N Müller

Chronic Norovirus Infection after Kidney Transplantation: Molecular Evidence for Immune-Driven Viral Evolution

BACKGROUND Norovirus infection is the most common cause of acute self-limiting gastroenteritis. Only 3 cases of chronic norovirus infection in adult solid organ transplant recipients have been reported thus far. METHODS This case series describes 9 consecutive kidney allograft recipients with chronic norovirus infection with persistent virus shedding and intermittent diarrhea for a duration of 97-898 days. The follow-up includes clinical course, type of immunosuppression, and polymerase chain reaction for norovirus. Detailed molecular analyses of virus isolates from stool specimens over time were performed. RESULTS The intensity of immunosuppression correlated with the diarrheal symptoms but not with viral shedding. Molecular analysis of virus strains from each patient revealed infection with different variants of GII.4 strains in 7 of 9 patients. Another 2 patients were infected with either the GII.7 or GII.17 strain. No molecular evidence for nosocomial transmission in our outpatient clinic was found. Capsid sequence alignments from follow-up specimens of 4 patients showed accumulation of mutations over time, resulting in amino acid changes predominantly in the P2 and P1-2 region. Up to 25 amino acids mutations were accumulated over a 683-day period in the patient with an 898-day shedding history. CONCLUSION Norovirus infection may persist in adult renal allograft recipients with or without clinical symptoms. No evidence for nosocomial transmission in adult renal allograft recipients was found in our study. Molecular analysis suggests continuous viral evolution in immunocompromised patients who are unable to clear this infection.

Obesity Trends and Body Mass Index Changes After Starting Antiretroviral Treatment: The Swiss HIV Cohort Study.

Increasing obesity rates in Swiss HIV+ persons may partially be due to aging, demographic changes and earlier ART start. Most BMI increase occurred in year 1 of ART. The effect of individual ART regimens was limited.

Hemolytic Uremic Syndrome in Prostatic Carcinoma

Background: Disseminated intravascular coagulation is a well-known complication of adenocarcinoma of the prostate, while hemolytic uremic syndrome (HUS) is not. Case Report: We describe the unusual case of a 61-year-old patient with adenocarcinoma of the prostate. Prior to any systemic therapy he developed hemolytic uremic syndrome (HUS) necessitating dialysis. Renal function has fully recovered and he is alive and well 7 years later. Conclusion: HUS is a rare complication of adenocarcinoma of the prostate and has a far better prognosis than chemotherapy-associated HUS.

Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals

OBJECTIVES Co-formulated elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line ART. A population approach was used to characterize the pharmacokinetics of elvitegravir and cobicistat and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between the two compounds. METHODS The study population included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively. First, distinct NONMEM(®) analyses were conducted for elvitegravir and cobicistat, including individual demographic, clinical and genetic factors as potential covariates. Elvitegravir and cobicistat interaction was then assessed through different inhibitory models. Simulations based on the final model served to compare expected drug concentrations under standard and alternative dosage regimens. RESULTS Clearance with between-subject variability was 7.6 L/h [coefficient of variation (CV) 16.6%] and volume of distribution 61 L for elvitegravir and 16.0 L/h (CV 41.9%) and 88.3 L, respectively, for cobicistat. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%, likely due to UDP-glucuronosyl transferase (UGT) 1A1 inhibition. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. The final interaction model included cobicistat exposure (AUC0-24) on elvitegravir clearance. Simulations confirmed that a reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produces a concentration-time course comparable to the standard regimen without atazanavir. CONCLUSIONS Elvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice. In these cases, therapeutic drug monitoring and surveillance for potential toxicities would be justified.

Torque Teno Virus Load and Acute Rejection After Orthotopic Liver Transplantation

decreases from 2.5% of total body weight in young people to about 1.6% in the nonagenarian population, and several morphological changes with aging indicate that the liver cells in advanced old age are in a hyperfunctioning state, possibly trying to compensate for the decline in total cell number. However, it has been suggested that aging has a limited effect on liver functions but more on its response to extrahepatic factors, disease states or increased metabolic demands to which elderly people may have an impaired ability to respond. Atheromatosis usually affects the celiac trunk in old donors but, although this happens rarely, when atheroma occurs distally at the level of the right hepatic artery or at the bifurcation of the gastroduodenal and the common hepatic artery, the liver graft must be discarded for LT. The LT procedure is a scenario in which many donor risk factors may be involved. Thus, in our previous brief communication on octogenarian liver donors, we recommended the use of liver grafts with no age limit but in good preprocurement condition (hemodynamic stability, low doses of vasopressor drugs), short intensive care unit stay, good liver function tests, soft liver consistency, absence of hepatic artery atheromatosis, cold ischemia time less than 9 hours, and macrosteatosis less than 30%. From that time, we have continued applying the same criteria, but in recent years we have added other conditions such as implanting

High Rates of Subsequent Asymptomatic Sexually Transmitted Infections and Risky Sexual Behavior in Patients Initially Presenting With Primary Human Immunodeficiency Virus-1 Infection

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.

