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A Tenofovir Disoproxil Fumarate Intravaginal Ring Completely Protects Against Repeated SHIV Vaginal Challenge in Nonhuman Primates
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Reported by Jules Levin
James Smith from the CDC delivered an oral late breaker presentation at CROI on opening day to describe their finding that an intravaginal ring protected 6 of 6 macaques monkeys, 100%, from HIV while the 12 control monkeys who did not receive the IVR were not protected, 11 of these 12 control monkeys were infected with HIV (SHIV, monkey HIV).
He started by explaining how adherence to PrEP in the tenofovir PrEP trials is crucial to successfully preventing HIV-infection., In the CAPRISA 004 trial over 80% adherence was associated with 54% effectivess vs 28% effectiveness when adherence was less than 50%, and in the iPREX trial adherence findings were even more compelling. He said the probability of HIV infection is significantly reduced in women if TFV concentration in the CVL is >1000 ng/ml and this is important to this study as below I refer to their drug levels findings in the macaque study reported here. Then Smith went on to ways to improve adherence: different drug delivery systems, there are a lot out there being tested right now--rings, injectables, next generation gels, tablets, oral. We also have a lot of sustained release with rings, implants, long-lasting injectables. Smith said, "Women must be given choices, adherence will come down to choices, if you give women enough choices they will find something they like to use and adherence will improve overall".
Why Develop a TDF ring?
- IVRs overcome some adherence isues with gels
- TDF is more bioavailable than TFV, with greater intracellular uptake
- and is 100 x more potent than TFV against HIV & HSV-2.
- Coitus independent drug delivery provides women additional choices for HIV prevention
- so this requires new materials and ring design to deliver TDF
Why has TDF not previously been advanced as a gel or IVR?
even though its much more potent than tenofovir----
- its rapidly hydolyzed to TDF which could cause some problems in production later on
- its thermally unstable
- its too polar of a molecule to be released from silicone at the target doses we did it to be at
The goal is despite these difficulties mentioned right above, you want to get the TDF delivered into the cellular compartment from the IVR where the drug can be properly converted into the form we want, to TFV & then to TDF-DP.
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The TDF IVR
- reservoir IVR design: hypdrophilic polyether urethane tubing
- TDF (120mg) for the macaques, and NaCL (85:15) as a dry formultion in the core
- tubing wall is loaded with TDF to reduce lag in release
- NaCL accelerates the establishment of internally soluble drug driving drug release by osmotically drawn vaginal fluid into the IVR core.
The TDF in vitro release rates targeted and they ended up getting very nicely in the macaques is 2.7 mg per day in vitro & 2.4 in macaques and they had plenty f dug in the macaues, but the question is - do we get enough drug in the macaques to protect the macaques.
"Protective TFV-DP Levels are achieved with TDF ring"....14 days after the ring was inserted they achieved levels in intracellular lymphocytes, levels that had achieved 100% efficacy in prior studied with a 30mg gel dose, in the upper vaginal, lower vaginal and cervical areas.
TDF IVR Delivers Sufficient Drug for ex vivo inhibition
Drug levels in the CVL are sufficient to inhibit HIV replication ex vivo, and inhibition correlates to drug levels
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EFFICACY STUDY: CAN TDF IVR deliver sufficient drug for protection?
12 normally cycling female pigtailed macaques: 6 TDF, 6 naive controls (+ 6 historical controls)
IVRs(120mg) exchanged every 4 weeks, 2 days after virus exposure
16 once weekly vaginal exposures SHIV162p3 (50 TCID50)
- first vaginal exposure 6 days after first IVR insertion
- vaginal fluid sampling at every change
- plasma viral loa, seroconversion monitored
Residual drug levels measured from rings after removal
100% of macaques (n=6) were protected from exposure, "normal menstrual cycles"
11/12 monkeys were infected with HIV.
PK: High sustained TDF/TFV levels in vaginal fluid "we're well above the 1000ng line as in Caprise, tenofovir levels are remarably stable ove the 16-week study period, TDF levels were also maintained throughout, so we are protecting the TDF with this ring.
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CONCLUSIONS:
First 100% protection against SHIV acquisition with a ring in RLD model
- rigorous model: 16 challenges over 4 months and 4 ring changes
- all TDF animals seronegative and vRNA negative
Sustained topical delivery afforded mucosal protection
No safety concerns observed (poster 986)
- the IVRs were retained and well tolerated by all macaques
- no changes in microflora
This IVR will be in a phase 1 clinical trial, 3rd quarter 2013
This model may emerge as the standard for evaluation of long duration PrEP formulation
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A Tenofovir Disoproxil Fumarate Intravaginal Ring Completely Protects against Repeated SHIV Vaginal Challenge in Nonhuman Primates
James Smith*1, R Rastogi2, R Teller2, P Srinivasan1, J Mitchell1, J McNicholl1, M Hendry1, P Mesquita3, P Kiser2, and B Herold3
1CDC, Atlanta, GA, US; 2Univ of Utah, Salt Lake City, US; and 3Albert Einstein Coll of Med, Bronx, NY, US
Background:Intravaginal rings (IVR) delivering ARV for pre-exposure prophylaxis (PrEP) against HIV have the potential to overcome some of the obstacles related to adherence and the need for sustained drug delivery. While a few have entered the clinical pipeline, 100% efficacy in a repeated low dose model macaque model has not been achieved. We developed a polyurethane reservoir ring that delivers on average 2.3 mg/day of tenofovir disoproxil fumarate (TDF) prodrug that is >500 fold more potent than tenofovir against HIV in vitro. Here we evaluated efficacy in a repeated low dose challenge model in normally cycling pigtailed macaques.
