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Objectives: We performed an observational, retrospective, cohort study to assess changes in insulin sensitivity after a switch from dolutegravir/lamivudine (DOL/3TC) or bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) to doravirine/tenofovir disoproxil fumarate/3TC (DOR/TDF/3TC) in virologically suppressed people living with HIV with recent significant weight gain., Methods: All non-diabetic patients with HIV treated with DOL/3TC or BIC/F/TAF for ≥12 months, with HIV RNA <20 copies/mL, and with a weight increase ≥3 kg in the last year, who underwent a switch to DOR/TDF/3TC were enrolled into the study. Serum levels of glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were evaluated every 6 months during a 12-month follow-up., Results: Overall, 81 patients were enrolled: 41 were treated with DOL/3TC and 40 with BIC/F/TAF. At baseline, median HOMA-IR index was 3.18 and insulin resistance (HOMA-IR index >2.5) was present in 49 subjects (60%). At 12 months after the switch to DOR/TDF/3TC, change in mean serum glucose concentration was not significant, but the reduction in median concentration of insulin was significant (-3.54 mcrUI/L [interquartile range -4.22 to -2.87]; p = 0.012), associated with a significant reduction in mean HOMA-IR index (-0.54 [interquartile range -0.91 to -0.18]; p = 0.021). A significant reduction in total and low-density lipoprotein cholesterol was also reported, whereas decreases in mean body weight and mean body mass index were not significant., Conclusions: In our retrospective study in virologically suppressed people living with HIV treated with DOL/3TC or BIC/F/TAF and with recent weight gain, the switch to DOR/TDF/3TC led to a significant improvement in insulin sensitivity and plasma lipids, with a trend to decreased body weight., (© 2024 British HIV Association.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Clinical trials of dual regimen dolutegravir/lamivudine (DOL/3TC) demonstrated potent efficacy and favorable safety in both antiretroviral therapy-naïve and -experienced patients, but data on older people are lacking. We aimed to evaluate virological efficacy and safety of DOL/3TC in suppressed older patients over a 12-month period. We performed a retrospective cohort study evaluating people living with HIV (PLWHIV) aged ≥65 years at our HIV Clinic who were switched to DOL/3TC. Eligible patients had baseline HIV-1 RNA <20 copies/mL, and no previous virological failures or known resistance mutations for lamivudine or dolutegravir. Inclusion criteria were met by 72 patients: 59 were men, median age was 69.2 years, and one or more comorbidities were present in 89% of patients. The most common reason for switch was simplification, followed by drug-drug interactions (DDIs) and toxicities. After 12 months, 64 (88.9%, by the intention-to-treat analysis) patients maintained HIV-1 RNA <20 copies/mL, and reasons for treatment failure were virological failure in three cases, adverse events in three, and missing data in two. Genotype resistance testing showed no resistance mutations for lamivudine or dolutegravir in subjects with virological failure. The number of potential DDIs decreased from 92 to 12 after switching to DOL/3TC, and a significant reduction in median total and low-density lipoprotein cholesterol was reported, while median change in body weight was not significant. In this real-life cohort, switching to DOL/3TC was associated with maintenance of virological control and good tolerability among persons aged >65 years, supporting use of this dual regimen in older PLWHIV.

Background: Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) showing high efficacy and tolerability in both naïve and experienced people living with HIV (PLWHIV) in randomized trials, but scarce data are available to date from the real-life experience., Methods: We performed an observational, retrospective study of PLWHIV on suppressive antiretroviral therapy who switched to a daily single-tablet regimen containing doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg., Results: As a whole, 62 suppressed patients (51 men, median age, 51.7 years; median CD4 T+ lymphocyte count, 577 cells/mm 3 ) were enrolled. After 12 months, 58 (93.5%) patients showed HIV RNA <20 copies/mL and reasons for treatment failure were virological failure in one case, missing data in one case, and adverse events in two cases. At month 12, a significant decrease in median serum level of triglycerides (median change -61.2 mg/dL; p = .009) and total cholesterol (median change -38.4 mg/dL; p = .021) was reported, while a not significant median weight increase was registered (+0.55 kg)., Conclusions: In our study, simplification to a single-tablet regimen of doravirine/lamivudine/tenofovir disoproxil fumarate in virologically suppressed PLWHIV was effective and showed a good tolerability profile, in association with a significant improvement in serum lipid levels., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Objectives: Hepatocellular carcinoma (HCC) has become a major issue in coinfected HIV/HCV patients with liver cirrhosis. We aimed to determine the rate of HCC occurrence after a direct-acting antiviral (DAA) treatment and to evaluate the factors associated with the risk of HCC in this population., Design: We conducted a retrospective multicenter observational study including cirrhotic HIV/HCV-coinfected patients treated with DAAs, between October 2014 and January 2017., Methods: We collected demographics characteristics, data regarding HIV and HCV infections and treatment with DAAs. We investigated the rate and the time of occurrence of HCC. Statistical analysis explored the factors associated to development of liver cancer., Results: During a median follow-up of 55 months, 24 out of 232 patients developed HCC, after a median of 22.5 months from starting DAAs. Factors associated with HCC were a higher Child--Pugh Turcotte (CPT) score (P = 0.002), HCV genotype 3 (P = 0.04), previous HCC (P < 0.001) and CD4+ cell count nadir greater than 350 cells/μl (P = 0.001), whereas antiretroviral therapy (ART) was associated to a lower rate of cancer (P = 0.02). At multivariable analysis CPT score and a history of HCC remained independently associated with HCC after DAAs (P = 0.003 and P < 0.001, respectively), and ART administration maintained its protective role (P = 0.047), regardless of HIV RNA at baseline., Conclusion: Our study highlights the importance of a long-lasting follow-up for HCC after HCV eradication, mostly in those patients with advanced cirrhosis and history of HCC. Furthermore, our data showed a potential role of ART itself (and not of undetectable HIV RNA) in reducing the risk for HCC development., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Since the end of February 2020, the Coronavirus Disease 2019 (COVID-19) outbreak rapidly spread throughout Italy and other European countries, but limited information has been available about its characteristics in HIV-infected patients., Methods: We have described a case series of patients with HIV infection and COVID-19 diagnosed at the S.Orsola Hospital (Bologna, Italy) during March and April, 2020., Results: We reported a case series of 26 HIV-infected patients with COVID-19. Nineteen subjects were men, the median age was 54 years, 73% of patients had one or more comorbidities. Only 5 patients with interstitial pneumonia were hospitalized, but there were no admissions to intensive care unit and no deaths., Conclusions: In our experience, COVID-19 associated with HIV infection had a clinical presentation comparable to the general population and was frequently associated with chronic comorbidities.

Weight gain associated with integrase inhibitor-based treatment has become a critical issue in the clinical management of HIV infection. We analyzed changes in weight and body fat mass in 54 virologically suppressed patients who switched to lamivudine plus raltegravir or dolutegravir. Overall, after 12 months we reported a not significant increase in weight (median, +1.74 kg; p  = .223) and total fat mass (median, +1.13 kg; p  = .188), and these changes were comparable between groups. The median change in lumbar spine bone mineral density (BMD) [interquartile range (IQR)] was +0.02 g/cm 2 (-0.02, +0.05; p  = .786), and the median change in femur neck BMD (IQR) was +0.04 g/cm 2 (-0.03, +0.06; p  = .598), and changes were comparable between groups. In conclusion, the switch to dolutegravir/lamivudine or raltegravir/lamivudine dual therapy in virologically suppressed patients did not produce significant increases in weight and body fat mass after a 12-month follow-up, in association with not significant changes in BMD.

