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.
Intensification therapy adding a boosted protease inhibitor (PI) to a failing regimen has the potential to worsen the resistance profile. Sixty-six patients included in four different boosted PI ...intensification studies were assessed and resistance mutations in the reverse transcriptase and protease genes were evaluated at baseline and 4 weeks after the initiation of the intensification strategy. Only one of the 66 patients developed changes in their pattern of mutations able to generate or increase resistance to new drugs.
To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different ...antiretroviral regimens.
Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up.
Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test).
In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.
The objectives of this study were to determine the genotypic and phenotypic patterns of resistance in a group of early-stage antiretroviral-naive patients failing initial therapy with didanosine, ...stavudine and nevirapine. These patterns of resistance were determined at baseline and at time of virological failure in 89 antiretroviral-naive patients with CD4 cells >500 cells/ml and viral load >5000 copies/ml who received initial antiretroviral therapy with didanosine plus stavudine and nevirapine as part of the SCAN study, and who failed after having reached undetectable plasma levels (<200 copies/ml). Of the 89 patients recruited in the SCAN study, 14 (16%) developed a virological failure after reaching a viral load below 200 copies/ml after a median of 20 months of follow-up. At baseline, none of these 14 patients had genotypic resistance. At time of failure, six out of 14 (43%) failing patients had wild-type genotype and no phenotypic resistance. Suboptimal compliance could be documented in four of these six patients. Seven patients (50%) had nevirapine resistance mutations (mainly K103N 4/7, Y181C/I 2/7, G190A/S 2/7 and V108I 1/7) associated with phenotypic high-level resistance to nevirapine, delavirdine and efavirenz (nevirapine >47.4- to 58.1-fold, delavirdine >74.4- to 168.9-fold and efavirenz >56.0- to 347.2-fold). Four of these seven patients also had thymidine analogue-associated mutations (TAM) (T215Y/F 2/4, M41L 1/4, D67N 2/4 and K70R 1/4). Finally, one patient (7%) had exclusively TAM mutations (M41L). None of the patients developed mutations associated with didanosine resistance or phenotypic resistance to didanosine or stavudine. Suboptimal compliance or selection of nevirapine resistance often with TAM mutations was frequently associated with virological failure in a cohort of early-stage chronic HIV-1-infected patients treated with a protease inhibitor-sparing regimen.
La imposibilidad de erradicar el virus de la immunodeficiencia humana (VIH-1) del organismo humano con las pautas terapéuticas de alta eficacia (TARGA), la adherencia a pautas terapéuticas complejas ...y el riesgo a una importante toxicidad farmacológica aguda y crónica, son los principales problemas en la administración prolongada de los fármacos antirretrovirales. Es iminente la necesidad de diseñar nuevas estrategias de tratamiento y en este sentido se han desarrollado las terapias inmuno-mediadas, siendo un ejemplo las interrupciones estrucutradas del tratamiento (IET), dirigidas a controlar la replicación del VIH en base a la recuperación de la respuesta inmune específica. Con estos antecedentes, el estudio virológico de la dinámica y evolución del VIH a lo largo de las diferentes interrupciones estructuradas del tratamiento, permitirá un mejor conocimiento de los cambios observados en la replicación viral durante el periodo de las IET, ya sea debido a factores inmunológicos, virológicos o ambos, para ello se determinó la dinámica viral durante las IET y su relación con la respuesta celular T VIH-1 específica en un grupo de pacientes sometidos a IET, en un grupo de pacientes sometidos a IET y un immunomodulador, la hidroxiurea y en un un grupo de pacientes sometidos a IET y un inmunosupresor, el ácido micofenólico. También se realizó un estudio de evolución del virus en el primer grupo de pacientes. Por último, el estudio de las mutaciones de resistencia en estos pacientes ayudarán a determinar el riesgo que puede comportar la aplicación de esta terapia a la práctica clínica.Los resultados obtenidos en el análisis de la dinámica viral fueron que en todos los pacientes se observó un rebrote de la carga viral en cada una de las interrupciones del tratamiento. Cabe destacar que se observaron atenuaciones significativas