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 AdultABSTRACT
The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.
El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.
Subject(s)
Adult , Humans , Male , Carbamates/adverse effects , Cardiomyopathies/drug therapy , Creatine Kinase/blood , Cyclohexanes/adverse effects , Chemical and Drug Induced Liver Injury/diagnosis , Fatty Liver/chemically induced , HIV Fusion Inhibitors/adverse effects , HIV Infections/drug therapy , HIV Integrase Inhibitors/adverse effects , HIV Protease Inhibitors/adverse effects , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/chemically induced , Organophosphates/adverse effects , Pyrrolidinones/adverse effects , Sulfonamides/adverse effects , Triazoles/adverse effects , Carbamates/therapeutic use , Cyclohexanes/therapeutic use , Drug Substitution , Drug Therapy, Combination , Fatty Liver/diagnosis , HIV Fusion Inhibitors/therapeutic use , HIV Integrase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic use , Liver Cirrhosis/diagnosis , Organophosphates/therapeutic use , Pyrrolidinones/therapeutic use , Sulfonamides/therapeutic use , Triazoles/therapeutic useABSTRACT
The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.
Subject(s)
Carbamates/adverse effects , Cardiomyopathies/drug therapy , Chemical and Drug Induced Liver Injury/diagnosis , Creatine Kinase/blood , Cyclohexanes/adverse effects , Fatty Liver/chemically induced , HIV Fusion Inhibitors/adverse effects , HIV Infections/drug therapy , HIV Integrase Inhibitors/adverse effects , HIV Protease Inhibitors/adverse effects , Hepatitis C, Chronic/drug therapy , Liver Cirrhosis/chemically induced , Organophosphates/adverse effects , Pyrrolidinones/adverse effects , Sulfonamides/adverse effects , Triazoles/adverse effects , Adult , Carbamates/therapeutic use , Cyclohexanes/therapeutic use , Drug Substitution , Drug Therapy, Combination , Fatty Liver/diagnosis , Furans , HIV Fusion Inhibitors/therapeutic use , HIV Integrase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic use , Humans , Liver Cirrhosis/diagnosis , Male , Maraviroc , Organophosphates/therapeutic use , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Sulfonamides/therapeutic use , Triazoles/therapeutic useABSTRACT
BACKGROUND: The MERIT study evaluated maraviroc versus efavirenz, both with zidovudine/lamivudine, in treatment-naïve patients with CCR5-tropic (R5) HIV-1. Post hoc analyses previously assessed week 48 outcomes in patients rescreened with R5 virus by a more sensitive tropism assay. METHODS: Week 96 efficacy (post hoc, n = 614) and safety (n = 721) were assessed. RESULTS: Proportions of subjects <50 copies/mL (58.8% maraviroc, 62.7% efavirenz) and time to loss of virologic response (TLOVR) responders (<50 copies/mL: 60.5% vs 60.7%) were similar. Maraviroc recipients had greater CD4 increases (+ 212 vs + 171 cells/mm(3)) and fewer adverse event discontinuations (6.1% vs 15.5%), malignancies, and category C events. CONCLUSION: Week 96 data confirm week 48 observations in MERIT.
Subject(s)
Anti-HIV Agents/therapeutic use , Benzoxazines/therapeutic use , Cyclohexanes/therapeutic use , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Lamivudine/therapeutic use , Triazoles/therapeutic use , Zidovudine/therapeutic use , Adolescent , Adult , Aged , Alkynes , Anti-HIV Agents/adverse effects , Benzoxazines/adverse effects , CCR5 Receptor Antagonists , Cyclohexanes/adverse effects , Cyclopropanes , Drug Therapy, Combination , Female , HIV Fusion Inhibitors/adverse effects , HIV Infections/immunology , HIV Infections/virology , Humans , Lamivudine/adverse effects , Male , Maraviroc , Middle Aged , Treatment Outcome , Triazoles/adverse effects , Zidovudine/adverse effectsABSTRACT
Enfuvirtide (T-20) is the first approved HIV-1 entry into cells' inhibitor. It is a peptide with an amino acid sequence analogue to HR2 region of the viral surface glycoprotein gp41. Its mechanism of action is the competitive binding to HR1 region of the gp41, preventing the interaction between HR1 and HR2 and impeding the conformational changes in gp41 necessary for fusion of the virus with the cell. Its application is by subcutaneous injection. The main clinical trials of enfuvirtide (TORO 1 and 2) were performed in HIV-infected patients with virological failure, high antiretroviral experience and highly resistant viral isolates. Those trials showed that the addition of enfuvirtide to an optimized HAART (chosen with a resistance test) provided better results than HAART alone, measured by drop in viral load and immunologic benefit. The best results were observed in the subgroup of patients with more useful drugs in HAART (according to the information of the resistance test), a lower viral load, and a higher CD4 cell count at baseline. The most important adverse event is the production of injection drug hypersensitivity reaction in 98% of patients. The high cost is compensated by a reduction in costs derived from admissions.
