RESUMO
BACKGROUND: A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). METHODS: A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues. RESULTS: The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue. CONCLUSIONS: This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Feminino , Previsões , Humanos , Masculino , New York , Profilaxia Pré-Exposição/tendências , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC0-12) and concentration prior to dosing (Cpredose) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC0-12 or Cpredose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacologia , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Humanos , Lopinavir/sangue , Lopinavir/farmacologia , Gravidez , Terceiro Trimestre da Gravidez , Ritonavir/sangue , Ritonavir/farmacologia , Comprimidos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.
Assuntos
Fármacos Anti-HIV/farmacologia , Sulfato de Atazanavir/farmacologia , Darunavir/farmacologia , Infecções por HIV , HIV-1 , Raltegravir Potássico/farmacologia , Ritonavir/farmacologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/uso terapêutico , Glicemia/efeitos dos fármacos , Darunavir/administração & dosagem , Darunavir/uso terapêutico , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lipídeos/sangue , Masculino , Raltegravir Potássico/administração & dosagem , Raltegravir Potássico/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/uso terapêuticoRESUMO
BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Sulfato de Atazanavir , Darunavir , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina , Feminino , Inibidores da Protease de HIV/efeitos adversos , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Oligopeptídeos/uso terapêutico , Organofosfonatos/uso terapêutico , Piridinas/uso terapêutico , RNA Viral/isolamento & purificação , Inibidores da Transcriptase Reversa , Sulfonamidas/uso terapêutico , Tenofovir , Equivalência Terapêutica , Carga ViralRESUMO
BACKGROUND: While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)-mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery. OBJECTIVE: We assessed whether the extent of persistent CD8+ T-cell activation (% CD38+/HLA-DR+) in the first few years of ART-mediated viral suppression predicted subsequent CD4+ T-cell recovery in 95 subjects with up to 15 years of observation on suppressive ART. RESULTS: Lower CD8+ T-cell activation and higher naïve CD4+ T-cell frequencies (CD45RA+/CD62L+) measured at year 3 to 5 after starting ART independently predicted greater subsequent CD4+ T-cell increases. The mean CD4 count increase from year 0 to year 5 and the increase to the average of year 10 to 15 in the low CD8 activation group (≤18.5%; mean = 13%) were 342 and 458 cells/mm,3 and the increases were 248 and 349 cells/mm3 for the high CD8 activation group (â¯18.5%; mean = 29%) (P = .002 and P = .016, respectively, comparing groups). At years 10 to 15, the mean CD4 counts in the groups were 579 and 484 cells/mm3, respectively (P = .026). CONCLUSION: These findings support the need to identify approaches to reduce immune activation in treated HIV disease.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Ativação Linfocitária , Adulto , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. METHODS: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. RESULTS: SP AUCs were â¼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were â¼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). CONCLUSIONS: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. CLINICAL TRIALS REGISTRATION: NCT00775294.
Assuntos
Fármacos Anti-HIV/farmacocinética , Cicloexanos/farmacocinética , Reto/metabolismo , Saliva/química , Sêmen/química , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/análise , Fármacos Anti-HIV/sangue , Área Sob a Curva , Cicloexanos/análise , Cicloexanos/sangue , Esquema de Medicação , Humanos , Masculino , Maraviroc , Triazóis/análise , Triazóis/sangue , Adulto JovemRESUMO
Menopause may affect antiretroviral treatment (ART) response. Immunologic and virologic responses to ART were compared in 220 premenopausal and 47 postmenopausal women enrolled in 2 studies involving ART-naive persons. Changes in CD4 counts or human immunodeficiency virus type 1 RNA levels were similar at 24, 48, and 96 weeks after treatment initiation. ART-naive women should respond to ART regardless of menopausal status.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade/métodos , HIV-1/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Contagem de Linfócito CD4 , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Resultado do Tratamento , Estados Unidos , Carga ViralRESUMO
The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Líquido Amniótico/metabolismo , Fármacos Anti-HIV/farmacocinética , Sangue Fetal/metabolismo , Genitália Feminina/metabolismo , HIV-1 , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/biossíntese , Feminino , Genitália Feminina/virologia , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Gravidez , RNA Viral/sangueRESUMO
