The use of drotrecogin alfa (activated) in solid organ transplant patients: a case series

Background. Drotrecogin alfa (activated) (DAA), a recombinant human activated protein C, is indicated for the reduction of mortality in patients with severe sepsis who have a high risk of death. In the initial trial, DAA demonstrated a significant reduction in mortality at 28 days for patients treated with DAA in comparison with standard supportive treatment (placebo). However, solid organ transplant recipients were excluded from the study. Transplant recipients are at an increased risk for sepsis and there is minimal literature describing the safety and efficacy of DAA in the transplant population.
Methods. Thirteen solid organ transplant recipients who received DAA between November 2001 and January 2004 were included in this case series. Patients were prospectively identified and data collection occurred concurrently and by retrospective chart review. All patients met the DAA use criteria based on the institutional standard protocol.
Results. We report the outcomes of the 13 adult transplant patients who received a total of 14 courses of DAA for severe sepsis. At the time of DAA initiation, all patients required mechanical ventilation, 86% necessitated vasopressor support, and had a median of 3 dysfunctional organs. The median Acute Physiology and Chronic Health Evaluation (APACHE) II score at initiation was 30. Overall, hemodynamic stability and APACHE II score improved at the end of DAA infusion. Causes of early discontinuation were bleeding (57%), scheduled procedure (14%), increased international normalized ratio (14%), and death (14%). In-hospital, 28-day, and 1-year mortality was 69%, 62%, and 83%, respectively.
Conclusion. DAA appears to be safe with appropriate monitoring. However, transplant recipients had a higher incidence of bleeding events leading to early discontinuation of DAA. Efficacy is difficult to assess without an appropriate control group for comparison.     

Bilateral pleural effusion and pulmonary edema caused by a fistulous aneurysm of the ductus arteriosus

We report an unusual case of pulmonary edema and rapid collection of bilateral pleural effusion caused by a fistulous large aneurysm of the ductus arteriosus (DAA). The diagnosis was performed by contrast CT and aortography. The cause of pulmonary edema and effusion was thought to be both elevated capillary pressure due to overload of the pulmonary circulation and decreased water clearance due to compression of the lymphatic system by the large DAA itself. Therefore, fistulous DAA should be considered when a continuous heart murmur and swelling in the aortic window are recognized. Once DAA is diagnosed, surgery should be performed without delay.     

Ductal Arteriosus Aneurysm,Right Aortic Arch,and Isolated Left Subclavian Artery in a Neonate

Ductal arteriosus aneurysm (DAA) is a well‐recognized condition, especially in infancy, and is usually asymptomatic. We report the first case of a newborn who presented with significant inspiratory stridor and, using multiple imaging investigations, was subsequently diagnosed with the rare constellation of a congenital DAA, a right aortic arch and an isolated left subclavian artery with normal intra‐cardiac anatomy. The patient underwent surgical resection of the DAA with significant improvement in symptoms.     

A Case Report of Alloimmune Hepatitis after Direct-acting Antiviral Treatment in a Liver Transplant Patient

Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.     

Isolated ductus arteriosus aneurysm in the fetus and infant: a multi-institutional experience

OBJECTIVES: The purpose of this study was to describe the clinical characteristics and outcome and to elucidate the pathogenesis of ductus arteriosus aneurysm (DAA). BACKGROUND: Ductus arteriosus aneurysm is a rare lesion that can be associated with severe complications including thromboembolism, rupture and death. METHOD: We reviewed the clinical records, diagnostic imaging studies and available histology of 24 cases of DAA, diagnosed postnatally (PD) in 15 and antenatally (AD) in 9 encountered in five institutions. RESULTS: Of PD cases, 13 presented at <2 months, and all AD cases were detected incidentally after 33 weeks of gestation during a late trimester fetal ultrasound study. Of the 24, only 4 had DAA-related symptoms and 6 had associated syndromes: Marfan, Smith-Lemli-Opitz, trisomies 21 and 13 and one possible Ehlers-Danlos. Three had complications related to the DAA: thrombus extension into the pulmonary artery, spontaneous rupture, and asymptomatic cerebral infarction. Six underwent uncomplicated DAA resection for ductal patency, DAA size or extension of thrombus. In the four examined, there was histologic evidence of reduced intimal cushions in two and abnormal elastin expression in two. Five of the 24 died, with only one death due to DAA. Of 19 survivors, all but one remain clinically asymptomatic at a median follow-up of 35 months; however, two have developed other cardiac lesions that suggest Marfan syndrome. A review of 200 consecutive third trimester fetal ultrasounds suggests an incidence of DAA of 1.5%. CONCLUSIONS: Ductus arteriosus aneurysm likely develops in the third trimester perhaps due to abnormal intimal cushion formation or elastin expression. Although it can be associated with syndromes and severe complications, many affected infants have a benign course. Given the potential for development of other cardiac lesions associated with connective tissue disease, follow-up is warranted.     

