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Objectives: To assess the effectiveness and tolerability of dolutegravir (DTG)/lamivudine (3TC) among treatment-naive and virologically suppressed treatment-experienced individuals in the multicentre cohort of the Spanish HIV/AIDS Research Network (CoRIS) during the years 2018-2021., Methods: We used multivariable regression models to compare viral suppression (VS) [HIV RNA viral load (VL) <50 copies/mL] and the change in CD4 cell counts at 24 and 48 (±12) weeks after initiation with dolutegravir/lamivudine or other first-line ART regimens., Results: We included 2160 treatment-naive subjects, among whom 401 (18.6%) started with dolutegravir/lamivudine. The remaining subjects started bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (n = 949, 43.9%), DTG + FTC/tenofovir disoproxil fumarate (TDF) (n = 282, 13.1%), DTG/3TC/abacavir (ABC) (n = 255, 11.8%), darunavir (DRV)/cobicistat(COBI)/FTC/TAF (n = 147, 6.8%) and elvitegravir (EVG)/COBI/FTC/TAF (n = 126, 5.8%). At 24 and 48 weeks after starting dolutegravir/lamivudine, 91.4% and 93.8% of the subjects, respectively, achieved VS. The probability of achieving VS with dolutegravir/lamivudine was not significantly different compared with any other regimen at 24 or 48 weeks, with the exception of a lower chance of achieving VS at 24 weeks for DRV/COBI/FTC/TAF (adjusted OR: 0.47; 95% CI: 0.30-0.74) compared with dolutegravir/lamivudine.For the analysis of treatment-experienced virally suppressed subjects we included 1456 individuals who switched to dolutegravir/lamivudine, among whom 97.4% and 95.5% maintained VS at 24 and 48 weeks, respectively. During the first 48 weeks after dolutegravir/lamivudine initiation, 1.0% of treatment-naive and 1.5% of treatment-experienced subjects discontinued dolutegravir/lamivudine due to an adverse event., Conclusions: In this large multicentre cohort, effectiveness and tolerability of dolutegravir/lamivudine were high among treatment-naive and treatment-experienced subjects., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

People living with HIV-1 and HTLV-2 concomitantly show slower CD4 + T cell depletion and AIDS progression, more frequency of the natural control of HIV-1, and lower mortality rates. A similar beneficial effect of this infection has been reported on HCV coinfection reducing transaminases, increasing the spontaneous clearance of HCV infection and delaying the development of hepatic fibrosis. Given the critical role of CD8 + T cells in controlling HIV-1 infection, we analysed the role of CD8 + T cell-mediated cytotoxic activity in coinfected individuals living with HIV-1. One hundred and twenty-eight individuals living with HIV-1 in four groups were studied: two groups with HTLV-2 infection, including individuals with HCV infection (N = 41) and with a sustained virological response (SVR) after HCV treatment (N = 25); and two groups without HTLV-2 infection, including individuals with HCV infection (N = 25) and with a sustained virological response after treatment (N = 37). We found that CD8 + T cell-mediated HIV-1 inhibition in vitro was higher in individuals with HTLV-2. This inhibition activity was associated with a higher frequency of effector memory CD8 + T cells, higher levels of granzyme A and granzyme B cytolytic enzymes, and perforin. Hence, cellular and soluble cytolytic factors may contribute to the lower HIV-1 pre-ART viral load and the HIV-1 proviral load during ART therapy associated with HTLV-2 infection. Herein, we confirmed and expanded previous findings on the role of HTLV-2 in the beneficial effect on the pathogenesis of HIV-1 in coinfected individuals.

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS)., Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen)., Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure., Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads.

