Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial

Skoler-Karpoff, Stephanie; Ramjee, Gita; Ahmed, Khatija; Altini, Lydia; Plagianos, Marlena; Friedland, Barbara; Govender, Sumen; Kock, A. De; Cassim, Nazira; Palanee, Thesla; Dozier, Gregory; Maguire, Robin A.; Lähteenmäki, Pekka

doi:10.1016/s0140-6736(08)61842-5

Cited by 455 publications

(370 citation statements)

References 32 publications

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“…Our experimental approach for testing these six inhibitors was a single dose of the product administered prior to exposure rather than the two doses of drug administered within 24 h as used in CAPRISA 004 (1). This experimental design is based on the more standard single-dose administration prior to exposure (19,23,29,35,44,47). This approach is simpler, more cost-effective than multiple applications per sexual encounter and has been postulated to help increase adherence among women (51).…”

Section: Resultsmentioning

confidence: 99%

“…each sexual encounter" protocol has been the most common microbicide application protocol applied in clinical trials and animal model studies (19,23,29,35,38,44,47,50,52). The six additional candidate microbicides that we tested using this experimental design represent a broad spectrum of inhibitors with distinct mechanisms capable of blocking HIV infection at several different steps of the viral replication cycle from preentry to postbudding (Table 1).…”

Section: Vol 85 2011 One Percent Tenofovir Limits Vaginal Hiv Transmentioning

confidence: 99%

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One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Denton

Othieno

Martinez-Torres

et al. 2011

J Virol

130

150

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Section: Resultsmentioning

confidence: 99%

Section: Vol 85 2011 One Percent Tenofovir Limits Vaginal Hiv Transmentioning

confidence: 99%

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Denton

Othieno

Martinez-Torres

et al. 2011

J Virol

130

150

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show abstract

“…Unfortunately, the outcomes of those trials were for the most part unfavorable. A large scale trial of the anionic polymer Carraguard suggested that this compound provided no protection against HIV acquisition when used as a vaginal microbicide (17). Worse yet, the results of a phase III clinical trial with another anionic polymer, cellulose sulfate, showed that women who received the compound had a higher rate of HIV acquisition relative to the placebo arm (18).…”

Section: Discussionmentioning

confidence: 99%

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

Roan

Sowinski

Münch

et al. 2010

Journal of Biological Chemistry

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In semen, proteolytic peptide fragments from prostatic acid phosphatase can form amyloid fibrils termed SEVI (semen-derived enhancer of viral infection). These fibrils greatly enhance human immunodeficiency virus (HIV) infectivity by increasing the attachment of virions to target cells. Therefore, SEVI may have a significant impact on whether HIV is successfully transmitted during sexual contact. Here, we demonstrate that surfen, a small molecule heparan sulfate proteoglycan antagonist, inhibits both SEVI-and semen-mediated enhancement of HIV type 1 infection. Surfen interferes with the binding of SEVI to both target cells and HIV type 1 virions but does not deaggregate SEVI fibrils. Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency. HIV2 is primarily a sexually transmitted disease. Worldwide, estimates suggest that the majority of all HIV infections are acquired through sexual contact. This includes sexual transmission from male to female, from male to male, and from female to male. In all these routes of infection, semen is either the vehicle carrying HIV (in the case of male-to-female and male-to-male transmission) or is often present during the infection process (in the case of female-to-male transmission).Recently, semen has been reported to enhance HIV infection (1). Fractionation of semen from healthy donors led to the identification of a factor that can enhance HIV infection up to 10 5 -fold in cell culture when viral inocula are limiting. This factor, termed SEVI (semen-derived enhancer of viral infection), corresponds to amyloid fibrils composed of internal 34 -40 amino acid proteolytic fragments from prostatic acid phosphatase (PAP), a protein present at a concentration of ϳ1-2 mg/ml in semen (1, 2). The predominant peptide fragment, PAP-(248 -286), has eight basic residues, rendering it very cationic (isoelectric point ϭ 10.21). The positively charged SEVI fibrils bind to both target cells and HIV virions and augment infection by increasing physical contact between these two components (1, 3), much in the same way that synthetic cationic polymers promote retrovirus attachment to target cells (4).Although we demonstrated that the cationic nature of SEVI is important for its pro-attachment effects (3), the surface components of target cells that interact with SEVI remained unknown. We previously observed that anionic polymers, such as heparin sulfate, interfere with the binding of SEVI to target cells (3). This led us to hypothesize that the fibrils may bind target cells by interacting with cell-surface heparan sulfate proteoglycans (HSPG), naturally occurring anionic carbohydrate polymers that are closely related in structure to heparin sulfate.We therefore sought to examine whether antagonists of HSPG might inhibit the viral enhancing activity of SEVI. Bis-2-methyl-4-amino-quinolyl-6-carbamide (surfen), a recently identified small molecule antagonist of H...

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“…However, microbicides could also increase the risk of HIV infection by inducing the production of proinflammatory cytokines, causing cell injury with release of prepackaged proinflammatory factors, interfering with host defenses, recruiting and activating target cells, and/or otherwise changing the genital environment. 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.…”

mentioning

confidence: 99%

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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Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial

Cited by 455 publications

References 32 publications

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

Aminoquinoline Surfen Inhibits the Action of SEVI (Semen-derived Enhancer of Viral Infection)

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

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