Pidotimod and Immunological Activation in Individuals Infected with HIV.

BACKGROUND: The improvements in HIV infection therapy and the large availability of antiretroviral drugs have led to an increased survival among HIV infected people, and simultaneously to a raised morbidity and mortality due to not-AIDS-related events in this group compared to the general population. An increased systemic inflammation and a persistent immune activation play a pivotal role in determining high rates of non-AIDS comorbidities. In the last years, many natural or synthetic immunomodulatory molecules acting by different mechanisms have been conceived. Pidotimod is a synthetic dipeptide molecule showing immunomodulatory properties. The aim of this pilot study was to evaluate the effects of Pidotimod supplementation on residual inflammation in HIV infected population. METHODS: Forty HIV positive individuals under cART were enrolled: 30 were treated with Pidotimod supplementation (study group) and 10 served as control group (without Pidotimod supplementation). For all participants, Cystatin C, PCR, ESR, microalbuminuria, TNF-α, INF-γ, IL-4, IL-10, IL1ß, IL-18 and IL-2 were measured at enrolment (T0), 4 weeks after of Pidotimod supplementation (T1), and 4 weeks after completing supplementation (T2). RESULTS: In HIV positive participants treated with Pidotimod, the evaluation of cytokine levels showed that IL-10, IFN gamma, and IL-4 were significantly higher at enrolment compared to the control group. The increase under Pidotimod treatment persisted after supplementation suspension, while the pro-inflammatory cytokines levels were reduced. Salivary IgA also increased during 4 weeks of supplementation and persisted at 4 weeks after completing supplementation. On the other hand, the Cystatin C and microalbuminuria levels decreased over time, at a greater extent the Cystatin C serum levels. CONCLUSION: The study findings showed that the HIV population receiving Pidotimod achieved a rebalancing of pro-inflammatory and anti-inflammatory cytokines as well as a significant reduction in cystatin C levels. The treatment further allowed for an increase in salivary IgA levels at all the analyzed times, as a secondary event to a remodulation of the immunological status obtained with pidotimod. This approach could represent a new way to design new intervention strategies aimed at improving the persistent immune activation status in the virologically suppressed HIV population.

Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE).

PURPOSE: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice. PARTICIPANTS: The ODOACRE cohort enrols all adult HIV-1-infected patients, both treatment-naïve and treatment-experienced, starting a DTG-based ARV regimen, in 11 clinical centres in Italy from 2014. FINDINGS TO DATE: In recent years, various works by the ODOACRE cohort have been produced, demonstrating the high efficacy and tolerability of DTG-based ARV regimens in clinical practice, both in ART-naïve (in the setting of acute HIV-1 infection and late presenters patient) and experienced patients. We confirmed the virological efficacy of DTG-based regimens and we evaluated predictors of virological failure. We investigated cause of discontinuation and evaluated tolerability and metabolic profile of the regimens. Within these investigations, we explored particularly the use of DTG in simplification in two-drug regimen with either rilpivirine or lamivudine. We also compared DTG-based regimens with other integrase inhibitors in clinical practice. FUTURE PLANS: To continue to study long-term efficacy and tolerability of DTG-based regimens is the purpose of the ODOACRE cohort.

Switch to rilpivirine improves diabetes in an elderly HIV-positive patient.

Glucose intolerance and diabetes are becoming increasingly common in HIV-infected patients in the cART era. Many factors are associated with the development of diabetes in HIV-infected individuals who receive cART, one of which is the assumption of specific antiretroviral classes or agents. We describe a case in a 72-year-old Caucasian man with long-term HIV infection. We observed the development of unbalanced diabetes treated with insulin and metformin which improved when we replaced zidovudine with rilpivirine. This switch improved diabetes to such an extent that insulin suspension was required. In several countries zidovudine has long been used due to its low cost, although several side effects have been observed, especially in the long term. In this case, the switch to rilpivirine was shown to be able to improve the toxicity of zidovudine on glucose metabolism, representing a good option to be used.

The impact of homocysteine, B12, and D vitamins levels on functional neurocognitive performance in HIV-positive subjects.

