Biguanides and glucagon like peptide 1 receptor agonists in the amelioration of post liver transplant weight gain; a scoping review of the mechanism of action, safety and efficacy.

Weight gain post-liver transplant can lead to adverse patient outcomes in the post-transplant period. Pharmacotherapy and other measures can be utilised to reduce the burden and occurrence of weight gain in this population. We explored the mechanism of action, safety, and efficacy of these medications, specifically GLP-1 receptor agonists and metformin, focusing on liver transplant patients. This scoping review was conducted in line with the scoping review structure as outlined by the PRISMA guidelines. Metformin and GLP-1 receptor agonists have been observed to be safe and effective in liver transplant patients. Experimental models have found liver-centric weight loss mechanisms in this drug cohort. There is a paucity of evidence about the use of antihyperglycemics in a post-transplant population for weight loss purposes. However, some small studies have shown strong safety and efficacy data. The evidence in relation to using these medications in patients with metabolic syndrome for weight loss warrants further study in a transplant population.

Changes in myocardial blood flow in a canine model of left sided breast cancer radiotherapy.

BACKGROUND: Left-sided breast cancer patients receiving adjuvant radiotherapy are at risk for coronary artery disease, and/or radiation mediated effects on the microvasculature. Previously our laboratory demonstrated in canines with hybrid 18FDG/PET a progressive global inflammatory response during the initial one year following treatment. In this study, the objective is to evaluate corresponding changes in perfusion, in the same cohort, where resting myocardial blood flow (MBF) was quantitatively measured. METHOD: In five canines, Ammonia PET (13NH3) derived MBF was measured at baseline, 1-week, 1, 3, 6 and 12-months after cardiac external beam irradiation. MBF measurements were correlated with concurrent 18FDG uptake. Simultaneously MBF was measured using the dual bolus MRI method. RESULTS: MBF was significantly increased at all time points, in comparison to baseline, except at 3-months. This was seen globally throughout the entire myocardium independent of the coronary artery territories. MBF showed a modest significant correlation with 18FDG activity for the entire myocardium (r = 0.51, p = 0.005) including the LAD (r = 0.49, p = 0.008) and LCX (r = 0.47, p = 0.013) coronary artery territories. CONCLUSION: In this canine model of radiotherapy for left-sided breast cancer, resting MBF increases as early as 1-week and persists for up to one year except at 3-months. This pattern is similar to that of 18FDG uptake. A possible interpretation is that the increase in resting MBF is a response to myocardial inflammation.

Single and Multifraction Spine Stereotactic Body Radiation Therapy and the Risk of Radiation Induced Myelopathy.

Purpose: This study reports on the risk of radiation-induced myelitis (RM) of the spinal cord from a large single-institutional experience with 1 to 5 fraction stereotactic body radiation therapy (SBRT) to the spine. Methods and Materials: A retrospective review of patients who received spine SBRT to a radiation naïve level at or above the conus medullaris between 2007 and 2019 was performed. Local failure determination was based on SPIne response assessment in Neuro-Oncology criteria. RM was defined as neurologic symptoms consistent with the segment of cord irradiated in the absence of neoplastic disease recurrence and graded by Common Toxicity Criteria for Adverse Events, version 4.0. Rates of adverse events were estimated and dose-volume statistics from delivered treatment plans were extracted for the planning target volumes and spinal cord. Results: A total of 353 lesions in 277 patients were identified that met the specified criteria, for which 270, 70, and 13 lesions received 1-, 3-, and 5-fraction treatments, respectively, with a median follow-up of 46 months (95% confidence interval [CI], 41-52 months) for all surviving patients. The median overall survival was 33.0 months (95% CI, 29-43). The median D0.03cc to the spinal cord was 11.7 Gy (interquartile range [IQR], 10.5-12.4), 16.7 Gy (IQR, 12.8-20.6), and 26.0 Gy (IQR, 24.1-28.1), for 1-, 3-, 5-fractions. Using an a/b = 2Gy for the spinal cord, the median single-fraction equivalent-dose (SFED2) was 11.7 Gy (IQR, 10.2-12.5 Gy) and the normalized biological equivalent dose (nBED2/2) was 19.9 Gy (IQR, 15.4-22.8 Gy). One patient experienced grade 2 RM after a single-fraction treatment. The cumulative probability of RM was 0.3% (95% CI, 0%-2%). Conclusions: Spine SBRT is safe while limiting the spinal cord (as defined on treatment planning magnetic resonance imaging or computed tomography myelogram) D0.03cc to less than 14 Gy, 21.9 Gy, and 30 Gy, for 1, 3, and 5-fractions, consistent with standard guidelines.

