Suchergebnisse

IntroductionLow bone mineral density (BMD) and osteoporosis are prevalent in HIV‐infected patients and were associated with HIV infection and tenofovir‐containing ART.Materials and MethodsThe GUSTA study (GUided Simplification with Tropism Assay) is a two‐arm, prospective, multicenter, 1:1 randomized controlled trial designed to demonstrate the non‐inferiority of therapeutic switch to maraviroc+darunavir/ritonavir (MVC+DRV/r) 300/800/100 mg QD against the continuation of previous triple cART in patients with stable virological suppression. Enrolment criteria include HIV1‐RNA <50 copies/mL for >6 months, R5 tropism and CD4>200 cells/µL for >3 months. Dual energy X‐ray absorptiometry scans of proximal femur and lumbar spine were performed at baseline and week 48. Bone composition was evaluated using L2‐L4 lumbar column and proximal femoral BMD, T‐score and the Z‐score. At the same timepoints, plasma bone metabolism biomarkers were measured. Linear regression was used to compare means of differences between arms. The association between BMD changes and the baseline variables was assessed by linear regression.Results27 patients were included, 13 from study group and 14 from control group, 74.1% were males, 44.4% heterosexuals, 81.5% Caucasian, median age was 47 years (IQR 41–53), time from HIV diagnosis 13.4 years (9–19), CD4 553/µL (406–739), nadir CD4 201/µL (76–283). At baseline, median ART duration was 10.5 years (5.7–15.3), the majority of patients (70.4%) was on tenofovir, 63% was on a PI‐based regimen and 14,8% on an NNRTI‐based regimen. Mean proximal femur BMD from baseline increased over 48 weeks by 2.06% (SD 2.24) in the study arm and decreased by −2.77% (SD 4.63) in control arm (p=0.003). The change over 48 weeks in proximal femur T‐score was significantly different between the study (+0.11, SD 0.22) and control arm (−1.14, SD 0.27, p=0.016). Also the changes in total alkalin phosphatase (−20 U/L vs −1.5, p=0.003) was significant between the two groups. After adjusting for time from HIV diagnosis and years of ART, study group was the only factor associated to higher mean percentage change from baseline femoral BMD (MVC+DRV/r +4.83, p=0.044).ConclusionsThe study demonstrated a significant improvement in femoral BMD and T‐score after treatment simplification with MVC+DRV/r.

IntroductionThe aim of our study was to investigate the potential relationship between liver fibrosis (LF) and cognitive performance in HIV+ patients.Materials and MethodsWe performed a cross‐sectional cohort study by consecutively enrolling HIV+ patients during routine outpatient visits at two clinical centres in Italy. Subjects with decompensated liver disease were excluded. All subjects underwent a comprehensive neuropsychological battery exploring memory, attention, psychomotor speed and language; cognitive impairment was defined as at least two abnormal [1.5 SD below the mean for appropriate norms] cognitive domains. LF was explored by calculating FIB4 index; in a subgroup of patients, LF was also assessed by transient elastography. Factors associated with cognitive impairment were investigated by logistic regression models.ResultsA total of 413 patients [77% males, median age 46 (IQR 39–52), 17% with past AIDS‐defining events, 19% past IDU, 3% with diabetes, 94% on cART, 90% with HIV RNA <50 copies/mL, 18% co‐infected with HCV] were enrolled. Seventeen patients (4%) had FIB4 >3.25 and 14/129 (3%) had liver stiffness >14KPa. Forty‐seven patients (11%) were diagnosed with cognitive impairment. At multivariate analyses patients with FIB4 >1.45 showed a higher risk of cognitive impairment in comparison with those with lower values (OR 2.19, 95% CI 1.02–4.72; p=0.044) after adjusting for education (OR 0.79, 95% CI 0.71–0.88; p<0.001), past IDU (OR 1.69, 95% CI 0.67–4.23; p=0.264), diabetes (OR 2.35, 95% CI 0.62–8.86; p=0.207), HIV RNA <50 copies/mL (OR 0.47, 95% CI 0.19–1.14; p=0.095) and HCV co‐infection (OR 0.88, 95% CI 0.33–2.39; p=0.807). Analyzing any single cognitive domain, a higher risk of abnormal psychomotor speed was associated with fibroscan score >14KPa in comparison with fibroscan score <7KPa (OR 285.07; 95% CI 2.42–33574.06; p=0.020) after adjusting for education (OR 0.54, 95% CI 0.31–0.92; p=0.024), age (for 10 years increase) (OR 2.03, 95% CI 0.55–7.53; p=0.288), past IDU (OR 4.43, 95% CI 0.35–7.57; p=0.526), HIV RNA <50 copies/mL (OR 0.01, 95% CI 0.00–0.18; p=0.003), HIV history (for 1 year increase) (OR 0.96, 95% CI 0.83–1.12; p=0.641), CD4 cells count at nadir (OR 1.10, 95% CI 0.56–2.16; p=0.779), and HCV co‐infection (OR 0.06; 95% CI 0.00–1.93; p=0.113).ConclusionsIn HIV‐infected patients higher LF, estimated through non‐invasive methods, is associated to a higher risk of cognitive impairment.

