Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202

Venuto, Charles S.; Mollan, Katie R.; Ma, Qing; Daar, Eric S.; Sax, Paul E.; Fischl, Margaret A.; Collier, Ann C.; Smith, Kimberly Y.; Tierney, Camlin; Morse, Gene D.; Bolívar, Héctor; Navarro, Sandi L.; Koletar, Susan L.; Gochnour, Diane; Seefried, E.; Hoffman, Julie; Feinberg, Judith; Saemann, M.; Patterson, Kristine B.; Pittard, D.; Upton, Kyle R.; Saag, Michael S.; Ray, G. Thomas; Johnson, Steven C.; Santos, Bartolo; Funk, Clare A.; Morgan, Mike; Jackson, Beth; Tebas, Pablo; Thomas, Aleshia; Kim, G.-Y.; Klebert, Michael; Santana, Jorge; Marrero, Sara; Norris, J.; Valle, Sandra Costa; Cox, Gary M.; Silberman, Martha; Shaik, S.; López, Rosa María; Vasquez, Matthew; Daskalakis, Demetre; Megill, Christina; Stroberg, Todd; Shore, Jessica; Taiwo, Babafemi; Goldman, Mitchell; Boston, Mark; Lennox, Jeffrey L.; Río, Carlos del; Lane, Timothy W.; Epperson, K.; Luetkemeyer, Anne F; Payne, Miranda; Gripshover, Barbara; Antosh, Danielle D.; Reid, Joel R.; Adams, M. Jacob; Storey, S. S.; Dunaway, Shelia B.; Gallant, Joel E.; Wiggins, Ilene; Świątek, Joanna; Timpone, Joseph; Kumar, Priti; Moe, Andrew; Palmer, Maria; Gothing, Jon A; Delaney, Joseph A.; Whitely, K.; Anderson, Albert M.; Hammer, Scott M.; Yin, Michael T.; Jain, Mamta K.; Petersen, Tess; Corales, Roberto; Hurley, Christine; Henry, Keith; Bordenave, B.; Youmans, Anne S.; Albrecht, Mary; Pollard, Richard B.; Olusanya, Aralola; Skolnik, Paul R.; Adams, Bonne J.; Tashima, Karen T.; Patterson, Helen; Ukwu, M.; Rogers, Lisa; Balfour, Henry H.; Fox, K. A.; Swindells, Susan; Meter, F. Van; Robbins, Gregory; Burgett-Yandow, N.; Davis, C. E.; Boyce, Catherine; O’Brien, William A.; Casey, Gerard J.; Hsaio, C.-B.; Meier, Julian; Stapleton, Jack T.; Mildvan, Donna; Revuelta, Manuel; Currin, D.; Sadr, Wafaa El; Loquere, A.; El-Daher, Nayef; Johnson, Tamara; Gross, Robert; Maffei, K.; Hughes, Valery; Sturge, G.; McMahon, Deborah; Rutecki, B.; Wulfsohn, Michael; Cheng, Andrew; Bischofberger, Norbert; Dix, Lynn P.; Liao, Qiming

doi:10.1093/jac/dku303

Cited by 16 publications

(12 citation statements)

References 28 publications

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“…Nevertheless, antiretroviral strategy and demographic data were not described in Fayet's study, raising questions about the reasons for such a difference compared with our study. Venuto et al reported a significant difference for total concentrations between male and female patients with HIV infection under ATV treatment, although this was not the case in our study, either for total or unbound concentrations. Although TDF is known to decrease ATV exposure , both total and unbound concentrations were not statistically different between patients with and without TDF co‐administration.…”

Section: Discussioncontrasting

confidence: 96%

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

Metsu

Seraissol

Delobel

et al. 2016

Fundam Clin Pharmacol

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To date, therapeutic drug monitoring (TDM) is carried out with antiretrovirals and is usually based on total concentrations (C ). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir (ATV), a HIV protease inhibitor. As the unbound concentration (C ) is the pharmacological active form, the aim of the study was to evaluate the value of C and the unbound fraction (f , f = C /C ) for the TDM of ATV. The variability of C and the corresponding f of ATV was explored in 43 patients treated with ATV for an average of 13.5 months. C was determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein (AAG), the correlation between f and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough C and C were 37.9 μg/L (Interquartile range (IQR) 20.6-94.9 μg/L) and 628.6 μg/L (IQR 362.7-1078.1 μg/L), respectively. f , C and C showed high variability, but the f variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response (P = 0.21 and P = 0.65 for C and f , respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for C ). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than C .