High rates of unprotected anal sex and use of generic direct‐acting antivirals in a cohort of MSM with acute HCV infection

The role of condomless anal intercourse (CAI) as a driver for the epidemic of hepatitis C in MSM is still debated. Timely access to direct‐acting antivirals (DAA) could represent an essential strategy to tackle this. Case notes of MSM diagnosed with acute hepatitis C (AHC) between July 2016 and June 2017 in a sexual health clinic in London were included. Behavioural data on sexual practices and STI monitoring in the 6 months prior to AHC diagnosis were collected. DAA routes of access and timing from AHC diagnosis to start of treatment were analysed. A total of 60 individuals were enrolled (median age 39 years, IQR = 33‐46, 62% HIV co‐infected, 72% genotype 1a). CAI was reported by 97%, drug use prior to or during sex by 73%; 46% was diagnosed with a rectal STI and 29% with syphilis. About 37% did not report any HCV risk factors other than condomless anal sex. About 36% had a new rectal STI in the 6 months following AHC. About 82% accessed DAA treatment and median time from AHC to DAA start was 278 days for those following the NHS standard of care route, 132 days for those accessing DAA via participation in trials and 114 for those who had self‐sourced DAA online (P < 0.0011). SVR12 was achieved in 100% of the patients who received DAA treatment.In conclusion, CAI is a significant risk factor for HCV acquisition in MSM, irrespective of their HIV status. Rapid and wider access to treatment with DAA could represent a powerful strategy to reduce onward transmission and risk of reinfection in MSM.     

Initial clinical experience of real-time three-dimensional echocardiography in neonates with isolated congenital ductus arteriosus aneurysm

BACKGROUND: Congenital ductus arteriosus aneurysm (DAA) was considered rare but potentially fatal abnormality, often followed by surgical intervention after careful evaluation. This prospective study used real-time three-dimensional echocardiography (RT3DE) to assist in evaluation of neonatal DAA. METHODS: A total of 1390 full-term neonates were enrolled in this study between 2002 and 2003. They received two-dimensional echocardiographic (2DE) screening and periodic follow-up. RT3DE was performed selectively for newborns with DAA. RESULTS: DAA were detected in 116 (8.34%) newborns using 2DE. Maximum diameter of the DAAs ranged from 6.8 to 14.0 mm (8.2+/-1.1 mm). None of the cases were symptomatic or had complications related to DAA. There were no significant differences in sex and gestational age between the newborns with and without DAA. Neonates with DAA had a higher birth body weight and a higher incidence of large-for-gestational-age (P<0.05). RT3DE provided instant, consistent and reliable 3D images of DAA and its related structures and allowed for more rapid examination times and reduction of baby wait times. CONCLUSIONS: Congenital DAA is as common as has been previously reported. RT3DE is useful in assisting evaluation of DAA. Preferred images of DAA were typically visualized in the high parasternal short-axis view before the third day of life. Routine use of RT3DE is suggested to enhance assessment of neonates with DAA detected by 2DE.     

Clinical outcome of treatment with a combined regimen of decitabine and aclacinomycin/cytarabine for patients with refractory acute myeloid leukemia

We conducted a clinical trial of low-dose decitabine plus aclacinomycin/cytarabine (AA) treatment (DAA) for 20 patients with refractory/relapsed de novo acute myeloid leukemia (AML) or AML transformed from myelodysplastic syndrome (MDS/AML) in order to examine its efficacy and tolerability. Additionally, P15^ink4b methylation status was analyzed (for 15 patients) pre- and post-DAA treatment, and in vitro drug sensitivity tests were performed for seven patients (AA or AA?+?decitabine) to explore the role of decitabine in this combination treatment regimen. A total of 11 patients (55.0?%) achieved complete remission (CR) after DAA treatment, including 7 of whom reached CR after only one treatment course. The other two patients achieved partial remission. The median overall survival (OS) was 10?months for all 20 patients. The median OS for those who achieved CR was significantly longer than that of patients with no response (NR; P?=?0.01). The treatment regimen was well tolerated, and there was no treatment-related mortality. The mean levels of P15^ink4b methylation decreased significantly in six patients who achieved CR, whereas very few changes in P15 ^ink4b methylation were detected for the five patients with NR following DAA treatment. The data from the methyl thiazolyl tetrazolium assays showed that the inhibition rates of AA and DAA for tumor cells were identical. We conclude that induction therapy with DAA for refractory/relapsed de novo AML or MDS/AML achieved high levels of CR and improved OS and demonstrated adequate tolerance. Moreover, the decitabine component of DAA may function through a demethylation effect.     

