RESUMEN
Simeprevir is a macrocyclic NS3/4A HCV protease inhibitor with potent activity against genotypes 1, 2, 4, 5 and 6 of the hepatitis C virus (HCV). Phase II and III studies of simeprevir combined with pegylated interferon (peg-IFN) and ribavirin (RBV) demonstrated that the combination was safe and effective in HCV genotype 1 patients, with more than 75% of treatment-naive patients attaining a sustained virological response (SVR). Simeprevir is administered once daily as a single 150-mg capsule. It has a moderate drug interaction potential, but less than that of the first-generation HCV protease inhibitors. Based on positive results from the product's phase III clinical program, simeprevir was approved and launched in Japan, the U.S. and Canada in late 2013 for use in combination with peg-IFN/RBV in HCV genotype 1 infections. Phase II interferon-free studies of simeprevir are ongoing.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Sulfonamidas/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacología , Aprobación de Drogas , Interacciones Farmacológicas , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C/virología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Inhibidores de Proteasas/uso terapéutico , Simeprevir , Sulfonamidas/efectos adversos , Sulfonamidas/farmacologíaRESUMEN
Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Animales , Antivirales/efectos adversos , Quimioterapia Combinada , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/patología , Hepatitis C Crónica/virología , Humanos , Hígado/patología , Monitoreo Fisiológico , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: Human babesiosis is an illness with clinical manifestations that range from asymptomatic to fatal. Although babesiosis is not nationally notifiable, the US incidence appears to be increasing. Babesia infection is a transfusion-transmissable disease. An estimated 70 cases were reported during 1979-2007; most of these cases were reported during the past decade. METHODS: We queried the 3 following US Food and Drug Administration safety surveillance systems to assess trends in babesiosis reporting since 1997: fatality reports for blood donors and transfusion recipients, the Adverse Event Reporting System (which includes MedWatch), and the Biological Product Deviations Reporting system.We analyzed fatality reports for time frames, clinical presentations, and patient and donor demographic characteristics. RESULTS: Eight of 9 deaths due to transfusion-transmitted babesiosis that were reported since 1997 occurred within the past 3 years (2005-2007). Four implicated donors and 5 patients lived in areas where Babesia infection is not endemic. Increasing numbers of Biological Product Deviations Reports were submitted to the US Food and Drug Administration over the past decade; the Adverse Event Reporting System received no reports. CONCLUSIONS: After nearly a decade with no reported death due to transfusion-transmitted babesiosis, the US Food and Drug Administration received 8 reports from November 2005 onward. The increased numbers of deaths reported and Biological Product Deviations Reports suggest an increasing incidence of transfusion-transmitted babesiosis. Physicians should consider babesiosis in the differential diagnosis in immunocompromised, febrile patients with a history of recent transfusion, even in areas where Babesia infection is not endemic. Accurate and timely reporting of babesiosis-related donor and transfusion events assists the US Food and Drug Administration in developing appropriate public health-control measures.
Asunto(s)
Babesiosis/epidemiología , Babesiosis/etiología , Reacción a la Transfusión , Adulto , Anciano , Anciano de 80 o más Años , Babesiosis/mortalidad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
OBJECTIVE: To evaluate in juvenile idiopathic arthritis (JIA) patients a biomarker panel of anti-cyclic citrullinated peptide (anti-CCP) antibodies, cartilage oligomeric matrix protein (COMP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IgM rheumatoid factor (RF), IgG RF, and IgA RF and compare to the presence of joint erosions (JE), joint space narrowing (JSN), and synovitis in order to evaluate aggressive disease. METHODS: Sixty-eight JIA patients (19 RF positive polyarthritis, 23 RF negative polyarthritis, 17 persistent oligoarthritis, and 9 systemic-onset) were evaluated using the biomarker panel and compared to 18 healthy controls. All RF isotypes, anti-CCP antibodies, and COMP were measured by enzyme-linked immunosorbent assays (ELISA). Statistically significant differences and associations were assessed for each biomarker in relation to JE, JSN, and synovitis. Multiple regression analysis was used to find the variables associated with joint damage and synovitis. RESULTS: Patients with JE and JSN had significantly elevated levels of IgA RF, IgM RF, and anti-CCP antibodies. COMP levels were higher in early disease, but also later in disease in patients with no JE or JSN. ESR, CRP, and IgA RF were significantly elevated in patients with active synovitis. Regression analysis showed IgM RF and disease duration to be associated with JE and JSN. Anti-CCP antibodies and COMP were also associated with JSN. CRP and IgA RF were associated with synovitis. CONCLUSION: Our findings demonstrate the importance of measuring IgM RF and IgA RF by ELISA and anti-CCP antibodies by ELISA, in addition to COMP in the assessment of JIA patients to determine severity of disease.
Asunto(s)
Anticuerpos Antiidiotipos/sangre , Artritis Juvenil/sangre , Proteína C-Reactiva/metabolismo , Proteínas de la Matriz Extracelular/sangre , Glicoproteínas/sangre , Péptidos Cíclicos/inmunología , Factor Reumatoide/sangre , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Artritis Juvenil/patología , Biomarcadores/sangre , Sedimentación Sanguínea , Proteína de la Matriz Oligomérica del Cartílago , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina M/sangre , Masculino , Proteínas Matrilinas , Análisis de Regresión , Sinovitis/sangre , Sinovitis/patologíaRESUMEN
Because the immune response to HIV depends on viral gene expression, we examined the HIV-specific immune responses in persons whose viral load after highly active antiretroviral therapy (HAART) was <400 on at least 3 occasions over a 12-month interval. Eleven patients were identified. While there was little change in mean HIV-binding antibody (Ab) titers in this group, two persons mounted increases in HIV envelope-specific binding antibody. Neutralizing antibody (NAb) titers against a panel of HIV-1 primary isolates (BZ167, US1, and CM237) increased post-HAART (80% neutralization titer against US1, p = 0.06; against CM237, p = 0.04). The two persons with large increases in binding antibody also had increases in primary isolate NAb. Roughly half of HAART recipients had significant increases in neutralizing antibody to the primary isolates US1 and CM237. Compared with CD4-matched, non-HAART controls, there were significant increases in NAb against the subtype B primary isolate US1 (p < 0.0009); no increases were seen against more easily neutralized primary isolate BZ167. There were no differences after HAART in antibody-directed cellular cytotoxicity (ADCC). HAART resulted in a partial restoration of lymphoproliferative responses to recall antigens (tetanus and diphtheria). New responses developed to HIV Gag p24. No patient responded to HIV Env gp160 or gp120 either before or after HAART. The data underscore the lack of functional reconstitution of HIV-specific, CD4-mediated responses despite durable suppression of viral replication. In the setting of stable anti-HIV Ab levels, the development of increased NAb in certain individuals suggests that control of the virus by HAART may assist in immune control of HIV.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Anticuerpos Anti-VIH/biosíntesis , Infecciones por VIH/inmunología , Inmunidad Celular , Recuento de Linfocito CD4 , Anticuerpos Anti-VIH/inmunología , Proteína p24 del Núcleo del VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/aislamiento & purificación , Humanos , Pruebas de Neutralización , ARN Viral/sangre , Carga ViralRESUMEN
Although human immunodeficiency virus type 1 (HIV-1) infection in the United States has predominantly involved subtype B, increasing global travel is leading to wider dissemination of genetically heterogeneous subtypes. While physicians depend on HIV-1 viral load measurements to guide antiretroviral therapy, commonly used molecular assays may underestimate the viral load of patients with non-B subtypes. Nine patients with non-B subtypes of HIV-1 were identified by physicians who suspected a non-B subtype on the basis of a low or undetectable HIV-1 viral load, by the Amplicor HIV-1 Monitor test, version 1.0, in conjunction with either a declining CD4 cell count or history of travel outside the United States. Use of version 1.5 of the Amplicor HIV-1 Monitor test detected a median HIV-1 viral load that was 2.0 log(10) RNA copies/mL higher than was determined with version 1.0. Clinical management was altered in all cases after diagnosis of a non-B-subtype infection. These cases demonstrate that it is critical for physicians to suspect and diagnose non-B subtypes of HIV-1 so that an assay with reliable subtype performance can be used to guide antiretroviral therapy.
