RESUMO
Several vaccination trials are evaluating the modified vaccinia virus Ankara (MVA) as a delivery vector in various clinical settings. In this paper, we present the reevaluation of a therapeutic vaccination trial in human immunodeficiency virus (HIV)-1-infected individuals treated with highly active antiretroviral therapy using MVA-expressing HIV-1 nef. Immunogenicity of MVA-nef was assessed using multicolor flow cytometry. Vaccine-induced polyfunctionality and proliferative capacity, which are associated with nonprogressive HIV-1 infection, were detectable by combining two immune assays. By means of short-term polychromatic intracellular cytokine staining, we observed a significant increase in polyfunctional Nef-specific CD4 T cells expressing interferon-γ, interleukin (IL)-2 and CD154 after vaccination, whereas changes in the quality of CD8 T-cell response could not be observed. Only the additional use of a long-term polychromatic Carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay revealed vaccine-induced Nef-specific CD8, as well as CD4 T cells with proliferative capacity. The correlation between vaccine-induced IL-2 production by CD4 T cells and the increase in proliferating Nef-specific CD8 T cells suggests a causal link between these two functions. These results highlight the importance of combining sophisticated immunomonitoring tools to unravel concealed effects of immunological interventions and support the use of the poxvirus-derived MVA vector to stimulate highly functional HIV-1-specific T-cell responses. However, the clinical benefit of these functional T cells remains to be determined.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Terapia Antirretroviral de Alta Atividade , Proliferação de Células , Vetores Genéticos/genética , HIV-1/genética , Humanos , Imunoensaio , Interferon gama/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Vacinas de DNA/imunologia , Vaccinia virus/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologiaRESUMO
BACKGROUND: Nucleoside analogues such as Didanosine and Stavudine are known to cause metabolic and body habitus changes during antiretroviral therapy. The most frequently observed are lactic acidosis, hypercholesterinaemia, hypertriglyceridaemia and lipodystrophy. METHODS: Over one year we monitored a cohort of 43 patients who switched from either Stavudine, Didanosine or the combination of both to Tenofovir. A group of 11 patients was kept on their original regimen and acted as control group. Blood samples were taken every 3 months from baseline, anthropometric measurements were performed at baseline, after 6 and 12 months. RESULTS: During observation the levels of lactic acid and cholesterol decreased significantly in the switch group while virologic and immunologic efficacy remained stable. Serum creatinine levels rose significantly in patients switched to Tenofovir, but remained within physiological limits. The mean skin fold thickness increased significantly by 1.8 mm in the switch group after 6 months (p < or =0.001 - p = 0.032). CONCLUSION: These results implicate an improvement of lipid profiles, serum lactate and lipodystrophy in HIV-positive patients after switch to Tenofovir. As a moderate increase in serum creatinine levels was observed, the renal function of patients on a Tenofovir-based regimen should be monitored closely.
Assuntos
Adenina/análogos & derivados , Didanosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Organofosfonatos/uso terapêutico , Dobras Cutâneas , Estavudina/uso terapêutico , Adenina/efeitos adversos , Adenina/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Peso Corporal , Contagem de Linfócito CD4 , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Creatinina/sangue , Didanosina/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Hemoglobinas Glicadas , Infecções por HIV/sangue , Infecções por HIV/metabolismo , Hemoglobinas/análise , Humanos , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Organofosfonatos/efeitos adversos , Fosfatos/sangue , Estavudina/efeitos adversos , Tenofovir , Resultado do Tratamento , Triglicerídeos/sangue , Ácido Úrico/sangue , Carga ViralRESUMO
Renal disease is becoming an increasingly prevalent entity in human immunodeficiency virus (HIV)-infected patients; it occurs in a variety of clinical settings and is associated with histopathological changes. HIV-related renal impairment can present as acute or chronic kidney disease; it can be caused directly or indirectly by HIV and/or by drug-related effects that are directly nephrotoxic or lead to changes in renal function by inducing metabolic vaculopathy and renal damage. Acute renal failure is frequently caused by the toxic effects of antiretroviral therapy or nephrotoxic antimicrobial substances used in the treatment of opportunistic infections. Chronic renal disease can be caused by multiple pathophysiological mechanisms, leading to HIV-associated nephropathy, a form of collapsing focal glomerulosclerosis, thrombotic microangiopathy, and various forms of immune complex glomerulonephritis. The increase in life expectancy and alteration of lipid metabolism due to receipt of highly active antiretroviral therapy are expected to result in an increased prevalence of diabetes and hypertension and, thus, to secondary diabetic and hypertensive renal damage. Antiretroviral agents, such as indinavir and tenofovir, have been associated with nephrotoxic drug effects that have been shown to be reversible in most cases. In this article, we review the current knowledge about acute and chronic HIV-associated renal disease, metabolic alterations and related nephropathies, and toxic drug effects of combination antiretroviral pharmacotherapy.
