Objective To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels.Design Meta-analysis.Studies reviewed Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke).

SPL7013 Gel (VivaGel®) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before coitus.Trial RegistrationThe study is registered at ClinicalTrials.gov under identifier: NCT00740584

Objectives The study was designed to assess the safety, adherence, acceptability, and effect on vaginal microflora of 3% SPL7013 Gel (VivaGel®), a novel dendrimer topical microbicide that inhibits HIV, HSV-2 and HPV in vitro and in animal models. Design Phase 1, randomized, double-blind, placebo-controlled study in sexually active women. Methods Sixty-one sexually active women aged 18–24 years were recruited from three sites in the United States. Participants were randomized 1:1:1 to receive VivaGel, VivaGel placebo, or a hydroxyethylcellulose (HEC) placebo twice daily for 14 consecutive days. Safety endpoints included genitourinary and/or other adverse events (AE). Changes in vaginal flora were determined from Gram-stained vaginal smears and quantitative vaginal culture. Results No serious AEs or withdrawals due to AEs were reported. Genitourinary symptoms were reported as follows: VivaGel (n=17/22; 77.3%), VivaGel placebo (n=14/21; 66.7%) and HEC (n=8/18; 44.4%) (NS, p=0.1). The incidence of abnormal pelvic exam findings was similar across all gel arms of the study. Using pair-wise comparison, women in the VivaGel arm had a significantly higher incidence of related genitourinary AEs compared with women in the HEC gel arm (0.297 versus 0.111 per 100 person years, respectively; p=0.003). Exposure to VivaGel and VivaGel placebo resulted in minor shifts in the vaginal microflora but there was no overall impact on incidence of bacterial vaginosis as assessed by Nugent score. Conclusions VivaGel was generally well tolerated and comparable with the VivaGel placebo, although there was a higher incidence of low grade related genital AEs compared to the HEC placebo gel.

SPL7013 Gel applied vaginally once daily for 7 days at concentrations of 0.5% to 3% was safe and well tolerated in healthy, sexually abstinent women, with no evidence of systemic toxicity or absorption.

Background Astodrimer Gel contains a novel dendrimer intended to treat and prevent bacterial vaginosis. We assessed the efficacy and safety of Astodrimer Gel for treatment of bacterial vaginosis. Methods 132 women with bacterial vaginosis were randomized 1:1:1:1 to Astodrimer 0.5% (N = 34), 1% (N = 33), or 3% (N = 32) Gel or hydroxyethyl cellulose placebo gel (N = 33) at a dose of 5 g vaginally once daily for 7 days at 6 centers in the United States. The primary endpoint was clinical cure (no bacterial vaginosis vaginal discharge and no more than one of 1) vaginal pH �4.5; 2) �20% clue cells; or 3) positive whiff test) at study days 21-30. Secondary analyses included clinical cure at study days 9-12, patient-reported symptoms, acceptability and adverse events. Results The Astodrimer 1% Gel dose was superior to placebo for the primary and selected secondary efficacy measures in the modified intent-to-treat population. Clinical cure rates at day 9-12 were superior to placebo for the Astodrimer 3%, 1% and 0.5% Gel groups (62.5% [15/ 24; P = .002], 74.1% [20/27; P < .001], and 55.2% [16/29; P = .001], respectively, vs. 22.2% [6/27]). At day 21-30, clinical cure rates were 46.2% (12/26) for the 1% dose vs. 11.5% for placebo (3/26; P = .006). A greater proportion of patients reported absence of vaginal discharge and vaginal odor at day 9-12 and day 21-30 for Astodrimer Gel groups compared with placebo. Adverse events considered potentially treatment-related occurred in only 25% of Astodrimer Gel-treated patients vs. 22% of placebo patients.

ObjectiveTo assess the safety of VivaGel® used vaginally twice daily for 14 days among healthy, sexually-abstinent women, aged 18–24 years in the USA and Kenya.DesignRandomized placebo controlled trial.MethodsParticipants were randomized 2∶1, VivaGel to placebo. Safety was assessed by comparing genitourinary (GU) adverse events (AEs), colposcopy findings, vaginal lactobacilli and laboratory abnormalities by arm.ResultsFifty-four women were enrolled; 35 in the VivaGel arm and 19 in the placebo arm. Twenty-six (74%) and 10 (53%) women reported taking all doses of VivaGel and placebo, respectively. No grade 3 or 4 AEs, or serious AEs occurred. Twenty-five (71%) participants in the VivaGel arm compared to 10 (53%) participants in the placebo arm had at least one grade 1 or 2 GU AE associated with product use (RR = 1.4, 95% CI 0.8-2.2). All seven grade 2 GU AEs associated with product use occurred among four women in the VivaGel arm. Vulvar and cervical erythema, cervical lesions, symptomatic BV, urinary frequency and metrorrhagia were more common in the VivaGel arm than the placebo arm. Twenty-nine (83%) participants in the VivaGel arm had a colposcopic finding compared to 10 (53%) participants in the placebo arm (RR = 1.6, 95%CI = 1.0-2.5). Two women in the VivaGel arm prematurely discontinued product use themselves due to a reported GU AE. Persistence of H2O2-producing and non-producing lactobacilli did not differ by study arm.ConclusionsGU AEs and colposcopic findings consistent with mild epithelial irritation and inflammation occurred more commonly among women in the VivaGel arm.Trial RegistrationClinicalTrials.gov NCT003311032

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Objectives To determine the safety of the candidate vaginal microbicide SPL7013 Gel (VivaGel®) when applied to the penis. Methods A randomized, double blind, placebo controlled study. Thirty-six healthy men (18 circumcised, 18 uncircumcised), were randomized in a 2:1 ratio and treated with 3% SPL7013 Gel (N=24) or placebo gel (N=12), applied once daily for 7 days. Genital toxicity was determined by interview, diary, and examination. Results There were 10 genital adverse events (AEs) in 6 men (25%) receiving SPL7013 Gel, and 5 genital AEs in 4 men (33%) receiving the placebo that were possibly or probably related to the study product (difference of −8%, 95% CI: −40% to 23%, p=0.70). The most common genital AEs were genital pruritus and application site erythema. All genital AEs were mild (grade 1), and all but one, in the placebo group, were transient. Analysis of vital signs, non-genital AEs, and laboratory results indicated no safety or tolerability issues with SPL7013 Gel, irrespective of circumcision status. There was no detectable absorption of SPL7013 into the plasma. Conclusions 3% SPL7013 Gel was safe and well tolerated, and comparable with placebo, when administered to the penis of both circumcised and uncircumcised men once daily for 7 days, with no evidence of systemic absorption or toxicity.