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BACKGROUND Fresh frozen plasma (FFP) transfusion is often used in the management of acute variceal haemorrhage (AVH) despite best practice advice suggesting otherwise. OBJECTIVE We investigated if FFP transfusion affects clinical outcomes in AVH. DESIGN, SETTING AND PATIENTS We performed a retrospective cohort study of 244 consecutive, eligible patients admitted to five tertiary health care centres between 2013 and 2018 with AVH. MAIN OUTCOME MEASUREMENTS Multivariable regression analyses were used to study the association of FFP transfusion with mortality at 42 days (primary outcome) and failure to control bleeding at 5 days and length of stay (secondary outcomes). RESULTS Patients who received FFP transfusion (n = 100) had higher mean Model for End Stage Liver Disease (MELD) score and more severe variceal bleeding than those who did not received FFP transfusion (n = 144). Multivariable analysis showed that FFP transfusion was associated with increased odds of mortality at 42 days (odds ratio [OR] 9.41, 95% confidence interval [CI] 3.71-23.90). FFP transfusion was also associated with failure to control bleeding at 5 days (OR 3.87, 95% CI 1.28-11.70) and length of stay >7 days (adjusted OR 1.88, 95% CI 1.03-3.42). The independent association of FFP transfusion with mortality at 42 days persisted when the cohort was restricted to high-risk patients and in patients without active bleeding. LIMITATIONS AND CONCLUSIONS Fresh frozen plasma transfusion in AVH is independently associated with poor clinical outcomes. As this an observational study, there may be residual bias due to confounding; however, we demonstrate no benefit and potential harm with FFP transfusions in AVH.

Colonoscopy for colorectal cancer screening is endoscopist dependent, and colonoscopy quality improvement programs aim to improve efficacy. This study evaluated the clinical benefit and safety of using a computer-aided detection (CADe) device in colonoscopy procedures.This randomized study prospectively evaluated the use of a CADe device at 5 academic and community centers by US board-certified gastroenterologists (n = 22). Participants aged ≥40 scheduled for screening or surveillance (≥3 years) colonoscopy were included; exclusion criteria included incomplete procedure, diagnostic indication, inflammatory bowel disease, and familial adenomatous polyposis. Patients were randomized by endoscopist to the standard or CADe colonoscopy arm using computer-generated, random-block method. The 2 primary endpoints were adenomas per colonoscopy (APC), the total number of adenomas resected divided by the total number of colonoscopies; and true histology rate (THR), the proportion of resections with clinically significant histology divided by the total number of polyp resections. The primary analysis used a modified intention-to-treat approach.Between January and September 2021, 1440 participants were enrolled to be randomized. After exclusion of participants who did not meet the eligibility criteria, 677 in the standard arm and 682 in the CADe arm were included in a modified intention-to-treat analysis. APC increased significantly with use of the CADe device (standard vs CADe: 0.83 vs 1.05, P = .002; total number of adenomas, 562 vs 719). There was no decrease in THR with use of the CADe device (standard vs CADe: 71.7% vs 67.4%, P for noninferiority.001; total number of non-neoplastic lesions, 284 vs 375). Adenoma detection rate was 43.9% and 47.8% in the standard and CADe arms, respectively (P = .065).For experienced endoscopists performing screening and surveillance colonoscopies in the United States, the CADe device statistically improved overall adenoma detection (APC) without a concomitant increase in resection of non-neoplastic lesions (THR).gov registration: NCT04754347.

Portal hypertension is the cause of the clinical complications associated with cirrhosis. The primary complications of portal hypertension are ascites, acute variceal bleed, and hepatic encephalopathy. Hepatic venous pressure gradient measurement remains the gold standard test for diagnosing cirrhosis-related portal hypertension. Hepatic venous pressure gradient more than 10 mmHg is associated with an increased risk of complications and is termed clinically significant portal hypertension (CSPH). Clinical, laboratory, and imaging methods can also aid in diagnosing CSPH non-invasively. Recently, deep learning methods have been demonstrated to diagnose CSPH effectively. The management of portal hypertension is always individualized and is dependent on the etiology, the availability of therapies, and the degree of portal hypertension complications. In this review, we discuss the diagnosis and management of cirrhosis-related portal hypertension in detail. Also, we highlight the history of portal hypertension and future research areas in portal hypertension.

