RESUMO
BACKGROUND: Smoking prevalence in persons with HIV (PWH) is high (40%) and cessation rates remain low. Lack of social support and poor adherence to nicotine replacement therapy (NRT) are related to poor cessation outcomes; thus, both factors represent possible targets for smoking cessation interventions. Peer navigators (PNs) have been integrated into HIV care with great success to improve engagement and adherence to antiretroviral therapy. However, no clinical trial has evaluated the potential for PNs to provide social support and improve NRT adherence for smoking cessation. We developed a treatment protocol that targets social support, adherence, and self-efficacy for quitting by incorporating PNs into a smoking cessation program. This randomized trial will test whether this approach results in higher rates of 7-day point prevalence abstinence at 12- and 24-weeks, compared to standard treatment. METHODS: Seventy-two smokers with HIV will be randomized to either Peer Navigation Social Support for smoking cessation (PNSS-S) or standard cessation counseling. All participants will meet with a nurse for a smoking cessation counseling session, which will include discussion of FDA-approved cessation pharmacotherapy. Participants assigned to PNSS-S will receive weekly phone calls from the PN for 12 weeks. The PN will address readiness to quit, using medication to quit, common barriers to cessation, high risk situations, slip management, and maintaining abstinence. Smoking cessation outcomes will be measured at 4, 12, and 24 weeks following the baseline appointment. CONCLUSION: Results from this study will provide preliminary evidence of whether incorporating a peer navigator-based intervention into smoking cessation treatment can improve smoking cessation outcomes in PWH.
Assuntos
Abandono do Hábito de Fumar , Aconselhamento , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fumantes , Fumar , Dispositivos para o Abandono do Uso de TabacoRESUMO
BACKGROUND: MB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally. METHODS AND FINDINGS: The clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively). The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys. Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 µg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 µg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 µg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 µg/mL); HSV8-N concentrations ranged from 80 to 601 µg/mL, well above the IC50 of 0.1 µg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation. CONCLUSIONS: Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception. TRIAL REGISTRATION: ClinicalTrials.gov NCT02579083.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Administração Intravaginal , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Amplamente Neutralizantes/metabolismo , Anticorpos Amplamente Neutralizantes/uso terapêutico , Feminino , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Profilaxia Pré-Exposição/métodos , Vagina/virologia , Adulto JovemRESUMO
BACKGROUND: The US Food and Drug Administration issued an Emergency Use Authorization for remdesivir use in patients with severe COVID-19. METHODS: We utilized data from 2 quaternary acute care hospitals. The outcomes of interest were the impact of remdesivir on in-hospital death by day 28 and time to recovery, clinical improvement, and discharge. We utilized Cox proportional hazards models and stratified log-rank tests. RESULTS: Two hundred twenty-four patients were included in the study. The median age was 59 years; 67.0% were male; 17/125 patients (13.6%) who received supportive care and 7/99 patients (7.1%) who received remdesivir died. The unadjusted risk for 28-day in-hospital death was lower for patients who received remdesivir compared with patients who received supportive care (hazard ratio [HR], 0.42; 95% CI, 0.16-1.08). Although this trend remained the same after adjusting for age, sex, race, and oxygen requirements on admission (adjusted HR [aHR], 0.49; 95% CI, 0.19-1.28), as well as chronic comorbidities and use of corticosteroids (aHR, 0.44; 95% CI, 0.16-1.23), it did not reach statistical significance. The use of remdesivir was not associated with an increased risk of acute kidney injury (AKI) or liver test abnormalities. Although not statistically significant, the rate ratios for time to recovery, clinical improvement, and discharge were higher in women and black or African American patients. CONCLUSIONS: Patients on remdesivir had lower, albeit not significant, all-cause in-hospital mortality, and the use of remdesivir did not increase the risk for AKI. Promising signals from this study need to be confirmed by future placebo-controlled randomized clinical trials.
