
or more drugs, understanding the pharmacologic aspects of coadministration is critical. This review summarizes the pharmacokinetic
properties affecting the administration of these recently approved drugs in light of highly active antiretroviral treatment
guidelines.
Current HIV/AIDS Reports 04/2012; 6(1):43-50.
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ABSTRACT: To determine whether the absorption of four antiretroviral agents-raltegravir, etravirine, emtricitabine, and tenofovir-is compromised when administered by gastrostomy tube.
Pharmacokinetic analysis.
University medical center.
A 52-year-old African-American man coinfected with advanced multidrug-resistant human immunodeficiency virus (HIV) and chronic hepatitis B, who was receiving treatment with raltegravir, etravirine, emtricitabine, and tenofovir, and developed ulcerative esophagitis with perforation, requiring a gastrostomy tube.
Due to the patient's esophageal perforations, all nutrition and drug therapy had to be provided by gastrostomy tube. As his antiretroviral regimen of raltegravir, etravirine, and emtricitabine-tenofovir was not available in liquid or powder formulations, the oral tablets were crushed or dispersed and mixed with water, then administered by gastrostomy tube. To ensure that the absorption of the drugs was sufficient for antiretroviral response, plasma samples were collected at 2 hours and 12 hours after dosing, and drug concentrations were quantitated by using validated assays. The 2- and 12-hour postdose plasma concentrations were 1220 and 446 ng/ml for raltegravir, 212 and 274 ng/ml for etravirine, 1148 and 164 ng/ml for emtricitabine, and 320 and 94 ng/ml for tenofovir, respectively. The patient's plasma concentrations were then compared with those in published pharmacokinetic studies of oral regimens administered to HIV-infected persons and healthy volunteers. Overall, the plasma concentrations of the antiretrovirals administered by gastrostomy tube were similar to published values. No drug toxicities were observed in this patient.
These pharmacokinetic data suggest that absorption of raltegravir, etravirine, emtricitabine, and tenofovir was not compromised when the drugs were administered by gastrostomy tube. These findings provide a basis for further investigation of the pharmacokinetics, safety, tolerance, and antiretroviral response to raltegravir, etravirine, and emtricitabine-tenofovir when the oral route of administration is not possible.
Pharmacotherapy 02/2012; 32(2):142-7. · 2.90 Impact Factor
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AIDS (London, England) 01/2012; 26(3):397-8. · 4.91 Impact Factor
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Babafemi Taiwo,
Lu Zheng,
Sebastien Gallien,
Roy M Matining,
Daniel R Kuritzkes,
Cara C Wilson,
Baiba I Berzins, Edward P Acosta,
Barbara Bastow,
Peter S Kim,
Joseph J Eron
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ABSTRACT: To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients.
Phase IIb, single-arm, open-label, multicenter study.
One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log(10) copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure.
Virologic failure rate was 16% [95% confidence interval (CI) 10-24] by week 24 and 26% (95% CI 19-36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51-200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100,000 copies/ml [hazard ratio 3.76, 95% CI (1.52-9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/μl increase (95% CI 0.61-0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100,000 copies/ml [hazard ratio = 4.67 (95% CI 1.93-11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41-8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100,000 copies/ml.
DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100,000 copies/ml.
AIDS (London, England) 08/2011; 25(17):2113-22. · 4.91 Impact Factor
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ABSTRACT: 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 (C(min)) 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 C(min) 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.
Antimicrobial Agents and Chemotherapy 06/2011; 55(9):4290-4. · 4.84 Impact Factor
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ABSTRACT: Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability.
In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment.
Median entry age was 43 years (n = 16). Median plasma log(10) HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/µL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC(12_total)) and maximum concentration (C(max_total)) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC(12_total) and C(max_total), respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG.
Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.