Donor acquired visceral leishmaniasis following liver transplantation.

Patients who undergo solid organ transplantation are at risk of opportunistic infection associated with immunosuppression. We report a case of confirmed donor derived visceral leishmaniasis (VL), in a patient following liver transplantation causing fever and pancytopenia. The diagnosis was confirmed by bone marrow biopsy, with confirmed positive donor serology, with no other route of transmission. To our knowledge, this is the first case report in the United Kingdom and Europe, of confirmed organ donor transmission of VL. This case report highlights an important consideration of donor derived infections, in the context of solid organ transplantation.

Type 2 Autoimmune Hepatitis and Nonadherence to Medication Correlate With Premature Birth and Risk of Postpartum Flare.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Biliary Strictures Are Associated With Both Early and Late Hepatic Artery Stenosis.

BACKGROUND: Hepatic artery stenosis (HAS) following liver transplantation results in hypoperfusion and ischemic damage to the biliary tree. This study aimed to investigate how vascular intervention, liver function test derangement, and time point of HAS onset influence biliary complications. METHODS: A single-center retrospective study of adult patients that underwent primary liver transplantation. Patients were grouped according to the presence or absence of HAS and then into early (≤90 d) or late (>90 d) subgroups. Biliary complications comprised anastomotic (AS) or non ASs (NASs). RESULTS: Computed tomography angiography confirmed HAS was present in 39 of 1232 patients (3.2%). This occurred at ≤90 and >90 days in 20 (1.6%) and 19 (1.5%), respectively. The incidence of biliary strictures (BSs) in the group with HAS was higher than the group without (13/39; 33% versus 85/1193; 7.1%, P = 0.01). BS occurred in 8/20 (40.0%) and 5/19 (26.3%) of the early and late groups, respectively. The need for biliary intervention increased if any liver function test result was ≥3× upper limit of normal (P = 0.019). CONCLUSIONS: BS occurs at a significantly higher rate in the presence of HAS. Onset of HAS at ≤90 or ≥90 days can both be associated with morbidity. Significant liver function test derangement at HAS diagnosis indicates a higher likelihood of biliary intervention for strictures.

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment.

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.

Validating robotic couch isocentricity with 3D surface imaging.

BACKGROUND: A proton therapy system with 190° gantries uses robotic couch rotations to change the treatment beam laterality. Couch rotations are typically validated clinically with post-rotation radiographic imaging. AIMS: This study assesses the specificity and sensitivity of a commercial 3D surface imaging system, AlignRT (Vision RT, London UK) for validating couch rotations. MATERIALS & METHODS: In clinical operation, a reference surface image of the patient is acquired after radiographic setup with couch at 270°, perpendicular to the gantry axis of rotation. The couch is then rotated ±90° to a typical treatment angle, and AlignRT reports a 3D displacement vector. Patient motion, changes in patient surface, non-coincidence between AlignRT and couch isocenter, and mechanical couch run-out all contribute to the 3D vector magnitude. To assess AlignRT sensitivity in detecting couch run-out, volunteers were positioned orthogonal to the proton gantry and reference surface images were captured without x-ray localization. Subjects were repeatedly rotated ±90° to typical treatment angles and displacement vectors were recorded. Additionally, measurements were performed in which intentional translations of 2, 4, 6, and 8 mm were combined with the intended isocentric rotations. Data sets were collected using a phantom; subjects with a thoracic isocenter and no immobilization; and subjects with a cranial isocenter and thermoplastic immobilization. A total of 300 rotations were measured. RESULTS: During isocentric rotations, the mean AlignRT displacement vectors for the phantom, immobilized, and non-immobilized volunteers were 0.1 ± 0.1 mm, 0.8 ± 0.1 mm, and 1.1 ± 0.2 mm respectively. 95% of the AlignRT measurements for the immobilized and non-immobilized subjects were within 1 mm and 2 mm of the actual displacement respectively. DISCUSSION: After characterizing the accuracy using phantoms and volunteers, we have shown that a three-pod surface imaging system can be used to identify gross non-isocentric patient rotations. Significant positional deviations, either due to improper couch rotation or patient motion, should be followed by radiographic imaging and repositioning. CONCULSION: AlignRT can be used to verify patient positioning following couch rotations that are applied after the initial x-ray guided patient setup. Using a three-pod AlignRt system, positional deviations exceeding 4 mm were flagged with sensitivity and specificity of 90% and 100% respectively.

