Switching tenofovir disoproxil fumarate to tenofovir alafenamide in a real life setting: what are the implications?

OBJECTIVES: Development of novel antiretrovirals aims at reducing long-term toxicities. Tenofovir disoproxil fumarate (TDF) has been associated with potential nephrotoxicity. The aim of our study was to assess the impact of switching from TDF to tenofovir alafenamide (TAF) on functional nephropathy and lipid parameters in a real-life setting. METHODS: We retrospectively analysed data from 347 HIV-infected patients switching from a TDF- to a TAF-containing regimen between April and December 2016. Sociodemographic, clinical and laboratory data were collected at TDF-to-TAF switch, and at 3 and 6 months thereafter. Proteinuria and albuminuria were classified according to Kidney Diseases Improving Global Outcomes (KDIGO) guidelines. RESULTS: At time of switch, moderately and severely increased proteinuria was detected in 32% and 8% of patients, respectively; however, urine dipstick analysis was negative in 84% and 42%, respectively. Moderately and severely increased albuminuria was found in 17% and 3% of patients, respectively. In patients with a urinary protein-to-creatinine ratio (UPCR) ≥ 150 mg/g, the mean value declined from 416 mg/g at baseline to 272 mg/g (P < 0.001) and 242 mg/g (P < 0.001) after 3 and 6 months, respectively. Patients with an albumin-to-creatinine ratio (UACR) ≥ 30 mg/g showed no significant decrease of albuminuria. Mean total cholesterol increased from 187 mg/dL at baseline to 202 (P < 0.001) and 208 mg/dL (P < 0.001) at 3 and 6 months, respectively, and mean low-density lipoprotein (LDL) cholesterol increased from 114 mg/dL at baseline to 124 (P < 0.001) and 128 mg/dL (P < 0.001), respectively. As mean high-density lipoprotein (HDL) cholesterol increased from 50 mg/dL at baseline to 54 (P < 0.001) and 57 mg/dL (P < 0.001) at 3 and 6 months, respectively, the LDL:HDL ratio remained stable. CONCLUSIONS: In an aging HIV-infected cohort, proteinuria and albuminuria were common findings and were underdiagnosed via urine dipstick. Our real-life data suggest that laboratory markers of moderately/severely increased proteinuria improved after TDF-to-TAF-switch. Lipid profiles were not aggravated. Long-term follow-up is needed to determine the clinical benefit of the TDF-to-TAF switch.

[Modern treatment of primary biliary cholangitis]. / Moderne Therapie der primär biliären Cholangitis.

For nearly 30 years ursodeoxycholic acid (UDCA) represented the only pharmacological treatment option available for primary biliary cholangitis (PBC). This changed at the end of 2016 when obeticholic acid was licensed in Europe for PBC patients not responding to UDCA. Novel treatment concepts involving the modulation of nuclear receptor signaling in cholestatic and other liver diseases have led to a host of new potential options, studies and drug candidates for the treatment of PBC. The analysis of large multinational cohorts has additionally confirmed the effectiveness of UDCA in slowing PBC progression, and has led to the development of new definitions for the risk assessment of PBC patients under therapy, which will be an asset for clinical decision making. One issue that remains unresolved is the therapeutic management of extrahepatic symptoms associated with PBC, namely fatigue and pruritus, which are the main factors influencing the quality of life of affected individuals. Their pathophysiological basis is poorly understood and treatment remains unsatisfactory.

A Step-by-Step Clinical Approach for the Management of Neuroendocrine Tumours.

Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut-NETs in terms of therapy.

Measles, mumps, rubella and VZV: importance of serological testing of vaccine-preventable diseases in young adults living with HIV in Germany.

