Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel
ABSTRACT An expanded Phase I trial was performed to assess the safety and acceptability of 6% cellulose sulfate gel (CS) in comparison with K-Y Jelly.
Sexually abstinent (cohort I) and sexually active (cohort II) women in India, Nigeria and Uganda applied 3.5 ml of either 6% CS gel or K-Y Jelly for seven consecutive days. Safety was assessed by symptoms and signs (including colposcopy) of genital irritation, review of adverse events, and by changes in vaginal health as assessed by microscopy.
One hundred and eighty women (90 on CS and 90 on K-Y Jelly) were enrolled. Baseline characteristics of women in both gel groups were similar. In cohort I, six (14%) women on CS and 12 (27%) on K-Y Jelly reported genital symptoms, two (in K-Y Jelly group) of whom withdrew from the study. New colposcopy findings or findings showing deterioration were detected in four (9%) women on CS and nine (21%) women on K-Y Jelly in cohort I. Two women on CS and three on K-Y Jelly in cohort II reported genital symptoms. Five women (11%) in each gel group in cohort II had new colposcopy findings or findings showing deterioration. The differences between the gel groups were not statistically significant. The majority of women had no problem with their assigned product.
A vaginal application of 6% cellulose sulfate twice daily for seven consecutive days is as safe and well tolerated as a similar regimen of K-Y Jelly. Further development of 6% CS for prevention of HIV and pregnancy is recommended.
- SourceAvailable from: Vanessa Pirrone
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- "Because the cervicovaginal environment is open, microbicide products can leak out over time. For example, in clinical trials involving Ushercell, compound leakage was reported by female users, and product leakage had a negative effect on product acceptability [41, 42]. In a scenario in which product leakage has sufficiently reduced the concentration of the active compound (i.e., cellulose sulfate) within the cervicovaginal environment, HIV-1 transmission may be enhanced rather than inhibited. "
ABSTRACT: An alternating copolymer of styrene and maleic acid (alt-PSMA) differs from other polyanionic antiviral agents in that the negative charges of alt-PSMA are provided by carboxylic acid groups instead of sulfate or sulfonate moieties. We hypothesized that alt-PSMA would have activity against human immunodeficiency virus type 1 (HIV-1) comparable to other polyanions, such as the related compound, poly(sodium 4-styrene sulfonate) (PSS). In assays using cell lines and primary immune cells, alt-PSMA was characterized by low cytotoxicity and effective inhibition of infection by HIV-1 BaL and IIIB as well as clinical isolates of subtypes A, B, and C. In mechanism of action assays, in which each compound was added to cells and subsequently removed prior to HIV-1 infection ("washout" assay), alt-PSMA caused no enhancement of infection, while PSS washout increased infection 70% above control levels. These studies demonstrate that alt-PSMA is an effective HIV-1 inhibitor with properties that warrant further investigation.BioMed Research International 05/2010; 2010(1110-7243):548749. DOI:10.1155/2010/548749 · 2.71 Impact Factor
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the functional envelope spike, which consists of trimers of gp120 bound to gp41. Most variants of HIV-1 enter cells through attachment of the envelope spike to the main cellular receptor CD4, allowing interaction with a co-receptor and eventually fusion of viral and cellular membranes. Neutralising antibodies inhibit HIV-1 entry by targeting epitopes on the functional spike. HIV-1 has, however, evolved several ways to evade recognition by antibodies, including variable regions, carbohydrates, and conformational masking. As a result, the neutralising antibody response in HIV-1 infection and post-immunisation is generally narrow, and only a handful of broadly neutralising monoclonal antibodies have been reported. In this thesis, the isolation and characterisation of novel, broadly neutralising antibody fragments derived from llamas is described. Llamas produce antibodies devoid of light chains, which have their antigen-binding properties confined to a single fragment, the VHH, and a preference for cleftrecognition. VHH were isolated from llamas immunised with recombinant gp120 using phage display-based methods. In order increase the chances of isolating neutralising VHH, a functional selection strategy was employed, involving a competitive elution with soluble CD4. Three VHH able to neutralise HIV-1 primary isolates of subtype B and C were characterised. These VHH bound to gp120 with high affinities and competed with soluble CD4 and antibodies to the CD4-binding site for this binding, indicating that their mechanism of neutralisation involves interacting with the functional envelope spike prior to binding to CD4. These results indicate that llama VHH can be potent HIV-1 entry inhibitors. Since VHH are stable and can be produced at a relatively low cost, they may be considered for HIV-1 microbicide development. Anti-gp120 VHH might also prove useful in defining neutralising and non-neutralising epitopes on HIV-1 envelope proteins, with implications for HIV-1 vaccine design.
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ABSTRACT: As the HIV/AIDS pandemic continues, the development of new prevention technologies is urgently needed. Microbicides, products applied to genital mucosal surfaces, are being developed to reduce the transmission of HIV during sexual intercourse. Microbicides have been designed to inhibit HIV from the time the virus enters the genital tract to any of the multiple steps in local virus replication. Preclinical research and development of microbicides has led to the advancement of many candidates into human clinical trials. This research has shown that cervicovaginal irritation is an important safety concern and needs to be evaluated carefully and early. New approaches to measuring local irritation are currently under investigation. Five broad-spectrum microbicides are now being tested in large-scale effectiveness trials to measure their effects on the reduction of HIV incidence. Next-generation candidates, based on highly active antiretroviral drugs, are currently undergoing safety studies. This paper reviews the findings from trials of these products and discusses several challenges that are encountered in the clinical development of microbicides. Although complex and resource intensive, the successful completion of ongoing studies and the initiation of efficacy trials of next-generation candidates are critical to the successful development of a microbicide.Current opinion in HIV and AIDS 12/2006; 1(6):514-9. DOI:10.1097/01.COH.0000247386.62743.b4 · 4.39 Impact Factor