Biomedical subjects

Hulin Wu

Publications and source records attributed to Hulin Wu.

At least 19 recordsLinked to original sources

PubMed2026

Sustained effects of auricular point acupressure on chemotherapy-induced neuropathy: a randomized controlled trial follow-up study.

PURPOSE: Chemotherapy-induced neuropathy (CIN) is a persistent condition that impairs function and quality of life. Auricular point acupressure (APA) has shown short-term benefit for CIN, but the durability of these effects after treatment completion is unknown. This study evaluated the sustainability of symptom improvements for 3 months following a 4-week APA intervention. METHODS: This prespecified secondary analysis of a randomized wait-list controlled trial compared mobile-supported APA (mAPA) and virtual APA (vAPA) in adults with moderate or greater CIN who received APA during the initial treatment phase (mAPA, n = 80; vAPA, n = 75). Outcomes at 1, 2, and 3 months post-intervention were analyzed using generalized estimating equations with multiple imputation. The primary outcome was CIN severity, measured with an individualized composite outcome (ICO); the secondary outcome was CIN interference. RESULTS: Reductions in CIN severity and interference were maintained throughout follow-up in both groups (all p < .001). ICO scores decreased by 3.10, 3.36, and 3.61 points in mAPA and by 2.88, 2.90, and 3.21 points in vAPA at 1, 2, and 3 months, respectively. Benefits were maintained post-treatment, with higher retention in the mAPA group. CONCLUSIONS: Improvements in CIN severity and interference after APA were sustained for up to 3 months post-treatment, suggesting a durable benefit as a self-management strategy. Larger studies with longer follow-up and untreated comparison groups are needed. IMPLICATIONS FOR CANCER SURVIVORS: APA may offer survivors a durable, self-administered, nonpharmacologic option for managing CIN well beyond active treatment, without requiring ongoing clinical visits. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT04920097 registered on 3 June 2021.

Acupressure↗

PubMed2026

Early immune dysregulation in Mtb/SIV co-infection resists cART treatment at the single-cell level.

Using single-cell transcriptomics of bronchoalveolar lavage cells from Mtb/SIV co-infected rhesus macaques on cART, we reveal profound immune dysregulation during early SIV co-infection of latent tuberculosis. SIV induces a sharp decline in CD4+ T cells, NK, and NKT cells, with incomplete recovery of Mtb-specific TH1 effector responses despite viral suppression. Instead, a persistent TH17-skewed environment emerges, alongside sustained myeloid inflammation driven by Type I interferon signaling and pro-inflammatory regulators such as KLF6 and NFKB1. Ligand-receptor network analyses demonstrate expanded CD4+ T cell-macrophage crosstalk and loss of immune homeostasis that cART fails to fully restore. These findings expose how SIV remodels the pulmonary immune landscape to impair protective immunity against Mtb, providing a transcriptomic framework to explain TB reactivation in HIV infection. Our work highlights the urgent need for adjunctive immunotherapies to complement cART, aiming to rebalance immune responses and improve TB control in co-infected individuals.

HIV↗

PubMed2006

Immune responses to vaccinia and influenza elicited during primary versus recent or distant secondary smallpox vaccination of adults.

The kinetics and frequency of the primary response to human smallpox vaccine was compared to that among subjects re-vaccinated within the last 2 years, or after several decades. Vaccination induced local and systemic reactions that were mildest in the distant cohort and more severe in the primary vaccinees. The timing of IFN-gamma responses was similar in all three groups, but of higher frequency in the primary vaccinees. Responses to vaccinia re-immunization between those immunized <2 years ago and those immunized >10 years ago were not significantly different. Neutralizing antibodies were boosted in all groups, with the highest titers observed among the distant cohort. However, the antibody and IFN-gamma responses did not correlate strongly with the local reactions at the vaccine site. This suggests that local immune events in the tissue are distinct from the parameters measured in the peripheral blood.

Adolescent↗

PubMed2006

Statistical determination of threshold for cellular division in the CFSE-labeling assay.

