RESUMO
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: 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: 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
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
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
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
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
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
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.
Assuntos
Antirretrovirais/farmacocinética , Endométrio/química , Endométrio/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções do Sistema Genital/imunologia , Infecções do Sistema Genital/virologia , Adulto , Antirretrovirais/administração & dosagem , Endométrio/virologia , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: Model systems that rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed. DESIGN: We explored the efficacy of maraviroc (MVC) and tenofovir (TFV) for HIV prevention by comparing Emax models from TZM-bl cells to vaginal tissue explants and evaluated their predictive capabilities with a dose-challenge clinical study. METHODS: HIV-1JR-CSF was used for viral challenge. Drug efficacy was assessed using a luciferase reporter assay in TZM-bl cells and real-time PCR to quantify spliced RNA in a tissue explant model. Cell and tissue concentrations of MVC, TFV, and the active metabolite tenofovir diphosphate were measured by liquid chromatography with tandem mass spectrometry and used to create Emax models of efficacy. Efficacy after a single oral dose of 600 mg MVC and 600 mg tenofovir disoproxil fumarate was predicted from cell and tissue models and confirmed in a clinical study with viral biopsy challenge postdose. RESULTS: TFV was >10-fold and MVC >1000-fold, more potent in TZM-bl cells compared with vaginal explant tissue. In the dose-challenge study, tissues from 3 of 6 women were protected from HIV infection, which was 49% lower than predicted by TZM-bl data and 36% higher than predicted by tissue explant data. CONCLUSIONS: Comparative effective concentration data were generated for TFV and MVC in 3 HIV chemoprophylaxis models. These results provide a framework for future early investigations of antiretroviral efficacy in HIV prevention to optimize dosing strategies in clinical investigations.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/farmacologia , Quimioprevenção/métodos , Cicloexanos/farmacologia , Transmissão de Doença Infecciosa/prevenção & controle , Infecções por HIV/prevenção & controle , Organofosfonatos/farmacologia , Triazóis/farmacologia , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Técnicas de Cultura de Células , Sobrevivência Celular , Cromatografia Líquida , Cicloexanos/administração & dosagem , Cicloexanos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Maraviroc , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Espectrometria de Massas em Tandem , Tenofovir , Triazóis/administração & dosagem , Triazóis/farmacocinética , Vagina/química , Vagina/virologia , Carga Viral , Adulto JovemRESUMO
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
Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P < 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9-fold > colorectal; vaginal ABCC2 2.9-fold > colorectal; colorectal ABCC4 2.0-fold > cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues.
Assuntos
Colo do Útero/metabolismo , Colo/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Reto/metabolismo , Vagina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Feminino , Expressão Gênica , Infecções por HIV/metabolismo , Infecções por HIV/prevenção & controle , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Menopausa/metabolismo , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , RNA Mensageiro/metabolismoRESUMO
OBJECTIVE: To investigate the concentration of the integrase strand inhibitor raltegravir (RAL) throughout gastrointestinal (GI) tissue, especially gut-associated lymphoid tissue (GALT), as an adjunct to current prevention and cure strategies. DESIGN: Open-label pharmacokinetic (PK) study. METHODS: HIV-negative men received RAL 400 mg twice daily for 7 days. Seven blood plasma specimens were collected over 12-h intervals; timed tissue specimens from terminal ileum, splenic flexure, and rectum were also obtained by colonoscopy following the first dose and on day 7 [multiple dose (MD)]. RAL concentrations were measured by validated LC-MS assay with 1 ng/ml lower limit of detection. Data were analyzed by noncompartmental methods (WinNonlin 6). Tissue exposures are reported as composite medians and tissue density of 1.04 g/ml is assumed for comparisons. RESULTS: Fourteen men completed evaluations. Median (range) age was 24 (19-49) years and BMI 25 (19-31) kg/m². After the first dose, area under the time-concentration curve (AUC)(0-12h) was highest in the terminal ileum (594 µg*h/ml). Exposures were 160, 68 and 39-fold greater than blood plasma at the terminal ileum, splenic flexure and rectum, respectively. After multiple doses, exposure was highest at the splenic flexure (2240 µg*h/ml); exposure at the terminal ileum and rectum were equivalent (both 788 µg*h/ml). Following multiple doses, exposures were 160 to 650-fold greater than blood plasma throughout the colon. CONCLUSION: RAL rapidly disseminates into GI tissue and concentrations remain significantly higher than blood plasma. RAL exposure in GI tissue remains higher than any antiretroviral investigated to date. These data suggest that RAL should result in full suppression of viral replication in GI tissue and GALT.
