Results of a phase 1, randomized, placebocontrolled 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

An Antiretroviral/Zinc Combination Gel Provides 24 Hours of Complete Protection against Vaginal SHIV Infection in Macaques

Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application.Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h.A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans

Music as a form of resistance: A critical analysis of the Puerto Rican new song movement\u27s oppositional discourse

This is a critical analysis of the music of the Puerto Rican new song movement placed within the cultural and political dynamics of Puerto Rican society. Its focus is the relationship between popular music and cultural politics using the music of the new song movement as a case study. The study is a discourse analysis of a sample of song texts that elucidates the elements and characteristics that define the new song\u27s discourse as an oppositional one. In addition, this study explores possible reasons why that oppositional discourse did not interpellate larger segments of the popular classes, or why it did not become a hegemonic discourse. This inquiry places the song texts in the context of the colonial relationship between Puerto Rico and the United States in order to study the sample using a combination of theoretical perspectives. The study draws from Latin American approaches to the analysis of popular culture, from Antonio Gramsci\u27s theory of hegemony and from various interpretations of Puerto Rican cultural identity. It also studies the texts\u27 articulation of a pro-independence ideology as a key aspect of its oppositional discourse. This analysis sheds light on the relationship between popular culture, cultural identity and nationalism in Puerto Rico. The discourse analysis showed that the Puerto Rican new song movement created a discourse in opposition to the dominant political, economic, military and cultural discourses articulating Puerto Rican society during the 1970\u27s and early 1980\u27s. The discourse of the new song movement was anti-capitalist, anti-colonialist, anti-militarist and advocated Puerto Rico\u27s independence. In its song texts the movement reflected its subscription to several oppositional discourses articulated by pro-independence groups in Puerto Rico. The music of the new song movement served as a form of resistance to the conditions of colonialism in Puerto Rico

Development of a vaginal fast-dissolving insert combining griffithsin and carrageenan for potential use against sexually transmitted infections

Precoital, on-demand topical microbicides to reduce a woman’s risk of sexually transmitted infections have been in development for nearly three decades, but no product has been approved due to acceptability issues and poor adherence in clinical trials. We set out to develop a self-administered vaginal fast-dissolving insert (FDI) produced by freeze-drying that would deliver safe and effective amounts of the antiviral agents griffithsin (GRFT) and carrageenan (CG) and would have properties women and their partners find acceptable. We evaluated FDI physical criteria, attributes of the gel produced upon dissolving, and GRFT stability. The lead formulation, FDI-024, was selected from 13 candidates and contains 4 mg of GRFT, 15 mg of CG, and excipients (the cryoprotectant sucrose and bulking agents dextran 40 and mannitol). The FDI exhibits good friability and hardness and is stable for at least 6 months at up to 40°C/75% relative humidity. It disintegrates in less than 60 seconds in a physiologically relevant volume (∼1 mL) of simulated vaginal fluid, forming a viscous semi-solid gel with favorable mucoadhesive and spreading properties. The formulation retains the antiviral activity of GRFT and CG against human immunodeficiency virus type 1 and human papillomavirus, respectively, in cell-based assays

Trypanocidal Activity of 8-Methyl-5′-{[(Z)-4-Aminobut-2-enyl]-(Methylamino)}Adenosine (Genz-644131), an Adenosylmethionine Decarboxylase Inhibitor ▿

Genzyme 644131, 8-methyl-5′-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine, is an analog of the enzyme activated S-adenosylmethionine decarboxylase (AdoMetDC) inhibitor and the trypanocidal agent MDL-7381, 5-{[(Z)-4-aminobut-2-enyl](methylamino)}adenosine. The analog differs from the parent in having an 8-methyl group on the purine ring that bestows favorable pharmacokinetic, biochemical, and trypanocidal activities. The compound was curative in acute Trypanosoma brucei brucei and drug-resistant Trypanosoma brucei rhodesiense model infections, with single-dose activity in the 1- to 5-mg/kg/day daily dose range for 4 days against T. brucei brucei and 25- to 50-mg/kg twice-daily dosing against T. brucei rhodesiense infections. The compound was not curative in the TREU 667 central nervous system model infection but cleared blood parasitemia and extended time to recrudescence in several groups. This study shows that AdoMetDC remains an attractive chemotherapeutic target in African trypanosomes and that chemical changes in AdoMetDC inhibitors can produce more favorable drug characteristics than the lead compound

