RESUMEN
There is limited information on the variations of HIV-1 DNA mutation profile in reverse transcriptase (RT) and protease (PR) genes during suppressive antiretroviral treatment (plasma HIV-1 RNA continuously <50 copies/ml) with raltegravir (RAL)-based regimens in patients with baseline RT/PR resistant HIV. Twelve multidrug resistant (RT: 12/12, PR: 8/12) HIV-infected patients were followed during effectively suppressive RAL-based therapy. Total and integrated HIV-1 DNA were assessed by real time PCR at baseline and every 6 months. Ultrasensitive (threshold: 2.5 copies/ml) plasma HIV-1 RNA and genotypic analysis of RT and PR in proviral DNA were performed at baseline and at 24 months. Half of the patients had full viral suppression (plasma HIV-RNA < 2.5 copies/ml) at month 12. Total HIV-1 DNA declined significantly after 12 months of therapy (from 249.2 to 145.7 copies/106 cells, P = 0.023), and remained stable until 24 months, when total HIV-1 DNA levels raised, concomitantly with a less stringent suppression of HIV-1 RNA (81.8% of patients with >2.5 copies/ml). Integrated HIV-1 DNA did not show fluctuations during the study period. Sequencing of the PR and RT regions from HIV-1 DNA revealed changes in the resistance mutation profile in five patients. Total HIV-1 DNA declined after the introduction of RAL-based therapy, with a rebound after 2 years. No changes were observed in levels of integrated DNA, suggesting limited effect on archived HIV. The RT and PR sequence changes in archived HIV-1 DNA suggest that variation of the mutation profile can occur even in the absence of detectable HIV-1 RNA. J. Med. Virol. 88:2115-2124, 2016. © 2016 Wiley Periodicals, Inc.
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Fármacos Anti-VIH/uso terapéutico , ADN Viral/genética , Farmacorresistencia Viral Múltiple , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-1/enzimología , VIH-1/genética , Raltegravir Potásico/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa , Femenino , Variación Genética , Genotipo , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mutación , ARN Viral/sangre , ARN Viral/genética , Raltegravir Potásico/efectos adversos , Carga ViralRESUMEN
Residual HIV viremia, defined by low levels of plasma HIV RNA with enhanced-sensitivity assays, may persist even in the presence of successful antiretroviral therapy, but little is known about its determinants. Our objective was to evaluate the rate and determinants of residual viremia in patients who show stable undetectable plasma HIV-1 RNA with conventional assays. Forty-four multidrug-experienced patients with undetectable levels of HIV RNA for at least 2 years under raltegravir-based regimens were evaluated. An ultrasensitive (2.5 copies/ml) real-time PCR method was used to quantify plasma HIV RNA. After 12 months of salvage treatment, 48.3% of the patients had residual viremia between 2.5 and 37 copies/ml. The proportion of patients with plasma HIV RNA below 2.5 copies/ml decreased from 51.7% at 12 months to 30.8% at 24 months. The presence of residual viremia was not associated with levels of viremia before starting raltegravir. Considering CD4 counts, hepatitis B or C virus (HBV or HCV) coinfection, or other demographic characteristics, for the time interval between HIV diagnosis and initiation of antiretroviral therapy, patients with a longer interval (>1 year) were significant less likely to have RNA levels below 2.5 copies/ml at 12 months compared to patients who started therapy within 1 year of HIV diagnosis (28.6% vs. 73.3%, p=0.027). Half of the patients showing undetectable HIV viremia with conventional assays had low-level viremia with ultrasensitive assays, with no predictive role of viroimmunological status at the start of the regimen. The potential influence of the interval between HIV diagnosis and initiation of treatment should be confirmed in subjects with a known date of seroconversion.
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Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Seropositividad para VIH/diagnóstico , Pirrolidinonas/uso terapéutico , Viremia/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Coinfección , ADN Viral/sangre , Femenino , Seropositividad para VIH/virología , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Raltegravir Potásico , Carga Viral , Viremia/virologíaRESUMEN
BACKGROUND: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited. AIM: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response. METHODS: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated. RESULTS: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found. CONCLUSIONS: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.