Objectives: The objective of this study was to evaluate the incidence, prevalence and clinical consequences of virological failure (VF) to raltegravir-based regimens in Spain., Methods: A multicentre, retrospective, observational study was performed in 10 tertiary hospitals (January 2006 to June 2013). The study included HIV-1-infected patients with loss of virological suppression (LVS; two consecutive HIV-1 RNA ≥50 copies/mL) while receiving raltegravir. VF and low-level viraemia (LLV) were defined as two consecutive HIV-1 RNA ≥200 copies/mL and 50 to <200 copies/mL, respectively. Integrase strand-transfer inhibitor resistance was investigated at LVS. During the 48 weeks following LVS, recorded data included clinical characteristics, treatment discontinuations, AIDS-associated events and deaths. Effectiveness of therapy following LVS was evaluated by ITT and PP. Multivariate regression was used to assess predictors of efficacy., Results: Of the 15 009 HIV-infected patients in participating centres, 2782 (18.5%) had received raltegravir-based regimens. Of those, 192 (6.9%), 125 (4.5%) and 67 (2.4%) experienced LVS, VF and LLV, respectively. The incidence of VF was 1.8 (95% CI, 1.5-2.1) per 100 patients/year. The prevalence of VF was 4.5% (95% CI, 3.8%-5.3%). Integrase-associated mutations were found in 78.8% of patients with integrase genotyping results available. High-level resistance to dolutegravir was not observed. Salvage therapy failed in 34.1% of patients; progression to AIDS/death occurred in 8.3% during the first year following LVS. The latter was associated with intravenous drug use, time on raltegravir and lower CD4+ count nadir in patients who started raltegravir-based treatments as salvage regimens., Conclusions: VF with raltegravir is infrequent, but often associated with major clinical complications in treatment-experienced patients., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: HIV-infected patients had a higher prevalence of insulin resistance (IR) and risk of diabetes mellitus (DM) than that observed in healthy controls, but there are no data about the current prevalence considering the changes in HIV presentation and the use of newer antiretroviral drugs., Design: Longitudinal study which involved 265 HIV patients without DM, receiving first (n=71) and advanced lines of antiretroviral therapy (n=194)., Methods: Prevalence of IR according to clinical and anthropometric variables, including dual X-ray absorptiometry (DXA) scan evaluation. IR was defined as homeostasis model assessment of IR≥3.8. Incident DM was assessed during the follow-up., Results: First-line patients had a short time of HIV infection, less hepatitis C virus coinfection, and received mainly an efavirenz-based regimen. Overall, the prevalence of IR was 21% (55 patients, 6% in first-line, 27% in pretreated). In a logistic regression analysis, significant associations were found between the waist/hip circumference ratio (RR 10; 95% CI 1.66-16; P<0.01, per unit), and central fat in percentage (RR 1.08; 95% CI 1.01-1.17; P=0.04, per unit) as evaluated by DXA, and IR. During 770.8 patient-years, DM was diagnosed in 8% (22 patients), mostly in pretreated patients (10 vs 4%; P=0.1). Thus, the overall rate of incident DM was 2.85 per 100 person-years, mostly in previous IR (10.39 vs 0.82/100 person-years; P=0.01)., Conclusions: A lower prevalence of IR is observed in the current HIV-infected patients with fewer risk factors and receiving newer antiretroviral drugs. IR continues to identify patients at high risk for developing DM in the short term., (© 2014 European Society of Endocrinology.)

Objectives: Limited data are available on resistance to etravirine, rilpivirine, darunavir and tipranavir in patients infected with HIV-1 non-B subtypes, in which natural polymorphisms at certain positions could influence the barrier and/or pathways to drug resistance., Methods: FASTA format sequences from the reverse transcriptase and protease genes recorded within the Spanish Drug Resistance database (ResRIS) were examined., Results: From 8272 genotypes derived from 5930 different HIV-1 patients included in ResRIS, 5276 genotypes had complete treatment information. Overall, 85% were from antiretroviral-experienced subjects and 7.5% belonged to HIV-1 non-B subtypes: CRF02&#95;AG, C, F and G being the most prevalent variants. For etravirine, only G190A was more prevalent in B than non-B subtypes, whereas V90I and V179E were more frequent in non-B than B subtypes. For rilpivirine, V108I and Y188I were more frequent in B than non-B subtypes, whereas V90I was more prevalent in non-B subtypes. Despite these differences, the overall prevalence of resistance did not differ significantly when comparing etravirine or rilpivirine in B versus non-B subtypes (11.3% versus 7.4%, P = 0.13, and 10.5% versus 7.4%, P = 0.23, respectively). Despite more frequent natural polymorphisms in non-B than B subtypes at tipranavir resistance positions, the prevalence of tipranavir resistance was greater in B than non-B subtypes (11% versus 4.3%, P = 0.004), reflecting a greater antiretroviral exposure in the former. Darunavir resistance did not differ significantly when comparing B and non-B subtypes (5.8% versus 5.5%, P = 0.998)., Conclusions: The rate of resistance to the most recently approved protease and non-nucleoside reverse transcriptase inhibitors is low in antiretroviral-experienced patients, regardless of the HIV-1 subtype.

Objective: Rilpivirine (RPV) is the latest approved nonnucleoside reverse transcriptase inhibitor (NNRTI). It displays in-vitro activity extending over other NNRTI-resistant HIV strains. There is scarce information about the rate of RPV resistance-associated mutations (RAMs) in patients failing other NNRTIs., Methods: RPV RAMs were examined in plasma samples collected from HIV patients that had recently failed NNRTI-based regimens at 22 clinics in Spain., Results: Resistance tests from a total of 1064 patients failing efavirenz (EFV) (54.5%), nevirapine (NVP) (40%) or etravirine (ETR) (5.5%) were examined. The prevalence of RPV RAMs was K101E (9.1%), K101P (1.4%), E138A (3.9%), E138G (0.3%), E138K (0.3%), E138Q (0.8%), V179L (0.2%), Y181C (21.8%), Y181I (0.5%), Y181V (0.2%), H221Y (8.3%), F227C (0.1%) and M230L (1.5%). K101E/M184I was seen in 1%. E138K/M184I were absent. Mutations L100I and V108I were significantly more frequent in patients failing EFV than NVP (7.9 vs. 0.2 and 12.2 vs. 7.3%, respectively). Conversely, Y181C, Y181I, V106A, H221Y and F227L were more prevalent following NVP than EFV failures. Using the Spanish resistance interpretation algorithm, 206 genotypes (19.3%) from patients failing NNRTI (NVP 52%, EFV 40.8% and ETR 7.8%) were considered as RPV resistant. In patients with ETR failure, cross-resistance to RPV was seen in 27.6%, mainly as result of Y181C (81.3%), V179I (43.8%), V90I (31.3%) and V108I (18.8%)., Conclusion: RPV resistance is overall recognized in nearly 20% of patients failing other NNRTIs. It is more common following ETR (27.6%) or NVP (25%) failures than EFV (14.5%). E138 mutants are rarely seen in this context.

Background: Raltegravir (RAL) constitutes the first available integrase strand transfer inhibitor (INSTI) available in clinical practice. Three independent pathways have been described to confer resistance to RAL. Secondary mutations with little effect on INSTI susceptibility and additional substitutions with an uncertain role have also been described especially in HIV-1 non-B variants., Methods: We evaluated the prevalence of primary, secondary, and additional resistance mutations to INSTIs in patients naïve to RAL or elvitegravir (EGV) carrying different HIV-1 variants., Results: A total of 83 patients infected by B HIV-1 subtype (64%) or non-B HIV-1 variants (36%) were evaluated. No primary mutations to RAL or EGV were found in the inte-grase sequences analyzed. Secondary mutations were detected in only 5 patients. Additional mutations were found in both in B and non-B variants. According to the geno2pheno algorithm, some of the secondary mutations detected (L74V, E138K, G163RS, and V151I) have been associated with a reduced estimated susceptibility to RAL and only the E138K mutation has been associated with a decreased estimated susceptibility to EGV. No virological failure was observed after RAL was administrated in 17 patients carrying 1 or more additional substitutions in the absence of primary or secondary mutations., Conclusions: No primary resistance mutations to INSTI were found in treatment-naïve or -experienced patients infected with B or non-B HIV-1 variants. The vast majority had some polymorphic and non-polymorphic substitutions; however response to RAL was excellent in patients who harbored one or more of these mutations. We could not identify any clinical factors associated with the presence of any of these mutations.

Purpose: Etravirine (ETR) has shown a good lipid profile in previous studies. The aim of this study was to determine the virologic, immunologic, and lipid outcome in HIV-infected patients switching to an ETR-based antiretroviral regimen due to intolerance or toxicity., Methods: Observational cohort study of 125 HIV-infected patients who switched therapy to an ETR-based regimen. The lipid profile, including total triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) was compared after 24 weeks., Results: Patients changed from efavirenz (n = 34; 28%) and ritonavir-boosted protease inhibitors (PI/r; 67 cases: 21 atazanavir, 21 lopinavir, 11 fosamprenavir, 14 darunavir). Hyperlipidemia was the cause in only 22 patients (18%). At 24 weeks, a significant decrease was observed in mean TC level (-8%), LDL-C (-8%), TC:HDL ratio (-6%), and TG level (-20%). For patients receiving previously efavirenz, there was a significant reduction in TC (-23 mg/dL; -13%) and LDL-C (-25 mg/dL; -21%) levels and a trend to a better TG level (-38 mg/dL; -21%;P = .06). In the case of prior PI/r therapy, there was also a significant reduction in TC (-14 mg/dL; -6%) and TG levels (-58 mg/dL; -16%), mostly in prior lopinavir- or fosamprenavir-based therapy (TC -15%; TG -53%). Median CD4+ count increased from 513 to 621 cells/µL (P = .03), and there were only 3 cases of virologic failure (2%)., Conclusions: In patients switching to an ETR-containing regimen, there is a significant improvement of lipids and maintenance of immunologic and virologic response. This lipid-lowering effect was irrespective of the presence of previous hyperlipidemia and for patients receiving different antiretroviral drugs.

