[Show abstract][Hide abstract] ABSTRACT: This article aims to investigate if the detection of preexisting drug-resistant minority variant (DRMV) and/or X4 HIV-1 variants could improve the efficacy of first-line combined antiretroviral therapy (ART) in late presenters.
Post-hoc, combined analysis of two open-label, prospective, randomized clinical trials comparing first-line ART with efavirenz (EFV) vs. ritonavir-boosted protease inhibitor (PI/r)-based regimens in ART-naive, HIV-1-infected patients, with CD4 T-cell counts less than 100 cells/μl and wild-type HIV-1 by bulk sequencing.
Pre-ART samples were reanalyzed for the presence of DRMVs and X4 HIV-1 using 454 sequencing. Kaplan-Meier curves and Cox regression were used to evaluate the association between X4 HIV and DRMVs and risk of virological failure.
From 141 evaluable patients, 57 received EFV, and 84 received PI/r, including first-line ART. Median pre-ART CD4 T-cell counts and HIV-1 RNA levels were 39 cells/μl and 257 424 copies/ml, respectively; 35.5% of patients had X4 HIV variants. Detection of DRMVs leading to an ART-specific cumulative HIVdb score of at least 10 increased the risk of virological failure in patients initiating EFV [log-rank P = 0.048, hazard ratio = 4.3 (95% confidence interval: 0.8, 25.0), P = 0.074], but not in those starting PI/r. Presence of X4 HIV did not affect virological outcomes, but was associated with impaired CD4 T-cell count recovery over 2 years (214 vs. 315 cells/μl with X4 vs. R5 HIV-1 tropism, respectively, P = 0.017).
Accounting for preexisting DRMVs may improve the outcomes of first-line nonnucleoside reverse transcriptase inhibitor-based ART in late presenters with advanced immune suppression. Presence of X4 HIV-1 at diagnosis predicts impaired immune restoration under ART.
AIDS 07/2015; 29(12-12). DOI:10.1097/QAD.0000000000000748 · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although virus-specific responses are rarely detected by conventional approaches, we report here the detection of T-cell responses in HIV-exposed seronegative (HESN) patients by two distinct assays.
HIV-specific T-cell responses were analyzed by enzyme-linked immunospot in peripheral blood mononuclear cells from HESN patients after a 48-h co-culture with boosted dendritic cells. Additionally, a boosted flow cytometry approach was used to capture antiviral T-cell responses. Host genetic factors and T-cell activation were also analyzed to assess their implication on HIV exposure.
Of the 45 HESN individuals tested, up to 11 (24.4%) showed at least one response to peptide pools covering HIV Gag and Nef. A positive correlation was observed between the intensity (P = 0.0022) and magnitude (P = 0.0174) of the response detected in the HESN, and the viral load of the HIV-positive partner. Moreover, the result from the boosted flow and cytomix analyses showed a dominant Th1-like response pattern against HIV antigens, especially in CD8 T-cell populations.
The combined use of our boosted dendritic cell technique with a boosted flow cytometric approach allows us both to detect specific HIV-positive responses in a higher percentage of HESN patients and to define specific effector function profiles. This study contributes to a better understanding of resistance to HIV infection.
AIDS (London, England) 06/2015; 29(11). DOI:10.1097/QAD.0000000000000728 · 6.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the availability of effective combined antiretroviral treatment, many patients still present with advanced HIV infection, often accompanied by an AIDS-defining disease. A subgroup of patients starting antiretroviral treatment under these clinical conditions may experience paradoxical worsening of their disease as a result of an exaggerated immune response towards an active (but also subclinical) infectious agent, despite an appropriate virological and immunological response to the treatment. This clinical condition, known as immune reconstitution inflammatory syndrome, may cause significant morbidity and even mortality if it is not promptly recognized and treated. This review updates current knowledge about the incidence, diagnostic criteria, risk factors, clinical manifestations, and management of opportunistic infections and immune reconstitution inflammatory syndrome in the combined antiretroviral treatment era.
[Show abstract][Hide abstract] ABSTRACT: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naïve, HIV-1-infected individuals by comparing an efavirenz-based regimen with 2 ritonavir-boosted protease inhibitor regimens.