IntroductionRaltegravir intensification is associated with an increase in 2‐LTR episomal HIV DNA= circles, indicating a persistent low‐level replication, in some individuals in ART with suppressed HIV RNA. We aimed at monitoring residual plasma HIV RNA and cellular HIV DNA in virologically suppressed patients switching to a raltegravir‐based regimen.Materials and MethodsForty‐six HIV‐infected subjects on PI or NNRTI based‐regimens, with plasma HIV RNA level <40 copies/mL for ≥6 months and CD4 >200 cells/µL for ≥12 months were enrolled. Thirty‐four patients switched to raltegravir‐based regimen (RASTA study group) and 12 continued a PI or NNRTI based‐regimen (control group). Ultrasensitive HIV residual viremia and total PBMC HIV DNA were assessed at baseline (W0), 24 (W24) and 48 (W48) weeks. HIV RNA levels were determined by an ultrasensitive test derived from a commercial real time PCR (limit of detection 5 copies/ml). A real time PCR was used to quantify HIV DNA copy numbers in PBMCs.ResultsAt W0, HIV DNA was detected in all patients while at W48 it was detectable in 82.3% of RASTA group vs 100% of controls (p=0.01). The difference between the average values of HIV DNA log10 copies/10°6 CD4 at W0 (median 3.11, IQR 2.70–3.45) and W48 (median 2.87, IQR 2.24–3.38) was statistically significant for RASTA group (p=0.035). Male gender (mean difference −0.37 log10 copies/10°6 PBMC, p=0.023) and previous PI based‐ART (mean difference +0.39 log10 copies/10°6 PBMC, p=0.036) were predictive of HIV DNA level at W0. After adjusting for previous PI based‐ART, male gender was the only variable independently associated with HIV DNA size at W0 (mean difference −0.326 log10 copies/10°6 PBMC, 95% CI −0.641, −0.011 p=0.043). Ultrasensitive HIV‐1 RNA was detectable at W0 in 50% of RASTA group versus 66.7% of controls and at W48 in 32.4% versus 45.5%, respectively. No differences were found between HIV RNA levels at W0 and W48 within and between the two groups.ConclusionsSwitching to raltegravir‐based regimens may be associated with a decrease of HIV reservoir, as measured by total PBMC HIV DNA. A larger sample size is required to confirm this finding.