The combination of flow cytometry and carboxyl fluorescent succinimidyl ester (CFSE) labeling techniques has been widely used in the study of cellular proliferation, including measurement of the percentage of proliferated cells and the number of cell divisions undergone by proliferated cells. However, the smallest numbers that represent true cell division rather than experimental variation are not known. To define a threshold that separates true proliferation from experimental variation, we performed a large number of replicate CFSE labeling experiments using polyclonal stimulation, obtained the percentages of proliferated cells using ModFit software, and then analyzed these data using several statistical methods. Our results indicate that the threshold of proliferation lies between 0.071% (95% confidence) and 0.114% (99% confidence) of total CFSE-labeled cells under our laboratory conditions. We offer our methods presented here for other investigators to calculate a threshold in their own CFSE-labeling experiments.

Cell Division↗

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

Hierarchical Bayesian methods for estimation of parameters in a longitudinal HIV dynamic system.

HIV dynamics studies have significantly contributed to the understanding of HIV infection and antiviral treatment strategies. But most studies are limited to short-term viral dynamics due to the difficulty of establishing a relationship of antiviral response with multiple treatment factors such as drug exposure and drug susceptibility during long-term treatment. In this article, a mechanism-based dynamic model is proposed for characterizing long-term viral dynamics with antiretroviral therapy, described by a set of nonlinear differential equations without closed-form solutions. In this model we directly incorporate drug concentration, adherence, and drug susceptibility into a function of treatment efficacy, defined as an inhibition rate of virus replication. We investigate a Bayesian approach under the framework of hierarchical Bayesian (mixed-effects) models for estimating unknown dynamic parameters. In particular, interest focuses on estimating individual dynamic parameters. The proposed methods not only help to alleviate the difficulty in parameter identifiability, but also flexibly deal with sparse and unbalanced longitudinal data from individual subjects. For illustration purposes, we present one simulation example to implement the proposed approach and apply the methodology to a data set from an AIDS clinical trial. The basic concept of the longitudinal HIV dynamic systems and the proposed methodologies are generally applicable to any other biomedical dynamic systems.

Antiretroviral Therapy, Highly Active↗

PubMed2006

Evaluation of a multiple-cycle, recombinant virus, growth competition assay that uses flow cytometry to measure replication efficiency of human immunodeficiency virus type 1 in cell culture.

Human immunodeficiency virus type 1 (HIV-1) replication efficiency or fitness, as measured in cell culture, has been postulated to correlate with clinical outcome of HIV infection, although this is still controversial. One limitation is the lack of high-throughput assays that can measure replication efficiency over multiple rounds of replication. We have developed a multiple-cycle growth competition assay to measure HIV-1 replication efficiency that uses flow cytometry to determine the relative proportions of test and reference viruses, each of which expresses a different reporter gene in place of nef. The reporter genes are expressed on the surface of infected cells and are detected by commercially available fluorescence-labeled antibodies. This method is less labor-intensive than those that require isolation and amplification of nucleic acids. The two reporter gene products are detected with similar specificity and sensitivity, and the proportion of infected cells in culture correlates with the amount of viral p24 antigen produced in the culture supernatant. HIV replication efficiencies of six different drug-resistant site-directed mutants were reproducibly quantified and were similar to those obtained with a growth competition assay in which the relative proportion of each variant was measured by sequence analysis, indicating that recombination between the pol and reporter genes was negligible. This assay also reproducibly quantified the relative fitness conferred by protease and reverse transcriptase sequences containing multiple drug resistance mutations, amplified from patient plasma. This flow cytometry-based growth competition assay offers advantages over current assays for HIV replication efficiency and should prove useful for the evaluation of patient samples in clinical trials.

Animals↗

PubMed2006

Modeling and estimation of replication fitness of human immunodeficiency virus type 1 in vitro experiments by using a growth competition assay.

