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We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation.A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome.A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14,Anticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Background Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. Methods We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. Results We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3–3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1–3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3–.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2–.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6–.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0–1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. Conclusions Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts., Integrase strand transfer inhibitor–based therapies are effective as first-line treatment of persons living with human immunodeficiency virus. Among 1419 patients, we identified a high baseline viral load, low CD4 cell counts, and an AIDS-defining event before treatment initiation as predictors for treatment failure.

Background It is unclear whether data-driven machine learning models, which are trained on large epidemiological cohorts, may improve prediction of comorbidities in people living with human immunodeficiency virus (HIV). Methods In this proof-of-concept study, we included people living with HIV in the prospective Swiss HIV Cohort Study with a first estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73 m2 after 1 January 2002. Our primary outcome was chronic kidney disease (CKD)—defined as confirmed decrease in eGFR ≤60 mL/minute/1.73 m2 over 3 months apart. We split the cohort data into a training set (80%), validation set (10%), and test set (10%), stratified for CKD status and follow-up length. Results Of 12 761 eligible individuals (median baseline eGFR, 103 mL/minute/1.73 m2), 1192 (9%) developed a CKD after a median of 8 years. We used 64 static and 502 time-changing variables: Across prediction horizons and algorithms and in contrast to expert-based standard models, most machine learning models achieved state-of-the-art predictive performances with areas under the receiver operating characteristic curve and precision recall curve ranging from 0.926 to 0.996 and from 0.631 to 0.956, respectively. Conclusions In people living with HIV, we observed state-of-the-art performances in forecasting individual CKD onsets with different machine learning algorithms., In people living with HIV who participate in the Swiss HIV Cohort Study, we observed state-of-the-art performances in forecasting individual onsets of chronic kidney disease with different machine learning algorithms.

BackgroundSince the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes.MethodsPLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure.ResultsOf 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1–4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93–1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76–1.00]) and less likely to develop resistance (14% vs 27%, P ConclusionsDespite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

BACKGROUND: For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS: We included individuals from the HIV-CAUSAL Collaboration who enrolled

Background Reconstructive vascular surgery has become increasingly common. Vascular graft infections (VGIs) are serious complications, leading to increased morbidity and mortality. Previously described risk factors for VGIs include groin incisions, wound infections, and comorbidities. We aimed to identify modifiable predictors for VGIs as targets for infection prevention strategies. Methods Participants of the prospective Vascular Graft Infection Cohort (VASGRA) with surgery between 2013 and 2017 were included. The observation time was calculated from surgery until a confirmed VGI or the last follow-up. Variables were assessed by infection status, using non-parametric tests. Univariable and multivariable Cox proportional hazard regression models, adjusted for demographic factors, were applied to assess risk factors for a VGI. Results A total of 438 predominantly male (83.1%) patients with a median age of 71 years (interquartile range [IQR] 63 – 76) contributed to 554 person years of follow-up. Thereof, 39 (8.9%) developed a VGI, amounting to an incidence rate of 7.0/100 person years. We found incisional surgical site infections (adjusted hazard ratio [aHR] 10.09, 95% CI 2.88 – 35.34); hemorrhage (aHR 4.92, 1.28–18.94); renal insufficiency (aHR 4.85, 1.20 – 19.61); inadequate perioperative prophylaxis in patients with an established antibiotic treatment, compared to the additional application of perioperative prophylaxis (aHR 2.87, 95% CI 1.17 – 7.05); and procedure time increases of 1-hour intervals (aHR 1.22, 95% CI 1.08 – 1.39) to be risk factors for VGIs. Conclusions We identified procedure time; inadequate perioperative prophylaxis, especially among patients with an established antibiotic treatment; and several postsurgical infectious and non-infectious complications as modifiable, predictive factors for VGIs and, therefore, as keys to improved surveillance programs and prevention strategies. Clinical Trials Registration NCT01821664

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

Objectives Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV before and after DAA therapy. Methods Before and 12 weeks after sustained virological response (SVR12) to DAA therapy, 22 cell populations were analysed by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with (ten patients) or without (ten patients) human immunodeficiency virus (HIV) infection. Results HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median, interquartile range (IQR); control, HCV, HCV/HIV) of intermediate monocytes (1.2, IQR 0.47–1.46; 1.76, IQR 0.83–2.66; 0.78, IQR 0.28–1.77), non-classical monocytes (1.11, IQR 0.49–1.26; 0.9, IQR 0.18–0.99; 0.54, IQR 0.28–1.77), conventional dendritic cells type 2 (0.55, IQR 0.35–0.59; 0.31, IQR 0.16–0.38; 0.19, IQR 0.11–0.36) and CD56dim natural killer cells (8.08, IQR 5.34–9.79; 4.72, IQR 2.59–6.05) 3.61, IQR 2.98–5.07) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07, IQR 0.06–0.10; 0.10, IQR 0.09–0.19; 0.19, IQR 0.12–0.25), activated CD4 T cells (0.28, IQR 0.21–0.36; 0.56, IQR 0.33–0.77; 0.40, IQR 0.22–0.53) and activated CD8 T cells (0.23, IQR 0.14–0.42; 0.74, IQR 0.30–1.65; 0.80, IQR 0.58–1.16) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12. Conclusions Chronic HCV and HCV/HIV infections induce profound and durable perturbations of innate and adaptive immune homeostasis.

Background Prevalence of potential drug–drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles. Methods The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01–12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged). Results In 9298 included individuals, median age was 51 years (IQR, 43–58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)–based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber—mostly with cardiovascular drugs—and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (−24%) and NNRTIs (−13%) but the use of co-medications was higher. Conclusions Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.

Our aim was to describe HPV16E6 antibody kinetics prior to anal cancer in people living with HIV/AIDS (PLWHA) and evaluate the possible contribution of HPV16E6 serology to anal cancer risk prediction. For 91 persons diagnosed with anal cancer in the Swiss HIV Cohort Study (1989-2017), serial serum/plasma samples were tested for HPV16E6 antibodies using multiplex serology, supplemented with samples from 1,356 participants without anal cancer. Anal cancer incidence was estimated for PLWHA from 40 years-old in the cART era, stratified by HPV16E6 serostatus. HPV16E6 seroprevalence was 23.3% in samples 10 years. Of 25 individuals with anal cancer who were HPV16E6-seropositive at any time during follow-up, the majority (n=18) remained seropositive in all samples following seroconversion, whereas for 7 cases, seropositivity was transitory. Among individuals with anal cancer, HPV16E6 seroprevalence was marginally higher in women versus men who have sex with men (adjusted OR=4.3, 95% CI: 1.1, 17.2) and in older participants (adjusted OR=6.2, 95% CI: 1.1, 34.8 for cases diagnosed at ≥55 versus

Background PIs cause drug–drug interactions (DDIs) with most statins due to inhibition of drug-metabolizing enzymes and/or the hepatic uptake transporter OATP1B1, which may alter the pharmacodynamic (PD) effect of statins. Objectives To assess the management of DDIs between antiretrovirals (ARVs) and statins in people living with HIV (PLWH) considering statin plasma concentrations, compliance with dosing recommendations and achievement of lipid targets. Methods PLWH of the Swiss HIV Cohort Study were eligible if they received a statin concomitantly with ARVs. HDL, total cholesterol (TC) and statin plasma concentration were measured during follow-up visits. Individual non-HDL and TC target values were set using the Framingham score and the 2018 European AIDS Clinical Society recommendations. Results Data were analysed for rosuvastatin (n = 99), atorvastatin (n = 92), pravastatin (n = 46) and pitavastatin (n = 21). Rosuvastatin and atorvastatin underdosing frequently led to suboptimal PD response. Insufficient lipid control was observed with PIs despite high atorvastatin concentrations, likely explained by inhibition of OATP1B1 resulting in less statin uptake in the liver. Target lipid values were more often achieved with unboosted integrase inhibitors due to both their favourable DDI profiles and neutral effect on lipids. Insufficient lipid control was common with pravastatin and pitavastatin regardless of co-administered ARVs and despite using maximal recommended statin doses. The latter suggests lower efficacy compared with rosuvastatin or atorvastatin. Conclusions Suboptimal management of DDIs with statin underdosing was observed in 29% of prescriptions. Integrase inhibitor-based regimens and/or treatment with rosuvastatin or atorvastatin should be favoured in patients with refractory dyslipidaemia.

Objective. There is limited data on abdominal obesity and the influence of genetics on weight change after ant iretroviral therapy (ART) initiation. We assessed body mass index (BMI) and waist hip ration (WHR) change over time in the Swiss HIV Cohort study (SHCS)., Methods. Mixed-effects models characterizing BMI and WHR change over time in 1090 SHCS participants initiating ART between 2005 and 2015 were developed and used to quantify the influence of demographics, clinical factors, and genetic background., Results. Individuals with CD4 nadir = 200, and 2.8 times more WHR than individuals with >= 100 (P < .001) during the first 1.5 and 2.5 years after ART initiation, respectively. The risk of being overweight or obese after 1.5 years increased with CD4 nadir = 200 (OR, 1.69; 95% CI, 1.26-2.32), persisting after 10 years of ART. The risk of abdominal obesity after 2.5 years increased with CD4 nadir = 100 (OR, 1.35; 95% CI, 1.17-1.54 [in men]; OR, 1.36; 95% CI, 1.18-1.57 [in women]), persisting after 10 years of ART No significant differences were found across antiretroviral drug classes or genetic scores., Conclusions. The risk of general and abdominal obesity increased with CD4 nadir

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.

Pegylated interferon-alpha (pIFN-α) is suggested to lower human immunodeficiency virus type-1 (HIV-1) DNA load in antiretroviral therapy (ART)-treated patients. We studied kinetics of HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV) coinfected patients, treated with pIFN-α for HCV and categorized into 3 groups according to start of ART: chronic HIV-1 infection (n = 22), acute HIV-1 infection (n = 8), no-ART (n = 10). Total HIV-1 DNA levels in 247 peripheral blood mononuclear cell samples were stable before, during, and after pIFN-α treatment in all groups. Our results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 reservoir.

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as “per-parasite pathogenicity”. Using viral load and CD4+ T cell measures from 2014 HIV-1 subtype B infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence — measured as the rate of decline of CD4+ T cells — and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T cell decline is 17% (5%–30%), and that of the per-parasite pathogenicity is 17% (4%–29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12%–46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genetype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

Background Humanized mice (hu mice) are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research. However, data about their hematopoiesis over time are scarce. We therefore characterized leukocyte reconstitution in NSG mice, which were sublethally irradiated and transplanted with human cord blood-derived CD34+ cells at newborn age, longitudinally in peripheral blood and, for more detailed analyses, cross-sectionally in peripheral blood, spleen and bone marrow at different time points. Results Human cell chimerism and absolute human cell count decreased between week 16 and 24 in the peripheral blood of hu mice, but were stable thereafter as assessed up to 32 weeks. Human cell chimerism in spleen and bone marrow was maintained over time. Notably, human cell chimerism in peripheral blood and spleen as well as bone marrow positively correlated with each other. Percentage of B cells decreased between week 16 and 24, whereas percentage of T cells increased; subsequently, they levelled off with T cells clearly predominating at week 32. Natural killer cells, monocytes and plasmacytoid dendritic cells (DCs) as well as CD1c + and CD141+ myeloid DCs were all present in hu mice. Proliferative responses of splenic T cells to stimulation were preserved over time. Importantly, the percentage of more primitive hematopoietic stem cells (HSCs) in bone marrow was maintained over time. Conclusions Overall, leukocyte reconstitution was maintained up to 32 weeks post-transplantation in our hu NSG model, possibly explained by the maintenance of HSCs in the bone marrow. Notably, we observed great variation in multi-lineage hematopoietic reconstitution in hu mice that needs to be taken into account for the experimental design with hu mice. Electronic supplementary material The online version of this article (doi:10.1186/s12865-017-0209-9) contains supplementary material, which is available to authorized users.

