RESUMEN
Antiretroviral therapy has significantly evolved in the last decade, with an increasing number of new drugs and classes. Currently, even heavily experienced patients can be successfully treated with new regimens. In Brazil, the recent incorporation of some new antiretroviral drugs made it possible to suppress HIV plasma viremia in most treated patients, with significant benefits in terms of quality of life and survival. However, little has been published on outcomes of patients under new drugs-based regimens. We reviewed the safety and efficacy of antiretroviral regimens using recently introduced drugs in Bahia. Our results confirm that patients using darunavir, raltegravir, enfuvirtide, or etravirine presented with a high rate of virological suppression without significant adverse events, after one year of follow-up.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Adulto , Brasil , Recuento de Linfocito CD4 , Darunavir/uso terapéutico , Esquema de Medicación , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Humanos , Masculino , Nitrilos , Fragmentos de Péptidos/uso terapéutico , Piridazinas/uso terapéutico , Pirimidinas , Calidad de Vida , Raltegravir Potásico/uso terapéutico , Terapia Recuperativa , Resultado del Tratamiento , Carga ViralRESUMEN
The effectiveness of switching from enfuvirtide to raltegravir in HIV-1-infected patients on a suppressive antiretroviral regimen has been poorly studied in the clinical practice of developing countries. We conducted a multicenter retrospective cohort study in HIV-1-infected, multidrug-experienced adults (≥18 years old) with plasma HIV-1-RNA <400 copies/ml for at least 4 months on an enfuvirtide-containing therapy between 2005 and 2010, in whom the attending physician switched from enfuvirtide to raltegravir. Effectiveness endpoints were measured at week 48 after switch. Analyses were conducted on an intent-to-treat basis and two strategies for handling missing outcome data were used (hereafter, strategies 1 and 2). Overall, 87 patients were eligible for analysis. At baseline, the median CD4(+) T cell count was 400 cells/µl and 91.9% of patients had <50 HIV-1-RNA copies/ml. At week 48, the proportions of patients with plasma HIV-1-RNA <50 and <400 copies/ml were, respectively, 86.2% (95% CI=77.1; 92.7%) and 88.5% (95% CI=79.9; 94.3%) (strategies 1 and 2) and 89.7% (95% CI=81.3; 95.2%) and 90.8% (95% CI=82.7; 95.9%) (strategies 1 and 2). This was a -10.3% (95% CI=-2.8; -17.9%) and -9.2% (95% CI=-2; -16.4%) difference from baseline in the proportion of patients with plasma HIV-1-RNA <400 copies/ml. The median increase in CD4(+) T cell counts was 41 and 64 cells/µl (p<0.001) (strategies 1 and 2). No patient withdrew raltegravir or developed opportunistic infections, but one was diagnosed with HIV-related dementia. In conclusion, switching from enfuvirtide to raltegravir in patients on a virologically suppressive regimen is an effective strategy even in a Brazilian clinical setting.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Fragmentos de Péptidos/uso terapéutico , Pirrolidinonas/uso terapéutico , Adolescente , Adulto , Brasil , Recuento de Linfocito CD4 , Estudios de Cohortes , Enfuvirtida , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Raltegravir Potásico , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
The present study describes a follow-up of a prospective and observational cohort of patients infected with HIV-1 and treated with raltegravir for salvage therapy in Brazil. Two groups of patients were analyzed: switching from T20 to RAL (Group 1, n = 9) and salvage therapy containing RAL (Group 2, n = 10). Blood samples were drawn for CD4(+) T-cell counts and HIV-1 viral load determinations. Protease, reverse transcriptase, and integrase genotyping were performed at baseline and at the time of virologic failure. CD4(+) T-cells increased at 6 and 12 months in both groups; HIV-1 viral load was continuously suppressed for Group 1, and for Group 2 it significantly decreased after starting a RAL-containing regimen. Three out of 10 patients from Group 2 could not suppress HIV-1 viral load. The mutations Q148H + G140S were observed for two patients and for the third patient only mutations to PR/RT inhibitors were detected. The genotypic sensitivity score (GSS) was analyzed for all patients of Group 2 and both patients who developed resistance to raltegravir presented a GSS < 2.0 for the RAL-containing scheme, which could be associated to the lack of effectiveness of the proposed scheme. The present study describes, for the first time in Brazil, the close follow-up of a series of patients using a raltegravir-containing HAART, showing the safety of the enfuvirtide switch to RAL and the effectiveness of a therapeutic regimen with RAL in promoting immune reconstitution and suppressing HIV replication, as well as documenting the occurrence of resistance to integrase inhibitors in the country.