We have developed a model of therapy for herpes simplex virus (HSV) infection in neonatal mice. Houston is often cited as a place where the HIV infection rate is twice the nation’s, which was affirmed by the federal Centers for Disease Control and Prevention’s three-year testing project. Regardless of the reasons behind packing your bags and needing to find the cheapest flights from IAH to HSV, we’ve got you covered here at Flights.com. Trends in Rates of Herpes Zoster–Related Hospitalizations Are They Real, Are They Costly, and Are They Linked to Varicella Vaccination?. The Centers For Disease Control and Prevention’s 2002 statistics book shows chlamydia incidents in Omaha are proportionately above the national average and ranked 28th in the nation for chlamydia infections. In suicide gene therapy, the tumor cells are modified to trigger body’s immune system to kill the tumor cells. Many affected babies will be stillborn or die shortly after birth.
Chiles Research Institute, Portland, OR; Karl Lewis, University of Colorado Cancer Center, Aurora, CO; Troy Guthrie, Baptist Cancer Institute, Jacksonville; Jonathan S. Male-to-male sexual activity accounted for 67% of the new diagnoses. Linette, Washington University School of Medicine, St Louis, MO; Kevin Harrington, Institute of Cancer Research, Royal Marsden Hospital, London; Mark R. Middleton, National Institute for Health Research Biomedical Research Centre, Oxford, United Kingdom; Wilson H. The city of Temple is currently experiencing a rapid growth in its population, which is also contributing to the spread of sexually transmitted diseases. Book your IAH to HSV flights with Expedia and find last-minute Houston to Huntsville airfare. Answer: When you’re flying from HSV to IAH, the day with the most flight times is Monday, with three different options.
Our STD testing sites all over United States of America can get you in and out in less than 5 minutes so there is really no reason for not getting tested today. Adolescents should be strongly encouraged to delay sexual intercourse, the report said, but those who are sexually active need access to information on sexual diseases and ways to prevent them, including access to condoms, testing and treatment. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. Results Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051).
T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. This history of violence leaves many sex workers with emotional trauma, and many may turn to drug use to deal with the harsh realities of their daily lives. Studies have not shown that circumcision will reduce an HIV-infected man’s chances of spreading the AIDS virus to women. No fatal treatment-related AEs occurred. No fatal treatment-related AEs occurred. This suggestion is particularly important given the evidence that the risk of HIV infection is increased for patients with STDs. T-VEC represents a novel potential therapy for patients with metastatic melanoma.
"Even if they are no longer with that person, maybe they broke up two months ago or something like that, we really do want that person to get examined or treated," McNear said. Improvement in overall survival (OS) has been reported with T-cell checkpoint inhibitors and BRAF inhibitors, with objective response rates ranging from 11% with single-agent ipilimumab to 76% with the combination of BRAF and MEK inhibitors, although drug resistance and recurrence are still challenges.1–3 New strategies promoting tumor cell death and/or inducing protective host antitumor immunity are of high priority. T-VEC has been evaluated in early-phase studies, which demonstrated intratumoral replication and expression of GM-CSF and an acceptable safety profile (low-grade fever, chills, myalgias, and injection site reactions) after intralesional administration.4,12 In a single-arm phase II study, an overall response rate (ORR) of 26% was reported in patients with stage IIIC to IV melanoma, with responses observed in both injected and uninjected lesions, including visceral lesions.12 Biopsy of regressing lesions suggested an association between response and presence of interferon γ–producing MART-1–specific CD8+ T cells and reduction in CD4+FoxP3+ regulatory T cells, consistent with induction of host antitumor immunity.13 Here we report the primary analysis results from the phase III OPTiM study designed to evaluate whether treatment with T-VEC resulted in an improved durable response rate (DRR) compared with GM-CSF in patients with unresected stage IIIB to IV melanoma. ORR and OS are also reported. Eligible patients were age ≥ 18 years with histologically confirmed, not surgically resectable, stage IIIB to IV melanoma suitable for direct or ultrasound-guided injection (at least one cutaneous, subcutaneous, or nodal lesion or aggregation of lesions ≥ 10 mm in diameter). Bidimensionally measurable disease, serum lactate dehydrogenase ≤ 1.5× upper limit of normal, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1, and adequate organ function were also required. Patients requiring intermittent or chronic treatment with an antiviral agent (eg, acyclovir) or high-dose steroids were excluded, as were those with primary ocular or mucosal melanoma, bone metastases, active cerebral metastases, more than three visceral metastases (except lung or nodal metastases associated with visceral organs), or any visceral metastasis > 3 cm; liver metastases had to be stable for ≥ 1 month before random assignment.
