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Introduction Some direct-acting antiviral regimens for hepatitis C virus (HCV) infection pose safety or efficacy concerns if coadministered with drugs containing ethinyl estradiol. The present analysis was conducted to examine the impact of concomitant oral contraceptive pills (OCP) or hormone replacement therapy (HRT) during treatment with elbasvir (EBR)/grazoprevir (GZR) in women with HCV genotype (GT)1 or GT4 infection. Methods This is a post hoc, integrated retrospective analysis of female participants with HCV GT1 or GT4 infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks in phase 2/3 clinical trials. The primary end point was sustained virologic response at 12 weeks after therapy completion (SVR12). For this analysis, participants were stratified according to whether they received OCP or HRT during the original treatment study. Results A total of 1,022 women with HCV GT1 or GT4 infection were included (receiving OCP/HRT, n=81; not receiving OCP/HRT, n=941). Most participants receiving OCP/HRT were treatment-naive (79%), noncirrhotic (91.4%), and aged >35 years (71.6%). SVR12 rates were similar in women receiving OCP/HRT and those not receiving OCP/HRT (95.1% vs 96.3%). SVR12 rates remained high across all subgroups within the population receiving OCP/HRT: SVR12 rates were 94.6%, 100%, and 100% in participants with GT1a, GT1b, and GT4 infection, and all women aged 18-35 years achieved SVR (21/21). Treatment-related adverse events occurred in 40.7% (33/81) and 30.1% (283/941) of women receiving and those not receiving OCP/HRT, respectively. Conclusion The efficacy and safety of EBR/GZR administered for 12 weeks was similar in women receiving OCP/HRT and those not on OCP/HRT. These data indicate that EBR/GZR can be safely used for the treatment of HCV GT1 or GT4 infection in women receiving concomitant OCP/HRT.

Background Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), −002 (NCT01704287), and −006 (NCT01866319). Methods Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. Results 1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11–29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7–2.8), with median overall survival (OS) of 11.3 months (7.7–16.6). ORR was 22% (95% CI 11–35%) and 15% (95% CI 5–32%) in ipilimumab-naive and ipilimumab-treated patients. Conclusion Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.

Elevated progesterone levels on the day of trigger negatively impact the outcome of assisted reproductive technique (ART) treatment and forced ovarian stimulation might be a cause of progesterone elevation during ovarian stimulation. To analyze the impact of forced and prolonged stimulation on the progesterone elevation, this data analysis from the Ensure study compared hormonal stimulation with corifollitropin alpha (CFA)-only with CFA plus recombinant (rec) follicle-stimulating hormone (FSH) after day 8 (CFA-plus group) of ovarian stimulation. In the Ensure study, 268 patients underwent ovarian stimulation with 100 µg CFA and 128 patients with recombinant FSH. A total of 35 patients (13.1%) from the CFA-arm received the hCG trigger after stimulation with CFA-only, 233 patients (86.9%) needed additional rec FSH from day 8 onwards to meet the criteria for trigger. Progesterone levels0.8 ng/ml on the trigger day occurred in 90 patients (38.6%) from the CFA plus FSH group and only in one patient (2.8%) in the CFA-only group (p .001). The ongoing pregnancy rate (OPR) was 31.4% (11/35) for patients in the CFA-only group and 24.5% (57/233) for patients CFA-plus group with additional recFSH after day 8 (p = .378). This set of data demonstrates that prolongation of stimulation in combination with intense stimulation leads to a statistically significant increased incidence of progesterone elevation on the day of trigger.摘要 诱发当天孕酮水平升高对辅助生殖技术（ART）的结果产生负面影响, 强的卵巢刺激可能是卵巢刺激过程中孕酮过早升高的原因。为了分析强的和长时间刺激对孕酮升高的影响, 来自Ensure研究的数据对卵巢刺激第8天后单用卵泡刺激素a进行刺激（CFA组）、与用CFA+重组（rec）卵泡刺激素（FSH）进行激素刺激（ CFA-plus组）进行了分析比较。在Ensure研究中, 268名患者接受了100μg CFA的卵巢刺激, 128名患者接受了重组FSH的卵巢刺激。来自CFA组的总共35名患者（13.1％）在单用CFA刺激后接受hCG诱发, 233名患者（86.9％）从第8天开始需要额外的rec FSH以满足诱发标准。CFA-plus组的90名患者（38.6％）和CFA组中仅一名患者（2.8％）出现了诱发日的孕酮水平0.8 ng/ml（p.001）。CFA组的持续妊娠率（OPR）为31.4％（11/35）, 在第8天后增加rec FSH的CFA-plus组的持续妊娠率（OPR）为24.5％（57/233）（p = .378）。这组数据表明, 刺激时间延长与强烈刺激相结合, 导致触发当天孕酮升高的发生率显著增加, 具有统计学意义。.

