Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/102987
Title: Penetration and antiviral activity of antiretroviral drugs in the Central Nervous System
Author: Tiraboschi, Juan Manuel
Director: Podzamczer Palter, Daniel
Keywords: VIH (Virus)
Antiretrovirals
Malalties neurodegeneratives
HIV (Viruses)
Antiretroviral agents
Neurodegenerative Diseases
Issue Date: 27-Nov-2015
Publisher: Universitat de Barcelona
Abstract: [eng] INTRODUCTION: With successful treatment and near-normal life expectancy of people living with HIV, the focus of care has shifted towards minimizing toxicity from long term exposure to antiretrovirals (ARVs) and preventing co-morbidities. The prevalence of neurocognitive abnormalities has been reported to remain high, including in patients treated with cART. A low level viral replication in the central nervous system (CNS) may persist even in patients presenting with HIV-1 suppression in plasma, leading to local inflammation, neuronal damage and a poorer neuropsychological performance. A poor penetration of ARV drugs into the CNS may allow local HIV replication and may be associated with asymptomatic and even symptomatic HIV-related neurocognitive impairment or neurologic symptoms, which may be severe and present as HIV encephalitis in some occasions. For this reason we consider it extremely important to conduct research in order to improve the knowledge of the newer antiretroviral drugs penetration into the CNS and so to carry out a pilot study based on these results. HYPOTHESIS: 1. Maraviroc may reach pharmacological concentrations above the IC50 range in the CSF. 2. Maraviroc in combination with other antiretroviral drugs may help to maintain HIV viral suppression in the CSF. 3. Etravirine concentrations in CSF may be low but higher than the IC50. 4. Etravirine in combination with other antiretroviral drugs may help to maintain HIV viral suppression in the CSF. 5. Amprenavir concentrations in CSF may be above the IC50. 6. Fosamprenavir/ritonavir monotherapy may be sufficient to maintain HIV viral suppression in CSF. 7. A treatment switch from tenofovir, emtricitabine and efavirenz to abacavir, lamivudine and maravicoc in patients with neurocognitive impairment may be associated with a reduction on CSF inflammatory markers, CSF HIV RNA and an improvement in their neurocognitive performance. CONCLUSIONS: 1. Maraviroc concentrations in CSF in HIV-infected patients. -In all except 1 CSF sample, MVC concentrations exceeded the median serum- adjusted IC90. -Our data suggest that MVC may contribute to inhibit HIV-1 replication in CNS. -Maraviroc in combination with nucleoside-sparing regimens, including new ARV drugs, seems to be locally active. 2. Etravirine concentrations in CSF in HIV-infected patients -In all samples Etravirine concentrations exceeded the IC50 range. -Our data suggest that Etravirine may contribute to inhibiting HIV-1 replication in the CNS and that combined nucleoside sparing regimens, including new antiretroviral drugs, seem to be locally active. 3. Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy. -Although the high percentage of viral failure with FPV/r monotherapy found in our study, this study is a proof of concept that boosted PI monotherapy could be enough to suppress HIV viral replication in CSF. 4. Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch. -There was a non-statistically significant reduction on the CSF HIV viral load after six months. -A significant reduction on TNF-α would suggest a reduction on local inflammatory reaction following treatment switch. This could be related to a reduction in CSF viral load, the anti-inflammatory effect of Maraviroc or both. -A trend towards an improvement in neurocognitive performance could be related to the above mentioned effects. - A switch to a regimen with a higher CPE score containing MVC was associated with a trend towards an improvement in neuropsychological performance and a reduction in TNF-α. In CSF. GENERAL CONCLUSION. The study of the concentrations and antiviral activity in CSF of the antiretroviral drugs will make possible the design for more effective combinations to be implemented in patients with NCI. A treatment switch can contribute to clinical and virological improvement as well as a reduction in the inflammatory markers.
[spa] INTRODUCCIÓN: En los últimos años diversos estudios han puesto en evidencia la persistencia de trastornos neurocognitivos (TNC) asociados al VIH, siendo en su mayoría formas asintomáticas o leves y moderadas. Si bien son múltiples los factores que favorecen la presencia de TNC en individuos infectados por el VIH (hepatopatía crónica, enfermedad cardiovascular, alcoholismo, uso de drogas, psicofármacos, etc), el virus –que ingresa en el SNC desde los primeros días de la infección- parece jugar un papel importante y ser causa de TNC incluso severos y/o enfermedad neurológica en forma de encefalitis aguda que puede llevar al coma y la muerte. En este contexto, la diferente penetración de los fármacos ARV podría jugar un papel en la prevención, y tratamiento de estas alteraciones. OBJETIVO GENERAL: Generar conocimiento sobre la penetración y actividad de diferentes fármacos antirretrovirales. Utilizar dicha información para poner en práctica una intervención destinada a mejorar la eficacia de una combinación antirretroviral en SNC. HIPÓTESIS: 1. Maraviroc alcanzaría niveles farmacológicos en LCR superiores a la CI50. 2. Maraviroc en combinación con otros fármacos antirretrovirales ayudaría a mantener la supresión viral en LCR. 3. Las concentraciones de Etravirina en LCR serían bajas aunque superiores a la CI50. 4. Etravirina en combinación con otros fármacos antirretrovirales contribuiría a mantener la supresión viral en LCR. 5. Las concentraciones de Amprenavir en LCR serían superiores a la CI50. 6. Fosamprenavir/ritonavir en monoterapia sería suficiente para mantener la supresión viral en LCR. 7. En pacientes que reciben una pauta de emtricitabina/tenofovir/ efavirenz y presentan deterioro neurocognitivo, el cambio a abacavir/lamivudina/maraviroc se asociaría a una disminución de marcadores inflamatorios, carga viral en LCR y a una mejoría en los TNC. CONCLUSIÓN: El estudio de las concentraciones de fármacos antirretrovirales y su actividad en LCR permitirá diseñar con mayor eficacia las pautas a utilizar en pacientes con TNC. Aunque hacen falta estudios más amplios, nuestros datos sugieren un posible beneficio clínico, virológico y de parámetros inflamatorios en pacientes con TNC que cambian a un TAR con mayor penetrabilidad en SNC.
URI: http://hdl.handle.net/2445/102987
Appears in Collections:Tesis Doctorals - Departament - Ciències Clíniques

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