Objectives: Metabolic syndrome (MetS) is usually associated in general population with systemic inflammation and higher cardiovascular risk, but data about the effect of statins in patients with HIV infection and MetS are lacking to date., Methods: Prospective cohort study of treated HIV-infected patients, aged from 40 to 60 years, with or without MetS, who started rosuvastatin (10 mg daily), and were followed-up for 12 months. The primary endpoint was change in serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). The secondary endpoint was change in the carotid intima-media thickness (IMT)., Results: One hundred and twenty-five patients were enrolled: 61 with MetS (MetS group) and 64 without MetS (control group). After 12 months, rosuvastatin produced a significant decrease in mean serum levels of hsCRP (-0.28 mg/dL; p  = .037), IL-6 (-2.1 pg/mL; p  = .018) and TNF-α (-6.3 pg/mL; p  = .004) in patients with MetS. On the contrary, in controls rosuvastatin did not lead to a significant change in mean levels of all biomarkers. After 12 months, the mean IMT increase at the carotid bifurcation was significantly lower in the MetS group than in the control group at the carotid bifurcation (0.017 vs. 0.031 mm; p  = .037) and in all other anatomical sites., Conclusion: Our findings suggest that rosuvastatin is effective in reducing serum inflammation markers and slowing atherosclerosis progression rate in HIV-infected patients on cART and with MetS, while its effects on serum biomarkers and IMT increase seem to be negligible in those without MetS.

Background: Antiretroviral dual regimens including lamivudine and one boosted PI or dolutegravir are warranted in order to optimize combination ART (cART), prevent long-term toxicity and reduce the cost of treatments., Objectives: We hypothesized that a maintenance dual regimen of lamivudine plus raltegravir would be effective and as well tolerated as the dual maintenance combination of lamivudine plus dolutegravir., Methods: We performed an observational, retrospective study of HIV-infected patients on suppressive ART who switched to a dual regimen containing lamivudine 300 mg once daily plus raltegravir 1200 mg once daily or dolutegravir 50 mg once daily., Results: In total, 109 patients (79 men; mean age 46.4 years; mean CD4+ T lymphocyte count 605 cells/mm3) were enrolled. Overall, 50 subjects switched to lamivudine plus raltegravir (Group A) and 59 to lamivudine plus dolutegravir (Group B). After 12 months, 45 patients (90%) in Group A and 52 (88.1%) in Group B had HIV RNA <20 copies/mL. No patients had severe adverse effects in either group, and the percentages of patients with mild adverse effects were comparable, except for a higher incidence of headache and sleeping disturbances in Group B than in Group A (30.5% versus 14%, P < 0.001). A comparable and non-significant weight increase was reported in both groups (+1.91 kg in Group A and +2.28 kg in Group B)., Conclusions: In our study, dual therapies containing lamivudine plus raltegravir or dolutegravir in virologically suppressed patients showed high and comparable efficacy, as well as good tolerability., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Cardiovascular disease has become one of the most common comorbidities among HIV-infected patients, but available data about the correlation between antiretroviral drugs and progression rate of atherosclerotic disease are still limited. We evaluated the progression rate of carotid atherosclerosis in patients starting an initial antiretroviral regimen including one integrase strand transfer inhibitor (INSTI). Methods: Observational, prospective study involving HIV-1-infected, antiretroviral therapy-naive, adult patients who started an antiretroviral regimen including tenofovir alafenamide/emtricitabine (TAF/FTC) plus raltegravir (RAL group), elvitegravir/cobicistat (EVG/c group), or dolutegravir (DTG group). Patients with known cardiovascular disease or diabetes mellitus were excluded from the study. The progression rate of atherosclerosis has been assessed by carotid Doppler ultrasonography at baseline and after 24 months. Results: Overall, 102 patients were enrolled into the study: 73 males, with mean age of 48.7 years: 32, 36 and 34 patients were included in the RAL, EVG/c and DTG groups, respectively. The baseline features of the enrolled patients were comparable across the three groups. At 24 months, the mean intima-media thickness (IMT) increase at the carotid bifurcation was 0.026 mm in the RAL group, 0.029 mm in EVG/c group and 0.032 mm in DTG group. The mean IMT increases after 24 months were comparable across the three groups and statistically not significant in all the evaluated anatomical sites. Conclusions: The initial antiretroviral therapy with TAF/FTC plus RAL, EVG/c or DTG for 24 months led to a comparable and not significant effect on the progression rate of carotid atherosclerosis.

Background: Weight gain after initiation of combination antiretroviral therapy (cART) is a possible side effect of all antiretroviral regimens, but it seems to be more evident in association with integrase strand transfer inhibitors (INSTIs). So, we aimed to evaluate weight change associated with an initial cART including one INSTI or darunavir-ritonavir (DRV/r)., Methods: A retrospective, observational, cohort study of antiretroviral therapy-naive adult HIV-positive patients starting an initial cART including raltegravir (RAL), dolutegravir (DTG), elvitegravir-cobicistat (EVG), or DRV/r. We compared changes in weight and body mass index (BMI) across the four groups during a 12-month follow-up., Results: As a whole, 680 patients (470 males, mean age 42.1 years) were enrolled: 196 starting RAL, 174 DTG, 158 EVG/c, and 152 DRV/r. Baseline mean CD4 lymphocyte count was 455 cells/mm 3 and 7.3% had an AIDS diagnosis. After 12 months, mean increase in body weight was 1.93 kg in the RAL group, 2.38 kg in the DTG group, 2.14 kg in the EVG group, and 1.85 in the DRV/r group. Mean increase in BMI was 0.71, 0.84, 0.77 and 0.63 kg/m 2 , respectively (p > 0.05 for each comparison). Therefore, no significant increases in weight and BMI were reported in each group, and no significant differences in weight and BMI changes were described across the four treatment groups., Conclusions: In our study, patients starting an initial cART including one INSTI or DRV/r after 12 months showed a small and comparable, but not significant, increase in body weight, whose long-term clinical consequences are unknown.

The HIV epidemic has not yet ended, and there are ever more challenges: the recent Italian National Plan of Interventions against HIV and AIDS (Piano Nazionale di Interventi Contro HIV e AIDS (PNAIDS) 2017-2019) was hailed for its comprehensiveness. Its likelihood of success across the HIV care continuum was therefore assessed. Awareness interventions are sporadic and continue to miss high risk populations; if effectively implemented, the prescriptive detail in PNAIDS may help address this. Combined prevention needs greater focus and investment. However, there has been recent progress: free anonymous testing is available at multiple settings although improvements to provide access to key vulnerable populations are needed. Clinical management is available to a high standard across the country, with some areas for improvement in ensuring equality of access. Long-term management of people living with HIV is often effective, but discrepancies exist across regions and settings of care. It is recommended to enable implementation of PNAIDS as a matter of urgency, develop integrated awareness and testing interventions for STIs and HIV, make condoms free for high-risk populations, and develop a network of multidisciplinary services for long-term holistic care of people living with HIV.

