"Values" in medical practice

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Minor mutations in HIV protease at baseline and appearance of primary mutation 90M in patients for whom their first protease-inhibitor ntiretroviral regimens failed

The association between minor mutations in human immunodeficiency virus (HIV) protease at baseline and development of common primary mutation 90M at virological failure (conferring some resistance to all protease inhibitors [PIs]) was evaluated in 93 previously drug-naive patients experiencing failure of their first PI-based antiretroviral regimens. In logistic regression analysis, the probability of accumulating a new 90M mutation at virological failure was associated with the presence at baseline of minor mutation 36I (naturally occurring in ∼25% of HIV clade B and in >80% of HIV non-clade-B viruses) (adjusted odds ratio, 13.5 [95% confidence interval, 1.89–95.6]; P=.009) and, possibly, of 10I/V. This suggests a potential role for the presence of 36I at baseline in predicting the appearance of 90M at virological failure

Recent transmission clustering of HIV-1 C and CRF17_BF strains characterized by NNRTI-related mutations among newly diagnosed men in central Italy

Increased evidence of relevant HIV-1 epidemic transmission in European countries is being reported, with an increased circulation of non-B-subtypes. Here, we present two recent HIV-1 non-B transmission clusters characterized by NNRTI-related amino-acidic mutations among newly diagnosed HIV-1 infected men, living in Rome (Central-Italy)

Selected amino acid mutations in HIV-1 B subtype gp41 are Associated with Specific gp120V3 signatures in the regulation of Co-Receptor usage

<p>Abstract</p> <p>Background</p> <p>The third variable loop (V3) of the HIV-1 gp120 surface protein is a major determinant of cellular co-receptor binding. However, HIV-1 can also modulate its tropism through other regions in gp120, such as V1, V2 and C4 regions, as well as in the gp41 protein. Moreover, specific changes in gp41 are likely to be responsible for of damage in gp120-CCR5 interactions, resulting in potential resistance to CCR5 inhibitors.</p> <p>In order to genetically characterize the two envelope viral proteins in terms of co-receptor usage, we have analyzed 526 full-length <it>env </it>sequences derived from HIV-1 subtype-B infected individuals, from our and public (Los Alamos) databases. The co-receptor usage was predicted by the analysis of V3 sequences using Geno2Pheno (G2P) algorithm. The binomial correlation phi coefficient was used to assess covariation among gp120_V3and gp41 mutations; subsequently the average linkage hierarchical agglomerative clustering was performed.</p> <p>Results</p> <p>According to G2P false positive rate (FPR) values, among 526 env-sequences analyzed, we further characterized 196 sequences: 105 with FPR <5% and 91 with FPR >70%, for X4-using and R5-using viruses, respectively.</p> <p>Beyond the classical signatures at 11/25 V3 positions (S11S and E25D, R5-tropic viruses; S11KR and E25KRQ, X4-tropic viruses), other specific V3 and gp41 mutations were found statistically associated with the co-receptor usage. Almost all of these specific gp41 positions are exposed on the surface of the glycoprotein. By the covariation analysis, we found several statistically significant associations between V3 and gp41 mutations, especially in the context of CXCR4 viruses. The topology of the dendrogram showed the existence of a cluster associated with R5-usage involving E25D_V3, S11S_V3, T22A_V3, S129DQ_gp41and A96N_gp41signatures (bootstrap = 0.88). Conversely, a large cluster was found associated with X4-usage involving T8I_V3, S11KR_V3, F20IVY_V3, G24EKR_V3, E25KR_V3, Q32KR_V3, A30T_gp41, A189S_gp41, N195K_gp41and L210P_gp41mutations (bootstrap = 0.84).</p> <p>Conclusions</p> <p>Our results show that gp120_V3and several specific amino acid changes in gp41 are associated together with CXCR4 and/or CCR5 usage. These findings implement previous observations that determinants of tropism may reside outside the V3-loop, even in the gp41. Further studies will be needed to confirm the degree to which these gp41 mutations contribute directly to co-receptor use.</p

Impact of HIV-1 Reverse Transcriptase Polymorphism F214L on Virological Response to Thymidine Analogue—Based Regimens in Antiretroviral Therapy (ART)—Naive and ART-Experienced Patients

Background.#160;A negative association between the polymorphism F214L and type 1 thymidine analogue (TA) mutations (TAMs) has been observed. However, the virological response to TAs according to the detection of F214L has not been evaluated. Methods.We studied 590 patients from EuroSIDA who started TA therapy for the first time as part of potent combination antiretroviral therapy (cART) and who were tested for genotypic resistance within the past 6 months. End points were median reduction in the week 24 viral load and time to virological failure (2 consecutive VL measurements >400 copies/mL after at least 6 months of the TA-containing cART). Results.In ART-naive patients, the prevalence of F214L was 17%. By 48 months after starting TA-based cART, the proportion of patients who experienced virological failure was 16% in patients with 214L and 36% in those with 214F (P = .03). In a multivariable Cox regression model, the relative hazard of virological failure for patients with 214L compared with those with 214F was 0.22 (95% confidence interval, 0.07—0.72). In ART-experienced patients, results were similar, and larger differences in virological response associated with the detection of 214L versus F were observed in patients with M41L/T215Y and mixed TAM profiles detected before the initiation of cART. Conclusions.This study provides evidence that the detection of polymorphism F214L is associated with a favorable virological response to TA-based cAR

Cytomegalovirus Glycoprotein B Genotype Distribution in Italian Transplant Patients.

Background: The cytomegalovirus (CMV) UL55 gene encodes for a glycoprotein implicated in virus pathogenesis. Based on UL55 polymorphism, CMV has been divided into 4 genotypes. Previous studies investigated the possible role of genotypes in the clinical outcome of infection in different categories of patients; however, few data are available, particularly in the transplant setting and Italian case records. Methods: Phylogenetic analysis through a maximum likelihood tree was used to evaluate the prevalence and distribution of CMV genotypes in whole blood specimens from 47 transplant patients and investigate the relation with demographic and clinical features. Results: Overall, 40.4% of patients were classified as single genotype (12.8% gB1, 23.4% gB2, 4.2% gB3); mixed genotypes were detected in 59.6%. Genotype 4 was detected only in mixed cases. In comparison to single genotypes, mixed genotypes were more frequently associated with a higher duration of DNA viremia and higher peak viral load. Conclusions: Mixed infections seem to be prevalent in Italian transplant patients; it is likely that mixed infections are more difficult to control by immunological response in comparison to single genotype infections. In this context, the genetic profile of infecting viruses and relation to clinical outcome should be investigated, also taking into account the CMV-specific cellular immune response

Phylogenesis and Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection

During the spring of 2009, a new influenza A (H1N1) virus of swine origin emerged and spread worldwide causing a pandemic influenza. Here, 329 naso-pharyngeal swabs collected from patients with flu-like symptoms were analyzed by real-time PCR for the presence of H1N1 2009 pandemic virus. Twenty-five samples collected from immunocompetent and immunodepressed patients contained the H1N1 pandemic virus. Phylogenetic analysis of the hemagglutinin and neuraminidase genes showed no obvious differences in terms of similarity and/or homology between the sequences identified in immunocompetent individuals and those obtained from immunocompromised patients. Pre-existing clinical conditions may influence the outcome of H1N1 disease

HDV can constrain HBV genetic evolution in hbsag: Implications for the identification of innovative pharmacological targets

Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-D sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection