scholarly journals Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

2012 ◽  
Vol 56 (6) ◽  
pp. 3011-3019 ◽  
Author(s):  
Joseph E. Rower ◽  
Amie Meditz ◽  
Edward M. Gardner ◽  
Kenneth Lichtenstein ◽  
Julie Predhomme ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Antiretroviral Drugs ◽  
Lean Body Weight ◽  
Prospective Longitudinal Study ◽  
Cellular Pharmacology ◽  
Prospective Longitudinal ◽  
Hiv Seropositive ◽  
Hiv 1

ABSTRACTThe cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC)in vivois not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (Css) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higherCssestimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P> 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [−19%, 38%];P= 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [−9%, 20%] and −5% [−26%, 12%] for HIV serostatus and race, respectively;P> 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacologyin vivoand provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.

scholarly journals Higher Selection Pressure from Antiretroviral Drugs in Vivo Results in Increased Evolutionary Distance in HIV-1 pol

Virology ◽  
1999 ◽  
Vol 259 (1) ◽  
pp. 154-165 ◽  
Author(s):  
Huldrych F. Günthard ◽  
Andrew J. Leigh-Brown ◽  
Richard T. D'Aquila ◽  
Victoria A. Johnson ◽  
Daniel R. Kuritzkes ◽  
...  
Keyword(s):  
Selection Pressure ◽  
Antiretroviral Drugs ◽  
Evolutionary Distance ◽  
Hiv 1

scholarly journals Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Said A. Hassounah ◽  
Ahmad Alikhani ◽  
Maureen Oliveira ◽  
Simrat Bharaj ◽  
Ruxandra-Ilinca Ibanescu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Single Cycle ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACT Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC50s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC50), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC50, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC50). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

scholarly journals The Roles of HIV-1 Proteins and Antiretroviral Drug Therapy in HIV-1-Associated Endothelial Dysfunction

2008 ◽  
Vol 56 (5) ◽  
pp. 752-769 ◽  
Author(s):  
Erik R. Kline ◽  
Roy L. Sutliff
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Highly Active Antiretroviral Therapy ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Opportunistic Infections ◽  
Antiretroviral Drugs ◽  
Hiv 1

Since the emergence of highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1)-infected patients have demonstrated dramatic decreases in viral burden and opportunistic infections, and an overall increase in life expectancy. Despite these positive HAART-associated outcomes, it has become increasingly clear that HIV-1 patients have an enhanced risk of developing cardiovascular disease over time. Clinical studies are instrumental in our understanding of vascular dysfunction in the context of HIV-1 infection. However, most clinical studies often do not distinguish whether HIV-1 proteins, HAART, or a combination of these 2 factors cause cardiovascular complications. This review seeks to address the roles of both HIV-1 proteins and antiretroviral drugs in the development of endothelial dysfunction because endothelial dysfunction is the hallmark initial step of many cardiovascular diseases. We analyze recentin vitroandin vivostudies examining endothelial toxicity in response to HIV-1 proteins or in response to the various classes of antiretroviral drugs. Furthermore, we discuss the multiple mechanisms by which HIV-1 proteins and HAART injure the vascular endothelium in HIV-1 patients. By understanding the molecular mechanisms of HIV-1 protein- and antiretroviral-induced cardiovascular disease, we may ultimately improve the quality of life of HIV-1 patients through better drug design and the discovery of new pharmacological targets.

scholarly journals A Polymorphism in the Regulatory Region of the CC-Chemokine Receptor 5 Gene Influences Perinatal Transmission of Human Immunodeficiency Virus Type 1 to African-American Infants

