Virological patterns of hepatitis C virus patients with failure to the current-generation direct-acting antivirals.

There are few data on the virological characterisation of patients with failure to current-generation direct-acting antivirals (DAAs), namely elbasvir/grazoprevir, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir. This study aimed to characterise virological patterns in patients with failure to current DAA regimens as well as the efficacy of re-treatment. All 61 consecutive hepatitis C virus (HCV) treatment-naïve patients with failure to current DAAs from January 2018 to February 2019 were enrolled. Sanger sequencing of NS3, NS5A and NS5B proteins was performed using homemade protocols. NS5A resistance-associated substitutions (RASs) were more frequent in the 17 patients treated with sofosbuvir/velpatasvir (89.5%) and 33 patients treated with elbasvir/grazoprevir (97%) compared with the 11 patients treated with glecaprevir/pibrentasvir (18.2%) (P = 0.002 and 0.000, respectively). NS3 RASs were more often detected in the 33 patients with failure to elbasvir/grazoprevir (30.3%) than in the 11 patients treated with glecaprevir/pibrentasvir (9.1%). NS3 RASs were also detected in 12% of sofosbuvir/velpatasvir-treated patients. NS5B RASs were infrequently identified. Of the glecaprevir/pibrentasvir-treated patients, 73% did not show RASs in any HCV regions, a prevalence higher than that observed in those treated with elbasvir/grazoprevir (0%; P < 0.05) or sofosbuvir/velpatasvir (12%; P < 0.05). Of the 61 patients, 21 (34.4%) were re-treated with sofosbuvir/velpatasvir and voxilaprevir. All patients achieved sustained virological response at 12 weeks (SVR12). To our knowledge, this is one of the first real-life studies describing patients who failed current-generation DAAs; the prevalence of RASs differed according to the DAA regimen used, and the efficacy of re-treatment was high.

In vivo evidence that the cannabinoid receptor 2-63 RR variant is associated with the acquisition and/or expansion of HIV infection.

OBJECTIVES: The aim of the study was to investigate whether the rs35761398 variants of the cannabinoid receptor 2 (CB2) gene may influence the acquisition of HIV infection and the clinical presentation of HIV/hepatitis C virus (HCV) coinfection. METHODS: We compared 166 HIV/HCV-coinfected patients with 186 HCV-monoinfected patients, all with biopsy-proven chronic hepatitis (using the Ishak scoring system), naïve for anti-HCV treatment and tested for the CB2 rs35761398 polymorphism (using the TaqMan assay). RESULTS: The HIV/HCV-coinfected patients were more frequently male (P < 0.002), were younger (P < 0.001), and had lower median BMI (P < 0.001) and HCV RNA (P < 0.05) and higher median aspartate aminotransferase (AST; P < 0.001), alanine aminotransferase (ALT; P < 0.001) and gamma glutamyl transferase (GGT; P < 0.001) levels than the HCV-monoinfected patients. The CB2 RR variant predominated in HIV/HCV-coinfected patients (45.8% vs. 31.2% in HCV-monoinfected patients; P < 0.001) and the CB2 QR variant in HCV-monoinfected patients (57.5% vs. 38.6% in HIV/HCV-coinfected patients; P < 0.00001), and the CB2 QQ variant was equally distributed. Focusing on patients with the CB2 QQ variant, the 26 HIV/HCV-coinfected patients, compared with the 21 HCV-monoinfected patients, showed less severe liver necroinflammation [lower histological activity index (HAI)] (P < 0.05). Of the patients with the CB2 RR variant, the 76 HIV/HCV-coinfected patients, compared with the 58 HCV-monoinfected patients, were more frequently male (P < 0.05), were younger (P < 0.001), and had a lower median body mass index (BMI; P < 0.001), a higher median AST level (P < 0.001), a higher mean HAI score (P < 0.05) and a higher rate of cases with severe steatosis (P = 0.05). In an analysis of variance (anova) of HCV/HIV-coinfected and HCV-monoinfected patient data, those with the CB2 RR variant (P = 0.003) and of male sex (P = 0.002) were more prevalent in the HCV/HIV-coinfected group. CONCLUSIONS: There is the suggestion of a positive effect of the CB2 RR variant on HIV acquisition and/or spread, which is in accordance with previous in vitro observations.

Eighteen-month lamivudine prophylaxis on preventing occult hepatitis B virus infection reactivation in patients with haematological malignancies receiving immunosuppression therapy.

This study evaluated the long-term efficacy and safety of an 18-month lamivudine prophylaxis in 68 HBsAg-negative/anti-HBc-positive patients with oncohaematological disease. All 68 consecutive HBsAg-negative/anti-HBc-positive patients with an oncohaematological disease and naïve for chemotherapy observed from April 2008 to December 2012 at 2 Hematology Units in Naples were treated with lamivudine for 18 months after stopping chemotherapy and monitored for HBsAg at months 1 and 3 during chemotherapy and then every 3 months after its discontinuation. During follow-up, 13 (19.1%) of the 68 patients died of complications related to their oncohaematological disease, and 3 (4%) showed a virological HBV reactivation (retroconversion to HBsAg positivity) 1-7 months after the discontinuation of lamivudine prophylaxis (2 treated for chronic lymphocytic leukaemia and one for Waldenstrom's disease); of these, 2 showed a biochemical reactivation. Comparing the demographic and clinical characteristics of the 3 patients with a virological HBV reactivation to the 65 without, the former were older (median age and range: 67 years [75-78] vs. 61 [24-88]; P = .05) and were less frequently treated for B-cell non-Hodgkin lymphoma (B-NHL) (0 vs. 70.7%, P = .03). In conclusion, a 18 months of lamivudine prophylaxis was effective in preventing HBV reactivation in HBsAg-negative/anti-HBc-positive patients treated for B-NHL. However, in patients with chronic and severe immunodepression, such as those with chronic lymphocytic leukaemia and Waldenstrom's disease, prophylaxis should be continued for an indefinite period.