Background: Chronic kidney disease (CKD) has become one of the most frequent non-infectious comorbidities in the aging HIV-infected population on long-standing combination antiretroviral therapy (cART)., Methods: We conducted a retrospective, cross-sectional study including HIV-infected adult patients attending our HIV outpatient clinic during the years 2017 and 2018 to assess prevalence and associated risk factors of CKD. Estimated glomerular filtration rate (eGFR) was measured by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. CKD was diagnosed and classified according to the National Kidney Foundation guidelines. Logistic regression was employed to identify factors associated with CKD., Results: We enrolled 2339 HIV-infected patients (91% were Caucasian) with a mean age of 45.3 years and a mean current CD4 lymphocyte count of 531 cells/mm 3 . CKD was diagnosed in 311 subjects (13.3%). Overall, 294 (12.6%) patients had albuminuria, 108 (4.6%) had eGFR < 60 mL/min/1.73 m 2 , and 78 (3.3%) had albuminuria plus eGFR < 60 mL/min/1.73 m 2 . Stages 4-5 of CKD were documented in 23 (1%) cases. Age greater than 50 years, male gender, hypertension, diabetes mellitus, high triglycerides, nadir CD4 cell count < 200 cells/mm 3 , current use of tenofovir disoproxyl fumarate (TDF) and of TDF plus a ritonavir-boosted protease inhibitors were independently associated with CKD, while current use of abacavir plus one integrase inhibitor was associated with a reduced risk of CKD., Conclusion: There is a significant prevalence of CKD among HIV-infected persons in association with both traditional and HIV-specific risk factors, requiring a careful periodic monitoring of renal function in these patients.

Background: The ritonavir-boosted protease inhibitor (PI/r) use has been associated with several metabolic abnormalities, and the non-alcoholic fatty liver disease (NAFLD) is becoming a very frequent comorbidity among HIV-infected patients. Methods: We performed an observational, prospective study of HIV-infected patients with NAFLD, receiving one PI/r plus two nucleoside analogues, who switched from the PI/r to raltegravir or were treated only with lifestyle modification, maintaining antiretroviral therapy unchanged. Changes in liver steatosis after 12 months were evaluated by transient elastography and measurement of controlled attenuation parameter (CAP). Results: As a whole, 61 patients (46 males; median age, 55.4 years) were enrolled, and 32 of them have been switched from PI/r to raltegravir. At baseline, median CAP was 259 dB/m, 28 (45.9%) subjects had a moderate-to-severe hepatic steatosis (CAP ≥260 dB/m), and 19 patients (31.1%) had elevated aminotransferases. Type-2 diabetes mellitus was present in 5 persons, and chronic HCV coinfection in 4. At month 12, the median decrease in CAP values was -27 dB/m in patients switched to raltegravir and -11 dB/m in those with unchanged cART ( p  = .021). The number of patients with CAP ≥260 dB/m decreased from 16 to 6 (-62.5%) in patients switched to raltegravir and from 12 to 8 (-33.3%) in the other group ( p  = .037). Conclusion: After 12 months, HIV-infected patients with NAFLD switching from a PI/r to raltegravir showed a significantly greater decrease in the hepatic steatosis degreee in comparison with those with unchanged cART and treated only with lifestyle modification.

The aim of our study was to assess risk factors associated with vitamin D deficiency among HIV-1-infected patients on combination antiretroviral therapy (cART). A retrospective, case-control study was conducted to assess risk factors associated with vitamin D deficiency among HIV-1-infected adults on stable cART. Vitamin D deficiency was defined as 25-OH vitamin D concentration <30 ng/mL. A total of 195 patients (77% males, mean age 49.2 years) were enrolled into the study: 98 subjects with vitamin D deficiency (cases) and 97 with normal vitamin D serum concentration (controls). The mean serum concentration + standard deviation (SD) of vitamin D was 18.2+6.7 ng/mL among cases and 39.6+13.4 ng/ mL among controls. Current cART including tenofovir disoproxil fumarate (TDF) (OR 1.65; 95% CI, 1.31 to 1.94), osteoporosis (OR 1.78; 95% CI, 1.25 to 2.09), males who have sex with males (MSM) risk category (OR 1.59; 95% CI, 1.19 to 2.21), chronic hepatitis C (OR 1.44; 95% CI, 1.17 to 1.86), previous or current cancer (OR 1.47; 95% CI, 1.13 to 1.79), metabolic syndrome (OR 2.57; 95% CI, 1.96 to 2.98), and hepatic steatosis (OR 1.59; 95% CI, 1.17 to 2.05) were significant associated with an increased risk of vitamin D deficiency. On the other hand, current CD4+ lymphocyte count >600 cells/mm3 and current HIV RNA <20 copies/mL were significantly associated with a lower risk of vitamin D deficiency. In our case-control study, vitamin D deficiency is associated with TDF exposure, osteoporosis, and metabolic disturbances.

Objectives: An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART)., Methods: Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up., Results: Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels., Conclusions: In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: We evaluated the association between pre-ART HIV DNA and HIV-infected participant characteristics at baseline as well as with their response to first-line ART., Methods: Four hundred and thirty-three patients from the ICONA cohort, starting first-line ART after the year 2000, were analysed. Pre-ART HIV DNA was quantified with the modified COBAS TaqMan HIV-1 Test and normalized by CD4+ T cells. Linear correlation between pre-ART HIV DNA and other continuous markers (HIV RNA, CD4 count, markers of inflammation and coagulation) at baseline was evaluated by means of Pearson correlation coefficient and a linear regression model. Survival analyses and Cox regression models were used to study the association between pre-ART HIV DNA and time to viro-immunoclinical events., Results: Pre-ART HIV DNA [median (IQR): 10 702 (3397-36 632) copies/106 CD4+ T cells] was correlated with pre-ART HIV RNA [R2 = +0.44, (P < 0.0001)], CD4+ T cells [R2 = -0.58, (P < 0.0001)] and CD4/CD8 ratio [R2 = -0.48, (P < 0.0001)], while weaker correlations were observed with CD8+ T cells (R2 = -0.20, P = 0.01), IL-6 (R2 = +0.16, P = 0.002) and soluble CD14 (R2 = +0.09, P = 0.05). Patients with higher pre-ART HIV DNA showed lower rate and delayed virological response (defined as HIV RNA ≤50 copies/mL), compared with those having lower HIV DNA (67.2% for >10 000, 81.1% for 1000-10 000 and 86.4% for 10-1000 copies/106 CD4+ T cells; P = 0.0004). Higher pre-ART HIV DNA was also correlated with increased risk of virological rebound (defined as HIV RNA >50 copies/mL) by 24 months (17.2% for >10 000, 7.4% for 1000-10 000 and 4.3% for 10-1000 copies/106 CD4+ T cells; P = 0.0048). Adjusted HRs of all virological rebound definitions confirmed these findings (P ≤ 0.02)., Conclusions: Pre-ART HIV DNA, along with HIV RNA and CD4+ T cell count, should be considered as a new staging marker to better identify people at lower (or higher) risk of viral rebound following achievement of virological suppression (≤50 copies/mL).

Direct-acting antivirals (DAAs) for the treatment of HCV have dramatically increased the rate of sustained virological response: patients not achieving sustained virological response represent a challenge and rates of late recurrent viremia are very low. We describe here the first case of a very late HCV relapse, following an atypical kinetics (characterized by a spontaneous but transient HCV clearance after an early virological relapse), in a HIV co-infected patient treated with DAAs. Optimal adherence to the therapy was well documented and a phylogenetic analysis ruled out a possible reinfection from a different HCV strain. In conclusion, our case underlines the importance of a long follow-up (> 48 weeks) after DAAs therapies in HCV-HIV co-infected patients who might benefit the most from a very rigorous virological surveillance.