Asunto(s)
Infecciones por VIH/diagnóstico , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Estudios de Seguimiento , Genotipo , Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Personal Militar , ARN Viral/sangre , ARN Viral/efectos de los fármacos , Factores de Tiempo , Carga ViralRESUMEN
Twelve laboratories collaborated in formulating and testing a standardized plaque reduction assay for cytomegalovirus (CMV) cell-associated clinical isolates. Four characterized and plaque-purified CMV strains, as well as six coded clinical isolates obtained after antiviral therapy, were distributed and tested. Good agreement was obtained for four of the clinical isolates, but a broad distribution of results was obtained for two isolates. Analysis of these results indicates the problems associated with clinical isolates, including the large genetic variability and the highly cell-associated phenotype. This collaborative effort, by addressing these problems, represents a significant step toward the development of a standardized assay.
Asunto(s)
Antivirales/farmacología , Infecciones por Citomegalovirus/virología , Citomegalovirus/efectos de los fármacos , Ensayo de Placa Viral/métodos , Ensayo de Placa Viral/normas , Células Cultivadas , Citomegalovirus/fisiología , Fibroblastos/virología , Foscarnet/farmacología , Ganciclovir/farmacología , Humanos , Laboratorios/normas , Pruebas de Sensibilidad Microbiana/métodos , Pruebas de Sensibilidad Microbiana/normas , Reproducibilidad de los ResultadosRESUMEN
The predominant mode of transmission of HIV-1 worldwide is sexual intercourse. Therefore, there has been growing interest in studying HIV-1 in genital secretions. Given the urgency to develop a vaccine to protect against HIV-1, techniques have been developed to isolate and quantitate HIV-1 from genital secretions.
RESUMEN
The continuing spread of the HIV-1 epidemic worldwide has stimulated efforts to develop vaccines and decrease transmission of HIV-1 as noted in Chapter 8 . Key to this effort is the characterization of the qualities of HIV-1 in genital secretions. Seminal cell and seminal plasma culture have been used to isolate HIV-1 from semen but have low recovery rates of 9-50% (1-11). Culture of vaginal cells have also had low recovery rates of 0-30% (12-14). In an attempt to overcome this problem, HIV-1 has been evaluated in genital secretions using polymerase chain reaction (PCR) techniques. Compared to culture techniques, PCR techniques, both DNA and RNA, have had a higher recovery rate of HIV-1 from genital secretions (2,3,7,9-11,13-25).
RESUMEN
High levels of human immunodeficiency virus type 1 (HIV-1) replication, as reflected in HIV-1 RNA concentrations in blood and semen, probably contribute to both rapid disease progression and enhanced sexual transmission. Semen and blood were collected from 49 Malawian and 61 US and Swiss (US/Swiss) HIV-1-seropositive men with similar CD4 cell counts and no urethritis or exposure to antiretroviral drugs. Median seminal plasma and blood plasma HIV-1 RNA concentrations were >3-fold (P = .034) and 5-fold (P = .0003) higher, respectively, in the Malawian men. Similar differences were observed in subsets of the Malawian and US/Swiss study groups matched individually for CD4 cell count (P = .035 and P < .002, respectively). These observations may help explain the high rates of HIV-1 sexual transmission and accelerated HIV-1 disease progression in sub-Saharan Africa.
Asunto(s)
Seropositividad para VIH/virología , VIH-1 , Semen/virología , Adulto , África del Sur del Sahara , Estudios Transversales , Seropositividad para VIH/sangre , Seropositividad para VIH/inmunología , VIH-1/genética , Humanos , Masculino , ARN Viral/sangreRESUMEN
The efficiency and duration of transmissibilty of HIV seems to be highly variable and dependent on a number of factors related to both the donor and the recipient as well as characteristics intrinsic to the virus itself. Some of the factors likely to be important in sexual transmission of HIV include stage of disease, antiretroviral therapy, and concomitant systemic or mucosal infections, including sexually transmitted diseases. This paper describes recent work from our group in each of these areas.