RESUMO
BACKGROUND: Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19). METHODS: We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale. RESULTS: In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%). CONCLUSIONS: In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Adulto , Idoso , Alanina/administração & dosagem , Alanina/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Esquema de Medicação , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , SARS-CoV-2 , Resultado do Tratamento , Tratamento Farmacológico da COVID-19RESUMO
Long-acting antiretroviral therapy holds the promise of new options for human immunodeficiency virus (HIV) treatment beyond the current paradigm of daily oral pills. Of particular interest is their potential role in addressing challenges with adherence to oral therapy and treatment fatigue. Similar to other conditions where long-acting formulations have proven effective such as contraception and mental health, long-acting antiretroviral therapy could provide additional treatment choices to people with HIV. This review provides an outline of the current landscape of long-acting antiretroviral therapy for HIV treatment, both approved and under development, including cabotegravir, rilpivirine, leronlimab, islatravir, albuvirtide, GS-6207, and broadly neutralizaing antibodies. However, there are a number of research gaps for long-acting antiretroviral therapy including issues regarding resistance and understudied populations, and this review highlights some of the challenges that will need to be addressed for clinical implementation of these novel treatment modalities.
Assuntos
Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Farmacorresistência Viral/efeitos dos fármacos , HumanosRESUMO
BACKGROUND: Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. METHODS: Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. RESULTS: At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96. CONCLUSIONS: HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. CLINICAL TRIALS REGISTRATION: NCT00537394.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral , Inibidores da Transcriptase Reversa/uso terapêutico , Terapia de Salvação , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , HIV-1/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Resposta Viral SustentadaRESUMO
To determine the relationships among body mass index (BMI), and HIV-associated neurocognitive impairment and the potential mediating effects of inflammatory cytokines. Among the HIV-infected individuals (N = 90) included in this study, obesity was associated with slower processing speed (ß = -.229, standard error (SE) = 2.15, p = .033), compared to participants with a normal BMI, after controlling for psychosocial and HIV clinical factors. Serum concentrations of the interleukin-16 (IL-16) cytokine were significantly associated with slowed processing speed (ß = -.235, SE = 1.62, p = .033) but did not mediate the relationship between obesity and processing speed These findings suggest that obesity may contribute to cognitive processing speed deficits in HIV-infected adults. Elevated concentrations of IL-16 are also associated with slowing, though the results suggest that obesity and IL-16 may exert independent effects.
Assuntos
Biomarcadores/sangue , Índice de Massa Corporal , Transtornos Cognitivos , Infecções por HIV/psicologia , Interleucinas/sangue , Adulto , Citocinas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/psicologiaRESUMO
BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. OBJECTIVE: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). SETTING: Outpatient HIV clinics. PARTICIPANTS: Treatment-experienced patients with HIV infection and viral resistance. INTERVENTION: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. MEASUREMENTS: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. RESULTS: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. LIMITATION: Unblinded study design, and the study may not be applicable to resource-poor settings. CONCLUSION: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PRIMARY FUNDING SOURCES: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Contagem de Linfócito CD4 , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , HIV/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversosRESUMO
Use of cardiovascular implantable electronic devices (CIED), including permanent pacemakers (PPM) and implantable cardioverter defibrillators (ICD), has increased dramatically over the past two decades. Most CIED infections are caused by staphylococci. Fungal causes are rare and their prognosis is poor. To our knowledge, there has not been a previously reported case of multifocal Candida endocarditis involving both a native left-sided heart valve and a CIED lead. Here, we report the case of a 70-year-old patient who presented with nausea, vomiting, and generalised fatigue, and was found to have Candida glabrata endocarditis involving both a native aortic valve and right atrial ICD lead. We review the literature and summarise four additional cases of CIED-associated Candida endocarditis published from 2009 to 2014, updating a previously published review of cases prior to 2009. We additionally review treatment guidelines and discuss management of CIED-associated Candida endocarditis.
Assuntos
Candida/isolamento & purificação , Candidíase/microbiologia , Desfibriladores Implantáveis/microbiologia , Endocardite/etiologia , Marca-Passo Artificial/microbiologia , Infecções Relacionadas à Prótese/microbiologia , Idoso , Aorta/microbiologia , Valva Aórtica/microbiologia , Candida/crescimento & desenvolvimento , Candidíase/complicações , Candidíase/tratamento farmacológico , Endocardite/diagnóstico , Endocardite/tratamento farmacológico , Endocardite/microbiologia , Feminino , Humanos , Marca-Passo Artificial/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológicoRESUMO
BACKGROUND: Regimen selection for highly treatment-experienced patients is complicated. METHODS: Using a web-based utility, study team members reviewed antiretroviral (ARV) history and resistance data and recommended individual ARV regimens and nucleoside reverse transcriptase inhibitor (NRTI) options for treatment-experienced participants consisting of 3-4 of the following agents: raltegravir (RAL), darunavir (DRV)/ritonavir, tipranavir (TPV)/ritonavir, etravirine (ETR), maraviroc (MVC), and enfuvirtide (ENF). We evaluated team recommendations and site selection of regimen and NRTIs. Associations between baseline factors and the selection of a complex regimen (defined as including four ARV agents or ENF) were explored with logistic regression. RESULTS: A total of 413 participants entered the study. Participants initiated the first or second recommended regimen 86% of the time and 21% of participants started a complex regimen. In a multivariable model, ARV resistance to NRTI (odds ratio [OR] = 2.2), non-nucleoside reverse transcriptase inhibitor (NNRTI, OR = 6.2) or boosted protease inhibitor (PI, OR = 6.6), prior use of integrase strand transfer inhibitor (INSTI, OR = 25), and race-ethnicity (all P ≤ 0.01) were associated with selection of a complex regimen. Black non-Hispanic (OR = 0.5) and Hispanic participants from the continental US (OR = 0.2) were less likely to start a complex regimen, compared to white non-Hispanics. CONCLUSIONS: In this multi-center trial, we developed a web-based utility that facilitated treatment recommendations for highly treatment-experienced patients. Drug resistance, prior INSTI use, and race-ethnicity were key factors in decisions to select a more complex regimen.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Terapia de Salvação , Adulto , Darunavir/uso terapêutico , Farmacorresistência Viral , Enfuvirtida , Feminino , Proteína gp41 do Envelope de HIV/uso terapêutico , Infecções por HIV/etnologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Fragmentos de Peptídeos/uso terapêutico , Piridazinas/uso terapêutico , Pirimidinas , Raltegravir Potássico/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/uso terapêuticoRESUMO
INTRODUCTION: Tobacco use has emerged as a leading killer among persons living with HIV, with effective approaches to tobacco treatment still unknown. HIV infection is nearly 3 times as prevalent in Latinos than in non-Latino Whites. This study reports the results of a randomized trial comparing a tailored intervention to brief counseling for smoking cessation among Latino smokers living with HIV (LSLWH). METHODS: LSLWH (N = 302; 36% female, 10% employed full-time, 49% born in United States) were randomized to 4 in-person sessions of a tailored intervention (Aurora) or 2 in-person sessions of brief advice (enhanced standard care [ESC]). Both groups received 8 weeks of nicotine replacement therapy (NRT) patch. Biochemically validated 6- and 12-month 7-day point-prevalence abstinence (PPA) rates were compared, along with secondary outcomes (e.g., reduction to light smoking, NRT adherence). RESULTS: Seven-day PPA rates reached 8% versus 11% at 6 months and 6% versus 7% at 12 months, for Aurora and ESC, respectively, with no between-group differences (p values > .40). Significant changes from baseline to 6 and 12 months among intervention targets were noted (percentage reduction in heavy smoking and dependence; increases in knowledge and self-efficacy). Baseline smoking frequency, older age, and higher intensity of patch use during the trial emerged as significant predictors of abstinence at 6 months. CONCLUSIONS: There was no evidence that the tailored intervention improved cessation rates. Interventions that encourage use of, and adherence to, empirically validated cessation aids require further development to reduce tobacco-related death and disease in this vulnerable population.