Background: Hyperlipidaemia is a risk factor for the progression of chronic kidney disease (CKD), which is a frequent comorbidity in patients with HIV-1 infection, but the renal effects of statins remain unclear., Methods: We performed an observational, prospective study of HIV-infected patients on suppressive antiretroviral therapy, with CKD and hyperlipidaemia, and starting a lipid-lowering treatment with rosuvastatin, atorvastatin or omega-3 fatty acids. CKD was defined as an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m 2 for >3 months., Results: As a whole, 69 patients (53 men, 58 Caucasian, median age 56.2 years) were enrolled. Overall, 25 patients started rosuvastatin (10 mg daily, group A), 23 patients atorvastatin (20 mg daily, group B), and 21 started omega-3 fatty acids (3 g daily, group C). At baseline, median eGFR was 54.4 mL/min/1.73 m 2 , and the eGFR ranged between 50 and 60 mL/min/1.73 m 2 in 87% of patients. After 12 months, the median eGFR decline was significantly lower in group A (-0.84 mL/min/1.73 m 2 ) and in group B (-0.91 mL/min/1.73 m 2 ) in comparison with the group C (-1.53 mL/min/1.73 m 2 ; p < 0.001 for both comparisons). The median decrease in prevalence of proteinuria and high-sensitivity C-reactive protein was also significantly greater in groups A and B than in group C, while the incidence of treatment discontinuations was comparable across the three groups., Conclusion: In our study, rosuvastatin and atorvastatin showed a significant protective effect on the renal function compared to omega-3 fatty acids in HIV-1-infected patients with CKD and dyslipidaemia.

Background: The ritonavir-boosted protease inhibitor (PI/r)-based dual regimens are warranted in order to optimize the combination antiretroviral therapy (cART), prevent the long-term toxicity and reduce the cost of treatments., Methods: We performed an observational, retrospective study of HIV-infected patients on suppressive antiretroviral therapy who switched to a dual regimen containing lamivudine (3TC) plus darunavir/ritonavir (DRV/r) 800/100 mg qd or atazanavir/ritonavir (ATV/r) 300/100 mg qd., Results: As a whole, 122 well-treated patients (mean age, 45.2 years; mean CD4 T + lymphocyte count, 589 cells/mm 3 ; mean duration of current cART, 3.1 years) were enrolled. Current antiretroviral regimen included tenofovir/emtricitabine in 91 subjects, abacavir/lamivudine in 25, lopinavir/r in 41, DRV/r in 38 and ATV/r in 33. Baseline mean estimated glomerular filtration rate (eGFR) was 94.2 mL/min/1.73 m 2 , and proteinuria was detected in 46 subjects (38%). Overall 70 subjects switched to 3TC + DRV/r (group A) and 52 to 3TC + ATV/r (group B). After 12 months, 65 patients (92.8%) in group A and 46 (88.4%) in group B showed HIV RNA <20 copies/mL. A significant and comparable increase in eGFR was observed in group A and B (+3.8 and +3.1 mL/min/1.73 m 2 , respectively), such as a significant decrease in prevalence of proteinuria. A significantly greater increase in total bilirubin concentration was reported in group B than in group A., Conclusion: In our study, simplification to a dual therapy containing 3TC + DRV/r or ATV/r in virologically suppressed patients was effective and showed a good tolerability profile.

We propose a multidimensional first-level diagnostic assessment easy to use in routine clinical practice to allow infectious disease specialists to have a general and complete overview of persons living with HIV. Following the Delphi method, articles published from January 1, 2011 on controlled trials, clinical reports and observational studies dealing specifically with HIV and its co-morbidities were selected for review by the authors. Participants in the poll were selected among clinicians and infectious diseases specialists, working in 38 different dedicated HIV centres in Italy. The participants were given access to a website dedicated to the project and received a standardized information package containing a synopsis of the study and a description of the Delphi process and the selected literature. A total of 131 Items were divided into 10 first-level survey areas: anamnesis, objective examination, infectious diseases, osteoporosis diagnosis, metabolic pathologies diagnosis, cardiovascular diagnosis, nephrologic diagnosis, hepatological diagnosis, central nervous system diagnosis, evaluation of quality of life (QoL). This simple and concise first level tool identifies a few areas of multi-organ diagnostic assessment beyond the infectivity area. The identification of these areas will allow us to find shared and validated evaluation procedures with the intent to increase the likelihood of early recognition of patients at risk of comorbidity development, in order to facilitate more effective prevention, thereby reducing the overall impact on the quality of life of patients affected by this chronic illness.

Objectives: An observational, prospective, cohort study was performed to compare efficacy and safety of a switch from ritonavir-boosted protease inhibitor (PI/r) to nevirapine or raltegravir with that of rosuvastatin addition to current antiretroviral therapy in HIV-infected patients with hyperlipidaemia., Methods: All HIV-infected patients receiving a stable PI/r-based antiretroviral regimen, with persistently suppressed viremia, naïve to non-nucleoside analogues and to integrase strand transfer inhibitors, with mixed hyperlipidaemia, and who underwent a switch from PI/r to nevirapine (Group A) or raltegravir (Group B) or who started rosuvastatin at 10 mg daily (group C) with unchanged antiretroviral regimen were enrolled into the study., Results: Overall, 136 patients were enrolled: 43 patients were included in the group A, 46 in the group B, and 47 in the group C. The mean age was 46.6 years, and 108 (79.4%) were males. After 48 weeks of follow-up, a significantly greater reduction in the mean low-density lipoprotein (LDL) cholesterol level was reported in group C (-28.2%) than in group A (-10.2%; p < .001) and B (-12.4%; p = .021), while a significantly greater reduction in the mean concentration of triglycerides was observed in group A (-31.2%) and B (-35.5%) than in group C (-11.9%; p = .034 and p = .004, respectively). The incidence of adverse events was <10% and comparable across the three groups., Conclusion: In HIV-positive subjects receiving a PI/r, the initiation of rosuvastatin treatment after 48 weeks yielded a greater decline in LDL cholesterol, while the switch from PI/r to nevirapine or raltegravir led to a greater decline in triglycerides.

Objectives: The aim of the study was to assess plasma concentrations of darunavir/ritonavir and raltegravir in older patients compared with younger patients with HIV-1 infection., Methods: In this observational, open-label study, adult HIV-infected out-patients aged ≤ 40 years (younger patients) or ≥ 60 years (older patients) and treated with tenofovir/emtricitabine plus darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) were asked to participate. The trough concentrations (C trough ) of darunavir/ritonavir and raltegravir were assessed at steady state using a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method., Results: A total of 88 HIV-positive patients were enrolled in the study. Forty-six patients were treated with darunavir/ritonavir, and 42 with raltegravir. The geometric mean plasma C trough (coefficient of variation) of raltegravir was comparable between the 19 older and 23 younger subjects: 106 ng/mL (151%) and 94 ng/mL (129%), respectively [geometric mean ratio (GMR) 0.85; 95% confidence interval (CI) 0.71-1.57; P = 0.087]. In contrast, the geometric mean plasma C trough of darunavir was significantly higher among the 21 older patients [2209 ng/mL (139%)] than among the 25 younger patients [1876 ng/mL (162%); GMR 1.56; 95% CI: 1.22-1.88; P = 0.004]. Similarly, the geometric mean C trough of ritonavir was significantly higher among older than among younger individuals., Conclusions: The mean plasma C trough of darunavir and ritonavir was significantly higher in older patients than in younger patients with HIV-1 infection, while the mean plasma level of raltegravir was comparable in the two groups. However, both regimens showed good tolerability in both younger and older subjects., (© 2017 British HIV Association.)

Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids.