Neonatal Systemic Thromboembolism Secondary to Ductus Arteriosus Aneurysm and Patent Foramen Ovale

Ductus arteriosus aneurysm (DAA) can be associated with neonatal thromboembolism. We report a neonate with systemic thromboembolism causing acute cerebral infarction with DAA, arterial, and venous thrombosis, discovered on CT angiography. The role of DAA was suspected as a potential etiology of systemic thromboembolism in this case. CT angiography with three‐dimensional reconstruction was valuable delineating the adjunctive vascular structures. Screening for presence of DAA may be considered in the neonatal thromboembolism.     

Isolated neonatal ductus arteriosus aneurysm.

OBJECTIVE: A prospective study was performed to evaluate the incidence, clinical manifestations and outcome of ductus arteriosus aneurysm (DAA) in full-term neonates. BACKGROUND: Ductus arteriosus aneurysm has been considered to be a rare congenital lesion and a potentially fatal abnormality. METHODS: A total of 548 full-term neonates received echocardiographic screening. RESULTS: There were 48 (8.8%) patients (28 boys and 20 girls) with DAA detected by echocardiography. The maximal diameter of the DAA ranged from 6.5 to 11.2 mm (8.2 +/- 1.2 mm). All cases were asymptomatic. There were no significant differences in gender, gestational age, maternal age or Apgar score between the newborns with or without DAA. Newborns with DAA had a higher birth body weight, higher incidence of maternal gestational diabetes mellitus and more mothers with blood group A, compared with newborns without DAA (p < 0.05). Follow-up echocardiograms showed spontaneous closure of the ductus arteriosus in all patients except those without DAA. The DAA became progressively smaller after ductal closure in 33 patients (70.2%) and completely disappeared by 7 to 35 days of life. The other 14 patients (29.8%) with DAA had echocardiographic evidence of progressive formation of thrombi between the third and tenth day of life. The DAA and thrombi spontaneously disappeared in all patients by one month after birth. CONCLUSIONS: There is a higher incidence of DAA with a good outcome in our series compared with previous reports. We speculate that the presence of DAA may be a normal variant of the ductal bump and part of a normal process of spontaneous ductal closure in full-term neonates.     

The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C‐infected patients treated with direct‐acting antivirals with and without pegylated interferon: A Belgian experience

Recently, concerns were raised of high rates of HCC recurrence in patients treated with direct‐acting antivirals (DAA) for hepatitis C infection. We investigated the HCC occurrence and recurrence rates within 6 months after treatment with DAA with or without pegylated interferon (PEG‐IFN) in real life. This is a retrospective, multicenter cohort trial, executed in 15 hospitals distributed across Belgium. Populations were matched based on fibrosis score (Metavir F3‐F4). Patients with a Child‐Pugh score ≥ B were excluded. In total, 567 patients were included, of whom 77 were treated with PEG‐IFN+DAA between 2008 and 2013 and 490 with DAA without PEG‐IFN between 2013 and 2015. Patients treated with PEG‐IFN+DAA (53±9y) were younger than patients treated with DAA without PEG‐IFN (59±12y) (P=.001). 47% of patients treated with PEG‐IFN+DAA were in the F4 stage vs 67% of patients treated with DAA without PEG‐IFN (P=.001). Screening was inadequate in 20% of both patient groups (P=.664). The early occurrence rate of HCC was 1.7% and 1.1% in patients treated with DAA with and without PEG‐IFN, respectively (P=.540). The early recurrence rate was 0% in patients treated with PEG‐IFN+DAA and 15.0% in patients treated with DAA without PEG‐IFN (P=.857). There is no difference in early occurrence of new HCC between patients treated with DAA with and without PEG‐IFN. We did observe a high early recurrence rate of HCC in patients treated with DAA without PEG‐IFN. However, these patients were at baseline more at risk for HCC. Finally, in 20%, screening for HCC was inadequate.     