Purpose of review To summarize the use of gastrointestinal peptides in the management of portal hypertension. Recent findings Vasoactive peptides are commonly used in the management of acute variceal hemorrhage and hepatorenal syndrome, which are portal hypertensive complications of cirrhosis. The main vasoactive peptides that are used are somatostatin and its long-acting analogue octreotide, and vasopressin and its analogue terlipressin. Early initiation of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome is associated with improved outcomes. Octreotide is the available vasoactive peptide in the Unites States. Recent developments and ongoing clinical trials may improve our understanding of hepatorenal syndrome and influence the use of vasoactive peptides, particularly terlipressin. Summary Here, we review the literature on the use of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome.

Direct acting antiviral agents (DAAs) have emerged as simple, short, safe, and effective treatments for chronic hepatitis C (CHC) infection. CHC is a systemic disease with frequent and multiple extrahepatic manifestations. The beneficial effects of DAA treatment regimens extend beyond improvement in liver-related outcomes to amelioration of extra hepatic manifestations and are likely to have economic implications. The purpose of this review is to evaluate the effect of DAAs on extra hepatic manifestations of CHC virus infection. Recent studies indicate that DAAs are associated with reduction in all-cause mortality, even in patients without significant hepatic fibrosis. They are also associated with reduction in incident cardiovascular disease and diabetes. DAAs are the mainstay of treatment in HCV-associated cryoglobulinemia and lymphoma. Successful HCV therapy with DAAs also improves patient-related outcomes such as health-related quality of life. DAAs improve extrahepatic manifestations of CHC virus infection. Future studies are needed to evaluate the long-term durability of treatment response and for accounting amelioration of extrahepatic manifestations into the cost effectiveness of DAA regimens.

Introduction: During the COVID-19 pandemic, outpatient colonoscopies throughout the US were postponed, creating a significant backlog of procedures. We estimated the number of missed high- risk adenomas and colorectal cancers in 2020 at an urban, tertiary-care, safety-net teaching hospital in Boston, Massachusetts. Methods: This observational study evaluated the number of high-risk adenomas (defined as ≥3 adenomas, adenoma ≥10 mm in size, adenoma with tubulovillous or villous histological features, or adenoma with high-grade dysplasia) and colorectal cancers diagnosed by outpatient colonoscopy from January 2020 to November 2020, and compared it with those diagnosed from January 2017 to December 2019. Patients with a personal history of colorectal cancer or a colonoscopy indication of inflammatory bowel disease, therapeutic procedure (other than removal of large polyp), or diarrhea were excluded (10% of all colonoscopies). A Poisson regression model using colonoscopy data from 2017 to 2019-adjusted for age, sex, race/ethnicity and indication-was used to predict expected highrisk adenomas and colorectal cancers per month in 2020. Predicted values were compared to actual values to estimate missed diagnoses. Results: A total of 6597, 7136, and 6816 colonoscopies were performed in 2017, 2018 and 2019, respectively. There were 40% fewer colonoscopies performed in January to November 2020 (n = 3704) compared to the same period in 2019. In January to November 2020, 505 high-risk adenomas (Figure 1a) and 21 colorectal cancers (Figure 1b) were diagnosed. We estimate that 284 (36%) highrisk adenomas and 9 (30%) colorectal cancers were missed during this period. The rate of colorectal cancer detection was 6 per 1000 cases performed in 2017 to 2019. Assuming similar patient characteristics and indications, 1349 additional colonoscopies will be needed to diagnose 9 missed colorectal cancers. Conclusion: This study provides one of the first real world estimates of missed high-risk adenomas and colorectal cancers due to the cancellation of outpatient colonoscopies during the COVID-19 pandemic. The results have implications on planning strategies to schedule elective colonoscopies to increase the yield of detection of these high-risk lesions.

