22 results on '"Heneine, Walid"'
Search Results
2. Weekly Oral Tenofovir Alafenamide Protects Macaques from Vaginal and Rectal Simian HIV Infection.
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Massud, Ivana, Nishiura, Kenji, Ruone, Susan, Holder, Angela, Dinh, Chuong, Lipscomb, Jonathan, Mitchell, James, Khalil, George M., Heneine, Walid, Garcίa-Lerma, J. Gerardo, and Dobard, Charles W.
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SIMIAN immunodeficiency virus ,HIV infections ,MACAQUES ,TENOFOVIR ,PRE-exposure prophylaxis ,ANTIRETROVIRAL agents - Abstract
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/106 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. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. Pharmacokinetic Study of Islatravir and Etonogestrel Implants in Macaques.
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Daly, Michele B., Wong-Sam, Andres, Li, Linying, Krovi, Archana, Gatto, Gregory J., Norton, Chasity, Luecke, Ellen H., Mrotz, Victoria, Forero, Catalina, Cottrell, Mackenzie L., Schauer, Amanda P., Gary, Joy, Nascimento-Seixas, Josilene, Mitchell, James, van der Straten, Ariane, Heneine, Walid, Garcίa-Lerma, J. Gerardo, Dobard, Charles W., and Johnson, Leah M.
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LONG-acting reversible contraceptives ,BIOABSORBABLE implants ,PHARMACOKINETICS ,MACAQUES ,UNPLANNED pregnancy ,HIV prevention ,PREGNANCY tests ,CONTROLLED release drugs - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection.
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Young, Isabella C., Massud, Ivana, Cottrell, Mackenzie L., Shrivastava, Roopali, Maturavongsadit, Panita, Prasher, Alka, Wong-Sam, Andres, Dinh, Chuong, Edwards, Tiancheng, Mrotz, Victoria, Mitchell, James, Seixas, Josilene Nascimento, Pallerla, Aryani, Thorson, Allison, Schauer, Amanda, Sykes, Craig, De la Cruz, Gabriela, Montgomery, Stephanie A., Kashuba, Angela D. M., and Heneine, Walid
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MACAQUES ,PRE-exposure prophylaxis ,INTEGRASE inhibitors - Abstract
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. In this study, the authors developed an ultra-long-acting injectable, biodegradable, and removable in-situ forming implant delivering cabotegravir (CAB ISFI). CAB ISFI was well tolerated and protected against multiple rectal SHIV challenges in female macaques. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Pharmacokinetics of vaginally applied integrase inhibitors in macaques.
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Nishiura, Kenji, Sharma, Sunita, Sterling, Mara, Makarova, Natalia, Martin, Amy, Dinh, Chuong, Mitchell, James, García-Lerma, J Gerardo, Heneine, Walid, and Dobard, Charles
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INTEGRASE inhibitors ,MACAQUES ,PHARMACOKINETICS ,HIV prevention ,SIMIAN immunodeficiency virus ,RALTEGRAVIR ,MAGNITUDE (Mathematics) ,RNA virus infections ,ANTI-HIV agents ,RESEARCH ,ANIMAL experimentation ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,PRIMATES ,COMPARATIVE studies ,VAGINAL medication ,RESEARCH funding ,ENZYME inhibitors ,THERAPEUTICS - Abstract
Objectives: We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge.Methods: Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing.Results: The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 μg/mL) and tissues (266.7 and 368.4 μg/g) was achieved 2-5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8-10 h) and remained 3-4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 μg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31-92-fold) than those in vaginal fluids.Conclusions: To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention. [ABSTRACT FROM AUTHOR]- Published
- 2021
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6. Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures.