Patients with history of autoimmune disease, but not use of high-dose steroids, were eligible. Patients provided written informed consent; study procedures received institutional approval. This open-label study was conducted at 64 centers in the United States, the United Kingdom, Canada, and South Africa and overseen by an independent data monitoring committee. Patients were assigned at a two-to-one ratio using central random assignment to receive intralesional T-VEC or subcutaneous recombinant GM-CSF. Random assignment was stratified by site of first recurrence, presence of liver metastases, disease stage, and prior nonadjuvant systemic treatment. The first dose of T-VEC was administered at 106 pfu/mL (to seroconvert HSV-seronegative patients). Subsequent T-VEC doses of 108 pfu/mL were administered 3 weeks after the first dose and then once every 2 weeks.
Total T-VEC volume was up to 4.0 mL per treatment session. Injected volume per lesion ranged from 0.1 mL for lesions < 0.5 cm to 4.0 mL for lesions > 5 cm in longest diameter. Injection of all lesions was not required, and different lesions could be injected at different visits based on prioritization of injection to any new or largest lesions. Injection into visceral lesions was not allowed. GM-CSF 125 μg/m2 was administered subcutaneously once daily for 14 days in 28-day cycles. Dose modifications for T-VEC were not permitted. GM-CSF doses could be reduced by 50% for absolute neutrophil count > 20,000/μL or platelets > 500,000/μL.
If absolute neutrophil count or platelets decreased below these thresholds, GM-CSF dose could be increased 25%; if they persisted, GM-CSF was permanently discontinued. Discontinuation of treatment because of progressive disease per response assessment criteria was not required before 24 weeks unless alternate therapy was clinically indicated. After 24 weeks, treatment continued until clinically relevant disease progression (progressive disease associated with reduced performance status), intolerability, withdrawal of consent, complete remission, lack of response by 12 months, or (T-VEC only) disappearance of all injectable lesions. After 12 months, patients with stable or responding disease could continue treatment for 6 additional months. The primary end point was DRR, defined as the rate of complete response (CR) plus partial response (PR) lasting ≥ 6 months continuously and beginning within the first 12 months. Increased funding and awareness is needed for public health programs that address this full range of issues sex workers face. Visible or palpable lesions were evaluated by clinical evaluation (caliper or ruler).
Deeper palpable lesions and nonpalpable subcutaneous and distant metastatic lesions were assessed by whole-body computed tomography (CT), positron emission tomography (PET) or PET-CT, and ultrasonography if appropriate. Baseline and new tumors were observed, and response was assessed per modified WHO criteria.14 If a response was suspected to have occurred, confirmatory assessments were to be performed within 1 week. The policy of treating inpatients would affect the test results for gonorrhea and chlamydial infection, especially at the Houston 2 site. Digital photography encompassing all visible disease was required for response assessment by EAC. Clinical evaluation was performed at baseline and day 1 of each cycle; other assessments were performed at baseline and every 12 weeks. Adverse events (AEs) occurring from day 1 to 30 days after last treatment were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). The planned population size was 430 patients (randomly assigned at a two-to-one ratio).
This provided 95% and 90% power for a two-sided α of 0.05 using Fisher’s exact test in the intent-to-treat and per-protocol populations, respectively, to detect an estimated DRR difference of 13% versus 3%. Primary efficacy analyses were based on the intent-to-treat population. Safety analyses included patients who received at least one dose of T-VEC or GM-CSF. Interim analysis of DRR was planned after 75 patients were enrolled (one-sided α = 0.0001) and after all patients were randomly assigned (one-sided α = 0.0005). Primary analysis of DRR (with one-sided type I error rate of 0.0244) was planned when no additional patients had the possibility of meeting the criteria for durable response, at which time, on a positive result, an interim analysis of OS was planned after 250 events and tested (one-sided α = 0.0001). OS was tested with an unadjusted log-rank test conditional on a statistically significant difference in DRR. Primary analysis of OS required at least 290 events with 90% power to detect a hazard ratio (HR) of 0.67 with two-sided α of 0.05, without adjustment for interim analysis.15 Difference in DRR per EAC between treatment arms was evaluated using an unadjusted Fisher’s exact test.
