Biomedical subjects

Edward P Acosta

Publications and source records attributed to Edward P Acosta.

At least 19 recordsLinked to original sources

PubMed2006

Improving data reliability using a non-compliance detection method versus using pharmacokinetic criteria.

Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues. One such technique by Lu et al. (Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343-362 (2001)) identifies occasions in pharmacokinetic (PK) data where the preceding dosing history is likely to be unreliable. We used this method, implemented in the software program NONMEM (beta) VI, to clean a dataset containing indinavir (IDV) plasma concentrations from HIV-1 infected patients. The data was also cleaned by inspection in Microsoft Excel using clinical PK criteria. A one-compartment model with first order absorption and elimination was fit to both sets of cleaned data. IDV population PK parameters obtained from these analyses were similar to those reported previously. It is established that IDV nephrotoxicity is related to high IDV exposure. However, no relationships were found between any PK parameters and nephrotoxicity in the "compliance cleaned" dataset. In the "PK cleaned" dataset, the oral clearance and apparent volume were lower by 9.1% and 6.6%, respectively in patients with any type of nephrotoxicity and the maximum IDV concentration (C(max)) was 12.1% higher. In patients suffering from nephrolithiasis in particular, C(max) was 15.5% higher. Accordingly, the use of the non-compliance detection method did not improve the reliability of our dataset over the usual method of applying clinical criteria. In fact, analyses on the compliance-cleaned dataset missed some exposure-toxicity relationships. Thus, automated methods must be tested rigorously with 'real life' datasets, used with caution, and always in conjunction with clinical reasoning to avoid overlooking a signal in noisy data.

Adult↗

PubMed2006

Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial.

CONTEXT: Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen. OBJECTIVE: To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection. DESIGN: The AIDS Clinical Trials Group (ACTG) A5095 study, a randomized, double-blind, placebo-controlled study with enrollment and follow-up conducted from March 22, 2001, to March 1, 2005, and enrolling treatment-naive, HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG. INTERVENTIONS: Zidovudine/lamivudine plus efavirenz (3-drug regimen) vs zidovudine/lamivudine/abacavir plus efavirenz (4-drug regimen). MAIN OUTCOME MEASURES: Time to virologic failure (defined as time to first of 2 successive HIV-1 RNA levels > or =200 copies/mL at or after week 16), CD4 cell count changes, and grade 3 or 4 adverse events. HIV-1 RNA data were intent-to-treat, regardless of treatment changes. RESULTS: Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 (72,444) copies/mL and CD4 cell count of 240 cells/mm3 were randomized. After a median 3-year follow-up, 99 (26%) of 382 and 94 (25%) of 383 patients receiving the 3-drug and 4-drug regimens, respectively, reached protocol-defined virologic failure; time to virologic failure was not significantly different (hazard ratio, 0.95; 97.5% confidence interval, 0.69-1.33; P = .73). In planned subgroup analyses, increased risk for virologic failure was seen in non-Hispanic black patients (adjusted hazard ratio, 1.66; 95% confidence interval, 1.18-2.34; P = .003). At 3 years, the HIV-1 RNA level was less than 200 copies/mL in 152 (90%) of 169 and 143 (92%) of 156 patients receiving the 3-drug and 4-drug regimens, respectively (P = .59), and less than 50 copies/mL in 144 (85%) of 169 and 137 (88%) of 156 patients (P = .39). CD4 cell count increases and grade 3 or 4 adverse events were not significantly different. CONCLUSIONS: In treatment-naive patients, there were no significant differences between the 3-drug and 4-drug antiretroviral regimens; overall, at least approximately 80% of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years. These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection; adding abacavir as a fourth drug provided no additional benefit. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov Identifier: NCT00013520.

Adult↗

PubMed2006

Pharmacodynamics of antiretroviral agents in HIV-1 infected patients: using viral dynamic models that incorporate drug susceptibility and adherence.

