Clusterization of co-morbidities and multi-morbidities among persons living with HIV: a cross-sectional study.

BACKGROUND: Among people living with HIV (PLWH), the prevalence of non-HIV related co-morbidities is increasing. Aim of the present study is to describe co-morbidity and multi-morbidity, their clustering mode and the potential disease-disease interactions in a cohort of Italian HIV patients. METHODS: Cross-sectional analysis conducted by the Coordinamento Italiano per lo Studio di Allergia e Infezioni da HIV (CISAI) on adult subjects attending HIV-outpatient facilities. Non-HIV co-morbidities included: cardiovascular disease, diabetes mellitus, hypertension, oncologic diseases, osteoporosis, probable case of chronic obstructive pulmonary disease (COPD), hepatitis C virus (HCV) infection, psychiatric illness, kidney disease. Multi-morbidity was defined as the presence of two or more co-morbidities. RESULTS: One thousand and eighty-seven patients were enrolled in the study (mean age 47.9 ± 10.8). One hundred-ninety patients (17.5%) had no co-morbidity, whereas 285 (26.2%) had one condition and 612 (56.3%) were multi-morbid. The most recurrent associations were: 1) dyslipidemia + hypertension (237, 21.8%); 2) dyslipidemia + COPD (188, 17.3%); 3) COPD + HCV-Ab+ (141, 12.9%). Multi-morbidity was associated with older age, higher body mass index, current and former smoking, CDC stage C and longer ART duration. CONCLUSIONS: More than 50% of PLHW were multi-morbid and about 30% had three or more concurrent comorbidities. The identification of common patterns of comorbidities address the combined risks of multiple drug and disease-disease interactions.

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.

Dynamics of Lipid Profile in Antiretroviral-Naïve HIV-Infected Patients, Treated with TAF-Based Regimens: A Multicenter Observational Study.

Background: The introduction of tenofovir alafenamide (TAF) in antiretroviral therapy has deeply modified the choice of the backbone for different treatment regimens, allowing the prevention of the bone and renal toxicity that was related to the previous formulation of tenofovir disoproxil fumarate (TDF). At the same time, literature data show an onset of dyslipidemia after a switch from TDF to TAF. To better understand the possible role of TAF in dyslipidemia, antiretroviral-naïve HIV-infected patients were evaluated, comparing those treated with TAF/emtricitabine with those with abacavir/lamivudine. Methods: We enrolled 270 antiretroviral-naïve HIV-infected patients in an observational, retrospective, longitudinal, multicenter study; they started treatment from 2017 to 2019 and were followed up for at least 72 weeks. We divided patients into two groups, one treated with a TAF-based backbone in their antiretroviral regimens (TAF group) and one without TAF (NO TAF group), to evaluate possible differences in the dynamics of lipid profiles from baseline(T0) to week 24 (T24), 48 (T48) and 72 (T72). Results: No significant differences were observed at baseline between the 2 groups. In the TAF group we observed a significant development of hypercholesterolemia throughout the follow-up (p < 0.0001), not evident in the NO TAF group, that instead showed a significant increase in high-density lipoprotein (HDL). There were no significant differences between the two groups regarding triglycerides, low-density lipoprotein (LDL) and cardiovascular risk index (CRI). A cholesterol-lowering treatment with statin, finally, was prescribed in 6 patients in both groups during the study. At binary logistic regression analysis, no factor was independently associated with hypercholesterolemia, except for higher age at T0. Conclusions: This real-life study shows that in HIV-naïve patients, TAF was associated with hypercholesterolemia throughout the follow-up. The clinical significance of this hypercholesterolemia will have to be clarified in further studies.

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.

Functional impairments of microcirculation in HIV-positive patients: a laser Doppler fluxometry-based investigation.

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.

A color Doppler ultrasound-based comparative study between stavudine and non-stavudine regimens in the onset of vascular lesions in HIV-1-positive patients.