OS, TTF, time to response, and duration of response were evaluated using unadjusted log-rank tests and Cox proportional hazards models. Difference in incidence of grade ≥ 3 AEs between arms was evaluated using χ2 test (analysis was not prespecified). Analyses were performed using SAS software (version 9.2; SAS Institute, Cary, NC). Between May 2009 and July 2011, 436 patients were assigned to treatment and included in intent-to-treat analyses (T-VEC, n = 295; GM-CSF, n = 141; Fig 1). Four patients in the T-VEC arm and 14 in the GM-CSF arm did not receive T-VEC or GM-CSF. Overall, 57% had stage IIIB, IIIC, or IVM1a disease, and 47% had not received prior systemic therapy for metastatic disease (Table 1). At time of analysis, all patients had discontinued study treatment in the main protocol but could have enrolled onto a treatment extension study if appropriate.
Median duration of treatment in the T-VEC and GM-CSF arms was 23.0 weeks (range, 0.1 to 78.9 weeks) and 10.0 weeks (range, 0.6 to 72.0 weeks), respectively. Median potential follow-up (time from random assignment to analysis) was 44.4 months (range, 32.4 to 58.7 months) at the primary analysis of OS. Disposition of patients. CR, complete response; GM-CSF, granulocyte macrophage colony-stimulating factor; PR, partial response. (*) Includes patients who were screened but did not meet eligibility criteria. Twenty-six patients in T-VEC arm (9%) and seven in GM-CSF arm (5%) were enrolled and randomly assigned but had at least one inclusion or exclusion criteria violation. (†) There were 439 random assignments; however, one patient was later determined to have been randomly assigned three times at three different sites and was excluded from intent-to-treat analysis set but was included in the safety analysis set.
The patient ultimately received talimogene laherparepvec (T-VEC) after two initial random assignments to GMCSF. (‡) T-VEC was administered intralesionally ≤ 4 mL × 106 pfu/mL once and, after 3 weeks, ≤ 4 mL × 108 pfu/mL every 2 weeks. (§) GM-CSF 125 μg/m2 subcutaneously for 14 days in 4-week cycles. DRR per EAC assessment (primary end point) was significantly higher in the T-VEC arm (16.3%; 95% CI, 12.1% to 20.5%) compared with the GM-CSF arm (2.1%; 95% CI, 0% to 4.5%; unadjusted odds ratio, 8.9; 95% CI, 2.7 to 29.2; P < .001; Table 2; Fig 2A). ORR was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%; P < .001 [not prespecified]); 32 patients (10.8%) in the T-VEC arm and one patient (< 1%) in the GM-CSF arm had a CR (Table 2). Antitumor activity of talimogene laherparepvec. Over one-third of the study subjects shared needles; however, of the injection drug users, 79% had shared needles.
Response assessments per end point–assessment committee (EAC) were not available for all patients, because EAC reviewed only subset of patients with overall response per investigator or who received treatment for > 9 months (see Patients and Methods). (B) Duration of response for all patients with response per EAC assessment. Duration of response was defined as longest period of response from entering response to first documented evidence of patient no longer meeting criteria for response. Arrows indicate patients for whom duration of response was censored at last tumor assessment because there was no evidence (per EAC assessment) that their response had ended. CR, complete response; GM-CSF, granulocyte macrophage colony-stimulating factor; PR, partial response. (*) Patients with > 150% increase in tumor dimensions. Median TTF was 8.2 months (95% CI, 6.5 to 9.9 months) in the T-VEC arm versus 2.9 months (95% CI, 2.8 to 4.0 months) in the GM-CSF arm (HR, 0.42; 95% CI, 0.32 to 0.54).
