Fluvastatin as an adjuvant to pegylated interferon and ribavirin in HIV/hepatitis C virus genotype 1 co-infected patients: an open-label randomized controlled study.

OBJECTIVES: Recent reports demonstrated in vitro the efficacy of fluvastatin in inhibiting hepatitis C virus (HCV) replication and a synergistic effect in association with interferon-alpha (IFN-alpha). In vivo the inhibition of HCV replication by statins has not been demonstrated. We evaluated in this open-label, randomized controlled study the efficacy of fluvastatin as adjuvant to pegylated-(PEG)-IFN and ribavirin in HIV/HCV genotype 1 co-infected patients. PATIENTS AND METHODS: Forty-four HIV/HCV co-infected patients were randomized to receive, in addition to PEG-IFN-alpha 2b and ribavirin, 80 mg of fluvastatin once daily or no medication. Primary and secondary endpoints were the achievement of sustained virological response (SVR) and rapid virological response (RVR), respectively. RESULTS: By intent-to-treat analysis, 25% of the patients achieved an SVR. An SVR was observed in 8/21 patients in the fluvastatin arm and in 3/23 patients in the standard therapy arm (P = 0.08). A significantly higher RVR rate was obtained in the fluvastatin arm compared with the standard therapy [7/21 (33%) and 1/23 (4%), respectively; P = 0.02]. Baseline alanine aminotransferase (ALT) values and fluvastatin treatment arm were the only predictors of RVR at the univariate analysis; however, no predictors were independently associated with RVR or SVR at the multivariate analysis. CONCLUSIONS: Fluvastatin addition to standard therapy did not significantly increase the SVR rate in HIV/HCV genotype 1 co-infected patients; however, it did significantly improve the RVR. Further studies are needed to confirm these promising results and to investigate the mechanisms of action of statins in HCV infection.

Telbivudine in the treatment of chronic hepatitis B: experience in HIV type-1-infected patients naive for antiretroviral therapy.

BACKGROUND: Telbivudine is a potent inhibitor of hepatitis B virus (HBV) replication without anti-HIV type-1 (HIV-1) activity demonstrated in vitro; however, very few clinical data on HIV-1-infected patients are available at present. Because it represents a therapeutic option in HIV-1-HBV-coinfected patients who do not require antiretroviral therapy, we strictly monitored three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy for chronic hepatitis B. METHODS: We performed molecular analysis of HBV DNA and of HIV-1 reverse transcriptase and protease RNA and DNA sequences in three HIV-1-HBV-coinfected patients treated with telbivudine monotherapy. RESULTS: Despite a transient and deep reduction of HIV-1 RNA, observed in two of the three patients studied, no genotypic resistance mutations were detected on both HIV-1 and HBV viruses. CONCLUSIONS: Telbivudine therapy for 24 weeks showed a potent anti-HBV activity in HIV-1-positive, hepatitis B e antigen-positive patients with high HBV viraemia. No direct anti-HIV-1 activity of telbivudine was demonstrated and no genotypic resistance mutations to anti-HIV-1 drugs was found; however, the transient but deep reduction of HIV RNA, after telbivudine introduction, deserves further investigation and a strict monitoring of HIV-1 viraemia in HIV-1-infected patients on treatment with this drug.

Reversible posterior leukoencephalopathy syndrome in 2 HIV-infected patients receiving antiretroviral therapy.

We describe 2 human immunodeficiency virus-infected patients who developed hypertension and severe neurological abnormalities while receiving successful antiretroviral therapy. Neuroimaging findings were characteristic of reversible posterior leukoencephalopathy syndrome, a brain-capillary leak syndrome with hypertension and endothelial damage. We discuss the role of antiretroviral therapy-associated metabolic alterations in endothelial damage, hypertension, and reversible posterior leukoencephalopathy syndrome.

Mother-To-Child Transmission of KPC Carbapenemase-Producing Klebsiella Pneumoniae at Birth.

We report on a mother-to-child transmission of KPC carbapenemase-producing Klebsiella pneumoniae at birth followed by subsequent cases in the neonatal intensive care unit. Molecular analysis of isolates showed production of KPC-3 enzyme. The only potential risk factor identified for the mother was previous activity as a caregiver. Present findings suggest consideration of proactive surveillance in pregnant women with risk factors for colonization.

Evidence of differential selection of HIV-1 variants carrying drug-resistant mutations in seroconverters.

