Administration of 9-[2-(Phosphonomethoxy)propyl] adenine (PMPA) for Prevention of Perinatal Simian Immunodeficiency Virus Infection in Rhesus Macaques

Rompay, Koen K. A. Van; Marthas, Marta; Lifson, Jeffrey D.; Berardi, Christopher J.; Vasquez, Gabriela M.; Agatep, Elmo; Dehqanzada, Zia A.; Cundy, Kenneth C.; Bischofberger, Norbert; Pedersen, Niels C

doi:10.1089/aid.1998.14.761

Cited by 82 publications

(110 citation statements)

References 44 publications

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“…The overall median increase in CD4 ϩ T cell counts at week 24 was 58 cells per mm 3 (range: Ϫ64 to 589 cells per mm 3 ; P ϭ .01 for change from baseline) (Fig 4). At week 48, the median CD4 ϩ T cell increase was 0 cells per mm 3 (range: Ϫ274 to 768 cells per mm 3 ; P ϭ .43 for change from baseline).…”

Section: Immunologic Responsesmentioning

confidence: 95%

“…At week 48, the median CD4 ϩ T cell increase was 0 cells per mm 3 (range: Ϫ274 to 768 cells per mm 3 ; P ϭ .43 for change from baseline). The CD4 ϩ cell response among the virologic responders was high and sustained.…”

Section: Immunologic Responsesmentioning

confidence: 97%

“…Tenofovir has shown potent antiviral activity in a number of animal models. Most pertinent to the pediatric setting are its demonstrated effects in primate postexposure prophylaxis and mother-to-infant transmission models 2,3 and its favorable resistance profile. Studies demonstrating its safety and efficacy among both treatment-naive and treatment-experienced, HIV-infected adults led to its approval as part of combination antiretroviral therapy for HIV-infected adults in 2001.…”

Section: H Ighly Active Antiretroviral Therapy (Haart)mentioning

confidence: 99%

“…The National Cancer Institute Common Toxicity Criteria (version 2.0) were used to grade laboratory and clinical events, except that CD4 ϩ cell counts and total leukocyte counts were not graded, absolute neutrophil counts of Ͻ500 cells per mm 3 were considered grade 3 toxicity, and absolute neutrophil counts of Ͻ250 cells per mm 3 were considered grade 4 toxicity. Subjects and their families were reminded verbally to bring back their tenofovir DF medication bottles.…”

Section: Assessmentsmentioning

confidence: 99%

“…The CD4 ϩ cell response among the virologic responders was high and sustained. Immunophenotypic analysis of circulating CD4 ϩ lymphocytes showed a median baseline naive CD4 ϩ cell count of 148 cells per mm 3 3 ) by week 48 (P ϭ .17 for change from baseline).…”

Section: Immunologic Responsesmentioning

confidence: 99%

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Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

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ABSTRACT. Objectives. Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children.Methods. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3-16.2 years) who had progressive disease with >2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks.Results. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3-5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log 10 copies per mL (range: 4.1-5.9 log 10 copies per mL) to 4.21 log 10 copies per mL at week 48 (n ‫؍‬ 15), with 6 subjects having <400 copies per mL, including 4 with <50 copies per mL. The overall median increases in CD4 ؉ T cell counts were 58 cells per mm 3 (range: ؊64 to 589 cells per mm 3 ) at week 24 and 0 cells per mm 3 (range: ؊274 to 768 cells per mm 3 ) at week 48. The CD4 ؉ cell responses among the virologic responders were high and sustained.The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log 10 copies per mL decreases in HIV plasma RNA levels.Conclusions. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatmentexperienced, HIV-infected children.

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Section: Immunologic Responsesmentioning

confidence: 95%

Section: Immunologic Responsesmentioning

confidence: 97%

Section: H Ighly Active Antiretroviral Therapy (Haart)mentioning

confidence: 99%

Section: Assessmentsmentioning

confidence: 99%

Section: Immunologic Responsesmentioning

confidence: 99%

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Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

et al. 2005

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Lasting Effects of Transient Postinoculation Tenofovir [9-R-(2-Phosphonomethoxypropyl)adenine] Treatment on SHIVKU2 Infection of Rhesus Macaques

et al. 2000

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SHIV(KU2) replicates to high levels in inoculated macaques and reproducibly causes an acute depletion of CD4(+) T cells. We evaluated the ability of treatment with the antiretroviral drug 9-R-(2-phosphonomethoxypropyl)adenine (PMPA; tenofovir), begun 7 days postinoculation, to inhibit viral replication and associated pathogenesis. Highly productive infection (plasma viral RNA > 10(6) copy eq/mL) was present and CD4 depletion had started when treatment was initiated. PMPA treatment was associated with a rapid decline in plasma viral RNA to undetectable levels, with parallel decreases in the infectivity of plasma and infectious cells in PBMCs and CSF and stabilization of CD4(+)T-cell levels. Viral dynamics parameters were calculated for the initial phase of exponential viral replication and the treatment-related decline in plasma viremia. Following cessation of treatment after 12 weeks, plasma viral RNA was detectable intermittently at low levels, and spliced viral transcripts were detected in lymph nodes. Although treatment was begun after viral dissemination, high viremia, and CD4 decreases had occurred, following withdrawal of PMPA, CD4(+) T-cell counts normalized and stabilized in the normal range, despite persistent low-level infection. No PMPA-resistance mutations were detected. These results validate the similar viral replicative dynamics of SHIV(KU2) and HIV and SIV, and also underscore the potential for long-term modulation of viral replication patterns and clinical course by perturbation of primary infection.

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Mucosal Exposure to Subinfectious Doses of SIV Primes Gut-Associated Antibody-Secreting Cells and T Cells: Lack of Enhancement by Nonneutralizing Antibody

et al. 2001

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It has been suggested that the presence of immunoglobulin and complement receptors on rectal epithelium may facilitate the entry of HIV complexed to nonneutralizing antibody. We tested this hypothesis using simian immunodeficiency virus (SIV) infection of rhesus macaques. First, in a pilot study, a nonneutralizing IgG fraction of macaque anti-SIV gp120 was shown to enhance the immunogenicity of SIV envelope following rectal immunization. The same antibody was then mixed with a subinfectious dose of SIV and the occurrence of rectal infection was compared with virus alone. Animals were not infected overtly and were rechallenged with a 10-fold higher dose of virus with and without addition of antibody. There was no evidence of antibody-mediated infection, since equal numbers of macaques became infected, regardless of the presence of antibody. In addition, the application of immune complexes did not alter significantly the subsequent virus load or the immune responses generated. In seronegative animals, in which virus and proviral DNA were undetectable in PBMC and tissues, SIV-specific T-cell responses and antibody-secreting cells were found in systemic and gut-associated sites. Our results show that nonneutralizing antibody neither facilitated nor enhanced rectal infection with SIV, in the small number of animals used, despite the consistent trend for this antibody to enhance antibody responses to gp120 following rectal immunization with immune-complexed antigen. However, mucosal exposure to subinfectious doses of virus primed both systemic and local immunity, regardless of addition of nonneutralizing antibody.

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Administration of 9-[2-(Phosphonomethoxy)propyl] adenine (PMPA) for Prevention of Perinatal Simian Immunodeficiency Virus Infection in Rhesus Macaques

Cited by 82 publications

References 44 publications

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Lasting Effects of Transient Postinoculation Tenofovir [9-R-(2-Phosphonomethoxypropyl)adenine] Treatment on SHIVKU2 Infection of Rhesus Macaques

Mucosal Exposure to Subinfectious Doses of SIV Primes Gut-Associated Antibody-Secreting Cells and T Cells: Lack of Enhancement by Nonneutralizing Antibody

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