1999 ◽  
Vol 73 (12) ◽  
pp. 10264-10271 ◽  
Author(s):  
Leondios G. Kostrikis ◽  
Avidan U. Neumann ◽  
Bruce Thomson ◽  
Bette T. Korber ◽  
Paul McHardy ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
African American ◽  
African Americans ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Regulatory Region ◽  
Perinatal Hiv ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT There are natural mutations in the coding and noncoding regions of the human immunodeficiency virus type 1 (HIV-1) CC-chemokine coreceptor 5 (CCR5) and in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygous for the CCR5-Δ32 allele, which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5′ regulatory region, some of which influence the rate of disease progression in adult AIDS study cohorts. We genotyped 1,442 infants (1,235 uninfected and 207 HIV-1 infected) for five CCR5 and CCR2 polymorphisms: CCR5-59353-T/C, CCR5-59356-C/T CCR5-59402-A/G, CCR5-Δ32, and CCR2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 AZT-untreated mother-infant pairs (554 uninfected and 113 HIV-1 infected). We found that the mutant CCR5-59356-T allele is relatively common in African-Americans (20.6% allele frequency among 552 infants) and rare in Caucasians and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively;P < 0.001). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were African-Americans. Among the African-American infants in the AZT-untreated group, there was a highly significant increase in HIV-1 transmission to infants with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those with no or one mutant allele (13.4 to 14.1% of 187 and 71, respectively;P < 0.001). The increased relative risk was 5.9 (95% confidence interval, 2.3 to 15.3; P < 0.001). The frequency of the CCR5-59356-T mutation varies between population groups in the United States, a low frequency occurring in Caucasians and a higher frequency occurring in African-Americans. Homozygosity for CCR5-59356-T is strongly associated with an increased rate of perinatal HIV-1 transmission.

scholarly journals Predictive Markers of Clinical Outcome in Vertically HIV-1–Infected Infants. A Prospective Longitudinal Study

2000 ◽  
Vol 47 (4) ◽  
pp. 509-515 ◽  
Author(s):  
Salvador Resino ◽  
Dolores Gurbindo ◽  
Jose Maria Bellń Cano ◽  
Silvia Sanchez-Ramón ◽  
Angeles Muñoz-Fernández
Keyword(s):  
Longitudinal Study ◽  
Clinical Outcome ◽  
Predictive Markers ◽  
Prospective Longitudinal Study ◽  
Prospective Longitudinal ◽  
Hiv 1

scholarly journals Associations between Perceived Racial Discrimination and Tobacco Cessation among Diverse Treatment Seekers

2020 ◽  
Vol 30 (3) ◽  
pp. 411-420
Author(s):  
Monica Webb Hooper ◽  
Patricia Calixte-Civil ◽  
Christina Verzijl ◽  
Karen O. Brandon ◽  
Taghrid Asfar ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Tobacco Cessation ◽  
Perceived Discrimination ◽  
Controlled Trial ◽  
Ethnic Discrimination ◽  
Post Intervention ◽  
American Black ◽  
Prospective Longitudinal ◽  
Racial Ethnic

Objectives: This study investigated a) racial/ethnic differences in past-year discrimination experiences and b) associa­tions between discrimination and smoking abstinence.Design: Prospective, longitudinal analysis of smoking status. Perceived past-year discrimi­nation was assessed at baseline. ANCOVAs and intent-to-treat hierarchical logistic regressions were conducted.Setting: Dual-site (Tampa, FL and Miami, FL) randomized controlled trial testing the effects of a group cessation intervention plus pharmacotherapy.Participants: Treatment-seeking adult smokers (N=347; non-Hispanic White, non-Hispanic African American/Black, or Hispanic).Main Outcome Measures: Biochemically verified 7-day point prevalence abstinence (7-day ppa) was assessed immediately post-intervention and at 6-month follow-up.Results: After controlling for covari­ates, African Americans/Blacks reported greater perceived discrimination compared with non-Hispanic Whites (P=.02), and Hispanics (P=.06). Non-Hispanic Whites and Hispanics did not differ in perceived racial/ethnic discrimination experiences over the past year. Irrespective of race/ ethnicity, past-year perceived discrimina­tion was inversely associated with 7-day ppa, both post-intervention (AOR=.97, CI: .95-.99) and at 6-months (AOR=.98, CI: .96-.99). Among African Americans/Blacks, past-year perceived discrimination was inversely associated with 7-day ppa, both post-intervention (AOR=.95, CI: .92-.97) and at 6-months (AOR=.97, CI: .94-.99). Perceived discrimination was unrelated to 7-day ppa among Hispanics. Among non-Hispanic Whites, past-year perceived discrimination was inversely associated with post-intervention 7-day ppa (AOR=.95, CI: .91-.99), but not 6-months.Conclusions: Perceived racial/ethnic discrimination was greater among African American/Black smokers compared with non-Hispanic Whites. Perceived discrimina­tion was negatively associated with tobacco cessation in the full sample, and for African Americans at 6-months post-intervention. These data have implications for interven­tion delivery and health disparities.Ethn Dis. 2020;30(3):411-420; doi:10.18865/ed.30.3.411

