Early predictors of prolonged intensive care utilization following liver transplantation.

INTRODUCTION: Creatinine, bilirubin, and fibrinolysis resistance are associated with multi-organ dysfunction and likely risk factors for prolonged intensive care unit (pICU) stay following liver transplantation (LT). We hypothesize postoperative day-1 (POD-1) labs will predict pICU. METHODS: LT recipients had clinical laboratories and viscoelastic testing with tissue plasminogen activator thrombelastography (tPA TEG) to quantify fibrinolysis resistance (LY30) on POD-1. pICU was defined as one week or longer in the ICU. Logistic regression was used to identify the relationship between POD-1 labs and pICU. RESULTS: Of 304 patients, 50% went to the ICU, with 15% experiencing pICU. Elevated creatinine (OR 6.6, P â€‹< â€‹0.001) and low tPA TEG LY30 (OR 3.7, P â€‹= â€‹0.004) were independent predictors of pICU after controlling for other risk factors. A 9-fold increase in the rate of 90-day graft loss (19% vs 2% p â€‹< â€‹0.001) was observed patients who had these risk factors for pICU. CONCLUSION: Elevated creatine and fibrinolysis resistance are associated with pICU and poor outcomes following LT.

Choledochoduodenostomy continues to be a safe alternative for biliary reconstruction in deceased-donor liver transplantation.

Debate continues as to whether choledochoduodenostomy (CDD) can be used instead of Roux-en-Y choledochojejunostomy (CDJ) when duct-to-duct (DTD) is not an option. We hypothesized that CDD and CDJ had similar rates of complications. All deceased-donor liver transplantations from September 2011 to March 2020 were categorized by biliary reconstruction. Primary outcomes were bleeding, bile leak, anastomotic stricture, and cholangitis. Of the 1,086 patients, 812 (74.8%) received a DTD; 225 (20.7%) received a CDD; and 49 (4.5%) received a CDJ. Cholangitis was significantly higher in CDJ compared to DTD and CDD (26.5% vs 6% vs 13.8%, p < 0.0001). When controlling for significant confounders, CDJ had 10.2 higher odds of cholangitis (95% CI 4.4-23.2) compared to DTD, and 3.3 higher odds compared to CDD (95% CI 1.4-7.8). When compared to DTD, CDJ and CDD had significantly lower odds of stricture. CDD continues to be a safe alternative for biliary reconstruction in deceased-donor liver transplantation.

Understanding the Impact of Pneumonia and Other Complications in Elderly Liver Transplant Recipients: An Analysis of NSQIP Transplant.

Despite an increasing demand for liver transplantation in older patients, our understanding of posttransplant outcomes in older recipients is limited to basic recipient and graft survival. Using National Surgical Quality Improvement Program Transplant, we tracked early outcomes after liver transplantation for patients >65. METHODS: We conducted a retrospective analysis of patients in National Surgical Quality Improvement Program Transplant between March 1, 2017 and March 31, 2019. Recipients were followed for 1 y after transplant with follow-up at 30, 90, and 365 d. Data were prospectively gathered using standard definitions across all sites. RESULTS: One thousand seven hundred thirty-one adult liver transplants were enrolled; 387 (22.4%) were >65 y old. The majority of older recipients were transplanted for hepatocellular carcinoma. The older cohort had a lower lab Model for End-Stage Liver Disease and was less likely to be hospitalized at time of transplant. Overall, older recipients had higher rates of pneumonia but no difference in intensive care unit length of stay (LOS), total LOS, surgical site infection, or 30-d readmission. Subgroup analysis of patients with poor functional status revealed a significant difference in intensive care unit and total LOS. Pneumonia was even more common in older patients and had a significant impact on overall survival. CONCLUSIONS: By targeting patients with hepatocellular carcinoma and lower Model for End-Stage Liver Diseases, transplant centers can achieve nearly equivalent outcomes in older recipients. However, older recipients with poor functional status require greater resources and are more likely to develop pneumonia. Pneumonia was strongly associated with posttransplant survival and represents an opportunity for improvement. By truly understanding the outcomes of elderly and frail recipients, transplant centers can improve outcomes for these higher-risk recipients.