Randomized, controlled, open-label multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naïve patients with <100 CD4 cells/mm were randomly assigned in a 1:1:1 ratio to efavirenz (n=29), atazanavir/ritonavir (n=30), or lopinavir/ritonavir (n=30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary endpoints were the proportion of patients with HIV-1 RNA <50 copies/mL, adverse events, disease progression, and death.
In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells/µL in the efavirenz arm, +197 (146-238) cells/µL in the ritonavir-boosted atazanavir arm, and +205 (178-327) cells/µL in the ritonavir-boosted lopinavir arm (P=0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks (efavirenz, 85.71% [95%CI, 68.5-94.3]; atazanavir, 80% [95%CI, 62.7-90.5]; and lopinavir, 82.8% [95%CI, 65.5-92.4]; p=0.88). Bacterial translocation, inflammation, immune activation, and apoptotic markers-but not D-dimer-declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died.
The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen (ClinicalTrials.gov registration number: NCT00532168).
[Show abstract][Hide abstract] ABSTRACT: Background. It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. Methods. ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Treatment with ritonavir-boosted protease inhibitors and nucleoside analogues frequently leads to rises in lipids, which might increase the cardiovascular risk. The aim of this study was to describe changes in lipid levels among HIV positive patients participating in the GARDEL study.
Materials and Methods
The GARDEL study compared the efficacy and safety of a dual therapy (DT) combination of LPV/r 400/100 mg BID+3TC 150 mg BID to a triple therapy (TT) with LPV/r 400/100 mg BID+3TC or FTC and a third investigator-selected NRTI in fixed-dose combination among HIV+ treatment naïve patients. We compared changes in lipid levels from baseline to week 48 in both arms.
Patient's characteristics were well balanced regarding mean baseline total cholesterol (157 mg/dL DT, 154 mg/dL TT), triglycerides (142 mg/dL DT, 139 mg/Dl TT), LDL-C (94 mg/dL DT, 91 mg/dL TT) and HDL-C (36 mg/dL DT, 35 mg/dL TT). Changes in total cholesterol, LDL-C and HDL-C were higher in DT arm, compared to TT (32% DT vs 26% TT for cholesterol; 25% DT vs 16% TT for LDL and 33% DT vs 28% TT for HDL). Increase in triglycerides was higher in TT compared to DT (55% DT vs 92% TT) (Table 1). In TT arm LDL-C and total cholesterol elevations were lower among patients receiving TDF compared to those treated with ZDV or ABC.
Changes in lipid parameters were observed in both arms. Albeit the increase was numerically higher for cholesterol (total and LDL-C) in DT arm while TT arm had higher increases in TG; no difference was observed when week 48 values were compared with the NCEP ATP III goals for cardiovascular risk reduction . So, the DT strategy, even missing the lipid-lowering effect observed with tenofovir, does not seem to add significant risk to patients treated with this novel strategy.
Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19554. DOI:10.7448/IAS.17.4.19554 · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m(2).
Journal of the International AIDS Society 11/2014; 17(4 Suppl 3):19561. DOI:10.7448/IAS.17.4.19561 · 4.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. There is an urgent need for alternative rescue therapies in invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We assessed the clinical efficacy and safety of the combination of fosfomycin and imipenem as rescue therapy for
MRSA infective endocarditis and complicated bacteremia.
Methods. The trial was conducted between 2001 and 2010 in 3 Spanish hospitals. Adult patients with complicated MRSA bacteremia or
endocarditis requiring rescue therapy were eligible for the study. Treatment with fosfomycin (2 g/6 hours IV) plus imipenem
(1 g/6 hours IV) was started and monitored. The primary efficacy endpoints were percentage of sterile blood cultures at 72
hours and clinical success rate assessed at the test-of-cure visit (45 days after the end of therapy).
Results. The combination was administered in 12 patients with endocarditis, 2 with vascular graft infection, and 2 with complicated
bacteremia. Therapy had previously failed with vancomycin in 9 patients, daptomycin in 2, and sequential antibiotics in 5.