Assuntos
Nefropatia Associada a AIDS/etiologia , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Nefropatia Associada a AIDS/epidemiologia , Injúria Renal Aguda/etiologia , Humanos , Falência Renal Crônica/etiologiaRESUMO
PURPOSE: Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposi's sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS: We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposi's sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS: A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION: Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposi's sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Doxorrubicina/efeitos adversos , Portadores de Fármacos , Humanos , Lipossomos , Estudos Prospectivos , Sarcoma de Kaposi/complicações , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Patients suffering from the acquired immune deficiency syndrome (AIDS) have a 20000-fold increased risk of developing a severe form of Kaposi's sarcoma (KS), a previously rare malignancy involving sharply defined nodular lesions of the skin and/or oral mucosa. Epidemiological evidence has long suggested that an infectious agent is the probable cause of KS. Recently sequences from a putative new herpesvirus have been found to be associated with KS in virtually 100% of the cases analyzed. The suspected etiological agent, a new human herpesvirus termed Kaposi's sarcoma associated herpes virus (human herpes virus 8) has now been propagated in cell culture. This significant advance should form the basis for a detailed analysis of the pathogenetic mechanisms involved in the development of KS.
Assuntos
Herpesvirus Humano 8/isolamento & purificação , Sarcoma de Kaposi/virologia , Adulto , Linhagem Celular , DNA Viral/análise , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/crescimento & desenvolvimento , Herpesvirus Humano 8/fisiologia , Humanos , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/terapia , Infecções Sexualmente Transmissíveis/virologia , Replicação ViralAssuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Adulto , Terapia Antirretroviral de Alta Atividade/normas , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Esquema de Medicação , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/transmissão , HIV-1 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Modelos de Riscos Proporcionais , Sensibilidade e Especificidade , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate ultrasound measurement of Kaposi's sarcoma (KS) tumour volume for follow-up during therapy. Two-dimensional evaluation of size and description of gross alteration (for example, colour, nodularity, resolution) was used to assess treatment of KS. Flattening of palpable cutaneous KS lesions during anti-KS therapy has not been quantified objectively by a reliable method. METHODS: In six patients with advanced AIDS and KS, a total of 17 cutaneous lesions were evaluated prospectively by ultrasound and surface measurements. KS lesions were examined histologically before and after 12 weeks of chemotherapy with liposomal doxorubicin. RESULTS: In comparison with size reduction, volume measurement showed a more pronounced reduction of tumour volume. The mean tumour volume was reduced by 94% from 451 mm3 +/- 655 mm3 to 66 mm3 +/- 165 mm3 at week 12 (P < 0.001). Histological evaluation of lesions no longer detectable by ultrasound after therapy showed abundant siderophages but no increase in spindle cells and no mitoses. CONCLUSIONS: Our findings suggest that ultrasound is a useful method with which to follow growth and remission of cutaneous KS. In contrast, pigmentation due to iron deposition is unaffected by chemotherapy because, despite histological remission, pigmentation can persist. Though ultrasound cannot replace histologic evaluation for complete response, we suggest the use of ultrasound assessment, thus introducing a more objective criterion than subjective rating of nodularity.
