MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel

Cranston, Ross D.; Lama, Javier R.; Richardson, Barbra A.; Carballo‐Diéguez, Alex; Ayudhya, Ratiya Pamela Kunjara Na; Liu, Karen; Patterson, Karen; Leu, Cheng-Shiun; Galaska, Beth; Jacobson, Cindy; Parikh, Urvi M.; Marzinke, Mark A.; Hendrix, Craig W.; Johnson, Sherri; Piper, Jeanna; Grossman, Cynthia; Ho, Ken; Lucas, Jonathan; Pickett, Jim; Bekker, Linda‐Gail; Chariyalertsak, Suwat; Chitwarakorn, Anupong; Gonzáles, Pedro; Holtz, Timothy H.; Liu, Albert Y.; Mayer, Kenneth H.; Zorrilla, Carmen; Schwartz, Jill L.; Rooney, James F.; McGowan, Ian

doi:10.1093/cid/ciw832

Cited by 44 publications

(59 citation statements)

References 20 publications

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“…The largest proportion of participants (87%) would be likely to use the daily oral regimen, followed by those likely to use the RAI rectal regimen (82%); the least favorite option was daily rectal regimen (72%). Cranston et al[27] report that participants liked the daily oral regimen significantly more than either rectal regimen and that their likelihood of using it was significantly higher than daily rectal. Not included in Table III, when the three acceptability endpoints were compared across country of residence adjusting for product order, there were three significant differences, with U.S. participants providing the lowest rating in each case: overall liking of daily rectal (liked by 85%, 82% and 86% in Thailand, South Africa, & Peru, respectively, compared to 59% in the U.S.; p = .002) overall liking of RAI rectal (liked by 91%, 73% and 86% in Thailand, South Africa, & Peru, respectively, compared to 70% in the U.S.; p = .027), and intentions to use daily rectal (likely to use by 80%, 88% and 89% in Thailand, South Africa, & Peru, respectively, compared to 55% in the U.S.; p < .001).…”

Section: Resultsmentioning

confidence: 99%

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Preference of Oral Tenofovir Disoproxil Fumarate/Emtricitabine Versus Rectal Tenofovir Reduced-Glycerin 1% Gel Regimens for HIV Prevention Among Cisgender Men and Transgender Women Who Engage in Receptive Anal Intercourse with Men

et al. 2017

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Oral pre-exposure prophylaxis (PrEP) can prevent HIV transmission. Yet, some may prefer not to take systemic daily medication. MTN-017 was a 3-period, phase 2 safety and acceptability study of microbicide gel applied rectally either daily or before and after receptive anal intercourse (RAI), compared to daily oral tablet. At baseline, cisgender men and transgender women who reported RAI (N=187) rated the daily oral regimen higher in overall liking, ease of use, and likelihood of future use than the gel regimens. After trying all three, 28% liked daily oral the least. Gel did not affect sexual enjoyment (88%) or improved it (7–8%). Most partners had no reaction to gel use. Ease of gel use improved significantly between the first and the last few times of daily use. A rectal gel used before and after RAI may constitute an attractive alternative to daily tablet. Experience with product use may increase acceptability.

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Section: Resultsmentioning

confidence: 99%

“…All participants were provided condoms and lubricants and were counseled on the unproven efficacy of the study gel and the consequent need to use protection. The main outcomes of the study and adherence to product use have been reported elsewhere [27, 28]. In this manuscript, we explore product acceptability in further detail.…”

Section: Methodsmentioning

confidence: 99%

Preference of Oral Tenofovir Disoproxil Fumarate/Emtricitabine Versus Rectal Tenofovir Reduced-Glycerin 1% Gel Regimens for HIV Prevention Among Cisgender Men and Transgender Women Who Engage in Receptive Anal Intercourse with Men

et al. 2017

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“…gel), and thus may be translatable to other formulations. Real-time drug level monitoring with feedback to participants during trial implementation—a strategy now being used in microbicide studies to monitor and encourage high adherence using “objective” biomarkers should be considered in future research with pregnant women [5, 17]. …”

