RESUMEN
Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner. Similar results were also obtained with tier 2 HIV-1 viruses using a human anti-gp41 nnAb, 246D. While nnAbs are demonstrably less effective than broadly neutralizing antibodies (bNAbs) against HIV-1 in vitro and in vivo, the data show that nnAbs can protect against and alter the course of HIV-1 infection in vivo. PAPERCLIP.
Asunto(s)
Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/fisiología , Vacunas contra el SIDA/inmunología , Animales , Antígenos CD4/química , Antígenos CD4/metabolismo , Modelos Animales de Enfermedad , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/genética , Humanos , Ratones , Mutación , Receptores Fc/inmunología , Linfocitos T/virologíaRESUMEN
Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
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Anticuerpos Neutralizantes/administración & dosificación , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4/administración & dosificación , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Ácidos Hidroxámicos/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/inmunología , Ratones , Receptores Fc/inmunología , VorinostatRESUMEN
Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Latencia del Virus/inmunología , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/inmunología , Sitios de Unión de Anticuerpos , Anticuerpos ampliamente neutralizantes , Portador Sano/tratamiento farmacológico , Portador Sano/inmunología , Portador Sano/virología , Combinación de Medicamentos , Farmacorresistencia Viral , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/inmunología , Proteínas gp160 de Envoltorio del VIH/inmunología , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Estudio Históricamente Controlado , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Filogenia , Viremia/tratamiento farmacológico , Viremia/inmunología , Viremia/prevención & control , Viremia/virología , Activación Viral/inmunología , Adulto JovenRESUMEN
Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/uso terapéutico , Sitios de Unión/efectos de los fármacos , Sitios de Unión/inmunología , Anticuerpos ampliamente neutralizantes , Antígenos CD4/metabolismo , Reservorios de Enfermedades/virología , Esquema de Medicación , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/antagonistas & inhibidores , Proteínas gp160 de Envoltorio del VIH/química , Proteínas gp160 de Envoltorio del VIH/inmunología , Proteínas gp160 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Estudio Históricamente Controlado , Humanos , Masculino , Persona de Mediana Edad , Provirus/efectos de los fármacos , Provirus/crecimiento & desarrollo , Provirus/inmunología , Factores de Tiempo , Distribución Tisular , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Adulto JovenRESUMEN
Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti-HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/virología , VIH-1/fisiología , Provirus/fisiología , Fármacos Anti-VIH/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/clasificación , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Filogenia , Provirus/clasificación , Provirus/genética , Provirus/crecimiento & desarrollo , Latencia del Virus , Replicación ViralRESUMEN
The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.
Asunto(s)
Antirretrovirales/administración & dosificación , Linfocitos T CD4-Positivos , ADN Viral/sangre , Infecciones por VIH , VIH-1/metabolismo , Ganglios Linfáticos , Provirus/metabolismo , Adulto , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/virología , Masculino , Persona de Mediana Edad , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/sangreRESUMEN
UNLABELLED: The purpose of this prospective cohort study was to compare the serologic response between human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) receiving two and three doses of hepatitis A virus (HAV) vaccine and HIV-uninfected MSM receiving two doses of HAV vaccine. Between June 2009 and December 2010, 582 MSM aged 18 to 40 years who were seronegative for HAV were enrolled in the study. HIV-infected MSM received either two doses of HAV vaccine (1,440 enzyme-linked immunosorbent assay units) (n = 140) with the second dose given at week 24 or three doses (n = 225) with the second and third dose given at weeks 4 and 24, respectively, while HIV-uninfected MSM (n = 217) received two doses. The primary endpoint was seroconversion at week 48. The geometric mean concentration (GMC) of anti-HAV antibody was determined at weeks 48 and 72. At week 48, the seroconversion rate was 75.7%, 77.8%, and 88.5% in intention-to-treat analysis for two-dose HIV-infected, three-dose HIV-infected, and two-dose HIV-uninfected MSM, respectively. The GMC of anti-HAV antibody at week 48 for three-dose HIV-infected MSM (2.29 ± 0.73 log10 mIU/mL) was significantly higher than that for two-dose HIV-infected MSM (1.94 ± 0.66; P < 0.01), but was lower than HIV-uninfected MSM (2.49 ± 0.42; P < 0.01). Multivariate analysis revealed higher CD4 counts (adjusted odds ratio [AOR] for per 50 cells/µL increase, 1.13; 95% confidence interval [CI], 1.05-1.21) and undetectable plasma HIV RNA load (AOR, 1.90; 95% CI, 1.10-3.28) before HAV vaccination were predictive of seroconversion in HIV-infected patients. CONCLUSION: Serologic response rate to three and two doses of HAV vaccine was similar in HIV-infected MSM, which was lower than that in HIV-uninfected MSM receiving two doses. HAV vaccination in HIV-infected patients with a higher CD4 count and suppression of HIV replication increased the seroconversion rate.