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Dobard, Charles, Makarova, Natalia, Nishiura, Kenji, Dinh, Chuong, Holder, Angela, Sterling, Mara, Lipscomb, Jonathan, Mitchell, James, Deyounks, Frank, Garber, David, Khalil, George, Spreen, William, Heneine, Walid, and García-Lerma, J Gerardo
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MACAQUES ,IMMUNODEFICIENCY ,HETEROSEXUAL men ,CONFIDENCE intervals ,URETHRA ,RNA virus infections ,PYRIDINE ,BIOLOGICAL models ,RESEARCH ,HIV integrase inhibitors ,PENIS ,ANIMAL experimentation ,RESEARCH methodology ,EVALUATION research ,MEDICAL cooperation ,PREVENTIVE health services ,PRIMATES ,COMPARATIVE studies ,CHEMOPREVENTION ,INFECTIOUS disease transmission - Abstract
We used a novel penile simian-human immunodeficiency virus (SHIV) transmission model to investigate whether long-acting cabotegravir (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once weekly for 12 weeks. Of these, 6 received human-equivalent doses of CAB LA, 6 received oral emtricitabine/tenofovir disoproxil fumarate, and 10 were untreated. The efficacy of CAB LA was high (94.4%; 95% confidence interval, 58.2%-99.3%) and similar to that seen with oral emtricitabine/tenofovir disoproxil fumarate (94.0%; 55.1%-99.2%). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA preexposure prophylaxis to heterosexual men. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies.
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Garber, David A., Adams, Debra R., Guenthner, Patricia, Mitchell, James, Kelley, Kristen, Schoofs, Till, Gazumyan, Anna, Nason, Martha, Seaman, Michael S., McNicholl, Janet, Nussenzweig, Michel C., and Heneine, Walid
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HIV ,IMMUNOGLOBULINS ,PRE-exposure prophylaxis ,HIV infections ,MACAQUES ,VIRUSES ,VIRAL antibodies ,CONCEPTION - Abstract
Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIV
SF162P3 ). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 μg ml−1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women. Here, using a repeat-exposure penile SHIV infection model in macaques, the authors show that a single subcutaneous administration of a broadly neutralizing antibody (bNAb) exerts long-acting protection against both penile and vaginal virus exposure, which highlights bNAbs as a potential therapeutic for LA-PrEP. [ABSTRACT FROM AUTHOR]- Published
- 2020
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8. Efficacy of Oral Tenofovir Alafenamide/Emtricitabine Combination or Single-Agent Tenofovir Alafenamide Against Vaginal Simian Human Immunodeficiency Virus Infection in Macaques.
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Massud, Ivana, Cong, Mian-Er, Ruone, Susan, Holder, Angela, Dinh, Chuong, Nishiura, Kenji, Khalil, George, Pan, Yi, Lipscomb, Jonathan, Johnson, Ryan, Deyounks, Frank, Rooney, James F, Babusis, Darius, Park, Yeojin, McCallister, Scott, Callebaut, Christian, Heneine, Walid, and García-Lerma, J Gerardo
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HIV infections ,SIMIAN immunodeficiency virus ,MACAQUES ,TENOFOVIR ,HIV - Abstract
Background: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to simian human immunodeficiency virus (SHIV) to investigate whether TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection.Methods: Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks. Animals received clinical doses of FTC/TAF (n = 6) or TAF (n = 9) orally 24 hours before and 2 hours after each weekly virus exposure. Infection was compared with 21 untreated controls.Results: Five of the 6 animals in the FTC/TAF and 4 of the 9 animals in the TAF alone group were protected against infection (P = .001 and P = .049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% confidence interval [CI], 34.9%-98.8%) and 57.8% (95% CI, -8.7% to 83.6%), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (P = .005 and P = .114). Median tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; P = .921).Conclusions: Emtricitabine/TAF provided a level of protection against vaginal challenge similar to FTC/TFV disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women. [ABSTRACT FROM AUTHOR]- Published
- 2019
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9. Efficacy of Vaginally Administered Gel Containing Emtricitabine and Tenofovir Against Repeated Rectal Simian Human Immunodeficiency Virus Exposures in Macaques.