OBJECTIVE: The aim of this study was to evaluate postpartum HIV care outcomes. DESIGN: A prospective clinical cohort of women with HIV and a live birth at the University of North Carolina, 1996-2014. METHODS: We estimated two stages of the HIV care continuum in the first 24 months postpartum: care retention (at least two visits per year, ≥90 days apart) and viral suppression (HIV RNAâ<â400âcopies/ml). Multivariable models were fit using logistic regression. RESULTS: Among 1416 women, 141 experienced a live birth at a median age of 28 years, with 74% virally suppressed at delivery. Among all women, 48% were retained in care and 25% maintained viral suppression for the first 24 months postpartum. Among women with available HIV RNA measures, 42% were suppressed at 24 months. HIV care retention estimates were stable across calendar years, but viral suppression rates at 24 months postpartum, among women with available HIV RNA measures, increased from 33 to 67% from 1996-2001 to 2009-2014 (Pâ=â0.04). Being at least 30 years old was positively, and receiving less than 12 weeks of antenatal antiretroviral therapy was negatively, associated with HIV care retention at 24 months postpartum [adjusted odds ratio (AOR): 2.41, 95% confidence interval (95% CI): 1.09-5.29 and AOR: 0.27, 95% CI: 0.08-0.86]. Older maternal age and viral suppression at delivery were both positively associated with virologic suppression at 24 months postpartum (AOR: 2.52, CI: 1.02-6.22, and AOR: 6.42 CI: 1.29-31.97, respectively). CONCLUSION: HIV care continuum outcomes decrease substantially postpartum, with younger women and those with less antenatal HIV care less likely to successfully remain engaged in HIV care following childbirth.
Assuntos
Continuidade da Assistência ao Paciente , Gerenciamento Clínico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Período Pós-Parto , Adolescente , Adulto , Feminino , HIV/isolamento & purificação , Humanos , Recém-Nascido , North Carolina , Estudos Prospectivos , Retenção nos Cuidados , Resposta Viral Sustentada , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Universal prenatal HIV antibody testing, which does not detect acute HIV, is standard for pregnant women in the United States. Unrecognized HIV acquisition during pregnancy may result in higher rates of perinatal transmission. OBJECTIVE: To determine the prevalence of acute (antibody-negative) HIV infection in pregnant women and to assess the potential for prompt initiation of antiretroviral therapy to prevent perinatal transmission. METHODS: From 1 November 2002 to 30 April 2005, all publicly funded HIV testing sites participated in North Carolina's Screening and Tracing Active Transmission (STAT) Program, which retested all specimens that were HIV antibody negative for HIV RNA using specimen pooling. All patients with acute HIV infection were immediately traced for evaluation, confirmatory testing, counseling, and referral services. For this study, all pregnant women with acute HIV were immediately initiated onto antiretroviral therapy and followed prospectively for pregnancy outcomes. RESULTS: During the study period, 443 women were HIV positive by antibody testing; 15 were HIV antibody negative but positive by RNA assay and of these five were pregnant at the time of testing. The pregnant women received antiretroviral drugs and delivered HIV-uninfected infants. Maternal testing records of all six HIV-infected infants born in North Carolina showed three mothers with chronic HIV infection and three HIV antibody negative at private prenatal testing facilities. CONCLUSIONS: In resource-rich settings, a substantial proportion of residual perinatal transmission may be from HIV acquisition during pregnancy. Standard antibody tests miss acute HIV infection and so algorithms that include pooled HIV RNA testing may improve its detection and represent a further opportunity to prevent perinatal transmission.
Assuntos
Algoritmos , Infecções por HIV/diagnóstico , HIV , Complicações Infecciosas na Gravidez/diagnóstico , RNA Viral/sangue , Doença Aguda , Fármacos Anti-HIV/uso terapêutico , Feminino , Seguimentos , HIV/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Soropositividade para HIV/diagnóstico , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Programas de Rastreamento/métodos , North Carolina , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Segundo Trimestre da Gravidez , Cuidado Pré-Natal/métodos , Prevalência , Zidovudina/uso terapêuticoRESUMO
OBJECTIVES: To describe first dose and steady state antiretroviral drug exposure in the female genital tract. DESIGN: Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women. METHOD: Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state. Drug concentrations were measured by validated HPLC/UV or HPLC-MS/MS methods. Pharmacokinetic parameters were estimated for 11 drugs by non-compartmental analysis. Descriptive statistics and 95% confidence intervals were generated using Intercooled STATA Release 8.0 (Stata Corporation, College Station, Texas, USA). RESULTS: For all antiretroviral drugs, genital tract concentrations were detected rapidly after the first dose. Drugs were stratified according to the genital tract concentrations achieved relative to blood plasma. Median rank order of highest to lowest genital tract concentrations relative to blood plasma at steady state were: lamivudine (concentrations achieved were 411% greater than blood plasma), emtricitabine (395%), zidovudine (235%) tenofovir (75%), ritonavir (26%), didanosine (21%), atazanavir (18%), lopinavir (8%), abacavir (8%), stavudine (5%), and efavirenz (0.4%). CONCLUSIONS: This is the first study to comprehensively evaluate antiretroviral drug exposure in the female genital tract. These findings support the use of lamivudine, zidovudine, tenofovir and emtricitabine as excellent pre-exposure/post-exposure prophylaxis (PrEP/PEP) candidates. Atazanavir and lopinavir might be useful agents for these applications due to favorable therapeutic indices, despite lower genital tract concentrations. Agents such as stavudine, abacavir, and efavirenz that achieve genital tract exposures less than 10% of blood plasma are less attractive PrEP/PEP candidates.
