Prognostic markers in lentigo maligna patients treated with imiquimod cream: A long-term follow-up study.

BACKGROUND More data are needed to define factors that predict long-term success after imiquimod therapy for lentigo maligna (LM). OBJECTIVE We sought to determine the demographic, clinical, and histologic prognostic markers of relapse-free survival in patients with LM who were treated with imiquimod. METHODS This was a single-arm, open-label, nonrandomized, prospective study. RESULTS Eighty-nine patients with histologically confirmed LM and a median follow-up time of 4.8 years after imiquimod treatment were included in our study. Sixteen patients (18%) relapsed. Statistically significant indicators of an increased risk of local recurrence included: the total number of melanocytes, the number of basal and suprabasal melanocytes and the number of pagetoid spreading melanocytes. LIMITATIONS Our study was a single-center, nonrandomized study. CONCLUSION An assessment of different melanocyte fractions in the diagnostic baseline biopsy specimen may help to predict the response of LM to imiquimod therapy.

The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study

UNLABELLED The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. INTRODUCTION This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

BACKGROUND Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT00544700.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy

BACKGROUND & AIMS Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc.

Metabolic and hormonal response to intermittent high-intensity and continuous moderate intensity exercise in individuals with type 1 diabetes: a randomised crossover study.

AIMS/HYPOTHESIS To investigate exercise-related fuel metabolism in intermittent high-intensity (IHE) and continuous moderate intensity (CONT) exercise in individuals with type 1 diabetes mellitus. METHODS In a prospective randomised open-label cross-over trial twelve male individuals with well-controlled type 1 diabetes underwent a 90 min iso-energetic cycling session at 50% maximal oxygen consumption ([Formula: see text]), with (IHE) or without (CONT) interspersed 10 s sprints every 10 min without insulin adaptation. Euglycaemia was maintained using oral (13)C-labelled glucose. (13)C Magnetic resonance spectroscopy (MRS) served to quantify hepatocellular and intramyocellular glycogen. Measurements of glucose kinetics (stable isotopes), hormones and metabolites complemented the investigation. RESULTS Glucose and insulin levels were comparable between interventions. Exogenous glucose requirements during the last 30 min of exercise were significantly lower in IHE (p = 0.02). Hepatic glucose output did not differ significantly between interventions, but glucose disposal was significantly lower in IHE (p < 0.05). There was no significant difference in glycogen consumption. Growth hormone, catecholamine and lactate levels were significantly higher in IHE (p < 0.05). CONCLUSIONS/INTERPRETATION IHE in individuals with type 1 diabetes without insulin adaptation reduced exogenous glucose requirements compared with CONT. The difference was not related to increased hepatic glucose output, nor to enhanced muscle glycogen utilisation, but to decreased glucose uptake. The lower glucose disposal in IHE implies a shift towards consumption of alternative substrates. These findings indicate a high flexibility of exercise-related fuel metabolism in type 1 diabetes, and point towards a novel and potentially beneficial role of IHE in these individuals. TRIAL REGISTRATION ClinicalTrials.gov NCT02068638 FUNDING: Swiss National Science Foundation (grant number 320030_149321/) and R&A Scherbarth Foundation (Switzerland).

Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody in HIV-1 infected adults

