Elena Ferrer

Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study.

Objective:To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients. Methods:This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks. Results:A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (−1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed. Conclusions:Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.

Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine.

Objective:To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir. Design and methods:NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements. Results:Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed. Conclusions:Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

Background:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. Methods:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure [“switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Results:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. Conclusions:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study.

Objectives:To evaluate the efficacy and safety of switching from boosted lopinavir (LPV/r) to boosted atazanavir (ATV/r) in virologically suppressed HIV-1-infected patients versus continuing LPV/r. Methods:Forty-eight weeks analysis of a randomized, open-label, noninferiority trial including patients with virological suppression (≤200 copies/mL for ≥6 months) on LPV/r-containing triple highly active antiretroviral therapy. Patients (n = 248) were randomized 1:1 either to continue LPV/r twice a day (n = 127) or to switch to ATV/r every day (ATV/r; n = 121), with no change in nucleoside reverse transcriptase inhibitor backbone. Those known to have >4 protease inhibitor (PI)-associated mutations and/or who had failed >2 PI-containing regimens were excluded. Results:Baseline characteristics were balanced. 30% harboured ≥1 PI-associated mutation (10% harboured ≥1 major mutation). Treatment failure at 48 weeks (primary end point) occurred in 20% (25 of 127) of the LPV/r arm and in 17% (21 of 121) of the ATV/r arm (difference −2.3%; 95% confidence interval: −12.0 to 8.0; P = 0.0018). Virological failure occurred in 7% (9 of 127) of the LPV/r arm and in 5% (6 of 121) of the ATV/r arm (difference −2.1%; 95% confidence interval: −8.7% to 4.2%, P < 0.0001 for noninferiorating). CD4+ changes from baseline were similar in each arm (approximately 40 cells/mm3). Adverse event rate leading to study drug discontinuation was 5% in both arms. Median fasting triglycerides and total cholesterol decreased significantly in the ATV/r arm (−53 and −19 mg/dL, respectively versus −4 and −4 mg/dL in the LPV/r arm; P < 0.001 in both comparisons). Alanine aminotransferase/aspartate aminotransferase hepatic abnormalities were similar in the 2 arms. Conclusions:Switching to ATV/r in virologically suppressed patients who were receiving a LPV/r-containing highly active antiretroviral therapy provided comparable (noninferior) efficacy and a safety profile with improved lipid parameters [ISRCTN24813210].

Comparison of twice-daily stavudine plus once- or twice-daily didanosine and nevirapine in early stages of HIV infection: the Scan Study.

ObjectivesTo evaluate the safety and effectiveness of once-daily didanosine and nevirapine plus twice-daily stavudine versus twice-daily administration of all three drugs. MethodsThis open-label, randomized, multicentre study enrolled 94 antiretroviral-naive patients with chronic HIV infection, CD4+ cell counts > 500 × 106 cells/l, and viral loads > 5000 copies/ml. Patients were treated with either 40 mg stavudine (twice daily) plus 400 mg didanosine (once daily) and 400 mg nevirapine (once daily) or 40 mg stavudine (twice daily) plus 200 mg didanosine (twice daily) and 200 mg nevirapine (twice daily). ResultsAfter 12 months, 68% of patients who received twice-daily didanosine and nevirapine had viral loads < 200 copies/ml in the intention-to-treat and 79% in the on-treatment analysis, respectively. The corresponding values for patients treated with didanosine and nevirapine, taken once-daily, were 73 and 85%. The percentages of patients in each group with viral loads < 5 copies/ml at 12 months were 40% (once daily ) and 45% (twice daily) for the intention-to-treat analysis. Five of 11 patients (45%) with plasma viral loads < 5 copies/ml at 12 months had detectable virus in tonsillar tissue. Genotypic resistance to nevirapine was noted in seven of the 14 patients with detectable viral load at month 12. Mean changes in CD4+ cell counts for patients treated with stavudine plus once- or twice-daily didanosine and nevirapine were 154 and 132 × 106 cells/l, respectively. Treatment was interrupted due to adverse events in seven patients (8%) (four who received once-daily didanosine and nevirapine and three treated with twice-daily doses). ConclusionsThe combination of twice-daily stavudine plus once-daily didanosine and nevirapine was as safe and well tolerated as twice-daily administration of all three agents. Both regimens were equally effective in reducing viral loads and in increasing CD4+ cell counts.