Assuntos
Antirretrovirais/administração & dosagem , Genitália Feminina/metabolismo , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/sangue , Adenina/farmacocinética , Administração Oral , Adulto , Alcinos , Antirretrovirais/sangue , Antirretrovirais/farmacocinética , Sulfato de Atazanavir , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Benzoxazinas/farmacocinética , Ciclopropanos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/sangue , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Humanos , Lamivudina/administração & dosagem , Lamivudina/sangue , Lamivudina/farmacocinética , Lopinavir , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/sangue , Organofosfonatos/farmacocinética , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinonas/administração & dosagem , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir , Zidovudina/administração & dosagem , Zidovudina/sangue , Zidovudina/farmacocinéticaRESUMO
Zidovudine-based antiretroviral therapies (ARTs) for treatment of HIV-infected pregnant women have markedly reduced mother-to-child transmission of the human immunodeficiency virus (HIV-1) from approximately 25% to <1%. However, zidovudine (ZDV; AZT), a nucleoside analogue, induces chromosomal damage, gene mutations, and cancer in animals following direct or transplacental exposure. To determine if chromosomal damage is induced by ZDV in infants exposed transplacentally, we evaluated micronucleated reticulocyte frequencies (%MN-RET) in 16 HIV-infected ART-treated mother-infant pairs. Thirteen women received prenatal ART containing ZDV; three received ART without ZDV. All infants received ZDV for 6 weeks postpartum. Venous blood was obtained from women at delivery and from infants at 1-3 days, 4-6 weeks, and 4-6 months of life; cord blood was collected immediately after delivery. Ten cord blood samples (controls) were obtained from infants of HIV-uninfected women who did not receive ART. %MN-RET was measured using a single laser 3-color flow cytometric system. Tenfold increases in %MN-RET were seen in women and infants who received ZDV-containing ART prenatally; no increases were detected in three women and infants who received prenatal ART without ZDV. Specifically, mean %MN-RET in cord blood of ZDV-exposed infants was 1.67 +/- 0.34 compared with 0.16 +/- 0.06 in non-ZDV ART-exposed infants (P = 0.006) and 0.12 +/- 0.02 in control cord bloods (P < 0.0001). %MN-RET in ZDV-exposed newborns decreased over the first 6 months of life to levels comparable to cord blood controls. These results demonstrate that transplacentalZDV exposure is genotoxic in humans. Long-term monitoring of HIV-uninfected ZDV-exposed infants is recommended to ensure their continued health.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Mutagênicos/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Zidovudina/efeitos adversos , Adolescente , Adulto , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Masculino , Troca Materno-Fetal , Período Pós-Parto , Gravidez , Reticulócitos/efeitos dos fármacosRESUMO
BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor approved for 200 mg twice-daily dosing in conjunction with other antiretrovirals (ARVs), has pharmacokinetic properties which support once-daily dosing. METHODS: In this single-arm, open-label study, 79 treatment-naive HIV-infected adults were assigned to receive ETR 400 mg plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 300/200 mg once daily to assess antiviral activity, safety and tolerability. ARV activity at 48 weeks was determined by proportion of subjects with HIV-1 RNA<50 copies/ml (intention-to-treat, missing = failure). RESULTS: Of 79 eligible subjects, 90% were men, 62% African-American and 29% Caucasian. At baseline, median (Q1, Q3) age was 29 years (23, 44) and HIV-1 RNA 4.52 log10 copies/ml (4.07, 5.04). A total of 69 (87%) completed a week 48 visit and 61 (77%, 95% CI 66%, 86%) achieved HIV-1 RNA<50 copies/ml at week 48. At time of virological failure, genotypic resistance-associated mutations were detected in three participants, two with E138K (one alone and one with additional mutations). Median (95% CI) CD4(+) cell count increase was 163 (136, 203) cells/µl. Fifteen (19.0%) participants reported a new sign/symptom or lab abnormality ≥ Grade 3 and three participants (3.8%) permanently discontinued ETR due to toxicity. Two participants had psychiatric symptoms of any grade. There were no deaths. CONCLUSIONS: In this study of ARV-naive HIV-positive adults, once-daily ETR with TDF/FTC had acceptable antiviral activity and was well-tolerated. Once-daily ETR may be a plausible option as part of a combination ARV regimen for treatment-naive individuals. ClinicalTrials.gov NCT00959894.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Piridazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Biomarcadores , Contagem de Linfócito CD4 , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Nitrilas , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Pirimidinas , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Fatores de Tempo , Falha de Tratamento , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized. METHODS: Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. RESULTS: CVF exposure increased linearly with dose for all antiretrovirals (r(2) ≥ 0.23, P ≤ 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r(2) ≥ 0.37, rectal tissue (2)r ≥ 0.50, P ≤ 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) ≥ 0.81, P < 0.001). The same was noted for rectal tissue (r(2) ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r(2) = 0.91, P < 0.001). CONCLUSIONS: Mucosal fluids were positively correlated with tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.