Asunto(s)
Infecciones por VIH/inmunología , Anticuerpos de Hepatitis A/sangre , Vacunas contra la Hepatitis A/uso terapéutico , Hepatitis A/prevención & control , Homosexualidad Masculina , Adolescente , Adulto , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , VIH/fisiología , Infecciones por VIH/sangre , Hepatitis A/sangre , Hepatitis A/inmunología , Anticuerpos de Hepatitis A/inmunología , Vacunas contra la Hepatitis A/administración & dosificación , Virus de la Hepatitis A/inmunología , Humanos , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Replicación Viral/fisiología , Adulto JovenRESUMEN
Outbreaks of sexually transmitted hepatitis C virus (HCV) infections have been recently reported in HIV-infected men who have sex with men (MSM) in Europe, Australia, and North America. Little is known concerning whether this also occurs in other Asia-Pacific countries. Between 1994 and 2010, a prospective observational cohort study was performed to assess the incidence of recent HCV seroconversion in 892 HIV-infected patients (731 MSM and 161 heterosexuals) who were not injecting drug users. A nested case-control study was conducted to identify associated factors with recent HCV seroconversion, and phylogenetic analysis was performed using NS5B sequences amplified from seroconverters. During a total followup duration of 4,270 person-years (PY), 30 patients (3.36%) had HCV seroconversion, with an overall incidence rate of 7.03 per 1,000 PY. The rate increased from 0 in 1994 to 2000 and 2.29 in 2001 to 2005 to 10.13 per 1,000 PY in 2006 to 2010 (P < 0.05). After adjustment for age and HIV transmission route, recent syphilis remained an independent factor associated with HCV seroconversion (odds ratio, 7.731; 95% confidence interval, 3.131 to 19.086; P < 0.01). In a nested case-control study, seroconverters had higher aminotranferase levels and were more likely to have CD4 ≥ 200 cells/µl and recent syphilis than nonseroconverters (P < 0.05). Among the 21 patients with HCV viremia, phylogenetic analysis revealed 7 HCV transmission clusters or pairs (4 within genotype 1b, 2 within genotype 2a, and 1 within genotype 3a). The incidence of HCV seroconversion that is associated with recent syphilis is increasing among HIV-infected patients in Taiwan.
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Infecciones por VIH/complicaciones , Hepatitis C/epidemiología , Adulto , Estudios de Casos y Controles , Análisis por Conglomerados , Estudios de Cohortes , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Filogenia , Estudios Prospectivos , Factores de Riesgo , Análisis de Secuencia de ADN , Homología de Secuencia , Taiwán/epidemiología , Proteínas no Estructurales Virales/genéticaRESUMEN
OBJECTIVES: Vancomycin-resistant enterococci (VRE), particularly vancomycin-resistant Enterococcus faecium (VREfm), have emerged among the leading pathogens causing hospital-acquired infections worldwide. We aimed to examine whether there were newly introduced clones contributing to this increase and to assess the risk factors for mortality in patients with VREfm bacteraemia. METHODS: Between 2003 and 2010, all medical records of adult patients diagnosed with VREfm bacteraemia at a university hospital in Taiwan were reviewed. Antibiotic susceptibility, genotyping and multilocus sequence typing of the VREfm isolates were performed. RESULTS: During the study period, the prevalence of non-duplicated blood VRE isolates increased significantly from 3.9% in 2003 to 18.9% in 2010 (Pâ<â0.0001). One-hundred-and-forty-nine patients with VREfm bacteraemia were noted and 102 isolates of VREfm were available for microbiological characterization. All isolates were susceptible to daptomycin and linezolid. Sequence type (ST) 18 and ST414 were the two predominant emerging STs from 2009 to 2010, accounting for 29.7% and 25.0% of all isolates, respectively. Patients who received immunosuppressives, had a high Charlson comorbidity index or experienced septic shock had a significantly higher 14 day mortality rate. Patients who had bacteraemia caused by ST414 isolates and received appropriate antibiotics had a lower 14 day mortality rate. CONCLUSIONS: The prevalence of the VRE that caused bacteraemia increased from 2003 to 2010. This increase might be attributed to the clonal spread of VREfm belonging to ST18 and ST414. The all-cause 14 day mortality rate was lower in patients with bacteraemia due to VREfm isolates that belonged to ST414.