Measles, mumps, rubella (MMR) and varicella zoster virus (VZV) infection can cause serious diseases and complications in the HIV-positive population. Due to successful vaccination programmes measles, mumps and congenital rubella syndrome has become neglected in Germany. However, recent outbreaks of measles have occurred from import-associated cases. In this cross-sectional study the serostatus for MMR and VZV in 2013 HIV-positive adults from three different university outpatient clinics in Bonn (n = 544), Cologne (n = 995) and Munich (n = 474) was analysed. Sera were tested for MMR- and VZV-specific immunglobulin G antibodies using commercial immunoassays. Seronegativity was found in 3% for measles, 26% for mumps, 11% for rubella and 2% for VZV. Regarding MMR, 35% of patients lacked seropositivity against at least one infectious agent. In multivariable analysis younger age was strongly associated with seronegativity against all four viruses, measles, mumps, rubella (P < 0·001, P < 0·001 and P = 0·001, respectively) and VZV (P = 0·001). In conclusion, there is high need for MMR and VZV vaccination in people living with HIV in Germany born in 1970 or later. Thus, systematic MMR and VZV antibody screening and vaccination should be implemented in the HIV-positive population to prevent serious disease and complications of vaccine-preventable diseases.

[Recent thrombosis of splanchnic veins : Two case reports of catheter-assisted local thrombolysis and thrombus aspiration]. / Frische venöse Thrombose splanchnischer Gefäße : Zwei Fallberichte zur kathetergestützten lokalen Thrombolyse und -aspiration.

Recent non-cirrhotic and non-malignant splanchnic vein thrombosis is now defined as extrahepatic portal vein thrombosis with or without involvement of the mesenteric vein according to the Baveno VI consensus from 2015. An early diagnosis is often challenging due to unspecific symptoms with abdominal pain or diarrhea but extremely important because of the potential acute and chronic complications, such as mesenteric ischemia and portal hypertension; therefore, rapid treatment is crucial. We present two cases of severe splanchnic vein thrombosis, which were treated with catheter-directed local thrombolysis and thrombus aspiration. These minimally invasive catheter-directed techniques have recently been successfully used in selected patients. A review of the literature is provided in this article. In summary, the management of splanchnic vein thrombosis must be individually planned for each patient and should be performed at experienced centers, which can provide all therapeutic options. In selected cases with the correct indications transjugular transhepatic catheter-directed local thrombolysis is a safe option with a good outcome.

[A 59-year-old woman with upper abdominal pain and fever]. / 59-jährige Patientin mit Oberbauchschmerzen und Fieber.

A 59-year-old woman suffered from fever and upper abdominal pain. The computed tomography (CT) scan revealed a liver lesion. Conventional imaging techniques (CT, magnetic resonance imaging, contrast-enhanced ultrasonography) did not allow for a consistent diagnosis. Fine needle biopsy of the liver lesion was performed. Histologically, fibrotic inflammation was found and an inflammatory pseudotumor (IPT) diagnosed. Despite treatment with steroids and antibiotics, the size of the IPT increased; thus, surgical resection was necessary. In case of fever of unknown origin, IPT should be considered as a potential diagnosis.

Cyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells.

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2α-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis.

Non-invasive fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient presenting with hypertensive disorder post interventionem.

Fecal microbiota transplantation has gathered much attention due to its high efficacy in resolving recurrent Clostridium difficile infection. Until today, it is recognized as a safe procedure without any severe side effects. Patients with impaired conscious states suffering from recurrent episodes of aspiration are at increased risk by endoscopic interventions needed during standard approaches for fecal microbiota transplantation application.Here, we illustrate the case of a tetraplegic patient undergoing fecal microbiota transplantation due to his fifth recurrent episode of Clostridium difficile infection using a self-advancing nasal jejunal feeding tube as effective minimal-invasive option of fecal microbiota transplantation application. Persistent aggravation of arterial hypertension, which developed post-intervention in this patient, could be interpreted as a hitherto unknown side effect of fecal microbiota transplantation in this setting. Moreover, this is a further hint for a link between the intestinal microbiome and arterial hypertension in general.

[Expert recommendations: Hepatitis C and transplantation]. / Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation.

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.

[Allocation systems in transplantation medicine: Advantages and disadvantages]. / Allokationssysteme in der Transplantationsmedizin: Vor- und Nachteile.

Donor organs for transplantations are a scarce commodity; therefore, allocation systems are needed that guarantee an ethically acceptable distribution to patients on the waiting list (equal treatment and fairness) but also take the probability of survival of the transplant in each recipient into consideration. In this article the allocation systems for lung, liver, kidney and pancreas transplants are presented.For lung transplantations an allocation system based on the lung allocation score (LAS) is currently used. The LAS predicts the probability of survival on the waiting list and the survival rate following transplantation. Organs with a limited range of utilization are distributed in a so-called mini-match procedure.For post-mortem kidney and pancreas transplantations a relatively complex but transparent allocation system has been created in which patients are subdivided into groups, each of which has its own allocation rules. The allocation is principally carried out according to criteria of fairness of distribution and according to the prospects of success. The probability of a mismatch also plays a role. The urgency is important for children and for patients who do not have the possibility of dialysis. Combined pancreas and kidney transplantations have priority over kidney transplantations alone.The criterion for the urgency of liver transplantation in Germany is currently the model for end-stage liver disease (MELD), which aims to reduce the waiting list mortality and to prioritize transplantations for those most in need. Because the system insufficiently describes the priority of transplantation for patients with tumors or genetic liver diseases, there is an additional set of rules for so-called standard exceptions.

Pulmonary hypertension in HIV infection: a prospective echocardiographic study.

OBJECTIVES: While idiopathic pulmonary arterial hypertension (PAH) is a rare disease, it is seen more frequently in patients with HIV infection. The aim of this study was to evaluate the prevalence of pulmonary hypertension (PH) in patients with HIV infection by echocardiographic screening. METHODS: Echocardiography and N-terminal of the prohormone brain natriuretic peptide measurement were used to examine the prevalence of PH prospectively in HIV-positive patients (n = 374) during routine follow-up visits for HIV disease. RESULTS: In echocardiographic screening, PH was detected in a total of 23 of 374 HIV-infected patients (6.1%). Of these, three patients (13%) presented with symptoms of dyspnoea and fatigue, and diagnosis of PAH was confirmed by right heart catheterization. Patients with systolic pulmonary artery pressure (sPAP) > 30 mmHg were more likely to be female, to have a history of injecting drug use and to originate from high-prevalence countries (HPCs). CONCLUSIONS: Echocardiographic screening detected PH in a substantial proportion of HIV-positive patients. Female gender, a history of injecting drug use and HPC origin were associated with a higher prevalence of HIV-associated PH. The relevance and long-term outcome of these findings need to be validated in follow-up studies, which are ongoing.

Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS.

BACKGROUND AND AIMS: Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS). METHODS: We analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2 weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated. RESULTS: Circulating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients. CONCLUSION: This study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.

Peginterferon-alfa mono-therapy in the treatment of acute hepatitis C in HIV-infection.

The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co-infected individuals. Cohort study of 105 HIV-infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN-alfa alone (group 1; n = 36) or pegIFN-alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV-RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm(3) . Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5-36 weeks after diagnosis (P = 0.03). PegIFN-alfa alone or in combination with ribavirin results in similar response rates in HIV-infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono-therapy might be sufficient to allow for an optimal treatment response.

Spontaneous bacterial peritonitis by Pasteurella multocida under treatment with rifaximin.

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis. Recently, rifaximin, a non-absorbable antibiotic which is used to prevent recurrent hepatic encephalopathy, has been proposed as effective prophylaxis for SBP. Here, we present an unusual case of SBP under treatment with rifaximin. A 50-year-old woman with liver cirrhosis was admitted because of tense ascites and abdominal pain. She was under long-term oral prophylaxis with rifaximin due to hepatic encephalopathy. Paracentesis revealed SBP caused by Pasteurella multocida, which was sensitive to multiple antibiotics, including rifaximin. Treatment with ceftriaxone resulted in rapid resolution of the peritonitis and restoration of the patient. Since P. multocida is usually transmitted from pets, the patient's cat was tested and could be identified as the most likely source of infection. This case should elicit our awareness that uncommon pathogens and unusual routes of transmission may lead to SBP, despite antibacterial prophylaxis with non-absorbable antibiotics. Nevertheless, such infections may still remain sensitive to systemic therapy with conventional antibiotics.

