Development and evaluation of a novel knowledge assessment tool for pediatric emergency medicine clerkships.

Objectives: This study seeks to determine validity evidence for a newly developed multiple-choice examination (MCE) tool to assess retention and application of medical knowledge of students enrolled in a pediatric emergency medicine (PEM) clerkship. Methods: A team of PEM physicians created a 110-item MCE covering the range of clinical topics in PEM relevant for medical students. The researchers determined examination content using the report of Clerkship Directors in Emergency Medicine and PEM Interest Group of the Society for Academic Emergency Medicine (SAEM). The authors administered the MCE to fourth-year medical students at the end of their PEM rotation from May 2020 to April 2023 at four institutions and then analyzed the examination using four of Messick's five sources of validity evidence: content, response process, internal structure, and relation to other variables. Results: A total of 158 students took the test. In academic year (AY)20-21, 47 students took the test and scored, on average, 81%. After revision of poor and indeterminate questions, the 111 medical students who took the revised version of the test in AY21-AY23 scored on average 77.3% with a standard deviation of 5.7% with a normal distribution in scores. The revised questions were rated as excellent (10.0%), good (26.4%), fair (34.5%), poor (24.5%), or indeterminate (4.5%) based on test item discrimination. There was a positive correlation between MCE scores and students' clinical evaluations but no correlation between MCE scores and scores that students received on their clinical notes or patient presentations during case conference. Conclusions: This novel PEM clerkship examination is a reliable test of medical knowledge. Future directions involve evaluating consequences of the MCE and offering the test to medical students in a dedicated PEM rotation at the national level.

Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals.

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

BACKGROUND: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSIONS: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

A Study to Evaluate Relative Bioavailability, Food Effect, and Pharmacodynamics of Tropifexor, a Farnesoid X Receptor Agonist, in Healthy Participants.

This open-label, randomized, 3-treatment, 3-period, 6-sequence, crossover study in healthy subjects compared the pharmacokinetic and pharmacodynamic properties of a lipid-based (soft gelatin capsule) prototype final market image (pFMI) formulation of tropifexor (90-µg) to its clinical service form (CSF) and assessed the food effect for the pFMI formulation. In the fasted state, drug exposure was higher for the pFMI. The geometric mean ratios for pFMI versus CSF of peak concentration and area under the concentration-time curve were 2.0 and 1.5, respectively. No food effect was apparent for the pFMI formulation, and the geometric mean ratios for pFMI fed versus pFMI fasted of peak concentration and area under concentration-time curve were 1.0 and 1.0 respectively. Despite having lower systemic exposure, the CSF formulation provided a higher pharmacological response for the gut biomarker fibroblast growth factor 19. Under fasted conditions, fibroblast growth factor 19 maximum change from baseline serum concentration after drug administration and area under the change from baseline serum concentration-time curve from time 0 to 24 hours were 36% for CSF and 12% for FMI. For a second biomarker, serum 7-alpha hydroxy-4-cholest-3-one, the pharmacological activity was comparable between CSF (fasted) and pFMI (both fasted and fed states). The pFMI offers advantages over the CSF in terms of insensitivity to food effect, lower intersubject variability, and overcoming solubility limitations.

Drug-Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects.

Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax ) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration-time curve [AUC] from time 0 to the last quantifiable concentration [AUClast ] and AUC from time 0 to infinity [AUCinf ] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug-drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf ) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.

Racial and Ethnic Differences in Ondansetron Use for Acute Gastroenteritis in Children.

