Intracellular Pharmacokinetics of Tenofovir Diphosphate, Carbovir Triphosphate, and Lamivudine Triphosphate in Patients Receiving Triple-Nucleoside Regimens

Hawkins, Trevor; Veikley, Wenoah; Claire, Robert L. St.; Guyer, Bill; Clark, Nicole F; Kearney, Brian P.

doi:10.1097/01.qai.0000167155.44980.e8

Cited by 196 publications

(204 citation statements)

References 11 publications

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“…[16][17][18][19][20][21][22] Furthermore, in some experiments, animals that became infected despite receiving TDF as PrEP or PEP showed delayed onset of viremia and delayed seroconversion, 18,20,23 demonstrating that even in the case of incomplete protection against infection, PrEP or PEP may lead to attenuated acute infection (perhaps by allowing the immune system to gain some control of the virus). The demonstrated efficacy of TDF in the treatment of HIV infection, the lack of reported serious safety problems associated with its use, 24 its long halflife, [25][26][27][28] and its relatively high threshold to drug resistance 29 make this antiretroviral agent an attractive candidate for systemic or topical prophylactic use. Tenofovir and related drugs have high concentrations in genital tissues, [30][31][32] so repeated exposure with locally aborted HIV infection is theoretically possible and, if it occurs, may lead to the development of HIVspecific cellular immune responses.…”

Section: Introductionmentioning

confidence: 99%

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

Excler

Rida²,

Priddy

et al. 2011

AIDS Research and Human Retroviruses

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While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as preexposure prophylaxis with antiretrovirals (PrEP) may have limited efficacy as well. The combined administration of vaccine and PrEP (VAXPREP), however, may have a synergistic effect leading to an overall benefit that is greater than the sum of the individual effects. We propose two test-of-concept trial designs for an AIDS vaccine plus oral or topical ARV. In one design, evidence that PrEP reduces the risk of HIV acquisition is assumed to justify offering it to all participants. A two-arm study comparing PrEP alone to VAXPREP is proposed in which 30 to 60 incident infections are observed to assess the additional benefit of vaccination on risk of infection and setpoint viral load. The demonstrated superiority of VAXPREP does not imply vaccine alone is efficacious. Similarly, the lack of superiority does not imply vaccine alone is ineffective, as antagonism could exist between vaccine and PrEP. In the other design, PrEP is assumed not to be in general use. A 2Â2 factorial design is proposed in which high-risk individuals are randomized to one of four arms: placebo vaccine given with placebo PrEP, placebo vaccine given with PrEP, vaccine given with placebo PrEP, or VAXPREP. Between 60 and 210 infections are required to detect a benefit of vaccination with or without PrEP on risk of HIV acquisition or setpoint viral load, with fewer infections needed when synergy is present.

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Section: Introductionmentioning

confidence: 99%

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

Excler

Rida²,

Priddy

et al. 2011

AIDS Research and Human Retroviruses

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show abstract

“…The effective delivery of TFV into lymphoid cells and tissues by GS7340 suggests a great potential for this prodrug in PrEP. Since the intracellular half-life of TFV-DP exceeds 4 days (18,31), use of the GS7340 prodrug might also reduce the frequency of drug dosing and allow for intermittent, coitally disassociated PrEP regimens.…”

mentioning

confidence: 99%

Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors

Garcı́a-Lerma

Aung

Cong

et al. 2011

J Virol

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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/10 6 cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10 6 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.The human immunodeficiency virus (HIV)/AIDS pandemic remains one of our greatest public health challenges. Globally, an estimated 33.2 million people were living with HIV infection or AIDS in 2007. In that year, the annual incidence of new infections was an estimated 2.7 million, and there were an estimated 2.0 million HIV-related deaths (20). The ongoing high incidence of HIV infection and the incomplete coverage of basic HIV prevention tools underscore the need for new, highly effective biomedical HIV interventions to complement existing prevention strategies.Oral administration of antiretroviral drugs prior to and during HIV exposure (preexposure prophylaxis [PrEP]) is a novel intervention to protect high-risk HIV-1-negative people from becoming infected (3, 12, 15). Drug candidates for oral PrEP have been selected from drugs currently approved for treatment of HIV-1-infected individuals. Among the drugs available, the well-established potency and tolerability of tenofovir disoproxil fumarate (TDF), the approved oral prodrug of the nucleotide analog tenofovir (TFV), makes it an attractive candidate for PrEP. A recently concluded human trial with a daily combination of TDF and emtricitabine (FTC) (Truvada) for HIV-seronegative men or transgender women who have sex with men has shown a 44% reduction in the incidence of HIV-1, giving ...

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“…Thus, we could not conclude that the single administration of FTC/TDF 2 weeks before virus challenge had no preventive effect. The median intracellular half-life of TDF was estimated to be approximately 150 to 180 h, and TDF was still detectable in some patients 14 and 28 days after the administration of the last dose (28,29). The long half-life of TDF might account for the results seen in group 2.…”

mentioning

confidence: 64%

Double Oral Administration of Emtricitabine/Tenofovir Prior to Virus Exposure Protects against Highly Pathogenic Simian/Human Immunodeficiency Virus Infection in Macaques

2012

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Intracellular Pharmacokinetics of Tenofovir Diphosphate, Carbovir Triphosphate, and Lamivudine Triphosphate in Patients Receiving Triple-Nucleoside Regimens

Abstract: An intracellular drug interaction does not explain the suboptimal viral response in patients treated with the nucleoside-only regimen of TDF, ABC, and 3TC.

Cited by 196 publications

References 11 publications

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

Natural Substrate Concentrations Can Modulate the Prophylactic Efficacy of Nucleotide HIV Reverse Transcriptase Inhibitors

Double Oral Administration of Emtricitabine/Tenofovir Prior to Virus Exposure Protects against Highly Pathogenic Simian/Human Immunodeficiency Virus Infection in Macaques

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