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Background Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants. Methods Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population—baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination). Results Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P <.05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses. Conclusions The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA. [ABSTRACT FROM AUTHOR]

In early 2020 the new respiratory syndrome COVID‐19 (caused by the zoonotic SARS‐CoV‐2 virus) spread like a pandemic, starting from Wuhan, China, causing severe economic depression. Despite some advances in drug treatments of medical complications in the later stages of the disease, the pandemic's death toll is tragic, as no vaccine or specific antiviral treatment is currently available. By using a systems approach, we identify the host‐encoded pathway, which provides ribonucleotides to viral RNA synthesis, as a possible target. We show that methotrexate, an FDA‐approved inhibitor of purine biosynthesis, potently inhibits viral RNA replication, viral protein synthesis, and virus release. The effective antiviral methotrexate concentrations are similar to those used for established human therapies using the same drug. Methotrexate should be most effective in patients at the earliest appearance of symptoms to effectively prevent viral replication, diffusion of the infection, and possibly fatal complications. Highlights: The COVID‐19 pandemic caused by the SARS‐CoV‐2 virus is a global public health threat causing over 800000 deaths, millions of infected people, and severe economic depression.No vaccine or specific antiviral treatments are currently available.By inhibiting the host‐encoded pathway, which provides ribonucleotides to viral RNA synthesis, the FDA‐approved drug methotrexate efficiently blocks SARS‐CoV‐2 replication. [ABSTRACT FROM AUTHOR]

Background & aims: We investigated the HCV‐RNA amount, variability and prevalence of resistance‐associated substitutions (RASs), in plasma, hepatic tumoral and non‐tumoral tissue samples in patients undergoing liver‐transplant/hepatic‐resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. Methods: Eighteen HCV‐infected patients undergoing LT/HR, 94.0% naïve to direct‐acting antivirals (DAAs), were analysed. HCV‐RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non‐tumoral tissues were analysed using Sanger and Ultra‐deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic‐variability and phylogenetic analysis were evaluated. Results: At the time of LT/HR, HCV‐RNA was quantifiable in all compartments of DAA‐naïve patients and was generally lower in tumoral than in non‐tumoral tissues (median [IQR] = 4.0 [1.2‐4.3] vs 4.3[3.1‐4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV‐RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non‐tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected‐patients, and by UDPS in other two patients. HCV‐compartmentalization resulted to be associated with HBcAb‐positivity (P = 0.013). UDPS showed approximately higher genetic‐variability in NS3/NS5A sequences in all compartments. Phylogenetic‐analysis showed defined and intermixed HCV‐clusters among/within all compartments, and were strongly evident in the only non‐cirrhotic patient, with plasma and non‐tumoral sequences generally more closely related. Conclusions: Hepatic compartments showed differences in HCV‐RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV‐strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs. [ABSTRACT FROM AUTHOR]

Background: The thiopurine S-methyltransferase (TPMT)/azathioprine (AZA) gene-drug pair is one of the most well-known pharmacogenetic markers. Despite this, few studies investigated the implementation of TPMT testing and the combined evaluation of genotype and phenotype in multidisciplinary clinical settings where patients are undergoing chronic therapy with AZA. Methods: A total of 356 AZA-treated patients for chronic autoimmune diseases were enrolled. DNA was isolated from whole blood and the samples were analyzed for the c.460G>A and c.719A>G variants by the restriction fragment length polymorphism (RFLP) technique and sequenced for the c.238G>C variant. The TPMT enzyme activity was determined in erythrocytes by a high-performance liquid chromatography (HPLC) assay. Results: All the patients enrolled were genotyped while the TPMT enzyme activity was assessed in 41 patients. Clinical information was available on 181 patients. We found no significant difference in the odds of having adverse drug reactions (ADRs) in wild-type patients and variant allele carriers, but the latter had an extra risk of experiencing hematologically adverse events. The enzyme activity was significantly associated to genotype. Conclusions: TPMT variant allele carriers have an extra risk of experiencing hematologically adverse events compared to wild-type patients. Interestingly, only two out of 30 (6.6%) patients had discordant results between genotype, phenotype and onset of ADRs. [ABSTRACT FROM AUTHOR]