The Journal of Clinical Pharmacology 01/2011; 51(11):1539-48. · 2.91 Impact Factor
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ABSTRACT: HIV dynamic studies have contributed significantly to the understanding of HIV pathogenesis and antiviral treatment strategies for AIDS patients. Establishing the relationship of virologic responses with clinical factors and covariates during long-term antiretroviral (ARV) therapy is important to the development of effective treatments. Medication adherence is an important predictor of the effectiveness of ARV treatment, but an appropriate determinant of adherence rate based on medication event monitoring system (MEMS) data is critical to predict virologic outcomes. The primary objective of this paper is to investigate the effects of a number of summary determinants of MEMS adherence rates on virologic response measured repeatedly over time in HIV-infected patients. We developed a mechanism-based differential equation model with consideration of drug adherence, interacted by virus susceptibility to drug and baseline characteristics, to characterize the long-term virologic responses after initiation of therapy. This model fully integrates viral load, MEMS adherence, drug resistance and baseline covariates into the data analysis. In this study we employed the proposed model and associated Bayesian nonlinear mixed-effects modeling approach to assess how to efficiently use the MEMS adherence data for prediction of virologic response, and to evaluate the predicting power of each summary metric of the MEMS adherence rates. In particular, we intend to address the questions: (i) how to summarize the MEMS adherence data for efficient prediction of virologic response after accounting for potential confounding factors such as drug resistance and covariates, and (ii) how to evaluate treatment effect of baseline characteristics interacted with adherence and other clinical factors. The approach is applied to an AIDS clinical trial involving 31 patients who had available data as required for the proposed model. Results demonstrate that the appropriate determinants of MEMS adherence rates are important in order to more efficiently predict virologic response, and investigations of adherence to ARV treatment would benefit from measuring not only adherence rate but also its summary metric assessment. Our study also shows that the mechanism-based dynamic model is powerful and effective to establish a relationship of virologic responses with medication adherence, virus resistance to drug and baseline covariates.
The Annals of Applied Statistics 01/2011; 5(1):551-577. · 1.58 Impact Factor
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Heather J Ribaudo,
Huan Liu,
Matthias Schwab,
Elke Schaeffeler,
Michel Eichelbaum,
Alison A Motsinger-Reif,
Marylyn D Ritchie,
Ulrich M Zanger, Edward P Acosta,
Gene D Morse,
Roy M Gulick,
Gregory K Robbins,
David Clifford,
David W Haas
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ABSTRACT: In AIDS Clinical Trials Group protocols 384, A5095, and A5097s, we characterized relationships between 22 polymorphisms in CYP2B6, ABCB1, and CYP3A5; plasma efavirenz exposure; and/or treatment responses. A stepwise logistic regression procedure selected polymorphisms associated with reduced drug clearance adjusted for body mass index and the composite CYP2B6 516/983 genotype. Relationships between selected polymorphisms and treatment responses were characterized by competing risk methodology. Association analyses involved 821 individuals (317 for pharmacokinetics and 643 for treatment response). Models that included CYP2B6 516/983 genotype best predicted pharmacokinetics. Slow-metabolizer genotypes were associated with increased central nervous system events among white participants and decreased virologic failure among black participants.
The Journal of Infectious Diseases 09/2010; 202(5):717-22. · 6.41 Impact Factor
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ABSTRACT: Under the Emergency Use Authorization issued in April 2009, oseltamivir can be used to treat 2009 influenza A (H1N1) virus infection in children aged <1 year. No data exist on the dosing of oseltamivir in premature babies. A hospital health care worker inadvertently exposed 32 neonatal intensive care unit babies to 2009 influenza A (H1N1); a protocol was expeditiously implemented to collect samples for pharmacokinetics and dosage evaluation. Results suggest 1.0 mg/kg/dose twice daily in premature babies produces oseltamivir carboxylate exposures similar to that in older children receiving 3.0 mg/kg/dose twice daily. These results provide initial guidance on dosing oseltamivir in this vulnerable population.