OBJECTIVES: There is limited research examining racial/ethnic disparities in antiemetic use for acute gastroenteritis (AGE). We assessed racial/ethnic differences in the care of children with AGE. METHODS: The Pediatric Health Information System was used to conduct a retrospective cohort study of children 6 months to 6 years old with AGE seen in participating emergency departments from 2016 to 2018. Cases were identified using International Classification of Diseases, Tenth Revision codes. The primary outcome was administration of ondansetron, secondary outcomes were administration of intravenous (IV) fluids and hospitalization, and primary predictor was race/ethnicity. Multivariable logistic regression followed by a mixed model adjusted for sex, age, insurance, and hospital to examine the association of race/ethnicity with each outcome. RESULTS: There were 78,019 encounters included; 24.8% of patients were non-Hispanic White (NHW), 29.0% non-Hispanic Black (NHB), 37.3% Hispanic, and 8.9% other non-Hispanic (NH) race/ethnicity. Compared with NHW patients, minority children were more likely to receive ondansetron (NHB: adjusted odds ratio, 1.36 [95% confidence interval, 1.2-1.55]; Hispanic: 1.26 [1.1-1.44]; other NH: 1.22 [1.07-1.4]). However, minority children were less likely to receive IV fluids (NHB: 0.38 [0.33-0.43]; Hispanic: 0.44 [0.36-0.53]; other NH: 0.51 [0.44-0.61]) or hospital admission (NHB: 0.37 [0.29-0.48]; Hispanic: 0.41 [0.33-0.5]; other NH: 0.52 [0.41-0.66]). Ondansetron use by hospital ranged from 73% to 95%. CONCLUSIONS: This large database analysis of emergency departments around the nation found that NHW patients were less likely to receive ondansetron but more likely to receive IV fluids and hospital admission than minority patients. These findings are likely multifactorial and may represent bias, social determinants of health, access to care, or illness severity among other possible causes.

Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-µg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.

Safety, Pharmacokinetics, and Causal Prophylactic Efficacy of KAF156 in a Plasmodium falciparum Human Infection Study.

BACKGROUND: KAF156 is a novel antimalarial drug that is active against both liver- and blood-stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model. METHODS: In part 1, healthy, malaria-naive participants received 800 mg KAF156 or placebo 3 hours before CHMI with P. falciparum-infected mosquitoes. In part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hours post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to 4 subjects to placebo. RESULTS: KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported-both resolved without sequelae and neither was considered related to KAF156. In part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3 of 14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hour postdose concentration of KAF156 of 21.5 ng/mL (90% confidence interval, 17.66-25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection. CONCLUSIONS: KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy. CLINICAL TRIALS REGISTRATION: NCT04072302.

Stiff Neck and Drooling in a Young Girl.

A 3-year-old girl was brought to the emergency department 4 days after she was playing with a button battery and subsequently had a choking episode. The patient was seen immediately at a different emergency department and was discharged home after a normal chest x-ray finding and able to tolerate an oral challenge with liquids. She was later evaluated by her primary care physician and started on amoxicillin for possible pharyngitis. On examination in our emergency department, the patient had pooling of secretions and was unwilling to range her neck due to pain. Soft tissue neck x-ray confirmed a 20-mm button battery in the esophagus with air lucencies in the prevertebral soft tissues.

Pharmacokinetics and tolerability of lefamulin following intravenous and oral dosing.

OBJECTIVES: To explore the pharmacokinetics (PK) of oral and intravenous (iv) lefamulin after single and multiple doses, and the effect of food on bioavailability. METHODS: Lefamulin PK was examined in four studies. In Study 1, PK was assessed in patients with acute bacterial skin and skin structure infections who received repeated iv lefamulin q12h (150 mg). In Study 2, a four-period crossover study, healthy subjects received a single dose of oral lefamulin [immediate-release (IR) tablet, 1 × 600 mg] in a fasted and fed state, oral lefamulin (capsule, 3 × 200 mg) in a fasted state, and iv lefamulin in a fasted state. In Study 3, a three-period crossover study, healthy males received a single oral lefamulin dose (IR) in the following states: fasted, fasted followed by a high-calorie meal 1 h post-dose, and fed. Study 4 had two parts; in part A, healthy males received a single lefamulin dose (IR) in a fasted and fed state; in part B, subjects received repeated doses of lefamulin (IR, q12h) or placebo. Adverse events (AEs) were recorded in each study. RESULTS: Single and repeated dosing of iv and oral lefamulin resulted in comparable exposure. Intravenous and oral lefamulin (given fasted or with a meal 1 h post-dose) resulted in bioequivalence. Bioequivalence was not established between oral lefamulin in the fed state and iv or oral administration in the fasted state. All AEs were mild or moderate in severity, no serious AEs were reported, and no participant discontinued because of an AE. CONCLUSIONS: The PK of lefamulin supports successful switch from iv to oral therapy; lefamulin was generally well tolerated.