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Dobard, Charles W, Makarova, Natalia, West-Deadwyler, Rolieria, Taylor, Andrew, Dinh, Chuong, Martin, Amy, Lipscomb, Jonathan, Mitchell, James, Khalil, George, Garcia-Lerma, Gerardo, and Heneine, Walid
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ANTIRETROVIRAL agents ,TENOFOVIR ,HIV infections ,ANAL sex ,MACAQUES - Abstract
Vaginal microbicides containing antiretrovirals (ARVs) have shown to prevent vaginally acquired human immunodeficiency virus (HIV), but these products may not protect women who engage in anal sex. Intravaginal dosing with ARVs has 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 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 = .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. [ABSTRACT FROM AUTHOR]
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- 2018
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10. Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV.
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Garber, David A., Mitchell, James, Adams, Debra, Guenthner, Patricia, Deyounks, Frank, Ellis, Shanon, Kelley, Kristen, Johnson, Ryan, Dobard, Charles, Heneine, Walid, and McNicholl, Janet
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HIV prevention ,MACAQUES ,EPIDEMICS ,PENIS diseases ,FORESKIN - Abstract
Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIV
sf 162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4–600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50 ) and urethra (16 TCID50 ) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1–12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men. [ABSTRACT FROM AUTHOR]- Published
- 2018
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11. Chemoprophylaxis With Oral Emtricitabine and Tenofovir Alafenamide Combination Protects Macaques From Rectal Simian/Human Immunodeficiency Virus Infection.
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Massud, Ivana, Mitchell, James, Babusis, Darius, Deyounks, Frank, Ray, Adrian S., Rooney, James F., Heneine, Walid, Miller, Michael D., García-Lermaad, J. Gerardo, and García-Lerma, J Gerardo
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CHEMOPREVENTION ,HIV prevention ,EMTRICITABINE ,TENOFOVIR ,IMMUNODEFICIENCY ,IMMUNOSUPPRESSION - Abstract
Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that efficiently delivers tenofovir diphosphate to lymphoid cells following oral administration. We investigated whether the combination of TAF and emtricitabine (FTC) could prevent simian/human immunodeficiency virus (SHIV) infection in macaques to determine the potential use of TAF for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus infection. Macaques were exposed rectally to SHIV once per week for up to 19 weeks and received saline or FTC/TAF 24 hours before and 2 hours after each virus inoculation. All 6 controls were infected, while the 6 PrEP-treated animals were protected from infection. Our results support the clinical investigation of FTC/TAF for PrEP. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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12. Protection Against Rectal Chimeric Simian/Human Immunodeficiency Virus Transmission in Macaques by Rectal-Specific Gel Formulations of Maraviroc and Tenofovir.
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Dobard, Charles W., Taylor, Andrew, Sharma, Sunita, Anderson, Peter L., Bushman, Lane R., Dinh Chuong, Chou-Pong Pau, Hanson, Debra, Lin Wang, Garcia-Lerma, J. Gerardo, McGowan, Ian, Rohan, Lisa, Heneine, Walid, Chuong, Dinh, Pau, Chou-Pong, and Wang, Lin
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SIMIAN immunodeficiency virus ,HIV infection transmission ,MACAQUES ,PHARMACOKINETICS ,MARAVIROC (Drug) ,TENOFOVIR ,PYROPHOSPHATES ,ANIMAL models in research ,PREVENTION of infectious disease transmission ,RNA virus infections ,ANIMAL experimentation ,BIOLOGICAL models ,CROSSOVER trials ,PHARMACEUTICAL gels ,HETEROCYCLIC compounds ,HYDROCARBONS ,PLACEBOS ,PRIMATES ,RESEARCH funding ,CUTANEOUS therapeutics ,TREATMENT effectiveness ,ANTI-HIV agents ,PREVENTION - Abstract
Background: Rectal human immunodeficiency virus (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 3 rectal gel formulationsMethods: 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 biopsy specimens, 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 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r(2) = 0.82). All 3 gel formulations were highly protective (82% efficacy; P ≤ .02 by the log-rank test).Conclusions: Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection. [ABSTRACT FROM AUTHOR]- Published
- 2015
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13. Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques.
