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author:("Sun, huiyang")
1.  Cost-effectiveness of Newer Antiretroviral Drugs in Treatment-Experienced Patients with Multi-drug Resistant HIV Disease 
Newer antiretroviral drugs provide substantial benefits but are expensive. We determined the cost-effectiveness of using antiretroviral drugs in combination for patients with multi-drug resistant HIV disease.
We built a cohort state-transition model representing treatment-experienced patients with low CD4 counts, high viral load levels, and multi-drug resistant virus. We estimated the effectiveness of newer drugs (those approved in 2005 or later) from published randomized trials. We estimated other parameters from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of two newer drugs and one conventional drug, compared to three conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness.
Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared to conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting three newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued.
In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior.
PMCID: PMC3932156  PMID: 24129369
Novel antiretroviral drugs; multi-drug resistant HIV infection; cost-effectiveness analysis; quality of life; health economics
2.  The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way 
The Prostate  2012;73(3):267-277.
The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that prostate cancer progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known.
We analyzed potential signaling pathways associated with AR-V7 constitutive activation in PTEN (−) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway.
In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation.
Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration resistant prostate cancer.
PMCID: PMC3961010  PMID: 22821817
Castration resistant prostate cancer; AR-V7; PI3K
3.  Factors associated with pretreatment and treatment dropouts: comparisons between Aboriginal and non-Aboriginal clients admitted to medical withdrawal management 
Addiction treatment faces high pretreatment and treatment dropout rates, especially among Aboriginals. In this study we examined characteristic differences between Aboriginal and non-Aboriginal clients accessing an inpatient medical withdrawal management program, and identified risk factors associated with the probabilities of pretreatment and treatment dropouts, respectively.
2231 unique clients (Aboriginal = 451; 20%) referred to Vancouver Detox over a two-year period were assessed. For both Aboriginal and non-Aboriginal groups, multivariate logistic regression analyses were conducted with pretreatment dropout and treatment dropout as dependent variables, respectively.
Aboriginal clients had higher pretreatment and treatment dropout rates compared to non-Aboriginal clients (41.0% vs. 32.7% and 25.9% vs. 20.0%, respectively). For Aboriginal people, no fixed address (NFA) was the only predictor of pretreatment dropout. For treatment dropout, significant predictors were: being female, having HCV infection, and being discharged on welfare check issue days or weekends. For non-Aboriginal clients, being male, NFA, alcohol as a preferred substance, and being on methadone maintenance treatment (MMT) at referral were associated with pretreatment dropout. Significant risk factors for treatment dropout were: being younger, having a preferred substance other than alcohol, having opiates as a preferred substance, and being discharged on weekends.
Our results highlight the importance of social factors for the Aboriginal population compared to substance-specific factors for the non-Aboriginal population. These findings should help clinicians and decision-makers to recognize the importance of social supports especially housing and initiate appropriate services to improve treatment intake and subsequent retention, physical and mental health outcomes and the cost-effectiveness of treatment.
PMCID: PMC3878858  PMID: 24325629
Aboriginal; Housing; Pretreatment dropout rate; Treatment dropout rate; Withdrawal management; Substance use disorders; Detoxification
4.  Defining dosing pattern characteristics of successful tapers following methadone maintenance treatment: Results from a population-based retrospective cohort study 
Addiction (Abingdon, England)  2012;107(9):1621-1629.
Identify dose tapering strategies associated with sustained success following methadone maintenance treatment (MMT).
Population-based retrospective cohort study.
Linked administrative medication dispensation data from British Columbia, Canada.
From 25,545 completed MMT episodes, 14,602 of which initiated a taper, 4,183 individuals (accounting for 4,917 MMT episodes) from 1996–2006 met study inclusion criteria.
The primary outcome was sustained successful taper, defined as a daily dose ≤5mg per day in the final week of the treatment episode and no treatment re-entry, opioid-related hospitalization, or mortality within 18 months following episode completion.