Physical and mechanical properties of mortars containing PET and PC waste aggregates.

Non-biodegradable plastic aggregates made of polycarbonate (PC) and polyethylene terephthalate (PET) waste are used as partial replacement of natural aggregates in mortar. Various volume fractions of sand 3%, 10%, 20% and 50% are replaced by the same volume of plastic. This paper investigates the physical and mechanical properties of the obtained composites. The main results of this study show the feasibility of the reuse of PC and PET waste aggregates materials as partial volume substitutes for natural aggregates in cementitious materials. Despite of some drawbacks like a decrease in compressive strength, the use of PC and PET waste aggregates presents various advantages. A reduction of the specific weight of the cementitious materials and a significant improvement of their post-peak flexural behaviour are observed. The calculated flexural toughness factors increase significantly with increasing volume fraction of PET and PC-aggregates. Thus, addition of PC and PET plastic aggregates in cementitious materials seems to give good energy absorbing materials which is very interesting for several civil engineering applications like structures subjected to dynamic or impact efforts. The present study has shown quite encouraging results and opened new way for the recycling of PC waste aggregate in cement and concrete composites.

Development of a functional bioassay for arylsulfatase B using the natural substrates of the enzyme.

A functional bioassay has been developed for measuring the intracellular activity of recombinant human arylsulfatase B (rhASB) on its natural glycosaminoglycan (GAG) substrates, dermatan sulfate (DS), and chondroitin sulfate (CS) when the enzyme is taken up into cultured ASB-deficient human fibroblasts (GM00519). The enzyme ASB is a lysosomal exohydrolase, cleaving sulfate from the N-acetylgalactosamine-4-sulfate (GalNAc-4S) residue at the nonreducing terminal of GAG structures. ASB-deficient cells accumulate DS and CS, which may be partially hydrolyzed by other lysosomal hydrolases, with the reactions stopping if a GalNAc-4S residue is reached on the nonreducing end of the oligosaccharide. When rhASB is added to the culture medium, the enzyme is taken up and translocates to the lysosomes and the intracellular DS and CS are depleted, demonstrating that the uptake of rhASB is able to restore lysosomal function in an in vitro cell-based assay. The accumulation and depletion of DS and CS are measured by digesting the residual intracellular DS and CS content with chondroitin ABC lyase and monitoring a characteristic disaccharide digestion product by laser-induced fluorescence-capillary zone electrophoresis (LIF-CZE). In the proposed assay format, GM00519 cells are cultured 5 weeks postconfluence to accumulate DS/CS, followed by incubation with rhASB (1-20 pM) for 5 days, and the CS/DS depletion profiles are compared between samples. The assay measures depletion of DS/CS independently of their molecular size or processing state; in this approach, all DS- and CS-like substances accumulating in the absence of ASB activity are considered to be natural substrates of the enzyme.

Future challenges for microsomal transport protein inhibitors.

Atherosclerosis is a leading cause of morbidity and mortality worldwide. Statins are established as first choice drugs for the management of hyperlipidaemia and cardiovascular risk. However, a residual cardiovascular risk, partially attributable to lipids, remains even after statin treatment. This risk appears to be associated with both high-density lipoprotein cholesterol and triglyceride lipid fractions. Several novel therapeutic approaches have been proposed to reduce lipid levels. Microsomal transfer protein (MTP) is involved in the assembly of very-low-density lipoprotein and chylomicron lipoprotein particles in the liver and the gut, respectively. In the preclinical setting, various agents that affect activity of MTP have shown that inhibition can result in profound reductions in blood triglycerides and cholesterol. Similarly, evidence of efficacy using the target has been confirmed in man with small molecule inhibitors and antisense oligonucleotides. Unfortunately, despite their efficacy in reducing lipids, the clinical utility of small molecule inhibitors has been restricted by their potential to induce hepatic steatosis. Continuing attempts to utilise this clinical target (to decrease cholesterol, triglycerides and weight) have involved the use of lower doses or non systemically absorbed MTP inhibitors.