We developed a novel HIV-1 dynamic model with consideration of pharmacokinetics, drug adherence and drug susceptibility to link plasma drug concentration to the long-term changes in HIV-1 RNA observation after initiation of therapy. A Bayesian approach is proposed to fit this model to clinical data from ACTG A5055, a study of two dosage regimens of indinavir (IDV) with ritonavir (RTV) in subjects failing their first protease inhibitor treatment. The HIV RNA testing was completed at days 0, 7, 14, 28, 56, 84, 112, 140, and 168. An intensive pharmacokinetic (PK) evaluation was performed on day 14 and multiple trough concentrations were subsequently collected. Pill counts were used to monitor adherence. IC(50) for IDV and RTV were determined at baseline and at virologic failure. Viral dynamic model fitting residuals were used to assess the significance of covariate effects on long-term virologic response. As univariate predictors, none of the four PK parameters C(trough), C(12 hour), C(max), and AUC was significantly related to virologic response (p > 0.05). By including drug susceptibility (IC(50)), or IC(50) and adherence measured by pill counts together, C(trough), C(12 hour), C(max) and AUC were each significantly correlated to long-term virologic response (p = 0.0055,0.0002,0.0136,0.0002 with IC(50) and adherence measured by pill counts considered). The IC(50) and adherence measured by pill counts alone were not related to the virologic response. In predicting virologic response adherence measured by pill counts did not provide any additional information to PK parameters (p = 0.064), to drug susceptibility IC(50) (p = 0.086), and to their combination (p = 0.22). Simple regression approaches did not detect any significant pharmacodynamic (PD) relationships. Any single factor of PK, adherence measured by pill counts and drug susceptibility did not contribute to long-term virologic response. But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates.

Algorithms↗

PubMed2006

Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness.

OBJECTIVE: To compare the prevalence of resistance by adherence level in patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI). Also to examine the mechanism of differential class-specific adherence-resistance relationships, focusing on the patient-derived capacity of wild-type and drug-resistant recombinant variants to replicate in vitro in the presence of variable drug levels. METHODS: Participants received unannounced pill count measures to assess adherence, viral load monitoring, and genotypic resistance testing. The replicative capacity of drug-susceptible and drug-resistant recombinants was determined using a single-cycle recombinant phenotypic susceptibility assay. Drug exposure was estimated using population-averaged pharmacological measurements adjusted by participant-specific levels of adherence. RESULTS: In the NNRTI-treated group, 69% had resistance at 0-48% adherence compared to 13% at 95-100% (P = 0.01). PI resistance was less common than NNRTI resistance at 0-48% adherence (69% versus 23%; P = 0.01). In multivariate analysis, the odds for PI resistance increased (P = 0.03) while the odds for NNRTI resistance decreased (P = 0.04) with improving adherence. Individuals with drug-resistant variants were more likely to have levels of drug exposure where the resistant variant was more fit than the drug-susceptible variant in vitro, while those with drug-susceptible virus were more likely to have levels of drug exposure where the drug-susceptible virus was more fit than the drug-resistant variant (P = 0.005). CONCLUSIONS: NNRTI resistance was more common than PI resistance at low levels of adherence. Class-specific adherence-resistance relationships are associated with the relative replicative capacity of drug-resistant versus wild-type variants to replicate in the presence of clinically relevant drug levels.

Adult↗

PubMed2006

Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy.

The introduction of HIV-1 protease inhibitors and non-nucleoside reverse transcriptase inhibitors in 1996 began an era described as that of highly active antiretroviral therapy. In addition, the more recent development and availability of HIV-1 genotypic and phenotypic resistance tests and advances in pharmacological assays that support therapeutic drug monitoring (TDM) have created tools that may help clinicians to provide more individualised treatment with HIV-1 protease inhibitors. All current treatment guidelines provide fixed doses of protease inhibitors with vague recommendations for the use of TDM in selected clinical situations. In patients with resistance to protease inhibitors, the combined use of resistance tests with TDM provide a mechanism for individualising the clinical pharmacodynamics of protease inhibitors. Current therapeutic approaches seek to include the monitoring of protease-inhibitor concentrations as part of a TDM programme with phenotypic assays to calculate an inhibitory quotient, virtual inhibitory quotient, or normalised inhibitory quotient, whereas genotypic tests are used with TDM to calculate a genotypic inhibitory quotient. Current investigation is focused on examining the predictive value of this approach for clinical monitoring.

HIV Infections↗

PubMed2006

Tipranavir: a novel nonpeptidic protease inhibitor of HIV.

