Maria Saumoy

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.

Delayed diagnosis of HIV infection in a multicenter cohort: prevalence, risk factors, response to HAART and impact on mortality.

To study the prevalence of Delayed HIV Diagnosis (DHD) and its associated risk factors, to evaluate the effect of DHD on virological and immunological responses to HAART and to estimate the impact of DHD on all-causes mortality. Prospective cohort of 2, 564 HIV-positive HAART-naïve subjects attending 19 hospitals in Spain, 2004-2006. Estimations were made by logistic regression and survival analyses by Cox regression models. Prevalence of DHD was 37.3% (35.0-39.6). DHD was related to low educational level (OR:1.31, 95% CI:1.0-1.7). Compared to men who have sex with men (MSM), DHD was more frequent in heterosexuals (OR:1.9 95% CI:1.5-2.5) and injection drug users (IDUs) (OR:2.0 95% CI:1.5-2.8). An interaction between age and sex was found. Although risk of having DHD did not increase after age 30 in women, it increased linearly with age in men. No differences in virological (OR 1.2 95% CI: 0.8-1.8) and CD4 T cell (OR 1.1 95% CI: 0.7-1.8) responses to HAART were seen. The adjusted hazard ratio for death in patients with DHD was 5.2, (95% CI: 1.9-14.5). DHD is very common, especially in older men, heterosexuals and IDUs. Although we did not find differences in virological and immunological responses to HAART, we did observe higher mortality in people with DHD. Increased efforts to early diagnose HIV infection are urgently needed.

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.

In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells

ABSTRACT We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P = 0.002) and TFV (P = 0.0001). The combination of 10 μM RTV and 40 μM LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.

Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine.

A 65-year-old man with chronic lymphocytic leukemia (CLL) diagnosed 11 years ago and treated with standard dose of fludarabine developed a rapidly fatal progressive neurological syndrome. Differential diagnoses included brain infiltration by CLL as opposed to progressive multifocal leukoencephalopathy (PML). A magnetic resonance imaging (MRI) scan showed a hyperintense T2-weighted signal in the left frontal region. Cerebro-spinal fluid polymerase chain reaction (PCR) was positive for virus JC (JCV). These findings were compatible with the diagnosis of PML. Fludarabine has been used to treat acute leukemias, CLL and follicular lymphomas. Its toxicity includes myelosuppression, immunosuppression and sporadic life-threatening neurotoxicity, although standard doses of it are considered safe. Late-onset fatal cerebral dysfunction caused by JCV after standard-dose fludarabine has been described previously. The widespread and increasing use of fludarabine makes it interesting to define the potential of standard doses of fludarabine for causing severe neurological side-effects such as PML.

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.

The Lipid-Lowering Effect of Tenofovir/Emtricitabine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial

BACKGROUND It is unknown if tenofovir disoproxil fumarate (TDF), which is often coformulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect. METHODS We performed a randomized, crossover, double-blind, placebo-controlled clinical trial on human immunodeficiency virus type 1 (HIV-1)-infected subjects with HIV-1 RNA < 50 copies/mL during ≥6 months on stable darunavir/ritonavir (800/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily) monotherapy, fasting total cholesterol (TC) ≥200 mg/dL or low-density lipoprotein cholesterol (LDL-c) ≥130 mg/dL, and no lipid-lowering drugs. In arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (washout) and 12 additional weeks of placebo (placebo period). Subjects in arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (washout). The primary endpoint was change in median fasting TC levels. RESULTS Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced TC from 234 to 205 mg/dL (P < .001), LDL-c from 155 to 128 mg/dL (P < .001), and high-density lipoprotein cholesterol (HDL-c) from 50.3 to 44.5 mg/dL (P < .001). It also decreased the proportion of subjects with fasting TC ≥200 mg/dL from 86.7% to 56.8% (P = .001), and LDL-c ≥130 mg/dL from 87.8% to 43.9% (P < .001). After 12 weeks, TDF/FTC exposure was associated with lower TC and LDL-c levels than placebo (P = .001 and P = .002, respectively). The TC/HDL-c ratio and triglyceride levels did not change with TDF/FTC exposure. CONCLUSIONS Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF. CLINICAL TRIALS REGISTRATION NCT01458977.

HIV-1-Infected Long-Term Non-Progressors have Milder Mitochondrial Impairment and Lower Mitochondrially-Driven Apoptosis in Peripheral Blood Mononuclear Cells than Typical Progressors

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

Polymorphism of RANTES chemokine gene promoter is not associated with long-term nonprogressive HIV-1 infection of more than 16 years

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions −28C>G, −109T>C, and −403G>A were assessed. The prevalence of the CCR5Δ 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the χ2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for −28G; 4%, 2%, and 2% for −109C; and 18%, 18%, and 18% for −403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Δ32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.

The IL-6 system in HIV-1-infection and in HAART-related fat redistribution syndromes.

We determined the IL-6 −174 G>C single nucleotide polymorphism, IL-6 mRNA expression in subcutaneous adipose tissue (SAT) and IL-6 plasma levels in HIV-1-infected patients with and without lipodystrophy and uninfected controls. HIV-1-infected patients had a greater prevalence of the IL-6 −174 C/C genotype and the C allele, higher SAT IL-6 mRNA expression and plasma IL-6 levels than controls. The IL-6 −174 G>C genotype distribution and allele frequencies, SAT IL-6 mRNA expression and IL-6 plasma levels were non-significantly different between HIV-1-infected patients with and without lipodystrophy.