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Next/2nd Generation PrEP for Men & Women: intravaginal rings, injectables, long-acting, rectal gel, intermittent PrEP
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Reported by Jules Levin, NATAP
HIV Prevention at CROI 2012 - written by Jared Baeten, MD PhD, Connie Celum, MD MPH, University of Washington - (03/14/12)
EXCERPTS From This Report
Rectal tenofovir gel (McGowan, abstract 34LB). A phase I randomized, double-blind, placebo-controlled trial of tenofovir 1% gel for rectal use was reported (MTN 007). This study was designed to study the safety and acceptability of a reduced glycerin formulation (836 mOsmol/kg compared to 3111 with original tenofovir gel tested in the vaginal studies, like CAPRISA 004 and VOICE). This study enrolled 65 healthy, persons from the US (69% men, 31% women) with a history of receptive anal sex who were willing to be abstinent during follow-up. Participants were randomized to one of four study arms: 1% reduced glycerin tenofovir gel, placebo gel, no treatment, or 2% nonoxynol-9 (a "positive control" known to cause some epithelial disruption). Incident adverse events were mostly mild/moderate with no difference by arm but a trend to more adverse events, as expected, in the nonoxynol-9 arm. The reduced glycerin formulation of rectal tenofovir gel was well tolerated and acceptable. No significant harmful changes in a battery of intensive laboratory measures were observed for the tenofovir gel and the formulation will next move to phase II evaluation.
Rilpivirine long-acting (Jackson, abstract 35). Rilpivirine is a potent NNRTI being formulated as a long-acting nanosuspension for injectable, depot use as PrEP. Three doses were tested in this phase I study: 300, 600, and 1200 mg (20 women per dose, plus 6 men receiving the 600 mg dose). Blood, biopsy, and genital fluid were sampled, to 28 days. Prolonged plasma and genital tract exposure was achieved, with higher concentrations in female genital fluid than in plasma. These data support ongoing work to further evaluate safety, pharmacokinetics, and pharmacodynamics of this potentially powerful PrEP strategy.
Other studies of PrEP. A themed discussion of animal and human studies of PrEP focused on emerging opportunities (http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16633&mediaType=podiumVideo). In a pharmacokinetics study in macaques (Radzio, abstract 1086), daily FTC/TDF achieved 10-fold lower concentrations of tenofovir in vaginal tissues compared to rectal tissues, consistent with what has been reported in biopsy studies in humans, and potentially explaining how vaginal transmission may be sensitive to PrEP non-adherence. Importantly, in macaque studies, where adherence is not a challenge, intermittent oral FTC/TDF provided 100% protection against SHIV vaginal challenge.
In a second macaque study (Kersh, abstract 1087), anti-SHIV T cell responses were explored in animals who had received PrEP. T cell responses were found in the majority of exposed, uninfected animals after receiving PrEP, suggesting that PrEP, by preventing infection in the face of viral challenge, may permit development of virus-specific T cell responses, in effect a "chemo-vaccination."
Intravaginal rings offer a strategy to deliver antiretroviral PrEP medications with lesser opportunities for adherence challenges than for daily oral pills or vaginal gels. A phase II assessment of dapivirine vaginal ring among African women, with use for 12 weeks, found the ring was well-tolerated, without safety concerns (Nel, abstract 1089). 3 seroconversions occurred, all in the placebo group (though this is too few to assess efficacy). Acceptability was high. Dapivirine vaginal ring is moving to phase III efficacy studies in 2012.