Diabetes mellitus and hyperglycemia are associated with increased susceptibility to bacterial infections and poor treatment outcomes. This post hoc evaluation of the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) aimed to evaluate baseline characteristics, efficacy, and safety in patients with and without diabetes treated with ceftolozane/tazobactam and comparators. Ceftolozane/tazobactam is an antibacterial with potent activity against Gram-negative pathogens and is approved for the treatment of cIAI (with metronidazole) and cUTI (including pyelonephritis). Patients from the phase 3 ASPECT studies with (n = 245) and without (n = 1802) diabetes were compared to evaluate the baseline characteristics, efficacy, and safety of ceftolozane/tazobactam and active comparators. Significantly more patients with than without diabetes were 65 years of age or older; patients with diabetes were also more likely to weigh ≥75 kg at baseline (57.1% vs 44.5%), to have renal impairment (48.5% vs 30.2%), or to have APACHE II scores ≥10 (33.8% vs 17.0%). More patients with diabetes had comorbidities and an increased incidence of complicating factors in both cIAI and cUTI. Clinical cIAI and composite cure cUTI rates across study treatments were lower in patients with than without diabetes (cIAI, 75.4% vs 86.1%, P = 0.0196; cUTI, 62.4% vs 74.7%, P = 0.1299) but were generally similar between the ceftolozane/tazobactam and active comparator treatment groups. However, significantly higher composite cure rates were reported with ceftolozane/tazobactam than with levofloxacin in patients without diabetes with cUTI (79.5% vs 69.9%; P = 0.0048). Significantly higher rates of adverse events observed in patients with diabetes were likely due to comorbidities because treatment-related adverse events were similar between groups. In this post hoc analysis, patients with diabetes in general were older, heavier, and had a greater number of complicating comorbidities. Patients with diabetes had lower cure rates and a significantly higher frequency of adverse events than patients without diabetes, likely because of the higher rates of medical complications in this subgroup. Ceftolozane/tazobactam was shown to be at least as effective as comparators in treating cUTI and cIAI in this population. cIAI, NCT01445665 and NCT01445678 (both trials registered prospectively on September 26, 2011); cUTI, NCT01345929 and NCT01345955 (both trials registered prospectively on April 28, 2011).

Ceftolozane/tazobactam is approved for treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) with renal function-based dose adjustment. Given that creatinine clearance, body weight and sex are highly correlated in severely/morbidly obese patients, this study investigated whether approved dosing regimens for ceftolozane/tazobactam are appropriate in severely/morbidly obese patients based on simulated pharmacokinetic/pharmacodynamic target attainment, with confirmation from observed clinical outcomes data from the phase 3 clinical development programme. Using a previously published population pharmacokinetic model, 1000 patients were randomly sampled from an internal pooled database of 201 severely/morbidly obese patients (BMI ≥ 35 kg/m2) and were used for Monte Carlo simulation to test whether the labelled dose regimens can achieve ≥90% probability of a target of 32.2% (1-log kill) time above free ceftolozane concentration against pathogens at an MIC up to 8 mg/L. Clinical outcomes data for severely/morbidly obese patients with cIAI or cUTI from pivotal phase 3 studies were summarised to calculate clinical and composite cure rates as a complimentary support. With the approved renal function-based dosing regimens, >90% target attainment of bactericidal activity was achieved at MICs up to 8 mg/L in the simulated severely/morbidly obese patients with cIAI or cUTI, similar to target attainment in non-obese patients and further confirmed by phase 3 outcomes where cure rates in severely/morbidly obese patients and non-obese patients are similar. Approved dosing regimens of ceftolozane/tazobactam, adjusted according to renal function, can achieve adequate target attainment and high clinical cure rates in severely/morbidly obese patients with cIAI or cUTI.

Interferon alfa has been used to treat chronic hepatitis C virus (HCV) infection since the early 1990s and remains the backbone of many treatment regimens involving HCV protease inhibitors [1–3]. Interferon alfa, however, has many side effects, including cytopenias [1]. When patients are treated with one of the long-acting, pegylated formulations of interferon, pegylated interferon (peg-IFN) alfa-2a, or peg-IFN alfa-2b, in combination with ribavirin (RBV) for up to 48 weeks, the incidence of severe neutropenia, defined as an absolute neutrophil count (ANC) of 3000) and the breadth of data collected, the Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study provides a unique opportunity to evaluate the incidence of and risk factors associated with acute infections among patients receiving HCV treatment with peg-IFN/RBV, with an emphasis on understanding the relationship between treatment-induced cytopenias and infection [15].

Background: 76 academic and 42 community-based US centers participated in the IDEAL study, providing an opportunity to evaluate various metrics of quality and site performance in this large multicenter study. Methods: 3070 treatment-naive, HCV genotype 1 infected patients received peg interferon (PEG) alfa-2b 1.5 or 1 µg/kg/wk plus ribavirin (RBV) 800-1400 mg/d or PEG alfa-2a 180 µg/wk plus RBV 1000-1200 mg/d for up to 48 weeks. We retrospectively evaluated rates of screen failure, completion, and discontinuation of treatment and follow-up, treatment adherence, and virologic response by site type. Results: Of 4469 subjects screened, 63% and 37% were in academic and community centers, respectively. Screen failure rates were similar (30-32%). Of the 1905 (62%) and 1165 (38%) patients treated in academic and community centers, respectively, baseline characteristics were comparable, except more African Americans (21% vs 15%) were treated at academic centers, and more Hispanics were treated at community centers (10% vs 5%) (Table). End-of-treatment (EOT) response, relapse, and sustained virologic response (SVR) rates in academic and community centers did not differ. 9% of patients in academic and 12% in community centers achieved rapid virologic response (undetectable HCV RNA at week 4); 39% and 42% achieved complete early virologic response (undetectable HCV RNA at week 12). Adherence to ≥80% of PEG and RBV dosing for ≥80% assigned duration was also similar (46% in academic and 47% in community centers). 54% of patients in both academic and community centers completed treatment; there were similar discontinuation rates for treatment failure and adverse events. Conclusions: No differences in adherence, incidence of adverse events, rates of discontinuation, on-treatment virologic response, and SVR were found when comparing academic and community sites. This large trial further supports that outcomes for patients are largely similar when comparing academic versus community based treatment for chronic hepatitis C.

Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results: One hundred eighteen subjects were randomized. Virologic failure (

OBJECTIVE The primary objectives of this study were to evaluate the safety, tolerability, and antiviral activity of pegylated interferon-alpha (PegIntron) in HIV-1 treatment-experienced patients failing their current antiretroviral regimen. DESIGN This was a phase II, multicenter, randomized, double-blind, placebo-controlled study. METHODS Patients were randomized to receive either weekly subcutaneous PegIntron 0.5, 1.0, 1.5, or 3 microg/kg or placebo added to their failing antiretroviral regimen for the first 4 weeks of study. Individuals who achieved more than 0.5 log10 reduction in HIV RNA at week 4 were allowed to continue study medication with optimization of their antiretroviral therapy for an additional 24 weeks. RESULTS In the 259 patients included in the intent-to-treat analysis, changes in plasma HIV RNA from baseline to week 4 were -0.25 (P > 0.5), -0.46 (P = 0.024), -0.39 (P = 0.008), -0.53 (P 0.5) log10 copies/ml in the 0.5, 1.0, 1.5, and 3.0 microg/kg and placebo arms, respectively. No significant changes were seen in CD4 T-cell parameters in any of the treatment or control arms. Adverse events (most commonly fever, flu-like symptoms, other constitutional symptoms, and psychiatric symptoms) resulted in discontinuation of study medication in 13, 17, 16, 28, and 2% of patients in the 0.5, 1.0, 1.5, 3.0 microg/kg, and placebo group, respectively. CONCLUSION The demonstration of significant antiviral activity in a heavily pretreated patient population with acceptable toxicity and only weekly dosing makes PegIntron a potentially valuable therapy for patients with HIV infection that warrants further investigation in a broader population of patients.

Background. Vicriviroc (VCV) is a CCR5 antagonist with nanomolar activity against human immunodeficiency virus (HIV) replication in vitro and in vivo. We report the results of a phase II dose-finding study of VCV plus dual nucleoside reverse-transcriptase inhibitors (NRTIs) in the treatment-naive HIV-1‐infected subjects. Methods. This study was a randomized, double-blind, placebo-controlled trial that began with a 14-day comparisonof3dosagesofVCVwithplacebointreatment-naivesubjectsinfectedwithCCR5-usingHIV-1.After14days of monotherapy, lamivudine/zidovudine was added to the VCV arms; subjects receiving placebo were treated with efavirenz and lamivudine/zidovudine; the planned treatment duration was 48 weeks. Results. Ninety-two subjects enrolled. After 14 days of once-daily monotherapy, the mean viral loads decreased frombaselinevaluesby0.07log10copies/mLintheplaceboarm,0.93log10copies/mLintheVCV25mgarm,1.18log10 copies/mL in the VCV 50 mg arm, and 1.34 log10 copies/mL in the VCV 75 mg arm (P .001 foreach VCV arm vs. the placebo arm). The combination-therapy portion of the study was stopped because of increased rates of virologic failureintheVCV25mg/dayarm(relativehazard[RH],21.6;95%confidenceinterval[CI],2.8‐168.9)andtheVCV 50 mg/day arm (RH, 11.7; 95% CI, 1.5‐92.9), compared with that in the control arm. Conclusions. VCV administered with dual NRTIs in treatment-naive subjects with HIV-1 infection had increased rates of virologic failure, compared with efavirenz plus dual NRTIs. No treatment-limiting toxicity was observed. Study of higher doses of VCV as part of combination therapy is warranted. Increasing rates of resistance, long-term metabolic and end-organ toxicities are driving factors in the develop

AIM: To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). METHODS: Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.

Background We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with boceprevir treatment failure. Methods Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥10,000 IU/mL) Results The high SVR rate in patients who received boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6–14 months following cessation of boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders. Conclusions We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response.