Antiviral activity and mode of action of Griffithsin against HSV-2 and HPV: Preliminary studies of a potential non-ARV combination microbicide

Background: Griffithsin (GRFT) is a promising HIV microbicide candidate. Nixon et al. have shown that GRFT blocks herpes simplex 2 (HSV-2) infection in a mouse model, proposing inhibition of cell-to-cell spread as the mode of action (MOA). Using in vitro studies we further investigated the MOA of GRFT against HSV-2 and studied its antiviral activity against human papillomavirus (HPV). We also combined GRFT with zinc acetate (ZA) and/or carrageenan (CG) to render a more potent microbicide. Methods: We used XTT assay to define non-cytotoxic concentrations of GRFT, ZA, CG or their combinations. Assays for anti-HIV, anti-HPV and anti-HSV-2 activities were performed in TZM-bl cells or PBMCs using MAGI and p24 ELISA; in HeLa cells using a luciferase assay; and in Vero cells using plaque forming units (pfu) assay. We performed time-of-addition and temperature dependence experiments to differentiate inhibition of viral adsorption from entry. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins and immunohistochemistry was used to determine the specific glycoprotein involved. Antiviral activities of prototype GRFT/CG (GC) and GRFT/ZA/CG (GZC) gels in a vaginal HSV-2 mouse model were evaluated. Results: GRFT shows modest in vitro antiviral activity against HSV-2 G (IC_50 = 5.8μg/ml) and HPV 6, 16, 18, 45 PsVs (IC_50 = 10.8-26.3μg/ml), compared to potent anti-HIV activity (IC_50 = 0.7-1.4ng/ml). As with HIV, GRFT blocks the entry but not the adsorption of HSV-2 and HPV to target cells. The combined analyses of SPR and immunohistochemistry for HSV-2 gD, suggest that GRFT binds to HSV-2 gD. GC and GZ had synergistic in vitro antiviral activity against HIV and HPV (CI \u3c 1). GC and GZC gels significantly reduced (p \u3c 0.05) HSV-2 vaginal infection in vivo when administered up to 2h before challenge with 10^6pfu/mouse. Conclusions: GRFT blocks HSV-2 and HPV entry to target cells and combination with CG and/or ZA may result in a potent/broad-spectrum non-ARV microbicide

Recruiting hard-to-reach populations via respondent driven sampling for mobile phone surveys in Colombia: a qualitative study

Background Uptake of mobile phone surveys (MPS) is increasing in many low- and middle-income countries, particularly within the context of data collection on non-communicable diseases (NCDs) behavioural risk factors. One barrier to collecting representative data through MPS is capturing data from older participants. Respondent driven sampling (RDS) consists of chain-referral strategies where existing study subjects recruit follow-up participants purposively based on predefined eligibility criteria. Adapting RDS strategies to MPS efforts could, theoretically, yield higher rates of participation for that age group. Objective To investigate factors that influence the perceived acceptability of a RDS recruitment method for MPS involving people over 45 years of age living in Colombia. Methods An MPS recruitment strategy deploying RDS techniques was piloted to increase participation of older populations. We conducted a qualitative study that drew from surveys with open and closed-ended items, semi-structured interviews for feedback, and focus group discussions to explore perceptions of the strategy and barriers to its application amongst MPS participants. Results The strategy’s success is affected by factors such as cultural adaptation, institutional credibility and public trust, data protection, and challenges with mobile phone technology. These factors are relevant to individuals’ willingness to facilitate RDS efforts targeting hard-to-reach people. Recruitment strategies are valuable in part because hard-to-reach populations are often most accessible through their contacts within their social network who can serve as trust liaisons and drive engagement. Conclusions These findings may inform future studies where similar interventions are being considered to improve access to mobile phone-based data collection amongst hard-to-reach groups