Background: The combination antiretroviral therapy (cART) has dramatically improved the life expectancy of patients with HIV infection, but may lead to several long-term metabolic abnormalities. However, data about the frequency of metabolic syndrome (MS) in HIV-infected people vary considerably across different observational studies., Methods: The prevalence of MS among HIV-infected patients was evaluated by a cross-sectional study conducted among subjects naive to cART or receiving the first antiretroviral regimen and referring to our Clinics from January 2015 to December 2015. The diagnosis of MS was made based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and International Diabetes Federation (IDF) criteria., Results: The study recruited 586 patients: 98 naive to cART and 488 under the first antiretroviral treatment. The prevalence of MS, according to NCEP-ATP III criteria, was significantly higher among treated patients than among naive ones (20.9% vs. 7.1%; p = 0.014). The most frequently reported components of MS among treated patients were high triglycerides (44.3%), low high-density lipoprotein cholesterol (41.1%), and hypertension (19.7%). On multivariate analysis, long duration of HIV infection, low nadir of CD4 lymphocytes, high body mass index, current use of one protease inhibitor, and long duration of cART were significantly associated with a higher risk of MS, while current use of one integrase inhibitor was significantly associated with a lower risk of MS., Conclusions: The non-negligible prevalence of MS among HIV-infected patients under cART requires a careful and periodic monitoring of its components, with particular attention to dyslipidemia and hypertension.

Background: Several studies have shown a significant association between vitamin D deficiency and an increased risk of statin-related symptomatic myalgia in the general population, but there are no data among HIV-infected persons., Methods: A retrospective, cohort study was conducted to assess the incidence of symptomatic myalgia and elevation in serum creatine kinase level among HIV-positive adults on combination antiretroviral therapy and treated with atorvastatin or rosuvastatin for at least 12 months between 2011 and 2015 in our outpatient unit., Results: A total of 545 patients (mean age 53.4 years) were enrolled into the study. Atorvastatin was prescribed in 55.8% of patients and rosuvastatin in 44.2%. After a mean duration of statin therapy of 29 months, an isolated symptomatic myalgia was diagnosed in 42 patients (7.7%) and a myalgia associated with elevated creatine kinase level in 25 (4.6%). The mean concentration of 25-hydroxyvitamin D was significantly lower in patients with myalgia (19.4 ng/ml) and with creatine kinase elevation and myalgia (22.8 ng/ml) than in those without muscle toxicity (32.1 ng/ml; P = 0.017 and 0.024, respectively). In stratified multivariable-adjusted logistic regression models, there was a statistically significant association between vitamin D deficiency and occurrence of symptomatic myalgia (P = 0.009) or creatine kinase elevation and myalgia (P = 0.046). Other factors significantly associated with development of myalgia were duration of statin therapy more than 24 months, history of myalgia, and age older than 60 years., Discussion: In our observational study, vitamin D deficiency was significantly associated with a statin-induced myalgia among HIV-infected patients on combination antiretroviral therapy, in conformity with data of the general population.

Aims: To contribute to the understanding of the role played by cytomegalovirus (CMV) in sustaining monocyte/macrophage-mediated immune activation in antiretroviral therapy treated HIV-infected subjects., Design and Methods: We selected 23 CMV-uninfected and 46 CMV-infected HIV+ subjects, matched for age, CD4 nadir, HIV infection duration, and viral hepatitis serostatus. All subjects were on successful antiretroviral therapy since at least 1 year. A group of 16 healthy donors with similar age and sex was also included. Plasma levels of tumor necrosis factor-alpha, interleukin-6, sCD163, sCD14, and CMV immunoglobulin G levels were measured in duplicate with human enzyme-linked immunosorbent assay kits., Results: We found significantly higher sCD163 plasma levels in HIV+CMV+ compared with HIV+CMV- subjects and healthy donors. This augmentation was confirmed also when subjects positive for hepatitis C virus-Ab were excluded from analysis. Interestingly, a correlation between anti-CMV immunoglobulin G levels and sCD163, tumor necrosis factor-alpha, interleukin-6, and sCD14 in HIV+CMV+ subjects was found., Conclusions: CMV coinfection could be a major driver of monocyte/macrophage activation in virally suppressed HIV+ individuals and might explain the increased risk of non-AIDS morbidity/mortality in HIV/CMV-coinfected subjects.

Objectives: Statins have shown anti-inflammatory and immune-modulatory properties in both general and HIV-infected population, but their effect on plasma D-dimer levels is controversial and it has not been investigated to date in HIV-positive patients. The aim of our study was to assess the effect of rosuvastatin on D-dimer and other serum inflammation markers among these subjects., Methods: Prospective, cohort study of HIV-1-infected adult patients receiving a stable combination antiretroviral therapy (cART), who started a lipid-lowering therapy with rosuvastatin (10 mg daily) and were followed up for at least 12 months. The primary endpoint was the change at month 12 in the median plasma concentration of D-dimer. The secondary endpoints included the variation in median plasma levels of these inflammatory biomarkers: interleukin-8 (IL-8), interleukin-10 (IL-10), and interleukin-12 (IL-12)., Results: Sixty-two patients were enrolled in the study, and the endpoints were available for 54 subjects. After 12 months, a significant decrease in median plasma concentration of D-dimer was observed (-21.4%; interquartile range [IQR], -35.5; -4.2; p = .029). With regard to the inflammatory biomarkers, a significant decrease in median levels of IL-8 (-24.6%; IQR, -30.8; -1.8; p = .012) and IL-12 (-18.7%; IQR, -25.8; +2.5; p = .033) was also observed. Rosuvastatin led to a significant reduction in serum lipid values and showed a good tolerability profile., Conclusions: Our findings show that a 12-month treatment with rosuvastatin associated with an effective cART can significantly decrease the plasma levels of D-dimer, IL-8, and IL-12, and suggest a potential role for this statin to reduce activated coagulation and systemic inflammation among HIV-infected persons.

Background: In clinical trials, toxicity leading to tenofovir disoproxil fumarate (TDF) discontinuation is rare (3% by 2 years); however in clinical practice it seems to be higher, particularly when TDF is co-administered with ritonavir-boosted protease inhibitors (PI/r). Aims of this study were to assess the rate of TDF discontinuations in clinical practice and to identify factors associated with the risk of stopping TDF., Methods: All antiretroviral treatment (ART)-naive patients initiating a TDF-based regimen were selected from the ICONA Foundation Study cohort. The primary outcome was TDF discontinuation regardless of the reason; secondary outcome measures were TDF discontinuation due to toxicity and selective TDF discontinuation (that is, TDF discontinuation or substitution, maintaining unchanged the remaining antiretroviral treatment)., Results: 3,618 ART-naïve patients were included: 54% started a PI/r-based and 46% a NNRTI-based based regimen. Two-hundred-seventy-seven patients discontinued TDF and reintroduced ART within 30 days without TDF. The probability of TDF discontinuation regardless of the reason was of 7.4% (95%CI:6.4-8.5) by 2 years and 14.1% (95%CI:12.2-16.1) by 5 years. The 5-year KM estimates in the PI/r vs. NNRTI group were 20.4% vs. 7.6%, respectively (log-rank p = 0.0001), for the outcome of stopping regardless of the reason, and 10.7% vs. 4.7% (p = 0.0001) for discontinuation due to toxicity. PI/r use and lower eGFR were associated with an increased risk of discontinuing TDF., Conclusion: In our cohort, the frequency of TDF discontinuations was higher than that observed in clinical trials. Co-administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. Further studies are needed to clarify the mechanisms that might have led to this outcome., Competing Interests: The authors of this manuscript have the following competing interests: SC received speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie and ViivHealthcare, travel grants from Gilead, ViivHealthcare and Bristol-Meyers and has been an employee of Gilead Sciences between 2012 and 2013; ACL received no grants; GL received speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie and Novartis and travel grants from Gilead, Merck, Abbvie, Boerhinger and Bristol-Meyers; SB received board membership grants and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare; GM received board membership grants and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare and travel meeting expenses from Janssen, Gliead Sciences and ViivHealthcare; FM received board membership grants from Gliead Sciences, Bristol-Meyers Squibb, Merck and ViivHealthcare and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb and ViivHealthcare; AA received consultancy and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare and travel meeting expenses from Abbvie and ViivHealthcare; MG received board membership grants consultancy and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare, travel meeting expenses from Abbvie and ViivHealthcare; GD received board membership grants and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare and speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare; PV received no grants; ADM received speaker grants from Janssen, Gliead Sciences, Bristol-Meyers Squibb, Abbvie and Merck; AG received board membership grants and speaker grants from Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare and speaker grants from Gliead Sciences, Bristol-Meyers Squibb, Abbvie, Merck and ViivHealthcare. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Objectives: Recent clinical studies and one meta-analysis have shown a modest but significant increase in the incidence of diabetes mellitus associated with statin exposure, so this correlation was investigated in a cohort of HIV-positive subjects., Methods: A retrospective cohort study including adult HIV-1-infected patients followed at our Clinic of Infectious Diseases between 2007 and 2014 was performed., Results: We assessed 3170 HIV-positive patients with a median follow-up of 5.2 years. The incidence of diabetes mellitus was 1.2 per 100 person-years and it was not significantly associated with the prescription of statins [hazard ratio (HR) 1.09 per year of statin exposure; 95% confidence interval (CI) 0.7-1.49; P = 0.067], while it was associated with older age, chronic hepatitis C, antiretroviral-naïve vs. antiretroviral experienced condition, high body mass index, and high serum concentration of triglycerides., Conclusions: In our study, a higher risk of diabetes mellitus was not associated with statin treatment, but with some traditional risk factors., (© 2016 British HIV Association.)