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Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/sangre , Ritonavir/sangre , Sulfonamidas/sangre , Adulto , Anciano , Cromatografía Líquida de Alta Presión/métodos , Darunavir , Quimioterapia Combinada , Femenino , Genotipo , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Ritonavir/uso terapéutico , Terapia Recuperativa , Sulfonamidas/uso terapéutico , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: The HIV integrase inhibitor raltegravir (RAL) can exacerbate autoimmune diseases in genetically predisposed mice. To evaluate whether this may occur in clinical practice, we clinically monitored HIV-positive patients treated with RAL and measured a panel of autoantibodies (auto-Abs) during the first year of RAL treatment. METHODS: This was a longitudinal study in 109 antiretroviral-experienced patients who started a RAL-based regimen and were followed up for more than 2 years. A total of 45 patients were tested at baseline (before starting RAL) and after 12 months for the presence of the following auto-Abs: anti-nuclear antibodies, anti-double-stranded DNA, anti-smooth-muscle antibodies, anti-thyreoglobulin and anti-thyroid peroxidase antibodies, anti-cardiolipin immunoglobulin G and immunoglobulin M and anti-nuclear extractable antigens, including anti-SM ribonucleoprotein antigen, anti-Ro antigen and anti-La antigen. RESULTS: A low rate of clinically relevant autoimmune diseases was observed at study entry (3/109; 2.8%; 95% CI 0.004, 0.059). No exacerbations were observed during follow-up. During the second year of RAL-based therapy a previously healthy patient developed psoriasis. At baseline, 17/45 (37.8%) patients tested for the presence of auto-Abs were positive. Most patients (n=13) were positive for anti-cardiolipin. After 12 months of RAL exposure, 9/45 patients were positive (20%; P=0.063). A positive correlation was found between HIV-1 RNA and anti-cardiolipin antibody concentration (P=0.010). CONCLUSIONS: According to these results, RAL does not promote antibody-mediated immune disorders, at least not in the mid-term. A prolonged follow-up and an extension of the panel of auto-Abs are recommended to support these results.
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Enfermedades Autoinmunes/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , VIH-1 , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Recuento de Linfocito CD4 , Femenino , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinonas/efectos adversos , Pirrolidinonas/uso terapéutico , Raltegravir Potásico , Receptores de IgE/sangre , Receptores de IgE/inmunología , Estudios Retrospectivos , Carga ViralRESUMEN
OBJECTIVES: To define the impact of coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) on viroimmunological response to raltegravir-based salvage regimens that also include new HIV inhibitors such as maraviroc, darunavir and etravirine. METHODS: We used data from a national observational study of patients starting raltegravir-based regimens to compare virological suppression and CD4 cell change from baseline in patients with and without concomitant HBV or HCV infection. RESULTS: Overall, 275 patients (107 coinfected and 168 non-coinfected) were evaluated. Coinfected patients were more commonly former intravenous drug users and had a longer history of HIV infection and higher baseline aminotransferase levels. Both HIV-RNA and CD4 response were similar in the two groups. Mean time to first HIV-RNA copy number <50 copies/mL was 4.1 months (95% CI 3.5-4.6) in non-coinfected patients and 3.9 months (95% CI 3.3-4.5) in coinfected patients (hazard ratio 1.039, 95% CI 0.761-1.418, P = 0.766, log-rank test). The risk of developing new grade 3-4 hepatic adverse events was significantly higher in coinfected patients (hazard ratio 1.779, 95% CI 1.123-2.817, P = 0.009). The two groups of coinfected and non-coinfected patients had similar rates of interruption of any baseline drug (hazard ratio 1.075, 95% CI 0.649-1.781, P = 0.776) and of raltegravir (hazard ratio 1.520, 95% CI 0.671-3.447, P = 0.311). Few AIDS-defining events and deaths occurred. CONCLUSIONS: Viroimmunological response to regimens based on raltegravir and other recent anti-HIV inhibitors is not negatively affected by coinfection with HBV or HCV. Liver toxicity, either pre-existing or new, is more common in coinfected patients, but with no increased risk of treatment interruption.
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Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Coinfección/epidemiología , Femenino , Estudios de Seguimiento , Infecciones por VIH/epidemiología , Hepacivirus/efectos de los fármacos , Hepatitis B/epidemiología , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis C/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Understanding the determinants of virus transmission is a fundamental step for effective design of screening and intervention strategies to control viral epidemics. Phylogenetic analysis can be a valid approach for the identification of transmission chains, and very-large data sets can be analysed through parallel computation. Here we propose and validate a new methodology for the partition of large-scale phylogenies and the inference of transmission clusters. This approach, on the basis of a depth-first search algorithm, conjugates the evaluation of node reliability, tree topology and patristic distance analysis. The method has been applied to identify transmission clusters of a phylogeny of 11,541 human immunodeficiency virus-1 subtype B pol gene sequences from a large Italian cohort. Molecular transmission chains were characterized by means of different clinical/demographic factors, such as the interaction between male homosexuals and male heterosexuals. Our method takes an advantage of a flexible notion of transmission cluster and can become a general framework to analyse other epidemics.
