RESUMO
Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6-8 and were present in plasma and genital-tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital-tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.
Assuntos
Fármacos Anti-HIV/farmacocinética , Soronegatividade para HIV , Modelos Biológicos , Nitrilas/farmacocinética , Pirimidinas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Química Farmacêutica , Relação Dose-Resposta a Droga , Feminino , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Injeções Intramusculares , Londres , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/sangue , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Reto/metabolismo , Rilpivirina , Vagina/metabolismo , Adulto JovemRESUMO
OBJECTIVES: The aim of the study was to identify possible causes of pancreatic insufficiency in patients with HIV infection. METHODS: A retrospective analysis of 233 HIV-positive patients for whom faecal elastase measurement was available was performed to investigate potential associations with core demographic data, HIV infection characteristics, degree of immunosuppresion, exposure to antiretroviral therapy (ART), alcohol misuse, diabetes, hepatitis C virus (HCV) infection, triglyceride and cholesterol levels and symptomatology. The response to pancreatic enzyme replacement for patients with evidence of insufficiency was also evaluated. RESULTS: Of 233 patients, 104 (45%) had evidence of pancreatic exocrine insufficiency (faecal elastase < 200 mcg/g). A positive association with exocrine pancreatic insufficiency was found for HCV infection (P = 0.007), previous or current HCV treatment (P = 0.003), alcohol misuse history (P = 0.006) and the presence of steatorrhoea (P = 0.03). There was no demonstrated association between exocrine pancreatic insufficiency and didanosine (ddI) exposure (P = 0.43) or stavudine (d4T) exposure (P = 0.62). Seventy-seven per cent of patients who were treated with pancreatic enzymatic supplementation reported a subjective improvement in symptoms. CONCLUSIONS: Faecal elastase sampling should form part of the routine work-up for HIV-positive patients with chronic diarrhoea even in the absence of 'traditional' risk factors such as ddI exposure. In particular, if the patient has steatorrhoea, a history of alcohol exposure or their HCV serology is positive, they should be considered for investigation. Treatment with pancreatic enzyme supplementation appears to be effective in the treatment of chronic diarrhoea caused by pancreatic insufficiency in the majority of patients.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Didanosina/efeitos adversos , Insuficiência Pancreática Exócrina/etiologia , Fezes/enzimologia , Infecções por HIV/tratamento farmacológico , Estavudina/efeitos adversos , Esteatorreia/etiologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Didanosina/administração & dosagem , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Elastase Pancreática/metabolismo , Estudos Retrospectivos , Fatores de Risco , Estavudina/administração & dosagem , Carga ViralRESUMO
To prevent the transmission of HIV infection during the postpartum period, the British HIV Association and Children's HIV Association (BHIVA/CHIVA) continue to recommend the complete avoidance of breast feeding for infants born to HIV-infected mothers, regardless of maternal disease status, viral load or treatment.
Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Aleitamento Materno/efeitos adversos , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Alimentação com Mamadeira , Feminino , Guias como Assunto , Infecções por HIV/tratamento farmacológico , Humanos , Recém-Nascido , Gravidez , Fatores de Risco , Reino UnidoRESUMO
BACKGROUND: Distinct functional subsets of natural killer cells potentially contribute to the pathology of inflammatory bowel disease (IBD). AIM: To report the phenotypic and functional characteristics of natural killer cells in blood and lamina propria of IBD patients, and the effect of azathioprine. METHODS: Natural killer cells from blood and lamina propria of healthy controls or patients with Crohn's disease, or ulcerative colitis were studied by flow cytometry. Activation, cytokine production, proliferation and apoptosis of natural killer cell subsets were studied in vitro. RESULTS: CD16(+) natural killer cells are increased in frequency in the lamina propria comparing Crohn's disease or ulcerative colitis with healthy controls. Azathioprine therapy was associated with a reduction in total natural killer cells in blood and lamina propria, preferentially of the CD16(+) subset. Azathioprine therapy did not impair natural killer degranulation, but reduced natural and cytokine-activated cytotoxicity and interferon-gamma (IFN-γ) production. Culture of resting peripheral blood mononuclear cells with azathioprine resulted in loss of natural killer cells and inhibition of activation and IFN-γ production. Azathioprine preferentially inhibited proliferation of CD16(+) natural killer cells and induced apoptosis in resting but not in pre-activated natural killer cells. CONCLUSIONS: Natural killer cells with cytolytic potential are enriched in the colonic lamina propria of individuals with IBD. Azathioprine is associated with a reduction in these cells and a normalization of natural killer cell populations.