Context: Despite tremendous strides in HIV treatment over the past decade, resistance remains a major problem. A growing number of patients develop resistance and require new therapies to suppress viral replication. ^ Objective: To assess the safety of multiple administrations of the anti-CD4 receptor (anti-CD4) monoclonal antibody ibalizumab given as intravenous (IV) infusions, in three dosage regimens, in subjects infected with human immunodeficiency virus (HIV-1). ^ Design: Phase 1, multi-center, open-label, randomized clinical trial comparing the safety, pharmacokinetics and antiviral activity of three dosages of ibalizumab. ^ Setting: Six clinical trial sites in the United States. ^ Participants: A total of twenty-two HIV-positive patients on no anti-retroviral therapy or a stable failing regimen. ^ Intervention: Randomized to one of two treatment groups in Arms A and B followed by non-randomized enrollment in Arm C. Patients randomized to Arm A received 10 mg/kg of ibalizumab every 7 days, for a total of 10 doses; patients randomized to Arm B received a total of six doses of ibalizumab; a single loading dose of 10 mg/kg on Day 1 followed by five maintenance doses of 6 mg/kg every 14 days, starting at Week 1. Patients assigned to Arm C received 25 mg/kg of ibalizumab every 14 days for a total of 5 doses. All patients were followed for safety for an additional 7 to 8 weeks. ^ Main Outcome Measures: Clinical and laboratory assessments of safety and tolerability of multiple administrations of ibalizumab in HIV-infected patients. Secondary measures of efficacy include HIV-1 RNA (viral load) measurements. ^ Results: 21 patients were treatment-experienced and 1 was naïve to HIV therapy. Six patients were failing despite therapy and 15 were on no current HIV treatment. Mean baseline viral load (4.78 log 10; range 3.7-5.9) and CD4+ cell counts (332/μL; range 89-494) were similar across cohorts. Mean peak decreases in viral load from baseline of 0.99 log10(1.11 log10, and 0.96 log 10 occurred by Wk 2 in Cohorts A, B and C, respectively. Viral loads decreased by >1.0 log10 in 64%; 4 patients viral loads were suppressed to < 400 copies/mL. Viral loads returned towards baseline by Week 9 with reduced susceptibility to ibalizumab. CD4+ cell counts rose transiently and returned toward baseline. Maximum median elevations above BL in CD4+ cell counts for Cohorts A, B and C were +257, +198 and +103 cells/μL, respectively and occurred within 3 Wks in 16 of 22 subjects. The half-life of ibalizumab was 3-3.5 days and elimination was characteristic of capacity-limited kinetics. Administration of ibalizumab was well tolerated. Four serious adverse events were reported during the study. None of these events were related to study drug. Headache, nausea and cough were the most frequently reported treatment emergent adverse events and there were no laboratory abnormalities related to study drug. ^ Conclusions: Ibalizumab administered either weekly or bi-weekly was safe, well tolerated, and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.^

Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention: prospective studies in HIV-uninfected men and women

Thesis (Ph.D.)--University of Washington, 2016-06

Safer Conception Among HIV-1 Sero-Discordant Couples in East Africa: Understanding Knowledge, Attitudes, and Experiences

Thesis (Master's)--University of Washington, 2016-06

Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments

After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.

Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients

BACKGROUND: The development of hyperlipidemia after liver transplant is frequently treated with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) such as atorvastatin. As atorvastatin and the primary immunosuppressant drug, cyclosporine, are metabolized by the same pathway, there is the potential for an interaction. OBJECTIVE: To determine the effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. METHODS: Six stable, long-term adult liver transplant recipients from a single center who developed posttransplant dyslipidemia were recruited to participate in a 14-day, open-label study of atorvastatin 10 mg/d coadministered with standard posttransplant immunosuppression using constant oral doses-of cyclosporine and corticosteroids. A 10-point pharmacokinetic profile was performed prior to and on day 14 after commencement of atorvastatin therapy. Cyclosporine concentrations were measured by HPLC-electrospray-tandem mass spectrometry. The AUC was calculated by the linear trapezoidal rule, with other parameters determined by visual inspection. RESULTS: Atorvastatin coadministration increased the cyclosporine AUC by 9% (range 0-20.6%; 3018 vs 3290 ng(.)h/mL; p = 0.04). No significant change was evident for other cyclosporine pharmacokinetic parameters. Total cholesterol and low-density lipoprotein cholesterol levels were significantly lower on day 14 than at baseline (p < 0.02). One patient developed a twofold increase in transaminases after 2 weeks of atorvastatin therapy, but no other clinical or biochemical adverse events were recorded. CONCLUSIONS: Atorvastatin coadministration increases the cyclosporine AUC by approximately 10% in stable liver transplant recipients. This change in systemic exposure to cyclosporine is of questionable clinical significance. Atorvastatin is effective in reducing cholesterol levels in liver transplant recipients.

Autologous hemopoietic stem cell transplantation in severe rheumatoid arthritis: A report from the EBMT and ABMTR

Objective. Since 1996, autologous hemopoietic stem cell transplantation (HSCT) has been used to treat severe rheumatoid arthritis (RA). To date, published reports have been individual cases or series containing small numbers. This study combined the worldwide experience in a single analysis. Methods. The Autoimmune Disease Databases of the European Group for Blood and Marrow Transplantation (EBMT) and the Autologous Blood and Marrow Transplant Registry (ABMTR) were used to identify patients with RA treated with autologous HSCT. Further information relating to patient and treatment-specific variables was obtained by questionnaire. Results. Seventy-six patients were registered from 15 centers. Seventy-three patients had received autologous HSCT, and in 3 patients hematopoietic stem cells (HSC) were mobilized but not transplanted. Transplanted patients (median age 42 yrs, 74% female, 86% rheumatoid factor positive) had been previously treated with a mean of 5 (range 2-9) disease modifying antirheumatic drugs (DMARD). Significant functional impairment was present, with a median Health Assessment Questionnaire (HAQ) score of 1.4 (range 1.1-2.0) and Steinbrocker score mean 2.39 (SD 0.58). The high dose treatment regimen was cyclophosphamide (CYC) alone in the majority of patients, mostly 200 mg/kg (n = 62). Seven patients received anti-thymocyte globulin (ATG) in addition to CYC, 2 patients busulfan and CYC (BuCYC), and one patient CYC with total body irradiation and ATG. One patient received fludarabine with ATG. Following treatment, one patient received bone marrow but the rest received chemotherapy and/or granulocyte colony-stimulating factor mobilized peripheral blood stem cells. The harvest was unmanipulated in 28 patients, the rest receiving some form of lymphocyte depletion, mostly through CD34+ selection. Median followup was 16 months (range 3-55). Responses were measured using the American College of Rheumatology (ACR) criteria. Forty-nine patients (67%) achieved at least ACR 50% response at some point following transplant. There was a significant reduction in the level of disability measured by the HAQ (p < 0.005). Most patients restarted DMARD within 6 months for persistent or recurrent disease activity, which provided disease control in about half the cases. Response was significantly related to seronegative RA (p = 0.02) but not to duration of disease, number of previous DMARD, presence of HLA-DR4, or removal of lymphocytes from the graft. There was no direct transplant related mortality, although one patient, treated with the BuCYC regimen, died 5 months post-transplant from infection and incidental non-small cell lung cancer. Conclusion. Autologous HSCT is a relatively safe form of salvage treatment in severe, resistant RA. In these open label studies significant responses were achieved in most patients, with over 50% achieving an ACR 50 or more response at 12 months. Although the procedure is not curative, recurrent or persistent disease activity may be subsequently controlled in some patients with DMARD. Clinical trials are necessary to develop this approach inpatients with aggressive disease who have failed conventional treatment including anti-tumor necrosis factor agents.

A preliminary case series on the use of quetiapine for posttraumatic stress disorder in juveniles within a youth detention center

Juveniles within the youth justice system have high rates of psychiatric morbidity, including posttraumatic stress disorder (PTSD). This case series describes 6 young people aged 15 to 17 years within a youth detention center who met the criteria for PTSD and reported an improvement in symptoms after 6 weeks of treatment with low-dose quetiapine. The primary outcome measure used was the Traumatic Symptom Checklist in Children. The dose of quetiapine ranged from 50 to 200 mg/d; T scores for PTSD symptoms decreased from 75 (SD, +/- 5.2; range, 68-82) to 54 (SD: +/- 7.4; range, 43-62) (P <= 0.01). Significant improvements in symptoms of dissociation (P <= 0.01), anxiety (P < 0.01), depression (P < 0.01).. and anger (P < 0.05) were also noted over the 6-week evaluation period. Low-dose quetiapine was tolerated well, with no persisting side effects or adverse events. Nighttime sedation was reported, although this was viewed as beneficial. All young people opted to continue with treatment after the assessment period. This preliminary case series suggests that juveniles in detention who have PTSD may benefit from treatment with quetiapine. Caution is needed in interpreting these findings. Both larger open-label and blinded trials are war-ranted to define the use of quetiapine in the treatment of PTSD in the adolescent forensic population.

Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline. Design: Open-label, prospective study and cross-sectional questionnaire and interview. Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001-October 2001 and October 2001-May 2002). Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment. Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again. Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.

Live Attenuated Chimeric Yellow Fever Dengue Type 2 (Chimeri Vax -DEN2) Vaccine: Phase 1 clinical trial for safety and immunogenicity

A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax™-DEN2) in comparison to that of YF vaccine (YF-VAX®). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAXâ by the subcutaneous route (SC). To determine the effect of YF pre-immunity on the ChimeriVaxTM-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVaxTM-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX® seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3, and 4 were observed in YF naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX®. In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2, and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that 1) the safety and immunogenicity profile of the ChimeriVax™-DEN2 vaccine is consistent with that of YF-VAX®, and 2) pre-immunity to YF virus does not interfere with ChimeriVaxTM-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.