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4(+) T cells in chronically HIV-1-infected patients receiving antiretroviral therapy., Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation., Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4(+) or CD8(+) counts, although a significant decrease was found in the proportion of HLA-DR(+)/CD38(+) CD4(+) and CD8(+) T-cells. LPS and sCD14 levels increased., Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results., Trial Registration: ClinicalTrials.gov NCT00795444.

The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C(max)), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0-tau)], similar values for the concentration at the end of the dosing interval (C(tau)), and 114% higher unbound C(tau) values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C(max) values, 27% lower AUC(0-24) values, 57% lower C(tau) values, and 21% higher unbound amprenavir C(tau) values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C(max) values, 23% lower AUC(0-24) values, 38% lower C(tau) values, and similar unbound amprenavir C(tau) values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

Objectives: The aim of this study was to identify mutations within the fingers, palm and thumb subdomains of the HIV-1 reverse transcriptase (RT) associated with therapy failure to various combinations of two nucleoside analogues., Methods: RT nucleotide sequences of 1893 HIV-1 isolates from 1680 persons with different treatment histories (including naive and treated patients) were analysed. chi(2) contingency tests were performed to detect mutations within positions 1-333 of HIV-1 RT, associated with therapy failure, and correlated mutations were identified using statistical methods., Results: Thymidine analogue resistance mutations were strongly associated with therapy failure to all nucleoside analogue combinations analysed. Previously identified accessory mutations at positions 35, 39, 43, 90, 98, 101, 122, 178, 196, 203, 208, 221, 223 and 228 were associated with therapy failure with at least one of the drug combinations studied. Interestingly, several mutations affecting RT thumb subdomain polymorphisms were strongly associated (P < 10(-3)) with therapy failure to abacavir/stavudine, stavudine/didanosine and abacavir/stavudine/didanosine. Mutations A272P, K277R and V293I were more prevalent in patients failing treatment with abacavir/stavudine than in naive individuals, while mutation frequencies of T286A, V292I and to a lesser extent E291D and E297K decreased in the treated population. These effects were also detected for A272P, T286A and V292I, when analysing didanosine/stavudine therapy failure, although statistical significance was higher for T286A., Conclusions: RT thumb subdomain polymorphisms are strongly associated with therapy failure to nucleoside analogues. Based on their structural location, we suggest a role for those residues in controlling the balance between RNase H degradation and nucleotide excision during DNA polymerization.

Background: Stroke risk is increased in AIDS patients, and highly active antiretroviral therapy (HAART) may accelerate atherosclerosis, but little is known about the incidence and risk factors for ischemic stroke in patients under HAART. We have studied the incidence, types of stroke and possible risk factors for cerebrovascular ischemic events in a large cohort of HIV-1-infected patients treated with HAART., Methods: We conducted a retrospective review of ischemic strokes and transient ischemic attacks occurring in a cohort of HIV-1-infected patients treated with HAART from 1996 to 2008. As a control group, consecutive unselected patients from the same cohort were included. Patients and controls were compared for demographic, clinical and laboratory variables, including vascular risk factors, data on HIV infection and duration of HAART. Variables with significant differences were included in a backward logistic regression model., Results: Twenty-seven cerebrovascular ischemic events occurred in 25 patients, with an incidence of 189 events (166 strokes) per 100,000 patients/year. Independent factors associated with cerebrovascular events were: history of high alcohol intake (OR 7.13, 95% CI 1.69-30.11; p = 0.007), a previous diagnosis of AIDS (OR 6.61, 95% CI 2.03-21.51; p = 0.002) and fewer months under HAART (OR 0.97, 95% CI 0.96-0.99; p < 0.001). Six patients (24%) had large artery atherosclerosis: they had a similar HAART duration to controls., Conclusions: Stroke incidence is high in patients with HIV-1 infection treated with HAART. Duration of HAART exerted a global protective effect for cerebrovascular ischemic events, and our results do not support a major role in large artery atherosclerosis stroke. High alcohol intake is a major risk factor for stroke in these patients.