Asunto(s)
Infecciones por VIH/virología , VIH-1 , Semen/virología , Esparcimiento de Virus , Fármacos Anti-VIH/uso terapéutico , Humanos , Masculino , ARN Viral/análisisRESUMEN
OBJECTIVE: The potential role of antiretroviral treatment on the infectiousness of HIV-1-infected men was examined by studying the effect of antiviral treatment on the shedding of HIV-1 in semen. METHODS: Forty-four patients enrolled in various treatment protocols were asked to donate a semen sample before they began a new antiviral treatment and at a follow-up visit after 6 to 15 weeks of treatment. Since most patients were on blinded protocols, patients were stratified by response of blood viral load. The effect of each patient's treatment was classified as good (n = 24), fair (n = 8) and marginal (n = 13) by measurement of the HIV RNA reduction in blood plasma (> 1.0 log10; 0.5-1.0 log10 and < 0.5 log10 HIV RNA copies/ml reduction, respectively). The effect of treatment on shedding of HIV-1 in semen was documented by the reduction of HIV RNA concentration in seminal plasma and by quantitative HIV-1 seminal cell culture. RESULTS: Overall, antiviral treatment resulted in a significant fall in the viral load in semen (RNA and culture) that paralleled the reduction of viral load in blood. More pronounced reductions of HIV RNA in semen were observed as the effectiveness of treatment on blood HIV RNA levels increased (median drop from baseline 0, 0.3 log10 and 0.8 log10 RNA copies/ml in patients with marginal, fair and good treatment effect, respectively). Thirteen patients lost detectable HIV RNA in blood on treatment and all of these had undetectable levels of HIV-1 in semen by culture and RNA analysis at follow-up. In 19 of the 31 patients (62%) who still had HIV RNA in their blood during treatment, semen HIV levels were below detection in semen at follow-up. CONCLUSIONS: Treatment-induced changes of HIV RNA concentration in blood are generally associated with a corresponding change in seminal HIV RNA: If confirmed in larger studies, potent antiretroviral therapy might reduce the spread of HIV-1.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Semen/virología , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Humanos , Masculino , ARN Viral/sangre , Estadísticas no Paramétricas , Cultivo de VirusRESUMEN
OBJECTIVE: This study examined the concentration of HIV in semen and the effects of biological factors on HIV excretion. METHODS: Semen samples from 101 men at different stages of the disease were evaluated by quantitative HIV culture and HIV RNA detection. Blood plasma samples were available from 56 patients. The effects of CD4 and CD8 count, blood plasma RNA levels, treatment status and clinical staging on the shedding of HIV were evaluated. RESULTS: HIV RNA levels in semen correlated with quantitative HIV culture of seminal cells and a strong association of positive seminal cell culture with high RNA levels was observed. CD4 count and antiviral treatment were inversely correlated with the concentration of HIV in semen. Blood plasma HIV RNA values were correlated with HIV RNA levels in semen, although some patients had highly discrepant results. CONCLUSIONS: The strong correlation between seminal cell culture and concentration of HIV RNA in seminal plasma suggested that HIV detected in seminal plasma was released by productively infected cells in the male genital tract. The study showed that the concentration of HIV in semen, which was likely to be correlated with HIV infectivity, was a function of the immune status of the HIV-infected individual. The results suggested that antiviral therapy may have reduced the concentration of HIV in semen.
