Maria Larrousse

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients.

Background: Current therapies for chronic hepatitis C virus (HCV) in HIV co-infected patients have a low success rate and are poorly tolerated. We have evaluated the efficacy and safety of interferon alfa-2b (IFN) + ribavirin (RBV) versus pegylated interferon alfa-2b (PEG-INF) + RBV. Methods: Randomized, single-centre, open-label clinical trial including patients with: detectable HCV-RNA, alanine aminotransferase > 1.5-fold upper limit of normal, abnormal liver histology, CD4 cell count > 250 × 106/l and HIV RNA < 10 000 copies/ml. Patients were assigned to INF (3 × 106 units three times/week) or PEG-IFN (100–150 μg/week) plus RBV (800–1200 mg/day). Duration of treatment was 48 weeks (only 24 weeks for HCV genotypes 2 or 3 and baseline HCV RNA < 800 000 IU/ml). The primary endpoint was a sustained virological response (SVR). Results: Ninety-five patients were randomized (43 INF + RBV, 52 PEG-INF + RBV), 68% males, 82% injecting drug users; 63% genotypes 1 or 4 and 36% genotypes 2 or 3; 62% fibrosis index grade ⩾2 and 30% bridging fibrosis/cirrhosis. SVR was significantly higher in the PEG-INF + RBV arm, 44% versus 21% (intent to treat; P = 0.017). Among patients with genotypes 1 or 4, SVR were 38% versus 7% (P = 0.007) and 53% versus 47% (P = 0.730) for genotypes 2 or 3. CD4 cell count but not its percentage dropped in both arms and HIV RNA viral load did not change from baseline. Side effects were very frequent in both arms leading to treatment discontinuation in 14 patients without statistical differences between arms (P = 0.565). Conclusion: PEG-INF + RBV was significantly more effective than INF + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4.

Increased risk of pre-eclampsia and fetal death in Hiv-infected pregnant women receiving highly active antiretroviral therapy

Background:Pre-eclampsia and/or fetal death have increased sharply in HIV-infected pregnant women receiving HAART. Methods:The occurrence of pre-eclampsia or fetal death was analysed in women who delivered after at least 22 weeks of gestation for all women (January 2001 until July 2003) and for HIV-infected women (November 1985 until July 2003). Results:In 2001, 2002 and 2003, the rates per 1000 deliveries of pre-eclampsia and fetal death, respectively, remained stable in all pregnant women at 25.4, 31.9 and 27.7 (P = 0.48) and 4.8, 5.8, and 5.0 (P = 0.89) (n = 8768). In 1985–2000 (n = 390) to 2001–2003 (n = 82), rates per 1000 deliveries in HIV-infected women rose from 0.0 to 109.8 (P < 0.001) for pre-eclampsia and from 7.7 to 61.0 (P < 0.001) for fetal death. In all pregnant women, factors associated with pre-eclampsia or fetal death were multiple gestation [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.3–5.6; P < 0.001], HIV infection (adjusted OR, 4.9; 95% CI, 2.4–10.1; P < 0.001), multiparity (adjusted OR, 0.76; 95% CI, 0.58–0.98; P = 0.040) and tobacco smoking (adjusted OR, 0.65; 95% CI, 0.46–0.90; P = 0.010). The use of HAART prior to pregnancy (adjusted OR, 5.6; 95% CI, 1.7–18.1; P = 0.004) and tobacco smoking (adjusted OR, 0.183; 95% CI, 0.054–0.627; P = 0.007) were risk factors in HIV-infected women. Conclusions:HIV infection treated with HAART prior to pregnancy was associated with a significantly higher risk for pre-eclampsia and fetal death.

Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study

Background:Switching to raltegravir in selected patients treated with ritonavir-boosted protease inhibitors may result in similar efficacy and lower plasma lipids. Methods:SPIRAL is a 48-week multicentre, open-label trial in which HIV-infected adults with less than 50 copies/ml of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1: 1) to switch from the ritonavir-boosted protease inhibitor to raltegravir or to continue on ritonavir-boosted protease inhibitor-based therapy. Primary endpoint was the proportion of patients free of treatment failure (noncompleter = failure) at 48 weeks. SPIRAL study was powered to show noninferior efficacy of raltegravir-based therapy with a margin of −12.5%. Results:Two hundred and seventy-three patients assigned to switch to raltegravir (n = 139) or to continue ritonavir-boosted protease inhibitor (n = 134) were included in the efficacy analysis. At 48 weeks, 89.2% (raltegravir-based therapy) and 86.6% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of treatment failure [difference 2.6%; 95% confidence interval (CI) −5.2 to 10.6]. A total of 96.9% (raltegravir-based therapy) and 95.1% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of virological failure (difference 1.8%; 95% CI −3.5 to 7.5). Switching to raltegravir was associated with significant decreases in plasma lipids and total-to-HDL cholesterol ratio relative to continuing ritonavir-boosted protease inhibitor. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4 and 2% of the patients in each group. Conclusion:In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitor to raltegravir demonstrated noninferior efficacy and resulted in a better lipid profile at 48 weeks than continuing ritonavir-boosted protease inhibitor.

Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area

Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV‐infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age‐matched general population living in the same geographical region.

Randomized trial comparing pegylated interferon α‐2b versus pegylated interferon α‐2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients

Although two pegylated interferons (Peg‐IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head‐to‐head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa‐2b (PEG 2b) versus PEG IFN alfa‐2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi‐center, open‐label clinical trial including 182 human immunodeficiency virus (HIV)–hepatitis C virus (HCV) patients naïve for HCV therapy was performed. Patients were assigned to PEG 2b (80‐150 μg/week; n = 96) or PEG 2a (180 μg/week; n = 86), plus RBV (800‐1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV‐RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 through 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 through 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 through 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; ≥2 log reduction from baseline or negative HCV‐RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). Conclusion: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety. (HEPATOLOGY 2009;49:22‐31.)

Risk of Metabolic Abnormalities in Patients Infected with HIV Receiving Antiretroviral Therapy that Contains Lopinavir-Ritonavir

The evolution of fasting glucose, triglyceride, and total and high-density lipoprotein (HDL) cholesterol level and the factors associated with development of clinically significant abnormalities in these metabolic parameters at 6 months were assessed in 353 consecutive human immunodeficiency virus (HIV)-infected patients who were receiving antiretroviral therapy containing lopinavir-ritonavir. Although glucose and HDL cholesterol levels did not change, triglyceride and total cholesterol levels significantly increased (P<.0001 for each), as did the proportion of patients with a triglyceride level of >400 mg/dL and a total cholesterol level of >240 mg/dL (P=.002). A baseline triglyceride level of >400 mg/dL and a baseline total cholesterol level of >240 mg/dL were identified as independent factors predicting clinically significant hypertriglyceridemia and hypercholesterolemia, respectively, at 6 months. These findings may have clinical implications when the therapeutic option of lopinavir-ritonavir is considered.

Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults

The rise in didanosine concentrations in plasma when given with tenofovir raises concern for a high risk of toxic effects. Recommendations to reduce didanosine dose have been issued, but only for adults weighing more than 60 kg. We reviewed cases of pancreatitis in patients receiving didanosine plus tenofovir, didanosine alone, and tenofovir alone to assess the incidence of and risk factors for pancreatitis. Between Aug 1, 2001, and Nov 30, 2003, five of 185 (2.7%) patients receiving didanosine plus tenofovir, one of 182 (0.5%) on didanosine without tenofovir, and none of 208 on tenofovir without didanosine developed pancreatitis (p=0.016). Co-administration of both drugs versus each of them individually was an independent risk factor for pancreatitis (crude hazard ratio 10.666, 95% CI 1.246-91.294, p=0.031). These results suggest that the risk of pancreatitis is heightened when didanosine and tenofovir are given together.

Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction.