The overall rate of sustained success was 13% among episodes meeting inclusion criteria (646/4,917), 4.4% (646/14,602) among all episodes initiating a taper, and 2.5% (646/25,545) among all completed episodes in the dataset. The results of our multivariate logistic regression analyses suggested that longer tapers had substantially higher odds of success (12–52 weeks vs. <12 weeks: Odds ratio: 3.58; 95% confidence interval: 2.76 – 4.65); > 52 weeks vs. < 12 weeks: 6.68 (5.13 – 8.70)), regardless of how early in the treatment episode the taper was initiated, and a more gradual, stepped tapering schedule, with dose decreases scheduled in only 25–50% of the weeks of the taper, provided the highest odds of sustained success (vs. <25%: 1.61 (1.22–2.14)).
The majority of patients attempting to taper from methadone maintenance treatment will not succeed. Success is enhanced by gradual dose reductions interspersed with periods of stabilization. These results can inform the development of a more refined guideline for future clinical practice.
PMCID: PMC3376663  PMID: 22385013
5.  Proteolytic Characteristics of Cathepsin D Related to the Recognition and Cleavage of Its Target Proteins 
PLoS ONE  2013;8(6):e65733.
Cathepsin D (CD) plays an important role in both biological and pathological processes, although the cleavage characteristics and substrate selection of CD have yet to be fully explored. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the CD cleavage sites in bovine serum albumin (BSA). We found that the hydrophobic residues at P1 were not only a preferential factor for CD cleavage but that the hydrophobicity at P1’ also contributed to CD recognition. The concept of hydrophobic scores of neighbors (HSN) was proposed to describe the hydrophobic microenvironment of CD recognition sites. The survey of CD cleavage characteristics in several proteins suggested that the HSN was a sensitive indicator for judging the favorable sites in peptides for CD cleavage, with HSN values of 0.5–1.0 representing a likely threshold. Ovalbumin (OVA), a protein resistant to CD cleavage in its native state, was easily cleaved by CD after denaturation, and the features of the cleaved peptides were quite similar to those found in BSA, where a higher HSN value indicated greater cleavability. We further conducted two-dimensional gel electrophoresis (2DE) to find more proteins that were insensitive to CD cleavage in CD-knockdown cells. Based on an analysis of secondary and three-dimensional structures, we postulated that intact proteins with a structure consisting of all α-helices would be relatively accessible to CD cleavage.
PMCID: PMC3688724  PMID: 23840360
6.  The Cost-Effectiveness and Value of Information of Three Influenza Vaccination Dosing Strategies for Individuals with Human Immunodeficiency Virus 
PLoS ONE  2011;6(12):e27059.
Influenza vaccine immunogenicity is diminished in patients living with HIV/AIDS. We evaluated the cost-effectiveness and expected value of perfect information (EVPI) of three alternative influenza vaccine dosing strategies intended to increase immunogenicity in those patients.
A randomized, multi-centered, controlled, vaccine trial was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine were used in HIV infected adults: two standard doses over 28 days (Strategy A), two double doses over 28 days (Strategy B) and a single standard dose of influenza vaccine (Strategy C), administered prior to the 2008 influenza season. The comparator in our analysis was practice in the previous year, in which 82.8% of HIV/AIDS received standard-dose vaccination (Strategy D). A Markov cohort model was developed to estimate the monthly probability of Influenza-like Illness (ILI) over one influenza season. Costs and quality-adjusted life years, extrapolated to the lifetime of the hypothetical study cohorts, were estimated in calculating incremental cost-effectiveness ratios (ICER) and EVPI in conducting further research.
298 patients with median CD4 of 470 cells/µl and 76% with viral load suppression were randomized. Strategy C was the most cost-effective strategy for the overall trial population and for suppressed and unsuppressed individuals. Mean ICERs for Strategy A for unsuppressed patients could also be considered cost-effective. The level of uncertainty regarding the decision to implement strategy A versus C for unsuppressed individuals was high. The maximum acceptable cost of reducing decision uncertainty in implementing strategy A for individuals with unsuppressed pVL was $418,000 - below the cost of conducting a larger-scale trial.
Our results do not support a policy to implement increased antigen dose or booster dosing strategies with seasonal, inactivated trivalent, non-adjuvanted intramuscular vaccine for individuals with HIV in Canada.
Trial Registration NCT00764998.
PMCID: PMC3232195  PMID: 22162988
7.  Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant 
The Journal of Clinical Investigation  2010;120(8):2715-2730.
Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.
PMCID: PMC2912187  PMID: 20644256
8.  Androgen Receptor Mutations Associated with Androgen Insensitivity Syndrome: A High Content Analysis Approach Leading to Personalized Medicine 
PLoS ONE  2009;4(12):e8179.
Androgen insensitivity syndrome (AIS) is a rare disease associated with inactivating mutations of AR that disrupt male sexual differentiation, and cause a spectrum of phenotypic abnormalities having as a common denominator loss of reproductive viability. No established treatment exists for these conditions, however there are sporadic reports of patients (or recapitulated mutations in cell lines) that respond to administration of supraphysiologic doses (or pulses) of testosterone or synthetic ligands. Here, we utilize a novel high content analysis (HCA) approach to study AR function at the single cell level in genital skin fibroblasts (GSF). We discuss in detail findings in GSF from three historical patients with AIS, which include identification of novel mechanisms of AR malfunction, and the potential ability to utilize HCA for personalized treatment of patients affected by this condition.
PMCID: PMC2785468  PMID: 20011049
9.  Impact of welfare cheque issue days on a service for those intoxicated in public 
In British Columbia (BC), the Ministry of Human Resources issues welfare cheques to eligible recipients monthly on the last Wednesday of each month. Previous studies have indicated that there are significant increases in hospital admission, ED admission, 911 calls and deaths shortly after the distribution of the monthly welfare cheques. The objective of this analysis was to rigorously examine the impact of welfare cheque issue dates on admission to the Sobering Unit (SU), a service for the publicly intoxicated, in Vancouver, Canada. Data on 1234 consecutive admissions to the SU over a 7-month period were assessed, and the average number of daily admissions on each of the 7 days of the welfare cheque issue week and similar weekdays in other weeks were compared. A Wilcoxon rank-sum test was performed for the comparisons. Our results showed that there were significant increases in the number of admissions on the 3 days starting with "Welfare Wednesday" compared to the similar weekdays in other weeks (Welfare Wednesday vs. other Wednesdays: 8.7 vs. 5.1, p = 0.02; Welfare Thursdays vs. other Thursdays: 9.6 vs. 5.3, p = 0.02; Welfare Fridays vs. other Fridays: 8.6 vs. 5.7, p = 0.04). The demonstrated impact of welfare cheque issue dates is an important consideration for the re-design, staffing and resource allocation of services for withdrawal management and potentially for other services offered to this population.
PMCID: PMC1876222  PMID: 17462093
10.  Highly active antiretroviral therapy and hospital readmission: comparison of a matched cohort 
Despite the known efficacy of highly active antiretroviral therapy (HAART), a large proportion of potentially-eligible HIV-infected patients do not access, and may stand to benefit from this treatment. In order to quantify these benefits in terms of reductions in hospitalizations and hospitalization costs, we sought to determine the impact of HAART on hospital readmission among HIV-infected patients hospitalized at St. Paul's Hospital (SPH) in Vancouver, BC, Canada.
All patients admitted to a specialized HIV/AIDS ward at SPH (Apr. 1997 – Oct. 2002) were selected and classified as being on HAART or not on HAART based upon their initial admission. Patients were then matched by their propensity scores, which were calculated based on patients' sociodemographics such as age, gender, injection drug use (IDU) status, and AIDS indication, and followed up for one year. Multivariate logistic regression was used to estimate the difference in the odds of hospital readmission between patients on and not on HAART.
Out of a total 1084 patients admitted to the HIV/AIDS ward between 1997 and 2002, 662 were matched according to their propensity score; 331 patients each on and not on HAART. Multivariate logistic regression revealed that patients on HAART had lower odds of AIDS hospital readmission (OR, 0.61; 95% CI, 0.42 – 0.89) compared to patients not on HAART. Odds of readmission among patients on HAART were also significantly lower for non-IDU related readmission (OR, 0.73; 95% CI, 0.53 – 0.99) and overall readmission (OR, 0.72; 95% CI, 0.53 – 0.98).