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Pirrolidinonas/uso terapéutico , Terapia Recuperativa/métodos , Terapia Antirretroviral Altamente Activa , Brasil/epidemiología , Recuento de Linfocito CD4 , Ciclohexanos/uso terapéutico , Enfuvirtida , Estudios de Seguimiento , Técnicas de Genotipaje , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Integrasa de VIH/genética , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , VIH-1/fisiología , Humanos , Maraviroc , Mutación , Fragmentos de Péptidos/uso terapéutico , Estudios Prospectivos , ARN Viral/sangre , Raltegravir Potásico , Resultado del Tratamiento , Triazoles/uso terapéutico , Carga Viral , Replicación ViralRESUMEN
OBJECTIVE: To evaluate the polymorphisms and resistance mutations in gp41 HR1 region of HIV-1. METHODS: The study included 28 HIV-positive patients undergoing enfuvirtide (ENF) treatment or not from Porto Alegre, Rio Grande do Sul state, and Rio de Janeiro, Rio de Janeiro state, between 2006 and 2009. Resistance mutations and polymorphisms of the gp41 HR1 region were detected using the genomic DNA of 12 ENF-untreated patients and 16 patients in ENF treatment, encompassing subtypes B, C, and F1. Sample subtypes were determined by neighbor-joining phylogenetic analysis with a Kimura's two-parameter correction. RESULTS: A high prevalence of polymorphisms unrelated to resistance was observed. Among ENF-untreated patients, 16% showed mutations related with resistance. Among patients in ENF treatment, 50% had resistance-related mutations. Overall, 17% of all isolates showed the N42S polymorphism related to ENF hypersusceptibility. The presence of ENF resistance mutations in the group of treated patients reduced viral load. The V38A substitution was the most frequent among treatment-experienced patients followed by the G36D/E, N42D, and V38M substitutions. CONCLUSIONS: The V38A substitution in the gp41 HR region was the most common resistance mutation among ENF-treated patients and was associated with increased viral load.
Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Proteína gp41 de Envoltorio del VIH/genética , Proteína gp41 de Envoltorio del VIH/farmacología , Infecciones por VIH/virología , VIH-1/genética , Fragmentos de Péptidos/farmacología , Polimorfismo Genético , Sustitución de Aminoácidos/genética , Fármacos Anti-VIH/uso terapéutico , Análisis por Conglomerados , Enfuvirtida , Genotipo , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , Mutación Missense , Fragmentos de Péptidos/uso terapéutico , Filogenia , Análisis de Secuencia de ADNRESUMEN
The study was carried out in a Hospital of Reference in Infectious Diseases of Ceará, from February 2006 to February 2007, and and aimed at identifying the socio-demographic profile of Enfuvirtide users and their main difficulties/facilities in previous and current treatment scheme. The initial sample analyzed the medical record of 23 patients;18 agreed to participate, comprising the final sample. The descriptive analysis of quantitative data was carried out through the distribution of frequencies and quantitative data, submitted for content analysis. It was observed that 83% were male, 78% were single and the majority was between 30 and 52 years old and, in average, eight years and a half of antiretroviral treatment. From qualitative data, two categories emerged: (1) Previous treatment: difficulties and adversities and (2) Current treatment: from cognition to ability. The difficulties to conduct previous treatments were related to the size and high amount of tablets and side effects. As for facility, the easy drug administration was indicated. Regarding the current treatment, the difficulties were self administration and nodules on the sites where Enfuvirtide was applied and the facilities were absence of gastrointestinal effects and improvement of viral load. It's important to implement an interdisciplinary work that helps patients overcome the difficulties of the treatment, in addition to works in groups in order to better address the difficulties and help increase adhesion to treatment.