Sex differences in HIV: Natural history, pharmacokinetics, and drug toxicity

Umeh, Obiamiwe C.; Currier, Judith S.

doi:10.1007/s11908-005-0026-9

Cited by 13 publications

(7 citation statements)

References 36 publications

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“…The findings indicated a greater exposure of women. Current evidence, though limited, suggested the existence of a gender disparity and thus provided motivation to conduct further investigations of intracellular AZT PK and pharmacodynamics in men and women, a group for which historically experience showed high rates of serious toxicity (37).…”

Section: Discussionmentioning

confidence: 99%

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Bazzoli

Bénech

Rey

et al. 2011

Antimicrob Agents Chemother

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The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once-versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.Zidovudine (AZT) and lamivudine (3TC) are common antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection, which causes AIDS. AZT and 3TC are nucleoside reverse transcriptase inhibitors (NRTIs) that are often used in highly active antiretroviral therapy (HAART) along with one protease inhibitor (PI) boosted with ritonavir in general or along with a non-NRTI. The 2009 recommendations of the World Health Organization recommended the use of AZT as a preferred first-line therapy option, a less toxic alternative to the use of stavudine (38). As AZT and 3TC are frequently prescribed together, they are combined in one tablet (Combivir).All NRTIs undergo a series of three sequential phosphorylation reactions producing monophosphates, diphosphates, and then triphosphates (TP) within the cell. AZT and 3TC are thus metabolized intracellularly to their active metabolites (AZT-TP and 3TC-TP, respectively), which block DNA synthesis by reverse transcriptase inhibition and chain termination. These active moieties are the determinants of the efficacy and toxicity of AZT and 3TC. Several studies have demonstrated that the antiviral activity of NRTIs does not always correlate with plasma concentrations of the parent nu...

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Section: Discussionmentioning

confidence: 99%

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Bazzoli

Bénech

Rey

et al. 2011

Antimicrob Agents Chemother

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“…It is possible that sex differences in pharmacokinetics and pharmacodynamics(17) (18) render WLHIV particularly susceptible to ART-induced ectopic fat deposition and/or metabolic dysregulation. Prospective studies comparing differential effects of newly-initiated contemporary ART regimens on salient metabolic parameters among ART-naive women vs. men with HIV could test this hypothesis.…”

Section: Sex-specific Mechanisms Underlying Heightened Cvd Risk Amongmentioning

confidence: 99%

Cardiovascular disease risk among women living with HIV in North America and Europe

Stone

Looby

Zanni

2017

Current Opinion in HIV and AIDS

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Purpose of review To examine the epidemiology and mechanistic underpinnings of heightened cardiovascular disease (CVD) risk among women living with HIV (WLHIV) in North America and Europe. Recent Findings WLHIV in North America and Europe exhibit high CVD incidence rates, on par with those of compatriot men living with HIV (MLHIV). Compared with uninfected women, WLHIV in these regions face a two- to four-fold increased relative risk for myocardial infarction (MI), stroke, and heart failure. HIV-associated CVD risk is fuelled by a negative synergy of traditional cardiometabolic risk factors and heightened systemic immune activation/inflammation. Among WLHIV, female sex and endogenous sex hormone production influence both traditional cardiometabolic risk factors and patterns of systemic immune activation/inflammation. WLHIV in North America and Europe may also experience heightened CVD risk in relation to a relatively increased prevalence of behavioral and psychosocial CVD risk factors, coupled with suboptimal therapeutic targeting of known traditional cardiometabolic risk factors. Summary Additional research on sex-specific mechanisms of HIV-associated CVD - based not only out of North America and Europe but also and especially out of Africa, Asia, and South America - will inform the development of CVD prediction algorithms and prevention guidelines clinically relevant to the 17 million women aging with HIV globally.

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“…The HIV-infected population constitutes a heterogeneous group of individuals of different age, gender, ethnic background, geographic setting, access to medical care and other demographic aspects. Age [1,2] and gender [3][4][5][6] as differential clinical, analytical and evolutive factors have already been analysed in different cohorts of HIV-infected patients. A large amount of information has also been reported regarding different clinical, immunological, virological and evolutive aspects of patients with either the sexual or parenteral transmission categories of the infection.…”

Section: Introductionmentioning

confidence: 99%

Association of HIV transmission categories with sociodemographic, viroimmunological and clinical parameters of HIV-infected patients

2009

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To analyse sociodemographic, viroimmunological and clinical parameters in different HIV-transmission categories at baseline and during treatment, 3039 patients were followed up for 12 months after the initiation of a nelfinavir-based regimen. Multiple baseline parameters were significantly different in the diverse categories, including CD4 counts (P<0.0001) and viral load (P=0.02). There were differences in the groups regarding the CD4 response (P=0.01), but not the virological response (P=0.4), to therapy over time. Multivariate analyses revealed that transmission categories were significantly related to baseline CD4 counts (P=0.01), viral load at 12 months (P=0.0006), poorer adherence to therapy of injecting drug users (IDUs) vs. each of the other groups (P<0.001) and failure to complete the 12-month evaluation of IDU vs. heterosexual (P=0.003) and men who have sex with men (MSM) groups (P=0.02). We conclude that transmission categories had a significant influence on several baseline parameters and viroimmunological outcomes following highly active antiretroviral therapy (HAART), as well as on adherence to therapy and to medical appointments.

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Sex differences in HIV: Natural history, pharmacokinetics, and drug toxicity

Cited by 13 publications

References 36 publications

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Cardiovascular disease risk among women living with HIV in North America and Europe

Association of HIV transmission categories with sociodemographic, viroimmunological and clinical parameters of HIV-infected patients

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