Assuntos
Azatioprina/uso terapêutico , Colo/imunologia , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Células Matadoras Naturais/efeitos dos fármacos , Mucosa/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Colo/patologia , Estudos Transversais , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Mucosa/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa) qd to achieve a qd regimen. METHODS: A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd. RESULTS: Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7-100%) vs. 96.6% (60.0-100%) (P=0.017); dosing compliance 97.1% (64.3-100%) vs. 91.9% (33.3-100%) (P=0.016); and timing compliance 95.5% (53.8-100%) vs. 86.3% (4.3-100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82-99%) vs. 85% (75-93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC. CONCLUSIONS: Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.
Assuntos
Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Lamivudina/uso terapêutico , Cooperação do Paciente , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Distribuição de Qui-Quadrado , Esquema de Medicação , Combinação de Medicamentos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estatísticas não Paramétricas , Carga ViralRESUMO
OBJECTIVE: The aim of the study was to determine whether the expression of CD38 on CD8 T cells can identify patients with virological failure on antiretroviral therapy (ART). DESIGN: This was a cross-sectional study of patients attending a single HIV clinic in London. METHODS: The expression of CD38 on CD8 T cells was assessed using a biologically calibrated flow cytometry protocol. Patients were characterized by lymphocyte subset and viral load measurements. Characteristics including historical CD4 T cell counts, therapeutic history, co-infections and demographics were obtained from medical records. RESULTS: Elevated levels of CD8 CD38(high) T cells were found in HIV-1-infected patients who failed to suppress viral replication with ART; however, this parameter lacked sufficient sensitivity and specificity to replace viral load testing in assessing the efficacy of ART. Increased levels of CD8 CD38(high) cells were associated with reduced CD4 T cell counts in HIV-1-infected patients on ART after correcting for known determinants of CD4 T-cell recovery. CONCLUSIONS: The expression of CD38 on CD8 T cells lacks sufficient sensitivity and specificity to be used as a surrogate marker for viral load to monitor HIV-1 infection. T-cell activation is associated with reduced CD4 T-cell reconstitution in patients receiving ART.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1 , Adulto , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Londres , Masculino , Falha de Tratamento , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologiaRESUMO
OBJECTIVE: Since the introduction of highly active antiretroviral therapy (HAART) there has been a dramatic reduction in the incidence of Kaposi sarcoma (KS) and an improvement in survival. We wished to examine whether the outcome in pulmonary KS (pKS) has also altered. METHODS: In a single-institution cohort of 1140 HIV-positive patients with KS, 305 patients were diagnosed in the HAART era (1996-2004). We examined the clinicopathological features and outcomes of these patients, of whom 25 had pKS and 280 did not. RESULTS: Patients with pKS had lower CD4 cell counts at the time of KS diagnosis (Mann-Whitney U-test P=0.005). The incidence of pKS was higher in African patients than in non-African patients in this sample (Fisher's test, P=0.001). There were no significant differences in age, gender, plasma HIV-1 viral load or prior HAART treatment at the time of KS diagnosis. Five-year overall survival in the pKS group was 49% [95% confidence interval (CI) 26-73%] as compared with 82% (95% CI 76-87%) for the non-pKS group (log rank, P<0.0001). CONCLUSION: PKS remains an ominous diagnosis in the era of HAART, with a median survival of just 1.6 years.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções por HIV/epidemiologia , HIV-1 , Neoplasias Pulmonares/epidemiologia , Sarcoma de Kaposi/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , População Negra , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/complicações , Humanos , Londres/epidemiologia , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sarcoma de Kaposi/complicações , Análise de SobrevidaRESUMO
