Results of a phase 1, randomized, placebo-controlled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel.

HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT's preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24-45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics.

OBJECTIVE: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. DESIGN: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. METHODS: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. RESULTS: Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. CONCLUSIONS: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Making the cut: evidence-based lessons for improving the informed consent process for voluntary medical male circumcision in Swaziland and Zambia.

The informed consent (IC) process for voluntary medical male circumcision (VMMC) was evaluated in Zambia and Swaziland as VMMC programs scaled up. In-depth interviews (IDIs) were conducted with clients 1 week after surgery to explore understanding of IC and gauge how expectations of MC surgery compared to actual experiences. In Zambia, key opinion leaders (KOLs) were also interviewed. Some clients equated written IC with releasing the clinic from liability. Most clients felt well prepared for the procedure, although many were surprised by the level of pain experienced during anesthesia and postsurgery. Clients were highly motivated to adhere to wound care, but some were overwhelmed by extensive instructions. Adolescents described barriers to accessing follow-up care and the need for support in overcoming adult gatekeepers. KOLs indicated that IC is not well understood in poorly educated communities. Results led to concrete programmatic changes, including revised patient education materials and more effective anesthesia for longer-lasting pain relief.

Sexually transmitted infections and reproductive health morbidity in a cohort of female sex workers screened for a microbicide feasibility study in Nellore, India.

UNLABELLED: Women constitute 38% of India's 2.4 million HIV-infected persons. Microbicides are potential HIV-prevention products currently undergoing clinical trials for efficacy. A four-month placebo vaginal gel trial was conducted in Nellore, India to determine the feasibility of recruiting a suitable cohort of female sex workers (FSWs) for a future vaginal microbicide efficacy trial. We report on the HIV and STI prevalence and reproductive health (RH) morbidity of FSWs screened for the trial.   RESULTS: 529 FSWs completed screening procedures; of those 33.6% were found ineligible.  The mean age was 30.9 years; 68.6% women were married and 57.5% were home-based FSWs.  Self-reported symptoms included abnormal vaginal discharge (31.6%), genital itching (3.4%), uterine mass/prolapse (3%) and painful intercourse (2.6%).  Gynecological surgery was reported by 73.2% of participants; of those 10.5% had undergone a hysterectomy. Female sterilization was the most commonly reported contraceptive method. Pelvic examination showed vaginal discharge (50.7%), cervical discharge (5.3%), uterine/vaginal wall prolapse (2.6%), and cervical mass/nodule/vesicles/genital warts (4.2%). Common epithelial findings included erythema (79.1%) and vesicles/bullae (6%); 46% of participants had Papanicolaou tests graded as inflammatory and 1.1% as malignant. HSV-2 was the mostly commonly detected STI (60.7%) followed by HIV (5.3%), syphilis (2.8%), chlamydia (2.2%), gonorrhoea (0.7%) and trichomoniasis (15.5%).  RTIs were more common: bacterial vaginosis (27.8%) and candidiasis (18.9%). CONCLUSIONS:  The low HIV prevalence and high RH morbidity in the population makes this site unsuitable for a future phase 2 or 3 microbicide efficacy trial.  HIV prevention programs targeting this population should include access to RH services.

Characteristics of female sex workers in southern India willing and unwilling to participate in a placebo gel trial.

Respondent-driven sampling was used to recruit female sex workers (FSWs) for a community survey conducted in southern India. After survey completion, participants were given a brochure describing a clinical trial that entailed daily use of a placebo vaginal gel for four months. This study assessed predictors of screening among survey respondents, predictors of enrollment among those eligible for the trial, and predictors of visit attendance and retention among those enrolled. FSWs who reported having symptoms of sexually transmitted infections (STI), engaging in sex work in the past month, and living in a subdistrict easily accessible by public transportation with a high concentration of FSWs, were more likely to screen. FSWs who had never been tested for HIV were more likely to enroll. This analysis suggests that the primary reason FSWs participated in the trial was a desire for health care-not other factors hypothesized to be important, e.g., HIV risk perception and poverty status.

Safety and acceptability of the candidate microbicide Carraguard in Thai Women: findings from a Phase II Clinical Trial.

OBJECTIVE: To determine the safety and acceptability of vaginal application of Carraguard, a carrageenan-derived candidate microbicide gel. DESIGN: A randomized, placebo-controlled, triple-blinded clinical trial was conducted in Chiang Rai, northern Thailand. METHODS: Women were asked to insert one applicator of study gel vaginally at least three times per week (with or without sex) and to use gel with condoms every time they had sex. Safety was assessed by visual inspection of the vagina and cervix, changes in vaginal flora and self-reported symptoms at day 14, month 1 and then monthly for up to 1 year. Acceptability was assessed through reported use of the gel, return of used and unused applicators, and quarterly interviews. RESULTS: One hundred sixty-five women were randomized: 83 to Carraguard and 82 to the placebo (methylcellulose gel) group. Study gel use was similarly high in both groups throughout the trial with an average of four applicators per week. Carraguard use was not associated with abnormal genital clinical findings, abnormal vaginal flora, Pap smear abnormalities or other abnormal clinical signs or symptoms. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. Participants in both groups reported high acceptability. CONCLUSIONS: Carraguard can safely be used an average of four times per week with or without sex and is acceptable to Thai women. A Phase III efficacy trial of Carraguard is warranted and is currently ongoing in South Africa.