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Section: Discussioncontrasting

confidence: 96%

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

Metsu

Seraissol

Delobel

et al. 2016

Fundam Clin Pharmacol

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“…In fact, most of the studies cited above had a much higher proportion of men than women. We are starting to appreciate the impact of sex on the safety and efficacy of cART 48,49 . But, similar to lessons learned from studying the independent impact of race on HIV outcomes 50 , a dedicated effort to specifically study the impact of sex on HIV outcomes must also be a priority.…”

Section: Discussionmentioning

confidence: 99%

Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation

Mathad

Gupte

Balagopal

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Women progress to death at the same rate as men despite lower plasma HIV RNA (VL). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. Methods Inflammatory and immune activation markers (IFN-γ, TNF-α, IL-6, IL-18, IP-10, CRP, LPS, sCD14) were measured at weeks 0, 24, and 48 post-cART in a random subcohort (n=215) who achieved virologic suppression in ACTG A5175 (PEARLS). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95%CI were estimated using multivariable models. Results At baseline, women had lower median log10VL (4.93 vs 5.18 copies/mL, p=0.01), CRP (2.32 vs 4.62 mg/L, p=0.01), detectable LPS (39% vs 55%, p=0.04), and sCD14 (1.9 vs 2.3 mcg/mL, p=0.06) versus men. By week 48, women had higher IFN-γ (22.4 vs 14.9 pg/mL, p=0.05), TNF-α (11.5 vs 9.5 pg/mL, p=0.02), and CD4 (373 vs 323 cells/mm3, p=0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared to men. Conclusions With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

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“…Sex-based differences in the pharmacokinetics, bioavailability, distribution, and metabolism of drugs have been reviewed [ 32 ] and differences in the clearance of ART have been described [ 111 ]. Factors such as body weight, fat distribution, intestinal absorption, protein binding and affinity, metabolism and excretion, and other metabolic functions differ between sexes [ 112 ] and might affect the distribution of the HIV reservoir within anatomic compartments.…”

Section: Discussionmentioning

confidence: 99%

Barriers to a cure for HIV in women

Gianella

Tsibris

Barr

et al. 2016

Journal of the International AIDS Society

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IntroductionDistinct biological factors exist that affect the natural history of HIV and the host immune response between women and men. These differences must be addressed to permit the optimal design of effective HIV eradication strategies for much of the HIV-positive population.Methods and resultsHere, we review the literature on sex-based differences in HIV pathogenesis and natural history in tissues and anatomic compartments, HIV latency and transcriptional activity, and host immunity including the role of sex hormones. We then outline the potential effects of these differences on HIV persistence, and on the safety and efficacy of HIV eradication and curative interventions. Finally, we discuss the next steps necessary to elucidate these factors to achieve a cure for HIV, taking in account the complex ethical issues and the regulatory landscape in the hopes of stimulating further research and awareness in these areas.ConclusionsTargeted enrolment of women in clinical trials and careful sex-based analysis will be crucial to gain further insights into sex-based differences in HIV persistence and to design sex-specific approaches to HIV eradication, if required.

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Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202

Abstract: Atazanavir clearance differed by sex. Females with fast clearance and males with slow clearance had increased risk of virological failure.

Cited by 16 publications

References 28 publications

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

Is the unbound concentration of atazanavir of interest in therapeutic drug monitoring?

Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation

Barriers to a cure for HIV in women

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