BACKGROUND: The use of highly active antiretroviral therapy (HAART) has profoundly altered the life expectancy of individuals infected with HIV. Metabolic abnormalities associated with antiretrovirals and cumulative exposure to combination antiretroviral therapy, including dyslipidaemia and insulin resistance, have been linked to an increased risk of myocardial infarction. METHODS: Longitudinal data from a large prospectively collected clinical database were analysed. All patients who commenced first antiretroviral therapy (ART) [two nucleoside reverse transcriptase inhibitors (NRTIs)+one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one active protease inhibitor (PI)] since 1996 were identified. Patients with elevated cholesterol levels [>5.5 mmol/L (215 mg/dL)] prior to therapy initiation were excluded. Quantitative data were categorized into quartiles and presented stratified by individuals developing abnormal levels of cholesterol during first-line HAART. Event time was defined as time from commencing first-line ART to either development of cholesterol level >6.5 mmol/L (254 mg/dL) or switch of first-line therapy. The Kaplan-Meier product limit survival method was used to estimate time to abnormal cholesterol level, and the chi2 test was used for comparisons between drug classes. Cox's proportional hazards regression analysis was used to identify factors predicting a likelihood of raised cholesterol level. RESULTS: A total of 1664 patients were included in the study: 57.1% on two NRTIs+one NNRTI, 38.4% on two NRTIs+one PI, and 4.4% on two NRTIs+a boosted PI regimen. Regimens containing stavudine or PIs were associated with a significantly higher event risk and earlier time to event. No differences between efavirenz and nevirapine or between didanosine and lamivudine were observed. In 28 patients exposed to the combination of tenofovir+lamivudine+efavirenz, there were no episodes of elevated cholesterol level. CONCLUSION: Dyslipidaemia has emerged as an important issue in HIV-infected individuals receiving antiretroviral therapy. This study demonstrates that age at start of therapy, baseline cholesterol level, stavudine use and PI use are all associated with increased risk of hypercholesterolemia on initial therapy. Both NRTI and NNRTI/PI choice influence risk of hypercholesterolaemia.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1 , Hipercolesterolemia/induzido quimicamente , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Fatores Etários , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Terapia Antirretroviral de Alta Atividade/métodos , Colesterol/sangue , Métodos Epidemiológicos , Feminino , Inibidores da Protease de HIV/efeitos adversos , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Estavudina/efeitos adversosRESUMO
Increasing numbers of patients are choosing to interrupt highly active antiretroviral therapy (HAART). We describe the effect of patient-directed treatment interruption (PDTI) on plasma viral loads (pVL), proviral DNA (pDNA), lymphocyte subsets and immune responses in 24 chronically HIV-1 infected individuals. Patients were divided into group A with pVL > 50 copies/ml and group B with pVL < 50 copies/ml, prior to the PDTI. pVL rose significantly in group B during the first month off HAART and was associated with a significant decrease in CD4 T-cell count. At baseline there was a significant difference in HIV-1 pDNA levels between groups A and B, however, levels significantly increased in group B, but not in group A during PDTI becoming equivalent after 1 month PDTI. We have previously shown no increase in pDNA over the time of substitution in patients switching HAART regimens despite a small rebound in pVL. These observations indicate that to protect low pDNA levels PDTI should be discouraged and that changing regimen at the first sign of failure should be advised where possible. Only transient, no longer than 4 week, HIV-1-specific responses were observed during PDTI in 5/24 patients, 2 from group A and 3 from group B. The low numbers of responders and the transient nature of the anti-HIV-1 immune responses do not favour the auto-vaccination hypothesis.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Adulto , Idoso , Contagem de Linfócito CD4 , Proliferação de Células , Doença Crônica , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga Viral , Suspensão de TratamentoRESUMO
PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.
