RESUMO
BACKGROUND: The effect of interleukin-2 (IL-2) in combination with antiretroviral therapy on HIV-1 replication and reservoirs was investigated. METHODS: In a prospective, open-label trial, 56 asymptomatic HIV-1-infected subjects (CD4 T cell count > 350 x 10(6) cells/l) were randomized to highly active antiretroviral therapy (HAART: stavudine, lamivudine, nelfinavir, saquinavir) with or without IL-2 (9 megaunits daily for 5 days in 6-weekly intervals for a total of eight cycles). Productive and latent infection were analysed in peripheral blood, and residual virus replication in the lymphoid tissue and in the cerebrospinal fluid. The influence of IL-2 on viral rebound after treatment discontinuation was studied. RESULTS: Virus replication was detected in 21 of 31 on-treatment lymph nodes despite undetectable plasma viraemia. Viral RNA was found in resting as well as in proliferating cells. RNA-negative patients tended towards more rapid proviral DNA elimination. Supplementary IL-2 led to a greater increase in CD4 T cell counts than HAART alone (P < 0.001), resulting in normalization in approximately 90% of IL-2-treated patients compared with approximately 50% HAART-only subjects. IL-2 had no beneficial effect on virus replication and on proviral DNA in peripheral blood. CONCLUSIONS: Viral persistence during HAART is partly a result of continued low-level replication, calling for more active regimens. IL-2 accelerates the normalization of CD4 T cell counts but does not impact on virus production or latency.
Assuntos
Terapia Antirretroviral de Alta Atividade , HIV-1/efeitos dos fármacos , Interleucina-2/farmacologia , Provírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adolescente , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , DNA Viral/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/uso terapêutico , Linfonodos/efeitos dos fármacos , Linfonodos/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Provírus/genética , RNA Viral/sangue , Viremia/tratamento farmacológicoRESUMO
BACKGROUND: This study presents preclinical data of a novel interferon (IFN)-α8 fusion protein, PF-04849285, and compares it with IFN-α2 and pegylated IFN-α2; the latter being the current standard of care for HCV. METHODS: The antiviral properties were evaluated in vitro using the HCV replication assay (replicon) and the general encephalomyocarditis virus assay. The binding affinity to both IFNR-subunits was assessed using surface plasmon resonance. Ex vivo experiments using cynomolgus monkey and human blood were used for the evaluation of induction of IFN-inducible biomarkers (interferon inducible protein 10 [IP-10], 2'-5'-oligoadenylate synthetase [OAS2] and interleukin-6 [IL-6]). The molecule was tested intravenously and subcutaneously in cynomolgus monkey in a single dose study for two weeks at 0.01, 1, 5 and 20 mg/kg. Each route and dose combination was given to a single male animal, blood samples were collected for evaluation of biomarkers and pharmacokinetics. The compound was also tested in cynomolgus monkey in a multiple dose study for four weeks, with a twice-a-week dosing prior to a three-week wash-out period for toxicokinetics, pharmacokinetics, and biomarker evaluation at 20, 50 or 100 mg/kg subcutaneously and 20 mg/kg intravenously. RESULTS: The molecule is 10× more potent than the pegylated IFN-α2a, with potency similar to the unmodified IFN-α2a. No unanticipated findings were observed in cynomolgus monkey when dosed up to 20 mg/kg, >10,000-fold margin over the anticipated efficacious human dose. CONCLUSIONS: The biomarker and toxicological findings were consistent with a potent IFN molecule. The potency and pharmacokinetic properties of the molecule are consistent with dosing at least every two weeks with the potential for monthly dosing' and not 'at least twice daily' as presented in the original [corrected].
Assuntos
Antivirais/farmacologia , Hepatite C/tratamento farmacológico , Interferon-alfa/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Vírus da Encefalomiocardite/efeitos dos fármacos , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/farmacocinética , Interferon-alfa/toxicidade , Macaca fascicularis , Masculino , Receptores de Interferon/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/toxicidade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Replicação Viral/efeitos dos fármacosRESUMO
Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials.