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Objectives: Our aim is to describe the impact of emtricitabine (FTC)/tenofovir (TDF) versus other nucleoside reverse transcriptase inhibitor (NRTIs)-based regimens on renal function of human immunodeficiency virus (HIV) naiive patients >50 years old who started combination antiretroviral therapy (cART). Design: National, retrospective cohort analysis of patients >50 years old when they started cART (January 1, 2006-December 31, 2009). Methods: We compared renal safety (changes in estimated glomerular filtration rate [eGFR] during the first year, and time to renal events during 4 years of follow-up) in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitors vs non-nucleoside reverse transcriptase inhibitors and Lopinavir/ritonavir vs Efavirenz. Results: We included 103 patients: median age: 54.9 years, 84% males, median CD4 count 247 cells/mu l, median viral load 4.7 log; median follow up 18 months (max: 48 months); 73 started with FTC/TDF and 30 with other NRTIs. Change in eGFR was significantly worse for ritonavir-boosted lopinavir (LPV/r) vs efavirenz (EFV) users in the FTC/TDF group (71.2 vs 98.9 ml/min/1.73 m(2) at month 12, P= 50 years old, renal safety was similar for FTC/TDF and other NRTI-based regimens, but worse for LPV/r as compared to other regimens.

Despite having demonstrated noninferior efficacy against atazanavir/ritonavir plus coformulated tenofovir/emtricitabine (cTDF/FTC), the combination of nevirapine plus cTDF/FTC is not included among preferred regimens in some international guidelines. This combination is frequently used in Spain. We analyzed its effectiveness and safety as first-line therapy in a routine clinical practice. A retrospective, multicenter study was performed in treatment-naive HIV-1-infected subjects who started nevirapine plus cTDF/FTC as first-line therapy according to the nevirapine CD4(+) cell count threshold. The primary endpoint was the proportion of subjects with plasma HIV-1 RNA

Objective: Currently, 12% of the Spanish population is foreign-born, and a third of newly diagnosed HIV-infected patients are immigrants. We determined whether being an immigrant was associated with a poorer response to antiretroviral treatment. Methods: Historical multicenter cohort study of naive patients starting HAART. The primary endpoint was time to treatment failure (TTF) defined as virological failure (VF), death, opportunistic disease, treatment discontinuation (D/C), or missing patient. Secondary endpoints were TTF expressed as observed data (TFO; censoring missing patients) and time to virological failure (TVF; censoring missing patients and D/C not due to VF). A multivariate analysis was performed to control for confounders. Results: A total of 1090 treatment-naive HIV-infected patients (387 immigrants and 703 autochthonous) from 33 hospitals were included. Most immigrants were from Sub-Saharan Africa (28.3%) or South-Central America/Caribbean (31%). Immigrants were significantly younger (34 y vs 39 y), more frequently female (37.5% vs 24.6%), with less HCV coinfection than autochthonous patients (7% vs 31.3%). There were no differences in baseline viral load (4.95 Log(10) vs 4.98 Log(10)), CD4 lymphocyte count (193.5/mu L vs 201.5/mu L), late initiation of HAART (56.4% vs 56.0%), or antiretrovirals used. Cox-regression analysis (HR; 95%CI) did not show differences in TTF (0.89; 0.66-1.20), TFO (0.95; 0.66-1.36), or TVF (1.00; 0.57-1.78) between immigrants and autochthonous patients. Losses to follow-up were more frequent among immigrants (17.8% vs 12.1; p=0.009). Sub-Saharan African patients and immigrant females had a significantly shorter TTF. Conclusions: The response to HAART among immigrant patients was similar to that of autochthonous patients, although they had a higher rate of losses to follow-up. Sub-Saharan Africans and immigrant females may need particular measures to avoid barriers hindering antiviral efficacy. 1.923 JCR (2010) Q3, 23/33 Virology; Q4, 103/134 Immunology, 44/58 Infectious Diseases

Objetivo estudiar las caracteristicas de la infeccion por el VIH en gitanos en Espana, en comparacion con las de la mayoria caucasica no gitana (CNG). Metodos estudio transversal y de cohortes historicas en la Cohorte VACH. Clasificamos a los pacientes que acudieron a las clinicas participantes en VACH entre el 1 de junio de 2004 y el 30 de noviembre de 2004 de acuerdo a su raza y etnia, como «gitanos», «nativos espanoles CNG» u «otros» (estos, excluidos de este estudio). Comparamos sus caracteristicas sociodemograficas y clinicoepidemiologicas, asi como sus curvas de Kaplan�Meier del tiempo hasta sida, muerte o progresion de la enfermedad (cualquiera de ambos). Resultados 4819 (48%) de 10.032 casos recogidos en la base de datos de VACH fueron incluidos en el estudio: 210 (4,2%) eran gitanos y 4.252 (84,8%) eran nativos CNG. Observamos diferencias en sus distribuciones por edad, domicilio, estudios, antecedentes penales, situacion laboral y marital. La inyeccion de drogas habia sido el mecanismo de transmision del VIH mas frecuente en los dos grupos, pero mas marcadamente en los gitanos (72% frente a 50%; p

