Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel

Malonza, Isaac; Mirembe, Florence; Nakabiito, Clemensia; Odusoga, Lawrence O; Osinupebi, OA; Hazari, K.; Chitlange, Shanta; Ali, Mohamed M; Callahan, Marianne M.; Damme, Lut Van

doi:10.1097/01.aids.0000194797.59046.8f

Cited by 55 publications

(22 citation statements)

References 5 publications

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“…Initial phase I/II clinical trials of Ushercell did not reveal any life-threatening adverse events, overt toxicity, or excessive urogenital irritation caused by cellulose sulfate; [20][21][22][23][24] however, because none of these studies examined HIV infection rates, it was premature to conclude that cellulose sulfate is "safe" for use as a vaginal microbicide. Unfortunately, no in vivo efficacy testing in a suitable nonhuman primate model was conducted prior to the human trials.…”

Section: Figmentioning

confidence: 99%

Short Communication:Enhancement of HIV Infection by Cellulose Sulfate

Wang

Richards

Hamer

2008

AIDS Research and Human Retroviruses

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Cellulose sulfate, a polyanionic compound derived from cotton, has been proposed as a topical microbicide to reduce the sexual transmission of HIV. However, a phase III clinical trial of a vaginal gel formulation of cellulose sulfate (Ushercell) had to be prematurely closed after early data indicated microbicide users had a higher rate of HIV infection than women using a placebo. The unexpected results of the cellulose sulfate trail prompted us to reexamine and attempt to replicate the available preclinical data for this compound and other polyanions. We show here that cellulose sulfate has a biphasic effect on HIV infection in vitro: at high concentrations it inhibits infection but at low concentrations it significantly and reproducibly increases HIV infection. This stimulatory effect is evident for the R5-tropic strains of virus responsible for sexual transmission, reflects the rate of infection rather than viral growth, and occurs at clinically relevant concentrations of the compound. An examination of published studies shows that the biphasic effect of cellulose sulfate was evident in previous research by independent laboratories and is also found for other polyanions such as dextrin sulfate and PRO2000. These data help in understanding the failure of the Ushercell clinical trial and indicate that cellulose sulfate is not safe for mucosal application in humans. 925T HERE IS AN URGENT NEED for safe and effective topical microbicides to reduce the sexual transmission of HIV. Among the various classes of molecules proposed for this purpose, there has been particular clinical interest in sulfated polymeric anionic compounds such as cellulose sulfate (a high-molecular-weight ␤1,4-glucose polymer derived from cotton), carrageenan (a polygalactose ϩ 3,6-anhydrogalactose copolymer extracted from seaweed), dextrin sulfate (a synthetic ␣1,4-D-glucose polymer), and PRO2000 (a synthetic naphthalene sulfonate polymer). 1,2 These compounds are thought to nonspecifically inhibit HIV entry into target cells by interacting with basic regions of the viral envelope. 3 Recently, however, the concept of polyanion microbicides was dealt a major setback when the Contraceptive Research and Development Program (CONRAD) announced that they had halted a phase III clinical trial of a formulated cellulose sulfate vaginal gel (Ushercell) being conducted in South Africa, Benin, Uganda, and India because the independent data monitoring committee detected increased HIV infection rates in the women who received cellulose sulfate compared to placebo gel. 4,5 The premature closure of the cellulose sulfate phase III trial prompted us to reexamine and attempt to replicate the available preclinical data for this compound and other polyanions. The current work focuses on the question of how such compounds affect HIV infection in vitro, an essential prerequisite for human testing. Our main finding is that cellulose sulfate at concentrations that would be present in humans using Ushercell can increase infection by sexually transmitted R5-tro...

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Section: Figmentioning

confidence: 99%

Short Communication:Enhancement of HIV Infection by Cellulose Sulfate

Wang

Richards

Hamer

2008

AIDS Research and Human Retroviruses

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“…1 Several microbicide candidates looked promising during preclinical evaluation but failed in efficacy trials: nonoxynol-9 (N-9), [2][3][4][5][6][7] Carraguard, 8 BufferGel, 9 PRO 2000, 10 and cellulose sulfate (CS). [11][12][13][14][15][16][17][18][19] CS did not prevent, and, when frequently used, may have increased the risk of HIV acquisition. 20,21 N-9, also when used frequently, raised the risk of HIV infection.…”

mentioning

confidence: 94%

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

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TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

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“…However, initial clinical studies evaluating OTC spermicides as potential microbicides had mixed results [21][22][23][24] and were eventually abandoned with the disappointing results from the COL-1492 study, showing that the OTC spermicide nonoxynol-9 (N-9) could be toxic to the vaginal tissue thereby increasing the risk of HIV infection [25]. There are other candidate microbicides currently in clinical trials that might demonstrate dual protection [26][27][28][29][30]. However, none of the products are proven contraceptives.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard® gel: a new formulation for “dual protection” contraception

et al. 2007

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Objective: The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/ LNG), designed for use as microbicide and contraceptive for potential dual-protection. Materials and methods:This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on day 10-12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following seven days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples.Results: Serum LNG maximum concentrations (C max ) were 14.1 ± 5.1 and 11.7 ± 6.5 nmol/L and T max was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of C max . Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low and high dose group, respectively. Conclusion:This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75 mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dualprotection method, possibly preventing conception and sexually transmitted infections.

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Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel

Abstract: 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.

Cited by 55 publications

References 5 publications

Short Communication:Enhancement of HIV Infection by Cellulose Sulfate

Short Communication:Enhancement of HIV Infection by Cellulose Sulfate

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Pharmacokinetic study to compare the absorption and tolerability of two doses of levonorgestrel following single vaginal administration of levonorgestrel in Carraguard® gel: a new formulation for “dual protection” contraception

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