Objective:To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers. Design:Sub-study of the BICOMBO study in which participants were randomized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine. Methods:We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), osteoprotegerin, interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), selectin E and P, adiponectin, insulin, and D-dimer in otherwise healthy, virologically suppressed HIV-infected patients randomly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease, no prior abacavir or tenofovir use, and no virological failure or AIDS during follow-up. Results:Eighty (46 abacavir/lamivudine and 34 tenofovir/emtricitabine) patients were included. Baseline characteristics were similar between groups and between patients in the sub-study vs. those not. There were no significant differences in baseline lipids and markers between groups. Although total (6.5 vs. −6.7%, P < 0.0001) and low-density lipoprotein (LDL) (8.6 vs. −9.1%, P = 0.004) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group, we found no significant changes in the biomarkers: CRP (−3.9 vs. 0.0%), MCP-1 (5.9 vs. 4.0%), osteoprotegerin (5.1 vs. −2.8%), IL−6 (0.0 vs. 0.0%), IL-10 (0.0 vs. 0.0%), TNF-alpha (0.0 vs. 0.0%), ICAM-1 (6.6 vs. 5.2%), VCAM-1 (0.02 vs. −0.01%), selectin E (−0.4 vs. 7.8%), selectin P (4.6 vs. 12.6%), insulin (−2.5 vs. 8.8%), adiponectin (−2.2 vs. 15.4%), and D-dimer (0.0 vs. 0.0%) (P ≥ 0.12 for all comparisons). Conclusion:Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine, but it did not cause inflammation, endothelial dysfunction, insulin resistance, or hypercoagulability in virologically suppressed HIV-infected patients.

Body composition changes after switching from protease inhibitors to raltegravir: SPIRAL-LIP substudy.

Objective:To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r. Design:Substudy of the prospective, randomized, open-label, multicenter SPIRAL study. Methods:Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences. Results:Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median [interquartile range (IQR)] visceral adipose tissue (VAT) [20.7 (−2.4 to 45.6) cm2, P = 0.002] and total adipose tissue (TAT) [21.4 (−1.3 to 55.4) cm2, P = 0.013] were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD [0.01 (0 to 0.02) g/cm2, P = 0.002], total hip BMD [0.01 (0 to 0.03) g/cm2, P = 0.015] and total hip T score [0.12 (−0.05 to 0.21) SD, P = 0.004] significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD [0.01 (−0.02 to 0.02) g/cm2, P = 0.032] and T score [0.01 (−0.18 to 0.18) SD, P = 0.016]. Conclusion:Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.

Urinary albumin excretion is associated with true resistant hypertension

Resistant (or refractory) hypertension (RH) is a clinical diagnosis based on blood pressure (BP) office measurements. About one third of subjects with suspected RH have indeed pseudo-resistant hypertension and 24-h ambulatory-blood pressure-monitoring aids to precisely identify them. Our aim was to determine those clinical, laboratory or echocardiographic variables that may be associated with subjects with sustained hypertension (namely true RH). We carried out a cross-sectional analysis of 143 patients consecutively enrolled with the clinical diagnosis of RH. All patients underwent clinical-demographic, laboratory evaluation, 2D-echocardiography and 24-h ambulatory-blood pressure-monitoring. Pseudo-resistant hypertension or white-coat RH was defined if office BP was ⩾140 and/or 90 mm Hg and 24-h BP <130/80 mm Hg. One-hundred and three (72%) patients had true RH and 40 (28%) patients had white-coat RH. True RH patients had significantly higher diabetes prevalence and higher office-systolic blood pressure (SBP) levels. Regarding target organ damage, left ventricular mass index (LVMI) and 24-h urinary albumin excretion (UAE) were also higher in true RH after adjustment for possible confounders (P=0.031 and P=0.012, respectively). In a logistic regression analysis, only office-SBP (multivariate OR (95%CI): 1.030 (1.003–1.057), P=0.030) and UAE (multivariate OR (95% CI): 2.376 (1.225–4.608), P=0.010) were independently associated with true RH. We conclude that true resistant hypertension is associated with silent target organ damage, especially UAE. In patients with suspected RH, assessment of 24 h ambulatory BP is the most accurate way to detect a population with high risk for target-organ damage.