Pharmacokinetics and Pharmacodynamics of Tenofovir Reduced-Glycerin 1% Gel in the Rectal and Vaginal Compartments in Women: A Cross-Compartmental Study With Directly Observed Dosing

Justman, Jessica; Nair, Gonasagrie; Hendrix, Craig W.; Piper, Jeanna; Marzinke, Mark A.; Pan, Zhenyu; Galaska, Beth; Levy, Lisa; Schwartz, Jill L.; Balar, Bhavna; Ayudhya, Ratiya Pamela Kunjara Na; Mushamiri, Ivy; McGowan, Ian; Dezzutti, Charlene S.; Team, Mtn Study

doi:10.1097/qai.0000000000001655

Cited by 11 publications

(5 citation statements)

References 33 publications

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“…A single product that protects both the (neo)vagina and rectum after dosing in only one mucosal location remains a challenge for topical agents, in contrast to systemically dosed FTC/TDF PrEP. Tenofovir poorly penetrates from rectum to vagina and vice versa; however, FTC and maraviroc dosed via an intravaginal ring achieve rectal fluid concentrations in the range of the in vitro IC 90 , indicating potential for dual-compartment protection for some drugs (43)(44)(45). A simpler development approach, although more complex in clinical use, would be a product that could be applied in whichever sexual compartment is at risk.…”

Section: Rectal Microbicide Formulations In Developmentmentioning

confidence: 99%

Topical Microbicides in HIV Prevention: State of the Promise

2020

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HIV topical microbicides are products with anti-HIV activity, generally incorporating a direct-acting antiretroviral agent, that when applied to the vagina or rectum have the potential to prevent the sexual acquisition of HIV in women and men. Topical microbicides may meet the prevention needs of individuals and groups for whom oral daily forms of pre-exposure prophylaxis (PrEP) have not been acceptable. Microbicides can provide personal control over HIV prevention and offer the possibility of discreet use, qualities that may be particularly important for receptive partners in sexual relationships such as women and transgender women and men, who together account for the clear majority of new HIV infections worldwide. Although the promise of such a product emerged nearly three decades ago, proof of concept has been demonstrated only within the last decade. A robust pipeline of microbicidal gels, films, inserts, and rings has been evaluated in multiple studies among at-risk women and men, and refinement of products for ease of use, reversibility, and high safety is the priority for the field.

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Section: Rectal Microbicide Formulations In Developmentmentioning

confidence: 99%

Topical Microbicides in HIV Prevention: State of the Promise

2020

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“…Daily vaginal dosing of the TFV 1% gel achieved very low TFV-DP concentrations in rectal tissue, detectable in only 15% of women (27 fmol/mg lower limit of quantification), indicating concentrations well below simultaneous vaginal tissue concentrations (166 fmol/mg). 78 These rectal tissue concentrations after vaginal dosing predict very low, if any, protection from RAI for women using these vaginal products.…”

Section: Vaginal Product Underperformancementioning

confidence: 93%

“…Participants were not so enamored of the rectal gel applicator, borrowed from the vaginal development program, and consensus among investigators was that applicator dosing would not be acceptable in extended RCTs . MTN‐014 demonstrated poor penetration of TFV into vaginal tissue after rectal RGVF dosing, indicating a future TFV rectal product applied rectally would not likely perform well protecting vaginal HIV infection …”

Section: Last and Next Generation Tfv Microbicide Developmentmentioning

confidence: 99%

“…41,100 MTN-014 demonstrated poor penetration of TFV into vaginal tissue after rectal RGVF dosing, indicating a future TFV rectal product applied rectally would not likely perform well protecting vaginal HIV infection. 78 In parallel with the RGVF studies and out of concern for hyperosmolar toxicity, interest grew in an iso-osmolar rectal optimized gel. A head-to-head clinical study of four different iso-osmolar nonmedicated rectal semisolid and liquid vehicles, developed by Wang et al, indicated a clearly superior formulation based on high levels of acceptability, including use during anal sex at home, GI distribution, safety, and ex vivo explant protection even without adding an ARV.…”

Section: Rectal Tfv Gel Developmentmentioning

confidence: 99%

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HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

Hendrix

2018

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

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“…4 This value provides a population-level estimate of protection among women with varying levels of adherence, whereas the causal parameter of interest to prospective ring users and their providers is product efficacy when used, with analyses conditioned on high adherence estimating ring efficacy of 65%–75%. 5 The ring does not provide protection in acts of anal intercourse (AI) due to minimal dissemination of drug from the vagina to the rectum, 6,7 although it may still provide some overall risk reduction by reducing transmission in acts of vaginal intercourse (VI). Prior analyses suggested that any AI in the trial would have a minimal impact on overall estimates of efficacy yet estimated that the ring reduced HIV-1 risk among women reporting any AI by only 18% (95% confidence interval: −57, 57).…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Dapivirine Ring HIV-1 Prevention Effectiveness for Women Engaged in Vaginal and Anal Intercourse: Insights From Mathematical Modeling

Peebles

Brown

Hendrix

et al. 2023

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background:The dapivirine vaginal ring reduces the risk of HIV-1 acquisition in acts of vaginal intercourse (VI), and although it does not offer HIV-1 protection in acts of anal intercourse (AI), it may provide some overall risk reduction for women for whom most sex acts are vaginal. We estimated the protective effect of the ring among women with high ring adherence engaged in both VI and AI. Methods:We developed a microsimulation model using data from the MTN-020/ASPIRE trial. Among women who reported any AI, we estimated the proportion of all sex acts that were AI. Model scenarios varied this proportion among women engaged in both VI and AI from 5% to 30%, including the trial-observed median proportion of 6.3% of all acts being AI. In primary analyses, dapivirine ring efficacy was model-calibrated at 70% for vaginal exposures and assumed to be 0% for anal exposures.Results: Among highly adherent women for whom 6.3% of sex acts were AI, the ring reduced HIV-1 risk by 53% (interquartile range: 44, 60), with a decline to 26% (interquartile range: 16, 36) among women for whom 30% of acts were AI. Ring effectiveness was less than 40% among women for whom AI accounted for greater than 16% of all sex acts, although this represented less than 5% of all women in the ASPIRE trial.Conclusions: For most women, including those who engage in AI, because most HIV-1 risk occurs in acts of vaginal sex, the dapivirine vaginal ring can provide important HIV-1 protection.

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Pharmacokinetics and Pharmacodynamics of Tenofovir Reduced-Glycerin 1% Gel in the Rectal and Vaginal Compartments in Women: A Cross-Compartmental Study With Directly Observed Dosing

Cited by 11 publications

References 33 publications

Topical Microbicides in HIV Prevention: State of the Promise

Topical Microbicides in HIV Prevention: State of the Promise

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

Brief Report: Dapivirine Ring HIV-1 Prevention Effectiveness for Women Engaged in Vaginal and Anal Intercourse: Insights From Mathematical Modeling

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