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Dobard, Charles W., Sharma, Sunita, Cong, Mian-er, West, Rolieria, Makarova, Natalia, Holder, Angela, Chou-Pong Pau, Hanson, Debra L., Novembre, Francis J., Garcia-Lerma, Jose Gerardo, and Heneine, Walid
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HIV prevention ,TENOFOVIR ,MACAQUES ,GENETIC mutation ,PYROPHOSPHATES ,DISEASES ,THERAPEUTICS - Abstract
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 (SHIV162P3
K65R ) 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/106 cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/106 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. [ABSTRACT FROM AUTHOR]- Published
- 2015
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14. Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques.
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Massud, Ivana, Martin, Amy, Chuong Dinh, Mitchell, James, Jenkins, Leecresia, Heneine, Walid, Chou-Pong Pau, and García-Lerma, J. Gerardo
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PHARMACOKINETICS ,INTEGRASE inhibitors ,RALTEGRAVIR ,MACAQUES ,DRUG dosage ,DRUG efficacy - Abstract
Objectives: Pharmacokinetic studies in animal models are important for assessing the prophylactic potential of antiretroviral drugs for HIV prevention. This study sought to identify clinically relevant doses of the marketed integrase inhibitors raltegravir, elvitegravir and dolutegravir in macaques and investigate drug penetration and antiviral activity in mucosal secretions. Methods: Macaques received one oral dose of raltegravir, elvitegravir or dolutegravir alone or in combination with emtricitabine and tenofovir disoproxil fumarate followed by drug level measurements in blood and rectal and vaginal secretions. Antiviral activity was investigated in TZM-bl cells exposed to SHIV
162p3 in the presence of rectal secretions collected from treated animals. Results: Plasma drug concentrations with 50 mg/kg raltegravir or elvitegravir were within the range seen in humans receiving 400-800 mg of raltegravir or 800 mg of unboosted elvitegravir but lower than with 150 mg of elvitegravir boosted with cobicistat. AUC0-24 values for dolutegravir increased proportionally with the dose, with a calculated human-equivalent dose of 20 mg/kg. Elvitegravir showed the highest penetration in rectal and vaginal fluids despite the absence of pharmacological boosting, followed by raltegravir and dolutegravir. Rectal secretions collected at 24 h from treated macaques blocked infection of TZM-bl cells by 50% at dilutions of 1/1000 (raltegravir), 1/800 (dolutegravir) and >1/30000 (elvitegravir). Conclusions: We defined macaque doses of HIV integrase inhibitors that recapitulate human clinical doses, which will facilitate efficacy and dose escalation studies in macaques. High and sustained drug concentrations and activity in mucosal secretions suggest that integrase inhibitors are promising candidates for HIV prevention. [ABSTRACT FROM AUTHOR]- Published
- 2015
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15. The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge.
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Radzio, Jessica, Spreen, William, Yun Lan Yueh, Mitchell, James, Jenkins, Leecresia, García-Lerma, J. Gerardo, and Heneine, Walid
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INTEGRASE inhibitors ,SIMIAN immunodeficiency virus diseases ,MACAQUES ,SIMIAN immunodeficiency virus ,EMTRICITABINE-tenofovir ,PREVENTIVE medicine ,DISEASES - Abstract
The article presents a research investigating how long-acting integrase inhibitor GSK1265744 protects macaques from repeated high-dose intravaginal simian-human immunodeficiency virus (SHIV). It mentions effective preexposure prophylaxis (PrEP) with preexposure prophylaxis (PrEP) with Truvada in a low-dose intrarectal SHIV. It concludes high efficacy with plasma drug concentrations that remained above the protein-adjusted inhibitory concentration during the dosing cycles.
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- 2015
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16. Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir.
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García-Lerma, J. Gerardo, Otten, Ron A, Qari, Shoukat H, Jackson, Eddie, Cong51, Mian-er, Masciotra, Silvina, Wei Luo, Kim, Caryn, Adams, Debra R, Monsour, Michael, Lipscomb, Jonathan, Johnson, Jeffrey A., Delinsky, David, Schinazi, Raymond F., Janssen, Robert, Folks, Thomas M., and Heneine, Walid
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ANTIRETROVIRAL agents ,HIV infections ,HIV ,MACAQUES - Abstract
Using a repeat-exposure macaque model, Walid Heneine and colleagues find that pre-exposure prophylaxis with combination antiretroviral drugs provides protection against rectal challenge with a SHIV virus. [ABSTRACT FROM AUTHOR]
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- 2008
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17. Depot-Medroxyprogesterone Acetate Does Not Reduce the Prophylactic Efficacy of Emtricitabine and Tenofovir Disoproxil Fumarate in Macaques.
