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This is the peer reviewed version of the following article: Bonjoch, A. [et al.]. Prevalence, progression, and management of advanced chronic kidney disease in a cohort of people living with HIV. "HIV Medicine", 26 Abril 2022, vol. 23, núm. 10, p. 1078-1084, which has been published in final form at https://onlinelibrary.wiley.com/doi/10.1111/hiv.13317. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited, Peer Reviewed, Postprint (published version)

Integrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks., The study was supported by Fundació Lluita Contra la SIDA (FLS-ANT 2015-01). IMZ was supported by a P-FIS grant (FI17/00294) and CSM by a Miguel Servet contract (CPII16/00048) from the Instituto de Salud Carlos III. NPA was partially supported by grants MTM2015-64465-C2-1-R (MINECO/FEDER) and 2017 SGR 622 (GRBIO), Peer Reviewed, Postprint (published version)

This is an openaccessarticledistributedunderthe termsof theCreativeCommonsAttributionLicense,whichpermitsunrestricted use, distribution, andreproductionin any medium,providedthe originalauthorand sourceare credited., Objective Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. Design Forty-two PLWH aged =40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. Methods We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks, Results Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of CD28-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. Conclusions The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. Clinical, Peer Reviewed, Ativle signat per 10 autors/es: Eugènia Negredo, Montse Jiménez, Jordi Puig, Cora Loste, Núria Pérez-Álvarez, Victor Urrea, Patricia Echeverría, Anna Bonjoch, Bonaventura Clotet, Julià Blanco, Postprint (published version)

Departament responsable de la tesi: Departament de Medicina., El enfoque exclusivamente biomédico en el abordaje de las enfermedades es una estrategia que se ha mostrado insuficiente en muchas ocasiones, especialmente en aquellas patologías que conllevan una carga de estigma y discriminación como la infección por el virus de la inmunodeficiencia humana (VIH) o, en determinados subgrupos poblacionales tales como los usuarios de drogas intravenosas, la causada por el virus de la hepatitis C (VHC). Por ello, identificar el impacto de factores biopsicosociales sobre el estado de salud de las personas con el VIH y/o el VHC puede ser una herramienta capaz de favorecer el cambio de paradigma que supondría el paso del abordaje exclusivamente biomédico a un abordaje multidisciplinar que supondría un enfoque biopsicosocial.La primera parte de la investigación de la presente tesis se centró en identificar factores de tipo biopsicosocial que condicionaran diferentes aspectos relativos al estado de salud de la monoinfección por el VIH o la coinfección por VIH y VHC en una muestra de pacientes atendidos en dos hospitales de Barcelona y área metropolitana.La segunda parte -vehiculizada a través de un sondeo online con participantes de toda España- analizó el impacto de los factores biopsicosociales en un subgrupo de personas con el VIH particularmente sensible como es el de las personas que envejecen por, entre otras razones, las comorbilidades y necesidades de apoyo social que se van acumulando durante el proceso de envejecimiento.La última parte -también realizada a través de un sondeo online con participación de personas de toda España- se centró en el papel de los factores biopsicosociales en el campo de la hepatitis C.Los hallazgos obtenidos durante las tres fases de investigación han permitido determinar aquellos perfiles de personas con el VIH y/o el VHC con una mayor tendencia a tener un peor estado de salud en base a diversos factores de tipo biopsicosocial. Así, las personas con más de 45 años, los inmigrantes, las personas coinfec, The exclusively biomedical approach to dealing with diseases is a paradigm that has proven insufficient on many occasions, especially in those pathologies that carry a burden of stigma and discrimination, such as infection with the human immunodeficiency virus (HIV) or -in certain population subgroups such as intravenous drug users - that caused by the hepatitis C virus (HCV). For this reason, identifying the impact of biopsychosocial factors on the health status of people with HIV and / or HCV can be a tool capable of favoring the paradigm shift that would imply moving from the exclusively biomedical approach to the multidisciplinary approach that would involve a biopsychosocial approach. The first part of the research in this thesis focused on identifying biopsychosocial factors that condition the response to antiretroviral treatment and / or the clinical symptoms of HIV monoinfection or HIV and HCV coinfection in a sample of patients treated in two hospitals in Barcelona and the metropolitan area. The second part -developed through an online survey with participants from all Spain- analyzed the impact of biopsychosocial factors on a subgroup of people with HIV particularly sensitive as is the case of older people due to, among other reasons, comorbidities and social support needs that accumulate during the aging process. The last part -also carried out through an online survey with the participation of people from all over Spain- focused on the role of biopsychosocial factors in the field of hepatitis C. The findings obtained during the three phases of research have allowed to determine those profiles of people with HIV and / or HCV with a greater tendency to have a worse state of health based on various biopsychosocial factors. Thus, people over 45, immigrants, coinfected people, those who have experienced discrimination, those with chronic pain, those who are not involved in decisions about their health, those with a pessimistic approach, people with symptomati

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of antimicrobial chemotherapy following peer review. The version of record Negredo, E., Langohr, K., Bonjoch, A., Perez, N., Estany, C., Puig, J., Echevarría, P., Clotet, B., Gómez Melis, G. High risk and probability of progression to osteoporosis at 10 years in HIV-infected individuals: the role of PIs. "Journal of antimicrobial chemotherapy", 1 Setembre 2018, vol. 73, núm. 9, p. 2452-2459 is available online at: https://academic.oup.com/jac/article-abstract/73/9/2452/5026321., Peer Reviewed, Postprint (author's final draft)

Kidney injury (defined as the presence of albuminuria, proteinuria, glycosuria [without hyperglycemia], hematuria, and/or renal hypophosphatemia) is an emerging problem in human immunodeficiency virus (HIV)-infected patients, although few data are available on the role of protease inhibitors (PIs) in this condition. To determine the time to kidney injury in a cohort of HIV-infected patients receiving a PI-containing regimen. We report the results of a subanalysis of a published cross-sectional study. The subanalysis included only patients receiving PI-containing regimens for more than 6 months (377 of the overall 970 patients). We determined associated factors and constructed receiver operating characteristic curves to estimate time to kidney injury depending on the PI used. The percentage of patients with kidney injury was 27.7% for darunavir, 27.9% for lopinavir, and 30% for atazanavir. Time to kidney injury was as follows: 229 days for atazanavir/ritonavir (area under the curve [AUC], 0.639; sensitivity, 0.89; specificity, 0.41); 332 days for atazanavir/ritonavir plus tenofovir (AUC, 0.603; sensitivity, 0.75; and specificity, 0.29); 318 days for nonboosted atazanavir (AUC, 0.581; sensitivity, 0.89; and specificity, 0.29); 478 days for lopinavir/ritonavir (AUC, 0.566; sensitivity, 0.864; and specificity, 0.44); 1339 days for lopinavir/ritonavir plus tenofovir (AUC, 0.667; sensitivity, 0.86; and specificity, 0.77); 283 days for darunavir/ritonavir (AUC, 0.523; sensitivity, 0.80; and specificity, 0.261); and 286 days for darunavir/ritonavir plus tenofovir (AUC, 0.446; sensitivity, 0.789; and specificity, 0.245). The use of lopinavir/ritonavir without tenofovir was a protective factor (odds ratio = 1.772; 95% CI, 1.070-2.93; P = 0.026). For all PIs, the percentage of patients with kidney injury exceeded 27%, irrespective of tenofovir use. The longest time to kidney injury was recorded with lopinavir/ritonavir. These results demonstrate the need for renal monitoring, Peer Reviewed, Postprint (published version)

Background. Prospective studies about the reversibility of tenofovir disoproxil fumarate- (TDF-) related renal impairment remain scarce. Methods. This is an observational prospective study including all patients that presented at our HIV Unit who interrupted TDF owing to nephrotoxicity. We assessed the evolution of renal parameters after discontinuation of this drug. Results. We included 59 patients, who were followed up for 72 weeks. Most were male (41, 69.5%), median (IQR) age was 53 (44; 58) years, and median time receiving TDF-containing regimens was 55.4 (28; 87.7) months. Most patients were receiving PI-based treatments (67%). At the final visit, most of the subjects showed complete recovery (35, 59.3%) or improvement (13 subjects, 22%). Significant improvements were observed in creatinine levels (from 84.9 [73.8; 97.5] to 78 [69.6; 91] mu mol/L, p = 0.013), estimated glomerular filtration rate (eGFR, CKD EPI equation, from 87.7 [67; 99] to 89.9 [73.6; 99.3] mL/min/1.73 m(2), p = 0.017), and number of patients with eGFR <60 mL/min/1.73 m(2) (from 9 [15.3%] to 1 [1.7%], p = 0.031). A trend toward significance was observed in abnormal urine proteinuria/creatinine ratio (from 22 [37%] to 8 [13.6%], p = 0.057). Conclusions. Our results corroborate the high frequency of complete or partial renal recovery in patients receiving TDF-containing regimens who discontinued therapy owing to nephrotoxicity., Peer Reviewed, Postprint (published version)

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600–1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care., Peer Reviewed, Postprint (published version)