Background and Aims Portal pressure can be used to identify patients with chronic liver disease who have progressed to cirrhosis. Portal pressure can also provide accurate prognostication for patients with cirrhosis. However, there are no practical means for assessment of portal pressure. Although it is well established that the gastric mucosal blood supply increases in patients with cirrhosis, this has been difficult to quantify reproducibly. Our group has developed a novel spectroscopic technology called spatially resolved subdiffuse reflectance spectroscopy (SRSRS), which enables quantification of mucosal microcirculation. We aim to ascertain if quantification of the gastric mucosal microcirculation with SRSRS correlates with clinical evidence of portal hypertension. Methods Patients undergoing EGD for clinical indications had 10 measurements taken in the endoscopically normal gastric fundus via SRSRS probe to assess the microcirculation. Cases were defined as patients with cirrhosis (n = 18), and controls were those without evidence of liver disease (n = 18); this was corroborated with transient elastography. Results The blood volume fraction (P = .06) and subdiffuse reflectance (P = .02) from a shallow depth in the gastric fundus were higher in patients with cirrhosis than those without. These markers were combined to yield an overall optical marker that can differentiate patients with cirrhosis from controls with a sensitivity of 72% and specificity of 94% (area under receiver operating curve, 0.82). Conclusions Spectroscopic quantification of gastric fundal mucosal microcirculation is a promising surrogate of clinical correlates of portal hypertension. This approach may represent a less-intrusive surrogate biomarker for liver disease prognostication and potentially response to therapy.

Chronic hepatitis B infection represents a global public health burden, infecting over 240 million persons worldwide. It is associated with significant morbidity and mortality and represents a leading cause for cirrhosis, liver failure, liver cancer, and liver-related death. Current treatment of hepatitis B is focused on identification of patients with active hepatitis within the immune clearance or reactivation phases of chronic infection, for whom antiviral therapy with peg-interferon or nucleos(t)ide analogs are recommended. Seven antiviral agents are currently approved by the US FDA for treatment of chronic hepatitis B, of which three are recommended as first-line agents by major liver societies. As none are associated with virologic cure, the primary objective of antiviral therapy in 2016 is long-term virologic suppression, which is associated with a decreased risk for cirrhosis and hepatocellular carcinoma, and may reverse liver fibrosis or cirrhosis in some patients. Although biochemical improvement in liver enzymes is common, HBeAg seroconversion occurs in only a minority of patients, and HBsAg seroconversion is rare. Due to ongoing deficits along multiple steps of the care cascade, including screening, diagnosis, linkage to care, and antiviral therapy, many patients with chronic hepatitis B remain undiagnosed, lack access to care by specialists with expertise in the management of CHB, or have not been treated with antiviral agents. Future therapies are currently in development with the aim of functional viral cure, which may transform the treatment of CHB and improve liver outcomes.

This review will focus on the efficacy and tolerability of the combination of sofosbuvir and simeprevir in genotype 1 chronic HCV infection. The goal of HCV therapy is to attain cure, which is defined by the US FDA as a sustained virologic response (SVR) or undetectable HCV RNA 12 weeks after HCV therapy, based on data confirming that over 99% patients who achieve this milestone have durable clearance of the infection. SVR12 (undetectable HCV RNA 12 weeks post-treatment) is the mostly commonly used end point to evaluate effectiveness of HCV therapy and will be used interchangeably with SVR in this review. Some of the data presented in this paper are from peer reviewed abstracts presented in major international conferences and are not yet published as manuscripts.