BACKGROUND: The correlation among high levels of total homocysteine, low levels of B12vitamin, and neurocognitive impairment in HIV negative patients has been the main research topic in some of the latest reviews. The aim of this study was to examine if the alteration of homocysteine, B12 vitamin, and D vitamins plasma levels was present in HIV-positive, and their relationship with cognitive function. METHODS: 57 HIV infected were enrolled and underwent the serum measurement of homocysteine, B12, and D vitamins. The neurocognitive evaluation investigated 5 cognitive domains, through a neuropsychological battery test RESULTS: Homocysteine was found to be elevated in 70.2% of cases, B12 vitamin mean levels were low in 8 participants (14.0%), and 8 patients had D hypovitaminosis (14.0%). Abnormal homocysteine levels were associated with worse performance of verbal fluency (p = 0.003) and worse executive function (Stroop E test p = 0.040). The 25-OH D hypovitaminosis was associated with worse performances in executive functions in three different tests: Stroop E (p = 0.049), Trail B (p = 0.035), and Wais Digit Span (p = 0.042). Pathological levels of B12 Vitamin were also associated to worse performances in executive functions (Trail B Test and Wais Digit Span respectively p = 0.002 and 0.029) and with a lower speed in psychomotor processing (Peg Board Test on dominant hand, p = 0.014). CONCLUSIONS: In this study serum homocysteine, B12, and D vitamin levels are associated with neurocognitive performances; in fact low performance neurocognitive was correlated with hyperhomocysteine and low B12vitamin, and D vitamin levels. Evidence of the alteration of these parameters could facilitate the early identification of a neurocognitive impairment.

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-week results of a randomized trial.

OBJECTIVES: Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. METHODS: Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). RESULTS: In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. CONCLUSION: Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy.

Safety and therapeutic efficacy of the switch to maraviroc+darunavir/ritonavir in HIV/HCV coinfected patients: initial results from GUSTA study.

INTRODUCTION: HIV/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 METHODS: GUSTA 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. RESULTS: We 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]). CONCLUSIONS: The 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.

Different strategies of 25OH vitamin D supplementation in HIV-positive subjects.

Summary A high incidence of 25OH vitamin D deficiency has been observed in HIV-infected subjects. The objective of this study was to evaluate the effect of cholecalciferol administration on serum 25OH vitamin D levels in HIV-infected patients. This prospective cohort study included 153 HIV-positive subjects; 47 were treated with 300,000 IU intramuscular cholecalciferol, 67 with 25,000 IU oral cholecalciferol monthly, while the remaining 39 did not receive any treatment. The group treated orally had an increase of serum 25OH vitamin D concentration, changing from 15.7 ± 12.2 ng/mL to 27.4 ± 11.6 ng/mL after 10 months (T10). The group treated with intramuscular supplementation had an improvement, changing from 18.5 ± 10.5 ng/mL to 32.9.0 ± 12.2 ng/mL at T10. One-way repeated measures analysis of variance indicated a significant difference for 25OH vitamin D variation (p = 0.002) among the three groups. A significant effect of time (p < 0.001) and group × time interaction (p < 0.001) was found: at T10, 25OH vitamin D values were significantly higher in the oral and intramuscular groups with respect to the control group. Our findings showed that the supplementation with cholecalciferol in patients with HIV-infection improved 25OH vitamin D serum levels, and suggest that the two types of administration are equivalent, but are insufficient for severe forms of hypovitaminosis.

Improved metabolic profile after switch to darunavir/ritonavir in HIV positive patients previously on protease inhibitor therapy.

Metabolic abnormalities associated with cumulative exposure to antiretroviral therapy have been linked to an increased risk of myocardial infarction in HIV positive individuals. The aim of this study was to evaluate whether the switch from lopinavir/ritonavir (LPV/r) or fosamprenavir/ritonavir (FPV/r) to darunavir/ritonavir (DRV/r) is able to improve the lipid profile. A total of 13 Caucasian subjects (7 from LPV/r and 6 from FPV/r) were enrolled in the study and received DRV/r at the dose of 800/100 mg, without change in their NRTI backbone. Viro-immunological parameters, triglycerides (TGs), total cholesterol (TCh), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, fasting glucose, HOMA-IR, indexes of hepatic and renal functionality, microalbuminuria and cystatin C were measured at baseline (T0), 3 months (T3), 6 months (T6), and 12 months (T12). The switch to DRV/r reduced levels of TCh, LDL, and TGs at T3. Similar improvements were confirmed further at T6 and at T12. A 14% increase in CD4+ count cells (P < 0.05) was observed. Serum cystatin C values showed a statistically significant decrease. After 12 months of switching to DRV/r from LPV/r or FPV/r, patients infected with HIV with TGs above 200 mg/dl, showed a 49% decrease in TGs, along with a 16% reduction of LDL and 19% reduction of TCh. Switching to DRV/r also improved immunological parameters, such as CD4+ cells count and cystatin C plasmatic levels, which may translate into a reduction of the cardiovascular risk. In conclusion, a switch to DRV/r should be considered in those HIV positive patients undergoing antiretroviral therapy, who also present abnormal lipid profiles.