Asunto(s)
Seropositividad para VIH/virología , VIH-1/aislamiento & purificación , Semen/virología , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/citología , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/inmunología , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Inmunidad , Masculino , ARN Viral/análisis , Esparcimiento de VirusRESUMEN
HIV-1 infection continues to spread worldwide, primarily through sexual intercourse. Because semen is a major vehicle for transmission of HIV-1, we evaluated the effects of reverse transcriptase inhibitor therapy on the amount of HIV-1 in semen. The semen and blood of 11 HIV-1-infected men (i.e. treatment group) were collected before the initiation of reverse transcriptase inhibitor therapy and then 8 to 18 weeks after initiation of therapy. The semen and blood of another 11 HIV-1-infected men (i.e., longitudinal group), who were not on or had no change in antiretroviral therapy for at least 2 months before study entry, were collected at approximately 2-week intervals for 10 to 26 weeks. In the treatment group, 82% of the seminal plasma HIV-1 RNA levels decreased from baseline after 8 to 18 weeks of therapy (median reduction of 1.01 log10, p = 0.01), and 100% of the blood plasma RNA levels decreased from baseline over the same period (median reduction of 0.92 log10, p = 0.003). Five of these patients were followed for at least 52 weeks and had a median seminal plasma HIV-1 RNA level of 0.66 log10 below baseline at 1 year. All subjects in the treatment group with positive cultures at baseline (50%) had negative cultures or a lower infectious units per ejaculate at the 8- to 18-week follow-up examinations. The HIV-1 RNA levels in blood and semen of the longitudinal group did not change significantly over 10 to 26 weeks. Initiation of reverse transcriptase inhibitor therapy effectively reduces shedding of HIV-1 in semen and may therefore reduce the spread of infection within populations.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Semen/virología , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , ARN Viral/sangreAsunto(s)
Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Semen/virología , Fármacos Anti-VIH/uso terapéutico , Didanosina/uso terapéutico , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , VIH-1/genética , Humanos , Masculino , ARN Viral/sangre , Esparcimiento de Virus , Zidovudina/uso terapéuticoRESUMEN
AIM: To review Track A, which is organized into five broad areas of emphasis. TOOLS: A variety of new virologic tools are allowing researchers to more effectively evaluate many aspects of HIV, from various therapies and vaccine candidates to the recombination and international spread of genotypes. PATHOGENESIS: The recent understandings of HIV-1 pathogenesis have led to potential new treatment strategies of early aggressive treatment with combination drugs and the potential for biologic or immunologic therapy directed to blocking viral entry through second receptors. TREATMENT: HIV treatment focused on chemical/drug advances and treatment, and immunologic/genetic advances. Some areas of development include optimizing combination therapies using the oncology model; continued work on new preclinical compounds (e.g. integrase and tat/rev inhibitors); evaluation of viral reduction in all compartments; and resistance surveillance and prevention. Biologics, including fusin/CC-CKR5 inhibitors and CD8 HIV-1 suppressor factors, ex vivo expansion of T cells and in vivo expansion of effector CD8 cells continue to be developed as possible future treatments. VACCINES: In order to obtain worldwide control over HIV, we must have a universally effective vaccine. The question remains as to what specifically is required for a protective response. Mechanisms of CD8 suppression, and cellular and antibody correlates of protection were discussed as areas of research that may shed light on the critical protective immune response. GENOTYPES: Discussion of HIV genotypes focused on international subtypes, correlates of diversity, and HIV-1 recombination. Numerous groups have shown an international intermixing of HIV-1 strains. Recombination during transcription was found to lead to extensive genomic shift and increased diversity, which may also increase HIV-1 fitness and enhance transmission. CONCLUSIONS: The spread and adaptation of HIV-1 is occurring independently of borders. Therefore, HIV-1 research must be global; vaccine development must be international in concept and application; collaboration in all areas is essential for success in combating HIV; and finally, the challenge for the future will be to actively involve all basic scientists in the science of the international epidemics.
Asunto(s)
Infecciones por VIH/terapia , VIH-1 , Vacunas contra el SIDA/uso terapéutico , Genotipo , HumanosRESUMEN
Human immunodeficiency virus type 1 (HIV-1) is transmitted by infected males in semen. However, the inoculum required for infection is unknown. The ability to collect such information will rely on the availability of reliable quantitative assays of HIV-1 in semen. We examined the comparative performance of NASBA and Amplicor Monitor RT-PCR in quantifying HIV-1 RNA in cell free seminal plasma from seropositive men and correlated the results obtained with viral titres measured by a seminal cell quantitative microculture (QMC) assay. Of samples analysed, 68% and 56% by both NASBA and RT-PCR contained measurable HIV-1 RNA, respectively. Amplification inhibition frequently affected RT-PCR but not NASBA. Excluding samples with complete RT-PCR inhibition, there was 90% qualitative concordance and a strong positive correlation (r = 0.86) of RNA levels measured by the two methods. Comparison of the concentration of HIV-1 RNA in seminal plasma samples, as measured by NASBA, with QMC viral titres indicated that RNA levels probably reflect the infectiousness of whole semen. NASBA is a reliable technique for quantitating HIV-1 RNA in seminal plasma and should become a valuable tool in the study of factors that influence the sexual transmission of HIV.