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Bacteriemia/microbiología , Infección Hospitalaria/microbiología , Enterococcus faecium/efectos de los fármacos , Enterococcus faecium/patogenicidad , Infecciones por Bacterias Grampositivas/microbiología , Tipificación Molecular , Resistencia a la Vancomicina , Adulto , Bacteriemia/epidemiología , Bacteriemia/mortalidad , Bacteriemia/patología , Análisis por Conglomerados , Estudios de Cohortes , Infección Hospitalaria/epidemiología , Infección Hospitalaria/mortalidad , Infección Hospitalaria/patología , Enterococcus faecium/genética , Enterococcus faecium/aislamiento & purificación , Femenino , Genotipo , Infecciones por Bacterias Grampositivas/epidemiología , Infecciones por Bacterias Grampositivas/mortalidad , Infecciones por Bacterias Grampositivas/patología , Hospitales Universitarios , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Epidemiología Molecular , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Taiwán/epidemiologíaRESUMEN
OBJECTIVES: Metabolic complications related to antiretroviral therapy are rarely investigated among HIV-infected patients in Asian countries. We investigated the prevalence of and factors associated with metabolic syndrome among HIV-infected patients who are ethnic Chinese in the era of highly active antiretroviral therapy (HAART). METHODS: A cross-sectional survey was performed to collect information on the demographic and clinical characteristics and antiretroviral therapy prescribed in 877 HIV-infected patients at a university hospital in Taiwan from May 2008 to April 2009. The modified Adult Treatment Panel III criteria were used to define metabolic syndrome after adjusting for the waist circumference criteria for Asians. RESULTS: Of the 877 patients, 75.3% were male homosexuals, 80.7% were receiving HAART and 88.7% had CD4 counts ≥ 200 cells/mm(3). Metabolic syndrome was diagnosed in 210 patients (26.2%). After adjusting for age, gender, smoking status, family history of diabetes mellitus, cardiovascular disease and hypertension, and baseline CD4 and plasma HIV RNA load, use of protease inhibitors (PIs) was significantly associated with the presence of metabolic syndrome (OR 1.63; 95% CI 1.10-2.43). In addition, exposure to PI for ≥ 3 years, to HAART for ≥ 6 years and to nucleoside reverse transcriptase inhibitor(s) for ≥ 6 years was significantly associated with the presence of metabolic syndrome with an adjusted OR of 1.96 (95% CI 1.13-3.42), 1.78 (95% CI 1.03-3.07), and 1.91 (95% CI 1.11-3.30), respectively. CONCLUSIONS: Approximately one-fourth of HIV-infected Taiwanese patients developed metabolic syndrome in the HAART era. Receipt of HAART and prolonged exposure to PI and nucleoside reverse transcriptase inhibitor(s) were associated with metabolic syndrome.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Síndrome Metabólico/inducido químicamente , Síndrome Metabólico/epidemiología , Adulto , Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Pueblo Asiatico , Estudios Transversales , Etnicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Taiwán/epidemiologíaRESUMEN
OBJECTIVES: To determine the impact of transmitted drug resistance (TDR) of HIV-1 on treatment outcome in areas where routine testing for drug resistance mutations may not be available before combination antiretroviral therapy (cART) is initiated. METHODS: Genotypic resistance assays were performed on HIV isolates from archived blood samples obtained from 1349 antiretroviral-naive HIV-1-infected patients in Taiwan from 2000 to 2010. Resistance mutations were interpreted with the use of the HIVdb program of the Stanford University HIV Drug Resistance Database. The genotypic sensitivity score (GSS) of the