OBJECTIVES: To estimate the relative efficiency of transmission of different HIV-1 drug-resistance mutations from patients failing treatment, considered as potential transmitters (PTs), to seroconverters (SCs). DESIGN: Ecological cross-sectional study. METHODS: HIV-1 protease and reverse transcriptase (RT) sequence data, obtained from 155 SCs and 2,690 PTs at the Department of Molecular Biology of the University of Siena, Italy, in the period 1997-2004 were used. The efficiency of transmission was studied by odds ratio (OR) analysis and evaluation of 95% confidence intervals (95% CIs). For mutations not detected in viruses from SCs, a binomial probability model was used, assuming P-values <0.05 as indicative of a negative selection at transmission. RESULTS: The overall prevalence of drug mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PIs) was 13.2%, 4.6% and 2.0% in SCs, and 69.9%, 27.6% and 33.7% in PTs, respectively. Among RT mutations present both in PTs and SCs, M1841/V and T215F/Y had the lowest relative efficiency of transmission, whereas V1181, Y181C/I and K219E/Q showed the highest relative efficiency. Of the three major protease mutations that could be evaluated by this approach, M46l/L had a lower rate of transmission than 184V and L90M. Among the mutations not detected in viruses from SCs, the RT E44D, V1081, Q151M and Y188C/H/L, and the protease D30N, G48V and V82A/F/S/T substitutions appeared to be negatively selected. CONCLUSIONS: The transmission rate of drug-resistant HIV-1 variants may be differentially affected by the mutational pattern. The binomial model enabled to evaluate the negative selection against specific substitutions. Given the low prevalence of some resistance mutations in SCs, very large data sets are required to evaluate the potential selection of such mutations.

Noncirrhotic portal hypertension in HIV-infected patients: a case control evaluation and review of the literature.

Idiopathic noncirrhotic portal hypertension (NCPH) is an infrequent but possibly underestimated cryptogenetic liver disease recently described in small series of HIV-infected patients. The exposure to antiretroviral drugs, a direct role of HIV itself, microbial translocation from the gut, or a thrombophilic propensity have been suggested as possible pathogenic mechanisms. In this case control study, we describe 11 HIV-infected patients with idiopathic NCPH and compare the activity of protein C and S, and soluble CD14 levels (a surrogate marker of the translocation of intestinal bacterial products) with 10 age- and gender-matched HIV-infected controls with no liver disease. The clinical presentation of the 11 patients with NCPH was characterised by acute variceal bleeding (2/11), ascites (2/11), portal thrombosis (2/11), and ultrasonographic and endoscopic signs of portal hypertension (11/11), with slightly high alanine transaminase (ALT) and γglutamyl transpeptidase (γ-GT) levels. The FibroScan median liver stiffness was 8.1 kPa, which is inconsistent with significant fibrosis, and nodular regenerative hyperplasia was diagnosed in the 5 patients who underwent liver biopsy. The NCPH patients showed no impairment of hepatic synthesis, but had lower serum albumin levels and a higher international normalized ratio (INR) than the controls (p = 0.01), and lower protein C and S activity, although within the normal range (p = 0.02 and 0.3, respectively). No significant difference in soluble CD14 was seen between the two groups. In conclusion, the etiology of NCHP is not still established, but in order to prevent the dramatic complications of portal hypertension, all HIV-infected patients with unexplained liver enzyme abnormalities or thrombocytopenia should be considered for further investigations by means of thrombophilic screening, Doppler ultrasound evaluation, and in the presence of portal hypertension, endoscopy and liver biopsy.

Effect of antioxidants on mitochondrial function in HIV-1-related lipoatrophy: a pilot study.