Assuntos
Fármacos Anti-HIV/farmacocinética , Líquidos Corporais/metabolismo , Colo do Útero/metabolismo , Ensaios Clínicos como Assunto/métodos , Reto/metabolismo , Vagina/metabolismo , Adulto , Biomarcadores/análise , Líquidos Corporais/efeitos dos fármacos , Colo do Útero/efeitos dos fármacos , Cicloexanos/farmacocinética , Emtricitabina/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Maraviroc , Raltegravir Potássico/farmacocinética , Reto/efeitos dos fármacos , Tenofovir/farmacocinética , Triazóis/farmacocinética , Vagina/efeitos dos fármacosRESUMO
BACKGROUND: HIV may amplify immunological, physiological and functional changes of ageing. We determined associations of frailty phenotype, a T-cell senescence marker (p16(INK4a) expression), age and demographics with exposures of the intracellular metabolites (IM) and endogenous nucleotides (EN) of tenofovir/emtricitabine (TFV/FTC), efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV). METHODS: Plasma and peripheral blood mononuclear cell samples for drug, IM and EN concentrations were collected at four time points in HIV+ adults receiving TFV/FTC with EFV or ATV/RTV. Subjects underwent frailty phenotyping and p16(INK4a) expression analysis. Non-compartmental analysis generated an area under the curve (AUC) for each analyte. Spearman rank correlation and Kruskal-Wallis tests were used to assess associations between AUC, demographics and ageing markers, adjusting for multiple comparisons with the Holm procedure. RESULTS: Subjects (n=79) ranged in age from 22-73 years (median 48 years); 48 were African-American, 24 were female, 54 received EFV. Three subjects (range 51-60 years) demonstrated frailty, with 17 subjects (range 26-60 years) demonstrating pre-frailty. Negative associations were observed between p16(INK4a) expression and each of FTC-triphosphate (r=-0.45), deoxyadenosine triphosphate (dATP; r=-0.47) and deoxycytidine triphosphate (dCTP; r=-0.57) AUCs (P-values <0.02). TFV and FTC AUCs were larger among subjects with lower renal function or higher chronological age (P-values ≤0.05). No associations were observed for EFV, ATV or RTV AUCs. CONCLUSIONS: Associations of IM/EN exposure and p16(INK4a) expression observed here suggest that senescence may alter drug phosphorylation, metabolism or transport. This finding warrants further mechanistic study to ensure optimal treatment in the ageing HIV+ population. Clinicaltrials.gov NCT01180075.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Emtricitabina/administração & dosagem , Emtricitabina/farmacocinética , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Tenofovir/administração & dosagem , Tenofovir/farmacocinética , Adulto , Idoso , Envelhecimento/genética , Envelhecimento/metabolismo , Alcinos , Fármacos Anti-HIV/sangue , Sulfato de Atazanavir/administração & dosagem , Benzoxazinas/administração & dosagem , Ciclopropanos , Quimioterapia Combinada , Emtricitabina/sangue , Feminino , Expressão Gênica , Infecções por HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/sangue , Ritonavir/administração & dosagem , Tenofovir/sangue , Adulto JovemRESUMO
Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4(+) TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/10(6) PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes.
