ABSTRACT
Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.
Subject(s)
CCR5 Receptor Antagonists , Cyclohexanes/adverse effects , Cyclohexanes/therapeutic use , HIV Infections/drug therapy , HIV-1/drug effects , Triazoles/adverse effects , Triazoles/therapeutic use , Adult , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Brazil , CD4 Lymphocyte Count , Darunavir , Drug Therapy, Combination , Female , HIV Fusion Inhibitors/adverse effects , HIV Fusion Inhibitors/therapeutic use , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/therapeutic use , Humans , Male , Maraviroc , Middle Aged , Protease Inhibitors/adverse effects , Protease Inhibitors/therapeutic use , Pyrrolidinones/adverse effects , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Treatment Failure , Viral Load/drug effects , Young AdultSubject(s)
HIV , HIV Infections , Antiretroviral Therapy, Highly Active , HIV Testing , Hematologic DiseasesABSTRACT
Cell-mediated immunity, leading to Mycobacterium tuberculosis (Mtb)-constraining granuloma formation, is the major component of host defense against tuberculosis and is regulated by the balance of cytokines secreted mostly by mononuclear phagocytes and lymphocytes. To better understand the role of monocytes in the regulation of the immune response against pulmonary tuberculosis, we examined IL-10, IL-12 and TNF-alpha release by monocytes from healthy purified protein derivative (PPD) reactors and pulmonary tuberculosis patients with or without systemic reactions (e.g., fever, weight loss, asthenia). Our study shows that, probably as a result of in vivo priming by circulating antigens, monocytes from patients, especially those with systemic manifestations, have a biased ex vivo cytokine secretion, with high IL-10 and TNF-alpha but low IL-12, in contrast with PPD reactors. Higher spontaneous IL-10 and TNF-alpha release persisted when monocytes were co-cultured with autologous lymphocytes. Challenge of patients' monocytes with a virulent Mtb strain led to a further enhancement of IL-10 and TNF-alpha, but not of IL-12. When lymphocytes were added to these cultures, IL-10 and TNF-alpha elevation persisted and, in the patients with a systemic reaction, both IL-12 and IFN-gamma were significantly reduced compared to PPD reactors. Intragroup comparisons revealed that in the patients with systemic reactions, the lymphocyte-monocyte interaction resulted in a positive feedback for IL-10 secretion, while in the patients without systemic reaction and PPD reactors, the feedback was positive for IL-12 secretion. Thus, in tuberculosis, there appears to exist a relationship between the immunological findings and the distinct clinical manifestations.
Subject(s)
Cytokines/biosynthesis , Monocytes/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/immunology , Adolescent , Adult , Asthenia/pathology , Cells, Cultured , Coculture Techniques , Cytokines/analysis , Female , Fever/pathology , Humans , Interleukin-10/analysis , Interleukin-10/biosynthesis , Interleukin-12/analysis , Lymphocytes , Male , Middle Aged , Tuberculosis, Pulmonary/blood , Tuberculosis, Pulmonary/pathology , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/biosynthesis , Weight LossABSTRACT
This study was done to determine the occurrence of mycobacteria in the bloodstreams of patients with fever and advanced AIDS in a Brazilian hospital. We also verified the capability of an automated method for recovering these bacteria. During a period of 19 months, 254 patients with AIDS were evaluated. Blood cultures were generally submitted in pairs and drawn separately. Blood cultures were processed by the BACTEC 460TB System (Becton Dickinson Microbiology Systems, Sparks, MD). Of the 530 vials submitted, 77 (14.5 percent) from 41 (16 percent) patients were positive. Mycobacterium avium complex was recovered from 45 (58.4 percent) of the 77 positive vials, corresponding to 22 (53.6 percent) patients with positive blood cultures. The average time to detect Mycobacterium avium complex was 15 days. Mycobacterium tuberculosis was recovered from 26 (33.8 percent) of the 77 positive vials, corresponding to 15 (36.6 percent) patients with positive blood cultures, with an average detection time of 24 days. Other species of mycobacteria were recovered from 6 (7.8 percent) of the 77 vials, corresponding to 4 (9.8 percent) patients. M. avium complex was fairly prevalent (8.7 percent) in severely ill patients with AIDS in our hospital. M. tuberculosis was also an important (6.0 percent) agent of systemic bacterial infections in these patients. The rapid diagnosis of mycobacteremia was possible with the implementation of this automated technology.