IntroductionAgeing of HIV‐infected patients led to an increasing rate of osteopenia and osteoporosis. The cause is multifactorial, including virus activity, drug toxicity and host factors. The aim of our analysis is to quantify this issue according to our department experience and to evaluate predictors of low BMD.Materials and MethodsHIV‐1‐infected patients, on stable HAART, were consecutively enrolled in this cross‐sectional study and underwent DEXA. We analyzed the prevalence and evaluated predictors of low BMD in our population.ResultsWe collected data from 208 patients, 148 of whom were male, with 49 years median age (IQR 24.1–68.3). About 39% of patients were heterosexuals, 33.7 MSM and 12.5% were IDU, 40.4% were smokers. Caucasians were 93.3%, and 13.9% were co‐infected with HCV virus. Around 6.7% of patients were on their first HAART regimen and all of them started TDF. Their median time of HAART exposure was 1.17 years (IQR 0.8–1.6). Conversely, median time of HAART exposure of multi‐experienced patients was 8.5 years (IQR 3.1–12.0). We stratified DEXA results for patients on first‐line regimen versus multi‐experienced one. We found that 42.9% of patients on first‐line HAART had low BMD of lumbar spine and 7.1% had osteoporosis. Regarding the multi‐experienced group of patients, lumbar spine osteopenia was observed in 36.6% of patients and 15.5% of them had osteoporosis. Median age of patients with low BMD of lumbar spine was 45.6 (IQR 24.1–68.3) for patients on first‐line regimen and 49.8 years for multi‐experienced (IQR 44.2–54.0) regimen. We found similar data for BMD of hip, but no patients in the first group had hip osteoporosis. We also analyzed predictors of low BMD in our population. MSM patients showed a 3.4‐fold higher risk to have osteoporosis of lumbar spine (OR 3.41, CI 1,105–9,269, p=0.03). As expected, we found that non‐Caucasian patients had 13.5‐fold higher risk to have osteoporosis of the hip (OR 13.52, CI 1.5–122.7, p=0.02). Exposure to HAART was also evaluated, but no predictors were found.ConclusionsOur data confirm how osteoporosis is highly prevalent and occurs earlier in HIV‐infected patients. Antiretrovirals play a crucial role. In our experience loss of BMD can occur within a year of treatment, when almost half of our patients starting TDF had a low BMD. MSM patients have a higher risk to develop spine osteoporosis and non‐Caucasian patients are more likely to have hip osteoporosis. We remark the importance of BMD assessment for HIV‐infected patients especially during their first months of treatment.

IntroductionAccording to recent evidence about boosted protease inhibitors (PIs/r)‐simplified regimens, the combination of 3TC and DRV/r 800/100 mg could represent a feasible option for optimizing antiretroviral therapy (ART) in treatment‐experienced HIV+ patients.Patients and MethodsWe retrospectively evaluated patients switching to 3TC+DRV/r, with at least six months of viral suppression, no resistance mutation to DRV or 3TC and not HBV‐coinfected: incidence of ART discontinuation and of virological failure (VF: 2 consecutive HIV‐RNA determinations>49 cps/mL or a single one≥1000 cps/mL) and the probability of remaining discontinuation‐free during one‐year follow‐up (FU), as well as changes in laboratory parameters at 1, 3, 6 and 12 months were estimated.ResultsWe included 94 patients: 74 males, mostly MSM (39.4%), with 49 years old, 9 years of HIV disease, 8 years of ART (median values). Median nadir CD4 count and zenith viral load (log10) were 194 cells/µL and 4.90, respectively. Ten patients were HCV‐coinfected and 38 had at least a previous VF. Seventy‐four patients were on an NRTIs‐based triple regimen (mainly TDF/FTC or 3TC/ABC) whereas 14 on another PI‐based dual therapy (mainly LPV/r). Incidence of treatment discontinuation was 12.4 per 100 patients‐year follow‐up (PYFU), but only 2 patients experienced a VF (3.5 per 100 PYFU). Mean time free from discontinuation was 5 years (95% CI 4–6), with a cumulative one‐year estimated probability of staying on 3TC+DRV/r of 85.9%. At three months, a trend of increased CD4 cells count (+42 cells/µL, p 0.059) was observed, but not confirmed at later time point; an increase of total cholesterol (TC, +17mg/dL, p 0.008) and LDL (+19 mg/dL, p 0.002), and a decreased level of AST and ALT (−2 UI/L, p 0.045; −5 UI/L, p 0.009, respectively) were also detected. Total bilirubin was reduced (−0.71 mg/dL, p 0.038). At 6 and 12 months, alteration of lipid profile was similar, with also an increased TC/HDL ratio (+0.48, p=0.030, at six months) and HDL/LDL ratio (−0.04, p=0.035, at 12 months). A significant decrease in ALT levels (−6 UI/L, 0.013) and a diminishing trend for AST and total bilirubin, as well as a significant increase in renal function (GFR +4mL/min, p 0.048) were observed at 12 months.ConclusionsThese observations on 3TC+DRV/r‐based dual therapy simplification in virologically suppressed patients show a good profile of efficacy and safety. An extended FU time is needed in order to establish the real impact of this promising therapeutic choice.

