Background: The D:A:D (Data Collection on Adverse Events of Anti‐HIV Drugs) Study, a prospective observational study on a cohort of 23 468 patients with HIV infection, indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). However, it remains unclear whether the observed increase in the rate of MI in this population can be attributed to changes in conventional cardiovascular risk factors.Objective: To compare the number of MIs observed among participants in the D:A:D Study with the number predicted by assuming that conventional cardiovascular risk equations apply to patients with HIV infection.Methods: The Framingham equation, a conventional cardiovascular risk algorithm, was applied to individual patient data in the D:A:D Study to predict rates of MI by duration of CART. A series of sensitivity analyses were performed to assess the effect of model and data assumptions. Predictions were extrapolated to provide 10‐year risk estimates, and various scenarios were modelled to assess the expected effect of different interventions.Results: In patients receiving CART, the observed numbers of MIs during D:A:D follow up were similar to or somewhat higher than predicted numbers: 9 observed vs 5.5 events predicted, 14 vs 9.8, 22 vs 14.9, 31 vs 23.2 and 47 vs 37.0 for4 years CART exposure, respectively. In patients who had not received CART, the observed number of MIs was fewer than predicted (3 observed vs 7.6 predicted). Nine per cent of the study population have a predicted 10‐year risk of MI above 10%, a level usually associated with initiation of intervention on risk factors.Conclusions: A consistent feature of all analyses was that observed and predicted rates of MI increased in a parallel fashion with increased CART duration, suggesting that the observed increase in risk of MI may at least in part be explained by CART‐induced changes in conventional risk factors. These findings provide guidance in terms of choosing lifestyle or therapeutic interventions to decrease those risk factors in much the same way as in persons without HIV infection.

Many practical clinical questions regarding the management of human immunodeficiency virus (HIV)–associated neurocognitive disorder (HAND) remain unanswered. We sought to identify and develop practical answers to key clinical questions in HAND management. Sixty-six specialists from 30 countries provided input into the program, which was overseen by a steering committee. Fourteen questions were rated as being of greatest clinical importance. Answers were drafted by an expert group based on a comprehensive literature review. Sixty-three experts convened to determine consensus and level of evidence for the answers. Consensus was reached on all answers. For instance, good practice suggests that all HIV patients should be screened for HAND early in disease using standardized tools. Follow-up frequency depends on whether HAND is already present or whether clinical data suggest risk for developing HAND. Worsening neurocognitive impairment may trigger consideration of antiretroviral modification when other causes have been excluded. The Mind Exchange program provides practical guidance in the diagnosis, monitoring, and treatment of HAND.

Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long‐term therapy may be required. We investigated whether adding on pegylated interferon (Peg‐IFN) to ETV therapy enhances serological response rates. In this global investigator‐initiated, open‐label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg‐IFN add‐on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add‐on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg‐IFN add‐on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6‐14.0; P = 0.004). Eleven (13%) of the add‐on‐treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add‐on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg‐IFN add‐on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Conclusion: Although the primary endpoint was not reached, 24 weeks of Peg‐IFN add‐on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add‐on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg‐IFN add‐on therapy may facilitate the discontinuation of nucleos(t)ide analogs. (Hepatology 2015;61:1512–1522)