PrEP 2: The Next Generation of Drugs and Technologies: in this oral symposium the intravaginal ring containing combination ART daprivirine+maraviroc is discussed currently being evaluated in safety/tolerability study, this is the 1st study of a combination ART vaginal ring. Also discussed is the TMC278/rilpivirine long-acting intramuscular injectable PrEP
Joseph Romano
Microbicide Trials Network and NWJ Group, Wayne, PA, US
LINK TO Oral symposium:
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16620&mediaType=podiumVideo
Background: In the past 18 months, a number of trials involving ARV-based HIV prevention products have reported mixed outcomes. Although positive results were obtained for oral (iPrEx, Partners Prep) and topical (CAPRISA 004) products, other trials involving the same products could not verify these efficacy signals (VOICE, FEM-PrEP). Possible explanations for these conflicting results include differences in trial design, dosing, trial populations, and product adherence. Although efforts to understand the basis of these outcomes continue, it is clear that new products with greater potential to affect the epidemic are still needed. Criteria for new high-impact products include innovations resulting in greater efficacy (either through increased potency or product adherence), single formulations that address exposure in the genital tract or rectum, and dual indication products that protect against HIV infection as well as pregnancy or other sexually transmitted infections (STI). Furthermore, such products should demonstrate technical feasibility and meaningful efficacy potential prior to phase 3, and be amenable to streamlined development through regulatory licensure.
Conclusions: One of the most relevant innovations in next-generation prevention is the development of long-acting injectable formulations capable of sustained delivery of ARV for as long as 3 months (e.g., TMC-278 LA). Such products eliminate dependence on user adherence, and potentially provide protection against HIV infection independent of compartment of exposure. Moreover, such products could at a minimum be co-administered with injectable contraception products, achieving a dual indication outcome; or, could possibly be developed as a co-formulation with contraceptives. In addition, to injectable products, other dual indication entities are being developed. These include vaginal rings that deliver an ARV and hormonal contraceptives. Also, combination barrier-drug products also designed to achieve dual protection are in development. Interestingly, development of these products is being supported by new innovative techniques for assessing the pharmacokinetics and pharmacodynamics of these products in animal models and humans. Thus, product innovation, designed to address the limitations of earlier generation products and supported by new development tools, is leading to a new generation of products with high-impact potential against the epidemic.
Rectal Tenofovir Gel Clears Hurdle of Safety and Acceptability Study - written by Mark Mascolini - (03/7/12)
MTN-007: A Phase 1 Randomized, Double-blind, Placebo-controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel
Ian McGowan*1, C Hoesley2, P Andrew3, L Janocko4, J Dai5,6, A Carballo-Dieguez7, R Kunjara Na Ayudhya4, J Piper8, R Cranston1, K Mayer9, and MTN-007 Protocol Team
1Univ of Pittsburgh Sch of Med, PA, US; 2Univ of Alabama at Birmingham, US; 3FHI 360, Durham, NC, US; 4Magee-Women's Res Inst, Pittsburgh, PA, US; 5Univ of Washington, Seattle, US; 6Fred Hutchinson Cancer Res Ctr, Seattle, WA, US; 7Columbia Univ, New York, NY, US; 8DAIDS, NIAID, NIH, Bethesda, MD, US; and 9Fenway Hlth, Boston, MA, US
Background: The study was designed to assess the safety, adherence, and acceptability of a reduced glycerin formulation of tenofovir (TDF) 1% gel that is currently being developed as a rectal microbicide for HIV prevention. A nonoxynol-9 (N9) arm was included as a positive control for the mucosal safety assays.
Methods: We recruited 65 participants (45 men and 20 women) aged 18 to 61 from 2 US sites (Pittsburgh, Pennsylvania, Birmingham, Alabama, and Boston, Massachusetts). Participants were randomized 1:1:1:1 to receive a reduced glycerin TDF 1% gel, a HEC placebo gel (HEC), a 2% N9, or a no treatment arm (No Rx). Participants were evaluated at baseline, after a single dose, and after 7 daily doses of study product. Systemic and mucosal safety, acceptability, and adherence were evaluated at all 3 visits. Comprehensive mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), flow cytometry of mucosal T cell phenotype, and rectal microflora. All mucosal assays were performed on biopsies collected at 9 and 15 cm from the anal margin. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response respectively.