IntroductionHIV/HCV coinfection is a risk factor for hepatic injury in patients receiving HAART and previous studies support a favourable effect of antiretroviral regimens including maraviroc (MVC) on the course of coinfection compared with other antiretroviral drugs. There are few observations about MVC use in simplified treatment of coinfected patients.Objective: To evaluate the efficacy and the safety of simplification to darunavir (DRV)/ritonavir (r)/maraviroc (MVC) in virologically HIV‐suppressed patients and to explore the effect of simplified treatment on coinfected patients.Material and MethodsGUSTA study is a randomized two arms trial that compares the switch to DRV/r/MVC with standard HAART with three drugs. The study enrols patients with HIV‐1 RNA<50cp/mL>6 months, R5 tropism, CD4>200 cells/mm. Survival analysis was used to analyze factors associated to time‐to a single viral load (VL) over 50cp/mL and FIB‐4>1.45.ResultsWe included 62 patients with at least the 24 week follow‐up for FIB‐4 analysis: males 75.8%, heterosexuals 48.4%, HCV+12.9% median age 48.3 years (IQR41.1;53.5), time from HIV diagnosis 11.0 years (IQR7.3;16.7), CD4 cells 659/mm (IQR478;882), nadir CD4 203/mm (IQR115;286), FPR 46 (IQR30;70), baseline (BL) FIB‐4 1.11 (IQR0.75;1.35). At BL no differences were observed in the two arms, except for platelets (−34.96 109/L, in the study arm, p=0.028) and CD4 at nadir (−70cell/µL, p0.051). After 24 weeks a significant reduction in total bilirubin (TB) (−0.55 mg/dL, p=0.025) and alkaline phosphatase(AP) (−12.96 UI/L, p=0.002) was observed in the study group. A statistically significant difference in mean change of TB (0.61 mg/dL, p=0.016) and AP (13.23 UI/L, p=0.04) at 24 week between control and study group was observed. No grade 3/4 transaminase elevation was observed for any patient even if HIV/HCV coinfected and receiving MVC. A single HCV negative patient in the control arm had grade 3 bilirubin increase. Including all patients with at least one follow‐up HCV status was not associated with an increased risk of detectable VL (n=114, 4072 person‐week‐follow‐up [IQR12;51.6]), nor with FIB‐4>1.45 (n=98, 3513 person‐week‐follow‐up [IQR11.4;50.9]).ConclusionsThe initial results from GUSTA study show that ART‐regimen including MVC did not increase the incidence of adverse events or severe laboratory liver abnormalities in HIV‐1‐infected patients with or without HCV coinfection. Coinfected patients did not show an increased risk of failure on simplification treatment with MVC/DRV/r.

