Development of a protective 'barrier' which can be controlled by the receptive partner independent of time of coitus remains a key goal in HIV prevention. A gel or ring-delivered combination of active anti-HIV agents may prove more efficacious than a single agent alone. Challenges in evaluating and manufacturing new candidates must be overcome before a well tolerated, effective, acceptable and affordable microbicide can be produced.

BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.Clinical Trials RegistrationEudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679

BackgroundMonoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied.ObjectivesTo assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women.DesignA randomized, double-blind, placebo-controlled phase 1 trial.MethodsTwenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose.ResultsAfter adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious.ConclusionsVaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems.Trial RegistrationISRCTN 64808733 UK CRN Portfolio 6470

Background Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. Methods A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. Results Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). Conclusions In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

HIV PN is a highly effective diagnostic strategy. Non-completion of PN thus represents a missed opportunity to diagnose HIV in at-risk populations. Vigorous efforts should be made to pursue PN to identify people living with, and at risk of, HIV infection.

ISRCTN 42867448.

Background We describe 11 cases of refractory vulvovaginal yeast infections (RVVYI) treated using oral voriconazole with or without concomitant topical agents. Methods Retrospective case-note review of all women prescribed oral voriconazole to treat RVVYI in five Sexual Health Clinics from Jan 2010-March 2020. Demographic details, clinical features, diagnostic results and treatment outcomes were collected. Results 11 women with vulvovaginal symptoms for a median of 1 year were treated with voriconazole. RVVYI was diagnosed clinically and confirmed on microscopy and culture with speciation. 10/11 isolates were fluconazole resistant, 1 intermediately sensitive, 10/11 were either fully or intermediately sensitive to voriconazole. All had received prior fluconazole and clotrimazole and 10/11 had used at least 2-weeks of one or more second-line antifungals with non-clearance of the yeast. Oral voriconazole 400 mg BD day-1, then 200 mg BD 13-days was prescribed and 10/11 women completed the course. Concomitant topical treatment was used by 6/11. Liver and renal function were monitored at 0, 7, 14 days. One woman stopped voriconazole after 5-days due to perioral tingling. Other transient side-effects were nausea ( n = 2), photosensitivity, muscle aches, hair thinning (all n = 1), peripheral visual disturbance ( n = 2). 8/11 experienced both symptom reduction and yeast clearance. Two women had an initial partial response but experienced resolution of symptoms following a second course of voriconazole. Conclusions Our observational data adds to the limited evidence to support voriconazole treatment for RVVYI. A 2-week course of voriconazole was tolerated and completed by 10/11 women. Eight women, five using concomitant topical agents, achieved mycological cure.

The highly transmittable nature of SARS-CoV-2 has increased the necessity for novel strategies to safely decontaminate public areas. This study investigates the efficacy of a low irradiance 405-nm light environmental decontamination system for the inactivation of bacteriophage phi6 as a surrogate for SARS-CoV-2. Bacteriophage phi6 was exposed to increasing doses of low irradiance (~0.5 mW cm À2 ) 405nm light while suspended in SM buffer and artificial human saliva at low (~10 3-4 PFU mL À1 ) and high (~10 7-8 PFU mL À1 ) seeding densities, to determine system efficacy for SARS-CoV-2 inactivation and establish the influence of biologically relevant suspension media on viral susceptibility. Complete/near-complete (≥99.4%) inactivation was demonstrated in all cases, with significantly enhanced reductions observed in biologically relevant media (P < 0.05). Doses of 43.2 and 172.8 J cm À2 were required to achieve ~3 log 10 reductions at low density, and 97.2 and 259.2 J cm À2 achieved ~6 log 10 reductions at high density, in saliva and SM buffer, respectively: 2.6-4 times less dose was required when suspended in saliva compared to SM buffer. Comparative exposure to higher irradiance (~50 mW cm À2 ) 405-nm light indicated that, on a per unit dose basis, 0.5 mW cm À2 treatments were capable of achieving up to 5.8 greater log 10 reductions with up to 28-fold greater germicidal efficiency than that of 50 mW cm À2 treatments. These findings establish the efficacy of low irradiance 405-nm light systems for inactivation of a SARS-CoV-2 surrogate and demonstrate the significant enhancement in susceptibility when suspended in saliva, which is a major vector in COVID-19 transmission.