Subject(s)
HIV Envelope Protein gp41/therapeutic use , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Peptide Fragments/therapeutic use , Antiretroviral Therapy, Highly Active , CD4 Antigens/drug effects , CD4 Lymphocyte Count , Drug Resistance, Viral , Enfuvirtide , HIV Envelope Protein gp41/adverse effects , HIV Fusion Inhibitors/adverse effects , HIV Infections/virology , HIV-1/drug effects , Humans , Peptide Fragments/adverse effects , Treatment Failure , Viral LoadABSTRACT
Enfuvirtide (antes T-20) es el primer inhibidor de la entrada a la célula del HIV-1 en ser aprobado. Es un péptido análogo de la porción HR2 de la glucoproteína de superficie viral gp41. Su mecanismo de acción consiste en la unión competitiva a la porción HR1 de la gp41 para impedir los cambios conformacionales del complejo gp41-gp120 tras la unión del HIV-1 a los receptores celulares, impidiendo así el acercamiento y posterior fusión entre el virus y la célula. Se aplica por vía subcutánea. Los resultados de los principales estudios clínicos (TORO 1 y 2) llevados a cabo en pacientes con fallo virológico, tratamientos previos con antirretrovirales y portadores de cepas virales altamente resistentes, mostraron que quienes recibieron enfuvirtide + HAART optimizado, elegido mediante un test de resistencia, presentaron mayores beneficios que quienes sólo recibieron HAART optimizado, en términos de mejor recuperación inmune y mayor descenso de la carga viral de HIV. Los mejores resultados se observaron en el subgrupo de pacientes con más drogas útiles en el HAART según el test de resistencia, una menor carga viral de HIV y un mayor recuento de linfocitos CD4 basales. El principal efecto adverso es el desarrollo de lesiones por hipersensibilidad en los sitios de aplicación. El alto costo de enfuvirtide se vio compensado por una reducción en los costos de internación.
Enfuvirtide (T-20) is the first approved HIV-1 entry into cells' inhibitor. It is a peptide with an amino acid sequence analogue to HR2 region of the viral surface glycoprotein gp41. Its mechanism of action is the competitive binding to HR1 region of the gp41, preventing the interaction between HR1 and HR2 and impeding the conformational changes in gp41 necessary for fusion of the virus with the cell. Its application is by subcutaneous injection. The main clinical trials of enfuvirtide (TORO 1 and 2) were performed in HIV-infected patients with virological failure, high antiretroviral experience and highly resistant viral isolates. Those trials showed that the addition of enfuvirtide to an optimized HAART (chosen with a resistance test) provided better results than HAART alone, measured by drop in viral load and immunologic benefit. The best results were observed in the subgroup of patients with more useful drugs in HAART (according to the information of the resistance test), a lower viral load, and a higher CD4 cell count at baseline. The most important adverse event is the production of injection drug hypersensitivity reaction in 98% of patients. The high cost is compensated by a reduction in costs derived from admissions.