Assuntos
Terapia Antirretroviral de Alta Atividade , Inflamação , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/imunologia , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SíndromeRESUMO
BACKGROUND: Adherence to antiretroviral therapy is critical to treatment outcomes. Adherence studies in other therapeutic areas of medicine suggest that once-daily regimens support improved adherence when compared to twice-daily therapy. An expansion in the range of once-daily antiretrovirals is making once-daily therapy possible for persons with HIV infection. METHODS: A 24-week randomized open-label simplification study of twice-daily regimens based on stavudine immediate release or zidovudine to an all once-daily regimen based on the stavudine prolonged-release capsule (PRC), in persons with complete virological suppression on regimens also including efavirenz and lamivudine, was carried out. Subjects were assessed for adherence [using the Medication Event Monitoring System (MEMS) cap; Aardex Corporation, Union City, CA, USA], quality of life, tolerability and efficacy. RESULTS: Forty-three patients were randomly assigned: 21 remained on their original regimen and 22 switched to once-daily therapy with stavudine PRC. Although high levels of adherence and good quality of life were present at study enrollment, adherence declined to a significantly lesser extent at week 24 in the group that switched to once-daily therapy. Efficacy was maintained in both groups and there were no differences in tolerability or toxicity. CONCLUSIONS: Subjects switching from twice-daily therapy to once-daily therapy demonstrate less of a decline in adherence over 24 weeks. A once-daily regimen including stavudine PRC is as effective and tolerable as a regimen containing the twice-daily formulation.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Cooperação do Paciente , Inibidores da Transcriptase Reversa/administração & dosagem , Estavudina/administração & dosagem , Adulto , Alcinos , Terapia Antirretroviral de Alta Atividade , Benzoxazinas , Contagem de Linfócito CD4 , Ciclopropanos , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxazinas/uso terapêutico , Qualidade de Vida , Inibidores da Transcriptase Reversa/uso terapêutico , Estatísticas não Paramétricas , Estavudina/uso terapêutico , Carga ViralRESUMO
BACKGROUND: Previous studies have reached differing conclusions about the utility of anal cytology as a screening tool for anal intraepithelial neoplasia (AIN). There is a need also to establish whether HPV typing offers a useful adjunct to screening. METHODS: We analysed data from 99 consecutive homosexual/bisexual male patients (89 HIV-1 positive) who underwent high resolution anoscopy. Follow up visits for these patients were also included, giving a total of 160 anoscopic procedures. Comparison was made between results of anal cytology using the sampling method of Palefsky, and histological findings of biopsies taken from abnormal areas seen on high resolution anoscopic examination of the anal canal. Swabs taken concurrently with the cytology were analysed for the presence of human papillomavirus (HPV) DNA and compared with the cytological and histological findings. RESULTS: The sensitivity of the cytology was 83%, and the specificity 38% when compared with histology. At screening of 34 asymptomatic men, 83% had anal cytological dysplasia and 78% had AIN. There were no significant differences in the prevalence of hrHPV genotypes between different cytological or histological grades of abnormalities. CONCLUSION: Anal cytology by the Palefsky method is simple to undertake, has a sensitivity and specificity comparable with cervical cytology, and can therefore be used as the basis of a pilot screening project in centres with large cohorts of HIV positive homosexual men who have a high risk of developing anal carcinoma. HPV genotyping is not a useful adjunct to cytological screening.