Extinguishing burnout: National analysis of predictors and effects of burnout in abdominal transplant surgery fellows.

Burnout among surgeons has been attributed to increased workload and decreased autonomy. Although prior studies have examined burnout among transplant surgeons, no studies have evaluated burnout in abdominal transplant surgery fellows. The objective of our study was to identify predictors of burnout and understand its impact on personal and patient care during fellowship. A survey was sent to all abdominal transplant surgery fellows in an American Society of Transplant Surgeons-accredited fellowship. The response rate was 59.2% (n = 77) and 22.7% (n = 17) of fellows met criteria for burnout. Fellows with lower grit scores were more likely to exhibit burnout compared with fellows with higher scores (3.6 vs 4.0, P = .026). Those with burnout were more likely to work >100 hours per week (58.8% vs 27.6%, P = .023), have severe work-related stress (58.8% vs 22.4%, P = .010), consider quitting fellowship (94.1% vs 20.7%, P < .001), or make a medical error (35.3% vs 5.2%, P = .003). This national analysis of abdominal transplant fellows found that burnout rates are relatively low, but few fellows engage in self-care. Personal and program-related factors attribute to burnout and it has unacceptable effects on patient care. Transplant societies and fellowship programs should develop interventions to give fellows tools to prevent and combat burnout.

Detection of early allograft dysfunction at 30 min of reperfusion in liver transplantation: An intraoperative diagnostic tool with real time assessment of graft function.

INTRODUCTION: During the anhepatic phase of liver transplantation (LT), fibrinolytic activity increases, since the liver clears tissue plasminogen activator (tPA). We hypothesize that patients who fail to reduce fibrinolytic activity following graft reperfusion will have an increased rate of early allograft dysfunction (EAD). METHODS: Assessment of fibrinolysis in liver transplant recipients was quantified with thrombelastography (TEG) LY30. Changes in LY30 were assessed after graft reperfusion. The 30-min post-reperfusion LY30 was subtracted from the anhepatic LY30 quantifying fibrinolytic changes (delta-LY30). RESULTS: Seventy-three primary LT patients were included in the analysis. Receiver operating characteristic curve (ROC) analysis identified an inflection point of delta-LY30-5.3% as a risk factor for EAD. EAD occurred in 44% of these patients compared to 5% in high delta-LY30 (p = 0.002). CONCLUSION: LT recipients that develop hyperfibrinolysis who fail to reduce fibrinolytic activity 30 min after graft reperfusion had an EAD rate 8-fold higher than patients who had a large reduction in LY30 following reperfusion.

A clinical coagulopathy score concurrent with viscoelastic testing defines opportunities to improve hemostatic resuscitation and enhance blood product utilization during liver transplantation.

BACKGROUND: An NIH clinical coagulopathy score has been devised for trauma patients, but no such clinical score exists in transplantation surgery. We hypothesize that that this coagulopathy score can effectively identify laboratory defined coagulopathy during liver transplantation and correlates to blood product utilization. METHODS: TEGs were performed and coagulopathy scores (1, normal bleeding - 5, diffuse coagulopathic bleeding) were assigned by the surgeons at 5 intra-operative time points. Blood products used during the case were recorded between time points. Statistical analyses were performed to identify correlations between coagulopathy scores, TEG-detected abnormalities, and blood product utilization. RESULT: Transfusions rarely correlated with the appropriate TEG measurements of coagulation dysfunction. Coagulopathy score had significant correlation to various transfusions and TEG-detected coagulopathies at multiple points during the case. High aggregate coagulopathy scores identified patients receiving more transfusions, re-operations, and longer hospital stays CONCLUSION: The combination of viscoelastic testing and a standardized clinical coagulopathy score has the potential to optimize transfusions if used in tandem as well as standardize communication between surgery and anesthesia teams about clinically evident coagulopathy.

The use of thromboelastography to assess post-operative changes in coagulation and predict graft function in renal transplantation.