Sarcopenia in nonalcoholic fatty liver disease: new challenges for clinical practice.

Introduction: Sarcopenia is increasingly recognized in patients with nonalcoholic liver disease (NAFLD). Initially recognized as a consequence of advanced liver disease, there is now emerging evidence that sarcopenia may be a novel risk factor for the development of NAFLD, with a role in fibrosis and disease progression.Areas covered: This review examines the epidemiology, pathogenesis, and complex interplay between NAFLD and sarcopenia. Furthermore, the authors discuss the challenges with diagnosis of sarcopenia in the clinic and the evidence-based management of sarcopenia in patients with NAFLD. A MEDLINE and PubMed search was undertaken using the terms; 'sarcopenia,' 'frailty,' 'muscle,' 'obesity,' 'non-alcoholic fatty liver disease,' 'non-alcoholic steatohepatitis', and 'cirrhosis' up to 31 September 2019.Expert opinion: Sarcopenia may be masked by the co-existence of morbid obesity, which is most notable in patients with NAFLD. Sarcopenia is a key indicator of adverse outcomes in patients with cirrhosis, such as hepatic decompensation, poor quality of life and premature mortality. Patients with NAFLD and advanced fibrosis/cirrhosis should undergo anthropometric measures (handgrip strength), dry body mass index, and measures of physical frailty (including muscle function, not just mass) to enable targeted early interventions of nutrition (low fat, 1.5 g/kg/day protein intake, 2-3 hourly food intake) and exercise (combined resistance and aerobic).

Peculiarities of Cirrhosis due to Nonalcoholic Steatohepatitis (NASH).

The prevalence of cirrhosis due to nonalcoholic steatohepatitis (NASH) has increased 2.5-fold in the United States in the last decade. These patients pose new challenges to hepatologists given their older age and higher frequency of coexisting metabolic diseases such as obesity and diabetes compared with other etiologies of liver disease. Patients with NASH cirrhosis are at higher risk for renal and cardiovascular disease, and the presence of these extrahepatic comorbidities has a significant impact on outcomes and survival. This review outlines how NASH cirrhosis differs from other etiologies of cirrhosis including natural history, noninvasive assessment, and the challenges in the management of the complications of cirrhosis including hepatic encephalopathy and hepatocellular carcinoma. Nutritional assessment and the impact of sarcopenic obesity and frailty in this population, and strategies to address the latter, are discussed. This review also addresses liver transplantation in patients with NASH cirrhosis in relation to assessment and posttransplant care.

[18F]FDG cardiac PET imaging in a canine model of radiation-induced cardiovascular disease associated with breast cancer radiotherapy.

Radiotherapy for the treatment of left-sided breast cancer increases the long-term risk of cardiovascular disease. The purpose of the present study was to noninvasively image the progression of radiation-induced cardiac inflammation in a large animal model using a hybrid PET and MRI system. Five canines were imaged using [18F]fluorodeoxyglucose PET to assess changes in myocardial inflammation. All animals were imaged at baseline, 1 wk, and 1, 3, 6, and 12 mo after focused cardiac external beam irradiation with image guidance. Radiation was delivered in a single fraction. The linear quadratic model was used to convert a typical multifractionated heart dose to a corrected single-fraction biologically equivalent dose. Immunohistochemistry was performed on excised left ventricular tissue samples from all five irradiated canines and one nonirradiated control canine to confirm the presence of inflammation. The mean doses delivered to the entire heart, left ventricle, left anterior descending artery, and left circumflex artery were 1.7 ± 0.2, 2.7 ± 0.2, 5.5 ± 0.9, and 1.1 ± 0.4 Gy, respectively. FDG standard uptake values remained persistently elevated compared with baseline (1.1 ± 0.03 vs. 2.6 ± 0.19, P < 0.05). The presence of myocardial inflammation was confirmed histologically and correlated with myocardial dose. This study suggests a global inflammatory response that is persistent up to 12 mo postirradiation. Inflammation PET imaging should be considered in future clinical studies to monitor the early changes in cardiac function that may play a role in the ultimate development of radiation-induced cardiac toxicity. NEW & NOTEWORTHY Using advanced cardiac PET imaging, we have shown the spatial and quantitative relationship between radiation dose deposition and temporal changes in inflammation. We have shown that the progression of radiation-induced cardiac inflammation is immediate and does not subside for up to 1 yr after radiation. Results are presented in a large animal model that closely resembles the size and vessel architecture of humans. The proposed imaging protocol can be easily replicated for clinical use.

The Observed Effect of Gastric Bypass Surgery on Direct-acting Antiviral Treatment: a Case Report.

Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (Ctrough) was determined. The simeprevir area under the-concentration time curve (AUClast) and Ctrough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and Ctrough was 0.532 mg/L. Sofosbuvir AUClast and Ctrough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUClast and Ctrough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment.

Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection.

BACKGROUND & AIMS: Treatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy. METHODS: We performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A. RESULTS: The presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m2 were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the "BE3A score." For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7). CONCLUSIONS: We identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis.

Spontaneous Hepatitis B Seroclearance upon Development of Hepatocellular Carcinoma.

The spontaneous seroclearance of hepatitis B upon development of a hepatocellular carcinoma (HCC) is extremely rare. To date, there has been one published case series reporting hepatitis B seroconversion following HCC resection. We describe two novel cases of spontaneous hepatitis B seroclearance following the development of HCC, prior to resection. Following resection, specimens were HBsAg- and HBcAg-negative in both tumor and peritumor tissues. Although the precise mechanism of this is poorly understood, nonuniform integration of hepatitis B virus DNA within the liver could lead to selective tumorigenesis of HBsAg-producing cells, explaining the observed clearance of serum HBsAg with the development of HCC.

Challenges in treating patients with inflammatory bowel disease and concurrent viral hepatitis infection.

INTRODUCTION: Inflammatory bowel diseases (IBD) require long-term administration of immunomodulatory treatments to maintain disease remission. Due to the high worldwide prevalence of hepatitis B (HBV) or C (HCV) virus infections, presence of concurrent hepatitis can be a relevant clinical issue to manage when treating IBD. Areas covered: The paper summarizes epidemiological data about IBD and HBV/HCV infection and reviews current knowledge about the natural history of HBV and HCV in the IBD setting, concentrating on risk of hepatitis reactivation during immunosuppressive treatment. Most updated recommendations for management of HBV and HCV infections in IBD patients are discussed. Expert commentary: The development of new drugs for IBD with different molecular targets and the availability of potent and efficacious antiviral drugs for HBV and HCV will simplify management of hepatitis infection in IBD patients in the near future.

Comprehensive dosimetric planning comparison for early-stage, non-small cell lung cancer with SABR: fixed-beam IMRT versus VMAT versus TomoTherapy.

Volumetric-modulated arc therapy (VMAT) is emerging as a leading technology in treating early-stage, non-small cell lung cancer (NSCLC) with stereotactic ablative radiotherapy (SABR). However, two other modalities capable of deliver-ing intensity-modulated radiation therapy (IMRT) include fixed-beam and helical TomoTherapy (HT). This study aims to provide an extensive dosimetric compari-son among these various IMRT techniques for treating early-stage NSCLC with SABR. Ten early-stage NSCLC patients were retrospectively optimized using three fixed-beam techniques via nine to eleven beams (high and low modulation step-and-shoot (SS), and sliding window (SW)), two VMAT techniques via two partial arcs (SmartArc (SA) and RapidArc (RA)), and three HT techniques via three different fan beam widths (1 cm, 2.5 cm, and 5 cm) for 80 plans total. Fixed-beam and VMAT plans were generated using flattening filter-free beams. SS and SA, HT treatment plans, and SW and RA were optimized using Pinnacle v9.1, Tomoplan v.3.1.1, and Eclipse (Acuros XB v11.3 algorithm), respectively. Dose-volume histogram statistics, dose conformality, and treatment delivery efficiency were analyzed. VMAT treatment plans achieved significantly lower values for contralat-eral lung V5Gy (p ≤ 0.05) compared to the HT plans, and significantly lower mean lung dose (p < 0.006) compared to HT 5 cm treatment plans. In the comparison between the VMAT techniques, a significant reduction in the total monitor units (p = 0.05) was found in the SA plans, while a significant decrease was observed in the dose falloff parameter, D2cm, (p = 0.05), for the RA treatments. The maximum cord dose was significantly reduced (p = 0.017) in grouped RA&SA plans com-pared to SS. Estimated treatment time was significantly higher for HT and fixed-beam plans compared to RA&SA (p < 0.001). Although, a significant difference was not observed in the RA vs. SA (p = 0.393). RA&SA outperformed HT in all parameters measured. Despite an increase in dose to the heart and bronchus, this study demonstrates that VMAT is dosimetrically advantageous in treating early-stage NSCLC with SABR compared to fixed-beam, while providing significantly shorter treatment times.

