Chiara Bellacosa

Early Markers of Tubular Dysfunction in Antiretroviral-Experienced HIV-Infected Patients Treated with Tenofovir Versus Abacavir

Tenofovir disoproxil fumerate (TDF) is an effective nucleoside reverse transcriptase inhibitor for HIV infection but it is potentially nephrotoxic. A selective mithochondrial toxicity has been hypothesized. To assess early markers of renal toxicity, we evaluated a cohort of antiretroviral (ARV)-experienced HIV patients who had been switched from a thymidinic backbone to either a TDF/emtricitabine regimen (TDF; 73 patients) or an abacavir/lamivudine (ABV) regimen (28 patients). Markers of mitochondrial toxicity (cytochrome c, Cyc) or cytosolic (α-glutathione S transferase, α-GST) together with common indicators of renal damage were assessed at baseline (T0) and after 1 (T1), 3 (T2), 6 (T3), and 12 (T4) months of patient exposure to therapy. Clinical features of both groups were comparable at T0. There was no significant variation in estimated glomerular filtration rate (eGRF), median urine protein excretion, or microalbuminuria and serum phosphate levels in both groups during the study period. There was a significant increase in urinary excretion of phosphate in patients on TDF compared to those on ABV at T3 and T4. Fractional excretion of uric acid was also altered in the two treatment groups; there was no change in the ABV (constantly less than 0.10), but a progressive increase in TDF patients. Serum potassium levels were significantly lower in ABV than in TDF treated patients. Urine concentrations of α-GST showed a nonsignificant variation in both groups, while Cyc excretion was significantly higher at T1 and T3 in TDF-treated compared to ABV-treated patients. In conclusion, TDF may be associated with subclinical mitochondrial damage, inducing at a later stage increased urinary excretion of phosphate and uric acid, as markers of incipient tubular injury.

Cardiovascular risk factors in patients on long-term treatment with nevirapine- or efavirenz-based regimens

OBJECTIVES The aim of this study was to evaluate the cardiovascular risk among patients treated for more than 5 years with regimens based on nevirapine or efavirenz. PATIENTS AND METHODS A total of 276 patients were retrospectively evaluated, 156 of whom were treated with nevirapine and 120 with efavirenz, by examining traditional risk factors and detecting the presence of subclinical carotid lesions with colour-Doppler ultrasonography. RESULTS When comparing the data at baseline and follow-up in the nevirapine group, total cholesterol, low-density lipoprotein cholesterol (LDLc) and triglycerides showed a significant decrease, while high-density lipoprotein cholesterol increased. Ultrasound data, obtained in a subgroup of 67 patients, did not show significant changes for those treated with nevirapine. In the efavirenz group, total cholesterol, LDLc, triglycerides, glycaemia, body mass index and the number of patients with a pathological ultrasound significantly increased. When comparing the two groups at baseline and follow-up, nevirapine patients had significantly higher values of total cholesterol, LDLc and triglycerides at baseline, while total cholesterol and LDLc differed non-significantly at follow-up; triglycerides became significantly lower in the nevirapine arm with respect to the efavirenz group. Glycaemia was comparable between the two groups at baseline, while it was significantly lower in the nevirapine group at follow-up. The number of pathological ultrasound findings was significantly higher in the efavirenz group at follow-up. CONCLUSIONS Patients treated with nevirapine demonstrated a better lipid and glucose profile and a lower tendency to develop subclinical atherosclerotic lesions.

Bone and kidney toxicity induced by nucleotide analogues in patients affected by HBV-related chronic hepatitis: a longitudinal study

OBJECTIVES Nucleotide analogues may promote renal and bone toxicity. The aim of the present study was to evaluate markers of osteorenal toxicity in patients affected by hepatitis B virus-related chronic hepatitis treated with lamivudine plus adefovir who were switched to tenofovir. PATIENTS AND METHODS We evaluated 60 consecutive patients at the time of the switch of treatment and after 1, 3, 6, 9 and 12 months. The mean baseline estimated glomerular filtration rate (eGFR) was 89.3 ± 19.0 mL/min/1.73 m(2). RESULTS During the study period we observed a reduction in mean eGFR up to 6 months after switching to tenofovir, and this remained stable for the last two timepoints. At the end of study, the mean eGFR was 82.6 ± 21.5 mL/min/1.73 m(2), a reduction of 7.5%. The mean baseline proteinuria was 202.6 ± 237.6 mg/24 h. Microhaematuria was observed in 22.6% of patients and hypophosphataemia in 18.6%. After 1 month of tenofovir, we observed a worsening of serum phosphate and parathyroid hormone levels, haemoglobinuria and 24 h proteinuria. After 3 and 12 months of tenofovir, these data tended to recover to baseline levels. A total of 92.6% of patients at baseline had hypovitaminosis D. After supplementation with cholecalciferol, this percentage decreased significantly. We observed a reduced bone mineral density (BMD) in 52.7% of patients at baseline; this increased to 77.8% after 6 months of tenofovir, but at the last timepoint the percentage of patients with a reduced BMD had fallen to a level above the baseline. CONCLUSIONS In conclusion, patients exposed to lamivudine plus adefovir showed relevant osteorenal damage. The switch to tenofovir provoked a slight reduction in eGFR that stabilized after 6 months. The reduced BMD at baseline did not worsen under tenofovir treatment.