Depressive symptoms cause major impairment and may accelerate HIV progression despite the use of antiretroviral medication. The somatic symptoms criteria for HIV infection and depression partially overlap, which can make differential diagnosis challenging. Because of chronic inflammation caused by HIV infection, HIV-positive patients may develop somatic and affective-cognitive symptoms of depression. Inflammation-related depression is primarily characterized with severe somatic symptoms such as fatigue and sleep disturbance. This study sought to explore the patterns of somatic and cognitive-affective depressive symptoms that characterize HIV-positive patients. Our specific aims were (1) to identify subtypes of depressive symptoms in a sample of HIV-positive patients; and (2) to test the subtypes' difference on inflammatory and HIV disease progression biomarkers. HIV-positive men and women (N=102) with and without depressive symptoms were randomly selected from an Italian HIV clinic. Depressive symptoms (PHQ-9), viral load (VL), CD4+, Il-6, TNF-α, and monocytes were assessed. The three subtypes formed using Latent Class Analysis (LCA) identified patients with (1) severe cognitive-affective and somatic depressive symptoms; (2) severe/moderate somatic symptoms; and (3) absent or low depressive symptoms. The subtype with severe/moderate somatic symptoms was characterized with elevated levels of Il-6 and monocytes. No difference on HIV progression biomarkers was found. The subtypes of depressive symptoms might help differentiating depressive symptoms from HIV- and inflammatory-related somatic symptoms. When present, cognitive-affective and/or somatic symptoms cause significant impairment to patients' lives and thus warrant further assessment and treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The introduction of potent combination antiretroviral therapy (cART) has had a remarkable impact on the natural history of HIV infection, leading to a dramatic decline in the mortality rate and a considerable increase in the life expectancy of HIV-positive people. However, cART use is frequently associated with several metabolic complications, mostly represented by lipid metabolism alterations, which are reported very frequently among persons treated with antiretroviral agents. In particular, hyperlipidaemia occurs in up to 70%-80% of HIV-positive subjects receiving cART and is mainly associated with specific antiretroviral drugs belonging to three classes of antiretroviral agents: NRTIs, NNRTIs and PIs. The potential long-term consequences of cART-associated dyslipidaemia are not completely understood, but an increased risk of premature coronary heart disease has been reported in HIV-infected patients on cART, so prompt correction of lipid metabolism abnormalities is mandatory in this population. Dietary changes, regular aerobic exercise and switching to a different antiretroviral regimen associated with a more favourable metabolic profile are the first steps in clinical management, but lipid-lowering therapy with fibrates or statins is often required. In this case, the choice of hypolipidaemic drugs should take into account the potential pharmacokinetic interactions with many antiretroviral agents., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Nucleoside reverse transcriptase inhibitor (NRTI)-sparing antiretroviral therapies may be useful in HIV-infected patients with resistance or intolerance to this class., Methods: We performed an observational study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted protease inhibitor who switched to a dual regimen containing raltegravir (400 mg twice daily) and darunavir/ritonavir (800/100 mg once daily) and were followed-up for 48 weeks., Results: As a whole, 82 patients were enrolled. Mean duration of current regimen was 4.6 years and mean duration of plasma HIV RNA < 50 copies/mL before the switch was 46.2 months. Reason for simplification was toxicity in 76 patients and resistance to NRTIs in 13. After switching, the percentage of patients with HIV RNA < 50 copies/mL at week 48 was 92.7% in the intent-to-treat-exposed analysis and 97.6% in the per-protocol analysis. The switch led to a significant reduction in the mean triglyceride value (-85.2 mg/dL), in the prevalence of tubular proteinuria (-56%) and in the mean level of interleukin-6 (-0.94 pg/mL), with a significant increase in the mean phosphoremia (+0.58 mg/dL). Mean trough concentrations of both raltegravir and darunavir were within the therapeutic range. Two patients (2.4%) had virological failure due to suboptimal adherence and 4 subjects (4.9%) discontinued treatment due to adverse events, but no patients experienced Grade 3 or 4 adverse events., Conclusion: In our study, simplification to a dual therapy containing raltegravir plus darunavir/ritonavir after 48 weeks maintained viral suppression in more than 90% of patients and showed a good tolerability with a favourable effect on proteinuria, ipophosphoremia, and lipid metabolism.

Background: The association between abacavir use and increased risk of myocardial infarction has been heavily debated, but cohort studies and randomized trials have provided conflicting results. Aim of our study is to compare the effect of abacavir and tenofovir on the inflammation and endothelial activation markers., Methods: We performed an observational study of HIV-infected naïve patients starting tenofovir/emtricitabine (group A) or abacavir/lamivudine (group B) plus efavirenz. In the present analysis, we measured serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), soluble vascular adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin at baseline and during a 48-week follow-up., Results: As a whole, 118 patients (93 males; mean age ± SD of 42.8 ± 10.1 years) were enrolled: 61 in group A and 57 in group B. In group A at weeks 24 and 48 the mean concentrations of IL-6, TNF-α, ICAM-1, VCAM-1, E-selectin and Pselectin decreased significantly in comparison with respective baseline values. In group B at week 24 a significant increase in mean values of these markers was reported in comparison with group A, but after 48 weeks they significantly decreased in group B too and no significant differences between groups A and B were found., Conclusion: In our study, naïve patients starting tenofovir/emtricitabine or abacavir/lamivudine plus efavirenz showed after 48 weeks a significant and comparable decrease in serum concentrations of IL-6, TNF-α, ICAM-1, VCAM-1, Eselectin and P-selectin, while the mean level of hs-CRP did not change significantly in any group.

