Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.

OBJECTIVES: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. METHODS: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. RESULTS: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). CONCLUSIONS: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

Intestinal colonization with resistant bacteria: a prognostic marker of mortality in decompensated cirrhosis.

Infections due to drug-resistant (DR) bacteria are increasingly recognized as an emerging problem worldwide. Asymptomatically colonized patients may contribute to the reservoir in the hospital setting, causing both horizontal transmission and endogenous infections. We aimed to evaluate the prevalence of intestinal colonization with DR bacteria on subsequent clinical infection development and prognosis in patients with decompensated cirrhosis. One hundred seven patients without infection at baseline were screened and prospectively followed-up for 3 months. Among the patients screened, DR bacteria were isolated in 47 (43.9%), 14 colonized with multidrug- (MDR) and 33 with extensively drug (XDR)-resistant bacteria or a mixture of MDR/XDR bacteria. Severity of liver disease and demographic characteristics were similar among groups. The 20 (42.6%) with DR vs 14 (23.3%) without had hepatic encephalopathy and/or spontaneous bacterial peritonitis episodes over the past 6 months (p = 0.034). One third of both DR and non-DR groups developed infection during follow-up but in only 7 and 5, respectively, the infection was microbiologically documented. In a 3-month-follow-up period, mortality was higher in patients colonized with XDR compared to those without (log rank p = 0.027). In multivariate analysis, colonization with XDR bacteria [HR = 1.074, (CI:1.024-1.126), p = 0.003] and MELD score [HR = 2.579 (1.109-5.996), p = 0.028] were independently associated with low survival. Asymptomatic GI colonization with DR bacteria is a risk factor for increased mortality in decompensated cirrhosis. Frequent hospitalizations for complications of the underlying disease and selective pressure induced by the use of antimicrobials are probably the main determinants.

Prevalence of drug resistance among HIV-1 treatment-naive patients in Greece during 2003-2015: Transmitted drug resistance is due to onward transmissions.

BACKGROUND: The prevalence of HIV-1 drug resistance among treatment-naïve patients ranges between 8.3% and 15% in Europe and North America. Previous studies showed that subtypes A and B were the most prevalent in the Greek HIV-1 epidemic. Our aim was to estimate the prevalence of resistance among drug naïve patients in Greece and to investigate the levels of transmission networking among those carrying resistant strains. METHODS: HIV-1 sequences were determined from 3428 drug naïve HIV-1 patients, in Greece sampled during 01/01/2003-30/6/2015. Transmission clusters were estimated by means of phylogenetic analysis including as references sequences from patients failing antiretroviral treatment in Greece and sequences sampled globally. RESULTS: The proportion of sequences with SDRMs was 5.98% (n=205). The most prevalent SDRMs were found for NNRTIs (3.76%), followed by N(t)RTIs (2.28%) and PIs (1.02%). The resistance prevalence was 22.2% based on all mutations associated with resistance estimated using the HIVdb resistance interpretation algorithm. Resistance to NNRTIs was the most common (16.9%) followed by PIs (4.9%) and N(t)RTIs (2.8%). The most frequently observed NNRTI resistant mutations were E138A (7.7%), E138Q (4.0%), K103N (2.3%) and V179D (1.3%). The majority of subtype A sequences (89.7%; 245 out of 273) with the dominant NNRTI resistance mutations (E138A, K103N, E138Q, V179D) were found to belong to monophyletic clusters suggesting regional dispersal. For subtype B, 68.1% (139 out of 204) of resistant strains (E138A, K103N, E138Q V179D) belonged to clusters. For N(t)RTI-resistance, evidence for regional dispersal was found for 27.3% and 21.6% of subtype A and B sequences, respectively. CONCLUSIONS: The TDR rate based on the prevalence of SDRM is lower than the average rate in Europe. However, the prevalence of NNRTI resistance estimated using the HIVdb approach, is high in Greece and it is mostly due to onward transmissions among drug-naïve patients.

Effects of first antiretroviral regimen on lipid levels in HIV (+) individuals.

OBJECTIVE: To evaluate the long-term effects of different boosted protease inhibitors (bPIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based antiretroviral regimens on lipid levels in HIV seropositive individuals who have not received lipid-lowering agents. METHODS: Data consisted of 595 patients participating in the population-based Athens Multicenter Cohort Study who were consistently followed up during 1996-2008. RESULTS: In naïve patients, lipid parameters increased sharply during the first 3 months of antiretroviral therapy and reached a plateau level approximately 6-9 months after therapy initiation. The plateau levels remained almost stable for up to 3.5 years. In general, bPIs exerted a more pronounced effect compared to NNRTIs. CONCLUSIONS: The administration of PI- or NNRTI-based regimens especially in naïve but also in unboosted PI experienced patients provoked a sharp increase in lipid levels that remained stable in higher levels for more than 3 years.