La incidencia de la enfermedad cardiovascular (ECV) se ha incrementado en los pacientes infectados por el VIH. La replicación del VIH y la terapia antirretroviral pueden contribuir de forma independiente al aumento del riesgo de ECV. Sin embargo, la causa de este aumento del riesgo es multifactorial. Métodos: Esta tesis se centra en el estudio de los trastornos metabólicos y cardiovasculares en una cohorte de pacientes infectados por el VIH. Para ello, se llevaron a cabo tres estudios: Un primer estudio, diseñado con el propósito de determinar si un análisis combinado de variantes genéticas en algunos de los genes responsables de las anomalías lipídicas ayudarían a discriminar los pacientes infectados por el VIH con niveles altos de triglicéridos y bajos niveles de HDL-colesterol (pacientes con perfil aterogénico), considerado un marcador claro de riesgo cardiovascular. Para ello, se realizó la caracterización genética y metabólica de 321 pacientes infectados por el VIH en tratamiento antirretroviral, a través de la determinación del perfil lipídico, la determinación de partículas remanentes de colesterol y la determinación de los genes implicados en la formación y en la eliminación de partículas remanentes de la circulación. Se identificaron varios genes responsables de la modulación de los parámetros lipídicos en esta población. Sin embargo, el diseño transversal del estudio y el pequeño tamaño de la muestra no permitió conclusiones definitivas acerca de la asociación entre polimorfismos en los genes asociados con el metabolismo de los lípidos y los trastornos de lípidos en pacientes infectados por el VIH. El segundo estudio, se centró en la detección precoz de la aterosclerosis subclínica. Para ello, se evaluó la elasticidad arterial a través de la determinación de la velocidad de la onda de pulso (VOP) en pacientes infectados por el VIH, en comparación con sujetos no infectados. Se identificaron factores de riesgo asociados con la alteración de la elasticidad ar, The incidence of cardiovascular disease (CVD) has increased among HIV-infected patients. Both HIV replication and antiretroviral therapy may contribute independently to increase the risk of CVD. However, the cause of this increased risk is multifactorial. Methods: This thesis focuses on the study of metabolic and cardiovascular disorders in a cohort of HIV-infected patients. Three studies were conducted: A first study was designed with the purpose of ascertaining whether a combined analysis of several genetic variants in some of the genes responsible of lipid abnormalities helped discriminate HIV-infected patients with high triglycerides and low levels of HDL-cholesterol (patients with atherogenic profile), clear marker of cardiovascular risk. It was carried out metabolic and genetic characterization of 321 HIV-infected patients receiving antiretroviral therapy, through the determination of the lipid profile, determination of remnant cholesterol particles and determination of genes involved in the formation, as in removing remaining particles from circulation. Several genes responsible for modulation of lipid parameters in this population were identified. However, the cross-sectional design of the study and the small sample size does not allow definitive conclusions about the association between polymorphisms in genes associated with lipid metabolism and lipid disorders in HIV-infected patients. The second study focused on the early detection of subclinical atherosclerosis. For this, arterial elasticity was evaluated through the determination of the pulse wave velocity (PWV) in HIV-infected patients, compared to non-infected subjects. Risk factors associated with impaired arterial compliance were identified. HIV-infected patients with virologic suppression showed similar arterial elasticity than non-infected subjects. HIV-related conditions were not associated with arterial stiffness. However, high diastolic pressure at the time of the PWV and high triglycerides wer

