Laura Bracciale

Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients

Background: Despite the availability of potent antiretroviral regimens (combination antiretroviral therapy [cART]), HIV-associated neurocognitive disorders (HAND) are increasingly recognized. Our aim was to investigate the prevalence and treatment-related correlates of HAND, exploring the potential neurotoxicity of antiretrovirals on cognitive functions. Methods: We performed a cross-sectional single cohort study by consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits. Each patient was submitted to a comprehensive neuropsychological battery and was considered cognitively impaired on the basis of results obtained in matched healthy HIV-negative subjects. CNS penetration effectiveness (CPE) rank was calculated for cART regimens according to 2010 CHARTER criteria. Factors associated with cognitive impairment were investigated by linear or logistic regression analysis. Results: A total of 146 patients were enrolled. Of these, 129 (88.4%) were on cART and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non-Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between CPE rank and cognitive impairment was observed. Conclusions: A high prevalence of HAND was observed in apparently asymptomatic HIV+ individuals. HAND was associated with efavirenz use, suggesting the potential neurotoxicity of this drug. Routine neuropsychological examinations could help clinicians make correct diagnoses and manage mild, but clinically relevant, forms of HAND.

Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice

OBJECTIVES To assess the inter-individual and intra-individual plasma concentration variabilities of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to investigate their relationships with virological failure. METHODS We retrospectively enrolled HIV-infected patients undergoing therapeutic drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma drug concentrations were measured by HPLC-UV and were considered therapeutic if above the proposed minimum efficacy trough concentration. Inter-individual and intra-individual variabilities were evaluated through the coefficient of variation (CV). RESULTS A total of 457 PI and 172 NNRTI plasma concentrations were measured from 363 patients (HIV-RNA <50 copies/mL in 70.8%, median CD4 count 434 cells/mm(3)). NNRTIs showed less inter-individual (CV(inter) 54.8% versus 84.3%) and intra-individual (CV(intra) 19.0% versus 38.1%) pharmacokinetic variabilities than PIs. Intra-individual variability was constantly lower than inter-individual variability for each drug. Subtherapeutic drug concentrations were observed in 106 samples (16.9%). Older age (P = 0.020) and higher viral load (P = 0.013) were associated with subtherapeutic levels. Patients with therapeutic levels had a viral load of <50 copies/mL more frequently than those with subtherapeutic levels (74.8% versus 63.2%, P = 0.020). The estimated proportion with virological failure at 24 weeks was 0.21 in patients with suboptimal baseline drug levels and 0.08 in those with optimal levels (P < 0.001). In the multivariate analysis, therapeutic drug levels showed an independent negative association with virological failure (P = 0.004). CONCLUSIONS A wide inter-individual and limited intra-individual pharmacokinetic variabilities, together with the demonstration of a concentration-response relationship, suggest that TDM is a useful tool for the clinical management of patients treated with NNRTIs or PIs.

Comparative determination of HIV-1 co-receptor tropism by Enhanced Sensitivity Trofile, gp120 V3-loop RNA and DNA genotyping

BackgroundTrofile® is the prospectively validated HIV-1 tropism assay. Its use is limited by high costs, long turn-around time, and inability to test patients with very low or undetectable viremia. We aimed at assessing the efficiency of population genotypic assays based on gp120 V3-loop sequencing for the determination of tropism in plasma viral RNA and in whole-blood viral DNA. Contemporary and follow-up plasma and whole-blood samples from patients undergoing tropism testing via the enhanced sensitivity Trofile® (ESTA) were collected. Clinical and clonal geno2pheno[coreceptor] (G2P) models at 10% and at optimised 5.7% false positive rate cutoff were evaluated using viral DNA and RNA samples, compared against each other and ESTA, using Cohens kappa, phylogenetic analysis, and area under the receiver operating characteristic (AUROC).ResultsBoth clinical and clonal G2P (with different false positive rates) showed good performances in predicting the ESTA outcome (for V3 RNA-based clinical G2P at 10% false positive rate AUROC = 0.83, sensitivity = 90%, specificity = 75%). The rate of agreement between DNA- and RNA-based clinical G2P was fair (kappa = 0.74, p < 0.0001), and DNA-based clinical G2P accurately predicted the plasma ESTA (AUROC = 0.86). Significant differences in the viral populations were detected when comparing inter/intra patient diversity of viral DNA with RNA sequences.ConclusionsPlasma HIV RNA or whole-blood HIV DNA V3-loop sequencing interpreted with clinical G2P is cheap and can be a good surrogate for ESTA. Although there may be differences among viral RNA and DNA populations in the same host, DNA-based G2P may be used as an indication of viral tropism in patients with undetectable plasma viremia.