Assuntos
Sarcoma de Kaposi/diagnóstico por imagem , Adulto , Doxorrubicina/uso terapêutico , Estudos de Avaliação como Assunto , Humanos , Masculino , Indução de Remissão , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/patologia , UltrassonografiaRESUMO
OBJECTIVE: The pathogenesis of neurologic and neuropsychologic dysfunction in HIV-1 infection is unclear. The purpose of the study was to determine an association between cerebral perfusion and HIV-1-related ocular microangiopathic syndrome. METHODS: We studied 28 HIV-1-infected patients, seven of whom presented with asymptomatic HIV infection, nine with lymphadenopathy syndrome or AIDS-related complex, and 12 with AIDS. Cerebral perfusion was semi-quantitatively measured by single photon emission computed tomography of the brain using technetium-99 hexamethyl-propylenamine oxime (HMPAO-SPECT). The conjunctival manifestation of HIV-1-related microangiopathic syndrome was measured by a rating scale determining blood-flow sludging and, retinal cotton-wool spots were counted. CD4 count, neopterin, beta 2-microglobulin (beta 2M), haemoglobin, and age were determined as putative confounding variables. RESULTS: Mean conjunctival sludge in patients with normal HMPAO-SPECT findings was 1.3 +/- 0.5 (mean +/- s.e.m.); no cotton-wool spots were present. In patients with slightly impaired HMPAO-SPECT, it was 2.1 +/- 0.6 and mean cotton-wool spot count was 1.1 +/- 0.4. In patients with severely impaired HMPAO-SPECT, mean conjunctival sludge was 4.5 +/- 0.3 and mean cotton-wool spot count was 4.9 +/- 1.1 HMPAO-SPECT findings were closely associated with conjunctival sludge (r = 0.72; P < 0.001) and number of cotton-wool spots (r = 0.78; P < 0.001), whereas only a slight association with staging of HIV disease was found (P = 0.052). Analysis of covariance controlling for CD4 count neopterin, beta 2M, age, and haemoglobin demonstrated a significant difference between the three HMPAO-SPECT groups for both the number of cotton-wool spots (P < 0.001) and the conjunctival sludge rating (P < 0.001). CONCLUSION: There was a close association between severity of HIV-1-related ocular microangiopathic syndrome and severity of cerebral hypoperfusion. Microvascular alterations might contribute to the pathogenesis of neurological and neuropsychological symptoms in patients with HIV-1 disease. Furthermore, the conjunctival sludge rating and the number of cotton-wool spots might be appropriate indicators for severity of microvascular changes of the central nervous system [corrected].
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Túnica Conjuntiva/irrigação sanguínea , Doenças da Túnica Conjuntiva/etiologia , Infecções por HIV/complicações , Infecções por HIV/diagnóstico por imagem , HIV-1 , Compostos de Organotecnécio , Oximas , Tomografia Computadorizada de Emissão de Fóton Único , Complexo Relacionado com a AIDS/complicações , Complexo Relacionado com a AIDS/diagnóstico por imagem , Adulto , Idoso , Biopterinas/análogos & derivados , Biopterinas/sangue , Linfócitos T CD4-Positivos , Doenças da Túnica Conjuntiva/diagnóstico por imagem , Infecções por HIV/sangue , Hemoglobinas/análise , Humanos , Contagem de Leucócitos , Masculino , Microcirculação , Pessoa de Meia-Idade , Neopterina , Síndrome , Tecnécio Tc 99m Exametazima , Microglobulina beta-2/análiseRESUMO
OBJECTIVE: To assess the factors associated with virologic response to non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens in a large clinic cohort. DESIGN: Inception cohort. SETTING: HIV clinics in Europe PATIENTS: We identified all patients in EuroSIDA who began a regimen including either nevirapine or efavirenz (not both) after July 1997 and for whom pre-therapy viral load and CD4 cell count were known. MAIN OUTCOME MEASURES: Virological failure. RESULTS: A total of 1325 patients initiated nevirapine and 878 efavirenz. Respectively, median start dates were October 1998 and May 1999. Other factors at baseline, including CD4 cell count, viral load, previous AIDS, previous antiretroviral drug use and make-up of the NNRTI-containing regimen were all approximately similar between the nevirapine and efavirenz groups. A total of 669 patients experienced virological failure during follow-up. In a Cox model, less protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) previously used, higher CD4 nadir, lower viral load at baseline, a previous AIDS diagnosis and less NRTIs in the regimen were associated with lower risk of virological failure. The relative hazard of virological failure comparing those on efavirenz with those on nevirapine was 0.57 (95% confidence interval, 0.47-0.69; P < 0.0001). CONCLUSIONS: The difference in virologic outcome between those using nevirapine and efavirenz in this almost entirely drug-experienced population could reflect differences in effectiveness of the drugs in this setting but, despite the similarity between groups at baseline, bias cannot be excluded as an explanation. Replication of these findings in randomized trials and other cohort studies is required.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Adulto , Estudos de Coortes , Esquema de Medicação , Quimioterapia Combinada , Europa (Continente) , Feminino , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
