RESUMO
BACKGROUND: This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus. METHODS: A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. RESULTS: This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. CONCLUSIONS: While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.
Assuntos
Benzoatos/toxicidade , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Piperazinas/toxicidade , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Compostos de Espiro/toxicidade , Adulto , Idoso , Benzoatos/farmacocinética , Dicetopiperazinas , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacocinética , HIV-1/imunologia , Humanos , Lopinavir , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacocinética , Pirimidinonas/farmacocinética , RNA Viral/imunologia , Receptores CCR5/uso terapêutico , Ritonavir/farmacocinética , Compostos de Espiro/farmacocinética , Adulto JovemRESUMO
Aplaviroc (APL) was a new CCR5 antagonist that was investigated in two dose-ranging studies with antiretroviral therapy-naïve, human immunodeficiency virus-infected adults: ASCENT, in which 147 subjects were randomized 2:2:1 to receive zidovudine-lamivudine (ZDV-3TC) plus APL 600 mg twice a day (BID), APL 800 mg BID, or efavirenz (EFV), respectively, and EPIC, in which 195 subjects were randomized 2:2:2:1 to receive lopinavir-ritonavir (LPV-RTV) plus APL 200 mg BID, APL 400 mg BID, APL 800 mg once a day, or ZDV-3TC BID, respectively. Both studies (and, ultimately, the clinical development of APL) were discontinued after a mean of 14 weeks of therapy because of higher than anticipated severe liver toxicity; grade 2 or higher treatment-emergent elevations in alanine aminotransferase (ALT) levels were observed in 17/281 (6.0%) APL recipients but only 2/55 (3.6%) control recipients, while grade 2 or higher elevations in total bilirubin levels occurred in 29/281 (10.3%) APL recipients but only 4/55 (7.3%) controls. Two APL recipients developed grade 3 or higher treatment-emergent elevations in both ALT and total bilirubin levels, and one of these individuals had a severe case of hepatic cytolysis that was attributed to APL. Despite the high intersubject variability in APL plasma exposures, a Pearson correlation analysis of the combined study data did not reveal any significant associations between plasma concentrations and the liver enzyme elevations observed during the study. The mechanism for the idiosyncratic hepatotoxicity observed in the clinical trials of APL is unknown but is likely intrinsic to the molecule rather than its novel mechanism of action.
Assuntos
Benzoatos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Inibidores da Fusão de HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piperazinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Adulto , Alanina Transaminase/sangue , Benzoatos/administração & dosagem , Benzoatos/farmacocinética , Benzoatos/farmacologia , Bilirrubina/sangue , Dicetopiperazinas , Método Duplo-Cego , Feminino , Inibidores da Fusão de HIV/administração & dosagem , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/virologia , Humanos , Fígado/efeitos dos fármacos , Masculino , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piperazinas/farmacologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologiaRESUMO
The clinical significance of early airflow decline after myeloablative allogeneic hematopoietic SCT is uncertain. We performed a retrospective cohort analysis to determine if airflow decline by day 100 is associated with later development of transplant-related airflow obstruction (AFO) and increased mortality risk. Overall, 750 (40%) patients had airflow decline by day 100. Development of airflow decline by day 100 was associated with an increased risk for AFO at 1 year (relative risk 2.6, 95% confidence interval 2.1-3.1) but not with an increase in mortality risk (hazard ratio (HR) 0.86, P=0.05). However, patients with the fastest rate of decline between day 100 and 1 year (12.5% per year +/-24) had the highest mortality risk (HR 3.2, P<0.001). In conclusion, airflow measurements made on day 100 do not predict the rate of airflow decline between day 100 and 1 year, and therefore are not useful as a single measurement for determining mortality risk associated with development of AFO. Closer monitoring of the rate of airflow decline during the first year may facilitate the timely detection and treatment of early airflow decline and prevent the development of fixed AFO and increased mortality risk after hematopoietic stem cell transplant.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Agonistas Mieloablativos/efeitos adversos , Ventilação Pulmonar , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/etiologia , Testes de Função Respiratória , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/mortalidade , Transplante HomólogoRESUMO