Methods: Macaque-sized reservoir IVR containing 130 mg of TDF and made from the hydrophilic elastomer HydroThane were administered to female pigtailed macaques and replaced every 28 days during the 16 week challenge period. IVR-treated macaques (n = 6) and naive controls (6 real time controls and 6 historical controls) were exposed vaginally to 50 TCID50 of the R5-tropic SHIV162p3 once weekly for up to 16 weeks. Plasma progesterone and SHIV-specific antibody were monitored throughout the study, and vaginal secretions at each ring change were collected for drug levels. Infection status was monitored by real-time polymerase chain reaction (RT-PCR) and Western blot. Residual TDF concentrations in IVR were determined by solvent extraction and liquid chromatography.
Results: All TDF IVR-treated animals remained seronegative and SHIV RNA negative after 16 weekly exposures. In contrast, 11/12 control animals became seropositive (p <0.0004, Fisher's exact test) with peak median viral RNA (vRNA) levels of 3.40x106 copies/mL of plasma. All infected animals were seropositive by Western blot within 2 weeks of confirmed vRNA detection. Controls became infected after a median of 4.0 exposures assuming an eclipse of 7 days from infection to virus RNA detection. Cumulative release of TDF in vivo from 2 sets of IVR removed after 28 days was 70+11 mg, and within the range of the in vitro release of 77+17 mg over a 28 day period. The IVR were retained and well tolerated by all macaques for 5 months.
Conclusions: This is the first extended IVR study to show 100% protection from repeated low-dose SHIV challenges that simulate multiple exposures in humans. These findings, coupled with previously demonstrated in vivo safety of the TDF IVR in NHP, support its rapid advancement into the clinical pipeline.
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A Novel Intravaginal Ring Design Releasing Tenofovir Delivers Comparable Tenofovir Diphosphate Levels in Vaginal Target Cells in Macaques to Gel Dosing
James Smith*1, R Rastogi2, R Teller2, P Srinivasan1, C-P Pau1, J McNicholl1, M Hendry1, P Mesquita3, B Herold3, and P Kiser2
1CDC, Atlanta, GA, US; 2Univ of Utah, Salt Lake City, US; and 3Albert Einstein Coll of Med, Bronx, NY, US
Background: Clinical oral and gel dosing pre-exposure prophylaxis (PrEP) trials and nonhuman primate models for PrEP have shown that high intracellular levels of tenofovir-diphosphate (TFV-DP) in tissue and target cells are needed to confer protection from HIV acquisition. However, adherence to dosing schedule is a key correlate for protection. In this study intravaginal rings (IVR) designed to deliver tenofovir disoproxyl fumarate (TDF), the more potent prodrug of tenofovir, were evaluated for their capacity to deliver high concentrations of drug to the vaginal vault and maintain protective intracellular TFV-DP levels in mucosal tissues of macaques for up to 28 days with a single IVR application.
Methods: Macaque-sized HydroThaneTM TDF reservoir IVR were administered to female pigtailed and rhesus macaques and left in place for 14 days (3 pigtails; 3 rhesus) or 28 days (6 pigtails). Mucosal tissue (days 7, 14, and 21) and secretions (days 3, 7, 14, 21, and 28) were collected for TDF and TFV quantitation by liquid chromatography-mass spectrometry (LC-MS). TFV-DP levels in monocytes derived from vaginal and cervical tissue were analyzed upon necropsy (3 rhesus, day 14). Anti-HIV activity was measured in cervicovaginal lavage (CVL).
Results: Mean combined TDF and TFV levels in vaginal secretions of 70.87 μg/mL (range 25.68-118.41) and 44.61 g/mL (range 20.19-74.35) were observed proximal and distal to the IVR, respectively. TFV-DP levels averaged 22.44 g/g of vaginal tissue (range 21.76-22.80). Mean TFV-DP concentrations were 4282 (1517-7514), 3215 (2291-4538), and 1913 (846-3192) fmol/106 monocytes isolated from vaginal tissue proximal and distal to the ring placement and the cervix, respectively. CVL inhibited HIV infection ex vivo and activity correlated with drug levels. Mucosal cytokines, chemokines, and microbiota were unchanged in response to TDF ring.
Conclusions: These novel reservoir TDF IVR continued to release detectable TDF 28 days after insertion that resulted in TFV-DP levels in vaginal monocytes that were above the fully protective levels previously observed 4 hours after application of a 1% TFV gel (30 mg/dose) in macaques. Furthermore, TFV levels in were 2 logs higher than what was reported to be effective in CAPRISA-004 after 2 gel applications (40 mg TFV/application) within 24 hours. These findings support further development and evaluation of these novel TDF IVR in vaginal repeat low-dose transmission studies.
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