Subject(s)
Humans , /therapeutic use , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Peptide Fragments/therapeutic use , Antiretroviral Therapy, Highly Active , /drug effects , Drug Resistance, Viral , /administration & dosage , /adverse effects , HIV Fusion Inhibitors/administration & dosage , HIV Fusion Inhibitors/adverse effects , HIV Infections/virology , HIV-1 , Peptide Fragments/administration & dosage , Peptide Fragments/adverse effects , Treatment Failure , Viral LoadABSTRACT
Enfuvirtide (antes T-20) es el primer inhibidor de la entrada a la célula del HIV-1 en ser aprobado. Es un péptido análogo de la porción HR2 de la glucoproteína de superficie viral gp41. Su mecanismo de acción consiste en la unión competitiva a la porción HR1 de la gp41 para impedir los cambios conformacionales del complejo gp41-gp120 tras la unión del HIV-1 a los receptores celulares, impidiendo así el acercamiento y posterior fusión entre el virus y la célula. Se aplica por vía subcutánea. Los resultados de los principales estudios clínicos (TORO 1 y 2) llevados a cabo en pacientes con fallo virológico, tratamientos previos con antirretrovirales y portadores de cepas virales altamente resistentes, mostraron que quienes recibieron enfuvirtide + HAART optimizado, elegido mediante un test de resistencia, presentaron mayores beneficios que quienes sólo recibieron HAART optimizado, en términos de mejor recuperación inmune y mayor descenso de la carga viral de HIV. Los mejores resultados se observaron en el subgrupo de pacientes con más drogas útiles en el HAART según el test de resistencia, una menor carga viral de HIV y un mayor recuento de linfocitos CD4 basales. El principal efecto adverso es el desarrollo de lesiones por hipersensibilidad en los sitios de aplicación. El alto costo de enfuvirtide se vio compensado por una reducción en los costos de internación.(AU)
Enfuvirtide (T-20) is the first approved HIV-1 entry into cells inhibitor. It is a peptide with an amino acid sequence analogue to HR2 region of the viral surface glycoprotein gp41. Its mechanism of action is the competitive binding to HR1 region of the gp41, preventing the interaction between HR1 and HR2 and impeding the conformational changes in gp41 necessary for fusion of the virus with the cell. Its application is by subcutaneous injection. The main clinical trials of enfuvirtide (TORO 1 and 2) were performed in HIV-infected patients with virological failure, high antiretroviral experience and highly resistant viral isolates. Those trials showed that the addition of enfuvirtide to an optimized HAART (chosen with a resistance test) provided better results than HAART alone, measured by drop in viral load and immunologic benefit. The best results were observed in the subgroup of patients with more useful drugs in HAART (according to the information of the resistance test), a lower viral load, and a higher CD4 cell count at baseline. The most important adverse event is the production of injection drug hypersensitivity reaction in 98% of patients. The high cost is compensated by a reduction in costs derived from admissions.(AU)
Subject(s)
Humans , Peptide Fragments/therapeutic use , HIV Envelope Protein gp41/therapeutic use , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Peptide Fragments/administration & dosage , Peptide Fragments/adverse effects , HIV Envelope Protein gp41/administration & dosage , HIV Envelope Protein gp41/adverse effects , HIV Fusion Inhibitors/administration & dosage , HIV Fusion Inhibitors/adverse effects , HIV Infections/virology , HIV-1/drug effects , Drug Resistance, Viral , CD4 Lymphocyte Count , Antiretroviral Therapy, Highly Active , Viral Load , Treatment Failure , CD4 Antigens/drug effectsABSTRACT
Enfuvirtide is the first of a new class of antiretroviral agents recently approved for the treatment of human immunodeficiency virus (HIV)-1 infection. Present available data suggest that enfuvirtide may be a promising agent for the control of HIV infection in patients who have previously received reverse transcriptase inhibitor and protease inhibitor regimens and who are either intolerant to such drugs and/or who have gone into virological failure. Perhaps the greater limitation to the clinical use of enfuvirtide is the cost, limiting its use in the developing world.
Subject(s)
CD4-Positive T-Lymphocytes/drug effects , HIV Envelope Protein gp41/administration & dosage , HIV Fusion Inhibitors/administration & dosage , HIV Infections/drug therapy , Peptide Fragments/administration & dosage , Enfuvirtide , HIV Envelope Protein gp41/adverse effects , HIV Fusion Inhibitors/adverse effects , Humans , Infusions, Parenteral , Peptide Fragments/adverse effectsABSTRACT
BACKGROUND: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. METHODS: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. RESULTS: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. CONCLUSIONS: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.