Background Although efavirenz and lopinavir/ritonavir(r) are both recommended antiretroviral agents in antiretroviral-naive HIV-infected patients, there are few randomized comparisons of their efficacy and tolerability. Methods A multicenter and randomized study was performed including 126 antiretroviral-naive patients, randomly assigned to efavirenz + Kivexa ® ( n = 63) or lopinavir/r + Kivexa ® ( n = 63). Efficacy endpoints were the percentage of patients with HIV-RNA ≤50 copies/mL at week 48 and CD4 recovery. Safety was assessed by comparing toxicity and discontinuations. Statistical analyses were performed on an intention-to-treat (ITT) basis (Missing = Failure). Results At week 48, 56.7% of patients in the efavirenz and 63.2% in the lopinavir/r groups showed HIV-1 RNA P = 0.770) (intention-to-treat analysis; Missing = Failure). Only 1 (1.53%) patient from each group experienced virological failure. CD4 values increased in both groups (298 cells in the efavirenz group, P = 0.001; 249 cells in the lopinavir/r group, P = 0.002; P = 0.126 between groups). HDL-cholesterol only increased in the efavirenz group (from 39 ± 12 mg/dL to 49 ± 11; P = 0.001). Discontinuations were more frequent in the lopinavir/r group (36.5% versus 28.5%; P = 0.193), but more patients with efavirenz interrupted due to toxicity (11.1% versus 6.3%); most of them were attributed to hypersensitivity reaction. Conclusions Similar virological efficacy was observed for efavirenz and lopinavir/r, when administered with Kivexa ® in antiretroviral-naive patients, while immunological improvement was slightly superior for efavirenz. The higher rate of discontinuation due to toxicity in the efavirenz group was related to a higher incidence of hypersensitivity reaction. Nowadays, the use of the new formulation of lopinavir/r and the HLA-B*5701 genotype test before starting abacavir should improve the safety profiles of these regimens.

Background: Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities. Methods: We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry. Results: Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls. Conclusions: HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content.

Objectives: The aim of this study was to assess the influence of hepatitis B virus or hepatitis C virus co-infection and the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics in HIV-infected subjects without liver function impairment. Methods: A cross-sectional, comparative study enrolling HIV-infected adults receiving saquinavir/ ritonavir 1000/100 mg twice daily or 1500/100 mg once daily was conducted. Patients with chronic viral hepatitis (HEP+) were grouped as having advanced liver fibrosis (HEP+/FIB+) or not (HEP+/FIB-) based on the FIB-4 index. Saquinavir and ritonavir trough concentrations (C trough ) in plasma were determined by HPLC. The geometric mean ratio (GMR) was used to compare saquinavir and ritonavir C trough between HEP― and HEP+ patients, and the influence of the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics was explored using analysis of variance. Results: One hundred and thirty-eight patients on twice-daily saquinavir/ritonavir (67 HEP―, 71 HEP+) and 36 patients on once-daily saquinavir/ritonavir (12 HEP―, 24 HEP+) were included. Saquinavir C trough was comparable between HEP― and HEP+ patients receiving either saquinavir/ritonavir 1000/ 100 mg twice daily [GMR 0.91, 95% confidence interval (CI) 0.60―1.37; P=0.655] or 1500/100 mg once daily (GMR 0.88, 95% CI 0.39―1.97; P=0.752). Similarly, ritonavir C trough was also comparable between HEP― and HEP+ patients. The extent of liver fibrosis was not significantly related to saquinavir or ritonavir C trough in patients receiving either of the two studied doses. Conclusions: Saquinavir C trough was not increased in HIV-infected patients with chronic viral hepatitis in the absence of liver function impairment. These results confirm that no specific dose modification of saquinavir/ritonavir should be recommended in this setting.

Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients. We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason. Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir((R))) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change = failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3-56.8 months) among patients on didanosine/lamivudine/efavirenz and 33.3 months (95% CI 25.6-41.1 months) in patients treated with zidovudine/lamivudine/efavirenz (P = 0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/lamivudine/efavirenz. Our data suggest that didanosine/lamivudine/efavirenz is a combination with an efficacy comparable to zidovudine/lamivudine/efavirenz as first-line therapy for HIV infection. The risk of treatment change was significantly higher among patients treated with zidovudine/lamivudine/efavirenz than in those starting therapy with didanosine/lamivudine/efavirenz.

Background The aim of this study was to analyze the incidence of new cases, survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy (PML), and the characteristics of PML-associated immune reconstitution inflammatory syndrome (IRIS). Methods Multicenter observational cohort study of all HIV-1-infected patients newly diagnosed of PML in 7 hospitals in Barcelona (Spain) from 2002 to 2006. The annual incidence of PML was calculated. Survival was estimated using the Kaplan-Meier method. IRIS was defined as new onset or rapid worsening of PML shortly after initiation of highly active antiretroviral therapy together with a decline in HIV-1 viral load and rising of CD4 lymphocytes. Results Sixty-one new cases of PML were diagnosed. The mean survival time was 15 months [95% confidence interval (CI), 11 to 19]. The Kaplan-Meier estimates of the probability of survival were 47.7% (95% CI, 35 to 59) at 6 months, 38.6% (95% CI, 25 to 51) at 12 months, 35.1% (95% CI, 22 to 48) at 24 months, and 25.1% (95% CI, 10 to 40) at 36 months. IRIS was diagnosed in 14 (23%) cases. Mortality was similar in patients with and without IRIS. Conclusions PML continues to be one of the deadliest opportunistic infections in acquired immunodeficiency syndrome patients. The development of PML-associated IRIS has no influence on prognosis.