BACKGROUND: End stage renal disease (ESRD) is associated with elevated fibrinogen levels and fibrinolysis inhibition. However, there is a paucity of data on how renal transplantation impacts coagulation. we hypothesize that renal transplantation recipients with good functioning grafts will have improved fibrinolytic activity following surgery. METHODS: Kidney recipients were analyzed pre-operatively and on post-operative day 1(POD1) using three different TEG assays with and without two concentration of tissue-plasminogen activator (t-PA). TEG indices and percent reduction in creatinine from pre-op to POD1 were measured, with >50% defining "good" graft function. Follow up was done at 6, 12, and 24 months. RESULTS: Percent lysis(LY30) on POD1 the t-PA TEG was significantly correlated to change creatinine from pre-op to POD-1(p = 0.006). A LY30 ≥ 23% was associated with good early graft function, and lower creatinine at 24-months(p = 0.028) compared to recipients with low POD1 LY30. CONCLUSIONS: Post-operative tPA-TEG LY30 is associated with favorable early and late outcomes in kidney transplant.

Reverse epidemiology and the obesity paradox for patients with chronic kidney disease: a Markov decision model.

BACKGROUND: Obesity has been associated with both increased progression of chronic kidney disease (CKD) as well as with a paradoxical improvement in survival among end-stage renal disease patients undergoing hemodialysis. As such, the optimal weight management strategy for obese CKD patients remains unclear. OBJECTIVE: To estimate the outcomes of obese, CKD stage 3b patients after 3 weight loss interventions, including medical weight management, sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB), were followed to determine which strategy optimizes long-term survival. SETTING: University hospital, Aurora, Colorado. METHODS: A decision analytic Markov state transition model was created to simulate the life of 30,000 obese patients with CKD stage 3b, as they progressed to end-stage renal disease, transplantation, and death. Life expectancy after conservative medical weight management, RYGB, and SG were estimated. Base case patients were defined as being 50 years old and having a preintervention BMI of 40 kg/m2. Sensitivity analysis of initial BMI was performed. All Markov parameters were extracted from literature review. RESULTS: RYGB and SG were associated with improved survival for patients with preintervention body mass index of >38 kg/m2. Compared with conservative weight management, base case patients who underwent RYGB gained 10.6 months of life, and gained 8.3 months of life after SG. CONCLUSIONS: Balancing progression of CKD with improved survival on end-stage renal disease for obese patients requires selective use of weight management strategies. RYGB and SG improved survival for CKD patients with Class II and III obesity, but not for patients with Class I obesity. As such, aggressive weight loss interventions should be reserved for patients with Class II and III obesity, while more conservative methods should be offered to those with Class I obesity.

Sleeve Gastrectomy Compared with Gastric Bypass for Morbidly Obese Patients with End Stage Renal Disease: a Decision Analysis.

INTRODUCTION: The use of bariatric surgery has increased for morbidly obese patients with end stage renal disease (ESRD) for whom listing on the waitlist is often restricted until a certain BMI threshold is achieved. Effective weight loss for this population improves access to life-saving renal transplantation. However, it is unclear whether sleeve gastrectomy (SG) vs Roux-en-Y gastric bypass (RYGB) is a more effective therapy for these patients. METHODS: A decision analytic Markov state transition model was created to simulate the life of morbidly obese patients with ESRD who were deemed ineligible to be waitlisted for renal transplantation unless they achieved a BMI less than 35 kg/m2. Life expectancy following weight management (MWM), RYGB, and SG were estimated. Base case patients were defined as having a pre-intervention BMI of 45 kg/m2. Sensitivity analysis of initial BMI was performed. Markov parameters were extracted from literature review. RESULTS: RYGB improved survival compared with SG and MWM. RYGB patients had higher rates of transplantation, leading to improved mean long-term survival. Base case patients who underwent RYGB gained 1.3 additional years of life compared with patient's who underwent SG and 2.6 additional years of life compared with MWM. CONCLUSIONS: RYGB improves access to renal transplantation and thereby increases long-term survival compared with SG and MWM. The use of SG may be incongruent with the goal of improving access to renal transplantation for morbidly obese patients.

A Vascular Anastomosis Simulation Can Provide a Safe and Effective Environment for Resident Skills Development.