Background: The recent availability of direct acting antiviral drugs (DAAs) has drastically changed hepatitis C virus (HCV) treatment scenarios, due to the exceedingly high rates of sustained virological response (SVR) and excellent tolerability allowing for treatment at all disease stages.Methods: A panel of Italian experts was convened twice, in November 2016 and January 2017, to provide further support on some open issues and provide guidance for personalized HCV care, also in light of forthcoming regimens.Results and conclusions: Treatment recommendations issued by international and national liver societies to guide clinicians in the management of HCV infection are constantly updated due to accumulating new data. Such recommendations may not be applicable to all healthcare settings for a variety of reasons. Moreover, some gaps still remain and the spectrum of patients to be treated is also evolving. [ABSTRACT FROM AUTHOR]

Background & Aims The proportion of HCV-infected patients over age 65 years in Western countries is increasing. This growth and the advent of new antiviral therapy bring into the question the real-world efficacy and safety of the combination of sofosbuvir ( SOF) and simeprevir ( SMV) plus a flat dose of 800 mg/d ribavirin ( RBV) in elderly patients with cirrhosis compared to younger patients. Methods Retrospective observational multicentre real-life investigation study of SOF/ SMV/ RBV for a duration of 12 weeks in HCV genotype 1-infected patients with cirrhosis. Results Of the 270 patients enrolled in this study, with compensated cirrhosis, 133 (49.2%) were ≥65 years of age. Sustained virological response at 12 weeks ( SVR12) was achieved by 94.2% (129/137) of those aged <65 years and 97.7% (130/133) of those ≥65 years. Diabetes was the most common comorbidity in patients ≥65 years compared to younger patients (26.3% vs 12.4% P<.003). The most common adverse event ( AE) in elderly patients was a grade 2 anaemia (35.3% vs 19.9% P<.004). Conclusions Sofosbuvir/simeprevir plus a daily flat dose of RBV 800 mg for 12 weeks was highly effective and safe in genotype 1 elderly patients with compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Introduction. The evolutionary and demographic history of the circular recombinant form CRF02_AG in a selected retrospective group of HIV-1 infected men who have sex with men (MSM) resident in Central Italy was investigated. Methods. A total of 55 HIV-1 subtype CRF02_AG pol sequences were analyzed using Bayesian methods and a relaxed molecular clock to reconstruct their dated phylogeny and estimate population dynamics. Results. Dated phylogeny indicated that the HIV-1 CRF02_AG strains currently circulating in Central Italy originated in the early 90's. Bayesian phylogenetic analysis revealed the existence of a main HIV-1 CRF02_AG clade, introduced in the area of Rome before 2000 and subsequently differentiated in two different subclades with a different date of introduction (2000 versus 2005). All the sequences within clusters were interspersed, indicating that the MSM analyzed form a close and restricted network where the individuals, also moving within different clinical centers, attend the same places to meet and exchange sex. Conclusions. It was suggested that the HIV-1 CRF02_AG epidemic entered central Italy in the early 1990s, with a similar trend observed in western Europe. [ABSTRACT FROM AUTHOR]

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor—containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P = .04, x² test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30–3.75; P = .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy. [ABSTRACT FROM AUTHOR]

In patients with virological failure during highly active antiretroviral therapy (HAART) and drug resistance, guidelines recommend the achievement of maximal virological suppression by the use of a new regimen with at least 2 active drugs. We describe the clinical outcome of a heavily antiretroviral-experienced patient who experienced early failure to raltegravir. [ABSTRACT FROM AUTHOR]

The article presents a study on the implementation of anti-retroviral triple therapy to prevent HIV mother-to-child transmission in Mozambique. The study provided highly active anti-retroviral therapy (HAART) to pregnant woman until six months postpartum, and formula, clean water, nutritional supplementation, and continuing HAART to mothers if necessary.