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Radzio, Jessica, Hanley, Krisztina, Mitchell, James, Ellis, Shanon, Deyounks, Frank, Jenkins, Leecresia, Heneine, Walid, and García-Lerma, J. Gerardo
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Concerns that the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) may increase the risk of HIV acquisition in women led to questions on whether DMPA could reduce efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model to investigate the impact of prolonged DMPA exposure on PrEP with emtricitabine/tenofovir disoproxil fumarate. Twelve pigtail macaques treated with DMPA were exposed vaginally to simian HIV once a week for up to 5 months and received either placebo (n = 6) or emtricitabine/tenofovir disoproxil fumarate (n = 6). All control macaques were infected, whereas the PrEP-treated animals remained protected (P = 0.0007). This model suggests that women using DMPA will fully benefit from PrEP. [ABSTRACT FROM AUTHOR]
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- 2014
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18. Lack of Prophylactic Efficacy of Oral Maraviroc in Macaques despite High Drug Concentrations in Rectal Tissues.
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Massud, Ivana, Aung, Wutyi, Martin, Amy, Bachman, Shanon, Mitchell, James, Aubert, Rachael, Tsegaye, Theodros Solomon, Kersh, Ellen, Chou-Pong Pau, Heneine, Walid, and García-Lerma, J. Gerardo
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MARAVIROC (Drug) , *ORAL medicine , *MACAQUES , *HIV prevention , *HIV infection transmission , *LABORATORY monkeys - Abstract
Maraviroc (MVC) is a potent CCR5 coreceptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV162p3 exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues and consisted of a human-equivalent dose given 24 h before virus exposure, followed by a booster postexposure dose. In rectal secretions, MVC peaked at 24 h (10,242 ng/ml) with concentrations at 48 h that were about 40 times those required to block SHIV infection of peripheral blood mononuclear cells (PBMCs) in vitro. Median MVC concentrations in rectal tissues at 24 h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced macrophage inflammatory protein 1β-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during five rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3+/CCR5+ cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3+/CCR5+ cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
19. Generation and mucosal transmissibility of emtricitabine- and tenofovir-resistant SHIV162P3 mutants in macaques
- Author
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Cong, Mian-er, Youngpairoj, Ae S., Aung, Wutyi, Sharma, Sunita, Mitchell, James, Dobard, Charles, Heneine, Walid, and Garcia-Lerma, J. Gerardo
- Subjects
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DRUG resistance , *HIV , *EMTRICITABINE , *TENOFOVIR , *INFECTIOUS disease transmission , *MACAQUES , *VIRION - Abstract
Abstract: Transmission of drug-resistant HIV has been widely documented. We generated tenofovir (TFV)- and emtricitabine (FTC)-resistant SHIV162P3 mutants that can be used to investigate the transmission efficiency of drug-resistant viruses and their impact on the efficacy of pre-exposure prophylaxis. Both SHIV162p3M184V and SHIV162p3K65R replicated in vitro at high titers. Drug resistance profiles were similar to those seen in HIV. Virus infectivity to virion particle ratios were 4- and 10-fold lower in SHIV162p3M184V and SHIV162p3K65R, compared to a concurrently generated WT SHIV162p3, respectively. Mucosal transmissibility studies using a repeat low-dose macaque model of rectal and vaginal transmission showed that both mutants were able to efficiently infect macaques only after the dose was increased to adjust for fitness reductions due to K65R and M184V. Our results in limited number of macaques suggest that the reduction in fitness due to M184V and K65R decreases virus transmissibility, and identify in vitro infectivity parameters that associate with mucosal transmissibility. [Copyright &y& Elsevier]
- Published
- 2011
- Full Text
- View/download PDF
20. Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques.