IntroductionThe 48‐week interim analysis of the MODAT study showed that confirmed virologic failure (CVF) was more frequent in patients simplifying to ATV/r monotherapy compared to maintaining ATV/r‐based triple therapy. The DSMB recommended stopping study enrollment but continuing follow‐up of enrolled patients. We present the 96‐week efficacy analysis.Material and MethodsMulticentre, randomized, open‐label, non‐inferiority trial (non‐inferiority margin −10%). Treatment failure (TF) was defined as CVF (two consecutive HIV‐RNA >50 cp/mL) or discontinuation for any cause. In the monotherapy arm, patients with CVF re‐introduced their previous NRTIs and remained in the study if HIV‐RNA <50 copies/mL within 12 weeks of re‐intensification.Results101 patients evaluated (Figure 1): 85% males, 21% HCV‐positive, median (IQR) age of 42 (36–48) years, baseline CD4+ 576 (447–743) cells/µL. In the 96‐week analysis (ITT; TF=failure), efficacy was 64% (32/50) in the monotherapy arm and 63% (32/51) in the triple‐therapy arm (difference +1.3%, 95% CI −17.5–20.1). Fourteen patients in monotherapy and two in triple‐therapy arm had CVF; median HIV‐RNA was 136 (72–376) copies/mL. In monotherapy arm, no PI or NRTI associated resistance mutations were observed at CVF. All patients who re‐intensified re‐suppressed. In monotherapy arm, TF was more frequent in HCV‐co‐infected patients (64% vs 28%; p=0.041). In the secondary analysis (ITT; re‐intensification=success), 82% (41/50) in monotherapy arm and 63% (32/51) in triple‐therapy arm were on study at week 96 (difference +19.3%, 95% CI 2.2–36.3). SAEs occurred in four (8%) patients in the monotherapy arm (one left basal pneumonia, one acute coronary stenosis, one traumatic lesion, one nephrolithiasis) and two (4%) in the triple therapy arm (one sepsis, one renal failure). Drug‐related adverse events (AEs) leading to discontinuation were three (6%) in the monotherapy arm (two AEs occurred in patients after successful re‐intensification) and 12 (23.5%) in the triple‐therapy (p=0.023).ConclusionsDespite the small sample size, the primary 96‐week analysis showed that simplification to ATV/r monotherapy showed inferior efficacy to maintaining ATV/r triple‐therapy but appeared to be superior when re‐intensification was considered success.

BackgroundTo assess efficacy and safety of treatment simplification to co‐formulated Rilpivirine/Emtricitabine/Tenofovir (RPV/FTC/TDF) in virologically suppressed patients.Materials and MethodsEndpoints of the analysis were: (a) treatment discontinuation of RPV/FTC/TDF for any reasons and (b) occurrence of virological failure (VF) defined as confirmed HIV‐RNA >50 cp/mL).ResultsOverall, 508 patients from five Italian reference centres were included: male gender 71.9%; median age 47 years (IQR 40–52); IVDU as HIV risk 17.7%; HCV‐AB positive 23.4%; CDC‐C stage 17.5%; median CD4 cells/µL at switch 655 (IQR: 487–843); median number of previous regimens three (IQR 2–7). In a median follow‐up of 196 days (IQR: 84–287), 31 patients discontinued RPV/FTC/TDF (virological failure n=5, hypersensitivity reaction n=2, GI‐toxicity n=6, liver toxicity n=1, CNS‐toxicity n=4, kidney toxicity n=5, patient's decision/lost in follow‐up n=10). Moreover, VF occurred in eight patients (five discontinued regimen, while three remained on RPV/FTC/TDF). At survival analysis, the probabilities of treatment discontinuation or VF were 5.5% and 1.2% at 6 months, 13.2% and 2.8% at 12 months, respectively (Figure 1). At adjusted Cox model, factors associated with discontinuation were: <200 CD4 cells/µL at switch (HR 5.3, 95% CI 1.1–25.9, p=0.038), number of pre‐switch regimens (for each extra regimen: HR 1.05, 95% CI 1.01–1.10, p=0.024), male gender (HR 0.4, 95% CI 0.2–0.9, p=0.032). Only the number of pre‐switch regimens was associated with VF (HR 1.13, 95% CI 1.06–1.21, p=0.001). Type of pre‐switch regimen was not associated with discontinuation or failure, but no VF was observed if switching from co‐formulated Efavirenz/FTC/TDF or from Raltegravir containing regimens. Switching to RPV/FTC/TDF led to significant improvement in fasting lipids levels: the decrease in cholesterol, LDL and triglycerides was observed switching from any regimen, but was more marked from boosted PI. In contrast, a moderate increase in transaminase (switching from all regimens except NNRTI‐containing) and creatinine (except from TDF‐containing regimens) were observed.ConclusionsOur data suggest that switching to RPV/FTC/TDF in virologically suppressed patients could be a good strategy with low risk of virological failure or treatment discontinuation; the switch is also associated with significant improvement in lipid profile.