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Clasificación/métodos , Infecciones por VIH/virología , VIH-1/clasificación , Filogenia , Algoritmos , Femenino , Productos del Gen pol/genética , Infecciones por VIH/transmisión , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , MasculinoRESUMEN
Response to HIV/AIDS epidemic in resource-constrained countries is still woefully disappointing. This paper highlights some priorities shared at recent Florence World Conference (Florence, Italy: January 21st-24th, 2004) on how to overcome the obstacles still delaying sustainable fight against HIV/AIDS in developing world areas. Messages reported here result from selection made by the authors among challenging topics by more than one hundred speakers and have been chosen because of their value as most practical ways to secure prevention, treatment and care and achieve self-managing in fighting epidemic in income-limited settings. Building for success means to set up combined strategies--actively involving people living with HIV/AIDS (PLWHA) and grounded on coordination, coalition and partnership among all players--to prevent HIV transmission at mother-to-child, young and adult levels and to improve availability and access to laboratory testing and monitoring as well as to essential drugs for HIV/AIDS and related diseases. Building for success also means to provide women with reliable and affordable vaginal microbicides and to look for control of co-infections such as viral hepatitis, intestinal and sexually transmitted diseases as well as tuberculosis and malaria. Among the measures taken into account, the need for education and training is emphasised because its value may be even more important than funding in some countries. Priorities suggested in this paper reinforce each other underscoring the bidirectional value and synergy of the treatment and prevention strategies together with the need for keeping prevention in people giving successful antiretroviral treatment. In the Author's opinion, the current HIV/AIDS scenario may be reversed if the priorities taken into account will entirely be applied through adaptation to the different cultural backgrounds and social settings, and based on achievement of government's political will and accountability as well as on properly coordinated technical, financial and human support from international health cooperation.
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Países en Desarrollo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Prioridades en Salud , Pobreza , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Niño , Preescolar , Femenino , Educación en Salud , Recursos en Salud , Accesibilidad a los Servicios de Salud , Humanos , Masculino , EmbarazoRESUMEN
OBJECTIVES: The objective was to study genotypic correlates of discordant interpretations of amprenavir (APV) resistance between a rules-based algorithm and either recombinant phenotype or virtual phenotype. METHODS: HIV resistance mutations found in patients from the GenPheRex study were interpreted with VGI-TRUGENE (version 5.0; VGI) and compared with either recombinant-phenotype (Antivirogram, r-PHT) or virtual-phenotype (Virtual-Phenotype, v-PHT) interpreted through Virco biological cut-offs. RESULTS: Among 180 samples available, 56 (31.1%) were discordant with the observed genotype interpretation results, as a result of being judged as sensitive by r-PHT or v-PHT but resistant by VGI (S/R). Only the I84V mutation was almost invariably found in concordant resistant isolates compared with S/R isolates (60% versus 0%, respectively; P < 0.0001). Notwithstanding this, the number of multi-protease inhibitor-associated mutations (PAMs) was significantly higher in the concordant resistant isolates; the prevalence of >3 PAMs was 56.52% versus 33.93% in R/R and S/R isolates, respectively (P = 0.01). Correspondence analysis confirmed the relevance of PAMs, although additional mutations appeared to be correlated with APV resistance. CONCLUSIONS: The rate of discordance between rules-based and either r-PHT or v-PHT interpretations for APV was high. Mutation I84V and accumulation of >3 PAMs were found to be associated with resistance as interpreted with all systems tested. However, our results indicate that a number of mutations may have an impact on APV resistance, but that they are missed by current interpretation algorithms and this merits further investigations.
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Farmacorresistencia Viral/genética , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Sulfonamidas/farmacología , Algoritmos , Carbamatos , Furanos , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Proteasa del VIH/genética , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/enzimología , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Mutación , Fenotipo , Estudios Prospectivos , Sulfonamidas/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Sandfly fever viruses are still a significant health problem in many regions of the world, such as Africa, the Mediterranean basin, the Middle East, and Central Asia. This review provides an update on the advances in knowledge about epidemiological, clinical, and laboratory aspects of infections caused by Toscana, Sicilian and Naples viruses. RECENT FINDINGS: Diagnosis of Toscana virus infection has been facilitated by new molecular methods and by immunoenzymatic tests based on the recombinant nucleoprotein. Gene analysis has allowed identification of circulating Toscana variants possibly involved in the protean pathomorphism and extreme variability of the clinical picture. New attention has been addressed to the antigenic properties of the viral proteins (the nucleoprotein N and the surface glycoproteins G1 and G2), in order to understand their immunogenetic role. High genetic divergence within the serocomplexes belonging to each of the Sicilian and the Naples viruses has suggested that infection with one genotype may not completely immunize against infection with all other genotypes in a given serocomplex. These findings could serve as a basis for vaccine development and may account for reports of multiple episodes of sandfly fever in the same host. Recently, the performance of analysis models based on weather data and reported vector surveys has allowed the prediction of the risk of acquiring sandfly infection in the endemic geographic areas. SUMMARY: Recent developments include a better knowledge of the epidemiological, clinical, and laboratory aspects of sandfly infection, while the search for effective drugs and vaccines is still in progress.
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Orthobunyavirus/clasificación , Fiebre por Flebótomos/epidemiología , Animales , Anticuerpos Antivirales/análisis , Humanos , Insectos Vectores/virología , Italia/epidemiología , Orthobunyavirus/genética , Orthobunyavirus/inmunología , Orthobunyavirus/aislamiento & purificación , Phlebotomus/virología , Fiebre por Flebótomos/patología , Fiebre por Flebótomos/transmisión , Fiebre por Flebótomos/virología , ARN Viral/análisisRESUMEN
Although new infections with drug-resistant human immunodeficiency virus type 1 have been recently reported to occur consistently, this is the first documented case of secondary transmission of a drug-resistant variant from 1 untreated subject to his sexual partner.