Objective The impact of the M184V/I mutation on the virological failure (VF) rate in HIV-positive patients with suppressed viremia switching to an abacavir/lamivudine/dolutegravir regimen has been poorly evaluated. Method This is an observational study from 5 European HIV cohorts among treatment-experienced adults with ≤50 copies/mL of HIV-1 RNA who switched to abacavir/lamivudine/dolutegravir. Primary outcome was the time to first VF (2 consecutive HIV-1 RNA >50 copies/mL or single HIV-1 RNA >50 copies/mL accompanied by change in antiretroviral therapy [ART]). We also analyzed a composite outcome considering the presence of VF and/or virological blips. We report also the results of an inverse probability weighting analysis on a restricted population with a prior history of VF on any ART regimen to calculate statistics standardized to the disparate sampling population. Results We included 1626 patients (median follow-up, 288.5 days; interquartile range, 154–441). Patients with a genotypically documented M184V/I mutation (n = 137) had a lower CD4 nadir and a longer history of antiviral treatment. The incidence of VF was 29.8 cases (11.2–79.4) per 1000 person-years in those with a previously documented M184V/I, and 13.6 cases (8.4–21.8) in patients without documented M184V/I. Propensity score weighting in a restricted population (n = 580) showed that M184V/I was not associated with VF or the composite endpoint (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.35–4.59 and HR 1.66; 95% CI, 0.81–3.43, respectively). Conclusions In ART-experienced patients switching to an abacavir/lamivudine/dolutegravir treatment, we observed few VFs and found no evidence for an impact of previously-acquired M184V/I mutation on this outcome. Additional analyses are required to demonstrate whether these findings will remain robust during a longer follow-up., In antiretroviral therapy-experienced patients on abacavir/lamivudine/dolutegravir, we observed few virological failures and found no evidence for an impact of previously-acquired M184V/I mutation on this outcome. Additional analyses are required to demonstrate whether these findings will remain robust during a longer follow-up.

Background Better knowledge of the efficacy and safety of single-dose 40 mg/kg oral praziquantel in preschool-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group. Methodology We analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged, Author summary Schistosomiasis is a diseases caused by helminths (parasitic worms) which affects the intestinal and urogenital systems. In areas where schistosomiasis is endemic, the disease is controlled by the large scale distributing of praziquantel, primarily targeting school-age children. Younger children (preschool-age) too might be affected by schistosomiasis, but are currently not receiving praziquantel within treatment campaigns. Instead, preschool-age children are treated on a case-by-case basis because the current praziquantel formulation is not adapted to young children. Questions have also been raised as to whether the standard dose of 40 mg/kg given once is effective in preschool-age children. To answer this question, we collected individual-participant data from a series of studies in which 40 mg/kg of praziquantel had been given to children with intestinal or urinary schistosomiasis, and compared its efficacy and tolerability across age-groups. Since few direct comparisons had been made, we used statistical tools to make these comparisons. We found no evidence that treatment is less efficacious in preschool- than in school-age children and conclude that 40 mg/kg praziquantel may be given to preschool-age children in large-scale programs. When this happens, efficacy and tolerability will have to be closely monitored.

Background: Vascular graft infections (VGI) are difficult to diagnose and treat, and despite redo surgery combined with antimicrobial treatment, outcomes are often poor. VGI diagnosis is based on a combination of clinical, radiological, laboratory and microbiological criteria. However, as many of the VGI patients are already under antimicrobial treatment at the time of redo surgery, microbiological identification is often difficult and bacterial cultures often remain negative rendering targeted treatment impossible. We aimed to assess the benefit of 16S rRNA gene polymerase chain reaction (broad-range PCR) for better microbiological identification in patients with VGI. Methods: We prospectively analyzed the clinical, microbiological, and treatment data of patients enrolled in the observational Vascular Graft Cohort Study (VASGRA), University Hospital Zurich, Switzerland. The routine diagnostic work-up involved microbiological cultures of minced tissue samples, and the use of molecular techniques in parallel. Patient-related and microbiological data were assessed in descriptive analyses, and we calculated sensitivity, specificity, negative and positive predictive value for broad-range 16S rRNA gene PCR versus culture (considered as gold standard). Results: We investigated 60 patients (median age 66 years (Interquartile range [IQR] 59-75)) with confirmed VGI between May 2013 and July 2017. The prevalence of antimicrobial pretreatment at the time of sampling was high [91%; median days of antibiotics 7 days (IQR 1-18)]. We investigated 226 microbiological specimens. Thereof, 176 (78%) were culture-negative and 50 (22%) were culture-positive. There was a concordance of 70% (158/226) between conventional culture and broad-range PCR (sensitivity 58% (95% CI 43-72); specificity 74% (67-80%)). Among the group of 176 culture-negative specimens, 46 specimens were broad-range PCR-positive resulting in identification of overall 69 species. Among the culture and/or broad-range PCR-positive specimens (n = 96), 74 (77%) were monomicrobial and 22 (23%) polymicrobial, whereas the rate of polymicrobial samples was higher in broad-range PCR-positive specimens (93%). Conclusions: Combined cultures and broad-range 16S rRNA gene PCR from periprosthetic tissue and/or explanted vascular grafts increased the diagnostic accuracy in VGI, particularly in patients already under antimicrobial treatment at the time of redo surgery. Ideally, antimicrobial treatment should be withheld until surgical sampling in order to optimize microbiological diagnostics.Clinical trials.gov identifier: NCT01821664.