To facilitate studies of the pharmacokinetic properties of zidovudine, the relationship between plasma and salivary concentrations of the drug was studied, after oral dosage, in 10 HIV-infected patients. Zidovudine concentrations were determined in plasma, unstimulated mixed saliva and citric-acid-stimulated mixed saliva over a period of 3 1/2 hours by high-performance liquid chromatography. Correlation coefficients were r = 0.97 (P less than 0.0001) for stimulated saliva compared with plasma and r = 0.89 (P less than 0.0001) for unstimulated saliva, with average values in unstimulated saliva being 113.8 +/- 44.6% in plasma and 67.8 +/- 25.4% in stimulated saliva. Stimulated saliva values found to be 70% of the total reflected the concentration of the unbound drug in plasma. Except for a shorter half-life time (t1/2) in saliva, pharmacokinetic parameters showed a good correlation in the three types of specimen. These findings and the convenience of sample collection suggest that citric-acid-stimulated saliva might be an appropriate specimen for monitoring zidovudine therapy.
Assuntos
Infecções por HIV/tratamento farmacológico , Saliva/metabolismo , Zidovudina/farmacocinética , Adulto , Estudos de Avaliação como Assunto , Infecções por HIV/diagnóstico , Infecções por HIV/metabolismo , Humanos , Masculino , Análise de Regressão , Zidovudina/uso terapêuticoRESUMO
OBJECTIVES: To determine whether the survival of patients with Kaposi's sarcoma as first manifestation of AIDS has changed between 1979 and 1989; and to define whether prognosis factors could be identified. PATIENTS AND METHODS: This is a multicentric retrospective cohort study from 52 centers in 17 European countries involving adults AIDS patients diagnosed between 1979 and 1989. Variables such as age, sex, geographical regions, transmission groups, date of Kaposi's sarcoma diagnosis, zidovudine use, CD4+ cell count and concomitant opportunistic infections or AIDS-related malignancies were evaluated by using uni- and multivariable proportional hazard models. Log-rank tests were used to determine which variables were associated with survival. RESULTS: From the 6,546 AIDS patients recruited in the database of the AIDS in Europe Study Group, 1,394 were diagnosed with Kaposi's sarcoma at the time of AIDS diagnosis, from 1979 and 1989. A total of 1,047 Kaposi's sarcoma patients died during the follow-up period. By Kaplan-Meier analyses, the median and mean survival for these Kaposi's sarcoma patients were 17 and 25 months, respectively, with no change over time. However, age, sex (female), geographic region, low CD4+ cell count (< 150 x 10(6)/l) and some opportunistic infections and non-Hodgkin's lymphoma were associated with a poorer prognosis. Zidovudine use, year of diagnosis and risk factor for HIV-1 infection brought no additional information as predictor of mortality. CONCLUSIONS: This study suggests that the survival of patients with Kaposi's sarcoma as first manifestation of AIDS has remained poor during the last decade in contrast with the overall AIDS survival which had significantly improved from a median of 13-18 months during the same period of observation. There is a need for further prospective information to explain the worse prognosis in women and the geographical variations.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Sarcoma de Kaposi/mortalidade , Adulto , Fatores Etários , Contagem de Linfócito CD4 , Estudos de Coortes , Europa (Continente) , Feminino , Seguimentos , Humanos , Masculino , Análise Multivariada , Estudos Retrospectivos , Fatores Sexuais , SobrevidaRESUMO
BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Teste de Tolerância a Glucose , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Resistência à Insulina , Adulto , Colesterol/sangue , Feminino , Infecções por HIV/sangue , Infecções por HIV/fisiopatologia , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
