Touching Base with Some Mediterranean Diseases of Interest from Paradigmatic Cases at the "Magna Graecia" University Unit of Infectious Diseases: A Didascalic Review.

Among infectious diseases, zoonoses are increasing in importance worldwide, especially in the Mediterranean region. We report herein some clinical cases from a third-level hospital in Calabria region (Southern Italy) and provide a narrative review of the most relevant features of these diseases from epidemiological and clinical perspectives. Further, the pathogenic mechanisms involved in zoonotic diseases are reviewed, focusing on the mechanisms used by pathogens to elude the immune system of the host. These topics are of particular concern for individuals with primary or acquired immunodeficiency (e.g., people living with HIV, transplant recipients, patients taking immunosuppressive drugs). From the present review, it appears that diagnostic innovations and the availability of more accurate methods, together with better monitoring of the incidence and prevalence of these infections, are urgently needed to improve interventions for better preparedness and response.

Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIV-1 subtype B and non-subtype B receiving a salvage regimen.

OBJECTIVES: The objective of this study was to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. METHODS: Darunavir-containing treatment change episodes (TCEs) in patients previously failing PIs were selected from large European databases. HIV-1 subtype B-infected patients were used as the derivation dataset and HIV-1 non-B-infected patients were used as the validation dataset. The adjusted association of each mutation with week 8 HIV RNA change from baseline was analysed by linear regression. A prediction model was derived based on best subset least squares estimation with mutational weights corresponding to regression coefficients. Virological outcome prediction accuracy was compared with that from existing genotypic resistance interpretation systems (GISs) (ANRS 2013, Rega 9.1.0 and HIVdb 7.0). RESULTS: TCEs were selected from 681 subtype B-infected and 199 non-B-infected adults. Accompanying drugs were NRTIs in 87%, NNRTIs in 27% and raltegravir or maraviroc or enfuvirtide in 53%. The prediction model included weighted protease mutations, HIV RNA, CD4 and activity of accompanying drugs. The model's association with week 8 HIV RNA change in the subtype B (derivation) set was R(2) = 0.47 [average squared error (ASE) = 0.67, P < 10(-6)]; in the non-B (validation) set, ASE was 0.91. Accuracy investigated by means of area under the receiver operating characteristic curves with a binary response (above the threshold value of HIV RNA reduction) showed that our final model outperformed models with existing interpretation systems in both training and validation sets. CONCLUSIONS: A model with a new darunavir-weighted mutation score outperformed existing GISs in both B and non-B subtypes in predicting virological response to darunavir.

Nasopharyngeal carcinoma: review of the literature with a focus on therapeutical implications.

Nasopharyngeal carcinoma (NPC) is a rare neoplasm which is associated with Epstein-Barr virus (EBV). First of all, we reviewed the literature on NPC treatment. Radio/chemotherapy is currently the gold standard but unfortunately is affected by rates of failure ranging from 7% up to 58%. Because NPC development is promoted by the EBV latent life cycle, EBV-targeted treatments were investigated. Firstly, forcing cytolytic virus activation through administration of gemcitabine and/or valproic acid before administration of a nucleoside analogue showed anti-tumoral activity in vitro as well as in murine model and it was also well tolerated in humans. Secondly, the association of autologous EBV-specific cytotoxic T lymphocytes with chemotherapy correlated with an improved median survival and was safe but not effective versus metastatic lesions. Thirdly, suppression of late membrane protein-1 in the clinic proved controversial because it gave resistance to chemotherapy and, on the other hand, increased radiosensitivity. Finally, we suggest future perspectives for clinical research which should include both prospective and observational cohort studies to assess the role of different risk factors in the development of NPC and the effectiveness of new investigational treatments.