The Journal of Infectious Diseases 08/2010; 202(4):563-6. · 6.41 Impact Factor
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ABSTRACT: Studies on HIV dynamics in AIDS research are very important in understanding the pathogenesis of HIV-1 infection and also in assessing the effectiveness of antiretroviral (ARV) treatment. Viral dynamic models can be formulated through a system of nonlinear ordinary differential equations (ODE), but there has been only limited development of statistical methodologies for inference. This article, motivated by an AIDS clinical study, discusses a hierarchical Bayesian nonlinear mixed-effects modeling approach to dynamic ODE models without a closed-form solution. In this model, we fully integrate viral load, medication adherence, drug resistance, pharmacokinetics, baseline covariates and time-dependent drug efficacy into the data analysis for characterizing long-term virologic responses. Our method is implemented by a data set from an AIDS clinical study. The results suggest that modeling HIV dynamics and virologic responses with consideration of time-varying clinical factors as well as baseline characteristics may be important for HIV/AIDS studies in providing quantitative guidance to better understand the virologic responses to ARV treatment and to help the evaluation of clinical trial design in response to existing therapies.
Biometrical Journal 08/2010; 52(4):470-86. · 1.25 Impact Factor
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ABSTRACT: Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.
Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.
On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.
Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
The Journal of Infectious Diseases 04/2009; 199(6):872-80. · 6.41 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The biggest challenge facing highly antiretroviral-experienced patients and their caregivers is the diminishing number of therapeutic options available that sustain activity despite increasing numbers of drug-resistance mutations. New options in antiretroviral treatment have been introduced: two new members of traditional antiretroviral classes (darunavir and etravirine) and two drugs with novel mechanisms of action (raltegravir and maraviroc). Each was approved for use in treatment-experienced patients. A fifth drug-containing efavirenz, tenofovir, and emtricitabine (Atripla; Bristol-Myers Squibb, New York, NY, and Gilead Sciences, Foster City, CA)-is a novel coformulation of existing drugs from two different classes, simplifying administration with the intent of increasing adherence. Because successful management of HIV infection requires the simultaneous use of three or more drugs, understanding the pharmacologic aspects of coadministration is critical. This review summarizes the pharmacokinetic properties affecting the administration of these recently approved drugs in light of highly active antiretroviral treatment guidelines.
Current Infectious Disease Reports 12/2008; 10(6):522-9.
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ABSTRACT: This work describes an assay system that has been developed to quantify raltegravir concentrations in human plasma using a liquid-liquid extraction technique paired with HPLC separation and MS-MS detection. The dynamic range of this assay extends from 1 to 3000 ng/mL, with a coefficient of determination (r(2), mean+/-SD) of 0.9992+/-0.0002. The mean precision values for calibration standards ranged from 0.6% to 3.0%, while accuracy values were 96.5-104.3%. This procedure is an accurate, precise, and sensitive method for raltegravir quantitation and was successfully validated using external proficiency testing.
Journal of Chromatography B 06/2008; 867(2):165-71. · 2.89 Impact Factor
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J Michael Kilby,
Ha Youn Lee,
J Darren Hazelwood,
Anju Bansal,
R Patterson Bucy,
Michael S Saag,
George M Shaw, Edward P Acosta,
Victoria A Johnson,
Alan S Perelson,
Paul A Goepfert
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ABSTRACT: Compare the initial phases of virologic decay when acute/early and advanced HIV-infected adults are administered the same treatment regimen.
Mathematical modeling of a previously completed prospective treatment pilot study involving treatment-naive patients with early and advanced immunosuppression.
We analyzed data from a treatment protocol in which 18 individuals with acute or recent HIV-1 seroconversion and six patients with advanced AIDS were administered the same four-drug antiretroviral regimen. Initial treatment responses were compared by fitting a mathematical model to frequent viral load measurements in order to calculate the first and second phase kinetics of viral clearance, and also by comparing viral load suppression over 24 weeks. Patients were also comprehensively compared in terms of protease inhibitor drug levels, HIV-specific immune responses at baseline, and the presence of drug resistance-conferring mutations.
There was no statistically meaningful difference in first phase clearance of comparable high-level viremia in the two groups, whether protease inhibitor levels were inserted into the model or 100% antiviral drug effectiveness was assumed. In contrast, acute/early patients had inferior sustained responses than advanced patients, reflecting erratic adherence.
Despite many years of intervening immune destruction, the initial virologic decay on therapy appears to be the same at the extremes of the HIV disease spectrum.
AIDS (London, England) 06/2008; 22(8):957-62. · 4.91 Impact Factor