We evaluated a single-class quadruple nucleoside/nucleotide regimen in a 96-week prospective one-arm pilot study in adult HIV-infected naive patients with CD4100 cells/microl. Standard zidovudine/lamivudine/abacavir and tenofovir doses were given. Virologic efficacy was evaluated by intent-to-treat (ITT), switch = failure and on-treatment (OT) analyses. A total of 54 patients were included (median CD4 count 254 cells/microl, VL 79,706 copies/ml). A median drop in VL of 2 log at 14 days and3 log since week 12 was observed. A total of 34/54 (63%) patients (ITT) and 34/39 (87%) patients (OT) had VL50 copies/ml at 96 weeks. Four (7%) patients switched therapy due to adverse events, 5 (9%) had virologic failure, and 1 died. Similar efficacy results were observed irrespective of baseline VL (or5 log) or CD4 cells (or250/microl). A median CD4 gain of +223 cells/microl was achieved. K65R + 41L + 219Q were detected in one patient at virologic failure. Only two patients presented fat loss on clinical evaluation. A decrease in total cholesterol (p = 0.007) and LDLc (p = 0.016) was observed. Our data suggest that zidovudine/lamivudine/abacavir plus tenofovir is a simple, effective, and well-tolerated NNRTI/PI-sparing regimen, even for patients with high viral loads. Larger trials comparing this option with standard initial antiretroviral regimens should be conducted.

Background The use of HAART combining 2 nucleoside analogues reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor (PI) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) has shown comparable efficacy. The study was designed to compare long term (2 years) effectiveness of two antiretroviral (ARV) treatment strategies in patients not previously treated: starting with a nelfinavir based HAART switching to nevirapine in case of failure or side effects or the reverse sequence. Methods This multicenter, randomized, open label clinical trial enrolled ARV-naive HIV patients with CD4 counts below 500 cells/mm3. They were randomly assigned to start ddI + d4T + nelfinavir (switching to ZDV + 3TC + NEV in case of failure or toxicity) (PI-NEV arm) or ddI + d4T + nevirapine, switching to ZDV + 3TC + NFV in case of failure or toxicity (NEV-PI arm). The primary study endpoint was the Kaplan-Meier estimates of the time to failure after switching to second regimen if necessary (considering failure as two consecutive plasma HIV-1 RNA determinations above 200 copies/mL, death, a new category C event or toxicity leading to treatment discontinuation of the second regimen) after a minimum follow-up of two years. Results A total of 137 patients were evaluable (67 and 70 in the PI-NEV and NEV-PI arms respectively). Baseline characteristics did not differ among groups. Kaplan-Meier estimates of time to failure did not show differences between the two arms neither in the on-treatment (OT) analysis (log rank test, p = 0.81) nor in the intent-to-treat (ITT) analysis (p = 0.58). At 24 months, the estimated proportion of patients free of failure were 72% and 66% respectively in the PI-NEV and NEV-PI arms OT analysis (p = 0.54) and 73% and 64% in the PI-NEV and NEV-PI arms in the ITT analysis (p = 0.49). The difference in the median in CD4+ lymphocyte count at 24 months was not significantly different in the two groups: 393 and307 CD4 cells/mm3 in the PI-NEV and NEV-PI arms respectively (p = 0.167). The incidence of adverse events (AEs) in the two arms was very similar: 50 (75%) in the PI-NEV and 54 (70%) in the NEV-PI group, as it was for grade 3-4 AEs leading to drug switching. Conclusion At two years both treatments strategies (PI-NEV vs NEV-PI) had a high and comparable efficacy and were generally well tolerated.

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31-51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85-7.78, p0.001), first-line treatment (OR: 3.02, 95% CI: 1.52-6.00, p = 0.002), and baseline CD4 cells400 cells/microl (OR: 2.34, 95% CI: 1.22-4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.

Background and Objectives: The influence of the polymorphisms of the CX3CR1 chemokine receptor gene on the natural history of HIV-1 infection is controversial. This study aimed to determine whether functionally active CX3CR1 genetic variants are associated with long-term nonprogressive infection of > 15 years in HIV-1-infected Spanish patients. Patients and Methods: Two single-nucleotide polymorphisms, V249I (G > A) and T280M (C > T), of the CX3CR1 gene were assessed in 271 Spaniards. These included 60 HIV-1-infected patients who were long-term nonprogressors (LTNPs) of > 15 years, 109 HIV-1-infected patients who were usual progressors (UPs), and 102 control subjects. The CCR5Δ32 was also assessed. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods on white cell DNA. Genotype and allele frequencies were compared by the χ 2 test and the Fisher exact test. Results: The frequencies of the 249I variant allele were 42% for LTNPs, 24.5% for UPs, and 35% for healthy controls; the differences between LTNPs and UPs were significant (odds ratio 0.46; 95% CI: 0.27 to 0.75; P = 0.0017). For 280M the distribution was 16% for LTNPs, 14% for UPs, and 17% for healthy controls (P = NS). The haplotype 249I280T was significantly more common in LTNPs than in UPs (P = 0.0007). These results persisted after excluding from the analysis the individuals carrying the CCR5Δ32. Conclusions: CX3CR1 249I variant allele is more frequent in Spanish HIV-1-infected LTNPs of > 15 years. This effect is independent of the presence of the CCR5Δ32 allele.