BackgroundTo assess the role of drugs used in dual therapy (DT), as cART simplification, over the risk of treatment failure.Materials and MethodsPatients starting DT regimen composed by a boosted protease inhibitor (PI/r): darunavir (DRV/r), lopinavir (LPVr) or atazanavir (ATV/r) plus a second drug: raltegravir (RAL), maraviroc (MRV) etravirine (ETR), lamivudine (3TC) or tenofovir (TDF), this one generally used in HBV co‐infected patients, were included. The effect of each drug as well as other clinical and virological cofactors over treatment failure was assessed using survival analysis.ResultsOverall, 480 patients from six reference Italian centres were included: all switched to DT with HIV‐RNA <500 cp/µL, 376 of them at <50 cp/µL. Patients who switched at <50 cp/µL showed a significant lower risk of treatment failure (13.3% versus 23.3% at 1 year and 28.0% versus 44.6% at 3 years, p=0.005), thus the analysis was focused on this subgroup. Among the patients who switched at <50 cp/µL, the proportion of drug used in DT was: DRV/r 63.0%, RAL 53.7%, ETR 19.4%, ATV/r 18.4%, MRV 17.3%, LPV/r 12.8%, TDF 6.4% and 3TC 5.9%; DRV/r‐RAL was the most widely used combination: 32.5%. Treatment failure was observed in 78 patients, of whom 38 virological and 35 for toxicity/intolerance, one patient died during follow‐up and four patients interrupted for personal decision with undetectable HIV‐RNA. At Cox Model, adjusted by gender, age, non‐Italian origin, AIDS diagnosis, time on cART, number of regimens, CD4 nadir, baseline CD4, all the drugs had a positive effect on probability of failure (Figure), however the effect was significant for DRV/r (HR:0.21, 95% CI 0.07–0.59, p=0.03), ATV/r (0.30, 0.09–0.97, p=0.044) and RAL (0.37, 0.15–0.93, p=0.034); higher CD4 count at baseline was also associated with lower risk of failure while number of previous regimens with a higher risk. Moreover, ATV/r was found significant associated with significant higher risk of failure by toxicity (as well as LPV/r) but lower risk of virological failure, while both 3TC and RAL with significant lower risk of toxicity.ConclusionsOur analysis suggest that using PI/r‐based DL is highly effective if switching from HIV‐RNA <50 cp/µL; DL should be used with caution in patients with low CD4 count and longer history of treatment; DRV/r is the best compromise among PI/r, ATV/r is effective but is associate with frequent interruption by toxicity; RAL showed high tolerability so that its use is related to the lowest risk of failure as second drug.

IntroductionWe report interim 24‐weeks efficacy data of ATLAS‐M trial, a phase IV, multicentre, open‐label, randomized study designed to show 48‐weeks, non‐inferior efficacy (margin of −12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3‐drugs ATV/r‐based cART.MethodsSubjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV‐RNA <50copies/mL for >3 months and CD4>200 cells/mm3 for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3‐drug regimen (arm two). Primary endpoint: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure (VF=two consecutive HIV‐RNA>50 copies/mL or a single value >1000 copies/mL). Enrollment of 266 patients was planned.ResultsA total of 266 patients (78% males, median age 44 years, median CD4 603 cells/µL, 79% treated with a tenofovir‐containing backbone) were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8–97.6) and 85.1% (95% CI 77.6–92.6) in arm one and two, respectively (difference +6.6%, 95% CI −2.9/+16.1). VF was observed in two patients randomized to arm one (one at baseline, before treatment simplification) and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 (mean change +90 vs +10 cells/µL, p=0.007). A greater increase in total cholesterol (+18 vs −2 mg/dL, p<0.001), HDL (+4 vs +0 mg/dL, p=0.001) and LDL (+12 vs +0 mg/dL, p=0.001) was also observed in arm one without differences in other lipid parameters. Renal function showed a significant improvement in arm one (mean change in eGFR +5 vs −2 mL/min/1.73m2 in arm two, p=0.001). No significant differences in bilirubin levels or other laboratory parameters were observed between the two arms.ConclusionsThis interim analysis suggests a 24‐weeks non‐inferior efficacy of treatment simplification to ATV/rit+3TC as compared to continuation of ATV/rit +2 NRTI in virologically suppressed patients. Follow‐up until 48‐weeks is scheduled to confirm these data.