Prevalence and risk factors for etravirine resistance among patients failing on non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Prevalence and factors associated with etravirine (EW) resistance mutations among patients failing on first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI) merit investigation. METHODS: The study comprised an analysis of all sequential patients attending the Institute of Infectious Diseases (Brescia, northern Italy) who performed a genotypic resistance testing (GRT) after > or =3 months of a stable NNRTI-based regimen between 2001 and 2006. Multivariable ordinal logistic regression analysis was performed to assess predictors of ETV resistance mutations. RESULTS: Out of 248 strains, 153 (61.7%) harboured > or =1 ETV resistance mutations. In particular, 88 (35.5%), 53 (21.4%) and 12 (4.8%) harboured one, two and three mutations, respectively. The most frequent mutations were G190A (230%), Y181C (23%) and K101E (14.1%). Use of nevirapine (odds ratio [OR] 2.73; 95% confidence level [CI] 1.62-4.62; P<0.001) and a longer time frame between first HIV RNA >500 copies/ml and GRT (per month, OR 1.05; 95% CI 1.01-1.09; P=0.012) were associated with a greater number of ETV resistance mutations. Conversely, higher CD4+ T-cell counts at nadir (per 100 cells/mm3, OR 0.81; 95% CI 0.67-0.98; P=0.029) and use of lamivudine/emtricitabine (OR 0.57; 95% CI 0.37-0.87; P=0.009) were protective. Accumulation of ETV resistance-associated mutations was demonstrated by sequential GRT in 4/35 patients (all treated with nevirapine). CONCLUSIONS: Mutations associated with ETW resistance were common among patients failing on NNRTI, but prevalence of viral strains harbouring three mutations was low. Use of efavirenz and co-administration of lamivudine reduced the risk of ETW resistance. The continued use of the current NNRTI in a failing regimen may select for additional resistant variants.

Influence of folate serum concentration on plasma homocysteine levels in HIV-positive patients exposed to protease inhibitors undergoing HAART.

BACKGROUND: Homocysteinemia (Hcy) increase and risk factors in HIV-positive patients are not clear yet. METHODS: HIV-positive patients on stable highly active antiretroviral therapy (HAART) regimens for at least 6 months were enrolled in this cross-sectional study. Among other factors, vitamin B12, folate and length of exposure to protease inhibitors (PIs) were evaluated for their possible correlation with hyper-Hcy (>13 micromol/l in females; >15 micromol/l in males) by logistic regression analysis. RESULTS: Ninety-eight HIV-positive patients were recruited. Twenty-eight (28.6%) had hyper-Hcy. Length of exposure to antiretroviral therapy and PIs did not result to be significantly associated with hyper-Hcy risk. Normal folate level was the only factor associated with the outcome, resulting protective from hyper-Hcy, either at univariate (OR = 0.22; CI 95% = 0.06-0.86; p = 0.029) and multivariable (OR = 0.24; CI 95% = 0.06-0.94; p = 0.04) logistic regression analysis. Folate predictive value of hyper-Hcy risk was driven by levels in the lowest quartiles of the study population (i.e. <10.9 nmol/l). CONCLUSIONS: No significant correlations were observed between hyper-Hcy and length of exposure to antiretroviral therapy or PIs. Folate could be a confounding factor in the association between hyper-Hcy and PI exposure found by others. The potential value of folate supplementation, in those who are deficient and in those with hyper-Hcy, merits study.

Selection of antiretroviral therapy guided by genotypic or phenotypic resistance testing: an open-label, randomized, multicenter study (PhenGen).

The phenotype/genotype (PhenGen) open-label, randomized, multicenter study evaluated the genotype/virtual phenotype (vPt) and real phenotype (rPt) for choosing a new highly active antiretroviral therapy regimen at failure. Patients with a plasma viral load (pVL) between 2000 and 200,000 copies/mL and a CD4 cell count >200/microL, failing > or =2 regimens (<6 drugs), were randomized for vPt or rPt. Three hundred three patients were enrolled: 111 and 108 patients received a new treatment in the vPt and rPt arms, respectively. The 2 groups were comparable for baseline patient characteristics and treatment history. The new therapy was in agreement with expert advice in 58.5% of cases. After 6 months, no statistical differences were found in the mean absolute change from baseline CD4 cells (+55 and +46 cells/muL; P = 0.7), mean pVL log decrease (-1.35 and -1.37; P = 0.8), or proportion of patients with a pVL <400 copies/mL (54.8% in vPt arm and 52.6% in rPt arm; P = 0.9). At multivariate analysis, variables independently associated with failure of the new regimen were: pVL at baseline (odds ratio [OR] = 1.81; P < 0.021), number of nucleoside reverse transcriptase inhibitor-associated mutations (OR = 1.21; P = 0.001), number of protease mutations (OR = 1.15; P < 0.001), and recycling of indinavir (OR = 4.63; P = 0.019). Patients' adherence to the prescribed regimen (OR = 0.23; P < 0.001), number of active drugs in the new regimen (OR = 0.55; P = 0.001), and adherence to expert advice (OR = 0.37; P < 0.001) predicted virologic response. The vPt is as predictive of treatment outcome as the rPT. Use of expert advice significantly improved the response to therapy.