Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-12 (of 12 Records) |
Query Trace: Dobard CW [original query] |
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Weekly oral tenofovir alafenamide protects macaques from vaginal and rectal Simian HIV infection
Massud I , Nishiura K , Ruone S , Holder A , Dinh C , Lipscomb J , Mitchell J , Khalil GM , Heneine W , Garcia-Lerma JG , Dobard CW . Pharmaceutics 2024 16 (3) Pre-exposure prophylaxis (PrEP) with a weekly oral regimen of antiretroviral drugs could be a suitable preventative option for individuals who struggle with daily PrEP or prefer not to use long-acting injectables. We assessed in macaques the efficacy of weekly oral tenofovir alafenamide (TAF) at doses of 13.7 or 27.4 mg/kg. Macaques received weekly oral TAF for six weeks and were exposed twice-weekly to SHIV vaginally or rectally on day 3 and 6 after each dose. Median TFV-DP levels in PBMCs following the 13.7 mg/kg dose were 3110 and 1137 fmols/10(6) cells on day 3 and 6, respectively. With the 27.4 mg/kg dose, TFV-DP levels were increased (~2-fold) on day 3 and 6 (6095 and 3290 fmols/10(6) cells, respectively). Both TAF doses (13.7 and 27.4 mg/kg) conferred high efficacy (94.1% and 93.9%, respectively) against vaginal SHIV infection. Efficacy of the 27.4 mg/kg dose against rectal SHIV infection was 80.7%. We estimate that macaque doses of 13.7 and 27.4 mg/kg are equivalent to approximately 230 and 450 mg of TAF in humans, respectively. Our findings demonstrate the effectiveness of a weekly oral PrEP regimen and suggest that a clinically achievable oral TAF dose could be a promising option for non-daily PrEP. |
Author Correction: Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
Young IC , Massud I , Cottrell ML , Shrivastava R , Maturavongsadit P , Prasher A , Wong-Sam A , Dinh C , Edwards T , Mrotz V , Mitchell J , Seixas JN , Pallerla A , Thorson A , Schauer A , Sykes C , De la Cruz G , Montgomery SA , Kashuba ADM , Heneine W , Dobard CW , Kovarova M , Garcia JV , Garcίa-Lerma JG , Benhabbour SR . Nat Commun 2024 15 (1) 1054 |
Pharmacokinetic study of islatravir and etonogestrel implants in macaques
Daly MB , Wong-Sam A , Li L , Krovi A , Gatto GJ , Norton C , Luecke EH , Mrotz V , Forero C , Cottrell ML , Schauer AP , Gary J , Nascimento-Seixas J , Mitchell J , van der Straten A , Heneine W , Garcίa-Lerma JG , Dobard CW , Johnson LM . Pharmaceutics 2023 15 (12) The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0-2.5], 1.9 [1.2-6.3] and 2.8 [2.3-11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229-1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model. |
Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection
Young IC , Massud I , Cottrell ML , Shrivastava R , Maturavongsadit P , Prasher A , Wong-Sam A , Dinh C , Edwards T , Mrotz V , Mitchell J , Seixas JN , Pallerla A , Thorson A , Schauer A , Sykes C , De la Cruz G , Montgomery SA , Kashuba ADM , Heneine W , Dobard CW , Kovarova M , Garcia JV , García-Lerma JG , Benhabbour SR . Nat Commun 2023 14 (1) 708 Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans. |
Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques
Dobard CW , Peet MM , Nishiura K , Holder A , Dinh C , Mitchell J , Khalil G , Pan Y , Singh ON , McCormick TJ , Agrahari V , Gupta P , Jonnalagadda S , Heneine W , Clark MR , García-Lerma JG , Doncel GF . EBioMedicine 2022 86 104361 BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. |
Comparative pharmacokinetics and local tolerance of tenofovir alafenamide (TAF) from subcutaneous implant in rabbits, dogs, and macaques
