RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

1 Center for HIV Prevention Research , UCLA AIDS Institute, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
AIDS research and human retroviruses (Impact Factor: 2.33). 09/2012; 28(11). DOI: 10.1089/AID.2012.0262
Source: PubMed


Abstract This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.

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Available from: Ian M Mcgowan, Oct 06, 2015
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    • "Our findings indicate that reduced glycerin rectal tenofovir 1% gel affects expression of a different and much broader range of genes than N-9 2% gel, potentially affecting mucosal immune homeostasis, mitochondrial function, and regulation of epithelial cell differentiation and survival. These results make biological sense given that tenofovir is a DNA chain terminator, with possible off-target effects in human cells (Lewis et al., 2003), and that topical application achieves at least 100-fold higher active drug concentrations in the mucosa than oral administration of 300 mg tenofovir disoproxil fumarate (Anton et al., 2012; Hendrix et al., 2013). Moreover, tenofovir caused similar changes in primary vaginal epithelial cells cultured from several healthy women. "
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    ABSTRACT: Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored.
    eLife Sciences 02/2015; 4(4). DOI:10.7554/eLife.04525 · 9.32 Impact Factor
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    • "In addition to its importance for vaccine studies, mucosal sampling is highly relevant in microbicide trials to understand how microbicides affect the mucosa [7]–[9] and to perform pharmacodynamic studies, such as determining ex vivo HIV infectivity of tissue from trial participants as a surrogate of product efficacy [10], [11]. Furthermore, mucosal sampling is integral to studies of the basic immunobiology of the FGT and of other sexually transmitted infections. "
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    PLoS ONE 01/2014; 9(1):e85675. DOI:10.1371/journal.pone.0085675 · 3.23 Impact Factor
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    • "To date, only one has demonstrated clinical efficacy, both against HIV and HSV-2 [80]: a vaginally applied 1% tenofovir gel, which was the first microbicide tested clinically that afforded study participants protection from viral transmission. While protection was only partial, CAPRISA004 served as the catalyst for further study on topical tenofovir gels, including those intended for rectal administration [81, 82]. While follow-up studies have failed to reproduce the partial protection observed in CAPRISA004 [83], post hoc data analysis suggests that this was due in large part to inadequate compliance of study subjects to the treatment regimen. "
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    ABSTRACT: The global impact of sexually transmitted infections (STIs) is significant. The sexual transmission of viruses such as herpes simplex virus type-2 (HSV-2) and the human immunodeficiency virus type-1 (HIV-1), has been especially difficult to control. To date, no effective vaccines have been developed to prevent the transmission of these STIs. Although antiretroviral drugs have been remarkably successful in treating the symptoms associated with these viral infections, the feasibility of their widespread use for prevention purposes may be more limited. Microbicides might provide an attractive alternative option to reduce their spread. In particular, topically applied small inhibitory RNAs (siRNAs) have been shown to not only block transmission of viral STIs to mucosal tissues both in vitro and in vivo, but also confer durable knockdown of target gene expression, thereby circumventing the need to apply a microbicide around the time of sexual encounter, when compliance is mostly difficult. Despite numerous clinical trials currently testing the efficacy of siRNA-based therapeutics, they have yet to be approved for use in the treatment of viral STIs. While several obstacles to their successful implementation in the clinic still exist, promising preclinical studies suggest that siRNAs are a viable modality for the future prevention and treatment of HSV and HIV.
    Infectious Diseases in Obstetrics and Gynecology 01/2014; 2014:125087. DOI:10.1155/2014/125087
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