Knowledge, attitudes, and practices about COVID-19 in Argentina: A cross-sectional study

Nuestro objetivo fue evidenciar el nivel de conocimientos, actitudes y prácticas frente al COVID-19. Fueron encuestados 3774 individuos mayores de 16 años entre el 18/09/20 y el 16/10/20. El 80% residía en la ciudad de Buenos Aires o la Provincia de Buenos Aires. El 58% había completado estudio terciario. El 72% tenía actividad laboral independiente o en relación de dependencia pública o privada. Utilizaban el sistema de salud prepago el 51%, obra social laboral el 34%, y sistema público de salud cerca del 10%. De acuerdo a las variables socio-demográficas analizadas, la mayoría de la población fue representativa de la clase media. Del total de encuestados, el 7% tuvo diagnóstico de COVID-19. Observamos un alto nivel de conocimiento de la enfermedad, con 80 a 90% de respuestas correctas. En relación a las medidas adoptadas por las autoridades, los juicios emitidos variaron entre “correctas”, “insuficientes”, “perjudiciales”, “innecesarias”, etc. El 44% se sentía protegido por el sistema de salud. En cuanto a los referentes válidos para transmitir información, la respuesta preponderante fue el personal médico. En cuanto al momento deconsultar por síntomas, un porcentaje importante (28%) lo haría en forma tardía. Observamos un alto grado de cumplimiento de las medidas de protección, a excepción del ítem “Asistencia a reuniones” (50%). Los resultados de estos estudios contribuyen a establecer estrategias comunicacionales para la prevención y el control de la enfermedad y de ese modo enfrentar de forma más eficiente eventuales rebrotes de la enfermedad.Our objective was to assess levels of knowledge, attitudes, and practices against COVID-19. A total of 3774 persons were surveyed between September 18 and October 16, 2020. Eighty% resided in Buenos Aires City or Buenos Aires Province: 58% had completed tertiary education; 72% worked either independently or as employees in the public or the private sector; 51% used a prepaid health care plan, 34% were covered by a trade union-based health system, and near 10% used the public health services. According to the socio-demographic variables analyzed, the population studied was representative of the middle class. A total of 7% had been diagnosed with COVID-19. There was a high level of knowledge about the disease, judging by the high proportion of correct answers (80-90%). Regarding the measures taken by the government, the answers varied widely (“correct”, “inadequate”, “harmful”, “unnecessary”, etc.). The medical staff was the preferred source of information; 44% of respondents felt protected by their health system; 28% would only seek healthcare when feeling very sick. There was a high degree of compliance with most protection measures, except for attendance to social events in poorly ventilated spaces (50%). The results of these studies contribute to establishing communication strategies for the prevention and control of COVID-19 and thus deal more efficiently with eventual outbreaks of the disease.Fil: Beltran, Marcelo Javier. Sociedad Argentina Interdiciplinaria de Sida; ArgentinaFil: Basombrío, Adriana M.. Sociedad Argentina Interdiciplinaria de Sida; ArgentinaFil: Gagliolo, Agostina Aixa. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Leroux, Claudia I.. Sociedad Argentina Interdiciplinaria de Sida; ArgentinaFil: Masso, Marcela Fabiana. Sociedad Argentina Interdiciplinaria de Sida; ArgentinaFil: Quarracino, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tablado Rodríguez, Maria Sol. Sociedad Argentina Interdiciplinaria de Sida; ArgentinaFil: Cesanelli, Violette. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Ciencias Antropológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodriguez, Enrique. Sociedad Argentina Interdiciplinaria de Sida; Argentin