scholarly journals Theoretical Design of a Gene Therapy To Prevent AIDS but Not Human Immunodeficiency Virus Type 1 Infection

2003 ◽  
Vol 77 (18) ◽  
pp. 10028-10036 ◽  
Author(s):  
Leor S. Weinberger ◽  
David V. Schaffer ◽  
Adam P. Arkin
Keyword(s):  
Gene Therapy ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiretroviral Drugs ◽  
Set Point ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Recent reports confirm that, due to the presence of long-lived, latently infected cell populations, eradication of human immunodeficiency virus type 1 (HIV-1) from infected patients by using antiretroviral drugs will be exceedingly difficult. An alternative to virus eradication may be to use gene therapy to induce a pseudo-latent state in virus-producing cells, thus transforming HIV-1 into a lifelong, but manageable, virus. Conditionally replicating HIV-1 (crHIV-1) gene therapy vectors provide an avenue for subduing HIV-1 expression in infected cells (by creating a parasite, crHIV-1, of the parasite HIV-1), potentially reducing the HIV-1 set point and delaying AIDS onset. Development of crHIV-1 vectors has proceeded in vitro, but the requirements for a crHIV-1 vector to proliferate and persist in vivo have not been explored. We expand a widely accepted mathematical model of HIV-1 in vivo dynamics to include a crHIV-1 gene therapy virus and derive a simple criterion for designing crHIV-1 viruses that will persist in vivo. The model introduces only two new parameters—HIV-1 inhibition and crHIV-1 production—and both can be experimentally engineered and controlled. Analysis demonstrates that crHIV-1 gene therapy can indefinitely reduce HIV-1 set point to levels comparable to those achieved with highly active antiretroviral therapy, provided crHIV-1 production is more efficient than HIV-1. Paradoxically, highly efficient therapeutic inhibition of HIV-1 was found to be disadvantageous. Thus, the field may benefit by shifting the search for more potent antiviral genes toward engineering optimized therapy viruses that package ultraefficiently while downregulating viral production moderately.

scholarly journals Guided Imagery for Stress and Symptom Management in Pregnant African American Women

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Nancy Jallo ◽  
R. Jeanne Ruiz ◽  
R. K. Elswick ◽  
Elise French
Keyword(s):  
African American ◽  
African American Women ◽  
Perceived Stress ◽  
Stress Reduction ◽  
Guided Imagery ◽  
Daily Stress ◽  
Prospective Longitudinal Study ◽  
American Women ◽  
Biologic Marker ◽  
Prospective Longitudinal

The purpose of this study was to evaluate the efficacy of a guided imagery (GI) intervention for stress reduction in pregnant African American women beginning early in the second trimester. This prospective longitudinal study of 72 women used a randomized controlled experimental design with two groups conducted over 12 weeks. The intervention was a CD with 4 professionally recorded tracts designed and sequenced to influence study variables. Participants in both GI and usual care (UC) completed measures and donated 5 cc of blood at baseline, 8 weeks and 12 weeks. Participants also completed a daily stress scale. A mixed-effects linear model tested for differences between groups for self-reported measures of stress, anxiety, and fatigue as well as corticotrophin releasing hormone (CRH), a biologic marker of stress. Significant differences in perceived stress daily scores and at week 8 but not week 12 were found in the GI group compared to UC group. The GI group reported significantly less fatigue and anxiety than the UC group at week 8 but not week 12. There were no significant differences in CRH levels between groups. Results suggest that GI intervention may be effective in reducing perceived stress, anxiety, and fatigue measures among pregnant African American women.

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