BACKGROUND: Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity. OBJECTIVE: A first phase I/II clinical study of ADA. METHODS: ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage. RESULTS: Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 x 10(6) cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/ 11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47-243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52-1.23). CONCLUSIONS: The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Compostos Azo/uso terapêutico , HIV-1 , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Contagem de Linfócito CD4 , Relação CD4-CD8 , Qualidade de Produtos para o Consumidor , Método Duplo-Cego , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
OBJECTIVES: The primary objective of this study was to expand the safety and immunogenicity database of recombinant gp160 as a therapeutic vaccine in the treatment of HIV-infection. Preliminary efficacy data was also sought. DESIGN: This trial was a randomized, double-blind, placebo-controlled study. Two-hundred and eight volunteers, 96 therapy-naive with CD4 cell count >500x10(6)/l (group A) and 112 with CD4 cell count of 200-500x10(6)/l (group B, 51 out of 112 on treatment with one or two nucleoside analogues), received monthly injections of rgp160 IIIB vaccine or placebo for the first 6 months of the study; booster immunizations with rgp160 MN or placebo were given at times 15, 18, and 21 months. METHODS: Safety and immunogenicity data were obtained and measurements of CD4 cell count, plasma viral RNA, and proviral DNA were performed. Clinical outcome was recorded for the 24 months of study. RESULTS: The vaccine was safe and well tolerated. Despite the induction of new rgp160-specific lymphoproliferative responses and the presence of positive delayed type hypersensitivity skin tests to rgp160 at the end of the 24 month study, no effect on the natural history of HIV infection was detected. Within 24 months, AIDS-defining illnesses had occurred in 19 of the vaccinated volunteers and in 18 of the placebo recipients. Persons with higher plasma viral RNA levels and higher proviral DNA had a more rapid decline in CD4 cell count when compared to persons with lower values. Vaccine did not alter viral RNA or proviral DNA levels. CONCLUSION: There was no clinical benefit to therapeutic immunizations with rgp160, despite the induction of new lymphoproliferative responses.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Proteína gp160 do Envelope de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Vacinas contra a AIDS/imunologia , Contagem de Linfócito CD4 , DNA Viral/sangue , Método Duplo-Cego , Proteína gp160 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Humanos , Esquemas de Imunização , Ativação Linfocitária , Provírus , RNA Viral/sangue , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
Neither single-agent therapy nor any combination treatment has been satisfactory enough to be regarded as standard in systemic advanced Kaposi sarcoma. In an attempt to achieve high efficacy in combination with low toxicity, we used a new liposomal formulation of doxorubicin. Pharmacologic data had established a long plasma half-life, an increased accumulation in tumor tissue, and a decrease in uptake by tissues such as liver, spleen, and bone marrow. In a phase I/II open-label, dose-escalating trial 40 male AIDS patients with advanced Kaposi sarcoma were enrolled to receive intravenous "stealth" liposomal doxorubicin biweekly at doses of 10 mg/m2 (n = 10), 20 mg/m2 (n = 27), and 40 mg/m2 (n = 3). The median CD4 count at baseline was 25/microL. After six cycles (12 weeks), 39 patients were evaluable. Three patients (7.5%) showed a complete response, which was histologically confirmed. A partial response was documented in 33 patients (85%). Stable disease was observed in three patients (7.5%). During a median treatment duration of 25 weeks, four patients developed stomatitis (10%), and four patients (10%) experienced alopecia. The most frequent hematologic toxicity was neutropenia. Grade 4 neutropenia was seen in 42.5%, and grade 3 toxicity was seen in 30%. Toxicity was dose-dependent and more frequent in the 40 mg/m2 stratum. During a median observation period of 25 weeks, opportunistic infections occurred in 57.5% of the patient population. We conclude that liposomal doxorubicin at dose levels of 10 and 20 mg/m2 is safe and effective for treatment of advanced Kaposi sarcoma in AIDS. A controlled trial comparing liposomal doxorubicin to conventional combination therapy is underway.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Doxorrubicina/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/etiologia , Adulto , Alopecia/induzido quimicamente , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Portadores de Fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/etiologia , Humanos , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/etiologia , Linfoma não Hodgkin/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/etiologia , Neutropenia/induzido quimicamente , Sarcoma de Kaposi/etiologia , Estomatite/induzido quimicamente , Resultado do TratamentoRESUMO