- Author
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Van Rompay, Koen K. A., Singh, Raman P., Heneine, Walid, Johnson, Jeffrey A., Montefiori, David C., Bischofberger, Norbert, and Marthas, Marta L.
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THERAPEUTICS , *MACAQUES , *INFECTION , *GENETIC mutation , *REVERSE transcriptase , *DISEASES - Abstract
We demonstrated previously that prolonged tenofovir treatment of infant macaques, starting early during infection with virulent simian immunodeficiency virus (SIVmac251), can lead to persistently low or undetectable viremia even after the emergence of mutants with reduced in vitro susceptibility to tenofovir as a result of a K65R mutation in reverse transcriptase; this control of viremia was demonstrated to be mediated by the generation of effective antiviral immune responses. To determine whether structured treatment interruptions (STI) can induce similar immunologic control of viremia, eight newborn macaques were infected with highly virulent SIVmac251 and started on a tenofovir STI regimen 5 days later. Treatment was withdrawn permanently at 33 weeks of age. All animals receiving STI fared much better than 22 untreated SIVmac251-infected infant macaques. However, there was a high variability among animals in the viral RNA set point after complete drug withdrawal, and none of the animals was able to achieve long-term immunologic suppression of viremia to persistently low levels. Early immunologic and viral markers in blood (including the detection of the K65R mutation) were not predictive of the viral RNA set point after drug withdrawal. These results, which reflect the complex interactions between drug resistance mutations, viral virulence, and drug- and immune-mediated inhibition of virus replication, highlight the difficulties associated with trying to develop STI regimens with predictable efficacy for clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
21. Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors.
- Author
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García-Lerma, J. Gerardo, Wutyi Aung, Mian-er Cong, Qi Zheng, Youngpairoj, Ae S., Mitchell, James, Holder, Angela, Martin, Amy, Kuklenyik, Susan, Wei Luo, Yen-Chin Lin, Carol, Hanson, Debra L., Kersh, Ellen, Chou-Pong Pau, Ray, Adrian S., Rooney, James F., Lee, William A., and Heneine, Walid
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NUCLEOSIDE reverse transcriptase inhibitors , *HIV , *LYMPHOCYTES , *MACAQUES , *MUCOUS membranes - Abstract
Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/106 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/106 mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
22. Complete Protection from Repeated Vaginal Simian-Human Immunodeficiency Virus Exposures in Macaques by a Topical Gel Containing Tenofovir Alone or with Emtricitabine.
- Author
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Parikh, Urvi M., Dobard, Charles, Sharma, Sunita, Cong, Mian-Er, Hongwei Jia, Martin, Amy, Chou-Pong Pau, Hanson, Debra L., Guenthner, Patricia, Smith, James, Kersh, Ellen, Garcia-Lerma, J. Gerardo, Novembre, Francis J., Otten, Ron, Folks, Thomas, and Heneine, Walid
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HIV prevention , *ANTISEPTICS , *ANIMAL models in research , *MACAQUES , *T cells , *THERAPEUTICS - Abstract
New-generation gels that deliver potent antiretroviral drugs against human immunodeficiency virus type 1 have renewed hopes for topical prophylaxis as a prevention strategy. Previous preclinical research with monkey models suggested that high concentrations and drug combinations are needed for high efficacy. We evaluated two long-acting reverse transcriptase inhibitors, tenofovir (TFV) and emtricitabine (FTC), by using a twice-weekly repeat challenge macaque model and showed that a preexposure vaginal application of gel with 1% TFV alone or in combination with 5% FTC fully protected macaques from a total of 20 exposures to simian-human immunodeficiency virus SF162p3. FTC and TFV were detected in plasma 30 min after vaginal application, suggesting rapid absorption. FTC was detected more frequently than TFV and showed higher levels, reflecting the fivefold-higher concentration of this drug than of TFV. Two of 12 repeatedly exposed but protected macaques showed limited T-cell priming, which did not induce resistance to infection when macaques were rechallenged. Thus, single drugs with durable antiviral activity can provide highly effective topical prophylaxis and overcome the need for noncoital use or for drug combinations which are more complex and costly to formulate and approve. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
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