Zidovudine, Lamivudine, and Abacavir Have Different Effects on Resting Cells Infected with Human Immunodeficiency Virus In Vitro

Saavedra-Lozano, Jesús; McCoig, Cynthia; Cao, Yanying; Vitetta, Ellen S.; Ramilo, Octavio

doi:10.1128/aac.48.8.2825-2830.2004

Cited by 9 publications

(5 citation statements)

References 47 publications

(84 reference statements)

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“…The cellular activation state significantly influences intracellular pharmacology of NRTIs and antiviral activity, based upon in vitro studies. 26,90 For instance, tenofovir-DP accumulated 2-to 3-fold higher in resting versus phytohaemaggutinin (PHA)-activated PBMCs in vitro. 20 The tenofovir-DP half-life was 3 times longer in resting than activated cells in the same study.…”

Section: Cell Activationmentioning

confidence: 99%

Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Anderson

Kiser

Gardner

et al. 2010

Journal of Antimicrobial Chemotherapy

166

147

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The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.

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Section: Cell Activationmentioning

confidence: 99%

Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Anderson

Kiser

Gardner

et al. 2010

Journal of Antimicrobial Chemotherapy

166

147

View full text Add to dashboard Cite

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“…The compound has potent antiviral efficacy, can cross the blood brain barrier to an extent similar to ZDV, and has good antiviral activity in macrophages in vitro [19] and microglia [20]. Furthermore, while ZDV is active against de novo infection of macrophages, but not against chronic infection in resting monocyte lineage cells, ABC is active against both [21]. Consequently, a controlled study was conducted to determine the efficacy of ABC as part of combination therapy in ADC.…”

Section: Introductionmentioning

confidence: 99%

Factors in AIDS Dementia Complex Trial Design: Results and Lessons from the Abacavir Trial

et al. 2007

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Objectives:To determine the efficacy of adding abacavir (Ziagen, ABC) to optimal stable background antiretroviral therapy (SBG) to AIDS dementia complex (ADC) patients and address trial design.Design:Phase III randomized, double-blind placebo-controlled trial.Setting:Tertiary outpatient clinics.Participants:ADC patients on SBG for ≥8 wk.Interventions:Participants were randomized to ABC or matched placebo for 12 wk.Outcome Measures:The primary outcome measure was the change in the summary neuropsychological Z score (NPZ). Secondary measures were HIV RNA and the immune activation markers β-2 microglobulin, soluble tumor necrosis factor (TNF) receptor 2, and quinolinic acid.Results:105 participants were enrolled. The median change in NPZ at week 12 was +0.76 for the ABC + SBG and +0.63 for the SBG groups (p = 0.735). The lack of efficacy was unlikely related to possible limited antiviral efficacy of ABC: at week 12 more ABC than placebo participants had plasma HIV RNA ≤400 copies/mL (p = 0.002). There were, however, other factors. Two thirds of patients were subsequently found to have had baseline resistance to ABC. Second, there was an unanticipated beneficial effect of SBG that extended beyond 8 wk to 5 mo, thereby rendering some of the patients at baseline unstable. Third, there was an unexpectedly large variability in neuropsychological performance that underpowered the study. Fourth, there was a relative lack of activity of ADC: 56% of all patients had baseline cerebrospinal fluid (CSF) HIV-1 RNA <100 copies/mL and 83% had CSF β-2 microglobulin <3 nmol/L at baseline.Conclusions:The addition of ABC to SBG for ADC patients was not efficacious, possibly because of the inefficacy of ABC per se, baseline drug resistance, prolonged benefit from existing therapy, difficulties with sample size calculations, and lack of disease activity. Assessment of these trial design factors is critical in the design of future ADC trials.

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“…Abacavir is more active in 'resting' cells than 'activated' cells, but carbovir-triphosphate concentrations have not been studied. On the other hand, tenofovir-diphosphate is actually higher in 'resting' versus 'activated' cells [15,16].…”

Section: Nucleoside Analog Reverse Transcriptase Inhibitortriphosphatmentioning

confidence: 98%

Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs

Anderson¹

2008

Current Opinion in HIV and AIDS

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Zidovudine, Lamivudine, and Abacavir Have Different Effects on Resting Cells Infected with Human Immunodeficiency Virus In Vitro

Cited by 9 publications

References 47 publications

Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Factors in AIDS Dementia Complex Trial Design: Results and Lessons from the Abacavir Trial

Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs

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