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Adulto , Enfuvirtida , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We analyzed the gp41 sequences of 80 HIV-infected enfuvirtide-naive individuals who were eligible to receive this antiretroviral according to Brazilian guidelines. We analyzed the genetic diversity of pol and the heptad repeat 1 and 2 (HR1 and HR2) regions of gp41, and compared the genetic profile of HR1 and HR2 found in PBMCs with the profile found in plasma. The similarity between sequences obtained from DNA and RNA in the HR1 and HR2 regions was, on average, 98.6% and 98.9%, respectively. We detected mutations related to enfuvirtide resistance (L44M or N43K) in HR1 DNA samples from three individuals (3.8%) and RNA samples from three individuals (4.6%). Other polymorphisms frequently detected were E137K (10% and 13.8%), L130I (8.8% and 9.2%), S129N (6.3% and 10.8%), L44M (2.5% and 4.6%), S138A (2.5% and 1.5%), and N43K (1.3% and 0%) in DNA and RNA, respectively. Subtype B was identified in 68.8% of the samples [protease (PR) B, reverse transcriptase (RT) B, gp41 B], subtype F in 5.0%, subtype C in 1.3%, and the remaining sequences presented with a mosaic profile. These results suggest that genotyping the gp41 region prior to introducing an expensive and complex approach, such as enfuvirtide, may be cost effective. Moreover, assessment of proviral DNA may be less expensive than RNA, as well as being sufficient for this purpose.
Asunto(s)
Farmacorresistencia Viral/genética , Proteína gp41 de Envoltorio del VIH/genética , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Fragmentos de Péptidos/uso terapéutico , Polimorfismo de Nucleótido Simple , Adulto , Brasil/epidemiología , ADN Viral/análisis , ADN Viral/sangre , ADN Viral/genética , Enfuvirtida , Variación Genética , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/sangre , Infecciones por VIH/epidemiología , VIH-1/efectos de los fármacos , VIH-1/metabolismo , Humanos , Leucocitos Mononucleares/virología , Persona de Mediana Edad , ARN Viral/análisis , ARN Viral/sangre , ARN Viral/genética , Resultado del Tratamiento , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
SUMMARY: A 41-year-old pregnant woman with multiple virological failures started darunavir, enfuvirtide, zidovudine and lamivudine at week 28 of pregnancy. During week 38, the patient had a viral load <400 copies/mL and a CD4 count of 180 cells/mm(3) (13%). The child was found to be in good health, with negative HIV-polymerase chain reactions at birth, at two and at six months.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Recuento de Linfocito CD4 , Darunavir , Farmacorresistencia Viral Múltiple , Quimioterapia Combinada , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/administración & dosificación , Inhibidores de Fusión de VIH/administración & dosificación , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/administración & dosificación , VIH-1/efectos de los fármacos , Humanos , Recién Nacido , Fragmentos de Péptidos/administración & dosificación , Embarazo , Resultado del Embarazo , Sulfonamidas/administración & dosificación , Resultado del Tratamiento , Carga ViralRESUMEN
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.
Asunto(s)
Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Fragmentos de Péptidos/uso terapéutico , Terapia Antirretroviral Altamente Activa , Antígenos CD4/efectos de los fármacos , Recuento de Linfocito CD4 , Farmacorresistencia Viral , Enfuvirtida , Proteína gp41 de Envoltorio del VIH/efectos adversos , Inhibidores de Fusión de VIH/efectos adversos , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Fragmentos de Péptidos/efectos adversos , Insuficiencia del Tratamiento , Carga ViralRESUMEN
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)
Asunto(s)
Humanos , Fragmentos de Péptidos/uso terapéutico , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/efectos adversos , Proteína gp41 de Envoltorio del VIH/administración & dosificación , Proteína gp41 de Envoltorio del VIH/efectos adversos , Inhibidores de Fusión de VIH/administración & dosificación , Inhibidores de Fusión de VIH/efectos adversos , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Farmacorresistencia Viral , Recuento de Linfocito CD4 , Terapia Antirretroviral Altamente Activa , Carga Viral , Insuficiencia del Tratamiento , Antígenos CD4/efectos de los fármacosRESUMEN
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.