OBJECTIVE: Vascular anastomoses are complex surgical procedures, performed in time-sensitive circumstances, making intraoperative teaching more challenging. We sought to evaluate whether a vascular anastomosis simulation was effective in developing resident skills. DESIGN, SETTING, PARTICIPANTS: General surgery residents participated in a vascular anastomosis simulation for 1 to 2hours during their transplant rotation. An attending transplant surgeon at the University of Colorado guided the resident through end-to-end and end-to-side anastomoses using bovine carotid artery (Artegraft). The residents completed a presimulation and postsimulation survey which quantitated their confidence. They also completed the MiSSES scale, which assessed the validity of the simulation. RESULTS: Twenty residents participated in the simulation and completed the surveys. The residents reported increased understanding in how to set up an end-to-end anastomosis and an end-to-side anastomosis (p = 0.001 and p = 0.009, respectively). They reported increased ability to suture, forehand and backhand with a Castro-Viejo needle driver (both p < 0.001). The residents reported increased ability to manipulate the needle (p = 0.006), and increased ability to manipulate tissue without causing trauma (p = 0.021). They reported increased confidence in tying a surgical knot with 6-0 Prolene and in operating while wearing loupes (p = 0.002, and p < 0.001, respectively). Overall, the residents reported increased confidence when asked to perform part of a vascular anastomosis in the operating room (p < 0.001). Seventeen residents completed the MiSSES scale with median scores of "somewhat agree" to "strongly agree" on all domains of the scale. CONCLUSIONS: The use of a simple, inexpensive vascular anastomosis simulation is an effective and safe environment to improve residents' surgical skills and the residents felt that the simulation was valid.

Donor preoperative oxygen delivery and post-extubation hypoxia impact donation after circulatory death hypoxic cholangiopathy.

AIM: To evaluate donation after circulatory death (DCD) orthotopic liver transplant outcomes [hypoxic cholangiopathy (HC) and patient/graft survival] and donor risk-conditions. METHODS: From 2003-2013, 45 DCD donor transplants were performed. Predonation physiologic data from UNOS DonorNet included preoperative systolic and diastolic blood pressure, heart rate, pH, SpO2, PaO2, FiO2, and hemoglobin. Mean arterial blood pressure was computed from the systolic and diastolic blood pressures. Donor preoperative arterial O2 content was computed as [hemoglobin (gm/dL) × 1.37 (mL O2/gm) × SpO2%) + (0.003 × PaO2)]. The amount of preoperative donor red blood cell transfusions given and vasopressor use during the intensive care unit stay were documented. Donors who were transfused ≥ 1 unit of red-cells or received ≥ 2 vasopressors in the preoperative period were categorized as the red-cell/multi-pressor group. Following withdrawal of life support, donor ischemia time was computed as the number-of-minutes from onset of diastolic blood pressure < 60 mmHg until aortic cross clamping. Donor hypoxemia time was the number-of-minutes from onset of pulse oximetry < 80% until clamping. Donor hypoxia score was (ischemia time + hypoxemia time) ÷ donor preoperative hemoglobin. RESULTS: The 1, 3, and 5 year graft and patient survival rates were 83%, 77%, 60%; and 92%, 84%, and 72%, respectively. HC occurred in 49% with 16% requiring retransplant. HC occurred in donors with increased age (33.0 ± 10.6 years vs 25.6 ± 8.4 years, P = 0.014), less preoperative multiple vasopressors or red-cell transfusion (9.5% vs 54.6%, P = 0.002), lower preoperative hemoglobin (10.7 ± 2.2 gm/dL vs 12.3 ± 2.1 gm/dL, P = 0.017), lower preoperative arterial oxygen content (14.8 ± 2.8 mL O2/100 mL blood vs 16.8 ± 3.3 mL O2/100 mL blood, P = 0.049), greater hypoxia score >2.0 (69.6% vs 25.0%, P = 0.006), and increased preoperative mean arterial pressure (92.7 ± 16.2 mmHg vs 83.8 ± 18.5 mmHg, P = 0.10). HC was independently associated with age, multi-pressor/red-cell transfusion status, arterial oxygen content, hypoxia score, and mean arterial pressure (r(2) = 0.6197). The transplantation rate was greater for the later period with more liberal donor selection [era 2 (7.1/year)], compared to our early experience [era 1 (2.5/year)]. HC occurred in 63.0% during era 2 and in 29.4% during era 1 (P = 0.03). Era 2 donors had longer times for extubation-to-asystole (14.4 ± 4.7 m vs 9.3 ± 4.5 m, P = 0.001), ischemia (13.9 ± 5.9 m vs 9.7 ± 5.6 m, P = 0.03), and hypoxemia (16.0 ± 5.1 m vs 11.1 ± 6.7 m, P = 0.013) and a higher hypoxia score > 2.0 rate (73.1% vs 28.6%, P = 0.006). CONCLUSION: Easily measured donor indices, including a hypoxia score, provide an objective measure of DCD liver transplantation risk for recipient HC. Donor selection criteria influence HC rates.