Short communication: proangiogenic hematopoietic cells in acute HIV infection.

Chronic HIV infection induces significant changes in the trafficking of circulating endothelial progenitor cells (EPCs). Specifically, it causes marked depletion of proangiogenic hematopoietic cells, the so-called colony-forming unit-endothelial cells (CFU-ECs). In this study we evaluated CFU-ECs in two subjects with acute HIV infection. We found that both patients already had a low CFU-EC level at the time of diagnosis. Nevertheless, after 6 months of antiretroviral therapy, the CFU-EC concentration reverted to normal values in both cases. HIV significantly depletes the CFU-EC compartment even in the early phase of infection, while 6-month therapy appears to be able to restore it.

Induction with ribavirin in a relapsing patient with chronic HCV hepatitis.

In this case, a new possible strategy for treatment of hepatitis C virus (HCV) relapsing patients is described. The target of anti-HCV therapy is sustained viral response, but strategies for improving sustained viral response in relapsing patients would be useful, and ribavirin is crucial for obtaining viral response. Six weeks of induction therapy with ribavirin were used to improve efficacy of standard combined antiviral therapy in a patient relapsing to standard therapy. In the present case, the patient had undergone a retreatment with the same regimen with the exception of the six-week induction period with ribavirin. Use of induction therapy with ribavirin in this case has allowed for a sustained viral response without prolonging the interferon exposure time in retreatment.

Induction with ribavirin in a relapsing patient with chronic HCV hepatitis

In this case, a new possible strategy for treatment of hepatitis C virus (HCV) relapsing patients is described. The target of anti-HCV therapy is sustained viral response, but strategies for improving sustained viral response in relapsing patients would be useful, and ribavirin is crucial for obtaining viral response. Six weeks of induction therapy with ribavirin were used to improve efficacy of standard combined antiviral therapy in a patient relapsing to standard therapy. In the present case, the patient had undergone a retreatment with the same regimen with the exception of the six-week induction period with ribavirin. Use of induction therapy with ribavirin in this case has allowed for a sustained viral response without prolonging the interferon exposure time in retreatment.

Cystatin C, adipokines and cardiovascular risk in HIV infected patients.

OBJECTIVES: To value the role of leptin, adiponectin and cystatin C in HIV infected patients treated with combined antiretroviral therapy (cART) subdivided for cardiovascular risk (CVR). METHODS: 56 HIV+ cART treated patients were screened by Framingham score and subdivided in 2 groups: A) 15 with "high" CVR (>10%) and B) 41 with "low" CVR (<10%). Viro-immunological parameters, triglycerides, total cholesterol, HDL and LDL cholesterol, blood pressure, microalbuminuria, fasting glucose, insulinemia, HOMA-IR, CRP, cystatin C, IL-18, IL-6, leptin, adiponectin, antropometric parameters and total abdominal tissue (TAT), subcutaneous (SAT) and visceral abdominal tissue (VAT) were measured. RESULTS: Group A showed statistically higher levels of parameters of glucose and lipid metabolism, cystatin-C, microalbuminuria, blood pressure and BMI. Moreover levels of IL-6, IL-18 and leptin were statistically higher in group A, whereas adiponectin was statistically increased in group B. Data showed a positive correlation between VAT, leptin levels (r=0.37, p=0.005) and IL-18 (r=0.32, p=0.01), and a negative correlation between VAT and adiponectin (r=-0.30, p=0.02). Finally group A showed statistically higher levels of cystatin C and there was a positive correlation between CVR and cystatin C (r=0.39, p=0.003). CONCLUSIONS: The main results of this study are that HIV positive subjects cART treated with "high" CVR have increased plasma levels of leptin, IL-6, IL-18 and cystatin C and hypoadiponectinemia. Moreover, the positive correlation between CVR and cystatin C found in this study for the first time in HIV positive patients, indicates that cystatin C could serve as early marker of enhanced CVR in the HIV-infected population.