BACKGROUND: The present study aimed to investigate the role of stavudine in the onset of premature vascular lesions using an ultrasound color Doppler evaluation of the carotid vessels. PATIENTS AND METHODS: A total of 266 patients were evaluated: 149 were treated with stavudine (group I) and 117 without stavudine (group II). RESULTS: Of the patients in group I, 41% exhibited vascular lesions vs. 26% in group II (p=0.0103). The two groups were further divided into subgroups Ia (stavudine and proteinase inhibitor, PI), Ib (stavudine and non-nucleotidic reverse transcriptase inhibitor, NNRTI), IIa (PI, without stavudine) and IIb (NNRTI without stavudine). A higher prevalence of lesions emerged in group Ia, while group IIa were at higher risk of developing vascular lesions than groups Ib and IIb. CONCLUSION: Although stavudine per se does not seem to determine damage of the epiaortic vessels, the association of a PI with stavudine is related to a significantly higher rate of lesions.

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.

Rapid progression of carotid lesions in HAART-treated HIV-1 patients.

To obtain data on the evolution of carotid lesions, we evaluated 133 patients at their first antiretroviral regimen, followed for at least 2 years; 77 treated with protease inhibitors (PIs): Group A and 56 with non-nucleosidic reverse transcriptase inhibitors (NNRTIs): Group B. All patients were subjected to carotid ultrasonography. In Group A, among the previously normal patients 22.5% developed lesions, 40% remained normal, 37.5% shifted to other antiretroviral regimens. Among the 37 previously pathologic patients, 46% worsened, 19% were stable, in 8% the lesions had disappeared, 27% shifted. In Group B, among the previously normal patients, 12.7% developed lesions, 80.8% remained unaltered, 6.5% shifted. Among the previously pathologic patients, 12.5% worsened, lesions reversed in 25%, remained stable in 50% and 12.5% shifted to PI. At statistical analysis, in Group A both the percentage of patients developing new lesions and the percentage of patients who worsened was significantly higher. In conclusion, we evidenced a more rapid onset of lesions in patients treated with PIs with respect to patients treated with NNRTIs and towards a more rapid evolution of the previous lesions. The shift from PIs to NNRTI/3 NRTI seems related to a lower rate of evolution. Interestingly, a disappearance of lesions was detected in both groups.

An ultrasound-based comparative study on carotid plaques in HIV-positive patients vs. atherosclerotic and arteritis patients: atherosclerotic or inflammatory lesions?

BACKGROUND: We have previously described two cases of HIV-1-positive patients undergoing surgery for stenosis of the internal carotid arteries. Histology revealed an extensive inflammatory infiltration of the vascular wall and no evidence of atheromasic plaque. This unexpected pattern of carotid damage prompted us to perform a more accurate investigation of the characteristics of carotid plaques in a group of HIV-positive patients. The results were compared with those obtained from young patients affected by atherosclerosis of the epi-aortic vessels and patients with arteritis. METHODS: The patients underwent ultrasonography of the epi-aortic vessels using one of the latest generation power color-Doppler with 7.5 MHz probes. RESULTS: The study population included 61 HIV-positive patients and 47 HIV-negative patients (37 atherosclerotic and 10 with arteritis). Compared with HIV-negative atherosclerotic patients, there were significantly higher proportions of HIV-positive patients with iso-hypoechogenic lesions (81.8 vs. 29%) that were homogeneous both in their parietal and endoluminal portions (96.7 vs. 21.6% and 88.5 vs. 54.0%, respectively), with a smooth or slightly irregular surface (99.0 vs. 56.7%) (P=0.001 for all differences). No statistically significant differences were seen between HIV-positive and arteritis patients. CONCLUSION: Our study evidenced that the ultrasonographic structure of the epi-aortic lesions in HIV-positive patients substantially differ from those of the plaques in atherosclerotic patients, although they share similar characteristics with patients affected by arteritis. Further investigations are warranted to better define the structure and the mechanism of onset of these lesions.

Cardiovascular risk in advanced naïve HIV-infected patients starting antiretroviral therapy: Comparison of three different regimens - PREVALEAT II cohort.