To investigate the effects of HIV infection on mitochondrial DNA (mtDNA) content and other mitochondrial parameters, we used peripheral blood mononuclear cells (PBMCs) from 25 asymptomatic antiretroviral-naive human immunodeficiency virus (HIV)-infected patients and from 25 healthy control subjects. HIV-infected patients had significant decreases in mtDNA content (decrease, 23%; P

The aim of the study was to assess differences in health-related quality of life (HRQoL) in HIV-infected naive patients treated with two HAART regimens at 12 months.The MOS-HIV questionnaire was used to measure HRQoL in a subgroup of 127 patients included in the COMBINE study, which was an open-label, randomized, multicenter study comparing zidovudine (ZDV) and lamivudine (3TC) plus nelfinavir (NFV) or nevirapine (NVP) regimens in HIV-infected naive patients. 63 patients were included in the ZDV/3TC/NFV arm and 64 in the ZDV/3TC/NVP arm.No statistically significant differences were observed at baseline in demographic and clinical variables and HRQoL scores between treatment groups, except that the proportion of homosexual men was higher in the ZDV/3TC/NVP arm. There were no statistically significant differences in HRQoL scores between arms at 12 months and over time; only ZDV/3TC/NVP patients showed statistically significant improvement in Physical Health Summary score (p.01) and a trend toward a better profile in Mental Health Summary score (p =.07). Overall, patients who were treated with ZDV/3TC/NVP showed greater changes in physical dimensions and patients who were treated with ZDV/3TC/NFV showed greater changes in mental health.Differences in HRQoL between study groups at 1 year follow-up were not detected. Nevertheless, a trend toward improvement was observed in summary health scores in ZDV/3TC/NVP-treated patients.

We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved.We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter.At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients. Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups.When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.

The importance of the metabolic disorders and their impact on patients with HIV infection requires an individualized study and continuous updating. HIV patients have the same cardiovascular risk factors as the general population. The HIV infection per se increases the cardiovascular risk, and metabolic disorders caused by some antiretroviral drugs are added risk factors. For this reason, the choice of drugs with a good metabolic profile is essential. The most common metabolic disorders of HIV infected-patients (insulin resistance, diabetes, hyperlipidemia or osteopenia), as well as other factors of cardiovascular risk, such as hypertension, should also be dealt with according to guidelines similar to the general population, as well as insisting on steps to healthier lifestyles. The aim of this document is to provide a query tool for all professionals who treat HIV-patients and who may present or display any metabolic disorders listed in this document. (C) 2014 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

ObjectivesEx vivo analysis of mitochondrial function may reveal HIV progression and the impact of ART. We propose a mitochondrial and apoptotic in vitro model using Jurkat T cells incubated with plasma. The objectives of this study were to evaluate mitochondrial and apoptotic lesions in this model in relation to HIV progression, and to assess the effect of >1 year of standard non-thymidine-containing therapy.MethodsThis was a cross-sectional comparison among three age- and gender-matched groups (n = 19 × 3): healthy non-HIV-infected participants, HIV-infected long-term non-progressors (LTNPs) and standard antiretroviral-naive chronically infected patients [standard progressors (Sps)], longitudinally evaluated before (Sp1) and after (Sp2) >1 year of efavirenz + tenofovir + emtricitabine therapy. We analysed mitochondrial DNA content by RT–PCR, mitochondrial function by spectrophotometry, mitochondrial protein synthesis by western blot analysis, mitochondrial dynamics by western blot analysis (MFN2), apoptotic transition pore formation by western blot analysis (VDAC-1) and mitochondrial membrane potential and annexin V/propidium iodide fluorescence by flow cytometry.ResultsThere was a decreasing non-significant trend towards lower mitochondrial parameters for HIV-infected values with respect to uninfected control reference values. HIV progression (LTNP versus Sp1) was associated with decreased mitochondrial genetic, functional and translational parameters, which partially recovered after treatment intervention (Sp2). Mitochondrial fusion showed a trend to decrease non-significantly in Sp patients compared with LTNP patients, especially after therapy. All apoptotic parameters showed a trend to increase in Sp1 with respect to LTNP, followed by recovery in Sp2.ConclusionsWe proposed an in vitro model for mitochondrial and apoptotic assessment to test the effects of HIV infection and its therapy, resembling in vivo conditions. This model could be useful for clinical research purposes.

Survey in 349 HIV infected subjects in 19 Spanish Hospitals in 2010-2011, to assess the reasons for antiretroviral treatment change. Simplification was the most frequent reason for change (37%), followed by toxicity (30%) and treatment failure (21%). There were statistically significant differences according to treatment line and transmission category. In conclusion, in many patients treatment is changed in order to obtain the benefits of a regimen easier to follow.

This consensus document is an update of metabolic disorders and cardiovascular risk (CVR) guidelines for HIV-infected patients.This document has been approved by an expert panel of GEAM, SPNS and GESIDA after reviewing the results of efficacy and safety of clinical trials, cohort and pharmacokinetic studies published in biomedical journals (PubMed and Embase) or presented in medical scientific meetings. Recommendation strength and the evidence in which they are supported are based on the GRADE system.A healthy lifestyle is recommended, no smoking and at least 30min of aerobic exercise daily. In diabetic patients the same treatment as non-HIV infected patients is recommended. HIV patients with dyslipidemia should be considered as high CVR, thus its therapeutic objective is an LDL less than 100mg/dL. The antihypertensive of ACE inhibitors and ARAII families are better tolerated and have a lower risk of interactions. In HIV-patients with diabetes or metabolic syndrome and elevated transaminases with no defined etiology, the recommended is to rule out a hepatic steatosis Recommendations for action in hormone alterations are also updated.These new guidelines update previous recommendations regarding all those metabolic disorders involved in CVR. Hormone changes and their management and the impact of metabolic disorders on the liver are also included.