Tipranavir is a novel nonpeptidic protease inhibitor (PI) with activity against wild-type and multidrug-resistant HIV-1 both in vitro and in HIV-infected patients. Tipranavir/ritonavir 500 mg/200 mg administered twice daily for 3 weeks to healthy volunteers produced a median (range) maximum plasma concentration and minimum plasma concentration of 79.1 (34.9-111.7) mg/L and 19.5 (0.43-42.8) mg/L, respectively. Concomitant administration with low-dose ritonavir significantly increases tipranavir plasma concentrations; therefore, the recommended dose is tipranavir 500 mg and ritonavir 200 mg twice daily. Tipranavir is a substrate and inducer of cytochrome P450 3A4 isoenzyme, thus is predisposed to interactions with other agents that are substrates, inducers or inhibitors of this enzyme family. Significant drug-drug interactions have been reported with co-administration of tipranavir/ritonavir and other PIs but not with the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine. Tipranavir/ritonavir 500 mg/200 mg twice daily in combination with an optimised background regimen was more effective than a ritonavir-boosted comparator PI plus an optimised background regimen. The adverse effect profile for tipranavir is similar to other boosted PI regimens and most commonly includes gastrointestinal complaints. Severe adverse events that require close monitoring include hepatotoxicity and lipid abnormalities. Tipranavir retains activity in many highly treatment-experienced patients with a large number of protease mutations. Therefore, this novel PI in combination with ritonavir represents an important new choice in the treatment of multiple-PI-experienced patients.

Adult↗

PubMed2005

Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study.

BACKGROUND: Efavirenz has a long plasma half-life and a low genetic barrier to resistance. Simultaneously stopping treatment with all agents in efavirenz-containing regimens may result in functional efavirenz monotherapy that selects for drug-resistant human immunodeficiency virus type 1. Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals. METHODS: We characterized relationships between this polymorphism and predicted plasma efavirenz concentration-time profiles after discontinuation of therapy with use of data obtained from subjects receiving therapy. Pharmacokinetic parameters were estimated using population-based methods. Concentrations after discontinuation of therapy were predicted from subject-specific estimates. RESULTS. Median estimated efavirenz half-lives were 23, 27, and 48 h for patients with CYP2B6 position 516 GG (78 patients), GT (60), and TT (14) genotypes, respectively (P<.001). After therapy was stopped, plasma efavirenz concentrations in patients with GG, GT, and TT genotypes were predicted to exceed 46.7 ng/mL (the estimated protein-adjusted 95% inhibitory concentration for wild-type virus) for a median of 5.8 days (interquartile range [IQR], 4.4-8.3 days), 7.0 days (IQR, 5.0-8.0 days), and 14 days (IQR, 11.1-21.2 days), respectively (P<.001). Plasma efavirenz levels were predicted to exceed 46.7 ng/mL for >21 days in 5% of subjects with GG genotype, 5% of subjects with GT genotype, and 29% of subjects with TT genotype. CONCLUSIONS: The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens. This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals.

BACKGROUND: Efavirenz is a commonly used antiretroviral drug that causes neurologic side effects in more than 50% of patients. OBJECTIVE: To characterize efavirenz-associated neurologic symptoms in a randomized, controlled study of initial antiretroviral treatment. DESIGN: Substudy of a randomized, double-blind, controlled trial of combination antiretroviral regimens (A5095) that was performed between March 2001 and January 2002. SETTING: Multicenter academic clinical trial units. PARTICIPANTS: HIV-infected patients who were initiating therapy in the context of a controlled trial. MEASUREMENTS: Neuropsychological performance measures, including the Digit Symbol Substitution Test and the Trail Making Test (Parts A and B); symptom questionnaires; standardized assessments of sleep quality, anxiety, and depression; and efavirenz plasma concentrations. RESULTS: Twenty of 303 (6.6%) enrolled participants prematurely discontinued the study. Neuropsychological performance improved in both groups over time without significant differences between patients who were receiving efavirenz and those who were not. The efavirenz group experienced more neurologic symptoms at week 1 (P < 0.001) but not at weeks 4, 12, or 24. A sleep index revealed that participants receiving efavirenz had more "bad dreams" during the first week of therapy (P = 0.038). No significant changes in anxiety or depressed mood were noted. Changes in efavirenz-associated neurologic symptoms were correlated to efavirenz plasma concentrations at week 1 but not at later time points. Twelve (6%) patients receiving efavirenz stopped taking the drug before the end of the study because of central nervous system symptoms. LIMITATIONS: Participant selection may have been biased in favor of patients with fewer psychiatric complications. The study design permitted substitution of a new drug in place of efavirenz in cases of treatment-limiting toxicity. CONCLUSIONS: In a large controlled trial, efavirenz use was associated with neurologic symptoms distinct from depression and anxiety that began early in therapy but resolved by week 4. Improvement in neuropsychological performance was comparable in patients who were receiving efavirenz and those who were not.

Adult↗

PubMed2005

Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359.