Blood cultures were negative 72 hours after the first dose of the combination in all cases. The success rate was 69%, and
only 1 of 5 deaths was related to the MRSA infection. Although the combination was safe in most patients (94%), a patient
with liver cirrhosis died of multiorgan failure secondary to sodium overload. There were no episodes of breakthrough bacteremia
Conclusions. Fosfomycin plus imipenem was an effective and safe combination when used as rescue therapy for complicated MRSA bloodstream
infections and deserves further clinical evaluation as initial therapy in these infections.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess changes in antibiotic resistance, epidemiology, and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our center from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/d) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4-6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR: gentamicin MIC ≥512 mg/L, streptomycin MIC ≥1024 mg/L or both) were observed in recent years (24% in 1997-2006 and 49% in 2007-2011; P=0.03). The use of A+C increased over time: 1997-2001, 4/18 (22%); 2002-2006, 5/16 (31%); and 2007-2011, 30/35 (86%) (P<0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (P=0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only 1 patient (3%) treated with A+C had to discontinue treatment (P<0.001). Only development of heart failure and previous chronic renal failure were independently associated with one-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR 0.7, 95%CI 0.2-2.2, P=0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Highly active antiretroviral therapy has helped to improved control of the HIV infection, and has led to a progressively older population with the infection having a life expectancy quite similar to that of the general population. On the other hand, it is also known that HIV infection, even in patients with undetectable viral loads and good immunity, carries an increased cardiovascular risk, as well as an increased incidence of certain cancers. Therefore, the majority of HIV-infected patients receive several drugs (either prescribed by the physician or self-administered) combined with antiretrovirals. This article reviews the interactions between antiretrovirals and other drugs that can cause significant damage to patients, or even be life-threatening and of whom clinicians, especially those not directly treating HIV-infected patients, should be aware. A review is also presented on the implications of interactions between antiretrovirals and other drugs in special situations, such as the co-administration with cytostatics, immunesuppressants used in solid organ transplantation, or patients receiving new treatments for hepatitisC. Generally, combinations with two nucleos(t)ide reverse transcriptase inhibitors and raltegravir (or in the near future, dolutegravir) are those with less potential for clinically significant interactions.
[Show abstract][Hide abstract] ABSTRACT: We tested if an increase of immune activation and drop of CD4+ T cells induced by different antigenic stimuli could be associated with changes in thymic function and IL-7/CD127 system.
Twenty-six HIV-infected patients under cART were randomized to receive during 12 months a complete immunization schedule (7 vaccines and 15 doses) or placebo. Thereafter, cART was interrupted 6 months. Changes in the thymic function and IL-7/CD127 system after 3 different antigenic stimuli (vaccines, episodes of low level intermittent viremia before cART interruption or viral load rebound after cART interruption) were assessed.
During the period on cART neither vaccines nor low level viremia influenced thymic function or IL-7/CD127 system parameters. Analyzing the cohort as a whole while on cART, a significant improvement was observed in thymic function as measured by an increase in the thymic volume (p=0.024), TRECs-bearing cells (p=0.012) and naive CD4+ and CD8+ T cells (p=0.069 both). No significant changes were observed in the IL-7/CD127 system. After cART interruption, a decrease of TRECs (p<0.001) and naïve CD8+ T cells (p<0.001), an increase of IL-7 and expression of CD127 on naïve and memory CD4+ T cells (p=0.028, p=0.088 and p=0.04, respectively) and a significant decrease of CD127 on naive and memory CD8+ T cells (p=0.01, p=0.006, respectively) were observed.
Low level transient antigenic stimuli during cART were not associated with changes on thymic function or IL-7/CD127 system. Conversely, viral load rebound very early after cART interruption influenced thymic function and IL-7/CD127 system.ClinicalTrials.gov number NCT00329251.
[Show abstract][Hide abstract] ABSTRACT: Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy.
The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age ≥18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100 000 vs ≥100 000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than -12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444.
Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88·3%) in the dual-therapy group and 169 (83·7%) in the triple-therapy group had viral response (difference 4·6%, 95% CI -2·2 to 11·8; p=0·171). Patients with baseline viral load of at least 100 000 copies per mL showed similar results (87·2% vs 77·9%, respectively; difference 9·3%, 95% CI -2·8 to 21·5; p=0·145). Toxicity-related or tolerability-related discontinuations were more common in the triple-therapy group (n=10 [4·9%]) than in the dual-therapy group (n=1 [0·4%]; difference 4·5%, 95% CI -8·1 to -0·9; p=0·011). 65 adverse events in the dual-therapy group and 88 in the triple-therapy group were possibly or probably drug related (p=0·007). Two serious adverse events occurred, both in the dual-therapy arm, one of which (a case of gastritis) was reported as possibly or probably related to drug treatment.