Prevalence of transmitted HIV-1 drug resistance in HIV-1 infected patients in Italy: evolution over 12 years and predictors

OBJECTIVES Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy. PATIENTS AND METHODS A retrospective analysis was performed to assess the prevalence and correlates of TDR in Italy over time. TDR was defined as the presence of at least one of the mutations present in the surveillance drug resistance mutation (SDRM) list. RESULTS Among 1690 antiretroviral therapy-naive patients, the most frequent HIV subtypes were B (78.8%), CRF02_AG (5.6%) and C (3.6%). Overall, TDR was 15%. TDR was 17.3% in subtype B and 7.0% in non-B carriers (P < 0.001). TDR showed a slight, although not significant, decline (from 16.3% in 1996-2001 to 13.4% in 2006-07, P = 0.15); TDR declined for nucleoside reverse transcriptase inhibitors (from 13.1% to 8.2%, P = 0.003) but remained stable for protease inhibitors (from 3.7% to 2.5%, P = 0.12) and non-nucleoside reverse transcriptase inhibitors (from 3.7% to 5.8%). TDR to any drug was stable in B subtype and showed a decline trend in non-B. In multivariable analysis, F1 subtype or any non-B subtype, compared with B subtype, and higher HIV RNA were independent predictors of reduced odds of TDR. CONCLUSIONS Prevalence of TDR to nucleoside reverse transcriptase inhibitors seems to have declined in Italy over time. Increased prevalence of non-B subtypes partially justifies this phenomenon.

Cardiovascular risk score change in HIV‐1‐infected patients switched to an atazanavir‐based combination antiretroviral regimen

We aimed to establish whether the limited impact of atazanavir on the plasma lipid profile could translate into a reduction in the predicted cardiovascular risk in antiretroviral (ARV)‐experienced patients switching to an atazanavir‐containing regimen.

Serological response to hepatitis B virus vaccine in HIV-infected children in Tanzania.

HIV‐infected children have a lower seroconversion rate to hepatitis B virus (HBV) immunization than healthy children. Previous studies have produced conflicting results on CD4 cell counts as predictors of vaccine response. No study has evaluated the response rate to HBV vaccination in HIV‐infected children receiving highly active antiretroviral therapy (HAART). Our aim was to vaccinate HIV‐infected children living in a close community and to investigate the anamnestic response rate after vaccination with its predictors.

Darunavir/ritonavir and raltegravir coadministered in routine clinical practice: potential role for an unexpected drug interaction