Triamcinolone and ritonavir leading to drug-induced Cushing syndrome and adrenal suppression: description of a new case and review of the literature.

The protease inhibitor (PI) ritonavir is a potent inhibitor of cytochrome P450 (CYP) 3A4 activity and frequently prescribed to boost the effectiveness of other PIs as part of highly active antiretroviral therapy. It is well established that ritonavir is capable of inducing iatrogenic Cushing syndrome (ICS) through a drug-drug interaction with inhaled fluticasone that leads to the inhibition of CYP3A activity. A rapidly increasing number of case reports are being published describing ICS induced by the interaction of ritonavir and injected corticosteroids, namely triamcinolone acetonide. A review of the current literature identified 15 cases (including the one reported here) of ICS and suppression of the hypothalamic-pituitary-adrenal axis after periradicular injection of triamcinolone acetonide. Considering an aging human immunodeficiency virus (HIV)-infected population an increasing number of patients will present with degenerative musculoskeletal disease and be seeking pain relief. Based on data reported in the literature and our own experience triamcinolone injections during ritonavir-based therapy should be avoided. After failure of all conservative therapeutic options methylprednisolone may represent a therapeutic alternative for steroid injections in HIV patients receiving PI-based antiviral therapy since it has to date not been associated with ICS.

[Secondary sclerosing cholangitis following liver transplantation: a rare cause for graft failure]. / Sekundär sklerosierende Cholangitis nach Lebertransplantation: Eine seltene Ursache für ein Transplantatversagen.

We report on a 25-year-old female patient who presented with recurrent cholestasis following liver transplantation due to primary sclerosing cholangitis. Abdominal ultrasound and computed tomography showed intrahepatic bile duct dilatation and stenosis of the common hepatic artery with flow acceleration and decreased resistance index. The patient developed a severe secondary sclerosing cholangitis (SSC) with biliary casts - despite interventional stent placement of the common hepatic artery - thus requiring retransplantation. After prolonged intensive care unit treatment the patient was discharged in a good general condition. This case report describes SSC as a rare cause for graft failure. In unclear cholestasis after liver transplantation SSC has to be considered as the underlying cause.

Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases.

BACKGROUND: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases. METHODS: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. RESULTS: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. CONCLUSIONS: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

Renal comorbidity after solid organ and stem cell transplantation.

After transplantation of solid organs or hematopoietic stem cells, a significant acute decrease in renal function occurs in the majority of patients. Depending on the degree of kidney injury, a large number of patients develop chronic kidney disease (CKD) and some develop end-stage renal disease requiring renal replacement therapy. The incidence varies depending on the transplanted organ, but important risk factors for the development of CKD are preexisting renal disease, hepatitis C, diabetes, hypertension, age, sex, posttransplant acute kidney injury and thrombotic microangiopathy. This review article focuses on the risk factors of posttransplant chronic kidney disease after organ transplantation, considering the current literature and integrates the incidence and the associated mortality rates of acute and chronic kidney disease. Furthermore, we introduce the RECAST (REnal Comorbidity After Solid organ and hematopoietic stem cell Transplantation) registry.

Secondary sclerosing cholangitis in critically ill patients: model of end-stage liver disease score and renal function predict outcome.

Secondary sclerosing cholangitis in critically ill patients (SSC - CIP) is an underdiagnosed emerging disease. The aim of this study was to characterize clinical features and prognostic factors for mortality in SSC - CIP. This retrospective study included 54 patients who were diagnosed via endoscopic retrograde cholangiopancreatography (ERCP) after cardiothoracic surgery (n = 21), sepsis (n = 13), polytrauma (n = 11), and others (n = 9). In total, 33 patients who either died (n = 27) or needed liver transplantation (n = 6) were compared with surviving patients (n = 21). The model for end-stage liver disease (MELD) score and need for renal replacement therapy were independent risk factors for mortality. Compared with ERCP, accuracy was 30% for ultrasound and 36 % for liver biopsies. As a result of microbiological bile analysis, 28 % of patients required a change in antibiotic treatment. SSC - CIP is frequently a fatal disease. ERCP should be considered in selected patients to establish the diagnosis and hence provide useful clinical information.