regimens prescribed was calculated. A matched case-control study was conducted to assess the impact of TDR on treatment outcomes. RESULTS: The overall prevalence of TDR to any antiretroviral agent was 8.0%, declining from 12.3% in 2003-06 to 5.1% in 2007-10. In the matched case-control study, 31 patients with high- or intermediate-level resistance, 16 with low-level resistance and 89 controls were enrolled. Compared with regimens with GSS >2.5, initiation of regimens with GSS ≤2.5 was associated with a higher treatment failure rate (39.3% versus 15.7%, P = 0.02) and shorter time to treatment failure (log-rank P < 0.001). In patients receiving regimens with GSS ≤2.5, protease inhibitor-based regimens were less likely to result in treatment failure, compared with non-nucleoside reverse-transcriptase inhibitor-based regimens (hazard ratio 0.26, 95% CI 0.06-1.12, P = 0.07). CONCLUSIONS: In Taiwan the prevalence of TDR of HIV-1 strains declined and stabilized between 2007 and 2010. Receipt of antiretroviral regimens with GSS ≤2.5 was associated with poorer treatment responses than regimens with GSS >2.5.
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Fármacos Anti-VIH/administración & dosificación , Terapia Antirretroviral Altamente Activa/métodos , Farmacorresistencia Viral , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Adulto , Femenino , Genotipo , Infecciones por VIH/transmisión , Humanos , Masculino , Prevalencia , ARN Viral/genética , Taiwán/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND/PURPOSE: Men who have sex with men (MSM) are at increased risk for hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections than the general population. Comparisons of the seroprevalence rates of these hepatitis viruses between HIV-positive and HIV-negative MSM are rarely performed in Taiwan. METHODS: Between January 2009 and June 2010, data on the serologies for HAV, HBV, and HCV were collected from two groups of patients: HIV-negative MSM, aged 18-40 years, who sought voluntary counseling and testing (VCT) for HIV infection, and HIV-positive MSM of the same age group who sought HIV care at the National Taiwan University Hospital. Both groups of patients were also tested for syphilis. RESULTS: During the 18-month study period, 690 HIV-negative MSM and 438 HIV-positive MSM were enrolled and tested for anti-HAV antibody, HBV surface antigen (HBsAg), hepatitis B core antibody (anti-HBc antibody), and anti-HCV antibody. HIV-positive MSM were older than HIV-negative MSM (30.5 ± 5.4 vs. 25.8 ± 4.7 years, p < 0.01). For HIV-positive MSM, the mean CD4 lymphocyte count was 477.6 ± 230.0 cells/µL and 46% of them had undetectable plasma HIV RNA load (< 40 copies/mL by reverse transcription-polymerase chain reaction assay). The overall seroprevalence rates of HAV, HBsAg, and HCV in HIV-positive MSM were 15.1%, 16.4%, and 5.5%, respectively, while in HIV-negative MSM, they were 7.4%, 6.2%, and 0.4%, respectively. In the multivariate analysis, age was significantly associated with seropositivity for HAV (OR [per one age group increase]: 1.96; 95% CI: 1.6-2.5), HBsAg (OR: 2.02; 95% CI: 1.6-2.6), anti-HBc (OR: 2.68; 95% CI: 2.3-3.2), anti-HCV (OR: 1.67; 95% CI: 1.0-2.7), and anti-HBs (OR: 1.25; 95% CI: 1.0-1.5). HIV infection was associated with seropositivity for HBsAg (OR: 1.73; 95% CI: 1.1-2.7), anti-HBc (OR: 2.44; 95% CI: 1.8-3.3), HCV (OR: 8.91; 95% CI: 2.5-31.4), and syphilis (OR: 11.21; 95% CI: 6.7-18.9). CONCLUSION: HIV-positive MSM have a higher seroprevalence rate of HBV and HCV infection than HIV-negative MSM in Taiwan. Vaccination and safe-sex counseling should be provided to prevent the transmission of hepatitis viruses among MSM who may be engaged in high-risk behaviors.