Growth competition assays have been developed to quantify the relative fitnesses of human immunodeficiency virus (HIV-1) mutants. In this article we develop mathematical models to describe viral/cellular dynamic interactions in the assay experiment, from which new competitive fitness indices or parameters are defined. These indices include the log fitness ratio (LFR), the log relative fitness (LRF), and the production rate ratio (PRR). From the population genetics perspective, we clarify the confusion and correct the inconsistency in the definition of relative fitness in the literature of HIV-1 viral fitness. The LFR and LRF are easier to estimate from the experimental data than the PRR, which was misleadingly defined as the relative fitness in recent HIV-1 research literature. Calculation and estimation methods based on two data points and multiple data points were proposed and were carefully studied. In particular, we suggest using both standard linear regression (method of least squares) and a measurement error model approach for more-accurate estimates of competitive fitness parameters from multiple data points. The developed methodologies are generally applicable to any growth competition assays. A user-friendly computational tool also has been developed and is publicly available on the World Wide Web at http://www.urmc.rochester.edu/bstools/vfitness/virusfitness.htm.

HIV-1↗

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

Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors.

Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

Alkynes↗

PubMed2005

Statistical methods for HIV dynamic studies in AIDS clinical trials.

Studies of HIV dynamics in AIDS research are very important for understanding pathogenesis of HIV infection and for assessing the potency of antiviral therapies. Since the viral dynamic results from clinical data were first published by Ho et al. and Wei et al., the study of HIV-1 dynamics in vivo has drawn a great attention from AIDS clinicians and researchers. Although the important findings from HIV dynamic studies have been published in many prestigious scientific journals, statistical methods for estimating viral dynamic parameters have not been paid enough attention by HIV dynamic investigators. The estimation methods in many viral dynamic studies are very crude and inefficient. In this paper, we review the statistical methods and mathematical models for HIV dynamic data analysis developed in recent years. We also address some practical issues and share our experiences in the design and analysis of viral dynamic studies. Some principles and guidelines for the design and analysis of viral dynamic studies are provided. The methodologies reviewed in this paper are also applicable to studies of other viruses such as hepatitis B virus or hepatitis C virus. We also pose some challenging statistical problems in this area in order to stimulate further study by the statistical research community.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Design considerations for a web-based database system of ELISpot assay in immunological research.

The enzyme-linked immunospot (ELISpot) assay has been a primary means in immunological researches (such as HIV-specific T cell response). Due to huge amount of data involved in ELISpot assay testing, the database system is needed for efficient data entry, easy retrieval, secure storage, and convenient data process. Besides, the NIH has recently issued a policy to promote the sharing of research data (see http://grants.nih.gov/grants/policy/data_sharing). The Web-based database system will be definitely benefit to data sharing among broad research communities. Here are some considerations for a database system of ELISpot assay (DBSEA).

Access to Information↗

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

Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior.

We characterized the viral dynamics of human immunodeficiency virus (HIV) type 1-infected adolescents receiving highly active antiretroviral therapy regimens (lamivudine [3TC]/zidovudine [ZDV]/efavirenz [EFV], 3TC/ZDV/nelfinavir [NFV], or other regimens) and studied the relationship of viral dynamics with baseline factors and virological responses. Viral decay rates for 115 evaluable subjects were estimated from a viral dynamic model. Viral dynamics in HIV-1-infected individuals aged 12-22 years were similar to those of HIV-1-infected adults and infants. Individuals who received 3TC/ZDV/EFV had a more rapid phase 1 viral decay rate than those who received 3TC/ZDV/NFV or other regimens. Phase 1 viral decay rates were positively correlated with baseline RNA levels and week 1 virus load reductions. Our findings indicate that the 3TC/ZDV/EFV regimen may be more potent than 3TC/ZDV/NFV or other regimens and that early viral dynamics or week 1 virus load reduction measurements may be useful in evaluating the potency of antiretroviral regimens.