We report on the genomic characterization of 47 multi-drug resistant, carbapenem resistant and ESBL-producing K. pneumoniae isolates from the influent (I) and effluent (E) of three wastewater treatment plants (WWTPs) and from Romanian hospital units which are discharging the wastewater in the sampled WWTPs. The K. pneumoniae whole genome sequences were analyzed for antibiotic resistance genes (ARGs), virulence genes and sequence types (STs) in order to compare their distribution in C, I and E samples. Both clinical and environmental samples harbored prevalent and widely distributed ESBL genes, i.e. bla_SHV, bla_OXA, bla_TEM and bla_{CTX M}. The most prevalent carbapenemase genes were bla_NDM-1, bla_OXA-48 and bla_KPC-2. They were found in all types of isolates, while bla_OXA-162, a rare bla_OXA-48 variant, was found exclusively in water samples. A higher diversity of carbapenemases genes was seen in wastewater isolates. The aminoglycoside modifying enzymes (AME) genes found in all types of samples were aac(6’), ant(2'')Ia, aph(3'), aaD, aac(3) and aph(6). Quinolone resistance gene qnrS1 and the multi-drug resistance oqxA/B pump gene were found in all samples, while qnrD and qnrB were associated to aquatic isolates. The antiseptics resistance gene qacEdelta1 was found in all samples, while qacE was detected exclusively in the clinical ones. Trimethroprim-sulfamethoxazole (dfrA, sul1 and sul2), tetracyclines (tetA and tetD) and fosfomycin (fosA6, known to be located on a transpozon) resistance genes were found in all samples, while for choramphenicol and macrolides some ARGs were detected in all samples (catA1 and catB3 / mphA), while other (catA2, cmIA5 and aac(6’)Ib / mphE and msrE) only in wastewater samples. The rifampin resistance genes arr2 and 3 (both carried by class I integrons) were detected only in water samples. The highly prevalent ARGs preferentially associating with aquatic versus clinical samples could ascribe potential markers for the aquatic (bla_SHV-145, qacEdelta1, sul1, aadA1, aadA2) and clinical (bla_OXA-1, bla_SHV-106,bla_TEM-150, aac(3)Iia, dfrA14, oqxA10; oqxB17,catB3, tetD) reservoirs of AR. Moreover, some ARGs (oqxA10; bla_SHV-145; bla_SHV-100, aac(6')Il, aph(3')VI, armA, arr2, cmlA5, bla_CMY-4, mphE, msrE, oqxB13, bla_OXA-10) showing decreased prevalence in influent versus effluent wastewater samples could be used as markers for the efficiency of the WWTPs in eliminating AR bacteria and ARGs. The highest number of virulence genes (75) was recorded for the I samples, while for E and C samples it was reduced to half. The most prevalent belong to three functional groups: adherence (fim genes), iron acquisition (ent, fep, fyu, irp and ybt genes) and the secretion system (omp genes). However, none of the genes associated with hypervirulent K. pneumoniae have been found. A total of 14 STs were identified. The most prevalent clones were ST101, ST219 in clinical samples and ST258, ST395 in aquatic isolates. These STs were also the most frequently associated with integrons. ST45 and ST485 were exclusively associated with I samples, ST11, ST35, ST364 with E and ST1564 with C samples. The less frequent ST17 and ST307 aquatic isolates harbored bla_OXA-162, which was co-expressed in our strains with bla_CTX-M-15 and bla_OXA-1.

Background: The Phase 3 ASSEMBLE study investigated aztreonam–avibactam versus best available therapy (BAT) for treatment of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) or bloodstream infection (BSI) caused by confirmed MBL-producing multidrug-resistant pathogens. Methods: This prospective, multicentre, randomized, open-label, central assessor-blinded study randomized hospitalized adults 2:1 to aztreonam–avibactam [+ metronidazole (cIAI)] or BAT for 5–14 (cIAI, cUTI and BSI) or 7–14 (HAP/VAP) days. Primary endpoint was clinical cure at test-of-cure (TOC) visit on Day 28 ± 3 [microbiological ITT (micro-ITT) analysis set]. Secondary endpoints included microbiological response at TOC, 28-day mortality and safety. No formal hypothesis testing was planned. Results: Fifteen patients were randomized [aztreonam–avibactam, n = 12; BAT, n = 3 (ITT and micro-ITT analysis sets)]. Most frequent baseline pathogens were Enterobacterales; Klebsiella pneumoniae was most common [aztreonam–avibactam, 6/12 (50%); BAT, 2/3 (67%)]. MBL subtypes/variants identified in the aztreonam–avibactam group were NDM-1 (n = 7), NDM-5 (n = 3), VIM-2 (n = 2) and L1 (n = 3); and for BAT were NDM-1 (n = 2) and NDM-5 (n = 1). Clinical cure rates at TOC were 5/12 (42%) for aztreonam–avibactam and 0/3 (0%) for BAT. Per-patient microbiological responses were generally consistent with clinical responses. Twenty-eight-day all-cause mortality rates for aztreonam–avibactam and BAT were 1/12 (8%) and 1/3 (33%), respectively. Aztreonam–avibactam was generally well-tolerated, with no treatment-related serious adverse events. Conclusions: These Phase 3 data provide support for aztreonam–avibactam as a potential therapeutic option for difficult-to-treat infections caused by MBL-producing Gram-negative bacteria.