Ocular microangiopathic syndrome is found frequently in patients with AIDS or severe HIV infection. Symptoms of this microvascular syndrome can include cotton-wool spots, hemorrhages, and Roth's spots. The clinical and functional significance of HIV-related ocular microangiopathic syndrome has not been clarified as yet. The objective of this study was to evaluate a possible association between HIV-related ocular microangiopathic syndrome and cognitive functioning. Thirty-seven patients infected with HIV (24 with AIDS) underwent ophthalmological and neuropsychological examination. HIV-related ocular microangiopathic syndrome was measured by counting the number of cotton-wool spots in both eyes. Neuropsychological examination included five standardized tests, with the first three primarily measuring function of short-term memory; these tests were as follows: the Auditory-Verbal Learning Test, the Benton Test, the Stroop Colour Word Test, the Trail-Making Part B test, and the Vocabulary for Measuring Premorbid Intelligence test. HIV-related ocular microangiopathic syndrome was found in 15 patients with AIDS (62.5%), and in one patient, staged Walter Reed 5. In 10 patients, one eye was affected (mean count of cotton-wool spots 1.5). In six patients, both eyes were affected (mean count of cotton-wool spots 7.0). Univariate correlations between the number of cotton-wool spots in both eyes and test scores were as follows: Auditory-Verbal Learning Test: 0.56 (p < 0.001); Benton Test: 0.51 (p < 0.001); Stroop Colour and Word: 0.50 (p < 0.001); Trail-Making Part B: 0.15 (not significant); Vocabulary for Measuring Premorbid Intelligence: -0.05 (not significant). Multiple correlation between the test scores and the number of cotton-wool spots was 0.70 (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Transtornos Cognitivos/complicações , Soropositividade para HIV/complicações , Vasos Retinianos , Adulto , Transtornos Cognitivos/sangue , Feminino , Soropositividade para HIV/sangue , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doenças Retinianas/sangue , Doenças Retinianas/complicações , Hemorragia Retiniana/complicações , Linfócitos TRESUMO
BACKGROUND AND OBJECTIVES: In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data. PATIENTS AND METHODS: In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined. RESULTS: The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses. CONCLUSIONS: The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.
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Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Lipídeos/efeitos adversos , Zidovudina/análogos & derivados , Zidovudina/efeitos adversos , Adulto , Alimentos , Humanos , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Masculino , Pessoa de Meia-Idade , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
BACKGROUND AND OBJECTIVES: A Phase I dose-escalating trial with single doses of fozivudine tidoxil (BM21.1290; FZD), in vitro, and experimental in vivo data indicated that further investigations with this compound were warranted. Advantages of fozivudine tidoxil are the direct delivery of zidovudine monophosphate intracellularly and high concentrations in lymphatic tissues. Our objectives were to evaluate safety, tolerability and efficacy of fozivudine tidoxil in human immunodeficiency virus (HIV)-infected patients. PATIENTS AND METHODS: In a Phase I/II dose-escalating trial, three doses of fozivudine tidoxil (400, 800 or 1200 mg/day) were administered for 1 week. The study was randomized and placebo controlled. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. The exclusion criteria were active opportunistic infection and prior antiretroviral treatment. RESULTS: The tolerability of fozivudine tidoxil was excellent in all dose groups. No treatment discontinuations were necessary. Steady-state pharmacokinetics did show slightly higher concentrations as compared with levels after the first dose (20%). Viral load reduction was most pronounced in the 1200 mg/day dose group (-0.64 log). No viral load reduction was seen in the placebo group. CONCLUSIONS: The zidovudine conjugate fozivudine tidoxil is safe and well tolerated at the three doses tested. Based on the differences in molecular weights, the 1200 mg dose is roughly equivalent to 400 mg zidovudine.