Asunto(s)
Hepatitis Viral Humana/epidemiología , Homosexualidad Masculina , Adolescente , Adulto , Biomarcadores/sangre , Estudios Transversales , Infecciones por VIH/complicaciones , Hepacivirus/inmunología , Virus de la Hepatitis A Humana/inmunología , Anticuerpos Antihepatitis/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis Viral Humana/sangre , Hepatitis Viral Humana/etiología , Humanos , Masculino , Factores de Riesgo , Estudios Seroepidemiológicos , Taiwán/epidemiología , Adulto JovenRESUMEN
BACKGROUND/PURPOSE: Pneumococcal polysaccharide vaccination may be associated with adverse outcomes in HIV-infected individuals who did not receive highly active antiretroviral therapy (HAART). Our aim was to evaluate the impact of vaccination with seven-valent pneumococcal conjugate vaccine (PCV) on the short-term clinical, virologic, and immunologic outcomes among HIV-infected adult patients in the HAART era. METHODS: A total of 429 HIV-infected adult patients were enrolled from October 2008 to March 2010: 213 received two doses of seven-valent PCV given at a 4-week interval and 216 received one dose. All patients were given 1-week diary to record any discomfort after vaccination. Data of serial CD4 and plasma HIV RNA load measurements were recorded. RESULTS: Of the 429 patients with a mean CD4 count of 305 cells/µL, 289 (67.4%) were receiving HAART and 175 (40.8%) had plasma HIV RNA load <40 copies/mL at vaccination. Of the 396 patients (92.3%) who returned the diary, injection site soreness (24.0%) and pain (10.4%) were the most commonly reported adverse effects. After 3-4 months of vaccination, CD4 count increased by 40 cells/µL in 278 patients (68.2%) who continued HAART, compared with a decrease of 38 cells/µL in 131 patients (31.8%) who were not on HAART (p < 0.001), while the respective change in plasma HIV RNA load was 0.8 versus 0.2 log(10) copies/mL (p = 0.09). One patient died, two developed opportunistic infections, and one developed pneumococcal pneumonia following vaccination. CONCLUSION: Vaccination with seven-valent PCV among HIV-infected patients is generally safe, which has no detrimental effect on CD4 count and plasma HIV RNA load in patients receiving HAART. (ClinicalTrials.gov number, NCT00885628).
Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH , Vacunas Neumococicas/efectos adversos , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Esquemas de Inmunización , Masculino , Vacunas Neumococicas/administración & dosificación , Estudios Prospectivos , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Carga ViralRESUMEN
We studied the antimicrobial activity of fosfomycin against 960 strains of commonly encountered bacteria associated with urinary tract infection using standard agar dilution and disk diffusion methods. Species studied included 3 common species of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia; methicillin-susceptible and -resistant Staphylococcus aureus; and vancomycin-susceptible and resistant Enterococcus faecalis and E. faecium. MICs and inhibition zone diameters were interpreted in accordance with both the currently recommended Clinical and Laboratory Standards Institute (CLSI) criteria for urinary tract isolates of Escherichia coli and Enterococcus faecalis and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria for Enterobacteriaceae. Tentative zone diameter interpretive criteria were developed for species not currently published by CLSI or EUCAST. Escherichia coli was uniformly susceptible to fosfomycin, as were most strains of Klebsiella pneumoniae and Enterobacter cloacae. A. baumannii was resistant to fosfomycin, while the prevalence of resistance in P. aeruginosa and S. maltophilia was greatly affected by the choice of MIC breakpoint. New tentative zone diameter criteria for K. pneumoniae, E. cloacae, S. aureus, and E. faecium were able to be set, providing some interim laboratory guidance for disk diffusion until further breakpoint evaluations are undertaken by CLSI and EUCAST.