Assuntos
Neoplasias do Ânus/patologia , Bissexualidade , Carcinoma in Situ/patologia , Homossexualidade Masculina , Infecções por Papillomavirus/patologia , Análise de Variância , Neoplasias do Ânus/virologia , Carcinoma in Situ/virologia , Humanos , Masculino , Papillomaviridae/isolamento & purificação , Proctoscopia/normas , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
A 41 year old HIV infected man with an extensive travel history developed intermittent fever and weight loss shortly after returning from abroad. Extensive and prolonged investigation identified the cause.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Febre de Causa Desconhecida/virologia , Doença de Hodgkin/complicações , Febre Q/complicações , Viagem , Infecções Oportunistas Relacionadas com a AIDS/complicações , Adulto , Homossexualidade Masculina , Humanos , Masculino , Febre Q/diagnóstico , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection. We investigated the use of a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in this setting. METHODS: Twenty-one antiretroviral-naïve individuals with early HIV-1 disease were treated with a combination of efavirenz and Combivir (GlaxoSmithKline, Uxbridge, Middlesex, UK). They were evaluated for immune and lymphocyte function by standard immunological assays. RESULTS: The median time to an undetectable HIV-1 viral load was 12 weeks (range 4-36 weeks). CD4 and CD16/56 counts increased during treatment and CD8 counts decreased minimally. The main side-effects observed were transient sleep disturbances (five patients). In addition, we observed a decrease in lymphocyte activation as assessed by CD38 surface expression. CONCLUSIONS: This study demonstrates that primary HIV-1 infection can be treated with NNRTI-based HAART.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Lamivudina/uso terapêutico , Oxazinas/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Zidovudina/uso terapêutico , Adulto , Alcinos , Terapia Antirretroviral de Alta Atividade/métodos , Benzoxazinas , Relação CD4-CD8 , Ciclopropanos , Combinação de Medicamentos , Quimioterapia Combinada , Citometria de Fluxo , Infecções por HIV/imunologia , Humanos , Ativação Linfocitária , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
BACKGROUND: Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi's sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. PATIENTS AND METHODS: Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m(2) every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. RESULTS: The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-alpha levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-alpha, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. CONCLUSIONS: Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neovascularização Patológica , Paclitaxel/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Antraciclinas/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Progressão da Doença , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Sarcoma de Kaposi/irrigação sanguínea , Sarcoma de Kaposi/virologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/virologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVES: There is increasing in vitro and in vivo evidence that reduced zidovudine (ZDV) susceptibility is generated by the selective pressure conferred by other nucleoside reverse transcriptase inhibitors (NRTIs). However, the degree to which this occurs in clinical practice remains unclear. We assessed phenotypic and genotypic resistance in ZDV-naive patients with virological failure on stavudine (d4T)-containing regimens, with particular reference to potential cross-resistance between d4T and ZDV. METHODS: Patients were identified from a clinical database. Treatment history was confirmed by case note evaluation and discussion with patients. Genotypic and phenotypic analyses were undertaken by Virco (Virco BVBA, Mechelen, Belgium). RESULTS: Sixty-seven drug-experienced, ZDV-naive patients who underwent a resistance test while failing a d4T-containing regimen were identified. Of these patients, 23% had received three or more NRTIs and 42% at least one non-nucleoside reverse transcriptase (RT) inhibitor; 22% had viruses with reduced d4T susceptibility (>1.8-fold resistance), and 25% had viruses with reduced ZDV susceptibility (>4-fold). The most frequently observed RT mutations were identified. A significant correlation was found between susceptibility to d4T and susceptibility to ZDV (r=0.36; P=0.003), and also between virtual resistance to d4T and that to ZDV (r=0.38; P=0.002). CONCLUSIONS: A significant minority of d4T-treated, ZDV-naive patients were found to have viruses with reduced ZDV susceptibility, with a variable association with classical ZDV resistance mutations. These data suggest that cross-resistance between d4T and ZDV may involve novel constellations of mutations. Correlations between d4T and ZDV susceptibilities and resistances further support cross-resistance between NRTIs.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/uso terapêutico , Zidovudina/uso terapêutico , Resistência a Múltiplos Medicamentos/genética , Farmacorresistência Viral/genética , Quimioterapia Combinada , Infecções por HIV/genética , Humanos , Mutação/genéticaRESUMO
Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1 , Interleucina-2/imunologia , Terapia Antirretroviral de Alta Atividade , Divisão Celular , Anergia Clonal , Inibidores da Protease de HIV/uso terapêutico , Humanos , Imunofenotipagem , Interleucina-4/imunologia , Estatísticas não Paramétricas , Carga ViralRESUMO
BACKGROUND: The mechanisms by which dyslipidemia and lipoatrophy develop during antiretroviral therapy are not clear. No treatment of lipoatrophy is currently established. METHODS: This was an open-label randomized study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of <50 copies/mL. Patients switched d4T to abacavir (ABC) (group 1), a PI or NNRTI to ABC (group 2), or d4T and PI or NNRTI to ABC plus AZT (group 3). Patients were followed-up with fasting blood levels, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT) scans for 48 weeks. RESULTS: Thirty patients were included, with 27 completing 48 weeks of therapy. One ABC hypersensitivity reaction was the only serious adverse event. All patients' viral loads remained at <50 copies/mL. CD4 cell counts rose in groups 2 and 3 but fell modestly in group 1. Total and low-density lipoprotein cholesterol improved significantly in groups 2 and 3. Triglycerides fell significantly in group 2. In contrast, total, arm, and leg fat mass (by DXA) rose significantly in group 1 but fell modestly in groups 2 and 3. Visceral adiposity (by CT scan) was unaffected in all groups. CONCLUSIONS: Abacavir represents a virologically effective replacement for d4T, PI, or NNRTI in persons on successful first-line therapy. Replacement of a PI or NNRTI with ABC leads to modest improvement in both cholesterol and triglycerides. Replacement of d4T with ABC leads to modest improvements in fat mass.
Assuntos
Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/complicações , Síndrome de Lipodistrofia Associada ao HIV/prevenção & controle , Hiperlipidemias/complicações , Hiperlipidemias/prevenção & controle , Adulto , Composição Corporal/efeitos dos fármacos , Didesoxinucleosídeos/efeitos adversos , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Síndrome de Lipodistrofia Associada ao HIV/etiologia , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/etiologia , Resistência à Insulina , Masculino , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Estavudina/administração & dosagem , Estavudina/efeitos adversos , Estavudina/uso terapêutico , Fatores de TempoRESUMO
The effect of altering antiretroviral therapy (ART) on responses to viral, recall and human immunodeficiency virus (HIV)-1-specific recombinant antigens and interleukin-2 (IL-2) in HIV-1-infected patients was assessed. A longitudinal cohort study in eight HIV-1 infected individuals following a clinically indicated therapy change (seven for drug intolerance and one for virological failure) from protease inhibitor (PI) to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimens was performed. CD4 T-cell counts, viral loads, lymphoproliferative responses, cytokine production and latent proviral deoxyribonucleic acid (DNA) were measured at baseline and at weeks 12 and 24 after therapy substitution. Following therapy-switch there was a 33% proportional increase in mitogen response (95% confidence interval (CI), 3-33%) and a 31% increase (95% CI, 15-48%) in viral and recall-antigen responses. Six patients developed proliferative responses to low concentration IL-2 stimulation. All patients demonstrated an increase in median HIV-1-specific responses, as three had detectable virus at baseline (two being viral rebound); this may reflect an autovaccination effect. Proviral DNA changes largely reflected plasma HIV-1 ribonucleic acid (RNA). In conclusion, NNRTI substitution for a PI may favour immune reconstitution with an improvement in HIV-1-specific responses, which may reflect differential effects on antigen processing and presentation, an autovaccination effect or alternatively a potential suppressive effect of the PI.