A case of acute hepatitis B in a chronic hepatitis C patient after daclatasvir and asunaprevir combination therapy: hepatitis B virus reactivation or acute self-limited hepatitis?

Reactivation of hepatitis B virus (HBV) in HBV surface antigen (HBsAg)-positive patients treated with cytotoxic chemotherapy is well known. HBV reactivation in patients with HBV and hepatitis C virus (HCV) coinfection caused by direct-acting antiviral (DAA) therapy has also recently been reported. We report a case of acute hepatitis B in a patient with HCV infection after DAA therapy. An 83-year-old woman was referred for chronic hepatitis C. She was infected with HCV genotype 1b and negative for HBsAg at baseline. She received daclatasvir and asunaprevir therapy, and HCV became negative at 4 weeks and remained negative until 6 months after the end of DAA therapy. Acute hepatitis B developed 5 months after ending DAA therapy. Genome sequencing revealed the subgenotype as B1, and the serological subtype as adr. T118 K mutation at the S region as an immune escape mutant was identified. These virologic features led to HBV reactivation. The presence of hepatitis B core antibody or HBs antibody was not determined before DAA therapy, so prior HBV infection status was unclear. This case is speculated to represent HBV reactivation in a patient with previously resolved HBV induced by DAA therapy, based on virologic analysis and clinical status. The risk might be very low, but DAA therapy can cause HBV reactivation in chronic hepatitis C patients with prior HBV infection. When acute hepatitis emerges in patients who have received DAA therapy for HCV, HBV reactivation should be considered to allow early initiation of anti-HBV therapy.     

Prevalence of HCV resistance‐associated substitutions among treatment‐failure patients receiving direct‐acting antiviral agents

Direct‐acting antiviral (DAA) failure, which is mainly associated with the selection of resistance‐associated substitutions (RASs), is not rare in HCV treatment. RAS data collected from published literature and RAS prevalence were integrated using meta‐analysis. DAA‐failure‐associated RASs were identified by comparing their prevalence between DAA‐failure and DAA‐naïve patients. Prevalences of emerging RASs that occurred during treatment were also estimated. A total of 2932 DAA‐naïve patients and 1466 DAA‐failure patients were included. Significant differences in the prevalence of RASs were found in 76 scenarios that involved 34 RASs (11 in NS3, 18 in NS5A and 5 in NS5B), 4 genotypes (GTs) (GT1a, GT1b and GT3‐4) and 14 DAAs (6 NS3 protease inhibitors [PIs], 6 NS5A inhibitors and 2 NS5B inhibitors). For NS3, the DAA‐failure‐associated RASs included V36L, Y56H, Q80K/R, R155K, A156T and D168A/E/L/T/V/Y. Substitutions at R155 and D168 were dominant for most NS3 PIs. For NS5A, DAA‐failure‐associated RASs included K24R, Q30R, L31M, and P32L in GT1a; R30Q/H, L31F/I/M/V, P58S, and Y93H in GT1b; A30K, L31M and Y93H in GT3; and M31V and Y93H in GT4. Y93H was the most prevalent RAS for NS5A inhibitors. DAA‐failure‐associated RASs were found at only five positions in NS5B. The majority of DAA‐failure patients relapsed. A significant difference was detected for only four RAS sites between relapse patients and nonresponse/breakthrough patients. The RAS prevalence in DAA‐failure patients varied among the HCV GTs and DAA regimens. The identified treatment‐selected resistance patterns for broadly used DAA regimens will enable the selection of optimized retreatment options.     

Risk factors for liver-related and non-liver-related mortality following a sustained virological response after direct-acting antiviral treatment for hepatitis C virus infection in a real-world cohort

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84–2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m² (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m² at baseline (p = .012; HR, 3.407) and albumin–bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.     

Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate

Purpose of Review

This review examines the issues in determining the decision to treat a HCV-positive patient who is a liver transplant (LT) candidate with highly effective and well-tolerated direct-acting antiviral (DAA) therapies.

Recent Findings

Cure of HCV with DAA can improve liver function and allow delisting in some patients. Beyond a threshold of hepatic impairment (likely MELD score >?16 to 20), patients may experience a decline in MELD score with HCV cure without improvement in liver-related complications resulting in decreased opportunity to receive a LT. Eradicating HCV from patients who need LT regardless also deprives them of the option of receiving HCV-positive donor organs. Patients with MELD >?16 or Child-Pugh B/C may also have reduced cure rates of HCV, increased risk of hepatic decompensation, and adverse events with DAA pre-LT compared to post-LT DAA therapy. Preliminary data demonstrates increase risk of hepatocellular carcinoma (HCC) recurrence after treatment with DAA with subsequent studies raising doubts about this association.