Acute systemic inflammation induced by influenza A (H1N1) vaccination causes a deterioration in endothelial function in HIV-infected patients.

OBJECTIVES: Vaccination of HIV-infected patients against the influenza A/H1N1 subtype was proposed as a mandatory precautionary measure during the 2009 pandemic. The immediate cardiovascular effects of the novel vaccine have been largely unexplored. We investigated the impact of vaccination on indices of endothelial function in a cohort of HIV-infected patients. METHODS: We included 24 HIV-infected patients in a study with a randomized, sham procedure-controlled design. A monovalent, adjuvanted vaccine against influenza A/H1N1 was used in the vaccine arm (n=16); patients in the control group (n=8) were subjected to a sham procedure. Endothelial function, as assessed by flow-mediated dilatation (FMD), and inflammatory markers were assessed prior to and 8 and 48 h post vaccination. RESULTS: FMD deteriorated following vaccination (baseline, 6.5 ± 1.1%; 8 h, 1.1 ± 1.5%; 48 h, 2.0 ± 1.4%; P=0.04). The white blood cell count increased at 8 h and remained elevated at 48 h. Soluble intercellular adhesion molecule-1 levels decreased after vaccination; the maximum decrease was noted at 48 h. Conversely, the sham procedure did not induce changes in endothelial function or inflammatory markers, apart from a reduction in the white blood cell count at 48 h. CONCLUSIONS: Acute systemic inflammation induced by vaccination against the influenza A/H1N1 virus resulted in a deterioration in endothelial function in HIV-infected patients, and this effect was sustained for at least 48 h. Our findings may have important implications in view of the high cardiovascular risk that HIV infection carries. The effect of the novel vaccine on endothelial function should be weighed against the immunological protection that it confers.

Cytokine profiling of pulmonary aspergillosis.

Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.

Invasive pulmonary aspergillosis transformed into fatal mucous impaction by immune reconstitution in an AIDS patient.

Reported here is the case of a newly diagnosed AIDS patient with end-stage HIV infection and biopsy-proven invasive pulmonary aspergillosis who responded to antifungal therapy but developed severe mucous impaction in association with rapid immune restoration that was ultimately fatal. Invasive pulmonary aspergillosis complicates about 4% of AIDS infections. A search of the medical literature revealed no previous report of this organism's involvement in immune restoration syndrome.

Mucormycosis: ten-year experience at a tertiary-care center in Greece.

Presented here are the results of a retrospective analysis of all mucormycoses infections recorded at a tertiary hospital in Greece during the last 10 years. A total of 24 patients were identified, 15 male and 9 female, with ages ranging from 37 to 80 years. Twelve of the patients had soft tissue infections (2 with concomitant pulmonary infections), and 12 had rhinocerebral infections. Transmission could be traced in two cases; to nitroglycerin patches in one patient and to a lemon-tree-thorn scratch in the other. Among the 17 patients who underwent surgery, 11 survived. All seven patients on whom surgery was not performed died. Rapid diagnosis and treatment of mucormycosis are essential for patient survival. The severity of the patient's underlying condition, the degree of immunosuppression, and prompt surgical treatment are the most important factors contributing to the outcome.

Pulmonary aspergillosis in a patient with chronic granulomatous disease: confirmation by polymerase chain reaction and serological tests, and successful treatment with voriconazole.

A 25-year-old male with chronic granulomatous disease developed severe bilateral pulmonary aspergillosis confirmed by a positive result of polymerase chain reaction for Aspergillus species from sputum and positive serological tests for Aspergillus. He was successfully treated with voriconazole. The diagnostic difficulties and the new therapeutic options in the era of new antifungal agents are discussed.

In vitro interaction of colistin and rifampin on multidrug-resistant Pseudomonas aeruginosa.

