To study the effect of highly active antiretroviral therapy (HAART) with and without hydroxyurea (HU) on changes in plasma viral load (VL) set-point, and on HIV-1-specific responses, after five ...cycles of structured treatment interruptions (STI).
A group of 20 patients taking HAART for chronic HIV infection with VL < 20 copies/ml were randomized to continue HAART or HAART plus HU for 24 weeks followed by five STI cycles. HU was also stopped in cycles 1-3 but continued in cycles 4 and 5. The number of individuals maintaining a VL set-point < 5000 copies/ml during the fifth interruption were determined.
VL remained < 5000 copies/ml in eight out of nine patients in the HU group and in four out of ten patients in the HAART group after a median 48 weeks of follow-up after the fifth interruption ( P=0.039). By STI cycle 5, there was a significant increase in the neutralizing activity (NA), in both magnitude and breadth of the total cytotoxic T lymphocyte (CTL) response and in lymphoproliferative response (LPR) from baseline. No significant differences were observed between HAART and HU groups in NA, CTL and LPR at any time-point. There were no differences in the NA titers at any time-point between responder and non-responder patients. There was a trend for higher CTL and LPR levels in responder patients (P= 0.10).
In this randomized, controlled study of STI with cycles of HAART or HAART plus HU, a lower peak VL rebound and a lower VL set-point was achieved in patients continuing HU while other drugs were discontinued. HU did not blunt anti-HIV-1-specific responses; however, control of VL did not correlate with anti-HIV-1-specific cellular immune responses.
Background The emerging relationship between microRNAs (miRNA) and viral-control is a topic of interest in the field of HIV. Host-genome might play an important role in the control of viremia. The ...aim of this study was to assess the specific miRNA profile that could contribute to the control of HIV replication in Elite Controllers Results After adequate normalization, expression profile of 286 human miRNAs (hsa-miR) was evaluated in phytohaemagglutinin-stimulated PBMCs from 29 individuals classified in 4 groups: 8 elite controllers (EC; viral load <50 cp/ml without treatment), 8 viremic progressors (VP; VL>5000 cp/ml without treatment), 8 patients under antiretroviral treatment (ART; VL<200 cp/ml) and 5 uninfected individuals (HIV-) through TaqMan Array Human microRNA Cards v3.0. A differential expression pattern consisting of 23 miRNAs became significantly different when comparing EC and VP. Profiling analysis segregated the population in two different blocks: while EC and HIV- clustered together in the same block (EC/HIV-_block 1), VP and ART individuals clustered together in a second block (VP/ART_block 2). Two inversely expressed miRNA patterns were determined within those two blocks: a set of 4 miRNAs (hsa-miR-221, -27a, -27b and -29b) was up-expressed in EC/HIV-_block and down-expressed in VP/ART_block while 19 miRNAs were down-expressed in block 1 and up-expressed in block 2. Differential miRNAs were successfully validated through individual RT-qPCR assays. Conclusions Profile in EC resembled HIV- and differentially clusters with VP and ART. Therefore, differential clustering does not rely on undetectable viremia.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We describe a probable case of HIV-1 transmission from a healthcare worker (HCW) to a patient during a caesarean section. Genetic distance comparisons of the viral sequence of the C2V4 region of the ...viruses from the patient and the obstetrician showed an average nucleotide sequence divergence of 3% (2.8-3.1). HIV can be transmitted from an infected HCW to a patient when percutaneous injuries with subsequent exposure of the patient to the blood of the HCW can occur.
Hypersensitivity reactions to abacavir occur in 5-8% of patients starting treatment with this drug and limits future treatment. Some host genetic factors, especially the HLA-B*5701 allele, have been ...identified as risk factors for hypersensitivity reaction in Caucasians. Consequently, the possibility of routine implementation of a genetic test to rule out the presence of this allele has been proposed to achieve a personalized therapeutic profile. The present article discusses all the information related to hypersensitivity to abacavir and its genetic and immunological markers, as well as the distinct techniques for HLA-B*5701 allele detection. The various studies performed to date in distinct population are also discussed.
La reacción de hipersensibilidad al abacavir (ABC) es un efecto adverso que se produce entre el 5 y el 8% de aquellas personas que inician el tratamiento con este fármaco y que limita el tratamiento ...en el futuro. Algunos factores genéticos del huésped, en especial el alelo HLA-B* 5701 , se han identificado como factores de riesgo para desarrollar la reacción de hipersensibilidad en la raza caucásica. Por esta razón se plantea la posibilidad de implementar en la práctica habitual un test genético que permita detectar la presencia de este alelo con la finalidad de conseguir un perfil terapéutico personalizado. En este capítulo se documenta toda la información relacionada con la hipersensibilidad al ABC y sus marcadores genéticos e inmunológicos, las distintas técnicas para la detección del alelo HLA-B*5701 , así como un resumen de los diferentes estudios realizados en el momento en distintas poblaciones.
The NEFA Study was a randomized study comparing nevirapine (NVP), efavirenz (EFV) or abacavir (ABC) as substitutes for protease inhibitors in a large group of HIV-1-infected patients successfully ...treated with antiretroviral regimens containing protease inhibitors.
To evaluate genotype and phenotype resistance patterns among patients who have experienced virological failure under one of the three study arms.
Patients with virological failure, defined as two consecutive determinations of HIV-1 RNA > 200 copies/ml, were analysed for phenotypic susceptibility and HIV-1 mutations.