At the primary analysis of OS, 290 deaths had occurred (T-VEC, n = 189; GM-CSF, n = 101). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) in the T-VEC arm and 18.9 months (95% CI, 16.0 to 23.7 months) in the GM-CSF arm (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051; Fig 3). Estimated 1-, 2-, 3-, and 4-year survival rates are listed in Table 2. Subgroup analyses were performed to investigate the relative effects of treatment across a number of key covariates for DRR, ORR, and OS. Differences in DRR between the T-VEC and GM-CSF arms were more pronounced in patients with stage IIIB or IIIC (33% v 0%) and IVM1a disease (16% v 2%) than in patients with stage IVM1b (3% v 4%) and IVM1c disease (7% v 3%; Fig 4A). Differences in DRR were also more pronounced in patients with treatment-naive metastatic melanoma (24% v 0%) than in those receiving treatment as second-line or greater therapy (10% v 4%). Similar patterns were seen for ORR in these subgroups (Appendix Fig A1, online only).
Effects of T-VEC on OS were also pronounced among patients with stage IIIB, IIIC, or IVM1a disease (HR, 0.57; 95% CI, 0.40 to 0.80) and previously untreated patients (HR, 0.50; 95% CI, 0.35 to 0.73; Figs 4B to 4F). Outcomes in patient subgroups. (A) Durable response rate (DRR) and (B) overall survival (OS) in patient subgroups defined by key baseline characteristics. OS in patients with (C) stage IIIB, IIIC, or IVM1a or (D) stage IVM1b or IVM1c disease. OS in patients receiving study treatment as (E) first- or (F) second-line or greater therapy. No α was allocated for evaluations of statistical significance. ECOG, Eastern Cooperative Oncology Group; diff, difference; GM-CSF, granulocyte macrophage colony-stimulating factor; HSV, herpes simplex virus; NE, not estimable; PS, performance status; T-VEC, talimogene laherparepvec.
(*) P < .001 per Gail and Simon18 quantitative treatment by covariate interaction test (for DRR). (†) One patient in the T-VEC arm had unknown disease stage. (‡) Twelve patients in the GM-CSF arm and four in the T-VEC arm had unknown ECOG status. The proportion of patients receiving subsequent selected effective antimelanoma therapy was similar between arms, although T-VEC patients received treatment approximately 2 months later than GM-CSF patients (Appendix Table A2, online only). Because between-arm imbalances in nonrandomization prognostic factors of disease stage (IIIB, IIIC, or IVM1a v IVM1b or IVM1c) and ECOG performance status were identified, a sensitivity analysis (stratified Cox proportional hazards model) was used to adjust for these factors; the HR for OS with T-VEC versus GM-CSF was 0.76 (95% CI, 0.59 to 0.98; adjusted log-rank P = .03; Appendix Table A3, online only). AEs occurring more frequently among patients receiving T-VEC included chills (T-VEC, 49% v GM-CSF, 9%), pyrexia (43% v 9%), injection-site pain (28% v 6%), nausea (36% v 20%), influenza-like illness (30% v 15%), and fatigue (50% v 36%; Table 3). Vitiligo was reported in 15 T-VEC patients (5%) and one GM-CSF patient (< 1%; all grade ≤ 2).
Injection-site erythema occurred more frequently among GM-CSF patients (T-VEC, 5% v GM-CSF, 26%). For T-VEC and GM-CSF, respectively, incidence of AEs of any grade was 99% and 95%, and incidence of treatment-related grade 3 or 4 AEs was 11% and 5%. The rate of discontinuation as a result of AEs was 4% and 2% with T-VEC and GM-CSF, respectively; disease progression was the most common reason for treatment discontinuation in both arms (Fig 1). African American race, a history of selling sex, and >5 sex partners in the last 4 weeks were not independently significant factors for syphilis in the multivariate analysis. The only grade 3 or 4 AE occurring in ≥ 2% of patients was cellulitis (T-VEC, n = 6 [2.1%]; GM-CSF, n = 1 [< 1%]). Of 10 fatal events in the T-VEC arm, none were considered treatment related per investigator, and most (80%) were associated with disease progression, with the exception of sepsis in the setting of Salmonella infection and myocardial infarction. Two fatal non–treatment-related AEs occurred in the GM-CSF arm, both associated with disease progression.