Assuntos
Aconselhamento/métodos , Infecções por HIV , Hispânico ou Latino , Abandono do Hábito de Fumar/métodos , Dispositivos para o Abandono do Uso de Tabaco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Abandono do Hábito de Fumar/etnologia , Inquéritos e Questionários , Resultado do Tratamento , Estados UnidosRESUMO
Impaired facial emotion recognition abilities in HIV+ patients are well documented, but little is known about the neural etiology of these difficulties. We examined the relation of facial emotion recognition abilities to regional brain volumes in 44 HIV-positive (HIV+) and 44 HIV-negative control (HC) adults. Volumes of structures implicated in HIV-associated neuropathology and emotion recognition were measured on MRI using an automated segmentation tool. Relative to HC, HIV+ patients demonstrated emotion recognition impairments for fearful expressions, reduced anterior cingulate cortex (ACC) volumes, and increased amygdala volumes. In the HIV+ group, fear recognition impairments correlated significantly with ACC, but not amygdala volumes. ACC reductions were also associated with lower nadir CD4 levels (i.e., greater HIV-disease severity). These findings extend our understanding of the neurobiological substrates underlying an essential social function, facial emotion recognition, in HIV+ individuals and implicate HIV-related ACC atrophy in the impairment of these abilities.
Assuntos
Encéfalo/patologia , Emoções , Expressão Facial , Infecções por HIV , Transtornos da Memória/etiologia , Reconhecimento Psicológico/fisiologia , Adulto , Idoso , Aprendizagem por Associação , Feminino , Infecções por HIV/complicações , Infecções por HIV/patologia , Infecções por HIV/psicologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reconhecimento Visual de Modelos/fisiologia , Vocabulário , Adulto JovemRESUMO
HIV-infected individuals frequently exhibit brain dysfunction despite antiretroviral treatment. The neuropathological mechanisms underlying these abnormalities remain unclear, pointing to the importance of identifying biomarkers sensitive to brain dysfunction. We examined 74 medically stable HIV-infected individuals using T1-weighted MRI. Volumes of the cortical grey matter (GM), white matter (WM), caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala, and ventricles were derived using automated parcellation. A panel of plasma cytokines was measured using multiplexed bead array immunoassay. A model selection algorithm was used to select the combination of clinical and cytokine markers that best predicted each brain volumetric measure in a series of linear regression models. Higher CD4 nadir, shorter HIV infection duration, and antiretroviral treatment were significantly related to higher volumes of the putamen, thalamus, hippocampus, and WM. Older age was related to lower volumes in most brain regions and higher ventricular volume. Higher IFN-γ, MCP-1, and TNF-α were related to higher volumes of the putamen, pallidum, amygdala, GM, and WM. Higher IL-1ß, IL-6, IL-16, IL-18, IP-10, MIP-1ß, and SDF-1α were related to lower volumes of the putamen, pallidum, thalamus, hippocampus, amygdala, GM, and WM; and higher ventricular volume. The current findings provide evidence linking smaller brain volumes to HIV disease history, antiretroviral treatment, and advanced age. Cytokine markers, especially IL-6 and IL-16, showed robust association with brain volumes even after accounting for other clinical variables, demonstrating their utility in examining the mechanisms of HIV-associated brain abnormalities.
Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/sangue , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Adulto JovemRESUMO
BACKGROUND: Dolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF). METHODS: ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16. RESULTS: Thirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16. CONCLUSIONS: The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199.
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Líquido Cefalorraquidiano/química , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Plasma/química , Piridonas , RNA Viral/sangue , RNA Viral/líquido cefalorraquidiano , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVES: In the current era of effective antiretroviral treatment, the number of older adults living with HIV is rapidly increasing. This study investigated the combined influence of age and HIV infection on longitudinal changes in verbal and visuospatial learning and memory. METHOD: In this longitudinal, case-control design, 54 HIV seropositive and 30 seronegative individuals aged 40-74 years received neurocognitive assessments at baseline visits and again one year later. Assessment included tests of verbal and visuospatial learning and memory. Linear regression was used to predict baseline performance and longitudinal change on each test using HIV serostatus, age, and their interaction as predictors. Multivariate analysis of variance (MANOVA) was used to assess the effects of these predictors on overall baseline performance and overall longitudinal change. RESULTS: The interaction of HIV and age significantly predicted longitudinal change in verbal memory performance, as did HIV status, indicating that although the seropositive group declined more than the seronegative group overall, the rate of decline depended on age such that greater age was associated with a greater decline in this group. The regression models for visuospatial learning and memory were significant at baseline, but did not predict change over time. HIV status significantly predicted overall baseline performance and overall longitudinal change. CONCLUSIONS: This is the first longitudinal study focused on the effects of age and HIV on memory. Findings suggest that age and HIV interact to produce larger declines in verbal memory over time. Further research is needed to gain a greater understanding of the effects of HIV on the aging brain.