AIDS Clinical Trials Group (ACTG) 359 was a randomized, partially double-blinded factorial study of 6 antiretroviral regimens, all including saquinavir, among HIV-infected persons in whom prior therapy had failed (n = 258). Counts of remaining saquinavir capsules were determined between weeks 0 and 4; at weeks 4, 8, and 16, self-reported adherence was estimated from 2-day report of doses skipped, therapeutic coverage, and percent of doses taken were determined by electronic monitoring devices applied to saquinavir bottles, and the saquinavir 24-hour area under the curve (AUC) was estimated. Relationships were evaluated among these 4 adherence measures and the primary endpoint of week 16 HIV RNA change. Thirty percent of 254 subjects had HIV RNA < or =500 copies/mL at week 16. Only self-reported adherence and saquinavir AUC were significantly associated with week 16 HIV RNA change (P = 0.019 and 0.023, respectively), and these measures were higher in subjects with week 16 HIV RNA < or =500 copies/mL (P = 0.03 and 0.008, respectively). The ability to detect a correlation between electronically monitored adherence and virologic response was limited by the small sample size. Self-reported adherence and saquinavir AUC were significant predictors of virologic response, in this evaluation. These findings provide insight into methods of assessing and improving adherence to antiretroviral regimens.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Effectiveness of a city-wide program to prevent mother-to-child HIV transmission in Lusaka, Zambia.

OBJECTIVE: To determine the population effectiveness of a city-wide perinatal HIV prevention program. DESIGN: An anonymous surveillance of newborn cord blood for HIV serology and nevirapine (NVP). METHODS: All 10 public-sector delivery centers in Lusaka, Zambia participated. All mother-infant pairs delivering during the 12-week surveillance period at the participating centers and who received antenatal care at a public-sector facility in Lusaka were included in the study. The main outcome measure was population NVP coverage, defined as the proportion of HIV-infected women and HIV-exposed infants in the population that ingested NVP. RESULTS: Of 8787 women in the surveillance population, 7204 (82%) had been offered antenatal HIV testing, of which 5149 (71%) had accepted, and of which 5129 (99%) had received a result. Overall, 2257 of 8787 (26%) were cord seropositive. Of the 1246 (55%) cord blood seropositive women who received an antenatal HIV test result, 1112 (89%) received a positive result; the other 134 comprise seroconverters and clerical errors. Only 751 of 1112 (68%) women who received a positive antenatal test result and a NVP tablet for ingestion at labor onset had NVP detected in the cord blood (i.e., maternal non-adherence rate was 32%). A total of 675 infants born to 751 adherent mothers (90%) received NVP before discharge. Thus, only 675 of 2257 (30%) seropositive mother-infant pairs in the surveillance population received both a maternal and infant dose of NVP. CONCLUSIONS: Successful perinatal HIV prevention requires each mother-infant pair to negotiate a cascade of events that begins with offering HIV testing and continues through adherence to the prescribed regimen. This novel surveillance demonstrates that failures occur at each step, resulting in reduced coverage and diminished program effectiveness.

Adolescent↗

PubMed2005

Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy.

OBJECTIVE: To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations. DESIGN: The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults. METHODS: Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection. RESULTS: Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008). CONCLUSIONS: The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.

Adult↗

PubMed2005

Modeling long-term HIV dynamics and antiretroviral response: effects of drug potency, pharmacokinetics, adherence, and drug resistance.

We propose a long-term HIV-1 dynamic model by considering drug potency, drug exposure, and drug susceptibility. Using a Bayesian approach, HIV-1 dynamic parameters were estimated by fitting the model to viral load data from a phase 1/2 randomized clinical study of 2 indinavir (IDV)/ritonavir (RTV)-containing highly active antiretroviral (ARV) therapy regimens in HIV-infected subjects who had previously failed protease inhibitor-containing ARV therapies. A large between-subject variation in estimated viral dynamic parameters was observed, even after accounting for variations in drug exposure and drug susceptibility, suggesting that characteristics of HIV-1 dynamics are host dependent. Significant correlations of baseline factors such as HIV-1 RNA levels and CD4 cell counts with viral dynamic parameters were found. These correlations coincide with biologic interaction mechanisms between HIV and the host immune system and also provide an explanation for the correlations between the baseline viral load and phase 1 viral decay rate, for which inconsistent results have been reported in the literature. The relations between viral dynamic parameters and virologic response were established, and these results suggest that viral dynamic parameters may play an important role in determining treatment success or failure. In particular, we estimated a drug efficacy threshold for each patient that can be used to assess whether an ARV regimen is potent enough to suppress HIV viruses in the individual patient. Our findings indicate that it is necessary to individualize the ARV regimen to treat HIV-1-infected patients. The proposed mathematic models and statistical techniques may provide a framework to simulate and predict antiviral response for individual patients.