Parainfluenza virus (PIV) infections may be significant causes of morbidity and mortality in patients undergoing stem cell transplantation, but data regarding their impact on transplant-related mortality is limited. This study sought to determine the risk factors of PIV acquisition and progression to lower respiratory tract infection, their impact on transplant-related mortality, and the effectiveness of antiviral therapy. A total of 3577 recipients of hematopoietic stem cell transplantation (HSCT) between 1990 and 1999 were studied. PIV infections occurred in 253 patients (7.1%); 78% of these infections were community acquired. Multivariable analysis identified the receipt of an unrelated transplant as the only risk factor for PIV acquisition; the dose of corticosteroids at the time of PIV infection acquisition was the primary factor associated with the development of PIV-3 pneumonia, both among allogeneic and autologous HSCT recipients. Both PIV-3 upper respiratory infection and pneumonia were associated with overall mortality. Pulmonary copathogens were isolated from 29 patients (53%) with pneumonia. Mortality was highly influenced by the presence of copathogens and the need for mechanical ventilation. Aerosolized ribavirin with or without intravenous immunoglobulin did not appear to alter mortality from PIV-3 pneumonia, nor did such therapy decrease the duration of viral shedding from the nasopharynx among patients with pneumonia. Corticosteroid administration thus drives the development of PIV pneumonia in a dose-dependent fashion, even among autologous HSCT recipients. Both upper and lower tract PIV infections are predictors of mortality after HSCT. Currently available antiviral therapy appears to be inadequate in reducing viral shedding or mortality once pneumonia is established. (Blood. 2001;98:573-578)
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Paramyxoviridae/etiologia , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Doadores de Sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Lactente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/epidemiologia , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Infecções Respiratórias/virologia , Estudos Retrospectivos , Ribavirina/administração & dosagem , Fatores de Risco , Resultado do TratamentoRESUMO
To determine the risk factors and outcomes associated with rising cytomegalovirus (CMV) antigenemia levels during preemptive therapy among stem cell allograft recipients, 119 patients with CMV antigenemia were studied. Patients were prospectively monitored for CMV antigenemia weekly; those with positive findings on antigenemia tests were treated with intravenous ganciclovir (5 mg/kg twice daily for 1 week, followed by 5 mg/kg per day for 5-6 d/wk). While on therapy, 47 of 119 (39%) patients demonstrated increases that were 2 or more times greater than their baseline values, whereas 33 of 119 (28%) patients demonstrated increases that were 5 or more times greater. Rising antigenemia was confirmed by polymerase chain reaction for CMV DNA. Multivariate analysis identified corticosteroids as the primary risk factor for increasing antigenemia: for increases greater than or equal to twice the baseline, 1 to 2 mg/kg steroids was associated with an odds ratio (OR) of 4.0. For increases greater than or equal to 2 mg/kg steroids, the OR was 10.1. CMV isolates obtained at the time of rising antigenemia were susceptible to ganciclovir, indicating that resistance was not a major factor. Overall, rising antigenemia levels were not correlated with CMV disease. All 4 patients in whom CMV disease developed during therapy, however, had rising antigenemia levels. Among the 47 patients with antigenemia increases greater than or equal to twice the baseline, 15 were re-induced with antivirals, whereas 32 continued to receive maintenance therapy. All 4 patients in whom CMV disease developed during therapy received maintenance therapy, and 3 died with CMV disease. Thus, host factors such as the receipt of corticosteroids explain increasing viral load during the early phase of preemptive therapy. Continued induction dosing or re-induction may protect against early breakthrough CMV disease and CMV-related death among patients with rising antigenemia on preemptive therapy. (Blood. 2001;97:867-874)
Assuntos
Antígenos Virais/sangue , Infecções por Citomegalovirus/sangue , DNA Viral/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fosfoproteínas/sangue , Transplante Homólogo/efeitos adversos , Proteínas da Matriz Viral/sangue , Viremia/sangue , Adolescente , Corticosteroides/efeitos adversos , Adulto , Idoso , Antivirais/uso terapêutico , Causas de Morte , Criança , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/transmissão , Feminino , Foscarnet/uso terapêutico , Ganciclovir/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Carga Viral , Ativação ViralRESUMO
Community respiratory viruses (CRVs) are an important cause of morbidity and mortality among recipients of hematopoietic stem cell transplants (HSCT). At the Fred Hutchinson Cancer Research Center, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) infections in HSCT recipients have been studied intensively for more than a decade. Over time, mortality from these infections has declined as the approach to diagnosis has become more aggressive and more stringent preventive measures have been instituted. However, mortality among HSCT recipients with RSV or PIV pneumonia remains high. Uncontrolled studies at our center suggest that prompt therapy with aerosolized ribavirin has reduced mortality from RSV pneumonia but does not appear to affect the course of established PIV pneumonia. Two controlled clinical trials of ribavirin therapy for RSV infection in HSCT recipients are in progress.