Results: A total of 16 (TDF), 17 (HEC), 16 (N9), and 16 (No Rx) sexually abstinent participants were enrolled in the study. Product adherence was ³94%. Adverse events were generally mild (G1, n = 121, 80%) or moderate (G2, n = 27, 18%). In the No Rx arm or before product use, 2 G3 and 1 G4 events occurred. There was no significant difference in the prevalence of adverse events across the 4 arms of the study. Likelihood of future product use (acceptability) was 86.7% (TDF), 93.3% (HEC), and 62.5% (N9). Fecal calprotectin and epithelial sloughing did not alter during the study. In contrast, significant changes were seen in mucosal cytokine/chemokine expression, T cell phenotype, and rectal microflora, which were mostly confined to the N9 arm.
Conclusions: The reduced glycerin formulation of 1% TDF was safe and well tolerated and should be advanced to phase 2 rectal microbicide development (MTN-017). The interpretation of the mucosal safety data is complex, but as expected most changes indicating irritation of the mucosa occurred in the N9 arm. Further evaluation of these parameters will form part of the MTN-017 Phase 2 study where TDF 1% gel will be administered rectally for up to 8 weeks.
Link to oral symposium at CROI wherein the studies are presented for TDF Gel 1% for Rectal Use & Rilpivirine Long-Acting PrEP
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16609&mediaType=podiumVideo
Rilpivirine-LA Formulation: Pharmacokinetics in Plasma, Genital Tract in HIV- Females and Rectum in Males
Akil Jackson*1, L Else2, J Tjia2, N Seymour1, M Stafford1, D Back2, B Gazzard1, and M Boffito1
1St Stephen's AIDS Trust, London, UK and 2Univ of Liverpool, UK
Background: Studies on HIV pre-exposure prophylaxis (PrEP) in women have shown mixed results, 2 large studies of oral PrEP being halted early. Even successful studies of oral PrEP has shown efficacy to be dependent on adherence to dosing. Rilpivirine Long-Acting (RPV-LA) is a parenteral formulation containing 300 mg/mL, allowing prolonged plasma exposure and potentially monthly or less frequent dosing. This study explores the pharmacokinetics in plasma, the female genital tract and male rectum over 84 days after a single intramuscular dose.
Methods: This prospective, open-label stratified-dose exploratory study investigated plasma and body fluid/tissue pharmacokinetics in healthy volunteers with low behavioral risk for HIV. Volunteers aged 18 to 50 were screened for general health, HIV and sexually transmitted infections. Female participants received a single intramuscular dose (gluteus maximus) at 300, 600, or 1200 mg with plasma for RPV levels collected on days 0 (pre-dose and 4 and 8 hours), 1, 3, 7, 11, 14, 21, 28, 42, 56, and 84 hours and genital tract fluid at a similar times from 8 hours onward. Biopsies of vaginal epithelium from the peri-cervical fornices were taken at days 14 and (7 or 28) for tissue pharmacokinetics. A small sub-study of males received an intramuscular dose of 600 mg, with plasma pharmacokinetics (a similar schedule) and rectal biopsies at days 7 and 14. RPV concentrations were determined by a validated HPLC-MS/MS method (calibration range 0.2 to 200 ng/mL); pharmacokinetics parameters (AUC84d and C84d, Cmax) were calculated using WinNonLin.
Results: At the St. Stephen's Center, London, we recruited 27 eligible female participants: >50% being of self-identified as African or African Caribbean ethnicity; 6 male participants were recruited to the rectum sub-study. Plasma and genital tract fluid pharmacokinetics and vaginal and rectal tissue concentrations are presented in the table. All doses were well tolerated; no serious adverse event and no prolongation of QT interval on ECG.
Conclusions: All 3 RPV-LA doses exhibit prolonged plasma and genital tract exposure supporting further exploration as potential PrEP agent. Partitioning between tissue compartments shows higher concentrations (at least equivalent or higher) in genital tract fluid, an important site of action. Vaginal tissue concentrations were slightly lower than genital tract fluid, possibly due to the non-secretory nature of this mucosa; more data needed to understand this phenomenon. Male rectum concentrations were equivalent to those in plasma. The safety, pharmacokinetics and pharmacodynamics after multiple IM RPV-LA doses will be important further information for future development.
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