Purpose Hepatocellular carcinoma (HCC) results from chronic inflammation/cirrhosis. Unfortunately, despite use of radiological/serological screening techniques, HCC ranks as a leading cause of cancer deaths. Our group has used alterations in high order chromatin as a marker for field carcinogenesis and hence risk for a variety of cancers (including colon, lung, prostate, ovarian, esophageal). In this study we wanted to address whether these chromatin alterations occur in HCC and if it could be used for risk stratification. Experimental design A case control study was performed in patients with cirrhosis who went on to develop HCC and patients with cirrhosis who did not develop cancer. We performed partial wave spectroscopic microscopy (PWS) which measures nanoscale alterations on formalin fixed deparaffinized liver biopsy specimens, 17 progressors and 26 non-progressors. Follow up was 2089 and 2892 days, respectively. Results PWS parameter disorder strength Ld were notably higher for the progressors (Ld = 1.47 ± 0.76) than the non-progressors (Ld = 1.00 ± 0.27) (p = 0.024). Overall, the Cohen’s d effect size was 0.907 (90.7%). AUROC analysis yielded an area of 0.70. There was no evidence of confounding by gender, age, BMI, smoking status and race. Conclusions High order chromatin alterations, as detected by PWS, is altered in pre-malignant hepatocytes with cirrhosis and may predict future risk of HCC.

The purpose of this article is to develop and validate a chemical-shift imaging-derived color mapping system for evaluation of liver steatosis.Opposed phase MRI was evaluated for 85 subjects (51 with presumed nonalcoholic fatty liver disease and 34 healthy volunteers). Liver signal intensity loss was compared with histologic analysis for 52 subjects, assuming grade 0 steatosis for healthy volunteers, to determine signal-intensity-loss threshold points differentiating steatosis grades and subsequent Spearman correlation. Color scale grading was then applied for 78 subjects. Interpretation of color maps for steatosis severity and heterogeneity was performed by three readers. Analyses of agreement among readers and of color map steatosis grade with biopsy were performed using weighted kappa values.The numbers of subjects with steatosis grades 0, 1, 2, and 3 were 41, 12, 13, and 19, respectively. A correlation of 0.90 was obtained using selected threshold values of 5.9% or less, 6-26.1%, 26.2-36.8%, and greater than 36.8% for steatosis grades 0, 1, 2, and 3, respectively. Interobserver agreement for color map grading of steatosis was excellent (κ = 0.93-0.94). Color map interpretation for all readers also showed excellent agreement with histologic findings for whole liver (κ = 0.82-0.86) and estimated biopsy site location (κ = 0.81-0.86; anterior region of right lobe). Heterogeneous steatosis on color maps was identified in 56-60% of subjects with nonalcoholic fatty liver disease and in 7% of healthy volunteers and was associated with greater disagreement between color map and histology grading (61-74%) compared with the whole group (37-40%).MRI-derived color map estimation of liver steatosis grade appears to be reproducible and accurate.

Background & Aims Statins decrease portal pressure in patients with cirrhosis and increase survival times of patients who have bled from varices. However, statins can be hepatotoxic. It is important to determine whether long-term statin use will be beneficial or detrimental for patients with cirrhosis because physicians are reluctant to prescribe statins to patients with liver disease. We investigated the effects of statins on decompensation and survival times in patients with compensated cirrhosis. Methods We performed a retrospective cohort using the Veteran Affairs Clinical Case Registry, which contains nationwide data from veterans infected with the hepatitis C virus (HCV). We identified patients with compensated cirrhosis from January 1996 through December 2009. Statin use was according to filled prescriptions. Cirrhosis and decompensation were determined from International Classification of Diseases, 9th revision codes, using a validated algorithm. Results Among 40,512 patients with HCV compensated cirrhosis (98% male; median age, 56 y), 2802 statin users were identified. We developed a propensity score model using variables associated with statin prescription, and new statin users were matched with up to 5 nonusers; 685 statin users were matched with 2062 nonusers. Discrimination of the propensity score model was 0.92. Statin users had a lower risk of decompensation (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.39–0.77) and death (HR, 0.56; 95% CI, 0.46–0.69), compared with nonusers. Findings persisted after adjustment for age, FIB-4 index score, serum level of albumin, model for end-stage liver disease and Child-Turcotte-Pugh scores (HR for decompensation, 0.55; 95% CI, 0.39–0.78), and death (HR, 0.55; 95% CI, 0.45–0.68). Conclusions Based on data from the Veteran Affairs Clinical Case Registry, statin use among patients with HCV and compensated cirrhosis is associated with a more than 40% lower risk of cirrhosis decompensation and death. Although statins cannot yet be recommended widely for these patients, their use should not be avoided.

Hyponatremia and hepatorenal syndrome are severe complications in patients with cirrhosis and ascites resulting from circulatory abnormalities (splanchnic and systemic vasodilatation) that develop with portal hypertension. Both conditions are associated with an increased risk of death. Hyponatremia and renal failure may develop in patients with cirrhosis due to causes other than portal hypertension. Making an accurate differential diagnosis is important both therapeutically and prognostically. In this article, we discuss the pathophysiology, diagnosis, differential diagnosis, and management of hyponatremia and hepatorenal syndrome in patients with cirrhosis.

Background. Understanding the predictors of mortality in individuals with human immunodeficiency virus and hepatitis C virus (HIV/HCV) coinfection can be useful in management of these patients. Methods. We used the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) for these analyses. Multivariate Cox-regression models were used to determine predictors of mortality. Results. Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV coinfection. The all-cause mortality rate was 74.1 (70.4–77.9) per 1000 person-years (PY) among veterans with HIV/HCV coinfection and 39.8 (36.3–43.6) per 1000 PY for veterans with HIV monoinfection. The multivariable adjusted hazard ratio (95% confidence interval) of all-cause mortality for HCV infection was 1.58 (1.36–1.84). Positive predictors of mortality included decompensated liver disease (2.33 (1.98–2.74)), coronary artery disease (1.74 (1.32–2.28)), chronic kidney disease (1.62 (1.36–1.92)), and anemia (1.58 (1.31–1.89)). Factors associated with reduced mortality included HCV treatment (0.41 (0.27–0.63)) and higher CD4 count (0.90 (0.87–0.93) per 100 cells/μL higher count). Data were insufficient to make informative analyses of the role of HCV virologic response. Conclusion. HCV coinfection was associated with substantial increased risk of mortality among HIV infected veterans. HCV treatment was associated with significantly lower risk of mortality.

Systemic mastocytosis is a myeloproliferative disorder characterized by extracutaneous involvement of at least one organ. Although rare, infiltration of inflammatory mast cells within the portal vein may lead to obstruction of the sinusoids resulting in non-cirrhotic portal hypertension. We present a patient with known history of systemic mastocytosis with bone marrow involvement presenting with new-onset esophageal variceal bleeding. Although systemic mastocytosis is uncommon, the subsequent development of hepatic involvement and non-cirrhotic portal hypertension are discussed. Further highlighted is a lack of organization guidelines and the potential for gastrointestinal and hepatic screening of mastocytosis patients with known extracutaneous involvement.

The impact of pretreatment anaemia on survival in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is not known. Moreover, HCV treatment is offered less frequently to individuals with anaemia, due to haematological side effects of the treatment regimen. This study aimed to determine the effect of HCV treatment on survival among HCV/HIV co-infected individuals with pretreatment anaemia using the Electronically Retrieved Cohort of HCV-Infected Veterans (ERCHIVES). Individuals with HCV/HIV co-infection were included in current analyses. Participants were considered treated if they were prescribed ≥ 4 weeks of HCV treatment. All-cause mortality data were obtained using record linkage. Survival analyses were performed using Cox proportional hazard models. Among 5000 HCV/HIV co-infected individuals, 1671 (33.4%) had pretreatment anaemia. In a follow-up period of up to 7 years (19,500 person-years), individuals with anaemia had significantly higher mortality rate compared with those without anaemia [144.2 (95% CI: 134.5-154.7) vs 47.5 (44.0-51.2) per 1000 person-years, respectively]. Among individuals with anaemia, HCV treatment was associated with significantly lower mortality rate [66.6 (44.3-100.2) vs 149.6 (139.2-160.5) per 1000 person-years, for treated vs untreated, respectively]. Treatment remained associated with substantial survival benefit after taking into account the effect of multiple comorbidities (hazards ratio: 0.34, 95% CI: 0.21-0.62). These data suggest that HCV/HIV co-infected individuals with pretreatment anaemia have significantly higher mortality compared with those without anaemia. HCV treatment is associated with substantial survival benefit in this group. Additional studies are needed to determine strategies to improve HCV treatment rates among this group.