Hepatitis C virus (HCV) genotype (GT) 1 is the most prevalent HCV GT worldwide [ 1 x [1] Messina, J.P., Humphreys, I., Flaxman, A., Brown, A., Cooke, G.S., Pybus, O.G. et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015; 61: 77–87 Crossref | PubMed | Scopus (604) | Google Scholar See all References ] [1] . In treatment-naïve GT1-infected patients, triple therapy with the first generation HCV NS3/4A protease inhibitor telaprevir and pegylated interferon/ribavirin (TPV + PegIFN/RBV) results in sustained virologic response (SVR) rates of approximately 75% [ 2 x [2] Jacobson, I.M., McHutchison, J.G., Dusheiko, G., Di Bisceglie, A.M., Reddy, K.R., Bzowej, N.H. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011; 364: 2405–2416 Crossref | PubMed | Scopus (2015) | Google Scholar See all References ] [2] . Among patients who previously failed to achieve SVR with PegIFN/RBV therapy, retreatment with TPV + PegIFN/RBV results in SVR rates of 31–84% depending on type of previous response [ 3 x [3] Incivek (telaprevir) film coated tablets: US prescribing information. Vertex Pharmaceuticals Inc., Cambridge, 538 MA; 2013 Google Scholar See all References ] [3] . TPV + PegIFN/RBV therapy requires up to 48 weeks of treatment and results in significant adverse events such as influenza-like symptoms, depression, rash, nausea, and pancytopenia, leading to a high discontinuation rate [ 2 x [2] Jacobson, I.M., McHutchison, J.G., Dusheiko, G., Di Bisceglie, A.M., Reddy, K.R., Bzowej, N.H. et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011; 364: 2405–2416 Crossref | PubMed | Scopus (2015) | Google Scholar See all References , 4 x [4] Fried, M.W., Shiffman, M.L., Reddy, K.R., Smith, C., Marinos, G., Goncales, F.L. Jr et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347: 975–982 Crossref | PubMed | Scopus (5561) | Google Scholar See all References , 5 x [5] Manns, M.P., McHutchison, J.G., Gordon, S.C., Rustgi, V.K., Shiffman, M., Reindollar, R. et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001; 358: 958–965 Abstract | Full Text | Full Text PDF | PubMed | Scopus (5619) | Google Scholar See all References , 6 x [6] McHutchison, J.G., Lawitz, E.J., Shiffman, M.L., Muir, A.J., Galler, G.W., McCone, J. et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009; 361: 580–593 Crossref | PubMed | Scopus (1022) | Google Scholar See all References ]. Many patients are PegIFN-intolerant or have contraindications to PegIFN/RBV therapy that preclude the treatment. New direct-acting antiviral (DAA) therapies that provide a significant advancement in chronic HCV treatment are approved and have replaced TPV + PegIFN/RBV in many areas. However, TPV + PegIFN/RBV is still widely available and remains the choice treatment in regions including Latin America and Asia. There is a lack of direct comparison between the IFN-free DAA regimens and previous standard of care such as TPV + PegIFN/RBV.