Acquired Immunodeficiency Syndrome↗

PubMed2003

MDR1 gene polymorphisms and phase 1 viral decay during HIV-1 infection: an adult AIDS Clinical Trials Group study.

Human CD4+ T cells express P-glycoprotein (P-gp), the ATP binding cassette efflux transporter encoded by MDR1. A common MDR1 single-nucleotide polymorphism in exon 26 (C3435T), which is linked to an exon 21 polymorphism (G2677T/A) and reportedly alters expression, has been associated with greater CD4+ T-cell increases during antiretroviral therapy. P-gp overexpression prevents apoptosis and inhibits HIV-1 replication in model systems, suggesting a potential effect on T-cell turnover. This study explored relationships between MDR1 polymorphisms and phase 1 viral decay among 31 HIV-infected individuals initiating antiretroviral therapy. Position 3435 genotypes were CC in 7 (23%), CT in 14 (45%), and TT in 10 (32%). Position 2677 genotypes were GG in 8 (26%), GT in 18 (58%), and TT in 5 (16%). There was no significant relationship between allelic variants in either exon 26 or 21 and phase 1 or phase 2 viral decay, changes in lymphocyte subsets over time, or plasma trough ritonavir concentrations. It is concluded with 95% confidence that phase 1 viral decay differences between exon 26 TT and CC groups are unlikely to exceed 18%.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Viral dynamics and their relations to baseline factors and longer term virologic responses in treatment-naive HIV-1-infected patients receiving abacavir in combination with HIV-1 protease inhibitors.

From a study of 71 HIV-1-infected patients receiving abacavir in combination with 1 of 5 different HIV-1 protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir, or amprenavir), we found that the baseline HIV-1 RNA levels were highly predictive of the viral decay rates. The baseline HIV-1 RNA levels were negatively correlated with the first phase viral decay rates (r = -0.77, P < 0.001) and positively correlated with the second phase viral decay rates (r = 0.68, P < 0.001). In addition, the first phase viral decay rate was positively correlated with CD4+ cell increases. No significant correlation was found between viral decay rates and longer term (24 weeks) virologic responses, and no difference in viral decay rates was found among the 5 study regimens. These data suggest that the potency of the 5 treatment regimens was similar and was not predictive of long-term virologic failure.

Adolescent↗

PubMed2003

Modeling HIV dynamics and antiviral response with consideration of time-varying drug exposures, adherence and phenotypic sensitivity.

Highly active antiretroviral therapies consisting of reverse transcriptase inhibitor drugs and protease inhibitor drugs, which can rapidly suppress HIV below the limit of detection, are currently the most effective treatment for HIV infected patients. In spite of this, many patients fail to achieve viral suppression, probably due to existing or developing drug resistance, poor adherence, pharmacokinetic problems and other clinical factors. In this paper, we develop a viral dynamic model to evaluate how time-varying drug exposure and drug susceptibility affect antiviral response. Plasma concentrations, in turn, are modeled using a standard pharmacokinetic (PK) one-compartment open model with first order absorption and elimination as a function of fixed individual PK parameters and dose times. Imperfect adherence is considered as missed doses in PK models. We discuss the analytic properties of the viral dynamic model and study how time-varying treatment efficacies affect antiviral responses, specifically viral load and T cell counts. The relationship between actual failure time (the time at which the viral growth rate changes from negative to positive) and detectable failure time (the time at which viral load rebounds to above the limit of detection) is investigated. We find that an approximately linear relationship can be used to estimate the actual rebound failure time from the detectable rebound failure time. In addition, the effect of adherence on antiviral response is studied. In particular, we examine how different patterns of adherence affect antiviral response. Results suggest that longer sequences of missed doses increase the chance of treatment failure and accelerate the failure. Simulation experiments are presented to illustrate the relationship between antiviral response and pharmacokinetics, time-varying adherence and drug resistance. The proposed models and methods may be useful in AIDS clinical trial simulations.

Anti-HIV Agents↗

PubMed2003

Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.

BACKGROUND: Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours. CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Adolescent↗