BH3-only proteins contribute to steatotic liver ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) to the liver continues to be a source of significant morbidity, especially in patients with hepatic steatosis. This is a growing problem given the increase in nonalcoholic fatty liver disease. B-cell lymphoma-2 homology3-only members of the B-cell lymphoma-2 protein family are known mediators of cellular apoptosis, although their role in hepatic IRI is still emerging. The goal of this study was to investigate the effect of Bim and Bid on warm hepatic IRI in the setting of steatosis. METHODS: Lean and obese Bim and/or Bid wild-type (WT) and double knockout (DKO) mice underwent 60 min of warm hepatic ischemia using a 70% segmental occlusion technique. Obesity and hepatic steatosis were induced using a high fat diet. Hepatocellular injury patterns were compared among lean and steatotic mice after reperfusion. Differences were analyzed using a Student t-test and reported as mean ± standard error of the mean. RESULTS: DKO mice were protected from IRI relative to WT. A high fat diet created equal degrees of steatosis in both WT and DKO mice. The IRI was increased in steatotic WT livers; however, DKO mice remained protected relative to WT despite hepatic steatosis. CONCLUSIONS: The B-cell lymphoma-2 homology3-only proteins are important mediators of hepatic IRI in both lean and steatotic livers. These mechanisms have been underappreciated in steatotic liver injury and may be leveraged as targets for intervention in clinical scenarios such as transplant and hypovolemic shock.

Novel in vitro model for studying hepatic ischemia-reperfusion injury using liver cubes.

BACKGROUND: Although inflow occlusion techniques have given surgeons the ability to carry out increasingly complex liver resections, ischemia-reperfusion (IR) injury continues to be a source of morbidity. Efforts to ameliorate IR injury have been hindered in absence of adequate preclinical models. The goal of the present study was to develop a simple, efficient, and cost-effective means of studying hepatic IR injury. METHODS: Liver cubes were procured from normal (C57BL/6) mice. After hepatectomy, 4-mm punch biopsies were taken for individual placement in culture wells containing hepatocyte media. Experimental cubes underwent hypoxia for 60 minutes, whereas controls remained normoxic. Supernatants were collected from individual wells after 0, 6, and 12 hours of rediffusion for transaminase and cytokine measurement. Histologic examination was performed on individual cubes. RESULTS: Extensive histologic injury was seen in the experimental cubes compared with controls with greater staining for activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling at 6 and 24 hours, respectively. Changes consistent with ischemic injury occurred more centrally in liver cubes, whereas markers for rediffusion injury were appreciated along the periphery. Transaminases were significantly higher at 6 hours after rediffusion in experimental cubes compared with controls (P = .02). tumor necrosis factor-α and interleukin-1ß were significantly higher in the media of experimental cubes compared with controls at 12 hours rediffusion (P = .05 and .03 respectively). CONCLUSION: In vitro IR of cubes produces a significant injury with a pattern reflective of hepatic lobular architecture. This novel technique may open new avenues for uncoupling the mechanisms of IR while facilitating rapid screening of potential therapies.

Management of excluded bile ducts in paediatric orthotopic liver transplant recipients of technical variant allografts.