Gatto GJ , Krovi A , Li L , Massud I , Holder A , Gary J , Mills P , Mitchell J , Luecke E , Demkovich ZR , Heneine W , Garca-Lerma JG , Marzinke MA , Brand RM , Dobard CW , Johnson LM , VanDerStraten A . Front Pharmacol 2022 13 923954 The administration of antiretrovirals (ARVs) for HIV pre-exposure prophylaxis (PrEP) is highly efficacious and may benefit from new long-acting (LA) drug delivery approaches. This paper describes a subcutaneous, reservoir-style implant for the LA delivery of tenofovir alafenamide (TAF) and documents the preclinical assessment of implant safety and pharmacokinetics (PK) in New Zealand White (NZW) rabbits (3 groups of n = 5), beagle dogs (2 groups of n = 6), and rhesus macaques (2 groups of n = 3). Placebo implants were placed in rabbits (n = 10) and dogs (n = 12). Implant parameters, including selection of the TAF form, choice of excipient, and PCL formulation were tuned to achieve targeted concentrations of the active anabolite of TAF, tenofovir diphosphate (TFV-DP), within peripheral blood mononuclear cells (PBMCs) and mucosal tissues relevant to HIV transmission. Sustained concentrations of TFV-DP in PBMCs over 100fmol/10(6) cells were achieved in all animal species indicating that the implants effectively delivered TAF for 3-6months. Unlike placebo implants without TAF, all active implants resulted in local adverse events (AEs) proximal to the implant ranging in severity from mild to moderate and included dermal inflammation and necrosis across all species. Despite these AEs, the implant performed as designed and achieved a constant drug release profile, supporting the continued development of this drug delivery platform. |
Development, characterization and in vivo pharmacokinetic assessment of rectal suppositories containing combination antiretroviral drugs for HIV prevention
Jhunjhunwala K , Dobard CW , Sharma S , Makarova N , Holder A , Dinh C , Mitchell J , Wang L , Zhang J , Patel SK , Heneine W , Rohan LC . Pharmaceutics 2021 13 (8) Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat-and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1-and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
Efficacy of vaginally administered gel containing emtricitabine and tenofovir against repeated rectal SHIV exposures in macaques
Dobard CW , Makarova N , West-Deadwyler R , Taylor A , Dinh C , Martin A , Lipscomb J , Mitchell J , Khalil G , Garcia-Lerma G , Heneine W . J Infect Dis 2018 218 (8) 1284-1290 Vaginal microbicides containing antiretrovirals (ARV) have shown to prevent vaginally acquired HIV but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs have shown to result in drug exposures in rectal tissues, thus raising the possibility of dual compartment protection. To test this concept, we investigated whether intravaginal dosing with emtricitabine (FTC)-tenofovir (TFV) gel, which fully protected macaques against repeated vaginal exposures to simian human immunodeficiency virus (SHIV), protects against rectal SHIV exposures. Pharmacokinetic (PK) studies revealed rapid distribution of FTC and TFV to rectal tissues and luminal fluids, albeit at concentrations 1-2 log10 lower than those in the vaginal compartment. Efficacy measurements against repeated rectal SHIV challenges demonstrated a 4.5-fold reduction in risk of infection in macaques that received intravaginal FTC/TFV compared to placebo gel (p=0.047; log-rank test). These data support the concept of dual compartment protection by vaginal dosing and warrants developing ARV-based vaginal products with improved bidirectional dosing. |
Assessment of penile erection methods in rhesus macaques to model pharmacokinetics of antiretroviral drugs and penile infection with simian immunodeficiency virus
Hayes J , Powell N , Lathrop G , Heneine W , Dobard CW . J Med Primatol 2016 45 (1) 34-41 BACKGROUND: An established macaque model to assess HIV interventions against penile transmission is currently not available. Physiological changes during penile erections may affect susceptibility to infection and drug pharmacokinetics (PK). Here, we identify methods to establish erections in macaques to evaluate penile transmission, PK, and efficacy under physiologic conditions. METHODS: Penile rigidity and length were evaluated in eight rhesus macaques following rectal electrostimulation (RES), vibratory stimulation (VS), or pharmacological treatment with Sildenafil Citrate (Viagra) or Alprostadil. RESULTS: Rectal electrostimulation treatment increased penile rigidity (>82%) and length (2.5 +/- 0.58 cm), albeit the response was transient. In contrast, VS alone or coupled with Viagra or Alprostadil failed to elicit an erection response. CONCLUSION: Rectal electrostimulation treatment elicits transient but consistent penile erections in macaques. High rigidity following RES treatment demonstrates increased blood flow and may provide a functional model for penile PK evaluations and possibly simian immunodeficiency virus (SIV) transmission under erect conditions. |
Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques
Dobard CW , Sharma S , Cong ME , West R , Makarova N , Holder A , Pau CP , Hanson DL , Novembre FJ , Garcia-Lerma JG , Heneine W . Retrovirology 2015 12 (1) 69 BACKGROUND: Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues. RESULTS: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice-weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R. CONCLUSION: Both the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses. |
Protection Against Rectal Chimeric Simian/Human Immunodeficiency Virus Transmission in Macaques by Rectal-Specific Gel Formulations of Maraviroc and Tenofovir
Dobard CW , Taylor A , Sharma S , Anderson PL , Bushman LR , Chuong D , Pau CP , Hanson D , Wang L , Garcia-Lerma JG , McGowan I , Rohan L , Heneine W . J Infect Dis 2015 212 (12) 1988-95 BACKGROUND: Rectal HIV transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of three rectal gel formulations METHODS: Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1%MVC/1%TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsies, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n=7), MVC (n=6), TFV (n=6), or MVC/TFV (n=6) gel 30 minutes before each challenge. RESULTS: MVC and TFV were detected in plasma 30 minutes after gel application and remained above IC95 levels in rectal fluids at 24h. MVC, TFV, and TFV-DP concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2h, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r2=0.82). All three gel formulations were highly protective (82% efficacy; log-rank test; p≤0.02). CONCLUSION: Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection. |
Role of human immunodeficiency virus type 1 integrase in uncoating of the viral core
Briones MS , Dobard CW , Chow SA . J Virol 2010 84 (10) 5181-90 After membrane fusion with a target cell, the core of human immunodeficiency virus type 1 (HIV-1) enters into the cytoplasm, where uncoating occurs. The cone-shaped core is composed of the viral capsid protein (CA), which disassembles during uncoating. The underlying factors and mechanisms governing uncoating are poorly understood. Several CA mutations can cause changes in core stability and a block at reverse transcription, demonstrating the requirement for optimal core stability during viral replication. HIV-1 integrase (IN) catalyzes the insertion of the viral cDNA into the host genome, and certain IN mutations are pleiotropic. Similar to some CA mutants, two IN mutants, one with a complete deletion of IN (NL-DeltaIN) and the other with a Cys-to-Ser substitution (NL-C130S), were noninfectious, with a replication block at reverse transcription. Compared to the wild type (WT), the cytoplasmic CA levels of the IN mutants in infected cells were reduced, suggesting accelerated uncoating. The role of IN during uncoating was examined by isolating and characterizing cores from NL-DeltaIN and NL-C130S. Both IN mutants could form functional cores, but the core yield and stability were decreased. Also, virion incorporation of cyclophilin A (CypA), a cellular peptidyl-prolyl isomerase that binds specifically to CA, was decreased in the IN mutants. Cores isolated from WT virus depleted of CypA had an unstable-core phenotype, confirming a role of CypA in promoting optimal core stability. Taken together, our results indicate that IN is required during uncoating for maintaining CypA-CA interaction, which promotes optimal stability of the viral core. |
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