Adhesive durability of bone cements containing gentamicin or gentamicin/clindamycin-based antibiotics on titanium used for oral implants

Abstract This study investigated the durability of adhesion of bone cements containing antibiotics to titanium. Titanium plates (15 mm × 15 mm × 1 mm) (N = 80, n = 10 per group) were obtained representing oral implants. Half of the titanium plates were air-abraded (30 μm CoJet) (distance: 10 mm; pressure: 2.8 bar; duration: 15 s/cm2) and silanized. They were then randomly divided into two subgroups and chemically polymerized bone cements containing either (a) gentamicin (Refobacin Bone Cement R, Biomet) (GT) or (b) gentamicin/clindamycin (Refobacin Bone Cement Revision, Biomet) (GTC) were bonded to the substrates. Half of the specimens were kept dry and the other half were thermocycled (5–55 °C, 6000 cycles). Shear force was applied to the adhesive interface until failure occurred (0.5 mm/min). Failure types were categorized considering the amount of cement on the substrate. Data (MPa) were analysed using one-, three-way ANOVAs and K-N-S tests (α = 0.05). Two-parameter Weibull modulus, scale (m) and shape (0) were calculated. Surface conditioning (p < 0.01) and ageing (p < 0.01) significantly affected the results, but bone cement did not (p > 0.05). In dry conditions, GT (without: 19.5 ± 2, with: 31.6 ± 1) showed higher bond strength than that of GTC (without: 14.1 ± 1.6, with: 20.4 ± 2.9) (p < 0.01). Thermocycling significantly increased the results for both cements without (GT: 50 ± 3; GTC: 48.6 ± 5.6) and with air-abrasion (GT: 74 ± 1.6; GTC: 76.1 ± 2.4) (p < 0.01). Weibull distribution presented the highest shape (0) for GT (Dry: 12.65; Thermocyled: 17.22). Failure types were predominantly Type 2 (46/80) (Mixed, cement remnants <¼ left on the substrate). Bone cements containing gentamicin may adhere to titanium surface more reliable but both cements benefited from air abrasion and silanization.

Inferring the age difference in HIV transmission pairs by applying phylogenetic methods on the HIV transmission network of the Swiss HIV Cohort Study

Abstract Age-mixing patterns are of key importance for understanding the dynamics of human immunodeficiency virus (HIV)-epidemics and target public health interventions. We use the densely sampled Swiss HIV Cohort Study (SHCS) resistance database to study the age difference at infection in HIV transmission pairs using phylogenetic methods. In addition, we investigate whether the mean age difference of pairs in the phylogenetic tree is influenced by sampling as well as by additional distance thresholds for including pairs. HIV-1 pol-sequences of 11,922 SHCS patients and approximately 240,000 Los Alamos background sequences were used to build a phylogenetic tree. Using this tree, 100 per cent down to 1 per cent of the tips were sampled repeatedly to generate pruned trees (N = 500 for each sample proportion), of which pairs of SHCS patients were extracted. The mean of the absolute age differences of the pairs, measured as the absolute difference of the birth years, was analyzed with respect to this sample proportion and a distance criterion for inclusion of the pairs. In addition, the transmission groups men having sex with men (MSM), intravenous drug users (IDU), and heterosexuals (HET) were analyzed separately. Considering the tree with all 11,922 SHCS patients, 2,991 pairs could be extracted, with 954 (31.9 per cent) MSM-pairs, 635 (21.2 per cent) HET-pairs, 414 (13.8 per cent) IDU-pairs, and 352 (11.8 per cent) HET/IDU-pairs. For all transmission groups, the age difference at infection was significantly (P < 0.001) smaller for pairs in the tree compared with randomly assigned pairs, meaning that patients of similar age are more likely to be pairs. The mean age difference in the phylogenetic analysis, using a fixed distance of 0.05, was 9.2, 9.0, 7.3 and 5.6 years for MSM-, HET-, HET/IDU-, and IDU-pairs, respectively. Decreasing the cophenetic distance threshold from 0.05 to 0.01 significantly decreased the mean age difference. Similarly, repeated sampling of 100 per cent down to 1 per cent of the tips revealed an increased age difference at lower sample proportions. HIV-transmission is age-assortative, but the age difference of transmission pairs detected by phylogenetic analyses depends on both sampling proportion and distance criterion. The mean age difference decreases when using more conservative distance thresholds, implying an underestimation of age-assortativity when using liberal distance criteria. Similarly, overestimation of the mean age difference occurs for pairs from sparsely sampled trees, as it is often the case in sub-Saharan Africa.

No Effect of Pegylated Interferon-α on Total HIV-1 DNA Load in HIV-1/HCV Coinfected Patients

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.

Impact of Direct-Acting Antivirals on the Burden of HCV Infection Among Persons Who Inject Drugs and Men Who Have Sex With Men in the Swiss HIV Cohort Study

Abstract In the Swiss HIV Cohort Study, the number of people who inject drugs with replicating hepatitis C virus (HCV) infection decreased substantially after the introduction of direct-acting antivirals (DAAs). Among men who have sex with men, the increase in DAA uptake and efficacy was counterbalanced by frequent incident HCV infections.