BACKGROUND: A strategy to increase the number of size- and weight-appropriate organs and decrease the paediatric waiting list mortality is wider application of sectional orthotopic liver transplantation (OLT). These technical variants consist of living donor, deceased donor reduced and split allografts. However, these grafts have an increased risk of biliary complications. An unusual and complex biliary complication which can lead to graft loss is inadvertent exclusion of a major segmental bile duct. We present four cases and describe an algorithm to correct these complications. METHODS: A retrospective review of the paediatric orthotopic liver transplantation database (2000-2010) at Washington University in St. Louis/St. Louis Children's Hospital was conducted. RESULTS: Sixty-eight patients (55%) received technical variant allografts. Four complications of excluded segmental bile ducts were identified. Percutaneous cholangiography provided diagnostic confirmation and stabilization with external biliary drainage. All patients required interval surgical revision of their hepaticojejunostomy for definitive drainage. Indwelling biliary stents aided intra-operative localization of the excluded ducts. All allografts were salvaged. DISCUSSION: Aggressive diagnosis, percutaneous decompression and interval revision hepaticojejunostomy are the main tenets of management of an excluded bile duct. Careful revision hepaticojejunostomy over a percutaneous biliary stent can result in restoration of biliary continuity and allograft survival.

Novel three-dimensional imaging technique improves the accuracy of hepatic volumetric assessment.

BACKGROUND: With pre-operative prediction of liver volume becoming increasingly important to safely carry out complex hepatic resections, the aim of the present study was to validate the accuracy of a three-dimensional (3-D) liver surgery operative planning software in performing hepatic volumetry. METHODS: Between 1999 and 2007, we performed 29 live donor liver resections for transplantation. Eleven patients had pre-operative volumetry performed by radiologists from either computed tomography (CT) or magnetic resonance (MR) imaging with documentation of the corresponding specimen weight. Retrospectively, images were uploaded into Scout™ where 3-D models of each case were generated to perform volumetry. A correlational analysis was performed followed by an accuracy comparison. RESULTS: Estimations by both radiologists and Scout™ were significantly correlated with the specimen weights, P ≤ 0.0001. Compared with radiologists' volumetry, Scout™ significantly improved overall accuracy [per cent error (PE) 20.0% ± 5.3 vs. 32.9% ± 5.7, P=0.005], accuracy of CT-based estimations (PE 23.2% ± 6.7 vs. 37.2% ± 6.9, P=0.023) and accuracy of the left lateral section (PE 11.1% ± 3.9 vs. 26.6% ± 6.8, P=0.027). DISCUSSION: This 3-D planning software is a valid tool for use in volumetry. Significance is greatest for CT-based models of the left lateral section. This approach gives surgeons the ability to assess volumetrics and actively plan resections.

Endoplasmic reticulum stress is a mediator of posttransplant injury in severely steatotic liver allografts.

Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance, and metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury after liver transplantation into strain-matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin-6 and interleukin-1ß. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer-binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation-associated caspase-11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after steatotic liver transplantation. These data confirm ER stress in steatotic allografts and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft.

Humoral immunity to immunodominant epitopes of Hepatitis C virus in individuals infected with genotypes 1a or 1b.

Cellular immunity against multiple Hepatitis C virus (HCV) proteins is observed in patients acutely infected with HCV most of whom later resolve infection. We wished to assess humoral immunity in patients infected with HCV 1a or 1b genotypes in relation to viral load using plasma samples from HCV-infected individuals and a panel of peptides representing immunodominant epitopes of HCV structural and nonstructural proteins. Plasma from HCV 1a- and 1b-infected patients, respectively, were divided into two groups: patients with low viral load (<==100,000 RNA copies/ml) and patients with high viral load (>/=10,000,000 RNA copies/ml). The antigens were peptides representing epitopes from immunodominant regions of HCV core, E2, NS3, and NS4 proteins, as well as the hypervariable (HVR) epitopes in E2 from genotypes 1a and 1b. Individuals infected with HCV 1a evoked a stronger immune response to many immunodominant epitopes of HCV relative to individuals infected with HCV 1b. Moreover, among individuals infected with HCV 1a, those with low viral loads mounted significantly greater responses against these epitopes than did individuals with high viral loads. Our observations demonstrate that quantitatively different antibody responses are elicited against HCV depending on the genotype of infecting virus, and suggest that humoral immunity directed against multiple immunodominant epitopes in HCV 1a-infected individuals may help lower viral load in vivo.