Human immunodeficiency virus type 1 (HIV-1) antiviral drug resistance is a major consequence of therapy failure and compromises future therapeutic options. Nelfinavir and lopinavir/ritonavir-based therapies have been widely used in the treatment of HIV-infected patients, in combination with reverse transcriptase inhibitors. The aim of this observational study was the identification and characterization of mutations or combinations of mutations associated with resistance to nelfinavir and lopinavir/ritonavir in treated patients. Nucleotide sequences of 1,515 subtype B HIV-1 isolates from 1,313 persons with different treatment histories (including naïve and treated patients) were collected in 31 Spanish hospitals over the years 2002-2005. Chi-square contingency tests were performed to detect mutations associated with failure to protease inhibitor-based therapies, and correlated mutations were identified using statistical methods. Virological failure to nelfinavir was associated with two different mutational pathways. D30N and N88D appeared mostly in patients without previous exposure to protease inhibitors, while K20T was identified as a secondary resistance mutation in those patients. On the other hand, L90M together with L10I, I54V, A71V, G73S, and V82A were selected in protease inhibitor-experienced patients. A series of correlated mutations including L10I, M46I, I54V, A71V, G73S, and L90M appeared as a common cluster of amino acid substitutions, associated with failure to lopinavir/ritonavir-based treatments. Despite the relatively high genetic barrier of some protease inhibitors, a relatively small cluster of mutations, previously selected under drug pressure, can seriously compromise the efficiency of nelfinavir- and lopinavir/ritonavir-based therapies., ((c) 2007 Wiley-Liss, Inc.)

HIV protease inhibitors (PI) have undergone the most significant evolution when considering the different families of antiretrovirals. Marketed in 2003, atazanavir (ATV) is the first azapeptide PI, and is considered a member of the second generation of PIs. Important characteristics make ATV different from other drugs in the same family of antiretrovirals. It is administered once daily, either as two capsules (200 mg) or boosted with ritonavir (100 mg) two capsules (150 mg) or one capsule (300 mg). No elevations in serum levels of total cholesterol, low-density lipoprotein cholesterol or triglycerides have been observed with unboosted ATV. Although some increases in these levels are found with boosted ATV, these were lower when compared with other PIs. Elevation in unconjugated bilirubin levels, which is usually not dose limiting, is the most frequent adverse event. Naive patients receiving ATV boosted with ritonavir do not develop PI mutations at failure, whereas unboosted ATV in the same scenario induces the I50L mutation, which does not confer cross-resistance to other PIs. The best scenario for unboosted ATV is simplification. In PI treatment-experienced patients with PI mutations, susceptibility to ATV is usually reduced, so it should be administered with ritonavir. As with other PIs, careful attention must be given to pharmacokinetic drug interactions; the coadministration of certain commonly used drugs among HIV-infected patients, tenofovir and members of the proton pump inhibitor family, leads to significantly lower plasma levels of ATV.

Objective: To estimate the impact of toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTI) on the total cost of medical care in HIV-1-infected patients., Methods: . A pharmacoeconomic model was developed from the data obtained by a prospective, observational, multicenter study performed in Spain (Recover). The study patients had developed one NRTI-associated adverse event (AE) that justified discontinuation of treatment with the drug. All costs derived from NRTI-associated AEs in the HAART regimens of HIV-1-infected patients over a period of one year were assessed. The cost assessment (2005 values) included direct medical costs (drugs and AE management) and indirect costs (loss of productivity). The healthcare resources used in AE management were estimated by an expert panel of clinicians., Results: The use and cost of resources rose with increasing severity of all the AE. The average total cost per patient was estimated to be 4012 euro, which included 1789 euro in drug costs (NRTI associated with therapy discontinuation due to AE), and 2223 euro in direct and indirect costs of AE management (45% and 55% of total cost, respectively). Seventy-three per cent of AE-associated costs per patient came from lipoatrophy (560 euro), lipodystropy (535 euro) and peripheral neuropathy (533 euro)., Conclusion: Management of NRTI-related toxicities is more costly than NRTI acquisition and produces a significant increase in the overall healthcare expenditure for HIV-1-infected patients. This fact should be taken into account when designing the most efficient antiretroviral treatment strategies.