Características clinicoepidemiológicas y tendencias en el tratamiento antirretroviral de una cohorte de pacientes con infección por el virus de la inmunodeficiencia humana. Cohorte PISCIS

Fundamento y objetivo: Los objetivos de este estudio fueron describir el proceso de implementacion de la cohorte PISCIS y las caracteristicas clinicoepidemiologicas y las tendencias en el tratamiento antirretroviral (TARV) de los pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH) incluidos desde 1998 hasta 2003. Pacientes y metodo: Estudio de cohorte prospectivo de pacientes con infeccion por el VIH de 16 anos de edad o mayores atendidos en primera visita en 10 hospitales de Cataluna y uno de las Baleares. El analisis estadistico de las tendencias se realizo mediante el test de la *2 de Mantel. Resultados: Se incluyo a un total de 5.968 pacientes (edad media: 39,5 anos; 75% varones) con un tiempo medio de seguimiento de 26,4 meses (13.130 personas-ano). Del total, 2.763 fueron nuevos diagnosticos, en los que la via de transmision mas frecuente fue la heterosexual (43%), seguida de la homosexual (31%). Se observo una tendencia significativamente creciente en la proporcion de sujetos de edad inferior a 35 anos e inmigrantes. Un 43% tenian una cifra de linfocitos CD4 inferior a 200 celulas/µl en la determinacion mas cercana al diagnostico de la infeccion por el VIH. Del total, un 87% estaban en TARV en el ano 2003. Entre los pacientes no tratados previamente que iniciaron pautas de TARV con 3 o mas farmacos, se observo una disminucion de las pautas que incluian inhibidores de la proteasa (del 85% en 1998 al 25% en 2003; p < 0,001), mientras que aumentaron otras que contenian inhibidores de la transcriptasa inversa no analogos y analogos de los nucleosidos. Conclusiones: Las cohortes de pacientes con infeccion por el VIH son viables en nuestro medio y tienen gran utilidad clinica y en salud publica. La via de transmision mas frecuente entre los nuevos diagnosticos es la heterosexual, el retraso en el diagnostico es elevado y las pautas de TARV han ido cambiando para adaptarse a las recomendadas por las guias.

Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in high-income countries.

BACKGROUND The lower tuberculosis incidence reported in human immunodeficiency virus (HIV)-positive individuals receiving combined antiretroviral therapy (cART) is difficult to interpret causally. Furthermore, the role of unmasking immune reconstitution inflammatory syndrome (IRIS) is unclear. We aim to estimate the effect of cART on tuberculosis incidence in HIV-positive individuals in high-income countries. METHODS The HIV-CAUSAL Collaboration consisted of 12 cohorts from the United States and Europe of HIV-positive, ART-naive, AIDS-free individuals aged ≥18 years with baseline CD4 cell count and HIV RNA levels followed up from 1996 through 2007. We estimated hazard ratios (HRs) for cART versus no cART, adjusted for time-varying CD4 cell count and HIV RNA level via inverse probability weighting. RESULTS Of 65 121 individuals, 712 developed tuberculosis over 28 months of median follow-up (incidence, 3.0 cases per 1000 person-years). The HR for tuberculosis for cART versus no cART was 0.56 (95% confidence interval [CI], 0.44-0.72) overall, 1.04 (95% CI, 0.64-1.68) for individuals aged >50 years, and 1.46 (95% CI, 0.70-3.04) for people with a CD4 cell count of <50 cells/μL. Compared with people who had not started cART, HRs differed by time since cART initiation: 1.36 (95% CI, 0.98-1.89) for initiation <3 months ago and 0.44 (95% CI, 0.34-0.58) for initiation ≥3 months ago. Compared with people who had not initiated cART, HRs <3 months after cART initiation were 0.67 (95% CI, 0.38-1.18), 1.51 (95% CI, 0.98-2.31), and 3.20 (95% CI, 1.34-7.60) for people <35, 35-50, and >50 years old, respectively, and 2.30 (95% CI, 1.03-5.14) for people with a CD4 cell count of <50 cells/μL. CONCLUSIONS Tuberculosis incidence decreased after cART initiation but not among people >50 years old or with CD4 cell counts of <50 cells/μL. Despite an overall decrease in tuberculosis incidence, the increased rate during 3 months of ART suggests unmasking IRIS.