To our knowledge, OPTiM is the first randomized controlled phase III study evaluating an oncolytic immunotherapy to demonstrate a therapeutic benefit in melanoma. The study met its primary end point: T-VEC significantly improved the rate of responses lasting continuously for ≥ 6 months in patients with unresected stage IIIB to IV melanoma compared with subcutaneous GM-CSF. ORR was also higher. Among responding patients in the T-VEC arm, median time to response was 4.1 months, and more than half experienced ≥ 25% increase in the size of lesions or appearance of new lesions before achieving a response. This pattern of pseudoprogression is consistent with that seen with other immunotherapies19–23 and illustrates the importance of continuing treatment in clinically stable patients even if individual lesions increase in size or new lesions develop. In the context of the low historical CR rate reported for other single-agent immunotherapies, the 10.8% CR rate with T-VEC is high.1,20 The duration of T-VEC responses is also notable, with two thirds of responses expected to last ≥ 1 year. OS was a secondary end point; in the intent-to-treat analysis (based on 290 events), patients in the T-VEC arm had a 21% reduced risk of death (HR, 0.79; 95% CI, 0.62 to 1.00; P = .051) and 4.4-month longer median OS compared with patients treated with GM-CSF.
Median TTF was 5.3 months longer with T-VEC. Combined with the limited toxicity observed, these are clinically important results. Several factors might have influenced the efficacy outcomes. GM-CSF was selected as a comparator based on its immune-mediated mechanism of action, established safety profile, and preliminary evidence of clinical benefit as adjuvant therapy in resectable stage III to IV melanoma.11,28,29 Although the duration of treatment was shorter in the GM-CSF arm, the reported activity of single-agent GM-CSF in advanced melanoma has been modest11; it is unlikely that shorter exposure contributed meaningfully to the reduced treatment effect. Effective subsequent antimelanoma therapies were received earlier by GM-CSF patients and could have overcome some of the OS benefit achieved with T-VEC. Furthermore, it is plausible that prior GM-CSF treatment may have had a beneficial impact on subsequent therapies, because concomitant administration of GM-CSF and ipilimumab has been shown to increase OS over ipilimumab alone.30 There were also small but meaningful imbalances in prognostic factors (disease stage and ECOG performance status) favoring the GM-CSF arm that may have affected the overall result, as suggested by a sensitivity analysis adjusting for these imbalances. In addition, the open-label study design may have influenced assessment of some end points (particularly TTF).
In conclusion, this randomized phase III study demonstrated that treatment with T-VEC, an oncolytic virus immunotherapy, improved DRR compared with GM-CSF in patients with unresected stage IIIB, IIIC, or IV melanoma. T-VEC treatment resulted in long-lasting CRs, suggesting T-VEC could delay or prevent relapses or preclude progression to later stages of disease. T-VEC represents a novel potential new treatment option for patients with injectable metastatic melanoma and limited visceral disease. The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution.
Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. We thank all patients who generously volunteered and participated in the trial; their families, friends, and caregivers; and the study staff. In addition, we thank Mark Shilkrut, MD (Amgen), for contributions to data collection and interpretation, Michael Wolf, MS (Amgen), for statistical support, and Ali Hassan, PhD (Complete Healthcare Communications), whose work was funded by Amgen, and Mee Rhan Kim, PhD (Amgen), for medical writing assistance in the development of this article. Overall response rate (ORR) by key subgroups. ECOG, Eastern Cooperative Oncology Group; diff, difference; GM-CSF, granulocyte macrophage colony-stimulating factor; HSV, herpes simplex virus; PS, performance status; T-VEC, talimogene laherparepvec. (*) P < .05 per Gail and Simon18 quantitative treatment by covariate interaction test.
 argued that because STDs have a high prevalence and a history of buying or selling sex for money or drugs is common among populations of drug abusers (one-third of the population in this study), STDs should be considered by discussing triple diagnoses for drug abusers: drug dependence or addiction, mental health disorders, and STDs. (‡) Twelve patients in the GM-CSF arm and four in the T-VEC arm had an unknown ECOG status.