Assuntos
Envelhecimento/fisiologia , Soropositividade para HIV/fisiopatologia , Memória/fisiologia , Percepção Espacial/fisiologia , Aprendizagem Verbal/fisiologia , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
STUDY OBJECTIVES: To identify factors associated with variability in rifampin plasma pharmacokinetics and explore the relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration. METHODS: In this randomized, cross-over study, 12 healthy volunteers received either efavirenz 600 mg/day or efavirenz 600 mg with rifampin 600 mg/day for 8 days. After a washout period of at least 2 weeks, subjects crossed over to the alternate 8-day regimen. Samples were obtained for pharmacokinetic assessment on day 8 of each study cycle. Drugs concentrations were determined by a validated high-performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental analysis. Multivariate analysis was used to examine factors associated with rifampin pharmacokinetics. Spearman correlation analysis was used to investigate relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration. MEASUREMENTS AND MAIN RESULTS: Of 11 evaluable subjects, the median interquartile range, rifampin peak concentration (Cmax) , area under the concentration-time curve (AUC0-24 hour ), and weight-normalized clearance were 8.9 (7.3-13.8) µg/ml, 48.8 (29.6-67.4) µg·h/ml, and 0.19 (0.11-0.29) L/h/kg, respectively. Solute carrier organic anion transporter family member 1B1 (SLCO1B1) c.388AâG and SLCO1B1 c.463CâA polymorphisms jointly had significant effect on rifampin Cmax (R(2) = 0.75). Male sex and SLCO1B1 c.463CâA polymorphism together influenced rifampin AUC0-24 hour (R(2) = 0.52) and weight-normalized clearance (R(2) = 0.65). All four volunteers with rifampin Cmax less than 8 µg/ml (lower end of the normal range) had c.463CA genotype. Rifampin Cmax and AUC0-24 hour had no significant relationship with the efavirenz AUC0-24 hour ratio or weight-normalized clearance ratio in the presence versus absence of rifampin (p>0.05). CONCLUSIONS: Men with the SLCO1B1c.463CA genotype are at increased risk of lower rifampin plasma exposure. However, plasma rifampin concentrations did not correlate with the extent of induction of efavirenz clearance by rifampin during coadministration.
Assuntos
Benzoxazinas/sangue , Interações Medicamentosas/genética , Variação Genética/genética , Transportadores de Ânions Orgânicos/genética , Rifampina/administração & dosagem , Rifampina/sangue , Adulto , Alcinos , Estudos Cross-Over , Ciclopropanos , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-IdadeRESUMO
With the widespread availability of highly active antiretroviral therapy (HAART), and increased life expectancy among HIV-infected individuals, liver-related mortality has emerged as the leading cause of non-AIDS-related death. The incidence of hepatocellular carcinoma (HCC), a sequela of chronic liver disease, is rising among HIV-infected individuals. While women are increasingly and disproportionately affected by HIV, little is known about HCC in HIV-infected women given HCC's predilection for men. In 2007, 2 out of 398 HIV-infected women seen at a Rhode Island HIV clinic were diagnosed with HCC. Of 351 HIV-infected individuals with HCC described in the published literature, 12 (3.4%) were women. These 2 cases add to the existing literature on this topic.