Comparison of neutralizing antibody assays for receptor binding and enzyme activity of the enzyme replacement therapeutic Naglazyme (galsulfase).

Most patients receiving Naglazyme (galsulfase, rhASB) enzyme replacement therapy for mucopolysaccharidosis type VI develop an antibody response. To evaluate the impact of this response, two in vitro neutralizing antibody (NAb) assays were developed based on the two steps of the mechanism of action. Neutralization of enzyme activity was detected by inhibition of rhASB cleavage of a fluorogenic substrate. Neutralization of receptor binding was detected by decreased binding of labeled rhASB to immobilized soluble receptor. For the enzyme activity NAb assay, serum pretreatment was required to isolate antibodies from interfering phosphate ions, with sensitivity of < or =5 microg/mL. The receptor binding NAb assay used a five-fold dilution, with sensitivity of < or =40 microg/mL. Cutpoints for percent inhibition were based on 95% confidence intervals from naïve sera. Clinical samples were similarly likely to be positive in both assays than positive for neutralization of only one step in the mechanism of action. The two NAb assays yielded complementary information about potential neutralization of rhASB. Relative estimated sensitivity between neutralization assays did not correlate with the number of positive clinical samples or patients. In vitro NAb assays based on a well-understood mechanism of action provide specific information about the NAb mechanism.

Microbial dynamics and enzyme activities during rapid composting of municipal solid waste - a compost maturity analysis perspective.

An investigation was carried out in the laboratory to find out the microbial dynamics and enzyme activities during rapid composting of municipal solid waste (MSW). Various treatments such as aeration (A), addition of chemical agents (glucose (G) and acetic acid (AA) and application of cellulolytic microbial (M) inoculum (Phanerochaete chrysosporium and Trichoderma reesei) were used to facilitate the decomposition of MSW. The result of the present investigation revealed that the degradation of organic substrates were quick (within 9-12 days) in case of rapid composting as indicated by the reduction (below 20) in C/N ratio. Whereas, normal composting took more than 20 days to attain C/N ratio of below 20. Estimation of selected enzymes (amylase, protease, phosphatase and cellulase) provided information on the substrate specific degradation profiles of various labile substrates contained in organic waste.

Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase.

Enzyme replacement therapy for lysosomal storage disorders depends on efficient uptake of recombinant enzyme into the tissues of patients. This uptake is mediated by oligosaccharide receptors including the cation-independent mannose 6-phosphate receptor and the mannose receptor. We have sought to exploit alternative receptor systems that are independent of glycosylation but allow for efficient delivery to the lysosome. Fusions of the human lysosomal enzymes alpha-l-iduronidase or acid alpha-glucosidase with the receptor-associated protein were efficiently endocytosed by lysosomal storage disorder patient fibroblasts, rat C6 glioma cells, mouse C2C12 myoblasts, and recombinant Chinese hamster ovary cells expressing individual members of the low-density lipoprotein receptor family. Uptake of the fusions exceeded that of phosphorylated enzyme in all cases, often by an order of magnitude or greater. Uptake was specifically mediated by members of the low-density lipoprotein receptor protein family and was followed by delivery of the fusions to the lysosome. The advantages of the lipoprotein receptor system over oligosaccharide receptor systems include more efficient cellular delivery and the potential for transcytosis of ligands across tight endothelia, including the blood-brain barrier.

Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers.

These two Phase I, open-label, single-dose, randomized, crossoverstudies in 40 healthymale subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and Cmax, and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, Cmax was lower with GW433908G. After a high-fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for GW433908G tablets, there was no influence on AUC(12% lower Cmax). After a low-fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (Cmax was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.