Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals

Anderson, Peter L.; Kakuda, Thomas N.; Kawle, Sagar P.; Fletcher, Courtney V.

doi:10.1097/00002030-200310170-00003

Cited by 125 publications

(119 citation statements)

References 30 publications

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“…Other sex differences related to antiretroviral therapy, including pharmacokinetics, pharmacodynamics and toxicities [12][13][14][15][16], have been described. Sex differences in response to HIV infection prior to antiretroviral therapy initiation have also been reported, including differences in CD4 cell counts [3,4], HIV RNA levels [5,6], and possibly HIV-1 disease progression [17,18].…”

Section: Discussionmentioning

confidence: 99%

Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy

et al. 2007

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BackgroundHighly active antiretroviral therapy (HAART) has increased longevity. Currently, women comprise 450% of HIV-infected individuals worldwide. It is not known if there are differences between the sexes in the immunological and virological responses to HAART across the age strata. MethodsImmunological reconstitution and virological response in the first 6 months of a first HAART regimen in two observational clinical HIV-infected cohorts were compared by both sex and age ( 50 vs. o50 years old). ResultsA total of 246 individuals (28% women) were included in the study; 63 cases ( 50 years old) and 183 controls (o50 years old). Over two-thirds of patients had HIV RNA levels o400 HIV-1 RNA copies/mL and CD4 count increases 50 cells/mL at 6 months from therapy initiation. There were no differences in immunological reconstitution across age and sex strata (P 5 0.81) and no differences in virological suppression, even after adjusting for type of HAART (P 5 0.68) or restricting the analysis to women only (P 5 0.81). These results suggest that younger and older women and men may have similar short-term initial HAART outcomes. ConclusionsFurther evaluation of longer term clinical response to initial HAART regimen based on sex and age is indicated, especially with more efficacious and simplified antiretroviral regimens and the associated decrease in mortality.Keywords: age, cohort study, highly active antiretroviral therapy, HIV infection, sex IntroductionWomen account for half of the estimated 46 million HIVinfected adults worldwide [1], and are increasingly affected by the US HIV epidemic [2]. Prior to receiving antiretroviral therapy, younger HIV-infected women have higher CD4 cell counts [3,4] and lower HIV RNA levels [5,6] when compared with HIV-infected men. Levels of endogenous female hormones, or other sex-linked factors, may be an underlying cause of this difference [7,8] and differences in short or longer term treatment responses. Therefore, premenopausal women may respond to a first highly active antiretroviral therapy (HAART) regimen differently from either postmenopausal women or men, regardless of age. In this study, we characterized the 6-month immunological and virological responses to initial HAART by age and sex to clarify sex differences or similarities. MethodsWe relied on the Johns Hopkins University (JHU) and the University of North Carolina (UNC) observational clinical (2) at least three NRTIs. CD4 cell counts and HIV RNA levels obtained closest to 6 months, and within 5-7 months, from therapy initiation were included in the 6 m analysis. All patients 50 years old at HAART initiation were included as cases, and all patients o50 years old at HAART initiation were eligible to be controls and were randomly selected within sex strata at a 1: 3 caseto-control ratio. We excluded 31% of cases (29 of 93) and 36% of controls (108 of 298) because of unavailable BL or 6 m CD4 cell counts and/or HIV RNA levels.Immunological reconstitution was defined as a 425% increase in CD4 cell count from BL to 6 m. A...