en el rebrote de la carga viral a lo largo de las IET.Un 25% de los pacientes mantuvieron valores de estabilización del la carga viral <5000 copias/ml durante una media de 52 semanas de la última interrupción, en los que se observó un incremento de la respuesta celular inmune específica frente al VIH-1. En la totalidad de los pacientes se consiguieron cargas virales indetectables una vez reintroducido el tratamiento.En los resultados obtenidos en la evolución genética del virus a lo largo de las IET no se observó una tendencia a la homogenización de las cuasiespecies virales. No se observaron diferencias significativas en la variabilidad genética entre los virus de pacientes con capacidad o no de neutralizar la replicación viral. En cambio si se detectó la reactivación con la consiguiente reemergencia de provirus ancestrales en el rebrote de carga viral como consecuencia de la interrupción del tratamiento. Al estudiar el riesgo de selección de mutaciones de resistencia durante las IET se observó que un 26% de los pacientes presentaban mutaciones, de los cuales la mitad los seleccionaron de novo durante el periodo de las IET. De estos pacientes un 23% presentaron mutaciones de novo a los inhibidores de la transcriptasa inversa no análogos de nucleósidos (ITIANN), 12% a los inhibidores de la transcriptasa inversa análogos de nucleósidos (ITIAN). No se detectaron mutaciones de resistencia a los inhibidotes de la proteasa (IP).El riesgo de selección de las mutaciones de resistencia fue superior a los ITIANN debido a la larga vida media de estos fármacos, hecho que se debe tener en cuenta cuando se realiza este tipo de estrategia terapéutica.
Highly active anti-retroviral therapy (HAART) represents perhaps the most significant therapeutic advance in HIV research to date, and is the basis of a significant decline in morbidity and mortality ...rates among patients. However, current antirretroviral regimens are limited by issues of potency, adherence, toxicity, resistance and cost. Hence, eradication of the virus has not been achieved and so treatment has to be maintained for the remainder of the patients' lives. Structured treatment interruptions (STI) offer an alternative to continuous HAART. STI involves alternating on-and-off cycles of HAART in order to enhance the utility of therapy. One of the main risks is selection of resistance mutations. In this review, we will examine if the presence of any drug-resistance mutations detected during STI are selected de novo or if they are from archived mutations. Moreover, we will review the relationship between the presence of drug resistance mutations and the achievement undetectable viral load after treatment reintroduction. Finally, we will study whether the appearance of drug resistance mutations during STI is favoured by specific antiretroviral drugs.
Metastatic breast cancer (MBC) diagnosis in young women negatively impacts on quality of life (QoL) and daily activities, disrupting their life project and forcing them to face new psychosocial ...challenges. The recently published results on the improvement of the overall survival of pre- or perimenopausal women with hormone-receptor-positive, HER2-negative MBC treated with CDK4/6 inhibitors plus endocrine therapy, while preserving, and in some items improving their QoL, will change the landscape of the management of this patient population. Their extended survival and potential improvement in QoL will, therefore, modify their specific needs in terms of psychosocial support.
The complexity of the care of young women with MBC is described herein, based on an extensive literature review. Further research about the specific psychosocial requirements of these women and a new multidisciplinary holistic approach is paramount to properly address their concerns and preferences. The communication with and support of their partners, parents and children is an important factor affecting the QoL of these patients. Altogether, a multidisciplinary care, open communication and personalized support is required to address the psychosocial implications of the new prognostic expectations on these patients with the incorporation of new targeted therapies.
•Life project disruption in young women with metastatic breast cancer.•Scarce research and lack of specific QoL questionnaires.•Multidisciplinary holistic approach key to address concerns of young MBC patients.•New therapies extend survival and improve quality of life of MBC patients.•Psychosocial support needs to be adapted to these new prognostic expectations.
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