Assuntos
Infecções Comunitárias Adquiridas/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ensaios Clínicos como Assunto , Controle de Doenças Transmissíveis/métodos , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/etiologia , Humanos , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/etiologia , Infecções Oportunistas/virologia , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/etiologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/etiologia , Estudos Retrospectivos , Ribavirina/administração & dosagem , Fatores de Risco , Taxa de SobrevidaRESUMO
The introduction of highly active antiretroviral therapy (HAART) for HIV has had a major impact on the treatment of CMV disease in HIV-infected individuals. There is mounting evidence that in patients with CMV retinitis who have a sustained response to HAART, CMV maintenance treatment can be discontinued without relapse of retinitis. In HAART-naïve individuals with newly diagnosed CMV retinitis, the optimal timing for the initiation of HAART relative to the start of anti-CMV treatment is currently unknown. New local therapies for CMV retinitis (e.g. ganciclovir implant, the new antisense compound fomivirsen) provide treatment options in situations where high local drug delivery is warranted. A treatment algorithm for CMV disease in the HAART era is proposed. In the transplant setting, ganciclovir and foscarnet remain the major compounds used for treatment of CMV disease. In marrow and stem cell transplant recipients, CMV pneumonia still carries a high mortality. Ganciclovir in combination with CMV-specific immunoglobulin or regular intravenous IG remains the treatment of choice for CMV pneumonia; extended antiviral maintenance for several months is recommended in patients with continued immunosuppression. Preemptive treatment based on virologic markers (e.g. pp65 antigenemia, CMV DNA) has been very successful in reducing the incidence of early CMV disease in the transplant setting. The duration of preemptive treatment should be guided by the underlying immunosuppression and virologic markers. Late CMV disease is a challenge in marrow and stem cell transplant recipients, and occurs increasingly in highly immunosuppressed solid organ transplant recipients as well. Recent advances in prophylaxis strategies include oral ganciclovir for liver transplant recipients and valacyclovir for kidney transplant recipients.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/prevenção & controle , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de ÓrgãosRESUMO
To optimize mucosal immune responses to the HIV-1 peptide vaccine candidate T1SP10 MN(A), we intranasally immunized BALB/c and C57BL/6 mice with C4/V3 HIV-1 peptide together with the mucosal adjuvant cholera toxin (CT). Four doses over a 4-wk period resulted in peak serum anti-peptide IgG titers of > 1:160,000 in BALB/c mice and > 1:520,000 in C57BL/6 mice, and significant levels (>1:30,000) persisted in both strains of mice for longer than 6 mo. Furthermore, intranasal immunization with peptide and CT induced serum IgG reactivity to HIV-1 gp120 and HIV-1(MN) neutralizing responses. The primary anti-peptide IgG subclass was IgG1, suggesting a predominant Th2-type response. In addition to elevated serum anti-peptide A responses, intranasal immunization with T1SP10 MN(A) and CT induced both vaginal anti-peptide IgG and IgA responses, which persisted for 91 days in both strains of mice. Vaginal anti-HIV IgA was frequently associated with secretory component, suggesting transepithelial transport of IgA into vaginal secretions. Cervical lymph nodes contained the highest relative concentration of anti-T1SP10 MN(A) IgG-producing cells, while the spleen was the next major site of anti-T1SP10 MN(A) IgG-producing cells. Ag-specific proliferative responses were also detected in cervical lymph node and spleen cell populations after intranasal immunization with T1SP10 MN(A) and CT. In addition, intranasal immunization with T1SP10 MN(A) and CT was able to induce anti-HIV cell-mediated immunity in vivo as indicated by the induction of delayed-type hypersensitivity. Therefore, intranasal immunization with hybrid HIV peptides provides a noninvasive route of immunization that induces both long-lived systemic and mucosal Ab responses as well as cell-mediated immunity to HIV.