BACKGROUND Little is known about prevalence of drug resistance among HIV-infected Ugandans, a setting with over 15 years of public-sector access to antiretroviral therapy (ART) and where virological monitoring was only recently introduced. SETTING This study was conducted in the adults' out-patient clinic of the Infectious Diseases Institute, Kampala, Uganda. METHODS HIV genotyping was performed in ART naive patients and in treatment experienced patients on ART for ≥ six months with virological failure (≥1000 copies/mL). RESULTS A total of 152 ART naive and 2511 ART experienced patients were included. Transmitted drug resistance was detected in 9 (5.9%) patients. After a median time on ART of 4.7 years (interquartile range (IQR): 2.5-8.7), 190 patients (7.6%) had virological failure with a median viral load of 4.4 log10 copies/mL (IQR:3.9-4.9). Additionally, 146 patients had a viral load between 51 and 999 copies/ml. Most patients with virological failure (142, 74.7%) were on first-line ART. For 163 (85.8%) ART experienced patients genotype results were available. Relevant drug resistance mutations were observed in 135 (82.8%), of which 103 (63.2%) had resistance to two drug classes, and 11 (6.7%) had resistance to all drug classes available in Uganda. CONCLUSION The prevalence of transmitted drug resistance was lower than recently reported by the WHO. With 92% of all patients virologically suppressed on ART, the prevalence of virological failure was low when a cut-off of 1000 copies/mL is applied, and is in-line with the third of the 90-90-90 UNAIDS targets. However, most failing patients had developed multi-class drug resistance.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

The prognostic factors and outcome of 58 acquired immunodeficiency syndrome-related diffuse large B-cell lymphoma (AR-DLBCL) patients from the Swiss HIV Cohort Study, diagnosed from 2004 to 2011, were compared with those of 326 immunocompetent (IC)-DLBCL from the Hematology Division of the Amedeo Avogadro University (Italy) and the Oncology Institute of Southern Switzerland. Median follow-up was 6 years; 5-year overall survival (OS) was 68% (95% CI: 63%-73%) in IC-DLBCL and 63% (95% CI: 49%-75%) in AR-DLBCL (P = .220). The acquired immunodeficiency syndrome-related lymphoma international prognostic index predicted OS in AR-DLBCL. Among 148 patients younger than 61 years (40 AR-DLBCL and 108 IC-DLBCL) treated with RCHOP/RCHOP-like regimens, 20 IC-DLBCL and 9 AR-DLBCL patients died and OS was not significantly different. A higher proportion of early deaths occurred in the AR-DLBCL: indeed, 1-year OS was 94% (95% CI: 87%-97%) in IC-DLBCL and 82% (95% CI: 66%-91%) in AR-DLBCL patients. After rituximab and active antiretroviral therapy introduction, AR-DLBCL and IC-DLBCL patients treated with curative intent have similar long-term survival.

We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/μl and initiation with CD4 cell count less than 350 cells/μl.Cohort study based on routinely collected data from the HIV-CAUSAL collaboration.For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics.In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/μl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/μl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/μl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2).Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Drug resistant HIV is a major threat to the long-term efficacy of antiretroviral treatment. Around 10% of ART-naïve patients in Europe are infected with drug-resistant HIV type 1. Hence it is important to understand the dynamics of transmitted drug resistance evolution. Thanks to routinely performed drug resistance tests, HIV sequence data is increasingly available and can be used to reconstruct the phylogenetic relationship among viral lineages. In this study we employ a phylodynamic approach to quantify the fitness costs of major resistance mutations in the Swiss HIV cohort. The viral phylogeny reflects the transmission tree, which we model using stochastic birth–death-sampling processes with two types: hosts infected by a sensitive or resistant strain. This allows quantification of fitness cost as the ratio between transmission rates of hosts infected by drug resistant strains and transmission rates of hosts infected by drug sensitive strains. The resistance mutations 41L, 67N, 70R, 184V, 210W, 215D, 215S and 219Q (nRTI-related) and 103N, 108I, 138A, 181C, 190A (NNRTI-related) in the reverse trancriptase and the 90M mutation in the protease gene are included in this study. Among the considered resistance mutations, only the 90M mutation in the protease gene was found to have significantly higher fitness than the drug sensitive strains. The following mutations associated with resistance to reverse transcriptase inhibitors were found to be less fit than the sensitive strains: 67N, 70R, 184V, 219Q. The highest posterior density intervals of the transmission ratios for the remaining resistance mutations included in this study all included 1, suggesting that these mutations do not have a significant effect on viral transmissibility within the Swiss HIV cohort. These patterns are consistent with alternative measures of the fitness cost of resistance mutations. Overall, we have developed and validated a novel phylodynamic approach to estimate the transmission fitness cost of drug resistance mutations., Author summary The introduction of antiretroviral therapy (ART) has decreased mortality and morbidity rates among HIV-infected people, and improved their quality of life. In fact, the WHO states that antiretroviral therapy programmes averted an estimated 7.8 million deaths worldwide between 2000 and 2014. However, the antiretroviral regimen prescribed to a patient may be unable to control HIV infection. Factors that can contribute to treatment failure include drug resistance, drug toxicity, or poor treatment adherence. In this study we aim to understand the dynamics of transmitted drug resistance by analysing the viral sequence data that was collected for resistance testing. We present a novel approach to quantify how drug resistance impacts virus lineage transmissibility, how fast resistance mutations evolve in sensitive strains and how fast they revert back to the sensitive type. We apply our approach to the Swiss HIV cohort study, and obtain patterns of viral transmission fitness that are consistent with alternative, harder to obtain measures of fitness.