BACKGROUND AND AIMS: PREVALEAT (PREmature VAscular LEsions and Antiretroviral Therapy) II is a multicenter, longitudinal cohort study aimed at the evaluation of cardiovascular risk among advanced HIV-positive, treatment-naïve patients starting their first therapy. We hypothesized that these patients, present a higher cardiovascular (CV) risk. METHODS: The study included all consecutive naïve patients with less than 200 CD4 cells/ml starting antiretroviral therapy. Our primary objective was to evaluate changes in carotid intima- media thickness (IMT). Secondary endpoints included changes in flow mediated vasodilation (FMD), inflammatory markers, triglycerides and cholesterol. Patients were evaluated at time 0, and after 3, 6 and 12 months. RESULTS: We enrolled 119 patients, stratified into three different groups: patients receiving atazanavir/ritonavir boosted (ATV/r) based regimens, efavirenz (EFV) based regimens and darunavir/ritonavir boosted (DRV/r) based regimens. At baseline, advanced naïve patients showed a relevant deterioration of CV conditions in terms of traditional CV risk factors, endothelial dysfunction and serum biomarkers. During the 12-month follow up period, mean blood lipids significantly increased: total cholesterol from 159 to 190 mg/dL, HDL-C from 31 to 41 mg/dL, and LDL-C from 99 to 117 mg/dL. D-dimers steadily decreased (median level 624 at baseline and 214 at T3), whereas ICAM and VCAM consistently raised. DRV/r and ATV/r determined a more marked decrease of D-dimers as compared to EFV. Regarding the epi-aortic changes (IMT >1 mm or presence of atherosclerotic plaques), patients in the DRV/r group were at risk of developing pathological IMT during the study (OR 6.0, 95% CI 0.9-36.9), as compared to EFV ones. CONCLUSIONS: CV risk was elevated in advanced naïve patients and tended to remain high in the first year of therapy.

Role of chlamydia infection in the pathogenesis of atherosclerotic plaques in HIV-1-positive patients.

BACKGROUND: Various authors have hypothesized a role of Chlamydia pneumoniae infection in the pathogenesis of atherosclerosis. To better understand the possible role of this infection in the pathogenesis of epi-aortic lesions in HIV-1-positive patients, the presence of anti-Chlamydia pneumoniae antibodies was evaluated in a group of individuals subjected to ultrasonography of the epi-aortic vessels. PATIENTS AND METHODS: The presence of specific antibodies in 129 subjects was determined; 59 patients were HIV-1-positive, of whom 30 had carotid plaques and 29 were without lesions. The control group was composed of 70 subjects. All were subjected to ultrasonography of the epi-aortic vessels. IgG, IgM and IgA anti-C. pneumoniae antibodies were measured with micro-immunofluorescence and positive sera were tested for C. trachomatis and C. psittaci. RESULTS: No subjects were positive for IgM. Both the IgA and IgG levels did not differ significantly in the three groups. The only highly significant variable was the use of protease inhibitors. CONCLUSION: Our data suggest that the damage to the carotid wall in HIV-1 patients was not due to C. pneumoniae.

Prevalence and Risk Factors for Significant Liver Fibrosis in Patients with HIV Infection.

AIM: The aim of the present study was the evaluation of liver fibrosis in a population of patients monoinfected with HIV using the transient liver elastography (FibroScan) method. PATIENTS AND METHODS: A total of 228 consecutive patients with HIV were evaluated: 80 (35.09%) were HIV-1 monoinfected and 148 (64.91%) (HIV)/hepatitis C virus (HCV) co-infected. Echoic liver diagnosis was also performed. RESULTS: F2 Metavir-score fibrosis or higher was found to be associated with drug addiction, alanine aminotransferase >80 UI/l, cluster of differentiation 4 (CD4(+)) T lymphocytes nadir <200 copies/ml, therapy duration, protease inhibitor (PI)-based antiretroviral regimen, HCV infection and AIDS diagnosis. Multivariate analysis highlighted a significant association with drug addiction, AIDS diagnosis, therapy duration and HCV co-infection. Echoic liver diagnosis showed signs of damage among 43.75% of monoinfected patients vs. 62.84% among co-infected. CONCLUSION: Monoinfected patients showed pathological signs both at liver ultrasonography and at FibroScan. In the onset of these changes, a significant role by HIV disease and duration of therapy is observed.

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

INTRODUCTION: 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). PATIENTS AND METHODS: All consecutive naïve patients with CD4 cell count<200/mL starting any PI/r-based or NNRTI-based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi-aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM-1 and VCAM-1) and inflammatory markers (IL-6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co-infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ(2) nonparametric method. RESULTS: In Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200. CONCLUSIONS: Our data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow-up epi-aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM-1 significantly worsens during the period of observation; also VCAM-1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D-dimers and high sensitivity C-reactive protein (hsCRP). IL-6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve-month follow-up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non-specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima-media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.

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.