The role of immune reconstitution in the onset of subclinical atheromasic lesions.

To the Editors: In recent studies, patients with low CD4 cell count showed an increased risk for cardiovascular disease (CVD). A hyperproduction of proinflammatory cytokines (interleukin-6, high sensitivity C-reactive protein [hsPCR]) have been hypothesized in these patients. Few data exist regarding the role of immune reconstitution in the onset of CVD, another condition that could be related to an increase of circulating proinflammatory factors. Aimed at the detection of subclinical atheromasic lesions in patients who experienced immune reconstitution, in the present study, we evaluated 263 patients starting antiretroviral therapy (ART) at baseline and after 12 months, with color Doppler ultrasonography of the epiaortic vessels, a well-validated technique, considered the gold standard for the detection of premature vascular lesions. The patients were subjected to color Doppler ultrasonography of the epiaortic vessels using a last-generation power color Doppler instrument with 7.5 mgHz probes (ACUSON sequoia 512). Ultrasonography was performed by physicians specifically trained on carotid vessels and had at least 15 years experience with the ultrasound color Doppler technique and about 10,000 documented epiaortic examinations. They were blinded to the patient’s treatment history and status and unaware of the diagnosis of the other colleagues. The patients were placed in a supine position after at least 10 minutes of acclimatization in a comfortable room. They were informed that the investigation was noninvasive. The 2 common carotids, the bifurcations and at least the first 2 cm of the internal and external carotid vessels were examined in the short and long axis during the telediastolic phase (T wave of the electrocardiogram). During the investigation, the head of the patient was hyperextended and extrarotated from the opposite side. The morphological investigation of the plaques was performed using both ultrasonography and the ultrasound power color Doppler to better characterize the profile of the plaque and the intima media thickness. An intima media thickness >0.9 mm and/or the presence of atherosclerotic plaques were considered pathologic findings. After 12 months of ART, patients with <50 CD4 cell count per cubic millimeter at baseline were divided into 3 groups based on CD4 at follow-up: group A: patients with <100 CD4 (# 41); group B: patients with 100–200 CD4 (# 50); and group C: patients with >200 CD4 (# 62). The CD4 cell count was detected on 2 separate occasions, measured sequentially at least 4 weeks apart. TABLE 1. Distribution of Demographics, Risk Factors for CVD, and Antiretroviral Therapies Among the Groups

Functional Impairments of Microcirculation in HIV-Positive Patients: A Laser Doppler Fluxometry-Based Investigation

Abstract Purpose: The aim of our study was to investigate the morphologic and functional characteristics of microcirculation in HIV-positive patients. Microcirculation was investigated by means of capillaroscopy and laser Doppler fluxometry (LDF). The results were compared with those obtained from healthy subjects and patients affected by sclerodermia. Method: We evaluated 140 subjects: 69 HIV-positive, 48 sclerodermic, and 23 healthy individuals. The groups were compared for resting flow (RF), mean flow during cold test, mean flow during the recovery, postocclusive reaction, and time of recovery after reactive hyperaemia. Results: RF (p = .0035), flow during the cold test (p = .008), recovery (p = .03), and postocclusive reaction (p = .007) results were higher in HIV-1 positive patients with respect to the other two groups. Recovery after postocclusive reaction in HIV-positive patients was longer than in healthy individuals. Time from diagnosis and a pathologic electromyography were significantly related to a vasospasm reduction induced by the cold test (p = .022). The recovery was also influenced by the time from disease diagnosis (p = .0016). Conclusions: HIV patients seem to have an altered microcirculation regulation, with increased perfusion of the capillary territory. This could be related to the length of period of infection and a coexisting neuropathy.

Epi-aortic lesions, pathologic FMD, endothelial activation and inflammatory markers in advanced naïve HIV-infected patients starting ART therapy

PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV‐infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART).

Does Iatrogenic Scleroderma due to Injection-Site Reaction to Enfuvirtide Impair Absorption of the Drug?

Background:Chronic iatrogenic scleroderma is a possible obstacle to the absorption of subcutaneously administered drugs. This study correlated the clinical and histopathological pattern of injection-site reactions (ISRs) to the pharmacokinetics of enfuvirtide in patients with HIV.Methods:Fourteen patients treated with an enfuvirtide-based antiretroviral regimen for a median of 45 weeks were enrolled and their ISRs were evaluated. Twelve patients with evidence of ISRs underwent cutaneous biopsies using a 4-mm punch. The maximum plasma enfuvirtide concentration (Cmax) and the area under the enfuvirtide concentration-time curve (AUC) were assessed using blood sampling.Results:Four different macroscopic patterns of ISR were identified: A — no evidence of cutaneous lesions; B — transient infiltrative lesions that auto-resolved within 24 hours; C — transient nodular lesions that auto-resolved within 7–15 days; and D–stable lesions after more than 30 days. Histological examination showed three morphological patterns: (1) acute urticaria/vasculitis-like pattern, (2) subacute pattern and (3) chronic scleroderma-like pattern. No differences among patients with the various patterns of ISRs were observed, except for a higher Cmax and AUC in patients with pattern 1.Conclusions:These results confirm that although iatrogenic scleroderma is not related to impaired enfuvirtide absorption, higher Cmax and AUC values are observed in patients with urticaria/vasculitis-like patterns.