Cardiovascular diseases are the main cause of mortality and morbidity in Western countries, but the underlying mechanisms are still poorly understood. Genetic polymorphisms, once thought to represent a major determinant of cardiovascular risk, individually and collectively, only explain a tiny fraction of phenotypic variation and disease risk in humans. It is now clear that non-genetic factors, i.e., factors that modify gene activity without changing the DNA sequence and that are sensitive to the environment can cause important alterations of the cardiovascular phenotype in experimental animal models and humans. Here, we will review recent studies demonstrating that distinct pathological events during the perinatal (transient perinatal hypoxemia), late foetal (preeclampsia), and early embryonic (assisted reproductive technologies) periods induce profound alterations of the cardiovascular phenotype in humans and experimental animals. Moreover, we will provide evidence that epigenetic modifications are contributing importantly to this problem and are conferring the potential for its transmission to subsequent generations.

The aim of this study was to evaluate the clinical value of positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG-PET/CT) for therapy control in patients with prosthetic vascular graft infections (PVGI). Methods: In this single-centre, observational, prospective cohort study, 25 patients with a median age of 66 years (range: 48-81) were included who had a proven PVGI. Follow-up FDG-PET/CT was performed at a median time interval of 170 days (range: 89-249) after baseline examination. Two independent and blinded readers measured maximum standardized uptake values (SUV max.) to quantify metabolic activity and analysed whole body datasets for secondary diagnosis (i.e., infectious foci not within graft vicinity). The metabolic activity of the graft was correlated with clinical information and two laboratory markers (C-reactive protein (CRP) and white blood cell count (WBC)). Results: FDG-PET/CT had an impact on management in all patients. In 19 of 25 patients (76%) antibiotic treatment was continued due to the results of follow-up FDG-PET/CT. Antibiotic treatment was stopped or changed in 8% and 16% of patients, respectively. In eight patients (32%) additional incidental findings were detected on follow-up FDG-PET/CT which had further impact on patient management. Only in a subgroup of patients with PVGI and no other sites of infection, a significant correlation between the difference in CRP at the time of baseline and follow-up FDG-PET/CT and the difference in SUV max. was found (n = 11; r = 0.84; P = 0.001). Conclusion: FDG-PET/CT represents a useful tool in therapy monitoring of PVGI and impacts on patient management. By providing quantitative data on the course of the graft infection and whole body imaging data, PET/CT differentiates between response of therapy to PVGI and other infectious foci.

BACKGROUND: Ethnic differences have the potential to confound associations between HIV-1 subtype and immunologic progression. We compared declines in CD4 cell counts during untreated infection for the most prevalent HIV-1 subtypes, focusing on distinguishing between the effects of viral subtype and ethnicity. METHODS: We combined data from 4 European and 6 Canadian cohorts, selecting adults in the stable chronic phase of untreated HIV infection. We estimated the change in square root CD4 cell count over time for subtypes and ethnicities using mixed models, adjusting for covariates selected for their potential effect on initial CD4 cell count or its decline. RESULTS: Data from 9772 patients were analyzed, contributing 79 175 measurements of CD4 cell count and 24 157 person-years of follow-up. Overall, there were no appreciable differences in CD4 cell count decline for viral subtypes A, CRF01_AE, CRF02_AG, C and G compared with viral subtype B; whereas the decline in CD4 cell count in patients of African ancestry was considerably slower than in patients of other ethnicity. When ethnic groups were studied separately, there was evidence for slower declines in CD4 cell count in viral subtypes C, and possibly A and G, compared with viral subtype B in patients of African ancestry but not among patients of other ethnicities, suggesting an interaction between subtype and ethnicity. INTERPRETATION: Ethnicity is a major determinant of CD4 cell count decline; viral subtype differences may have existed but were small compared with the effect of ethnicity and were most apparent in patients of African ancestry. In developing countries, slower CD4 cell count declines among individuals of African descent may translate to a longer asymptomatic phase and increase the opportunity for HIV transmission.

Concern has been expressed that tenofovir-containing regimens may have reduced effectiveness in the treatment of human immunodeficiency virus type 1 (HIV-1) subtype C infections because of a propensity for these viruses to develop a key tenofovir-associated resistance mutation. We evaluated whether subtype influenced rates of virological failure in a cohort of 8746 patients from the United Kingdom who received a standard tenofovir-containing first-line regimen and were followed for a median of 3.3 years. In unadjusted analyses, the rate of failure was approximately 2-fold higher among patients infected with subtype C virus as compared to those with subtype B virus (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.50–2.31; P < .001). However, the increased risk was greatly attenuated in analyses adjusting for demographic and clinical factors (adjusted HR, 1.14; 95% CI, .83–1.58; P = .41). There were no differences between subtypes C and subtypes non-B and non-C in either univariate or multivariate analysis. These observations imply there is no intrinsic effect of viral subtype on the efficacy of tenofovir-containing regimens.