Assuntos
Terapia Antirretroviral de Alta Atividade , Carcinoma Hepatocelular/epidemiologia , Infecções por HIV/epidemiologia , Neoplasias Hepáticas/epidemiologia , Saúde da Mulher , Adulto , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Comorbidade , Evolução Fatal , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , RNA Viral/sangue , Estudos Retrospectivos , Rhode Island/epidemiologia , Carga ViralRESUMO
Both HIV infection and high levels of early life stress (ELS) have been related to abnormalities in frontal-subcortical structures, yet the combined effects of HIV and ELS on brain structure and function have not been previously investigated. In this study we assessed 49 non-demented HIV-seropositive (HIV+) and 47 age-matched HIV-seronegative healthy control (HC) adults. Levels of ELS exposure were quantified and used to define four HIV-ELS groups: HC Low-ELS (N = 20); HC High-ELS (N = 27); HIV+ Low-ELS (N = 24); HIV+ High-ELS (N = 25). An automated segmentation tool measured volumes of brain structures known to show HIV-related or ELS-related effects; a brief neurocognitive battery was administered. A significant HIV-ELS interaction was observed for amygdala volumes, which was driven by enlargements in HIV+ High-ELS participants. The HIV+ High-ELS group also demonstrated significant reductions in psychomotor/processing speed compared with HC Low-ELS. Regression analyses in the HIV+ group revealed that amygdala enlargements were associated with higher ELS, lower nadir CD4 counts, and reduced psychomotor/processing speed. Our results suggest that HIV infection and high ELS interact to increase amygdala volume, which is associated with neurocognitive dysfunction in HIV+ patients. These findings highlight the lasting neuropathological influence of ELS and suggest that high ELS may be a significant risk factor for neurocognitive impairment in HIV-infected individuals.
Assuntos
Tonsila do Cerebelo/patologia , Cognição/fisiologia , Infecções por HIV/patologia , Infecções por HIV/psicologia , Estresse Psicológico/psicologia , Adulto , Encéfalo/patologia , Contagem de Linfócito CD4 , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Desempenho Psicomotor/fisiologia , Inquéritos e Questionários , Escalas de WechslerRESUMO
BACKGROUND: The benefits of antiretroviral therapy during early human immunodeficiency virus type 1 (HIV-1) infection remain unproved. METHODS: A5217 study team randomized patients within 6 months of HIV-1 seroconversion to receive either 36 weeks of antiretrovirals (immediate treatment [IT]) or no treatment (deferred treatment [DT]). Patients were to start or restart antiretroviral therapy if they met predefined criteria. The primary end point was a composite of requiring treatment or retreatment and the log(10) HIV-1 RNA level at week 72 (both groups) and 36 (DT group). RESULTS: At the June 2009 Data Safety Monitoring Board (DSMB) review, 130 of 150 targeted participants had enrolled. Efficacy analysis included 79 individuals randomized ≥72 weeks previously. For the primary end point, the IT group at week 72 had a better outcome than the DT group at week 72 (P = .005) and the DT group at week 36 (P = .002). The differences were primarily due to the higher rate of progression to needing treatment in the DT group (50%) versus the IT (10%) group. The DSMB recommended stopping the study because further follow-up was unlikely to change these findings. CONCLUSIONS: Progression to meeting criteria for antiretroviral initiation in the DT group occurred more frequently than anticipated, limiting the ability to evaluate virologic set point. Antiretrovirals during early HIV-1 infection modestly delayed the need for subsequent treatment. CLINICAL TRIALS REGISTRATION: NCT00090779.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Lopinavir/uso terapêutico , Organofosfonatos/uso terapêutico , Ritonavir/uso terapêutico , Carga Viral , Adenina/uso terapêutico , Adulto , Desoxicitidina/uso terapêutico , Progressão da Doença , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , RNA Viral/sangue , Tenofovir , Resultado do TratamentoRESUMO
HIV-associated neurocognitive dysfunction persists in the highly active antiretroviral therapy (HAART) era and may be exacerbated by comorbidities, including substance use and hepatitis C virus (HCV) infection. However, the neurocognitive impact of HIV, HCV, and substance use in the HAART era is still not well understood. In the current study, 115 HIV-infected and 72 HIV-seronegative individuals with significant rates of lifetime substance dependence and HCV infection received comprehensive neuropsychological assessment. We examined the effects of HIV serostatus, HCV infection, and substance use history on neurocognitive functioning. We also examined relationships between HIV disease measures (current and nadir CD4, HIV RNA, duration of infection) and cognitive functioning. Approximately half of HIV-infected participants exhibited neurocognitive impairment. Detectable HIV RNA but not HIV serostatus was significantly associated with cognitive functioning. HCV was among the factors most consistently associated with poorer neurocognitive performance across domains, while substance use was less strongly associated with cognitive performance. The results suggest that neurocognitive impairment continues to occur in HIV-infected individuals in association with poor virologic control and comorbid conditions, particularly HCV coinfection.