Background Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. Objective To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. Design Randomized, open-label, multicentre trial. Setting Twelve centres in Spain (9) and Argentina (3). Patients One hundred and forty-two HIV-infected naive patients without AIDS. Interventions Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. Results At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5–71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65–85) in the zidovudine/lamivudine/nevirapine arm ( P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3–61.7) and 65% (95% CI 54.2–76.2), respectively ( P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100 000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/ nevirapine in 25%, due to toxicity ( P>0.2). Conclusions Our results suggest that zidovudine/ lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Summary Zidovudine (ZDV), a nucleoside analogue which inhibits viral replication, is currently used in the treatment of type 1 human immunodeficiency virus (HIV-1) infection. It has been considered to be the cause of an acquired form of myopathy associated with a depletion of mitochondrial DNA (mtDNA) in muscle fibres, although the fact that the patients previously studied were clearly symptomatic, and the theoretical difficulty in differentiating an HIV-related myopathy from the effects of ZDV, led to a controversy on the possible deleterious effect of ZDV on muscle fibres. We studied the muscle biopsy taken from 42 HIV-1 infected patients, regardless of their medical complaints, and two series of controls: 12 HIV-negative patients suffering from diverse neuromuscular diseases and 10 normal patients who underwent orthopaedic surgery. Whole DNA was extracted following standard procedures and analysed by means of Southern blotting and polymerase chain reaction (PCR). We found that mtDNA was only depleted in HIV-1 infected patients treated with ZDV, but not in controls or patients untreated with this antiretroviral drug. Moreover, the depletion was more marked in patients who either presented weakness, myalgia, raised serum creatine kinase (CK), or ragged-red fibres. Mitochondrial DNA deletions were found in low proportion in all groups of patients, regardless of their HIV infection or ZDV status, but not in normal controls. We conclude that ZDV treatment in HIV-1 positive patients produces depletion of muscle mtDNA. The depletion can be demonstrated even in asymptotic patients, but is more marked in patients with clinical symtoms or abnormalities in their muscle biopsies. Other mtDNA abnormalities such as deletions seemed to be more related to other circumstances concurring in HIV-1 infected patients than to the effects of ZDV.

Currently, 2',3'-dideoxyinosine (ddI) is used in AIDS therapy. To investigate the possible myotoxicity of ddI in patients infected with human immunodeficiency virus (HIV), we examined the effect of ddI in vitro in tissue cultures of skeletal muscles of rats exposed to ddI at doses equivalent to plasma ddI levels obtained in the treatment of HIV patients. Control cultures were exposed to normal saline and zidovudine (AZT). After 4 weeks no changes were noted in the ddI and normal saline cultures, but AZT cultures showed abnormal accumulation of mitochondria. The creatine kinase values in culture supernatants were all normal. We also reviewed the clinical, nutritional and biological parameters, AZT and ddI dosage, and histochemical findings in muscle specimens of 14 HIV patients receiving ddI therapy. All patients had previously received AZT. The mean cumulative dose of ddI was 91.6 gm. Two patients had myalgia, 9 muscle atrophy, and 13 weakness. All patients were malnourished. Five patients had mitochondrial myopathy related to AZT, 4 had ddI-associated neuropathy and 2 patients had only selective type 2 fiber atrophy. One patient had necrotizing vasculitis, one had scattered necrotic fibers and type 2 fiber atrophy and 2 had a normal muscle biopsy. On the basis of the results, we have been unable to implicate ddI as a cause of skeletal myopathy.

Objectives: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naive patients who are >= 50 years. Design: National, retrospective cohort analysis of patients who were >= 50 years old when they began the first cART (January 1, 2006 to December 31, 2009). Methods: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. Results: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/mu L, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event >= grade 3, 5.6% interrupted cART due to adverse events, 19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non-FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% Cl, 1.34-3.29). Conclusions: In a population of HIV-infected subjects who were years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens.

We analyzed differences in response to combined antiretroviral therapy (cART) according to sex and geographic origin in a retrospective comparative study of Spanish-born and immigrant patients initiating cART. The primary endpoint was time to treatment failure (TTF), defined as virological failure, death, opportunistic infection, interruption of cART, or loss to follow-up. Late diagnosis was defined as a CD4+ cell count ≤ 200 cells/mm3 and/or AIDS at initiation of cART. Survival was analyzed using Kaplan-Meier analysis and Cox regression. We followed 1,090 patients, of whom 318 were women (45.6% immigrant women [IW]). At initiation of treatment, women had a higher CD4+ count than men (217 vs 190 cells/mm3), a lower viral load (4.7 vs 5 log), and fewer were late starters (49% vs 59%). The adjusted risk of TTF between women and men was not significantly different (hazard ratio [HR], 1.10; 95% CI, 0.79-1.53). TTF was shorter among IW than Spanish-born women (124 weeks [95% CI, 64-183] vs 151 [95% CI, 127-174]) and loss to follow-up was double that of Spanish-born women (25.5% vs 11.6%). Although response to cART was similar for both sexes, men started treatment later. IW were more frequently lost to follow-up and switched treatment. Measures to improve medical follow-up after initiation of cART should be promoted among this minority group. Response to Combined Antiretroviral Therapy According to Gender and Origin in a Cohort of Naïve HIV-Infected Patients: GESIDA-5808 Study. Available from: https://www.researchgate.net/publication/224971412_Response_to_Combined_Antiretroviral_Therapy_According_to_Gender_and_Origin_in_a_Cohort_of_Naive_HIV-Infected_Patients_GESIDA-5808_Study. 2.304 JCR (2012) Q2, 122/261 Pharmacology & pharmacy; Q3, 42/70 Infectious diseases