Genotype and Phenotype at Baseline and at Failure in Human Immunodeficiency Virus–Infected Antiretroviral-Naive Patients in a Randomized Trial Comparing Zidovudine and Lamivudine plus Nelfinavir or Nevirapine

For the 127 Spanish patients enrolled in the Combine Study, a resistance substudy was performed with 100 (79%) plasma samples obtained at baseline and with 18 samples obtained from 19 patients at the time they experienced treatment failure. At baseline, primary mutations to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors were not detected, whereas mutations to nucleoside reverse-transcriptase inhibitors were observed in 10% of patients. At failure, mutations were detected in 7 of 16 patients. An agreement in the results of virtual and real phenotypes was observed in the 93 samples in which both tests were performed.

Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score

BACKGROUND Limited data exists regarding biomarker use to predict left ventricular (LV) reverse remodeling (R2). Our aim was to examine the value of soluble ST2 (ST2), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and galectin-3 relative to LV-R2 in systolic heart failure (HF), and to develop a clinical score for LV-R2 prediction. METHODS R2 was defined as a) LV ejection fraction (LVEF) increase ≥15%, or b) LVEF increase ≥10% plus reduction of LV end-systolic diameter index ≥20% or LV end-systolic volume ≥40%, for 12 months. RESULTS We studied 304 patients (79.6% men, mean age 66.1 ± 12.3 years) with baseline LVEF <40%. R2 was observed in 104 patients (34.2%). In univariable logistic regression, factors associated with R2 were age (p=0.02), non-ischemic etiology of HF (p<0.001), NYHA functional class (p=0.02), baseline LVEF (p=0.005), absence of left bundle branch block (LBBB; p=0.002), ST2 (p=0.004), NT-proBNP (p=0.005), and hs-cTnT (p<0.001); HF duration achieved borderline significance (p=0.08). In multivariable analysis, ST2 remained the only biomarker associated with LV-R2. We developed the ST2-R2 score for use in clinical practice for predicting R2; variables included were ST2 <48 ng/mL, non-ischemic etiology, absence of LBBB, HF duration <12 months, baseline LVEF <24%, and β-blocker treatment. The score had an area under the curve of 0.79 in the derivation cohort and 0.73 in a separate validation cohort. CONCLUSIONS The ST2-R2 score, which includes the novel biomarker ST2 and five clinical variables, reasonably predicts LV-R2 in systolic HF patients. ST2 was the only studied biomarker that was independently associated with R2.

Detection of latent tuberculosis by the tuberculin skin test and a whole-blood interferon-γ release assay, and the development of active tuberculosis in HIV-seropositive persons

This study evaluated the QuantiFERON-TB Gold In-Tube (QFT-GIT; Cellestis, Carnegie, Australia) test and the tuberculin skin test (TST) for the detection of latent tuberculosis infection (LTBI) in HIV-infected adults. One hundred thirty-five HIV-seropositive persons and 135 controls underwent TST and QFT-GIT. HIV-infected patients who gave a positive result on either test were offered chemoprophylaxis. The prevalence of LTBI was 6.7% by TST and 9.6% by QFT-GIT (P = 0.3) in HIV-seropositive subjects, and 34.8% by TST and 21.5% by QFT-GIT (P = 0.02) among controls. TST reactivity declined sharply as CD4(+) cells fell (15.8%, 10.3%, and 0% for >500, 301-500 and ≤300 CD4(+) cells/mm(3), respectively; P = 0.002). A less pronounced fall occurred with QFT-GIT (15.8%, 13.8%, and 0% for >500, 301-500, and <100 CD4(+) cells/mm(3), respectively; P = 0.03). No cases of tuberculosis occurred during follow-up (0.26 per 100 person-years). Simultaneous testing with TST and QFT-GIT for targeting of chemoprophylaxis, early in the course of HIV infection, might minimize the risk of tuberculosis in these patients.