Background: The antiretroviral regimens including tenofovir and a ritonavir-boosted protease inhibitor (r/PI) have been associated with a reduced bone mineral density (BMD), increased bone turnover markers and renal tubular dysfunction., Methods: An observational, prospective study was performed including HIV-1-infected, virologically suppressed patients treated with tenofovir/emtricitabine plus an r/PI for at least 12 months who switched to raltegravir plus nevirapine. The primary end point was changes after 48 weeks in estimated glomerular filtration rate (eGFR), prevalence of tubular dysfunction, BMD and concentration of two serum markers of bone turnover: collagen type-1 cross-linked C-telopeptide (CTX) and bone-specific alkaline phosphatase (BAP)., Results: A total of 46 patients were enrolled: 78% were male, 96% were Caucasian, the mean age was 45 years and the mean CD4(+) T-lymphocyte count was 681 cells/mm(3). A renal impairment was present in 72% of patients and was the main reason for the switch. After 48 weeks, prevalence of proximal tubular dysfunction decreased significantly (-72%; P<0.001), whereas the mean value of eGFR did not change significantly. At the same time, after 48 weeks a significant increase in both lumbar spine and total hip BMD, T-score and Z-score was reported (+11.5% in lumbar spine T-score; P<0.001), and there was a significant reduction in both CTX and BAP mean serum concentrations (-15% and -13%, respectively; P<0.001). Two (4.3%) patients had virological failure due to suboptimal adherence and one (2.2%) subject discontinued treatment due to a skin rash., Conclusions: Switching virologically suppressed patients from tenofovir/emtricitabine plus one r/PI to raltegravir plus nevirapine after 48 weeks significantly improved proximal tubular function, increased BMD and reduced serum markers of bone turnover.

Background: The objective of the study was to assess plasma concentrations of efavirenz, darunavir/ritonavir and raltegravir in patients with human immunodeficiency virus-hepatitis C virus (HIV-HCV)-coinfection without liver cirrhosis., Methods: In this observational, open-label study, adult HIV-infected outpatients treated with tenofovir/emtricitabine plus efavirenz (600 mg daily), darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) for at least 4 weeks were asked to participate. Subjects with liver cirrhosis were excluded. The trough concentration (C trough) of darunavir/ritonavir and raltegravir and the mid-dose concentration (C12h) of efavirenz were assessed at steady state by a validated high-performance liquid chromatography (HPLC)-tandem mass spectrometry method., Results: A total of 96 HIV-positive patients were enrolled into the study. Thirty-four patients were treated with efavirenz, 33 with darunavir/ritonavir and 29 with raltegravir. The geometric mean plasma C trough [coefficient of variation (%)] of darunavir was comparable between HIV+/HCV+ and HIV+/HCV- subjects: 2644 ng/ml (155%) and 2491 ng/ml (139%), respectively (geometric mean ratio (GMR) = 0.81; 95% confidence interval (CI) = 0.79-1.56; p = 0.69). These values were comparable for raltegravir: 108 ng/ml (149%) in the HIV+/HCV+ group and 96 ng/ml (161%) in the HIV+/HCV- group (GMR = 0.84; 95% CI = 0.61-1.44; p = 0.72). On the contrary, the geometric mean plasma C12h of efavirenz was significantly higher among the 15 HIV+/HCV+ patients (1915 ng/ml, 159%) than among the 19 HIV+/HCV- patients (1505 ng/ml, 167%; GMR = 1.41; 95% CI = 1.19-1.71; p = 0.009)., Conclusions: The mean plasma concentration of efavirenz was significantly higher in HCV-positive than in HCV-negative patients without liver cirrhosis, while the mean plasma levels of darunavir/ritonavir and raltegravir were comparable in both groups.

Human immunodeficiency virus (HIV)-infected patients have an increased risk of developing osteopenia or osteoporosis compared with healthy individuals. Our aim was to compare dual X-ray absorptiometry (DXA), the gold standard for measuring bone mineral density (BMD), with bone quantitative ultrasound (QUS), an alternative technique for predicting fractures and screening low BMD, at least in postmenopausal populations. We analyzed DXA and QUS parameters to investigate their accuracy in the diagnosis and prediction of bone alterations in a cohort of 224 HIV-1-positive patients. The speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) parameters showed a moderate correlation with DXA, especially with total-body BMD (r coefficient of 0.38, 0.4 and 0.42 respectively), particularly in the female subgroup. In addition, multivariate analysis of HIV-positive patients assessed for vertebral fractures indicated that QUS was more effective than DXA at predicting the risk of fracture. QUS can be used as an additional tool for analyzing bone density in HIV-positive patients and its case of use and low cost make it especially suitable for resource-limited settings where DXA is not employed.

An HIV-infected 49-year-old man was admitted with polyuria, fever, chills and a dull left lumbar pain. Laboratory tests showed increased C-reactive protein while urine analysis and abdomen ultrasound scan were negative. Blood cultures revealed a Salmonella paratyphi B, identified through MALDI-TOF mass spectrometry. Targeted antibiotic therapy with intravenous piperacillin/tazobactam was started and a multi-phase contrast-enhanced abdomen CT-scan was performed at 24 hours from admission showing a saccular aneurysm of the abdominal aorta with a 1 cm penetrating aortic ulcer on posterior wall. The patient underwent emergency vascular surgery at 34 hours from admission for debridement and homo-graft placement of sub-renal aorta, and surgical samples were sent for microbiological analysis. Unfortunately, the patient died on post-surgical day 7 after haemorrhagic shock due to laceration of his graft. Salmonella paratyphi infection can be responsible for sepsis in severely immunosuppressed patients with poorly controlled HIV, requiring careful work-up for cardiovascular involvement.

Low bone mineral density (BMD) is frequent in HIV infection regardless of the use of antiretroviral therapy (ART). Uncertainties remain, however, as to when in HIV infection BMD screening should be performed. We designed a prospective study to estimate the efficacy of universal BMD screening by dual-energy X-ray absorptiometry (DXA). Since April 2009 through March 2011, HIV patients attending our Center were offered femoral/lumbar DXA to screen BMD. Low BMD for chronological age, that is significant osteopenia, was defined as a Z-score ≤ -2.0 at femur and lumbar spine. Nontraumatic bone fractures (NTBFs) were evaluated. The final sample included 163 patients. A Z-score ≤ -2.0 at any site was observed in 19.6% of cases: among these, 18.8% had no indication to DXA using current Italian HIV guidelines for BMD screening. A lower femoral Z-score was independently associated with lower BMI, AIDS diagnosis, HCV co-infection, antiretroviral treatment, and NTBFs; a lower lumbar Z-score with age, BMI, Nadir CD4 T-cell counts, and NTBFs. Prevalence of NTBFs was 27.0%, predictors being male gender, HCV co-infection, and lower femoral Z-scores. Our results suggest that measuring BMD by DXA in all HIV patients regardless of any further specification may help retrieving one-fifth of patients with early BMD disorders not identified using current criteria for selective screening of BMD.

In our HIV outpatient centre where over 1,200 patients are followed, maraviroc as an entry inhibitor was introduced in 2010. We aimed to assess the background, the therapeutic challenges and the prospective monitoring of all patients treated with a combination antiretroviral therapy (cART) including maraviroc. Sixty-six patients started a maraviroc-containing cART with a history of HIV infection lasting 13.9±10.7 years. This interim analysis presents patients who had at least 12 (mean 16.9±12.8) months of follow-up. One to 17 previous cART changes prompted the introduction of maraviroc in rescue regimens in the great majority of patients considered (53 of 66); in 13 cases, maraviroc was given to patients with advanced HIV disease and no immune recovery after 2-3 years of a virologically-effective cART. The most frequent companion antiretroviral agents were: darunavir/ritonavir (51 cases), raltegravir (49 subjects), and etravirine (36 cases). The most common underlying conditions were: AIDS (41 cases), liver cirrhosis (21), AIDS-related or other malignancies (20 cases), major cardiovascular events (18 cases), osteonecrosis and haemodialysis-treated kidney failure (3 cases each). A chronic HCV and HBV hepatitis were of concern in 25 and 13 patients. The addition of maraviroc added favourably to clinical-laboratory markers of HIV disease progression, and those of comorbid conditions. HIV viraemia became (or remained) undetectable in 55 patients of 66 (83.3%). An improvement in CD4+ count was observed in all 66 patients, based on a mean 24.9±19.2% increase versus baseline, paralleled by an improvement in mean absolute CD4+ count of 134.7±121.1 cells/μL. A tendency towards an increased mean and peak CD4+ count was observed in the subgroup receiving a maraviroc-raltegravir-based cART. As no clinical-laboratory adverse events attributable to maraviroc occurred, nobody discontinued the study drug. Only mild-transient gastrointestinal disturbances, fatigue and anorexia, were reported during maraviroc administration, but their relationship with the study drug was difficult to assess because of the multiple comorbidities and polypharmacy. Our preliminary experience with maraviroc, even considering the limits of the proportionally reduced sample, the patients' salvage stage of advanced disease and the related-unrelated morbidities, underlines its excellent efficacy and safety profile.