Propensity score matching allowed us to reliably estimate the association between exposure (on or not on HAART) and outcome (readmitted to hospital). We found that HIV-infected patients who were potentially eligible for, but not on HAART had higher odds of being readmitted to hospital compared to those on HAART. Given the low level of uptake (31%) of HAART observed in our pre-matched hospitalized cohort, a large potential to achieve clinical benefits, reduce hospitalization costs and possibly slow disease progression from improved HAART uptake still exists.
PMCID: PMC1617096  PMID: 17022826
11.  Predictors of Early Hospital Readmission in HIV-infected Patients with Pneumonia 
Although hospitalization patterns have been studied, little is known about hospital readmission among HIV-infected patients in the era of highly active antiretroviral therapy. We explored the risk factors for early readmission to a tertiary care inner-city hospital among HIV-infected patients with pneumonia in Vancouver, Canada.
Case-control study.
Tertiary care, university-affiliated, inner-city hospital.
All HIV-infected patients who were hospitalized with Pneumocystis carinii pneumonia (PCP) or bacterial pneumonia (BP) between January 1997 and December 2000. Case patients included those who had early readmissions, defined as being readmitted within 2 weeks of discharge (N = 131). Control patients were randomly selected HIV-infected patients admitted during the study period who were not readmitted within 2 weeks of discharge (N = 131), matched to the cases by proportion of PCP to BP.
Sociodemographic, HIV risk category, and clinical data were compared using χ2 test for categorical variables, and the Wilcoxon rank-sum test was used for continuous variables. Multivariable logistic regression was performed to determine the factors independently associated with early readmission. We also reviewed the medical records of 132 patients admitted to the HIV/AIDS ward during the study period and collected more detailed clinical data for a subanalysis.
Patients were at significantly increased odds of early readmission if they left the hospital against medical advice (AMA) (adjusted odds ratio [OR], 4.26; 95% confidence interval [95% CI], 2.13 to 8.55), lived in the poorest urban neighborhood (OR, 2.03; 95% CI, 1.09 to 3.77), were hospitalized in summer season (May though October, OR, 2.36; 95% CI, 1.36 to 4.10), or had been admitted in the preceding 6 months (OR, 2.55; 95% CI, 1.46 to 4.47). Gender, age, history of AIDS-defining illness, and injection drug use status were not significantly associated with early readmission.
Predictors of early readmission of HIV-infected patients with pneumonia included: leaving hospital AMA, living in the poorest urban neighborhood, being hospitalized in the preceding 6 months and during the summer months. Interventions involving social work may address some of the underlying reasons why these patients leave hospital AMA and should be further studied.
PMCID: PMC1494845  PMID: 12709090
case-control; hospital readmission; HIV; AIDS; bacterial pneumonia; PCP; antiretroviral therapy
12.  Leaving hospital against medical advice among HIV-positive patients 
Hospital discharge against medical advice, especially among substance-abusing populations, is a frustrating problem for health care pro-viders. Because of the high prevalence of injection drug use among HIV- positive patients admitted to hospital in Vancouver, we explored the factors associated with leaving hospital against medical advice in this population.
We reviewed records for all HIV/AIDS patients admitted to St. Paul's Hospital, Vancouver, between Apr. 1, 1997, and Mar. 1, 1999. After identifying the first (“index”) admission during this period, we followed the patients' records for 1 year. Multivariate models were applied to identify the determinants of discharge against medical advice and to estimate the impact of such discharge on readmission rate, readmission frequency and length of stay in hospital.
Of 981 index admissions among HIV/AIDS patients, 125 (13%) of the patients left the hospital against medical advice. Departure on the day on which welfare cheques were issued and a history of injection drug use were significant predictors of leaving against medical advice. After adjusting for sex, age, severity of illness, injection drug use and homelessness, we found that patients leaving against medical advice were readmitted more frequently than those who were formally discharged (frequency ratio 1.25, 95% confidence interval [CI] 1.11–1.42), were more likely to be readmitted with a related diagnosis within 30 days (odds ratio 5.00, 95% CI 3.04–8.24) and had significantly longer lengths of stay in the follow-up period.
Discharge against medical advice among HIV-positive patients was associated with frequent readmissions with the same diagnosis. Preventing such discharges is likely to benefit patients (by improving their health status) and the health care system (by reducing unnecessary readmissions).
PMCID: PMC122025  PMID: 12358196

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