The Effectiveness of Carraguard, a Vaginal Microbicide, in Protecting Women against High-Risk Human Papillomavirus Infection

Marais, Dianne J.; Gawarecki, Daniel G.; Allan, Bruce; Ahmed, Khatija; Altini, Lydia; Cassim, Nazira; Gopolang, Felicity; Hoffman, Margaret; Ramjee, Gita; Williamson, Anna‐Lise

doi:10.3851/imp1890

Cited by 61 publications

(63 citation statements)

References 13 publications

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“…It has been shown to be safe and acceptable in numerous preclinical and clinical studies (7,19,22,(25)(26)(27)(28)(29)(30)(31)(32) despite contradictory observations using in vitro systems that CG can enhance HIV infection (22,33). Additionally, CG may have activity against HPV (34)(35)(36). Because the 14 mM ZA formulation (but not lower concentrations) afforded efficacy comparable to that of the 23 mM ZA formulation in mice (7), we advanced the 14 mM ZA/CG gel for macaque testing.…”

Section: Discussionmentioning

confidence: 99%

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

Kenney

Rodríguez

Kizima

et al. 2013

Antimicrob Agents Chemother

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We previously showed that a prototype gel comprising zinc acetate (ZA) in carrageenan (CG) protected mice against vaginal and rectal herpes simplex virus 2 (HSV-2) challenge as well as macaques against vaginal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) challenge. In this work, we modified buffers and cosolvents to obtain a stable, nearly iso-osmolal formulation and evaluated its safety and efficacy against SHIV-RT and HSV-2. In vitro toxicity to lactobacilli and Candida albicans was determined. Macaques were given daily doses of ZA and CG (ZA/CG) or CG alone vaginally for 14 days and challenged with SHIV-RT 24 h later. Mice were challenged vaginally or rectally with HSV-2 immediately after a single gel treatment to measure efficacy or vaginally 12 h after daily gel treatment for 7 days to evaluate the gel's impact on susceptibility to HSV-2 infection. The modified ZA/CG neither affected the viability of lactobacilli or C. albicans nor enhanced vaginal HSV-2 infection after daily ZA/CG treatment. Vaginal SHIV-RT infection of macaques was reduced by 66% (P ‫؍‬ 0.006) when macaques were challenged 24 h after the last dose of gel. We observed 60% to 80% uninfected mice after vaginal (P < 0.0001) and rectal (P ‫؍‬ 0.008) high-dose HSV-2 challenge. The modified ZA/CG gel is safe and effective in animal models and represents a potential candidate to limit the transmission of HIV and HSV-2. S everal recent clinical trials have shown that microbicides containing antiretroviral drugs (ARVs) reduce the sexual transmission of HIV and other sexually transmitted diseases (STIs) (1). The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial (CAPRISA-004) showed that pericoital use (before and after sex) of vaginally applied 1% tenofovir (TFV) gel reduced human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus 2 (HSV-2) acquisition by 39% and 51%, respectively (2). Similarly, three oral pre-exposure trials (iPrex, Partners PrEP, and TDF2) targeting men who have sex with men (MSM) and transgender women, HIV-serodiscordant couples, or heterosexual men and women demonstrated between 44% and 73% efficacy (1). Conversely, a lack of efficacy was seen in two trials (FEM-PrEP and VOICE) in which women received daily oral emtricitabine-TFV and TFV (1, 3). A recent analysis of these two studies suggested that the lack of efficacy could have been due to poor regimen adherence (1, 3, 4).Although ARV-containing topical microbicides will likely be available soon, there are important questions regarding their use. (i) Does topical administration of an ARV in people with an undiagnosed HIV infection lead to resistance development and affect their treatment outcomes? (ii) How accessible will these products be (i.e., will they be available over the counter or by prescription only)? (iii) Can the introduction of an HIV-specific microbicide increase the transmission of other STIs?Given these unanswered questions and the potential limitations of ARV-containing topical microbicides, we are ...

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Section: Discussionmentioning

confidence: 99%

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

Kenney

Rodríguez

Kizima

et al. 2013

Antimicrob Agents Chemother

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“…CG gels were also potent inhibitors of cervicovaginal infection in mouse and rhesus macaque models [22, 27, 28]. In a clinical trial of a CG-based microbicide primarily directed at HIV prevention, there were one-third fewer genital HPV infections detected at study exit in the most adherent subgroup of women, compared to controls [38]. Two randomized placebo controlled clinical trials evaluating a commercial CG-based product, Divine #9, as a topical microbicide to specifically prevent genital HPV infection in young women are now underway.…”

Section: Hpv Prevention Strategies: Learning From Success and Moving mentioning

confidence: 99%

Multipurpose prevention technologies: the future of HIV and STI protection

Fernández-Romero

Deal

Herold

et al. 2015

Trends in Microbiology

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Every day, more than 1 million people are newly infected with sexually transmitted infections (STIs) that can lead to morbidity, mortality, and an increased risk of human immunodeficiency virus (HIV) acquisition. Existing prevention and management strategies, including behavior change, condom promotion, and therapy have not reduced the global incidence and prevalence, pointing to the need for novel innovative strategies. This review summarizes important issues raised during a satellite session at the first HIV R4P conference, held in Cape Town, on October 31, 2014. We explore key STIs that are challenging public health today; new biomedical prevention approaches including multipurpose prevention technologies (MPTs); and the scientific and regulatory hurdles that must be overcome to make combination prevention tools a reality.

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“…It has been shown to prevent human papillomavirus (HPV) infection in mice (43), while closer analysis of a subgroup of highly adherent subjects in the Carraguard phase 3 clinical trial suggested that the carrageenan gel reduced the prevalence of HPV (34). Carrageenan-based gels have been shown to prevent significant HSV-2 infection in the HSV-2 mouse model when challenged with low viral doses of HSV-2 (30,32,53).…”

mentioning

confidence: 99%

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

Fernández-Romero

Abraham

Rodríguez

et al. 2012

Antimicrob Agents Chemother

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Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10 6 -PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.

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The Effectiveness of Carraguard, a Vaginal Microbicide, in Protecting Women against High-Risk Human Papillomavirus Infection

Abstract: The prevalence of HR-HPV infection was lower in compliant Carraguard users than compliant placebo users. To our knowledge, this is the first report showing a negative association of HPV infection with a vaginal microbicide.

Cited by 61 publications

References 13 publications

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

A Modified Zinc Acetate Gel, a Potential Nonantiretroviral Microbicide, Is Safe and Effective against Simian-Human Immunodeficiency Virus and Herpes Simplex Virus 2 Infection In Vivo

Multipurpose prevention technologies: the future of HIV and STI protection

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

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