La generalització del tractament antiretroviral de gran activitat (TARGA) va canviar profundament la perspectiva de la infecció pel VIH-1. Amb la incorporació de nous agents terapèutics es va fer possible el control de la replicació viral, el que va repercutir en un allargament en la perspectiva vital dels pacients infectats pel VIH-1. Com a conseqüència el mantenir una bona adherència al tractament va esdevenir de vital importància, així com l'establiment de pautes de tractament que fossin el suficientment senzilles per a ser portades a terme de manera continuada. La tesi s'ha estructurat en tres grans escenaris: pacients amb experiència antiretroviral limitada; pacients en fracàs virològic i sense possibilitats de dissenyar una pauta supressora; pacients que han aconseguit el control de la replicació viral, però amb una llarga experiència antiretroviral i sota una pauta de que conté enfuvirtida. En els primer dels articles, la diana poblacional foren pacients sota el seu primer TARGA, sense antecedents de teràpies subòptimes anteriors, i en supressió viral continuada als què se'ls simplificà la teràpia a una pauta contenint exclusivament anàlegs a la transcriptasa. Es van incloure un total de 134 pacients als què s'aleatoritzà a canviar tractament a Trizivir ® (grup experimental) o nevirapina més dos anàlegs (grup control). Els resultats va mostrar la no inferioritat de la branca experimental quant al control de la replicació vírica i una tolerància i satisfacció vers la teràpia superior en la branca experimental respecte a la branca control i al moment basal. Dels dos següents treballs presentats com a part de la tesi en pacients altament pretractats en fracàs terapèutic, es conclou que, en pacients amb virus multiresistent que presenten mutacions associades a resistència als anàlegs de nucleòsids (TAMS i M184V), i sense possibilitat de porta a terme un tractament plenament actiu, un règim de transició amb Trizivir® i tenofovir es mostra segur. Aquesta afirmació, The generalization of highly active antiretroviral therapy (HAART) radically changed the perspective of HIV-1. With the addition of new therapeutic agents made possible the control of viral replication which resulting in greater control of clinical progression and a lengthening in life perspective of patients infected by HIV-1, being of vital importance that the established treatment for infection control was carried out continuously. The thesis is structured in three main areas of action, the first one, represented in the first article, is the establishment of simplification strategies in patients with limited antiretroviral experience. Secondarily explored the possibilities of simplifying therapy in patients with virologic failure and unable to devise a suppressive regimen. A third area of action, in patients on long-lasting viral suppression, but with a long experience and under complex antiretroviral rescue treatment containing enfuvirtide, we assessed the possibility of discontinuing this drug. In the first article submitted as part of this doctoral thesis, the target population was patients undergoing their first HAART with no history of previous suboptimal therapy, and on continued viral suppression. These patients were simplified to a pattern containing only NRTIs. We included a total of 134 patients who were randomized to change the previous treatment for Trizivir ® (experimental group) or nevirapine plus two NRTIs (control group). The results showed non-inferiority of the experimental arm in terms of controlling viral replication and tolerance to the therapy and higher satisfaction in regard to the experimental arm versus the control arm and from baseline. The next two papers were carrying out in heavily pretreated patients on viral failure. It is concluded that in patients with multidrug-resistant viruses that have mutations associated with resistance to nucleoside analogues (TAMS and M184V) and carries no possibility of fully active after treatment, tran

Consultable des del TDX, Títol obtingut de la portada digitalitzada, El tratamiento antirretroviral de alta eficacia ha reducido drásticamente la morbi-mortalidad de los pacientes con infección por el VIH al conseguir una supresión mantenida del virus. Sin embargo, la erradicación de éste es aún un objetivo a alcanzar y por tanto, por el momento, la terapia antirretroviral debe mantenerse de forma indefinida. Esto lleva a la aparición de un gran número de efectos adversos asociados al tratamiento antiviral, que en muchos casos son el motivo principal de un mal cumplimiento y del rechazo a la medicación antiviral o de interrupciones de la misma. Así pues, es necesario investigar sobre los mecanismos de producción de estos efectos secundarios, así como investigar nuevas estrategias terapéuticas para su prevención y nuevas combinaciones menos complejas para asegurar un correcto cumplimiento del tratamiento a largo plazo. Entre los efectos secundarios que en la actualidad están motivando más estudios destacan los cambios en la redistribución de la grasa corporal, las alteraciones del metabolismo lipídico y la resistencia a la insulina. En la primera parte de nuestro proyecto presentamos una revisión exhaustiva de estos trastornos, sus características clínico-analíticas, su prevalencia, así como sus posibles causas y mecanismos etiopatogénicos. Posteriormente se describen los objetivos, el diseño y los resultados de nuestros propios trabajos de simplificación. Los dos primeros trabajos presentados estudian la eficacia virológica-inmunológica y la seguridad de pautas de simplificación cuando se sustituyen los inhibidores de la proteasa (IP) por inhibidores de la transcriptasa inversa no análogos a nucleósidos (ITINAN). Ambos estudios, randomizados y prospectivos, demuestran una potencia antiviral similar entre las combinaciones que incluyen ITINANs y los que incluyen IPs. Sin embargo, las pautas basadas en ITINAN se asocian a una menor toxicidad metabólica y a una significativa mejoría de la calidad de vida por la mayor simplicidad de las, The eradication of HIV infection is unattainable at present in the clinical setting despite the initial expectations derived from the ability of highly active antiretroviral therapy (HAART) to profoundly suppress viral replication and to limit morbidity and mortality of HIV/AIDS disease. Consequently, antiretroviral treatment has to be maintained for life, once it is initiated. This derives in the occurrence of adverse events such as lipodystrophy syndrome and metabolic disturbances (dyslipemia and insuline resistance) that are often cumulative. Additionally, this toxicity often leads to a bad adherence or to treatment interruptions. For these reasons, it is necessary to assess the etiopathogenic mechanism of these abnormalities and to design strategies to prevent or to revert them. Likewise, simpler antiretroviral combinations should be provided to assure a properly long-term adherence. Metabolic HAART-related toxicity has been described in the first part of our project including its characteristics, prevalence, aetiology and its possible pathogenic mechanism. The second part summarizes the results of three different simplification studies conducted in our HIV Unit. Two of these trials find out the antiviral efficacy and safety of different simplification approaches where the protease inhibitors (PI) were replaced by a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or efavirenz. These prospective randomised studies showed a similar antiviral potency between PIs and NNRTIs-containing regimens. Combinations including NNRTIs, mainly nevirapine, were associated with less metabolic toxicity and with an improvement in quality of life. In addition, a similar antiviral potency between both commercialised NNRTIs, nevirapine and efavirenz, was demonstrated in one of these studies for first time in a comparative randomised study. Finally, the third trial was designed to evaluate in detail the qualitative and quantitative changes on lipids and lipoproteins