Asunto(s)
Antibacterianos/farmacología , Fosfomicina/farmacología , Acinetobacter baumannii/efectos de los fármacos , Enterobacteriaceae/efectos de los fármacos , Enterococcus faecalis/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
OBJECTIVES: This study investigated the correlation between antibiotic consumption and antimicrobial resistance in Gram-negative bacteria causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. METHODS: Disc susceptibility data of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus spp., Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia and other non-fermentative Gram-negative bacilli causing healthcare-associated infections were evaluated. Data on annual patient-days and annual consumption (defined daily doses per 1000 patient-days) of extended-spectrum cephalosporins, ß-lactam/ß-lactamase inhibitor combinations, carbapenems, aminoglycosides and ï¬uoroquinolones were analysed. RESULTS: The trend of total consumption of extended-spectrum cephalosporins, ß-lactam/ß-lactamase inhibitor combinations, carbapenems, aminoglycosides and fluoroquinolones significantly increased between 2000 and 2003 and remained stable between 2004 and 2009. The decreasing use of gentamicin and amikacin in recent years was associated with increasing susceptibility of E. coli, E. cloacae, S. marcescens and P. aeruginosa to gentamicin, as well as increasing susceptibility of P. aeruginosa to amikacin. The use of piperacillin/tazobactam was positively correlated with the prevalence of piperacillin/tazobactam-resistant E. coli and S. maltophilia. In contrast, the use of cefotaxime and piperacillin/tazobactam was negatively correlated with the prevalence of cefotaxime-resistant E. coli and piperacillin/tazobactam-resistant S. maltophilia, respectively. The consumption of fluoroquinolones was positively correlated with the rates of ciprofloxacin-resistant E. coli, piperacillin/tazobactam-resistant P. aeruginosa and ceftazidime-resistant S. maltophilia. CONCLUSIONS: The relationship between antibiotic prescription and the rates of resistance for Gram-negative bacteria is complicated; every type of antimicrobial agent or even individual agent can have distinct associations with different pathogens.
Asunto(s)
Antibacterianos/uso terapéutico , Infección Hospitalaria/microbiología , Farmacorresistencia Bacteriana , Utilización de Medicamentos/estadística & datos numéricos , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/microbiología , Antibacterianos/farmacología , Bacterias Gramnegativas/aislamiento & purificación , Hospitales Universitarios , Humanos , Pruebas de Sensibilidad Microbiana , TaiwánRESUMEN
Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir1,2. Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy3. However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8+ T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption4. Increased CD4+ T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined.
Asunto(s)
Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Inmunoterapia/métodos , Linfocitos T/inmunología , Adulto , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Epítopos/inmunología , Femenino , Productos del Gen gag/metabolismo , Infecciones por VIH/virología , VIH-1 , Humanos , Sistema Inmunológico , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/virología , ViremiaRESUMEN
HIV-1 infection requires lifelong therapy with antiretroviral drugs due to the existence of a latent reservoir of transcriptionally inactive integrated proviruses. The goal of HIV-1 cure research is to eliminate or functionally silence this reservoir. To this end, there are numerous ongoing studies to evaluate immunological approaches, including monoclonal antibody therapies. Evaluating the results of these studies requires sensitive and specific measures of the reservoir. Here, we describe a relatively high-throughput combined quantitative PCR (qPCR) and next-generation sequencing method. Four different qPCR probes covering the packaging signal (PS), group-specific antigen (gag), polymerase (pol), and envelope (env) are combined in a single multiplex reaction to detect the HIV-1 genome in limiting dilution samples followed by sequence verification of individual reactions that are positive for combinations of any two of the four probes (Q4PCR). This sensitive and specific approach allows for an unbiased characterization of the HIV-1 latent reservoir.
Asunto(s)
Genoma Viral , Infecciones por VIH/genética , VIH-1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Virales/genética , Antirretrovirales/administración & dosificación , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , MasculinoAsunto(s)
Pneumocystis carinii/aislamiento & purificación , Neumonía por Pneumocystis/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Biopsia , Diagnóstico Diferencial , Humanos , Pulmón/diagnóstico por imagen , Pulmón/microbiología , Pulmón/patología , Masculino , Neumonía por Pneumocystis/microbiología , Neumonía por Pneumocystis/patologíaRESUMEN
A clinical trial was performed to evaluate 3BNC117, a potent anti-HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.