Background Knowledge of the risk factors of individuals with an asymptomatic sexually transmitted infection (STI) is essential for implementation of targeted STI screening strategies. Methods Between June 2015 and January 2017, an STI screening was offered to all participants in the Zurich Primary human immunodeficiency virus (HIV)-1 Infection study. Patients were tested for gonorrhea, chlamydia, syphilis, and hepatitis C virus (HCV). Results Of 214 participants, 174 (81%) were screened at least once. Most patients were men who have sex with men (MSM) (87.4%). Presenting with a primary HIV infection was associated with higher odds for later risky sexual behavior, as compared with presenting in the chronic phase (odds ratio [OR], 5.58; 95% confidence interval [CI], 3.68-8.8). In total, 79 STIs were detected, reflecting a high period prevalence of 33.3% (58 of 174 patients). Sixty-six percent of patients (52 of 79) were asymptomatic. Most common STIs were chlamydia (50.6%; 40 of 79 patients), gonorrhea (25.3%; 20 of 79), and syphilis (19%; 15 of 79). In a multivariable model, engaging in insertive (OR, 6.48; 95% CI, 1.14-36.76) or both insertive and receptive (4.61; 1.01-20.96) anal intercourse, STI symptoms (3.4; 1.68-6.89), and condomless sex (2.06; 1.14-3.74) were positively correlated with a positive screening result. The hazard of an incident STI increased with the presence of STI symptoms (hazard ratio, 3.03; 95% CI, 1.17-7.84) and any recent drug use (2.63; 1-6.9). Conclusions A trimonthly STI screening including asymptomatic individuals should be considered in this population, particularly in MSM who report sexual risk behavior. Clinical trial registration NCT 00537966.

Purpose This cross-sectional study took place in the integrated tuberculosis (TB) clinic of a large outpatient clinic for HIV-infected patients in Kampala, Uganda. The purpose of this study was to describe the proportion of TB/HIV co-infected adults with virological failure, type and frequency of HIV drug resistance-associated mutations, and the proportion of patients with suboptimal efavirenz levels. Methods HIV-1 plasma viral loads, CD4 cell count measurements, and efavirenz serum concentrations were done in TB/HIV co-infected adults. Genotypic resistance testing was performed in case of confirmed virological failure. Results After a median time on ART of 6 months, virological failure was found in 22/152 patients (14.5%). Of 147 participants with available efavirenz serum concentration, 26 (17.6%) had at least one value below the reference range, including 20/21 (95.2%) patients with confirmed virological failure. Genotypic resistance testing was available for 16/22 (72.7%) patients, of which 15 (93.8%) had at least one major mutation, most commonly M184V (81.2%) and K103NS (68.8%). Conclusion We found a high proportion of TB/HIV co-infected patients with virological failure, the majority of which had developed relevant resistance-mutations after a median time on anti-retroviral treatment (ART) of 6 months. Virological monitoring should be prioritized in TB/HIV co-infected patients in resource-limited settings.

Supplemental Digital Content is available in the text, After several years of steady decline, syphilis is reemerging globally as a public health hazard, especially among people living with human immunodeficiency virus (HIV). Syphilis resurgence is observed mainly in men who have sex with men (MSM), yet other transmission groups are affected too. In this manuscript, we study the factors associated with syphilis incidence in the Swiss HIV cohort study in the era of highly effective antiretrovirals. Using parametric interval censored models with fixed and time-varying covariates, we studied the immunological, behavioral, and treatment-related elements associated with syphilis incidence in 3 transmission groups: MSM, heterosexuals, and intravenous drug users. Syphilis incidence has been increasing annually since 2005, with up to 74 incident cases per 1000 person-years in 2013, with MSM being the population with the highest burden (92% of cases). While antiretroviral treatment (ART) in general did not affect syphilis incidence, nevirapine (NVP) was associated with a lower hazard of syphilis incidence (multivariable hazard ratio 0.5, 95% confidence interval 0.2–1.0). We observed that condomless sex and younger age were associated with higher syphilis incidence. Moreover, time-updated CD4, nadir CD4, and CD8 cell counts were not associated with syphilis incidence. Finally, testing frequency higher than the recommended once a year routine testing was associated with a 2-fold higher risk of acquiring syphilis. Condomless sex is the main driver of syphilis resurgence in the Swiss HIV Cohort study; ART and immune reconstitution provide no protection against syphilis. This entails targeted interventions and frequent screening of high-risk populations. There is no known effect of NVP on syphilis; therefore, further clinical, epidemiological, and microbiological investigation is necessary to validate our observation.

Background Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients. Objectives To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients. Methods TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations. Results Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) μg/mL, 7.39 (IQR 5.10-10.20) μg/mL, 7.00 (IQR 6.05-10.95) μg/mL and 3.86 (IQR 2.81-14.24) μg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P = 0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) μg/mL and those who did not 2.21 (1.45-3.11) μg/mL ( P = 0.49). Conclusions There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, and the riskfactors for hepatitis C virus (HCV) among HIV-coinfected and HIV negative men who have sex with men (MSM). A meta-analysis of 28 studies was carried out by pooling HCV incidence data of HIV-coinfected and HIV negative MSM. Differences in incidence outcome depending on the prospective or retrospective nature of the individual studies were investigated. The pooled incidence of HCV in MSM was 6.3 per 1000 person-years (95% CI 5.0–7.5). The overall estimated incidence was 19-fold higher in HIV positive compared to HIV negative MSM living in resource-rich countries. This result was confirmed when the analysis was restricted to high-quality studies. Factors associated with an increased risk for incident HCV included behavioural factors (sexual risk behaviour and recreational drug use) as well as biological characteristics (HIV coinfection and a recent history of syphilis). In conclusion, incident HCV predominantly affects HIV positive MSM. The incidence rate varied largely between studies, factors such as study design might play an important role.

BACKGROUND Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS We included 11 084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of ≥1 major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on the patient's risk of harboring drug-resistant viruses. RESULTS The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of 3-class resistance decreased from 9.0% to 4.4% and was always

Darunavir was designed for activity against HIV resistant to other protease inhibitors (PIs). We assessed the efficacy, tolerability and risk factors for virological failure of darunavir for treatment-experienced patients seen in clinical practice.