Section: Discussionmentioning

confidence: 99%

Acceptability of and Adherence to an Antiretroviral-Based Vaginal Microbicide among Pregnant Women in the United States

et al. 2017

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The MTN-008 trial was the first multi-dose study conducted to evaluate the safety of a microbicide gel (2:1 randomized to tenofovir 1% or hydroxycellulose (HEC) placebo gel) during pregnancy. The study aim was to evaluate safety, tolerability and pharmacokinetics of the study products. Procedures included daily gel administration, with Day 0 and Day 6 in clinic, and Days 1–5 at home. Because pregnancy may pose unique challenges to consistent gel use and acceptability, evaluation of adherence and acceptability was a secondary objective of the trial. The study enrolled healthy, HIV-negative, pregnant women aged 18–40 in Pittsburgh, PA and Birmingham, AL, USA in 2 consecutive groups: cohort 1 was 37–39 weeks gestation, cohort 2 was 34–36 weeks. Ninety-one women completed the study (45 and 46 in each cohort, respectively) and were evaluable per protocol. Adherence was evaluated using self-reports: participants completed a web-based computer-assisted self-interview (CASI) at Days 0 and 6 about gel attitudes and behaviors. At Day 6 trained research staff conducted a short interviewer-administered questionnaire with both structured and open-ended questions. Frequencies of quantitative data were tabulated in SAS and descriptive statistics are presented; open-ended textual data were summarized by a behavioral scientist experienced in qualitative analysis. Participants reported generally neutral perceptions of gel characteristics. A small number of women (7–8%) reported pain (6/90), other physical discomfort (7/90), or mental discomfort (7/90) associated with the process of applicator insertion. About 5% reported the same for the gel itself. Two-thirds (61/90) thought the gel was runny, many complained of bothersome gel leakage and several cited this reason for not inserting a full dose. The majority were not worried the gel would cause problems for their pregnancy or babies. Ninety-seven percent (83/86) said they would use the gel in the future if they were pregnant, and 90% (81/90) when nonpregnant. Self-reported adherence was high with 88% (79/90) reporting daily gel use on both the computerized and interviewer-administered questionnaires. The majority (67/90) reported no difficulty with daily use. However, drug was undetectable (<0.31 ng/mL) among 45% (27/60; 95% CI 32–58%) of the women on active product prior to observed dosing at Day 6. The most common reason for reported nonuse (N = 6) was forgetting. Study gel was generally acceptable, but many complained of a runny consistency (61/90) and leakage (83/90). No frequent or strong concerns about the effects of the study gel on the pregnancy/fetus were reported. Self-reported adherence to study gel self-administered at home for 5 days was high, however plasma drug levels suggest actual use may have been considerably lower. Findings from this study can provide insights relevant to use of other antiretroviral-based, vaginally-inserted HIV prevention methods during pregnancy.

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“…Directly observed dosing studies simulated a range of adherence patterns (daily to weekly) in a variety of matrices (plasma, peripheral blood mononuclear cells (PBMCs), dried blood spots, and hair) to provide adherence benchmarks for quantitative interpretation of HIV outcomes and adherence covariates . These benchmarks were also used for ongoing quantitative adherence assessment in several trials to target adherence interventions . These tools are widely used to assess adherence in PrEP demonstration projects and clinical practice.…”

Section: Understanding Heterogeneous Prep Outcomesmentioning

confidence: 99%

“…Despite the RCT proven efficacy and population level impact of oral TDF/FTC PrEP, there remains a substantial demand for alternative PrEP methods. Some acceptability assessments indicate one‐quarter of persons at risk prefer on‐demand, coitally related dosing to daily dosing . Long‐acting formulations (e.g., the DPV IVR) frees users from the challenges of sustaining daily pill‐taking behavior.…”

Section: Unique Prep Development Challengesmentioning

confidence: 99%

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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MTN-017: A Rectal Phase 2 Extended Safety and Acceptability Study of Tenofovir Reduced-Glycerin 1% Gel

Abstract: NCT01687218.

Cited by 44 publications

References 20 publications

Preference of Oral Tenofovir Disoproxil Fumarate/Emtricitabine Versus Rectal Tenofovir Reduced-Glycerin 1% Gel Regimens for HIV Prevention Among Cisgender Men and Transgender Women Who Engage in Receptive Anal Intercourse with Men

Preference of Oral Tenofovir Disoproxil Fumarate/Emtricitabine Versus Rectal Tenofovir Reduced-Glycerin 1% Gel Regimens for HIV Prevention Among Cisgender Men and Transgender Women Who Engage in Receptive Anal Intercourse with Men

Acceptability of and Adherence to an Antiretroviral-Based Vaginal Microbicide among Pregnant Women in the United States

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

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