Assuntos
Fármacos Anti-HIV/farmacocinética , Emtricitabina/farmacocinética , Cooperação do Paciente/estatística & dados numéricos , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/sangue , Benchmarking , Líquidos Corporais/química , Esquema de Medicação , Emtricitabina/sangue , Feminino , Infecções por HIV/prevenção & controle , Voluntários Saudáveis , Humanos , Masculino , Profilaxia Pré-Exposição , Curva ROC , Comprimidos , Tenofovir/sangueRESUMO
BACKGROUND: This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP). METHODS: Three cohorts of women were enrolled sequentially in a single-site, open-label pharmacokinetic study of oral raltegravir 400 mg twice daily: HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women. BP and CVF were collected over 12 h after a single observed dose and at steady state. RAL concentrations were measured by HPLC-MS methods. Data are expressed as median (IQR). The ANOVA rank-sum test was used to evaluate between-group differences in steady state raltegravir exposure (area under the concentration-time curve over the 12-h dosing interval [AUC0-12 h]). RESULTS: First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV-infected post-menopausal women only. The median (IQR) BP AUC0-12 h was 3,099 (985-5,959) and 4,239 (2,781-13,695) ngâ¢h/ml and the median (IQR) CVF AUC0-12 h was 1,720 (305-5,288) and 13,797 (11,066-19,563) ngâ¢h/ml for HIV-negative premenopausal and HIV-infected post-menopausal women, respectively. All cohorts contributed to steady-state pharmacokinetic profiles. Median (IQR) BP AUC0-12 h did not differ between the groups: 8,436 (3,080-10,111), 5,761 (1,801-10,095) and 6,180 (5,295-8,282) ngâ¢h/ml in HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women, respectively. There was a trend for lower CVF AUC0-12 h among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,725-17,138) and 9,568 (4,271-24,306) ngâ¢h/ml HIV-infected premenopausal and HIV-infected post-menopausal women, respectively, but this was not statistically significant (P=0.08). HIV-negative premenopausal women had a median (IQR) CVF:BP AUC0-12 h ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF:BP AUC0-12 h ratio of 3.9 (1.2-6.7) and 1.4 (0.7-4.3), respectively. CONCLUSIONS: This is the first study to investigate RAL exposure in BP and CVF in premenopausal HIV-negative and pre- and post-menopausal HIV-infected women. These data indicate HIV and menopausal status may influence antiretroviral distribution into the female genital tract.
Assuntos
Fármacos Anti-HIV/farmacocinética , Genitália Feminina/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Menopausa , Raltegravir Potássico/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Estudos de Coortes , Feminino , Genitália Feminina/virologia , Infecções por HIV/virologia , Humanos , Pessoa de Meia-Idade , Raltegravir Potássico/administração & dosagem , Adulto JovemRESUMO
The population of older people living with HIV in the United States is growing. Little is known about specific challenges older HIV-infected women face in coping with the disease and its attendant stressors. To understand these issues for older women, we conducted semi-structured in-depth interviews with 15 women (13 African American, 2 Caucasian) 50 years of age and older (range 50-79 years) in HIV care in the southeastern United States, and coded transcripts for salient themes. Many women felt isolated and inhibited from seeking social connection due to reluctance to disclose their HIV status, which they viewed as more shameful at their older ages. Those receiving social support did so mainly through relationships with family and friends, rather than romantic relationships. Spirituality provided great support for all participants, although fear of disclosure led several to restrict connections with a church community. Community-level stigma-reduction programs may help older HIV-infected women receive support.
Assuntos
Adaptação Psicológica , Negro ou Afro-Americano/psicologia , Infecções por HIV/psicologia , Autorrevelação , Vergonha , Estigma Social , Apoio Social , Espiritualidade , Idoso , Envelhecimento , Revelação , Feminino , Amigos , Infecções por HIV/etnologia , Humanos , Relações Interpessoais , Entrevistas como Assunto , Pessoa de Meia-Idade , Pesquisa Qualitativa , Sudeste dos Estados UnidosRESUMO
: A comparative analysis of cellular and soluble markers of immune activation in HIV-infected women on combination antiretroviral therapy showed that the upper genital tract (UGT) compared to the lower female genital tract was characterized by higher frequencies of potential HIV target cells and increased inflammatory molecules. Despite the activated UGT milieu, HIV RNA could not be detected in paired samples of plasma, cervicovaginal or endometrial lavage. As antiretroviral concentrations were ≥3-fold higher in the endometrium than in the lower genital tract, high antiretroviral penetration and/or metabolism may limit viral replication in the UGT.