Clinical Utility of the Signal-to-Cutoff Ratio of Reactive HIV Antigen/Antibody Screening Tests in Guiding Emergency Physician Management.

BACKGROUND: The signal-to-cutoff (S/CO) ratio of the HIV antigen/antibody test may help immediately to differentiate true-positive results from false-positive results, which may be particularly useful in time-sensitive circumstances, such as when providing emergency department (ED) care. SETTING: Seven US EDs with HIV screening programs using HIV antigen/antibody assays. METHODS: This cross-sectional study of existing data correlated S/CO ratios with confirmed HIV status. Test characteristics at predetermined S/CO ratios and the S/CO ratio with the best performance by receiver operator characteristic (ROC) curve were calculated. RESULTS: Of 1035 patients with a reactive HIV antigen/antibody test, 232 (22.4%) were confirmed HIV-negative and 803 (77.6%) were confirmed HIV-positive. Of the 803 patients, 713 (88.8%) experienced chronic infections and 90 (11.2%) experienced acute infections. S/CO ratios were greater for HIV-positive (median 539.2) than for HIV-negative patients (median 1.93) (P < 0.001) and lower for acute infection (median 22.8) than for chronic infection (median 605.7) (P < 0.001). All patients with an S/CO ratio < 1.58 (n = 93) were HIV-negative (NPV 100%), and nearly all with an S/CO ≥ 20.7 (n = 760) (optimal level by ROC analysis) were HIV-positive (PPV 98.6%). Of patients with S/CO values between 1.58 and 20.7 (n = 182), 29.7% were HIV-positive. CONCLUSIONS: The S/CO ratio may be used in real time to classify most ED patients as almost certain to be either HIV-positive or HIV-negative long before nucleic acid confirmatory testing is available. When combined with clinical judgment, this could guide preliminary result disclosure and management.

High prevalence of injection drug use and blood-borne viral infections among patients in an urban emergency department.

BACKGROUND: The opioid epidemic has led to an increase in the number of persons who inject drugs, and this population accounts for 12% of new human immunodeficiency virus (HIV) and 60% of new hepatitis C virus (HCV) infections in the United States annually. While persons who inject drugs disproportionately utilize the emergency department (ED), accurate data is lacking on the prevalence and patterns of injection drug use, and prevalence of co-occurring HIV and HCV infections among ED patients. OBJECTIVE: The primary outcome was to assess the prevalence of injection drug use and co-occurring HIV and HCV infection among patients presenting to an urban ED. METHODS: This was a cross sectional study conducted at an urban ED, with an annual census of 65,000 visits. A closed-response questionnaire was developed based on publicly available validated surveys to assess patterns of injection drug use and HIV and HCV infection status, and administered by trained research assistants to all registered adult patients during 4-hour blocks of time. RESULTS: Of the 2,319 eligible patients, 2,200 (94.9%) consented and completed the survey. 241 (11.0%) had ever used injection drugs, 103 (4.7%) currently used injection drugs, and 138 (6.3%) formerly used injection drugs. White patients age 25 to 34 years and white patients age 55 to 64 years had the highest prevalence of current (25.6%) and former (27.1%) injection drug use, respectively. Persons who use injection drugs had a higher prevalence of HCV infection (52.7% vs. 3.4%) and HIV infection (6.2% vs. 1.8%) than the rest of the population. CONCLUSION: A high prevalence of ED patients report injection drug use, and this population self-reports a high prevalence of HIV and HCV infection. Emergency departments are in a unique position to engage with this population with regards to substance use treatment and linkage to care for HIV and HCV infection.

Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel.

BACKGROUND: Pre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy. MATERIALS AND METHODS: Data were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry. RESULTS: Median values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001). CONCLUSION: Consistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.

Androgen decline and survival during docetaxel therapy in metastatic castration resistant prostate cancer (mCRPC).

BACKGROUND: Multiple androgens drive prostate cancer progression and higher pre-treatment levels of androgens, even within the castrate range, have been previously shown to be associated with an improved overall survival (OS) in mCRPC. Docetaxel impairs microtubules, has androgen receptor (AR) inhibitory effects and is used in both the castration resistant and sensitive settings, where androgen dynamics may impact outcome. The present analysis evaluates the association of decline in serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA in docetaxel-treated mCRPC patients with OS. METHODS: Data from 1050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were evaluated. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment, 6 week and progression serum assays for T, A and DHEA were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS). Changes in T, A and DHEA levels from baseline to 6 weeks were calculated as the ratio of 6-week over baseline. The proportional hazards model was used to assess the prognostic significance of changes in T, A, and DHEA from baseline to 6 weeks in predicting OS adjusting for known prognostic factors. RESULTS: Median baseline values for T, A, and, DHEA were 1.0, 13.5, and 8.1 ng/dL respectively while 6 week levels were 0.64, 7.0, and 6.8 ng/dL respectively. Median OS for low testosterone decline is 20.9 months vs 26.3 months for high testosterone decline. In multivariable analysis including known prognostic variables, change in testosterone levels was independently associated with greater OS; the hazard ratio for death with each unit increase in the 6-week/baseline ratio is 1.02 (95% CI = 1.01-1.03, p = 0.001). Decline in A and DHEA were not significant predictors of OS. In multivariable analysis change in the serum changes did not predict PFS however the ratio of T at 6-weeks over baseline was prognostic of ≥50% decline in PSA with an odds ratio of 0.93 (95% CI = 0.85-0.98, p-value = 0.039). CONCLUSIONS: Declines in testosterone during docetaxel treatment is associated with a longer survival, consistent with a favorable prognostic significance of higher serum androgens in the CRPC.

HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer.

IMPORTANCE: The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3ß-hydroxysteroid dehydrogenase isoenzyme 1 (3ßHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). OBJECTIVE: To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. DESIGN, SETTING, AND PARTICIPANTS: An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. EXPOSURES: Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. MAIN OUTCOMES AND MEASURES: The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. RESULTS: A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). CONCLUSIONS AND RELEVANCE: Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.

High-Dose Abiraterone Acetate in Men With Castration Resistant Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) inhibits androgen biosynthesis and prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) when combined with prednisone (P). Resistance to therapy remains incompletely understood. In this open-label, single-arm, multicenter phase II study we investigated the clinical benefit of increasing the dose of AA at the time of resistance to standard-dose therapy. PATIENTS AND METHODS: Eligible patients had progressive mCRPC and started AA 1000 mg daily and P 5 mg twice daily. Patients who achieved any prostate-specific antigen (PSA) decline after 12 weeks of therapy continued AA with P until PSA or radiographic progression. At progression, AA was increased to 1000 mg twice daily with unchanged P dosing. Patients were monitored for response to therapy for a minimum of 12 weeks or until PSA or radiographic progression. The primary end point was PSA decline of at least 30% after 12 weeks of therapy at the increased dose of AA. RESULTS: Forty-one patients were enrolled from March 2013 through March 2014. Thirteen men experienced disease progression during standard-dose therapy and were subsequently treated with AA 1000 mg twice per day. Therapy was well tolerated. No PSA declines ≥ 30% nor radiographic responses were observed after 12 weeks of dose-escalated therapy. Higher baseline dehydroepiandrosterone levels, lower circulating tumor cell burden, and higher pharmacokinetic levels of abiraterone and abiraterone metabolites were associated with response to standard-dose therapy. CONCLUSION: Increasing the dose of abiraterone at the time of resistance has limited clinical utility and cannot be recommended. Lower baseline circulating androgen levels and interpatient pharmacokinetic variance appear to be associated with primary resistance to AA with P.