Assessment of Intrafraction Breathing Motion on Left Anterior Descending Artery Dose During Left-Sided Breast Radiation Therapy.

PURPOSE: To use 4-dimensional computed tomography (4D-CT) imaging to predict the level of uncertainty in cardiac dose estimates of the left anterior descending artery that arises due to breathing motion during radiation therapy for left-sided breast cancer. METHODS AND MATERIALS: The fast helical CT (FH-CT) and 4D-CT of 30 left-sided breast cancer patients were retrospectively analyzed. Treatment plans were created on the FH-CT. The original treatment plan was then superimposed onto all 10 phases of the 4D-CT to quantify the dosimetric impact of respiratory motion through 4D dose accumulation (4D-dose). Dose-volume histograms for the heart, left ventricle (LV), and left anterior descending (LAD) artery obtained from the FH-CT were compared with those obtained from the 4D-dose. RESULTS: The 95% confidence interval of 4D-dose and FH-CT differences in mean dose estimates for the heart, LV, and LAD were ±0.5 Gy, ±1.0 Gy, and ±8.7 Gy, respectively. CONCLUSION: Fast helical CT is a good approximation for doses to the heart and LV; however, dose estimates for the LAD are susceptible to uncertainties that arise due to intrafraction breathing motion that cannot be ascertained without the additional information obtained from 4D-CT and dose accumulation. For future clinical studies, we suggest the use of 4D-CT-derived dose-volume histograms for estimating the dose to the LAD.

Key drug-drug interactions with direct-acting antiviral in HIV-HCV coinfection.

PURPOSE OF REVIEW: We reviewed the most recent data on pharmacokinetic interactions between hepatitis C direct-acting antiviral (DAA) agents and HIV antiretrovirals (ARVs). RECENT FINDINGS: Drug interactions between DAAs and HIV ARVs are extrapolated from phase 1 drug-drug interaction (DDI) studies in healthy volunteers. Safety and efficacy data of DAA-ARV combinations are largely limited to the drug combinations permitted in phase 2 and 3 HIV-HCV coinfection trials. Paritapervir/ritonavir with ombitasvir and dasabuvir (3D) should not be coadministered with efavirenz, etravirine, elvitegravir/cobicistat or with additional doses of ritonavir. Atazanavir, darunavir and rilpivirine require cautious monitoring when used with 3D. The combination of sofosbuvir and ledipasvir can be safely used with most ARVs, but there is a risk of hyperbilirubinaemia with atazanavir. Tenofovir exposure is significantly increased when used with sofosbuvir-ledipasvir and a boosted protease inhibitor or emtricitabine/efavirenz, and therefore should be used with cautious monitoring for renal toxicity only when alternative therapy is not possible. Daclatasvir requires dosage modification with atazanavir, efavirenz and cobicistat. The coadministration of simeprevir with efavirenz, etravirine or ritonavir-boosted and cobicistat-boosted regimens is not recommended. SUMMARY: The safety and efficacy of HCV therapy in HIV-HCV coinfection is now comparable with HCV monoinfection, but drug interactions need to be carefully considered before instituting therapy to minimize potential harm. Real-world data are required to further assess the clinical implications of some DDIs.

Drug interactions between antiretrovirals and new or emerging direct-acting antivirals in HIV/hepatitis C virus coinfection.

PURPOSE OF REVIEW: We reviewed the pharmacokinetic interactions between direct-acting antivirals against hepatitis C virus (HCV) and antiretroviral agents. RECENT FINDINGS: Most relevant pharmacokinetic studies involve healthy individuals and refer to the already licensed HCV protease inhibitors, boceprevir and telaprevir. Data from a phase II clinical trial question the clinical relevance of the interactions between boceprevir and HIV protease inhibitors. The use of a higher dose of telaprevir appears to offset the effect of efavirenz on telaprevir metabolism according to another phase II trial. Boceprevir and particularly telaprevir substantially increase the exposure to maraviroc, similarly to other potent CYP3A4 inhibitors. Different dosages of faldaprevir and daclatasvir have been recommended to be used in combination with a boosted HIV protease inhibitor vs. an efavirenz-based antiretroviral regimen. HIV protease inhibitors appear to substantially increase the exposure to simeprevir. The interactions between sofosbuvir and most antiretroviral agents do not appear to be of clinical relevance or to require dosage modifications. SUMMARY: The drug-drug interaction studies for HCV direct-acting antivirals and antiretrovirals are important in determining the appropriate drug combinations and dosages. The clinical implications of these interactions need further assessment in different categories of patients, including those with cirrhosis.