Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2–45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4–19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1–4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

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BackgroundInfections caused by multidrug-resistant Enterobacteriaceae are hard to treat and life-threatening due to reduced therapeutic options. Systemic infections caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains have increased in many European regions, becoming frequent in many clinical settings, and are associated with high mortality. The co-formulation of ceftazidime, a third-generation cephalosporin, with avibactam, a new suicide inhibitor beta-lactamase inhibitor able to block most Klebsiella pneumoniae carbapenemases, has been recently licensed, with promising results in patients with limited or absent therapeutic options. Little is known, however, as to the efficacy of such a combination in patients with soft tissue infections caused by multidrug-resistant Klebsiella pneumoniae carbapenemase-producing strains of Klebsiella pneumoniae.Case presentationA Caucasian 53-year-old man with paraplegia suffered multiple vertebral fractures due to a car crash. He was treated with external fixators that became infected early after insertion and were repeatedly and inefficiently treated with multiple antibiotics. He suffered repeated septic episodes caused by Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae strains with a multidrug-resistant profile. Meropenem, tigecycline, and colistin combinations allowed only temporary improvements, but septic shock episodes recurred, in spite of removal of infected external fixators. After approval of pre-marketing prescription by our local Ethics Committee, full clinical resolution was obtained with a compassionate treatment using meropenem and ceftazidime/avibactam in combination for 16 days.ConclusionsOur experience provides additional evidence that ceftazidime/avibactam, possibly in combination with meropenem rescued by avibactam, may be an efficacious treatment option also for complicated skin and soft tissue infections caused by multidrug-resistant strains of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae.

The clinical spectrum of mixed cryoglobulinemia embraces several manifestations: recurrent vascular purpura, weakness, arthralgia/arthritis, glomerulonephritis, peripheral neuropathies, and Raynaud's phenomenon. Mixed cryoglobulinemia is currently treated with steroids, low-antigen content diet, immunosuppressors, plasma exchange, and antiviral therapy, namely, alpha -interferon alone or, more recently, in association with ribavirin. In the present research, we verified the effectiveness of combined therapy with interferon and ribavirin on asymptomatic mixed cryoglobulinemia in naïve (never treated before) patients with chronic hepatitis C. We enrolled 50 consecutive patients, 31 males and 19 females, with chronic hepatitis C who showed a sustained response to combined antiviral therapy (interferon and ribavirin). Before treatment, cryoglobulins were detected in 25 subjects (50%). Only 1 of the 25 patients with asymptomatic mixed cryoglobulinemia had persistence of cryoglobulins at the end of the follow-up period. Unexpectedly, in 7 of 25 subjects without mixed cryoglobulinemia before treatment, cryoglobulins became detectable after antiviral therapy. Our present study first reports the onset of asymptomatic mixed cryoglobulinemia in hepatitis C virus patients after clearance of the virus from blood obtained with a combined antiviral treatment. Possible explanations are discussed. Our data also suggest that the appearance of a clinically evident mixed cryoglobulinemia cannot be excluded in this kind of subject.

In recent years, hepatitis C virus-related arthritis (HCVrA) has been recognised as an autonomous rheumatic disorder. Two subsets of the disease have been identified: a polyarthritis involving small joints that resembles rheumatoid arthritis, but is usually milder, and a mono-oligoarthritis that shows an intermittent course and is frequently associated with the presence of cryo-globulins in serum. Few data about HCVrA treatment are reported in the literature. As a consequence, the therapeutic approach for this disorder is still largely empirical. Hydroxychloroquine, low doses of corticosteroids and NSAIDs are frequently administered to patients with HCVrA, but some authors describe an incomplete relief of symptoms, especially in the rheumatoid-like subset. Intake of low doses of corticosteroids and NSAIDs is more effective in subjects belonging to the mono-oligoarthritis group. Use of antiviral drugs (IFN plus ribavirin) shows good results, but IFN can induce or worsen autoimmune disorders. For this reason, in our opinion, this approach should be prescribed only when required by the coexistent liver disease. On the basis of the poor available data, the administration of anti-TNF-alpha agents seems safe in HCV patients, but the usually non-aggressive course of HCVrA does not justify their use as a current therapy.