Of the 460 patients included in the study, 51 (11%) experienced virological failure after 24 months of follow-up while on assigned study medication. A higher proportion of patients in the ABC 25 (17%) than in the NVP 14 (9%) or EFV 12 (8%) arms selected resistance to the study drug (P = 0.04). Moreover, a much higher number of resistance mutations to one or more of the backbone nucleoside reverse transcriptase inhibitor drugs contained in the failing regimen were observed in the ABC than in the EFV or NVP arms. In general, there was a good concordance among genotype and phenotype resistance testing, except for ABC, stavudine and didanosine, where phenotypic resistance testing added valuable information (fold change in the median inhibitory concentration).
Cross-resistance involving nucleoside reverse transcriptase inhibitor drugs might explain the higher risk of virological failure in patients switched to ABC-containing antiretroviral therapy. Phenotypic resistance testing may be helpful in interpreting unclear genotypic results.
Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses ...(LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.
To describe the epidemiological and clinical characteristics and the evolution of a cohort of patients with primary HIV-1 infection from the Barcelona area.
Prospective cohort study of HIV-infected ...patients diagnosed with primary HIV infection in a tertiary hospital in Barcelona (Spain) from 1997 through 2003. Descriptive analysis of epidemiological and clinical characteristics and effect of highly active antiretroviral treatment (HAART) on outcome.
A total of 75 patients were diagnosed, accounting for 2.9% of the total of newly diagnosed HIV patients during the same time period. Eighty-one percent of the patients were males and the median age was 30 years (IQR 26-38). The most frequent transmission route was homosexual (72%), followed by heterosexual (17%) and intravenous drug abuse (11%). Seventy-seven percent of patients presented symptoms, the most frequent being fever (98%), asthenia (86%), arthralgia-myalgia (65%), lymphadenopathy (55%), night sweats (48%) and rash. Sixty-five percent started HAART, although the proportion of patients that received HAART decreased from 79% during the period 1997-2000 to 49% during the period 2001-2003 (p
<
0.01). After a median follow-up of 37 months (IQR 26-66), one patient died and eight cases were lost to follow-up. The patients who did not receive HAART had a higher probability of immunological or clinical deterioration during the follow-up when compared to the group that received HAART (42.3% versus 12.3%; p
<
0.001). In treated patients, dyslipidemia and lipodystrophy were diagnosed in 58% and 37% of cases, respectively.
Primary HIV-1 infection was diagnosed more frequently in homosexual males, and its clinical characteristics were similar to those observed in previous studies. HAART given during primary HIV infection was effective, but was associated with a high percentage of adverse effects.
Describir las características epidemiológicas, clínicas y evolutivas de una cohorte de pacientes con una infección aguda por el virus de la inmunodeficiencia humana (VIH) en el área de Barcelona.
Estudio prospectivo de pacientes diagnosticados de infección aguda por el VIH en un hospital terciario de Barcelona durante el período 1997-2003. Análisis descriptivo de las características epidemiológicas y clínicas e influencia del tratamiento antirretroviral (TARV) en la evolución.
Se diagnosticaron 75 pacientes, lo que representó el 2,9% del total de pacientes diagnosticados de infección por el VIH en el mismo período de tiempo. El 81% eran varones y la mediana de edad fue de 30 años (rango intercuartil RIC, 26-38). Las vías de contagio fueron las relaciones homosexuales (72%), seguida de las heterosexuales (17%) y del uso de drogas intravenosas (11%). El 77% de los pacientes presentó síntomas, siendo los más frecuentes: fiebre (98%), astenia (86%), artromialgias (65%), linfoadenopatías (55%), sudoración nocturna (48%) y exantema (45%). El 65% comenzó TARV, disminuyendo el número de pacientes tratados del 79% en el período 1997-2000 al 49% en el período 2001-2003 (p
<
0,01). Tras una mediana de seguimiento de 37 meses (RIC, 26-66), un paciente falleció y 8 casos se perdieron de seguimiento. Los pacientes que no recibieron TARV presentaron una mayor probabilidad de presentar deterioro inmunológico o clínico durante el seguimiento en comparación con el grupo que recibió TARV (42,3% frente a 12,3%; p
<
0,001). La dislipemia y la lipodistrofia se diagnosticaron en el 58 y 37% de los pacientes tratados, respectivamente.
La infección aguda por VIH se diagnosticó con más frecuencia en los varones homosexuales, siendo sus características clínicas similares a las descritas previamente. El TARV instaurado en esta fase de la infección por VIH fue eficaz pero se asoció a una frecuencia elevada de efectos adversos.
The objective was to analyse which baseline factors could predict a favourable outcome after structured therapy interruption (STI).
Data of three Spanish pilot studies of STI in early stage chronic ...HIV-1-infected patients were analysed. A set of 37 variables at baseline was used. Plasma and tonsillar tissue viral load (VL), lymphocyte immunophenotyping and proliferative responses (LPR) to mitogens and specific antigens, and HIV-1 specific cytotoxic T lymphocyte responses were assessed at baseline. Response was defined as a VL set-point after 6 months off antiretroviral therapy after the last interruption of < 5000 copies/ml and 0.5 log(10) below baseline PVL before any antiretroviral therapy.
After STI, the 44 patients were classified as follows: 18 (41%) as responders, 26 (59%) as non-responders. In the univariate analysis patients who responded had a significantly lower baseline level of CD4CD38 (P = 0.0068) and naive CD4 T cells (P = 0.03), and a higher level of memory CD4 T cells (P = 0.03) and proliferative response to tetanus toxoid (TT) (P = 0.01) and HIV-1 p24 (P = 0.03) than non-responders. A model incorporating five qualitative variables transformed according to the median value (CD4CD38, CD4 naive and memory T cells and stimulation index to TT and HIV-1 p24) at baseline could classify 97% of patients correctly (P = 0.0001).
A level of memory CD4 T cells and proliferative response to recall antigens above the median may predict a good response to STI, suggesting that preserved memory response in CD4 T cells is important factor.
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