Anti-HIV Agents↗

PubMed2005

Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results.

OBJECTIVE: To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk. DESIGN: Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects. METHODS: A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001). RESULTS: Amprenavir mean area under the curve over 12 h (AUC0-12 h) and concentration at 12 h (C12 h) (microg/ml) were, respectively, 42.7 microg x h/ml (range, 33.1-55.1) and 2.4 microg/ml (range, 1.4-3.2) in arm B and 17.4 microg x h/ml (range, 4.6-41.3) and 0.9 microg/ml (range, 0.2-2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P < or = 0.0001). Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 microg x h/ml (range, 60.3-119.3) and 6.3 microg/ml (range, 2.2-9.2) in arm A and 54.4 microg x h/ml (range, 23.5-112.2) and 3.0 microg/ml (range, 0.4-7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P < or = 0.0008). Ritonavir exposure was not significantly different between arms. CONCLUSION: APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.

Adult↗

PubMed2005

Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403.

INTRODUCTION: Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI). METHODS: This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy. RESULTS: : The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data. CONCLUSION: : Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults.

Adolescent↗

PubMed2004

Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study.

OBJECTIVES: Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with efavirenz central nervous system side effects and pharmacokinetics. DESIGN: Twenty-four week cohort from a randomized study. METHODS: Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing. RESULTS: Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (GlnHis) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater efavirenz plasma exposure (P < 0.0001). The median efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mug.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P = 0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied. CONCLUSIONS: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Comparison of two indinavir/ritonavir regimens in the treatment of HIV-infected individuals.

BACKGROUND: Pharmacokinetic enhancement of protease inhibitors (PIs) with low-dose ritonavir (RTV) for salvage therapy is increasingly common. The purpose of this study was to compare the pharmacokinetics, safety, and tolerability of indinavir (IDV)/RTV at 800/200 mg (arm A) and 400/400 mg (arm B) administered twice daily in HIV-infected subjects failing their first PI-based regimen. METHODS: A phase I/II, randomized, open-label, 24-week study was conducted. Formal 12-hour pharmacokinetic evaluations were performed, and study visits occurred at baseline; at weeks 1, 2, and 4; and every 4 week thereafter for 24 weeks. Clinical symptoms and laboratory assessments were collected. Subjects were allowed to switch arms because of toxicity. RESULTS: Forty-four subjects were enrolled (22 per arm). IDV predose concentration, maximum plasma concentration and area under the curve were significantly higher in arm A. Fifty-five percent and 45% of subjects in arms A and B responded (<200 copies/mL at week 24; P = 0.76), respectively. CD4 cell responses were similar. All subjects had IDV-sensitive virus at baseline and at virologic failure. Tolerability was comparable, but all grade 3 or higher triglyceride increases occurred in arm B and more subjects in arm B switched because of toxicity (5 vs. 1 triglyceride increases). CONCLUSIONS: This is the largest formal pharmacokinetic evaluation of 2 dosage combinations of IDV/RTV in HIV-infected individuals. Pharmacokinetic parameters were consistent with previous results in patients but lower than in seronegative controls. Both regimens exhibited similar tolerability and response rates. High toxicity with a low response suggests that the optimum IDV/RTV combination would include an RTV dose <400 mg and an IDV dose <800 mg in this population.

Adolescent↗

PubMed2004

Weighted phenotypic susceptibility scores are predictive of the HIV-1 RNA response in protease inhibitor-experienced HIV-1-infected subjects.

We analyzed retrospectively, by use of logistic regression, the role of the phenotypic susceptibility score (PSS) as a determinant of virologic outcome in a study of treatment-experienced human immunodeficiency virus (HIV) type 1-infected subjects. A model for PSS in which each drug was treated equally and scored as active or inactive was not predictive of HIV-1 RNA load (VL) suppression. However, weighting the potential contribution of each drug on the basis of inferred potency and by use of a continuous scale to quantify drug susceptibility revealed significant associations between PSS and outcome. Entry VL was a strong independent predictor of therapy outcome, and PSS was a strong predictor of the magnitude of the initial decrease in VL. This suggests that the prospective evaluation of PSS to identify regimens that maximize decreases in VL to reduce the probability of virologic rebound could improve antiretroviral treatment.

Anti-HIV Agents↗

PubMed2004

Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection.

BACKGROUND: Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS: This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS: We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS: In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.

Adult↗