Summary

Patients with HCV cirrhosis on the LT waiting list with MELD score >?16, CTP-B/C, and HCC are best treated after LT with better response, tolerability, and the ability to receive organs from a larger donor pool that includes HCV-positive donors. Larger, prospective studies are needed to assess whether increased HCC recurrence after DAA is a true effect.

     

Hepatocellular carcinoma risk assessment by the measurement of liver stiffness variations in HCV cirrhotics treated with direct acting antivirals

BackgroundDirect-acting antivirals (DAA) are an effective treatment for hepatitis C virus infection. However, sustained virologic response (SVR) after DAA treatment does not seem to reduce the risk of hepatocellular carcinoma (HCC) development in these patients. Liver stiffness measurement (LSM) may predict the risk of developing HCC in liver cirrhosis patients.AimsThe aim of our study was to evaluate the role of LSM variation as predictor of HCC development in patients treated with DAA.MethodsIn 139 HCV-related cirrhotic patients, LSM and laboratory tests were carried out at baseline (BL) and at the end of DAA treatment (EOT). Patients were followed for at least 6 months after the EOT. LSM reduction was expressed as Delta LS (∆LS). Cox regression analysis was used to identify prognostic factors for HCC development after DAA.ResultsMedian LSM values were significantly reduced from BL to EOT (from 18.6 to 13.8 kPa; p < 0.001). The median ∆LS was −26.7% (IQR: −38.4% −13.6%). During a median follow-up of 15 months after DAA treatment, 20 (14.4%) patients developed HCC. Significant LSM reduction was observed both in patients who developed HCC and in those who did not, but this was significantly lower in the patients who developed HCC (−18.0% vs −28.9% p = 0.005). At multivariate analysis, ∆LS lower than −30%, Child-Turcotte-Pugh-B and history of HCC were independently associated with HCC development.ConclusionOur results indicate that ∆LS is a useful non-invasive marker for predicting HCC development after DAA treatment.     

Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C‐infected Egyptian cohort: A comparative analysis

In Egypt, hepatocellular carcinoma (HCC) is the most common form of cancer and direct‐acting antivirals (DAA) are administered on a large scale to patients with chronic HCV infection to reduce the risk. In this unique setting, we aimed to determine the association of DAA exposure with early‐phase HCC recurrence in patients with a history of HCV‐related liver cancer. This was a prospective cohort study of an HCV‐infected population from one Egyptian specialized HCC management centre starting from the time of successful HCC intervention. The incidence rates of HCC recurrence between DAA‐exposed and nonexposed patients were compared, starting from date of HCC complete radiological response and censoring after 2 years. DAA exposure was treated as time varying. Two Poisson regressions models were used to control for potential differences in the exposed and nonexposed group; multivariable adjustment and balancing using inverse probability of treatment weighting (IPTW). We included 116 patients: 53 treated with DAAs and 63 not treated with DAAs. There was 37.7% and 25.4% recurrence in each group after a median of 16.0 and 23.0 months of follow‐up, respectively. Poisson regression using IPTW demonstrated an association between DAAs and HCC recurrence with an incidence rate ratio of 3.83 (95% CI: 2.02‐7.25), which was similar in the multivariable‐adjusted model and various sensitivity analyses. These results add important evidence towards the possible role of DAAs in HCC recurrence and stress the need for further mechanistic studies and clinical trials to accurately confirm this role and to identify patient characteristics that may be associated with this event.     

Rapidly growing hepatocellular carcinoma recurrence during direct-acting antiviral treatment for chronic hepatitis C

We herein report the case of a woman in her 80s with a recurrent hepatocellular carcinoma (HCC) tumor that rapidly increased in size during direct-acting antiviral (DAA) treatment. She suffered from HCC at her initial visit to our department and underwent hepatectomy. Thereafter, she underwent DAA treatment for chronic hepatitis C; however, her alpha-fetoprotein (AFP) level rapidly increased, and a liver tumor of >?1 cm in diameter was observed that had not been seen immediately before DAA treatment. She underwent hepatectomy again and moderate to poorly differentiated HCC was diagnosed. The patient’s AFP level showed a rapid increase immediately after the start of DAA treatment; however, the increase ceased after the first month, and the influence from the surrounding environment of the tumor was considered to be temporary.