The present study aimed to investigate potential drug interactions between darunavir and raltegravir in patients treated for HIV infection. We enrolled HIV-infected subjects on darunavir-containing regimens that underwent measurement of plasma darunavir trough concentration (12±3 h after dosing). Two groups of patients were compared: those taking darunavir plus a nucleoside/nucleotide backbone (group 1) or a backbone+raltegravir (group 2). Interindividual pharmacokinetic variability was evaluated through the coefficient of variation (CV(inter)). We obtained 156 plasma samples from 63 patients, of which 44 in group 1 and 19 in group 2. Overall, darunavir geometric mean concentration was 2.90 mg/L (95% CI 2.34-3.60) while ritonavir geometric mean concentration was 0.21 mg/L (95% CI 0.17-0.27). We observed a high inter-individual variability in darunavir (CV(inter) 59%) and ritonavir (CV(inter) 103%) plasma levels. Darunavir concentration correlated with concomitant ritonavir levels (r=0.476, p<0.001). Patients in group 1 had a higher darunavir geometric mean concentration than those in group 2 [3.44 mg/L (95% CI 2.79-4.23) versus 1.95 mg/L (95% CI 1.19-3.20), p=0.017]. However, the proportion of subjects with concomitant HIV-RNA <50 copies/mL was higher in group 2 (78.9% versus 47.7%, p=0.028). In a multivariable model, raltegravir co-administration was independently related to a lower darunavir concentration (mean difference -0.25 log(10) mg/L, 95% CI -0.46/-0.04, p=0.020) after adjusting for time from last drug intake and concomitant drugs used. In conclusion, a potential drug interaction between darunavir and raltegravir was observed, although this did not seem virologically significant. For the distinct metabolic pathways of these drugs, its mechanism remains to be determined.

Lipid-lowering effect of tenofovir in HIV-infected patients

3 Falagas ME, Manta KG, Ntziora F et al. Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence. J Antimicrob Chemother 2006; 58: 273–80. 4 Raad I, Hanna H, Jiang Y et al. Comparative activity of daptomycin, linezolid and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm. Antimicrob Agents Chemother 2007; 51: 1656–60. 5 Buchanan LV, Dailey CF, LeMay RJ et al. Time-dependent antibacterial effects of linezolid in experimental rabbit endocarditis. J Antimicrob Chemother 2002; 50: 440–2. 6 Pistella E, Campanile F, Bongiorno D et al. Successful treatment of disseminated cerebritis complicating methicillin-resistant Staphylococcus aureus endocarditis unresponsive to vancomycin therapy with linezolid. Scand J Infect Dis 2004; 36: 222–5.

Tenofovir discontinuation could predispose to urolithiasis in atazanavir-treated patients

Urolithiasis has been recognized as a potential complication of antiretroviral therapy. Protease inhibitors are the drugs most commonly involved: indinavir can cause renal colic in about 8% of patients and lopinavir/ritonavir has been associated with seven cases of nephrolithiasis. The occurrence of renal colic during treatment with atazanavir is a rare, but reported event. Here we describe the case of a 43 years-old male patient enrolled in a pilot study evaluating the efficacy, safety and tolerability of treatment simplification to a dual therapy with atazanavir/ritonavir plus lamivudine in HIV-positive patients with optimal virological response (AtLaS study). The study was conducted in accordance with the Declaration of Helsinki and national and institutional standards and was approved by local ethic committee; signed informed consent was collected from all participants. At baseline, the patient, treated with atazanavir/ ritonavir þ tenofovir þ lamivudine for 4 years, with a CD4 count of 718 cells/mL and an HIV-RNA < 50 copies/mL, without hepatitis B or C co-infection, discontinued tenofovir according to the study design. Eight weeks thereafter he was hospitalized for severe right flank pain and fever. Serum blood exams revealed increased creatinine (1.6 mg/dL) with normal calcium, phosphate and uric acid levels. Urinanalysis showed a pH of 6.5, with no calcium, phosphate and uric acid abnormalities. The same day a spontaneous urinary stone emission occurred. A renal TC scan performed 3 days later revealed a right pyelic dilatation without any other stone. Two stones, weighting 5.9 and 13.6 mg respectively, were analyzed. They were dissolved in 250 mL of 20% H2SO4 and the supernatants were injected in an HPLC-UV apparatus for atazanavir measurement, as previously described. Drug concentrations in the two stones were 3.72 and 3.33 mg/mL. The estimated total amount of atazanavir was 0.93 and 1.08 mg respectively, which corresponded to a percent compositionof atazanavir ranging from7.9% to15.8% (Fig. 1). Four and 12 weeks after tenofovir discontinuation, atazanavir plasma levels increased from 3.84 to 3.89 and 6.27 mg/mL, respectively (all samples collected 9 h after drug intake).