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Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Lipídeos/efeitos adversos , Zidovudina/análogos & derivados , Zidovudina/efeitos adversos , Adulto , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
PURPOSE: Color vision deficits in patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) disease were reported, and a retinal pathogenic mechanism was proposed. The purpose of this study was to evaluate the association of color vision deficits with HIV-related retinal microangiopathy. METHODS: A computer graphics system was used to measure protan, deutan, and tritan color contrast sensitivity (CCS) thresholds in 60 HIV-infected patients. Retinal microangiopathy was measured by counting the number of cotton-wool spots, and conjunctival blood-flow sludging was determined. Additional predictors were CD4+ count, age, time on aerosolized pentamidine, time on zidovudine, and Walter Reed staging. The relative influence of each predictor was calculated by stepwise multiple regression analysis (inclusion criterion; incremental P value = < 0.05) using data for the right eyes (RE). The results were validated by using data for the left eyes (LE) and both eyes (BE). RESULTS: The only included predictors in multiple regression analyses for the RE were number of cotton-wool spots (tritan: R = .70; deutan: R = .46; and protan: R = .58; P < .0001 for all axes) and age (tritan: increment of R [Ri] = .05, P = .002; deutan: Ri = .10, P = .004; and protan: Ri = .05, P = .002). The predictors time on zidovudine (Ri = .05, P = .002) and Walter Reed staging (Ri = .03, P = .01) were additionally included in multiple regression analysis for tritan LE. The results for deutan LE were comparable to those for the RE. In the analysis for protan LE, the only included predictor was number of cotton-wool spots. In the analyses for BE, no further predictors were included. The predictors Walter Reed staging and CD4+ count showed a significant association with all three criteria in univariate analysis. Additionally, tritan CCS was significantly associated with conjunctival blood-flow sludging. CONCLUSION: CCS deficits in patients with HIV disease are primarily associated with the number of cotton-wool spots. Results of this study are in accordance with the hypothesis that CCS deficits are in a relevant part caused by neuroretinal damage secondary to HIV-related microangiopathy.
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Defeitos da Visão Cromática/fisiopatologia , Sensibilidades de Contraste/fisiologia , Infecções por HIV/fisiopatologia , HIV-1 , Vasos Retinianos/fisiopatologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Adulto , Testes de Percepção de Cores , Defeitos da Visão Cromática/etiologia , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doenças Retinianas/complicações , Vasos Retinianos/patologia , SíndromeRESUMO
Analyses of serum samples and blood cells have revealed a dysregulation of the Fas/Fas ligand (FasL) system during HIV infection, which may be related to disease progression. As Fas and FasL have been suggested to participate in brain injury in a variety of CNS disorders, the aim of this study was to determine (1) whether soluble Fas and FasL can be detected in cerebrospinal fluid (CSF) samples from HIV-infected patients, (2) whether levels of these molecules are related to disease progression, and (3) whether levels of sFasL are related to other laboratory findings. Soluble Fas was detected in 38 of 56 (68%) and soluble Fas ligand in 17 of 56 (30%) CSF samples from HIV-infected patients. CSF levels of both molecules correlated neither with the CSF-to-serum albumin ratio nor with corresponding serum concentrations. This finding suggests that they are at least in part produced intrathecally. Levels of both CSF sFas and sFasL correlated significantly and inversely with the blood CD4+ cell counts, suggesting that the intrathecal release of both molecules is increased during progression to advanced immunodeficiency.