The administration of colistin is considered as the last alternative for infections by multidrug-resistant isolates of Pseudomonas aeruginosa; however its use is limited due to its considerable toxicity and poor pharmacokinetics. In order to define the in vitro activity of colistin combined with rifampin, 28 isolates resistant to piperacillin, ceftazidime, imipenem, meropenem, ciprofloxacin, amikacin, rifampin and colistin were tested. Seventeen of them that were found by PFGE to be genetically distinct were over time exposed to 2 microg/ml of colistin, to 2 microg/ml of rifampin and to their combination. Applied concentrations were selected to correspond to the mean serum level of the tested antimicrobials. Synergy between colistin and rifampin was found in four (23.5%), six (35.3%), seven (41.7%) and two (11.8%) isolates after 2, 4, 6 and 24 hours of growth, respectively. Bacterial re-growth was detected after 24 hours of exposure to the tested interaction. It is concluded that colistin and rifampin express a considerable in vitro synergistic effect on multidrug-resistant P. aeruginosa. The reported interaction should be tested in animal studies before introduction in clinical practice.

Low-dose IFN-alpha monotherapy in treatment-naive individuals with HIV-1 infection: evidence of potent suppression of viral replication.

To evaluate the safety and antiviral action of interferon-alpha (IFN-alpha) in HIV-1 infection, we undertook a proof of concept study in 27 treatment-naive patients. Eligible patients comprised two groups: the IFN-alphaT group (n = 17), which received 5 MIU IFN-alpha s.c. daily for 32 consecutive days, and the IFN-alphaNT group (n = 10), which did not receive IFN-alpha prior to highly active antiretroviral therapy (HAART), which was commenced on day 28 in both groups. IFN-alphaTreatment was well tolerated in 14 of the 17 patients of the IFN-alphaT group who completed the study. The mean HIV RNA reduction in the IFN-alphaT group on day 14 was 1.1 log(10). Viral load suppression was inversely associated with baseline viral load (p = 0.031). Four weeks after initiation of HAART, IFN-alphaT and IFN-alphaNT group patients had 2.40 and 1.82 log(10) HIV RNA reduction from baseline, respectively (p < 0.001). There was no evidence of cross-resistance with existing antiretrovirals in patients with HIV-RNA rebound after initial plasma viral load decline > or = 1 log(10) during IFN-alpha monotherapy. Thus, low daily IFN-alpha exhibits potent anti-HIV-1 activity in vivo without serious adverse effects. These properties render IFN-alpha an attractive candidate for further assessment as a constituent of HAART.

Pharmacokinetics of fluoroquinolones in uncompensated cirrhosis: the significance of penetration in the ascitic fluid.

In order to study the penetration of routinely used fluoroquinolones in the ascitic fluid of patients with uncompensated cirrhosis the following doses were given. Three patients received three consecutive iv doses of 200 mg of ciprofloxacin, six patients, three consecutive iv doses of 300 mg of ciprofloxacin, seven others, three consecutive iv doses of 400 mg of pefloxacin and six, three consecutive iv doses of 400 mg of ofloxacin. Drug levels in serum and the ascitic fluid were monitored at regular time intervals. Peak levels of the 200 mg dose of ciprofloxacin, of the 300 mg dose of ciprofloxacin, of pefloxacin and of ofloxacin in serum were 2.11,2.45,9.21 and 8.86 microg/ml, respectively and in the ascitic fluid 0.67, 0.45, 6.09 and 5.83 microg/ml, respectively T(1/2) was 3.19+/-0.73, 3.55+/-1.68, 15.60+/-12.40 and 9.45+/-3.14 h, respectively with AUC of 3.62+/-4.02, 7.39+/-4.70, 137.85+/-63.96 and 119.8+/-16.83 mg/l h. Urinary excretion of ciprofloxacin and of ofloxacin was similar to healthy individuals but pefloxacin showed a mean urinary excretion of 30.11%. It is concluded that pefloxacin and ofloxacin at the administered iv doses result in serum and ascitic fluid levels above the MICs of the common pathogens causing spontaneous bacterial peritonitis and that they should be administered to cirrhotic patients in dosing regimens similar to those in patients with normal hepatic function. The use of ciprofloxacin requires further studies to define the appropriate dose.

Virological and immunological response to HAART therapy in a community-based cohort of HIV-1-positive individuals.

PURPOSE: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. METHOD: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. RESULTS: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/microL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. CONCLUSION: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.

Sitafloxacin (DU-6859a) and trovafloxacin: postantibiotic effect and in vitro interactions with rifampin on methicillin-resistant Staphylococcus aureus.