Because of the increased cardiovascular risk (CVR) in HIV-positive patients, preventive measures are essential, requiring algorithms for risk estimation, such as the Framingham risk equation, the Prospective Cardiovascular Munster Study (PROCAM) algorithm and the Systematic Coronary Risk Evaluation (SCORE) chart. Classical cardiovascular risk factors (CVRF) are closely related to CVR in HIV-infected patients but whether this risk is comparable to that in the general population is unknown. Therefore, these algorithms probably underestimate the risk in these patients. Currently, application of the same strategies as those used in the general population is recommended, without forgetting the specific characteristics of HIV positive patients or the importance of their inflammatory status, which can accelerate the development of arteriosclerosis and lead to an increase in cardiovascular morbidity and mortality. Therefore, in addition to traditional CVRF, biological markers of inflammation could help to identify the patients most at risk of a cardiovascular event. These markers, as well as the diverse techniques for assessment of subclinical atherosclerosis that could help in the early identification of at-risk patients, are reviewed in the present study. Lifestyle changes (healthy diet, smoking cessation, maintaining a healthy weight and daily physical exercise) reduce the probability of a coronary event by up to 80% in the general population. Traditional therapeutic measures (dyslipidemia, hypertension, diabetes mellitus) and those specific to HIV infection (viral suppression, discontinuous treatment, etc.) are reviewed.

BackgroundTumor necrosis factor alpha (TNF-α) is thought to be involved in the various immunogenetic events that influence HIV-1 infection.MethodsWe aimed to determine whether carriage of theTNF-α-238G>A, -308G>Aand-863 C>Agene promoter single nucleotide polymorphisms (SNP) and theCCR5Δ32variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration).TNF-αSNP and theCCR5Δ32allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the χ 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis.ResultsThe distribution ofTNF-α-238G>A, -308G>Aand-863 C>Agenetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals:-238G>A, p = 0.7 and p = 0.3;-308G>A, p = 0.05 and p = 0.07;-863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the threeTNF-αgenetic variants assessed was non-significantly different between TP and LTNP:-238G>A, p = 0.35 and p = 0.7;-308G>A, p = 0.7 and p = 0.6:-863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that theTNF-α-238Avariant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). TheCCR5Δ32distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively).ConclusionsIn our cohort of Caucasian Spaniards,TNF-αgenetic variants could be involved in the vulnerability to HIV-1 infection.TNF-αgenetic variants were unrelated to disease progression in infected subjects. The-238G>ASNP may modulate the control of viremia in LTNP. Carriage of theCCR5Δ32variant allele had no effect on the risk of infection and disease progression.

Background: The strategy of switching nevirapine (NVP) twice daily to once daily was evaluated. Methods: Forty-eight-week randomized, open, multicenter trial. Stable HIV-infected patients on NVP twice daily for > 12-18 weeks with alanine aminotransferase (ALT)

Background Reports have shown that the publication of practice guidelines does not guarantee their use in clinical practice. The objective of this study was to evaluate the agreement between antiretroviral treatments (ARTs) prescribed in clinical practice and the recommendations in published guidelines. Methods A retrospective cohort study was carried out in ART-naive adults of the Spanish Asociacion Medica Vach de Estudios Multicentricos (VACH) Cohort for the period from 2003 to 2006. Results A total of 945 patients initiated ART. Of these patients, 12.3% had a CD4 cell count above 350 cells/mu L. A 'nonrecommended' antiretroviral regimen was prescribed to 5.3, 5.1 and 7.8% of patients with CD4 counts < 200, 200-350 and > 350 cells/mu L, respectively. Multivariate analyses demonstrated that only a higher viral load was associated with the selection of a combination treatment that was recommended by the guidelines. Conclusions Most patients were prescribed initial treatments in agreement with the recommendations. Appropriate routine data collection in databases can be used to evaluate the level of antiretroviral guideline compliance. We propose that routine evaluations of the guidelines must be part of quality assessment to improve medical care.

Stavudine (d4T) has shown a favourable short and long-term tolerability profile. Nevertheless, its usage is currently decreasing due to some safety concerns. We aimed to evaluate the efficacy and safety of d4T low-dose-based regimens.This was a multicenter and retrospective review chart of patients receiving standard doses of d4T foror = 6 months (weight60 kg: 40 mg/12 h; weight60 kg: 30 mg/12 h) and having undetectable viral load for at least 3 months before the d4T dose reduction (weight60 kg: 30 mg/12 h; weight60 kg: 20 mg/12 h). Immunological and viral parametres, lipid profile and side effects were determined.A total of 982 patients were included. The main reason for reducing the dose was prevention of toxicity (76%). After 6 months of follow-up, 97% and 84% patients had less than 400 and 50 cp/ml, respectively, and the CD4 cell count increased by 38 cel/ml. Lipids, lipodystrophy and peripheral polineuropathy improved but there was no statistical significance.A d4T dose reduction in an immuno-virologically stable population does not affect treatment efficacy. Longer follow-ups are required to confirm improvements in the safety profile.

Mitochondrial parameters in peripheral blood mononuclear cells (PBMC) and their relationship with mitochondrially- driven PBMC apoptosis were investigated in a group of HIV-1-infected long-term nonprogressors (LTNP) and compared with untreated asymptomatic HIV-1 infected typical progressors (TP) and uninfected healthy controls (HC). Twenty-six LTNP, 27 TP and 31 HC were evaluated. Studies were performed in PBMCs. Mitochondrial DNA content (mtDNA) was assessed by quantitative real-time PCR. Activities of mitochondrial respiratory chain complexes (MRC) II, III and IV were determined by spectrophotometry. Caspase-3 activity was assessed by fluorimetry, and caspase-9 activation and Bcl-2 levels were assessed by immunoblotting. mtDNA abundance (p < 0.05), MRC complex II (p < 0.001), complex III (p < 0.01) and complex IV (p=0.01) were lower in the TP group than in the HC group. In the LTNP group these parameters were similar to those of the HC group except for complex II, which was decreased (p < 0.01). The PBMC of TP showed the highest overall apoptotic activation, since their caspase-3 activity was greater than that of HC (p < 0.05) and LTNP. In the case of LTNP, however, the difference was non-significant. Caspase-9 and the caspase-9/Bcl-2 ratio were both over-expressed in TP compared to HC (p < 0.01) and LTNP (p < 0.05). Both of these measurements indicate that mitochondrially- driven apoptosis in TP is greater than in LTNP and HC. A relationship between mitochondrial damage and apoptotic activation was found in TP. Mitochondrial damage is associated with increased PBMC apoptosis in patients with active HIV-1 replication (TP). These abnormalities are slight or not present in LTNP.

Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.

BACKGROUND AND OBJECTIVES: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection, although data are inconsistent. Our aim was to determine whether functionally active CCR2 and CCL2 genetic variants influence the risk of infection and disease progression in a cohort of white Spaniards. PATIENTS AND METHODS: This was a multicenter genetic association case-control study. Two single nucleotide polymorphisms (SNPs), V64I (G > A) of the CCR2 gene and -2518 (A > G) of the CCL2 gene, were assessed in 318 individuals: 73 HIV-1-infected long-term nonprogressors (LTNPs) of >16 years duration, 109 HIV-1-infected usual progressors (UPs), 36 heavily exposed to HIV-1 but uninfected individuals (EUs), and 100 control subjects. The distribution of the CCR5Delta32 allele was also assessed. Genotyping was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) or PCR and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared by the chi2 test and the Fisher exact test. RESULTS: CCR2 genotype distribution and allele frequencies showed nonsignificant differences between groups. The distribution of CCL2 alleles showed no significant differences between groups. HIV-1-infected individuals had, however, a significantly higher prevalence of the variant homozygous CCL2 GG genotype compared with EUs (P = 0.02). This result persisted when we studied only individuals with wild-type CCR5. Genotype and allele distribution of CCL2 was similar in HIV-1-infected UPs and LTNPs. CONCLUSIONS: In our cohort of white Spaniards, homozygosity for the variant CCL2-2518GG genotype is overrepresented in HIV-1-infected subjects.

Smoking is the most important modifiable cardiovascular risk factor. Bupropion administration is an effective method to achieve smoking cessation (SC), but the drug is metabolized by the cytochrome P450 enzyme system and this might cause interactions with antiretroviral drugs. We present a prospective study of bupropion SC therapy in HIV-positive patients under antiretroviral treatment. A total of 21 patients were studied; 38% of them stopped smoking for more than one year. No clinically significant drug interactions were found. Bupropion SC therapy was effective in HIV-positive patients and did not cause significant clinical interactions with antiretroviral drugs.

Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity.Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART.Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL (P = NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly (P0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients (P0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P0.05), complex III activity (127%, P0.05), complex IV activity (86%, P = 0.37) and oxygen consumption (194%, P0.05).Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.

We investigated atorvastatin effectiveness and tolerance in HIV patients with hypercholesterolemia related to antiretroviral treatment.Prospective study that included HIV+ patients under antiretroviral treatment who displayed secondary dyslipemia and medical treatment criteria (according to NCEP-III). These patients were given 10 mg/day atorvastatin and hygienic-dietetic measures. If the therapeutic objectives were not achieved, the dose of atorvastatin was increased to 20 mg/day. Patients were followed up for 6 months.32 patients were included. In 5 cases it was necessary to increase the dose from 10 mg atorvastatin to 20 mg. The therapeutic objective was obtained in 62% cases, with a good clinical tolerance. Only one adverse effect was noticed, which forced the removal of the drug.In our study atorvastatin was effective for the treatment of dyslipemia in HIV patients, and it was safe and well tolerated.

To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR).Patients received pegylated interferon (peg-INF)-alpha2a 180 microg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm).One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%.This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.

Patients on methadone maintenance therapy who are administered nelfinavir show a decrease in methadone plasma levels. However, the clinical relevance of this fact is seldom significant because it does not correlate with the appearance of opioid withdrawal symptoms (OWS). The objective of this study was to assess the clinical and pharmacokinetic interactions between methadone and nelfinavir.A prospective multicenter study of human immunodeficiency virus (HIV) positive patients on stable methadone therapy who initiated nelfinavir was performed. To determine the presence of OWS, 2 questionnaires, objective and subjective, were administered at weeks 1, 2, 3 and 4. A pharmacokinetic study measuring the minimal plasmatic concentration of methadone was done at baseline and at week 4.29 patient were included. In 7 patients who underwent pharmacokinetic studies, the minimal plasmatic concentration of methadone decreased after 4 weeks of nelfinavir treatment from 6.889 ng/ml to 4.354 ng/ml (37%; p = 0.046). However the results of the questionnaires did not show the significant OWS, which precluded an increase in the dose of methadone.In patients under stable methadone treatment, antiretroviral therapy including nelfinavir does not require any significant modification of methadone dose. The decrease in methadone plasmatic levels does not correlate with OWS.