Objective: To analyze the safety and effectiveness of abacavir, lamivudine, and zidovudine (ABC/3TC/ZDV) in antiretroviral therapy (ART)-naive HIV-infected patients., Design: Retrospective observational cohort study., Methods: We analyzed all consecutive ART-naive HIV-infected patients who initiated ABC/3TC/ZDV in 71 centers throughout Spain and had a clinical visit and laboratory data at least 16 weeks after initiating this regimen. We assessed safety, mortality, new AIDS-defining conditions (ADCs) and treatment failure, the latter defined by any of the following: (1) reduction in plasma HIV-1 viral load (pVL) <1 log during the first 12 weeks of ART, unless it was less than the lower limit of quantification (LOQ); (2) failure to achieve a pVL or = LOQ after achieving a pVL

Purpose: To compare outcomes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz versus abacavir-based regimens with a backbone of zidovudine and lamivudine as initial therapy of treatment-naive adults with HIV-1 infection in routine clinical care., Method: All patients starting their first antiretroviral therapy with any of the studied regimens from January 1999 to December 2002 were included in the analysis. Rates of viral suppression (HIV-RNA below 50 copies/mL) and discontinuation of any component of the regimen were compared at 48 weeks., Results: Fifty-one patients started with one of the two NNRTI-based regimens and 49 started with the triple nucleoside regimen (3-NRTI). After 48 weeks, more patients in the NNRTI regimens (76.5%) than in the 3-NRTI (51.1%) regimen achieved a HIV-1 RNA level below the limit of detection (<1.7 log10 copies/mL; p = .008). Time to change the antiretroviral regimen was shorter with 3-NRTI (median [range]: 234 [139-329] days) than with NNRTI (346 [0-756] days) (p = .0901). More withdrawals related to drug toxicity or intolerance occurred with the 3-NRTI-based regimen., Conclusion: In a routine clinical care setting, initial antiretroviral treatment with an NNRTI (nevirapine or efavirenz) plus zidovudine and lamivudine was virologically superior and safer than a 3-NRTI therapy (abacavir with the same NRTI backbone).

We evaluated the impact of HIV risk practice on immune reconstitution in a prospective cohort of 288 patients (176 former injecting drug users) who maintained complete virus suppression for more than 24 months. Significant differences in CD4 cell counts at 6 and 24 months were detected. Multivariate analysis showed that drug use was an independent predictor of poor immunological recovery. Injection drug abuse impairs short and long-term CD4 cell recovery in HIV-positive patients initiating successful highly active antiretroviral therapy.

Increased drug levels could overcome resistance and improve the response to a salvage regimen. We evaluate the inhibitory quotient (IQ, Ctrough/protein-binding corrected IC50) as a predictor of virological response in 52 patients included in two dual protease inhibitor (PI)-based salvage regimens. The HIV-RNA level decrease at 12 weeks was greater in patients who achieved an IQ greater than 1. The IQ could be useful to improve the virological response to a dual PI salvage regimen.

Objective: To determine the importance of resistance and drug levels in the response to a dual-protease inhibitor (PI) combination., Methods: Prospective study of 62 HIV-positive patients who switched to a salvage regimen including nelfinavir plus saquinavir. Virological response was defined as a decrease in viraemia > 0.5 log10 after 24 weeks. Optimal PI levels were defined as those above the protein binding-corrected 95% inhibitory concentration (IC95), as estimated in the presence of 50% human serum., Results: Baseline median HIV load was 4.78 log10 copies/ml. The median number of mutations in the protease gene was nine (range, 2-25), predominantly at residues 82 (52%), and 90 (40%). After 24 weeks, 45% of patients had responded and 19% were < 50 copies/ml. A higher number of mutations in the protease gene (12 versus 8;P = 0.001), and the L90M mutation (36% versus 67%; P = 0.001) were associated with treatment failure. Trough levels of nelfinavir and saquinavir were two- and fivefold, respectively, greater than those reached when used as the only PI (2480 and 260 ng/ml, respectively), and they were above the estimated protein-corrected IC95 in 96% and 32% of cases. Thus, the Cmin : IC95 ratio ranged from 0.1 to 10 for nelfinavir and from 0.12 to 3.24 for saquinavir. Suboptimal PI levels were associated with a poorer response, but there was no correlation between optimal drug levels and a better response., Conclusion: Genotypic resistance predicts the virological response to a nelfinavir-saquinavir salvage regimen. Our data suggest that higher than optimal drug levels could be necessary to control the replication of many PI-resistant viruses.

The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5–25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL (p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated (p = 0.040). miR-20a and miR-21 were independently associated with cHL (p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR−) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL (p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated (p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals (p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL (p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 (p = 0.074) with a slight LR+ value of 2 and a slight LR− of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome (p < 0.001), while sCD14 and sCD30 were higher (p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy. [ABSTRACT FROM AUTHOR]