BACKGROUND: Raltegravir (RAL) achieved remarkable virologic suppression rates in randomized-clinical trials, but today efficacy data and factors for treatment failures in a routine clinical care setting are limited. METHODS: First, factors associated with a switch to RAL were identified with a logistic regression including patients from the Swiss HIV Cohort Study with a history of 3 class failure (n = 423). Second, predictors for virologic outcome were identified in an intent-to-treat analysis including all patients who received RAL. Last observation carried forward imputation was used to determine week 24 response rate (HIV-1 RNA >or= 50 copies/mL). RESULTS: The predominant factor associated with a switch to RAL in patients with suppressed baseline RNA was a regimen containing enfuvirtide [odds ratio 41.9 (95% confidence interval: 11.6-151.6)]. Efficacy analysis showed an overall response rate of 80.9% (152/188), whereas 71.8% (84/117) and 95.8% (68/71) showed viral suppression when stratified for detectable and undetectable RNA at baseline, respectively. Overall CD4 cell counts increased significantly by 42 cells/microL (P < 0.001). Characteristics of failures were a genotypic sensitivity score of the background regimen

Large-scale administration of anthelminthic drugs currently is the most widely used intervention for controlling morbidity due to schistosomiasis and soil-transmitted helminthiasis. An important issue is drug efficacy monitoring. However, the optimal time points post-treatment for assessing the efficacy of praziquantel against Schistosoma mansoni and albendazole against hookworm infections are not known. Forty-nine schoolchildren infected with S. mansoni and 52 infected with hookworm were treated with a single oral dose of praziquantel (40 mg/kg) and albendazole (400 mg), respectively. Stool samples were collected on 19 occasions over a 44-day post-treatment follow-up period, and two Kato-Katz thick smears per sample were examined at each time point. Both the mean egg counts and observed cure rates varied depending on the time point post-treatment. The highest reduction in the geometric mean egg counts (>97%) and the highest observed cure rate (>97%) of S. mansoni infections were found 15-20 days after praziquantel administration. Among the hookworm-infected children, egg counts decreased rapidly within the first week after albendazole administration (>95%), whereas infection rates showed high and heterogeneous (45.0-71.2%) levels at later time points. Both praziquantel and albendazole were highly efficacious in reducing the overall egg burden of S. mansoni and hookworm, respectively. We suggest that 15-20 days post-treatment is the most appropriate time point for efficacy evaluation of praziquantel against S. mansoni. Although no clear conclusion can be drawn for the optimal timing of efficacy evaluation of albendazole against hookworm, a 2-3-week time frame seems a reasonable compromise. This is justified on logistical grounds (i.e. collection of stool samples only once) and growing emphasis on integrating the control of schistosomiasis and soil-transmitted helminthiasis, including drug efficacy monitoring.

OBJECTIVES: Etravirine (ETV) is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with reduced cross-resistance to first-generation NNRTIs, which has been primarily studied in randomized clinical trials and not in routine clinical settings. METHODS: ETV resistance-associated mutations (RAMs) were investigated by analysing 6072 genotypic tests. The antiviral activity of ETV was predicted using different interpretation systems: International AIDS Society-USA (IAS-USA), Stanford, Rega and Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS). RESULTS: The prevalence of ETV RAMs was higher in NNRTI-exposed patients [44.9%, 95% confidence interval (CI) 41.0-48.9%] than in treatment-naive patients (9.6%, 95% CI 8.5-10.7%). ETV RAMs in treatment-naive patients mainly represent polymorphism, as prevalence estimates in genotypic tests for treatment-naive patients with documented recent (

WHAT THIS PAPER ADDS This study introduces a new visual grading score that improves the accuracy of FDG-PET/CT in the detection of prosthetic vascular graft infections (PVGIs). This will not only improve and speed up the diagnosis of PVGI but also allow for the monitoring of medical and surgical therapy thereof. Morbidity, mortality, and costs of treatment may significantly decrease in the near future because of the enhanced diagnostic accuracy and improved therapeutic management. Objective: The aim of this study was to evaluate the diagnostic accuracy of positron emission tomography/ computed tomography with 18 F-fludeoxyglucose (FDG-PET/CT) in a population with suspected graft infection and to validate a new diagnostic imaging score for FDG-PET/CT. Methods: This was a prospective cohort study. FDG-PET/CT was performed prospectively in 34 patients with suspected graft infection, in 12 of them before the start of antimicrobial treatment. Diagnostic accuracy was assessed using a new five point visual grading score and by using a binary score. Maximum standardized uptake values (SUVmax) were calculated for quantitative measurements of metabolic activity, and cut off points were calculated using the receiver operator curve (ROC). The standard of reference was a microbiological culture, obtained after open biopsy or graft explantation. Results: Using the new scale, FDG-PET/CT correctly recognized 27 patients with graft infection, one patient was diagnosed as false positive, six patients were correctly classified as true negative, and no patients were rated false negative. Hence, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FDG-PET/CT for the diagnosis of graft infections were 100%, 86%, 96%, 100%, and 97%, respectively. Using a previously established binary score, sensitivity, specificity, PPV, NPV, and accuracy were 96%, 86%, 96%, 86%, and 94% respectively. ROC analysis suggested an SUVmax cut off value of � 3.8 to differentiate between infected and non-infected grafts (p < .001). Additionally, FDG-PET/CT provided a conclusive clinical diagnosis in six of seven patients without graft infection (i.e., other sites of infections). Conclusions: The diagnostic accuracy of FDG-PET/CT in the detection of aortic graft infection is high. A newly introduced five point visual grading score and early imaging prior to antimicrobial treatment may further improve the diagnostic accuracy.