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Section: Discussionmentioning

confidence: 99%

Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy

et al. 2007

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“…61,[69][70][71] The half-life of ZDV-TP is about 7 hours and that for 3TC-TP is about 22 hours. 69 These half-lives for the pharmacologically active moieties are several-fold longer than the parent drug in plasma, and form the pharmacokinetic rationale for the dosing frequencies used in patients today (twice daily for ZDV and once-or twice-daily for 3TC). This later point bears special importance and need for reflection.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…16,74 Plasma and intracellular characteristics for ZDV and 3TC are shown in Table 1. 8,51,69 Patient factors that influence the intracellular triphosphate profiles for these drugs are largely unknown, although some in vitro information may give hints to potentially important factors in vivo. 75 First, possible genetic variability in the enzymes responsible for governing NRTI-TP such as deoxycytidine kinase, may be a source of variability for intracellular pharmacology.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

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Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

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“…NRTI pharmacokinetic information is limited because of the difficult procedures needed to measure NRTI anabolites [17], but four studies have been performed investigating relationships between intracellular nucleoside triphosphate concentrations, sex and ARV response among persons taking zidovudine, lamivudine or abacavir [18][19][20][21]. In one study, women had statistically higher intracellular zidovudine and lamuvidine triphosphate concentrations compared with men enrolled in the clinical trial, and were noted to suppress their HIV RNA level to less than 50 copies/ml twice as fast as men [18]. In a second Phase I study of the pharmacokinetics of total zidovudine phosphates (the sum of the mono-, di-and tri-phosphates in peripheral blood mononuclear cells), women's mean total zidovudine phosphate area under the curve was 45% higher compared with men [19].…”

Section: Sex Influence On Pharmacokinetic Profilesmentioning

confidence: 99%

Considerations for the Antiretroviral Management of Women in 2008

Clark

2008

Womens Health (Lond Engl)

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Clinicians should be familiar with sex-specific considerations when managing antiretroviral (ARV) treatment among women. Pregnancy is a critical influence on when to start treatment and what ARVs should be included in a regimen. Sex, pregnancy and hormonal contraceptive therapies can each influence ARV pharmacokinetic profiles. Women may be prone to have higher serum levels with selected ARV treatments, which may improve potency but also increase the risk for toxicities. Several studies have demonstrated that women do have higher frequencies of selected ARV-associated adverse events when compared with men. Although HIV treatment guidelines for nonpregnant women do not differ from men, clinicians should be aware of the high potential for certain ARV-related toxicities and follow suggestions in order to decrease the risk of side effects.The most recent statistics from the US CDC as of March 2008 show that the cumulative total number of women reported to have AIDS in the USA was 189,566 and women accounted for 26% of persons infected with HIV [101]. It has become increasingly clear that women have unique antiretroviral (ARV) management issues and clinicians should be familiar with sex-specific considerations. Women may metabolize selected drugs differently from men, which can result in different ARV pharmacokinetic profiles and the potential for adverse side effects. In addition, women of child-bearing potential have reproductive concerns that include optimal contraception and potential fetal toxicity for selected ARV therapies. When to start ARVsPregnancy status is the first consideration when determining whether to or when to initiate ARVs, since this will affect timing [102,103]. All pregnant women need to initiate ARVs regardless of their CD4 cell count or HIV RNA level. Those who have ARVs initiated only to prevent maternal-fetal transmission can afford to delay starting ARVs until after the first trimester, but others who require medication for their own health can start immediately, regardless of their gestational stage.The decision is more complicated for nonpregnant women. Over the years, the pendulum has swung both ways with regard to early versus late ARV initiation, with CD4 cell count criteria ranging from 500 down to 200 cells/mm 3 for asymptomatic HIV-infected nonpregnant individuals. Experts have carefully weighed possible survival benefits against long-term toxicities demonstrated in cohort studies and randomized clinical trials. The most recent version of the Department of Health and Human Services (DHHS) guidelines from January 2008 recommend initiating ARVs when the CD4 cell count drops to less than 350 cells/mm 3 for both men and nonpregnant women. The consideration for initiating ARVs for nonpregnant individuals with higher CD4 cell counts should take into account the specific patient scenario and comorbidities. Women with HIV-associated nephropathy or those who require treatment for a hepatitis B infection should have HIV treatment initiated, regardless of their CD4 cell count [102].In most c...

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Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals

Cited by 125 publications

References 30 publications

Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy

Effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy

Zidovudine and Lamivudine for HIV Infection

Considerations for the Antiretroviral Management of Women in 2008

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