Advanced directives documents (ADD), allow respect and know patient's intentions in health matters, when they are not able by themselves, for decision making. The aim of this study is making a valoration of the knowledgment of this documents in human immunodeficiency virus (HIV) infected patients, as well as their own knowledgment about this patology and possible complications.HIV infected patients controlled in 2 centers (Hospital de Mataró and Hospital de Granollers). Plained interview as a questinonary, that permits evaluate: own knowledge of the patology, received medical information level of satisfaction, patient s medical decision making involving desire, aptitudes in front of different hypothetical health status, and ADD knowledge. Factors associated to both knowledges (patology and ADD) are also evaluated.74.3% of the interviewed patients, showed a good patology knowledge. This result was associated with: youth, less functional level according to Karnofsky's scale, subjective perception on severity, previous admission at an intensive care unit, chronic hepatopathy, and previous parenteral drugs addiction. In the same way was associated with the negative to depend of mechanical ventilation or another people, and not being uncomfortable talking about this subjects. ADD's knowledge was relationated with the fact of being female (42.0% vs 26.8%; p = 0.024), higher academic formation (55.1% vs 25.5%; p0.001) and belief that medical decision making must be done by themselves (78.3% vs 53.6%; p = 0.002).Patology understanding and its complications, may be considered optimal in HIV population. One third of this group, has a good knowledge of ADDs, and is directly relationated with female sex, academic level, and clinical decisions making implication by the patients.

To provide an update of the metabolic and morphologic alterations in patients infected with HIV with an in-depth analysis of their clinical management and treatment.These recommendations were agreed by consensus by a committee of experts in metabolic alterations and HIV patient care, under the auspices of the Secretariat for the National AIDS Plan. To do this, the latest clinical, epidemiological and physiopathological advances described in studies published in the scientific literature and/or presented in congresses were reviewed.The most frequent metabolic alterations in HIV patients and in antiretroviral treatment (ART) are dyslipidemia with an atherogenic profile and alterations in carbohydrate metabolism/insulin resistance. A high prevalence of cardiovascular risk factors, especially smoking, has been described. The same criteria for their management as those used in the general population have been employed, with specific nuances. Diet and exercise should be the first therapeutic recommendation. In patients with dyslipidemia who require drug treatment, statins and/or fibrates are indicated. Glitazones have demonstrated efficacy in the treatment of insulin resistance. The approach to anomalous fat distribution continues to be controversial. The main approaches at present are a switch of ART, reparative surgery, psychological support and lifestyle changes. Lactic acidosis is an infrequent but highly serious complication, and the first step is withdrawal of ART. In bone metabolism alterations, prevention and early detection are essential, especially in children and perimenopausal women. Sexual dysfunction is a frequent problem in both men and women; because the causes are highly varied, treatment should be individualized.The prevalence of metabolic and morphologic alterations has increased since the introduction of highly active antiretroviral treatment (HAART). Knowledge of the various aspects involved in their diagnosis and treatment is essential for the appropriate care of patients with HIV infection.

In vitro studies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear.A cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddl+d4T)--collectively known as HIV+PI--as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochorldrial DNA content was measured by real-time PCR.BCL2 expression was lower in HIV+ than in HIV-patients (P0.01), whereas levels of caspase-9 were higher (P = 0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV-individuals (P0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV-patients (P0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddl+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI.NFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions -28C>G, -109T>C, and -403G>A were assessed. The prevalence of the CCR5Delta 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the chi2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for -28G; 4%, 2%, and 2% for -109C; and 18%, 18%, and 18% for -403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Delta32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.

To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients.Multicentre, prospective, observational study.Eleven hospitals in Spain during the period 2002-2003.One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-alpha2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm(3) (neutrophil-endpoint) and a platelet count below 50,000/mm(3) (platelet-endpoint).Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (+/-3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46-9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31-8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm(3) (HR: 3.59; 95% CI: 1.77-7.28) and baseline weight60 kg (HR: 2.21; 95% Cl: 1.04-4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm(3) decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint.Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.

We studied the frequency of the SDF-1 3'A allelic variant (801G-->A) in a cohort of white Spaniards made up of (1) HIV-1-infected long-term nonprogressors (LTNPs) older than 16 years of age (n = 57), (2) HIV-1-infected usual progressors (UPs; n = 107), and (3) a group of healthy controls (n = 100). The mutant SDF-1 3'A allele was observed in 28% of LTNPs, 19% of UPs, and 26% of healthy controls (P = not significant). Homozygosity for the 3'A mutation was detected in 7%, 4%, and 3% of LTNPs, UPs, and healthy controls, respectively (P = not significant). Polymorphism at the SDF-1 locus is not associated with LTNP disease of longer than 16 years in Spanish HIV-1-infected patients. This effect is independent of the CCR5Delta32 allele.

Increased apoptosis in CD4+ T lymphocytes plays an important role in the pathogenesis of HIV infection and it has also invoked some HIV-related as well as antiretroviral-related adverse events. We assessed whether increased apoptosis is also present in the skeletal muscle of HIV-infected patients. We included 36 consecutive individuals, 18 without (group A) and 18 with HIV infection. The latter group consisted of five asymptomatic antiretroviral-naive HIV-infected individuals (group B), six asymptomatic HIV-infected individuals on highly active antiretroviral therapy (HAART, group C), and seven HIV-infected individuals on HAART with lipodystrophy (group D). Immunohistochemical reaction using deoxyribonucleotidyltransferase-mediated- dUTP-biotin nick-end labeling (TUNEL) was performed on skeletal muscle samples. None of the uninfected patients (group A) showed data of increased apoptosis, while 16 out of 18 infected patients did (p < 0.001). All subgroups of infected subjects (groups B-D) showed a significant increase of apoptosis in TUNEL with respect to uninfected individuals, but the comparison between the different subgroups of infected patients did not reveal significant differences. We conclude that skeletal muscle of HIV-infected patients exhibits increased apoptosis compared with that of uninfected patients, but the role of HAART in inducing apoptosis remains to be established.