Background The control of schistosomiasis emphasizes preventive chemotherapy with praziquantel, which aims at decreasing infection intensity and thus morbidity in individuals, as well as transmission in communities. Standardizing methods to assess treatment efficacy is important to compare trial outcomes across settings, and to monitor program effectiveness consistently. We compared customary methods and looked at possible complementary approaches in order to derive suggestions for standardizing outcome measures. Methodology/Principal Findings We analyzed data from 24 studies conducted at African, Asian, and Latin American sites, enrolling overall 4,740 individuals infected with Schistosoma mansoni, S. haematobium, or S. japonicum, and treated with praziquantel at doses of 40–80 mg/kg. We found that group-based arithmetic and geometric means can be used interchangeably to express egg reduction rates (ERR) only if treatment efficacy is high (>95%). For lower levels of efficacy, ERR estimates are higher with geometric than arithmetic means. Using the distribution of individual responses in egg excretion, 6.3%, 1.7% and 4.3% of the subjects treated for S. haematobium, S. japonicum and S. mansoni infection, respectively, had no reduction in their egg counts (ERR = 0). The 5th, 10th, and 25th centiles of the subjects treated for S. haematobium had individual ERRs of 0%, 49.3%, and 96.5%; the corresponding values for S. japonicum were 75%, 99%, and 99%; and for S. mansoni 18.2%, 65.3%, and 99.8%. Using a single rather than quadruplicate Kato-Katz thick smear excluded 19% of S. mansoni-infected individuals. Whilst the effect on estimating ERR was negligible by individual studies, ERR estimates by arithmetic means were 8% lower with a single measurement. Conclusions/Significance Arithmetic mean calculations of Schistosoma ERR are more sensitive and therefore more appropriate to monitor drug performance than geometric means. However, neither are satisfactory to identify poor responders. Group-based response estimated by arithmetic mean and the distribution of individual ERRs are correlated, but the latter appears to be more apt to detect the presence and to quantitate the magnitude of suboptimal responses to praziquantel., Author Summary To identify whether a person is infected with parasitic worms, stool or urine samples are examined for worm eggs. The drug praziquantel is used against the parasitic disease schistosomiasis. However, there is no definitive agreement as to how the efficacy of praziquantel is best expressed. We put together a database from various studies of the efficacy of praziquantel against schistosomiasis. Efficacy was measured using customary methods: cure rate (CR: percentage of people with eggs in their stool/urine before treatment who became egg-negative after treatment); and egg reduction rate (ERR; percentage reduction in the number of eggs in the stool/urine after treatment, where the mean number of eggs from all people treated is calculated using either geometric or arithmetic means). We found that arithmetic and geometric means can be used interchangeably only if treatment efficacy is very high; arithmetic means are more sensitive to capture drops in efficacy expressed by ERR. A valid complement for drug efficacy monitoring is to study the distribution of individual responses in egg excretion that allows identifying in a single measure both those who had an adequate response to treatment and those who respond less well; e.g., the 5% of the patients with the lowest ERRs.

BACKGROUND: Transmitted human immunodeficiency virus type 1 (HIV) drug resistance (TDR) mutations are transmitted from nonresponding patients (defined as patients with no initial response to treatment and those with an initial response for whom treatment later failed) or from patients who are naive to treatment. Although the prevalence of drug resistance in patients who are not responding to treatment has declined in developed countries, the prevalence of TDR mutations has not. Mechanisms causing this paradox are poorly explored. METHODS: We included recently infected, treatment-naive patients with genotypic resistance tests performed ≤1 year after infection and before 2013. Potential risk factors for TDR mutations were analyzed using logistic regression. The association between the prevalence of TDR mutations and population viral load (PVL) among treated patients during 1997-2011 was estimated with Poisson regression for all TDR mutations and individually for the most frequent resistance mutations against each drug class (ie, M184V/L90M/K103N). RESULTS: We included 2421 recently infected, treatment-naive patients and 5399 patients with no response to treatment. The prevalence of TDR mutations fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in the prevalence of TDR mutations (odds ratio, 1.13; P = .010), punctuated by sharp decreases in the prevalence when new drug classes were introduced. Overall, the prevalence of TDR mutations increased with decreasing PVL (rate ratio [RR], 0.91 per 1000 decrease in PVL; P = .033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with the PVL of nonresponding patients carrying M184V (RR, 1.50 per 100 increase in PVL; P < .001). Such association was absent for K103N (RR, 1.00 per 100 increase in PVL; P = .99) and negative for L90M (RR, 0.75 per 100 increase in PVL; P = .022). CONCLUSIONS: Transmission of antiretroviral drug resistance is temporarily reduced by the introduction of new drug classes and driven by nonresponding and treatment-naive patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1 infection.

OBJECTIVE: The presence of minority nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 variants prior to antiretroviral therapy (ART) has been linked to virologic failure in treatment-naive patients. DESIGN: We performed a large retrospective study to determine the number of treatment failures that could have been prevented by implementing minority drug-resistant HIV-1 variant analyses in ART-naïve patients in whom no NNRTI resistance mutations were detected by routine resistance testing. METHODS: Of 1608 patients in the Swiss HIV Cohort Study, who have initiated first-line ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and one NNRTI before July 2008, 519 patients were eligible by means of HIV-1 subtype, viral load and sample availability. Key NNRTI drug resistance mutations K103N and Y181C were measured by allele-specific PCR in 208 of 519 randomly chosen patients. RESULTS: Minority K103N and Y181C drug resistance mutations were detected in five out of 190 (2.6%) and 10 out of 201 (5%) patients, respectively. Focusing on 183 patients for whom virologic success or failure could be examined, virologic failure occurred in seven out of 183 (3.8%) patients; minority K103N and/or Y181C variants were present prior to ART initiation in only two of those patients. The NNRTI-containing, first-line ART was effective in 10 patients with preexisting minority NNRTI-resistant HIV-1 variant. CONCLUSION: As revealed in settings of case-control studies, minority NNRTI-resistant HIV-1 variants can have an impact on ART. However, the sole implementation of minority NNRTI-resistant HIV-1 variant analysis in addition to genotypic resistance testing (GRT) cannot be recommended in routine clinical settings. Additional associated risk factors need to be discovered.