Dual therapy with lopinavir and ritonavir plus lamivudine regimen warrants further clinical research and consideration as a potential therapeutic option for antiretroviral-therapy-naive patients.
Fundación Huésped and AbbVie.
[Show abstract][Hide abstract] ABSTRACT: Background. Staphylococcus aureus endocarditis has a high mortality rate. Vancomycin minimum inhibitory concentration (MIC) has been shown to affect the outcome of methicillin-resistant S. aureus (MRSA) bacteremia, and recent data point to a similar effect on MSSA bacteremia. We aimed to evaluate the effect of vancomycin MIC on left-sided S. aureus infective endocarditis (IE) treated with cloxacillin. Methods. We analyzed a prospectively collected cohort of patients with IE in a single tertiary-care hospital. Vancomycin, daptomycin, and cloxacillin MIC was determined by E-test. S. aureus strains were categorized as low vancomycin MIC (< 1.5 µg/mL) and high vancomycin MIC (≥ 1.5 µg/mL). The primary endpoint was in-hospital mortality. Results. We analyzed 93 patients with left-sided IE treated with cloxacillin, of whom 53 (57%) had a vancomycin MIC<1.5 µg/mL and 40 (43%) a vancomycin MIC≥1.5 µg/mL. In-hospital mortality was 30% (16/53) in patients with a low vancomycin MIC and 53% (21/40) in those with a high vancomycin MIC (p=0.030). No correlation was found between oxacillin MIC and vancomycin or daptomycin MIC. Logistic regression analysis showed that higher vancomycin MIC increased in-hospital mortality 3-fold (OR 3.1, 95% CI 1.2-8.2) after adjustment for age, year of diagnosis, septic complications, and non-septic complicated endocarditis. Conclusion. Our results indicate that vancomycin MIC could be used to identify a subgroup of patients with methicillin-susceptible S. aureus IE at risk of higher mortality. The worse outcome of staphylococcal infections with a higher vancomycin MIC cannot be explained solely by suboptimal pharmacokinetics of antibiotics.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To determine the relationship between measures of renal function [current estimated glomerular filtration rate (eGFR) and proportion of follow-up with a low eGFR (%FU <= 60 ml/min)] and fatal/ nonfatal AIDS, non-AIDS events and all-cause mortality. Design: An observational, longitudinal cohort study of 12 155 persons from EuroSIDA. Methods: Persons with at least one eGFR measurement after 1 January 2004, using the CKD-EPI formula, were included. Poisson regression analyses were used to determine whether current eGFR or %FU of 60 ml/min or less were independent prognostic markers for clinical events. Results: During 61 425 person-years of follow-up (PYFU), the crude incidence of deaths was 11.1/1000 PYFU [95% confidence interval (CI) 10.0-12.1] at current eGFR more than 90 ml/min and 199.6 (95% CI 1144.3-254.3/1000 PYFU) when current eGFR was 30 ml/min or less. Corresponding figures for AIDS were 12.2 (11.1-13.3) and 63.9 (36.5-103.7) and for non-AIDS were 16.0 (14.8-17.3) and 203.6 (147.7-259.5). After adjustment, current eGFR of 30 ml/min or less was a strong predictor of death [adjusted incidence rate ratios (aIRR) 4.35; 95% CI 3.20-5.91] and non-AIDS events (3.63; 95% CI 2.57-5.13), although the relationship with AIDS was less strong (1.45; 95% CI 1.01-2.08). After adjustment, %FU of 60 ml/min or less was associated with a 22% increased incidence of death (aIRR 1.22 per 10% longer; 95% CI 1.18-1.27), a 13% increased incidence of non-AIDS events (95% CI 1.08-1.18) and a 15% increased incidence of AIDS events (95% CI 1.06-1.24). Conclusion: Both current eGFR and %FU of 60 ml/min or less were associated with death and non-AIDS events in HIV-positive persons. Our findings highlight the association between underlying renal dysfunction and morbidity and mortality in HIV infection, although reverse causality cannot be excluded.
AIDS (London, England) 03/2014; 28(5):727-737. DOI:10.1097/QAD.0000000000000134 · 6.56 Impact Factor