Sitafloxacin (DU-6859a) and trovafloxacin are novel quinolones potent on methicillin-resistant Staphylococcus aureus (MRSA) that are designed for once daily administration. In order to define the adequacy of the above regimen for the therapy of infections by multiple drug-resistant MRSA, their postantibiotic effect (PAE), their bactericidal activity, and their interactions with rifampin were determined on 14 MRSA isolates resistant to both ciprofloxacin and rifampin. PAE was defined after 1-h exposure to 1x, 4x, and 10x MIC and the killing effect after exposure to 1x and 4x MIC. Rifampin was applied for interactive studies at a concentration of 2 micrograms/mL, which is equal to its mean serum level. Median PAEs produced by 1x, 4x, and 10x MIC of sitafloxacin were 1.39, 3.75, and 6.61 h respectively, and by 1x, 4x, and 10x MIC of trovafloxacin 0.87, 2.07, and 2.23 h respectively. PAEs achieved by sitafloxacin were statistically shown to be longer than those achieved by trovafloxacin; PAEs achieved by a concentration of 10x MIC of each quinolone did not differ significantly from those achieved by a concentration of 4x MIC. Both the 4x and 10x MIC concentrations produced a more prolonged PAE than the 1x MIC concentration. A rapid bactericidal activity was expressed over the first 6 h of growth by each quinolone involving 80% of isolates enhanced in some isolates by their interaction with rifampin. The above findings revealed an extended PAE and a rapid killing effect of both sitafloxacin and trovafloxacin on MRSA resistant to ciprofloxacin and to rifampin, thus supporting their once daily administration in the therapy of infections by multiple drug-resistant MRSA. However little in vitro benefit is derived by their interaction with rifampin.

In vitro activity of quinupristin/dalfopristin and newer quinolones combined with gentamicin against resistant isolates of Enterococcus faecalis and Enterococcus faecium.

In a study designed to obtain data on compounds active against enterococci, the minimum inhibitory concentrations (MICs) of quinupristin/dalfopristin (RP 59500) and the novel quinolones DU-6859a, trovafloxacin, levofloxacin, and sparfloxacin were determined for 122 Enterococcus faecalis and seven Enterococcus faecium isolates. In addition, 15 Enterococcus faecalis isolates resistant to gentamicin, DU-6859a, and trovafloxacin were exposed over time to combinations of DU-6859a plus gentamicin and trovafloxacin plus gentamicin. DU-6859a and trovafloxacin were found to be the most active compounds against Enterococcus faecalis and DU-6859a and RP 59500 against Enterococcus faecium. Synergy between either DU-6859a or trovafloxacin and gentamicin was observed with 27 to 35% of the isolates. It is concluded that DU-6859a and trovafloxacin are very potent against enterococci, especially when combined with gentamicin.

In-vitro activity and killing effect of quinupristin/dalfopristin (RP59500) on nosocomial Staphylococcus aureus and interactions with rifampicin and ciprofloxacin against methicillin-resistant isolates.

Quinupristin/dalfopristin (RP59500) is a novel streptogramin and a semisynthetic derivative of pristinamycins IA and IIB. The following properties of RP59500 were investigated: (i) its in-vitro activity against 164 hospital isolates of Staphylococcus aureus, 101 of which were methicillin-resistant (MRSA); (ii) its killing effect against 24 MRSA and seven methicillin-susceptible (MSSA) isolates; (iii) its interactions with rifampicin and ciprofloxacin against 18 MRSA isolates, six susceptible to both rifampicin and ciprofloxacin and 12 resistant to both, at 1 x MIC, 2 x MIC and 4 x MIC. Rifampicin and ciprofloxacin were applied at a concentration equal to their mean serum levels in order to establish the clinical relevance of the results. The MIC50, MIC90, MBC50 and MBC90 of quinupristin/dalfopristin were, respectively, < or = 0.015, 2, 0.12 and 2 mg/L for MRSA isolates and < or = 0.015, 0.06, < or = 0.015 and 0.25 mg/L for MSSA isolates. All isolates were inhibited by quinupristin/dalfopristin. Its killing effect varied with concentration and time, being optimal at 4 x MIC and after 24 h growth. Strains surviving 24 h exposure to this agent had much higher MICs than the parent strain, but only a limited number of them became resistant. Quinupristin/dalfopristin at 2 x MIC and 4 x MIC showed in-vitro synergy with rifampicin against highly resistant isolates mainly at 6 h and 24 h of growth involving 50-83% of MRSA isolates, and showed synergy with ciprofloxacin at 24 h involving 42-75% of isolates. The MIC increase in colonies surviving at 24 h was restricted by the presence of rifampicin or ciprofloxacin. In contrast, the above combinations acted synergically over the total number of MRSA strains susceptible to both rifampicin and ciprofloxacin. The above findings show that quinupristin/dalfopristin is a very potent antistaphylococcal agent, and that its activity against MRSA isolates is enhanced when it is combined with rifampicin or ciprofloxacin.