Consultable des del TDX, Títol obtingut de la portada digitalitzada, El tratamiento antirretroviral de alta eficacia ha reducido drásticamente la morbi-mortalidad de los pacientes con infección por el VIH al conseguir una supresión mantenida del virus. Sin embargo, la erradicación de éste es aún un objetivo a alcanzar y por tanto, por el momento, la terapia antirretroviral debe mantenerse de forma indefinida. Esto lleva a la aparición de un gran número de efectos adversos asociados al tratamiento antiviral, que en muchos casos son el motivo principal de un mal cumplimiento y del rechazo a la medicación antiviral o de interrupciones de la misma. Así pues, es necesario investigar sobre los mecanismos de producción de estos efectos secundarios, así como investigar nuevas estrategias terapéuticas para su prevención y nuevas combinaciones menos complejas para asegurar un correcto cumplimiento del tratamiento a largo plazo. Entre los efectos secundarios que en la actualidad están motivando más estudios destacan los cambios en la redistribución de la grasa corporal, las alteraciones del metabolismo lipídico y la resistencia a la insulina. En la primera parte de nuestro proyecto presentamos una revisión exhaustiva de estos trastornos, sus características clínico-analíticas, su prevalencia, así como sus posibles causas y mecanismos etiopatogénicos. Posteriormente se describen los objetivos, el diseño y los resultados de nuestros propios trabajos de simplificación. Los dos primeros trabajos presentados estudian la eficacia virológica-inmunológica y la seguridad de pautas de simplificación cuando se sustituyen los inhibidores de la proteasa (IP) por inhibidores de la transcriptasa inversa no análogos a nucleósidos (ITINAN). Ambos estudios, randomizados y prospectivos, demuestran una potencia antiviral similar entre las combinaciones que incluyen ITINANs y los que incluyen IPs. Sin embargo, las pautas basadas en ITINAN se asocian a una menor toxicidad metabólica y a una significativa mejoría de la calidad de vida por la mayor simplicidad de las, The eradication of HIV infection is unattainable at present in the clinical setting despite the initial expectations derived from the ability of highly active antiretroviral therapy (HAART) to profoundly suppress viral replication and to limit morbidity and mortality of HIV/AIDS disease. Consequently, antiretroviral treatment has to be maintained for life, once it is initiated. This derives in the occurrence of adverse events such as lipodystrophy syndrome and metabolic disturbances (dyslipemia and insuline resistance) that are often cumulative. Additionally, this toxicity often leads to a bad adherence or to treatment interruptions. For these reasons, it is necessary to assess the etiopathogenic mechanism of these abnormalities and to design strategies to prevent or to revert them. Likewise, simpler antiretroviral combinations should be provided to assure a properly long-term adherence. Metabolic HAART-related toxicity has been described in the first part of our project including its characteristics, prevalence, aetiology and its possible pathogenic mechanism. The second part summarizes the results of three different simplification studies conducted in our HIV Unit. Two of these trials find out the antiviral efficacy and safety of different simplification approaches where the protease inhibitors (PI) were replaced by a non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine or efavirenz. These prospective randomised studies showed a similar antiviral potency between PIs and NNRTIs-containing regimens. Combinations including NNRTIs, mainly nevirapine, were associated with less metabolic toxicity and with an improvement in quality of life. In addition, a similar antiviral potency between both commercialised NNRTIs, nevirapine and efavirenz, was demonstrated in one of these studies for first time in a comparative randomised study. Finally, the third trial was designed to evaluate in detail the qualitative and quantitative changes on lipids and lipoproteins