We investigated the effect of antioxidant supplementation on mitochondrial function, fat distribution, and lipid and glucose metabolism in HIV-1-infected patients with antiretroviral therapy (ART)-related lipoatrophy. 61 ART-treated HIV-1-infected patients with lipoatrophy were randomized to receive either n-acetyl-L-carnitine (n = 21), lipoic acid + n-acetylcisteine (LA/NAC) (n = 20), or no supplementation (n = 20) for 48 weeks. At baseline and at the end of treatment, mitochondrial function was studied by (13)C-methionine breath test and by mitochondrial (mt)-DNA quantification on circulating T-cells and subcutaneous adipose tissue. Body composition was assessed by dual-energy X-ray absorpiometry (DEXA). (13)CO(2)-exhalation increased between baseline and week 48 in both supplementation arms as evidenced by a higher delta over baseline excretion at 45 min (from mean ± SEM of 7.8 ± 1.08 to 9.9 ± 0.6, p = 0.04 in the n-acetyl-carnitine arm, and from 7.4 ± 0.8 to 11.5 ± 1.6, p = 0.01 in LA/NAC arm). Cumulative (13)CO2 excretion increased from median (interquartile range; IQR) of 3.25 (2.55-4.2) to 4.51 (4.12-5.2) in the carnitine arm; from 3.79 (2.67-4.37) to 4.83 (4.25-5.56) in the LA/NAC arm; p = 0.004, 0.02, respectively. mtDNA content increased in CD4+ T-cells from patients who received n-acetyl-carnitine (+30 copies/cell; p = 0.03), without significant difference by the overall comparison of the study groups. Fat body mass and lipid profile did not change significantly in any of the arms. Our study showed that antioxidant supplementation may have a protective role on mitochondrial function, with limited effects on the reversal of clinical lipodystrophic abnormalities in HIV-1-infected patients.

Transmitted HIV Type 1 drug resistance and Non-B subtypes prevalence among seroconverters and newly diagnosed patients from 1992 to 2005 in Italy.

The patterns of transmitted drug-resistant (TDR) HIV-1 variants, non-B subtype spread, and epidemiological trends were evaluated either in seroconverters or in newly diagnosed individuals in Italy over a 13-year period. We analyzed 119 seroconverters, enrolled from 1992 to 2003 for the CASCADE study, and 271 newly diagnosed individuals of the SPREAD study (2002-2005), of whom 42 had a known seroconversion date. Overall, TDR was 15.1% in the CASCADE and 12.2% in the SPREAD study. In the 1992-2003 period, men having sex with men (MSMs) and heterosexuals (HEs) were 48.7% and 36.8%, respectively; TDR was found to be higher in MSMs compared to HEs (78.9% vs. 21%, p = 0.006). The same groups were 39.1% and 53.3% in the SPREAD study; however, no association was detected between modality of infection and TDR. Overall, 9.2% and 22.1% of individuals harbored a non-B clade virus in the CASCADE and SPREAD study, respectively. As evidence of onward transmission, 40% (24/60) of non-B variants were carried by European individuals in the latter study; among these patients the F1 subtype was highly prevalent (p = 0.00001). One of every eight patients who received a diagnosis of HIV-1 in recent years harbored a resistant variant, reinforcing the arguments for baseline resistance testing to customize first-line therapy in newly infected individuals. The spread of non-B clades may act as a dilution factor of TDR concealing the proportion of TDR in seroconverters and MSMs.

Enterococcus gallinarum endocarditis in a diabetic patient.

Recent studies pointed out the increasing rate of infective endocarditis (IE) in diabetic patients. As diabetes mellitus (DM) prevalence is expected to increase in the coming years, infective endocarditis could be more frequently reported in these patients. We here describe a rare case of Enterococcus gallinarum endocarditis developing on normal native heart valve in an elderly diabetic woman. Therapeutic options were restricted due to resistance factors of the microorganism, limited guidance in the medical literature, and the patient's history and underlying condition. Despite these challenges, adequate antibiotic therapy led to the patient's recovery.

Recombination analysis and structure prediction show correlation between breakpoint clusters and RNA hairpins in the pol gene of human immunodeficiency virus type 1 unique recombinant forms.

Recombination is recognized as a primary force in human immunodeficiency virus type 1 (HIV-1) evolution, increasing viral diversity through reshuffling of genomic portions. The strand-switching activity of reverse transcriptase is required to complete HIV-1 replication and can occur randomly throughout the genome, leading to viral recombination. Some recombination hotspots have been identified and found to correlate with RNA structure or sequence features. The aim of this study was to evaluate the presence of recombination hotspots in the pol gene of HIV-1 and to assess their correlation with the underlying RNA structure. Analysis of the recombination pattern and breakpoint distribution in a group of unique recombinant forms (URFs) detected two recombination hotspots in the pol region. Two stable and conserved hairpins were consistently predicted corresponding to the identified hotspots using six different RNA-folding algorithms on the URF parental strains. These findings suggest that such hairpins may play a role in the higher recombination rates detected at these positions.