Raltegravir, as the first HIV integrase inhibitor, has been used and prospectively monitored since 2010 in our HIV outpatient centre, where over 1,200 patients are monitored. The aim of our report is to perform an interim assessment of the background, the safety profile and the clinical-laboratory monitoring of all patients treated with a combination antiretroviral therapy (cART) including raltegravir, for at least 12 months. In all, 109 pretreated patients started a raltegravir-containing cART when aged 44.8 plus or minus 19.2 years, with a history of HIV infection lasting 13.4 plus or minus 9.7 years. All subjects were monitored for at least 12 months (mean 17.2 plus or minus 10.3 months). In the vast majority of cases (93 of 109: 85.3%), multiple (3-16) prior cART changes prompted raltegravir introduction in advanced-salvage lines: 72 of 109 (66.1%) patients had even developed a concurrent triple-class resistance to anti-HIV compounds. The most frequent companion antiretroviral agents were: darunavir/ritonavir (75 cases), maraviroc (47 subjects), and etravirine (38 cases). The most common underlying conditions were: AIDS (46 patients), liver cirrhosis (31 cases), AIDS-related or other malignancies (23 cases), and major cardio-cerebro-vascular events (18 cases). A chronic HCV and HBV hepatitis were of concern in 48 and 23 patients, respectively. The adjunct of raltegravir favourably affected all clinical-laboratory markers of HIV disease progression, and those of the broad spectrum of comorbidities, except for two patients who failed the raltegravir-containing cART due to insufficient adherence. Despite the already compromised clinical situation, a minority of subjects experienced mild-transient clinical-laboratory untoward events possibly attributable to raltegravir, such that no patients discontinued raltegravir during the observation period. Only three AIDS-defining conditions became apparent during raltegravir-based cART; chemotherapy and/or radiotherapy cycles were performed as scheduled in patients suffering from cancer; chronic hepatitis B and C progressed to liver cirrhosis and/or hepatocarcinoma in only 2 and 6 patients. Otherwise, treatment with pegylated interferon-ribavirin became feasible in 25 patients of 48 with chronic HCV. During raltegravir-containing cART, neither autoimmune disorders nor novel malignancies were diagnosed. Only mild-transient gastrointestinal disorders, fatigue, dizziness, insomnia and cutaneous rash were reported, although their relationship with the study drug was difficult to assess due to multiple comorbidities and polypharmacy. Abnormal liver function testings were observed in 57 patients (52.3%), all suffering from concurrent hepato-biliary disorders. Significant increases in serum lipids and/or lipase levels versus baseline values were never registered: serum lipid levels significantly improved after raltegravir introduction. Our experience with raltegravir underlines its excellent efficacy and safety profile, which exploits a novel mechanism of action, and displays no cross-resistance with any other antiretroviral. A progressively extended prescription in naive patients and early cART lines will allow the therapeutic potential of raltegravir to be exploited.

To evaluate the frequency of myopathy and serum creatine kinase (CK) elevation associated with the use of the integrase inhibitor raltegravir we conducted a retrospective, cohort analysis assessing the incidence of skeletal muscle toxicity among HIV-infected patients treated with raltegravir. Adult HIV-infected patients who started a raltegravir-containing therapy were enrolled into the study. The skeletal muscle toxicity was defined by the presence of one or more of the following parameters: (1) isolated and significant CK elevation without signs or symptoms; (2) diffuse myalgia without weakness; (3) proximal muscle weakness; (4) rhabdomyolysis. On the whole, 155 patients were included in the study, with a mean age of 49.2 years; the median duration of the raltegravir treatment was 30.7 months. The overall frequency of skeletal muscle toxicity was 23.9%, with an incidence of 4.7/100 person-years. An isolated CK elevation was reported in 21.3% of cases, while less than 3% of patients complained of myalgia or muscle weakness. The CK elevation was usually of grade 1 or 2 and self-limiting, and laboratory or clinical abnormalities did not require discontinuation of raltegravir in any patient. Factors significantly associated with skeletal muscle toxicity were previous use of zidovudine, higher baseline CK levels, previous increase of the CK levels, and a higher body mass index. Skeletal muscle toxicity is not an unusual adverse event in subjects receiving raltegravir, but it is usually represented by a mild-to-moderate increase in CK concentration, while clinical symptoms of myopathy are very uncommon.

This study compared the cost-efficacy ratios of lopinavir/ritonavir monotherapy (LPV/r-MT) and of standard of care in virologically suppressed HIV-infected patients. The results of the efficacy and safety analyses are presented. We conducted a multicentre, randomised, open-label trial of HIV-infected adults on stable treatment, with HIV- RNA <50 copies/mL, randomised to continue the ongoing regimen (cART-arm) or to switch to LPV/r (400/100 mg BID) MT (MT-arm). Time to virological rebound (VR = confirmed HIV-RNA ?50 copies/mL) was estimated by Ka- plan-Meier method and changes in laboratory values during follow-up were evaluated by univariate mixed-linear models. Ninety-four patients were randomised and analysed (43 in the MT-arm and 51 in the cART-arm). Five (four in the MT and 1 in the cART-arm; p=0.175) had VR, but time to VR did not statistically differ between the two arms (p=0.143). Major PI mutations were not detected at VR. Patients on MT had significant increases in total choles- terol [difference in mean change between MT and cART arm: 0.77 (±0.30) mg/dL per month; p=0.012] and eGFR [difference in mean change between MT and cART arm: 0.24 (±0.11) mL/min/1.73 m2 per month; p=0.029]. LPV/r-MT seems safe in most patients and should be considered in patients who have developed kidney toxicity from tenofovir.

Permanent monitoring of adherence to combination antiretroviral therapy (cART), together with the assessment and management of related adverse events, plays a key role for optimised management of HIV infection. In our HIV outpatient clinic a dedicated pharmacist provides direct drug distribution and accountability, and gives information on administration mode, possible side effects and drug interactions. A survey card regarding cART adherence and adverse drug reactions (ADRs) is administered to all patients. All figures are recorded in an electronic database. In an ad interim analysis 659 consecutive patients' data were evaluated, of whom 74% were fully adherent to cART. A lower adherence rate was found to be correlated with the presence of concurrent medications, and with the increasing number of daily cART tablets/capsules. A significant impact of cART adherence on a favourable course of the main laboratory surrogate markers of HIV disease progression (CD4+ T-lymphocyte count and HIV viral load) was also observed. Darunavir-containing cART was related to a lower incidence of early gastrointestinal and neuropsychiatric disturbances and also a reduced perception of morphological/physical changes. A multidisciplinary approach based on strict interaction between pharmacists and infectious diseases physicians may significantly improve cART adherence and the monitoring of adverse events, making a considerable contribution to the better management of HIV-infected patients.