Acute aortic dissection (AAD) is a life-threatening condition associated with high morbidity and mortality. The most important recognized acquired cause that leads to dissection is chronic arterial hypertension. With respect to the anuria and renal failure, aortic dissection is not something that is always considered and is still not a very common presentation unless both renal arteries come off the false lumen of the dissection. However, when present, preoperative renal failure in patients with acute type B dissection has been noted to be an independent predictor of mortality. Early recognition and diagnosis is the key and as noted by previous studies as well, almost a third of these patients are initially worked up for other causes until later when they are diagnosed with aortic dissection. Here we present a case of a patient presenting with severe hypothyroidism, long-standing hypertension, and anuria. Through the case, we highlight the importance of having aortic dissection as an important differential in patients presenting with anuria who have a long standing history of uncontrolled hypertension. Pathophysiology relating to severe hypothyroidism-induced renal dysfunction is also discussed.

Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies.

Systemic therapies for cancer, including pancreatic cancer, have provided only limited efficacy for patients to date. Adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents. However, unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. So far, insufficient cancer selectivity at the stage of infection has greatly hampered efficacy of Ad-based therapy upon systemic administration. The controlled distribution and selective transduction of the vector would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer. We have recently developed transductionally-targeted Ads by high-throughput screening of high-diversity (10^9-level) Ad-library. Mesothelin (MSLN) is highly overexpressed in pancreatic cancers. Ad with redesigned AB-loop targeted to MSLN (AdMLVTIN)was successfully isolated from the high throughput screening of Ad library by infectivity for MSLN-expressing 293 cells (293-MSLN). The in vitro binding of AdML-VTIN corresponded to MSLN-expression of each cell line, and the suppression of MSLN-expression with siRNA or antibody blocked the binding to MSLN-expressing cells, which indicates the vector is targeted to mesothelin. In MSLN-positive cells (Panc-1), this virus exhibited higher binding ability than that of Ad with 5/3 modified fiber which is known to exhibit highest infectivity in pancreatic cancer cells. The in vivo antitumor effect was compared in Panc-1 (MSLN-positive) and MiaPaCa-2 (MSLN-negative) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and disappearance of tumors was observed in 4 out of 8 mice. Contrarily, the same virus showed no antitumor effect in MiaPaCa-2. Viral DNA amount in the tumors correlated to the anti-tumor effect. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, AdML-VTIN showed significantly lower liver sequestration compared to the wild-type Ad5, and the copy number of this retargeted virus was significantly (1000-fold) higher in the tumor. These data indicates that this vector enables efficient systemic delivery and treatment of MSLN-expressing pancreatic cancer xenografts. In this study, our MSLN-targeted Ad vector exhibited selective infectivity to MSLN-positive pancreatic cancer cells in vitro and in vivo. Moreover, this virus showed dramatically augmented delivery to the tumors and significantly reduced liver sequestration upon systemic administration. This new genetically modified Ad, which is transductionally retargeted to pancreatic cancer, may embody a next generation systemic therapy for this devastating disease.

samples were applied. The aim was to re-analyze sequential plasma and PBMC samples from patients who resolved CHC and became HCVRNA negative by clinical laboratory testing. Methods: Plasma samples (n = 60) from 11 randomly selected patients who resolved CHC after a standard course of PEG/IFN/RBV therapy were collected before (n = 12), during (range 48–68 wks; n =28) and up to 33.1 (range 12–88) wks post-treatment (n = 20). PBMCs (n =26) from 4 patients before (n =5), during (n =13) and post-treatment (n = 8) were also analyzed. Total RNA was extracted from 250 or 750ml plasma and intact or PHA-stimulated PBMCs. HCVRNA was detected by RT-PCR/nucleic acid hybridization (RTPCR/NAH; sensitivity