Impact of PNPLA3 variants on liver histology of 168 patients with HIV infection and chronic hepatitis C.

This study analysed the impact of PNPLA3 variants on liver histology of 168 HIV/hepatitis C virus (HCV)-coinfected patients who were naïve for HCV treatment. A athologist unaware of the patients' condition graded liver fibrosis and necroinflammation (Ishak) and steatosis (Kleiner). Patients were tested for PNPLA3 variants and genotyped for the PNPLA3 rs738409 C to G variant underlying the I148M substitution. All were hepatitis B surface antigen negative and stated no alcohol abuse. The mean age was 40.6 (37.6-44.1) years, 72.6% were males, 42% had HCV genotype 3, 38.9% HCV genotype 1 and 79.2% were receiving highly active antiretroviral therapy. The 79 patients with the PNPLA3 p.148I/M or M/M variants more frequently showed severe steatosis (score 3-4) than the 89 with PNPLA3 p.148I/I (43% vs. 24.7%, p 0.001), whereas no difference was observed in the degree of necroinflammation or fibrosis. Compared with 112 patients with lower scores, 56 with severe steatosis showed higher body mass index (p 0.03), higher rate of HCV genotype 3 (55.6% vs. 35.2%, p 0.01), PNPLA3 p.148I/M or M/M (60.7% vs. 39.3%, p 0.01) and lower CD4(+) cells/mm(3) (514.00 (390.5-673.0) vs. 500.00 (399.0-627.0); p 0.002). At multivariate analysis, body mass index (p 0.01), HCV genotype 3 (p 0.006), CD4(+) cell count (p 0.005) and PNPLA3 p.148I/M or M/M variants (p 0.01) were found to be independent predictors of severe liver steatosis. The PNPLA3 p.148 I/M or M/M variants and CD4(+) cell count were the only independent predictors of severe steatosis in patients with HCV non-3 genotypes. This is the first study to show that among HIV/HCV-coinfected patients the PNPLA3 p.148I/M or M/M variant have substantially less impact on steatosis for those with HCV genotype 3 than non-genotype 3.

Clinical and virological characteristics associated with severe acute hepatitis B.

To identify early predictors of a severe or fulminant course in patients with acute viral hepatitis B (AVH-B). One hundred and thirty-eight patients with symptomatic acute hepatitis B observed from 1999 to 2012 were enrolled. For each patient, the demographics, risk factors for the acquisition of hepatitis B virus (HBV) infection, clinical, biochemical and virological data (HBV DNA, HBV DNA sequences) were recorded and analysed. The HBV mutants in the polymerase region were sought in 110 (87%) patients by direct sequencing, and the rtM204V/I mutations also by an allele-specific PCR. AVH-B was severe in 13 (9.4%) of the 138 patients enrolled, fulminant in 6 (4.3%) and with a normal clinical course in 119. The 19 patients with severe or fulminant AVH-B more frequently than the 119 with a normal course stated intravenous drug use (63.2% versus 36.1%, p 0.04) and were HBV-DNA negative (31.6% versus 11.8%, p 0.03) and anti-hepatitis C virus (HCV) positive (57.9% versus 19.3%, p 0.0008); the prevalences of different HBV genotypes and of the rtM204V/I mutant were similar in these three forms of AVH-B. A multivariate logistic regression analysis identified a pre-existing HCV chronic infection as the only factor independently associated with a severe or fulminant clinical course of AVH-B (OR 4.89, 95% CI 1.5-15.94, p 0.01). A pre-existing HCV chronic infection was identified as the only factor independently associated with a severe clinical presentation of acute hepatitis B, an association most probably due to the combination of the liver lesions caused by acute hepatitis B and the pre-existing histological abnormalities related to HCV chronic infection.

Mutation model for nucleotide sequences based on crystal basis.

A nucleotide sequence is identified, using a two (four)-letter alphabet, by the the labels of a vector state of an irreducible representation of Uq-->0(sl(2)) (Uq-->0(sl(2) plus sign in circle sl(2))). A master equation for the distribution function is written, where the intensity of the one-spin flip is assumed to depend on the variation of the labels of the state. In the two-letter approximation, the numerically computed equilibrium distribution for short sequences is fitted nicely by a Yule distribution, which is the observed distribution of the ranked short oligonucleotides frequency in DNA. The four-letter alphabet description, applied to the codons, is able to reproduce the form of the fitted rank-ordered usage frequencies distribution.

Universality and Shannon entropy of codon usage.

The distribution functions of codon usage probabilities, computed over all the available GenBank data for 40 eukaryotic biological species and five chloroplasts, are best fitted by the sum of a constant, an exponential, and a linear function in the rank of usage. For mitochondria the analysis is not conclusive. These functions are characterized by parameters that strongly depend on the total guanine and cytosine (GC) content of the coding regions of biological species. It is predicted that the codon usage is the same in all exonic genes with the same GC content. The Shannon entropy for codons, also strongly dependent on the exonic GC content, is computed.