Assuntos
Trato Gastrointestinal/metabolismo , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/farmacocinética , HIV/efeitos dos fármacos , Pirrolidinonas/farmacocinética , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Infecções por HIV/tratamento farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Raltegravir Potássico , Carga Viral/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Antiretrovirals that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase I open-label pharmacokinetic (PK) study was performed to describe first dose (PK1) and steady-state (PK2) PKs of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT) and vaginal tissue (VT) in HIV type-1-negative women. METHODS: A total of 8 healthy females given DTG 50 mg daily for 5-7 days had 11 paired BP and CVF samples collected over 24 h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analysed by validated liquid chromatography-tandem mass spectrometry methods. Non-compartmental PK analysis was performed and Spearman rank correlations determined between matrices. RESULTS: BP areas under the concentration-time curve (AUCs) were similar to previous reports and concentrations remained greater than the protein-adjusted (PA) 90% inhibitory concentration (IC90) for wild-type HIV (64 ng/ml). CVF exposures were approximately 6% of BP with low inter-individual variability. CT and VT exposures were 7% of BP at PK1, and 9-10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (ρ=0.70, P=0.003), and to CVF at steady state (ρ=0.52, P=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT and VT, but only marginally in CVF. CONCLUSIONS: DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.
Assuntos
Fármacos Anti-HIV/farmacocinética , Colo do Útero/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/sangue , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Vagina/efeitos dos fármacos , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Feminino , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/efeitos adversos , Inibidores de Integrase de HIV/sangue , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Oxazinas , Piperazinas , Piridonas , Adulto JovemRESUMO
OBJECTIVES: To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. DESIGN: A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. METHODS: Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. RESULTS: BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and â¼2-fold greater than the PA-IC90. RF AUCs were â¼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. CONCLUSIONS: DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained â¼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations.
Assuntos
Colo/efeitos dos fármacos , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Reto/efeitos dos fármacos , Sêmen/efeitos dos fármacos , Adulto , Colo/imunologia , Relação Dose-Resposta a Droga , Inibidores de Integrase de HIV/sangue , Compostos Heterocíclicos com 3 Anéis/sangue , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , Reto/imunologia , Sêmen/imunologia , Resultado do TratamentoRESUMO
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
OBJECTIVE: To investigate the intraindividual pharmacokinetics (PKs) of total (protein bound plus unbound) and unbound lopinavir/ritonavir (LPV/RTV) and to assess whether the pediatric formulation (100 mg/25 mg) can overcome any pregnancy-associated changes. DESIGN: Prospective longitudinal PK study. METHODS: HIV-infected pregnant antiretroviral therapy-naive and experienced women receiving LPV/RTV 400 mg/100 mg tablets twice daily. Intensive PK evaluations were performed at 20-24 weeks (PK1), 30 weeks (PK2) followed by empiric dose increase using the pediatric formulation (100 mg/25 mg twice daily), 32 weeks (PK3), and 8 weeks postpartum (PK4). RESULTS: Twelve women completed prespecified PK evaluations. Median (range) age was 28 (18-35) years and baseline BMI was 32 (19-41) kg/m. During pregnancy, total area under the time concentration (AUC0-12h) for LPV was significantly lower than postpartum (PK1, PK2, or PK3 vs. PK4, P = 0.005). Protein-unbound LPV AUC0-12h remained unchanged during pregnancy [PK1: 1.6 (1.3-1.9) vs. PK2: 1.6 (1.3-1.9) µg·h/mL, P = 0.4] despite a 25% dose increase [PK2 vs. PK3: 1.8 (1.3-2.1) µg·h/mL, P = 0.5]. Protein-unbound LPV predose concentrations (C12h) did not significantly change despite dose increase [PK2: 0.10 (0.08-0.15) vs. PK3: 0.12 (0.10-0.15) µg/mL, P = 0.09]. Albumin and LPV AUC0-12h fraction unbound were correlated (rs = 0.3, P = 0.03). CONCLUSIONS: Total LPV exposure was significantly decreased throughout pregnancy despite the increased dose. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose. Predose concentrations of unbound LPV were not affected by the additional dose and were 70-fold greater than the minimum efficacy concentration. These findings suggest dose adjustments may not be necessary in all HIV-infected pregnant women.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Lopinavir/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Ritonavir/farmacocinética , Adolescente , Adulto , Proteínas Sanguíneas/metabolismo , Feminino , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , Humanos , Lopinavir/administração & dosagem , Lopinavir/metabolismo , Lopinavir/uso terapêutico , Gravidez , Complicações Infecciosas na Gravidez/virologia , Trimestres da Gravidez , Estudos Prospectivos , Ligação Proteica , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence. METHODS: Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined. RESULTS: The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively. CONCLUSIONS: ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence.