Biomedical subjects

Hugo R Rosen

Publications and source records attributed to Hugo R Rosen.

At least 37 records · Page 2Linked to original sources

PubMed2004

Changing compliance to the American College of Gastroenterology guidelines for the management of variceal hemorrhage: a regional survey.

OBJECTIVES: In mid-1997 the American College of Gastroenterology (ACG) published guidelines for the management of varices. The aim of this study is to assess the change in regional practice patterns between early 1997 (preguidelines) and 2000 (postguidelines). METHODS: Gastroenterologists in Oregon and Southwestern Washington state were sent a self-reporting questionnaire regarding the management of varices in March 1997 (prior to the publication of the guidelines) and again in August 2000. RESULTS: Fifty-seven of 75 (76%) and 68 of 92 (74%) of the surveys were completed in 1997 and 2000, respectively. Fifty to 60% of the respondents saw between three and five cirrhotic patients per month. Significantly, more respondents followed the guidelines to screen and treat large varices to prevent initial variceal hemorrhage in 2000 than in 1997, 54% versus 18% (p < 0.005). Of the respondents who performed screening of EGDs, the majority treated large varices with beta-blocker therapy (93% in 1997 and 97% in 2000). All respondents used early endoscopy to treat variceal bleeding. Significantly, most of the respondents began pharmacologic therapy prior to endoscopy if active variceal hemorrhage was suspected (with most choosing octreotide) in 2000 than in 1997, 83% versus 56% (p < 0.005). The majority of the respondents pursued repeat endoscopic therapy after cessation of the initial variceal bleeding episode (96% in 1997 and 95% in 2000), and most performed surveillance EGD once the varices had been eradicated (72% in 1997 and 79% in 2000). CONCLUSIONS: After the publication of the ACG guidelines, significantly more gastroenterologists screened for varices to prevent initial variceal hemorrhage and significantly more used pharmacologic therapy prior to endoscopic treatment for variceal hemorrhage.

Esophageal and Gastric Varices↗

PubMed2004

Liver and intestine transplantation.

The most significant development in liver transplantation in the USA over the past year was the full implementation of the MELD- and PELD-based allocation policy in March 2002, which shifted emphasis from waiting time within broad medical urgency status to prioritization by risk of waiting list death. The implementation of this system has led to a decrease in pretransplant mortality without increasing post-transplant mortality, despite a higher severity of illness at the time of transplant. The trend over the last few years of rapidly increasing numbers of adult living donor liver transplants was reversed in 2002 by a decline of more than 30% in the number of these procedures. In 2002, a greater percentage of women received livers from living donors (43%) than deceased donors (34%), possibly because of size considerations. From 1993 to 2001, the waiting list increased more than sixfold, from 2902 patients to 18,047 patients. For the first time since 1993, the waiting list size decreased in 2002, dropping 6% to 16,974 candidates. The percentage of temporarily inactive liver candidates also increased from 2001, thus the net decrease in the active waiting list for 2002 was 12%. This may reflect a trend toward less pre-emptive listing practices under MELD. Intestine transplantation remains a low-volume procedure limited to a few transplant centers and is still accompanied by significant pre- and post-transplantation risks. As this procedure matures, its application may increase to include recipients at an earlier stage of their disease with better likelihood of success.

Humans↗

PubMed2004

Comparative analysis of outcome following liver transplantation in US veterans.

The purpose of this study was to evaluate whether there was a difference in mortality following orthotopic liver transplantation (OLT) in a US veteran (VA) population (n = 149) compared to a non-VA (university) population (n = 285) and what factors could explain this difference. Survival following OLT for 149 VA patients was compared with that of 285 university patients. By Kaplan-Meier survival analysis, VA patients had higher mortality than university patients with respective 1-year, 3-year, and 5-year survival of 82%, 75%, and 68% vs. 87%, 82%, and 78% (p = 0.006). Gender, etiology of end-stage liver disease (ESLD) and donor age (i.e. older than 34 years) also significantly influenced survival. However, when donor and recipient age, gender, model for end-stage liver disease (MELD) score, and etiology of liver disease were included with hospital status in a multivariate Cox proportional hazards model, the VA population did not have higher mortality. A final model to predict mortality following transplantation was derived for all 434 patients where individuals were assigned risk scores based on the equation R = 0.219 (gender) + 0.018 (donor age) + 0.032 (recipient age) + 0.021 (MELD), where recipient age, donor age, and MELD score are the respective continuous variables and gender = 1 (men) and 0 for women (c-statistic = 0.71).

Adult↗

PubMed2004

Treatment of hepatitis C in solid organ transplantation.

Hepatitis C virus (HCV) infection is highly prevalent worldwide, and results in significant morbidity and mortality. HCV frequently infects haemodialysis patients and appears to impact on long-term survival of kidney transplant recipients. Therefore, treatment is recommended for kidney transplant candidates before transplantation and should be avoided following transplantation because of a high risk of allograft rejection. HCV infection does not appear to influence survival in cardiac transplant recipients and cardiac transplant recipients should also not be treated. In general, HCV-infected patients with cirrhosis are not considered as candidates for either kidney or cardiac transplantation given their risk of decompensation. HCV is the most common indication for liver transplantation and re-infection with varying degrees of liver injury is universal. Survival after liver transplantation is reduced among HCV-infected patients when compared with uninfected controls. Therefore, treatment using interferon and ribavirin is advocated; however, such therapy is frequently limited by adverse effects. Thus, improved antiviral treatment modalities are eagerly awaited in the transplant setting.

Antiviral Agents↗

PubMed2003

Outcome and management of hepatitis C in liver transplant recipients.

Hepatitis C virus (HCV)-related cirrhosis is the leading indication for liver transplantation. Reinfection of the allograft with HCV is universal in all patients with pretransplantation viremia, and leads to histologically proven hepatitis in 50%-80% of these patients. Recent data have demonstrated significantly higher mortality among HCV-positive liver transplant recipients. For this subgroup of patients, retransplantation remains highly controversial. As current antiviral therapy is limited in efficacy and tolerability, an improved understanding of those patients at greatest risk of developing serious HCV-induced graft injury is necessary to optimize treatment.

Antiviral Agents↗

PubMed2003

Hepatitis C virus in the human liver transplantation model.

Hepatitis C virus-related liver failure is the single leading indication for liver transplantation, and the study of HCV in the transplant setting has enhanced the understanding of the natural history of disease and putative mechanisms by which HCV causes liver injury. In a subset of patients, allograft cirrhosis develops within a few years after transplantation, and recent findings suggest these individuals are immunologically impaired compared with individuals with mild HCV recurrence at long-term follow-up. Fig. 9 shows a conceptual paradigm of mechanisms potentially involved in shaping HCV outcome after transplantation. It is possible that relative antiviral control by innate and adaptive immune responses (to maintain HCV replication below a certain threshold) prevents direct cytopathic injury and induction of oxidative stress and apoptosis of cells. Additional phenomena that may contribute to induction of apoptosis (eg, genetic polymorphisms within the donor organ. CMV coinfection, and ischemic-preservation injury) may augment the initial cascade of liver injury. Recruitment to the allograft of nonspecific cells may decrease viral replication by way of noncytolytic mechanisms or augment viral replication (eg, Th2 phenotype) and direct cytopathic injury. The immune response is likely insufficiently vigorous to keep viral replication under control, but may maintain chronic liver injury. The liver transplant model is unique in that distinct phenotypic outcomes can be observed over a short period of time. A consideration of the temporal evolution of different mechanisms is also important, because mechanisms that initially predominate may become less important over time, and conversely, as suggested with the inverse correlation between viral load at 5 years and allograft fibrosis, new immune responses may emerge that modify the host-virus interaction. Prospective characterization of the immunoregulatory and virologic mechanisms involved in the liver transplantation model hopefully will help unravel the causal basis of reported associations, lead to the development of highly specific therapeutic strategies, and ultimately diminish the rate of graft loss from recurrent disease.

Animals↗

PubMed2003

Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.

Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively infrequent event, and these individuals provide a unique opportunity to characterize correlates of protective immunity as an important first step in the development of vaccine candidates. The aim of this study was to directly and comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4(+) and CD8(+) T cells ex vivo from HLA diverse individuals who had been successful in spontaneously resolving HCV infection. We measured interferon gamma (IFN-gamma) production with an ELISPOT assay using magnetic bead-separated CD4(+) or CD8(+) T cells in response to autologous DCs that had been pulsed with 15mer per peptides overlapping by 11 amino acids and spanning all of the NS3 protein (150 total peptides). All subjects with spontaneously recovered HCV infection demonstrated vigorous and multispecific CD4(+) T-cell responses to NS3 peptides, and 6 of 10 subjects demonstrated CD8(+) T-cell responses. More importantly, we identified novel, previously unpredicted antigenic regions, which in most cases elicited high frequencies within a given individual. In conclusion, subjects who have spontaneously eradicated HCV infection up to 35 years earlier demonstrate persistent CD4(+) and CD8(+) T-cell responses specific to NS3. By providing a comprehensive screening of all potential T-cell epitopes contained in the NS3 region, our strategy defines the breadth of the T-cell response and identifies novel, unpredicted specificities.

Amino Acid Sequence↗

PubMed2003

Validation and refinement of survival models for liver retransplantation.

Orthotopic liver retransplantation (re-OLT) is highly controversial. The objectives of this study were to determine the validity of a recently developed United Network for Organ Sharing (UNOS) multivariate model using an independent cohort of patients undergoing re-OLT outside the United States, to determine whether incorporation of other variables that were incomplete in the UNOS registry would provide additional prognostic information, to develop new models combining data sets from both cohorts, and to evaluate the validity of the model for end-stage liver disease (MELD) in patients undergoing re-OLT. Two hundred eighty-one adult patients undergoing re-OLT (between 1986 and 1999) at 6 foreign transplant centers comprised the validation cohort. We found good agreement between actual survival and predicted survival in the validation cohort; 1-year patient survival rates in the low-, intermediate-, and high-risk groups (as assigned by the original UNOS model) were 72%, 68%, and 36%, respectively (P <.0001). In the patients for whom the international normalized ratio (INR) of prothrombin time was available, MELD correlated with outcome following re-OLT; the median MELD scores for patients surviving at least 90 days compared with those dying within 90 days were 20.75 versus 25.9, respectively (P =.004). Utilizing both patient cohorts (n = 979), a new model, based on recipient age, total serum bilirubin, creatinine, and interval to re-OLT, was constructed (whole model chi(2) = 105, P <.0001). Using the c-statistic with 30-day, 90-day, 1-year, and 3-year mortality as the end points, the area under the receiver operating characteristic (ROC) curves for 4 different models were compared. In conclusion, prospective validation and use of these models as adjuncts to clinical decision making in the management of patients being considered for re-OLT are warranted.

Adult↗

PubMed2003

Duration of antiviral therapy for cholestatic HCV recurrence may need to be indefinite.

Progressive liver allograft injury related to hepatitis C virus (HCV) recurrence occurs in 20% to 30% of liver transplant recipients within the first 5 years. In particular, the subset of patients who develop the severe cholestatic variant has an extremely high mortality. We report our center's experience with 7 cholestatic patients who were treated with interferon alfa-2b (3 million IU three times per week initially) in combination with ribavirin. In 4 of the 7 patients, HCV-RNA in serum became undetectable, and in an additional patient, normalization of serum bilirubin was achieved despite persistent viremia. Discontinuation of antiviral therapy by patient choice, intolerance of side effects, or occurrence of infection were followed temporally by rapid relapses of the cholestatic syndrome, allograft failure, and death. The only 2 patients alive in remission of this syndrome have been maintained on antiviral therapy for an average of 32 months. Thus, based on our experience, we recommend that duration of antiviral therapy in the subset of patients with cholestatic HCV recurrence should be indefinite.

Antiviral Agents↗

PubMed2003

Tumor necrosis factor-alpha promoter polymorphisms and the risk of rejection after liver transplantation: a case control analysis of 210 donor-recipient pairs.

After orthotopic liver transplantation (OLT), allograft rejection remains an important problem and is the major reason that immunosuppressive therapy must be administered. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory mediator that is central to the immune response, and intragraft expression of this cytokine is increased during acute cellular rejection (ACR). Polymorphisms within the TNF promoter have been identified and correlated with alterations in production. The aims of this study were to determine if an individual patient's propensity to develop ACR is related to the presence of these genetic polymorphisms (either alone or in combination) within donor and recipient tissue and to determine if these polymorphisms affect patient survival after OLT. The study group consisted of 210 patients who underwent OLT between 1989 and 1999 with at least 6 months survival, including 42 cases who had evidence of acute cellular rejection (biopsy-proven, elevated enzymes, and response to increased immunosuppression) and were matched 4:1 to controls (n = 168) with similar age, gender, underlying liver disease, date of transplant, and baseline immunosuppression. The underlying liver diseases were hepatisis C virus (HCV)/alcohol (70), HCV alone (50), alcohol (30), primary biliary cirrhosis (15), primary sclerosing cholangitis (15), autoimmune hepatitis/cirrhosis (10), cryptogenic (15), and hepatitis B virus (HBV) (5). DNA was extracted from paraffin-embedded donor and recipient liver tissue (total 420 samples), amplified, and sequenced for TNF single-nucleotide polymorphisms (TNFA-308 A/G and TNFA-238 A/G). We found no differences between the TNF allelic distributions among donors without liver disease (presumably representative of a normal control population) and patients with end-stage liver disease undergoing OLT. Multivariate analysis revealed no association with TNF polymorphisms (within donor or recipient tissue) and rejection risk or patient survival after transplantation. In this large case control analysis of patients undergoing liver transplantation for diverse etiologies, TNF promoter polymorphisms were not independently associated with rejection or survival.

Adult↗

PubMed2003

Hepatitis C pathogenesis: mechanisms of viral clearance and liver injury.

1. The development of hepatitis C virus (HCV) quasispecies has a number of biological consequences, including the development of escape mutants to humoral or cellular immunity, the generation of "defective" viral particles, variable cell tropism, and the development of drug resistance. 2. Accumulating evidence shows that HCV affects the early innate immune response mediated by natural killer and dendritic cells. 3. Recent data suggest that clearance of HCV bestows antibody to HCV immunity that affords partial protection against persistent infection. However, after spontaneous recovery from HCV infection, titers of HCV-specific antibodies decline and disappear in a subset of patients, whereas viral-specific CD4(+) and CD8(+) T-cell responses persist for decades. 4. HCV-specific CD8(+) T-cell responses are phenotypically and functionally diverse and may be associated with either viral eradication or chronic hepatic immunopathologic states. 5. Novel HCV genome-wide screening approaches have shown that the breadth of the immune response is considerably greater than was initially appreciated using more conventional assays, but why the majority of patients remain chronically infected despite the presence of viral-specific immune responses remains undefined.

Antibody Formation↗

PubMed2003

Graft failure from severe recurrent primary sclerosing cholangitis following orthotopic liver transplantation.

UNLABELLED: Speculation that primary sclerosing cholangitis (PSC) may recur in the transplanted liver is based on the relative increase in frequency of biliary abnormalities and histologic evidence of periportal fibrosis without other causes. A recent study demonstrated almost 9% of patients undergoing liver transplantation (OLT) for primary sclerosing cholangitis (PSC) develop recurrent sclerosing cholangitis although the patient and graft survival is not different from those in whom recurrence does not develop. Most reports of PSC recurrence post-OLT estimate rates of 1% to 14%, but to date, no center has reported rapidly progressive fibro-obliterative cholangitis leading to graft failure. CASE REPORT: DV was a 39-year-old white man with ulcerative colitis, since age 21, who developed jaundice and pruritus in 1992. ERCP and liver biopsy were consistent with PSC, and he developed thrombocytopenia and bleeding esophageal varices. He underwent an uneventful OLT in May 1994 with an ABO-compatible organ and normal ischemic times. There was no evidence of postoperative cytomegalovirus infection, hepatic artery thrombosis, or rejection. In October 1994, mild abnormalities of liver function tests (LFTs) led to liver biopsy that revealed inflammatory infiltrate in triad with spillover into lobules and mild periportal fibrosis. LFTs normalized without any treatment, but in February 1995 repeat liver biopsy for increased LFTs revealed moderate periportal fibrosis with inflammatory cells in triads and lobules. Viral shell and CMV titers were negative. No evidence of infectious etiology or rejection was noted. The patient was started on ursodeoxycholic acid at that time and percutaneous transhepatic cholangiogram (PTC) revealed marked narrowing of the intrahepatic ducts. Esophagogastroduodenoscopy (EGD) revealed esophageal varices. Hepatic arteriogram and Doppler ultrasound were negative. He developed progressive graft failure, and died at home while awaiting re-transplant. CONCLUSIONS: Although most series report mild recurrence of PSC following OLT, this case illustrates that early, severe recurrence of PSC may occur, leading to graft failure and need for re-transplantation.

Adult↗

PubMed2003

DNA vaccination protects mice against challenge with Listeria monocytogenes expressing the hepatitis C virus NS3 protein.

The goal of this study was to develop a new surrogate challenge model for use in evaluating protective cell-mediated immune responses against hepatitis C virus (HCV) antigens. The use of recombinant Listeria monocytogenes organisms which express HCV antigens provides novel tools with which to assay such in vivo protection, as expression of immunity against this hepatotropic bacterial pathogen is dependent on antigen-specific CD8(+) T lymphocytes. A plasmid DNA vaccine encoding a ubiquitin-NS3 fusion protein was generated, and its efficacy was confirmed by in vivo induction of NS3-specific, gamma interferon-secreting T cells following vaccination of BALB/c mice. These immunized mice also exhibited specific in vivo protection against subsequent challenge with a recombinant L. monocytogenes strain (TC-LNS3) expressing the NS3 protein. Notably, sublethal infection of naive mice with strain TC-LNS3 induced similar NS3-specific T-cell responses. These findings suggest that recombinant strains of L. monocytogenes expressing HCV antigens should prove useful for evaluating, or even inducing, protective immune responses against HCV antigens.

Amino Acid Sequence↗

PubMed2002

A longitudinal analysis of T-cell epitope-coding regions of hepatitis C virus after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV)-related liver failure is the single leading indication for orthotopic liver transplantation (OLT) worldwide. The mechanisms that underlie the observed differences in natural history of HCV recurrence remain poorly understood. We have previously demonstrated that differential T-cell responses correlate with histologic severity after OLT. We hypothesized that amino acid substitutions within critical T-cell epitopes could lead to increased severity of HCV disease. METHODS: We determined the peptide sequences from sequential serum-derived viral RNA by reverse transcription and direct polymerase chain reaction sequence analysis from 32 HCV genotype 1-infected patients with well-characterized outcomes after liver transplantation. Serum samples were analyzed for HCV sequence the day of OLT and at least one time point post-OLT. To construct evolutionary relationships among the different patient samples, phylogenetic analyses of core and NS3 sequences were performed using a matrix fed into a neighbor-joining tree algorithm. RESULTS: The phylogenetic analyses revealed remarkable conservation within a given individual and no significant differences when comparing patients with severe versus mild recurrence. Accordingly, the synonymous mutation rate was consistently greater than the nonsynonymous substitution rate. The nine epitopic regions analyzed were also preserved so that, with the exception of one patient with mild recurrence, none of the patients demonstrated a shift in viral peptide sequence. CONCLUSIONS: HCV core and NS3 viral peptide sequences are identical before and after OLT in most patients, suggesting that the prevalent sequence is preserved in most cases, and viral variants are competent to establish infection after OLT. Although these results do not support viral mutation as a dominant pathogenic mechanism after OLT, other viral regions need to be analyzed.

Adult↗

PubMed2002

Immunosuppression impact on long-term cardiovascular complications after liver transplantation.

BACKGROUND: With current early transplant patient and allograft survivals nearly optimized, long-term medical complications have become a significant focus for potential improvement in patient outcomes. Cardiovascular disease and associated risk factors have been shown in renal transplant patients to be related to the pharmacologic immunosuppression employed. OBJECTIVE: The objective of this study is to investigate at 3 years postliver transplant (OLTx) the incidence of hypertension (HTN), hyperlipidemia (HLIP), diabetes mellitus (DM), nephrotoxicity (NTX), and cardiovascular disease (MI, angioplasty, CHF, CVA, and seborth) as well as rejection in two cohorts of liver transplant recipients who received either tacrolimus (FK-506) or cyclosporine (CSA) and to analyze the consequences of these complications on mortality following transplantation. METHODS: Eighty-seven sequential patients (CSA: n = 50, mean age 48 years, M/F 32/18; and FK-506: n = 37, mean age 45 years, M/F 22/15) who underwent OLTx between 1994 and 1998, were >/=18 years, and had a minimum of 3 years of complete follow-up were included in the analysis. All OLTx candidates over age 50, who had a history of alcoholic cirrhosis, or had a history of cardiac conditions/events underwent complete cardiac consultation including an echocardiogram with additional cardiac investigation as indicated prior to OLTx. RESULTS: At 3 years following OLTx, the incidence of acute rejection (40% versus 19%, P < 0.05), HTN (62% versus 38%, P < 0.05), HLIP (14% versus 5%, P = 0.08), and cardiovascular disease (18% versus 0%, P < 0.001), were significantly greater for the CSA patients compared with the FK-506 patients. Eight (20%) of the CSA patients who died before 3 years had their death attributed to cardiovascular events versus none in the FK-506 group. CONCLUSION: Compared with CSA, FK-506 was associated with significantly less rejection and a reduced incidence of HTN and cardiovascular disease.

Cardiovascular Diseases↗

PubMed2002

Early hepatitis C viral kinetics correlate with long-term outcome in patients receiving high dose induction followed by combination interferon and ribavirin therapy.

BACKGROUND/AIMS: The majority of patients with genotype 1 do not respond to interferon (IFN) plus ribavirin. Limited data exist on the use of induction followed by combination therapy. METHODS: In this prospective study of 28 patients infected with genotype 1, randomization involved either daily or twice daily high dose IFN for 6 weeks, followed by standard therapy of 3 million units three times a week in combination with ribavirin for an additional 42 weeks. Hepatitis C virus (HCV) RNA was quantitated before and frequently during treatment. RESULTS: The best correlate of response was delta (the infected cell loss rate). Sixteen patients continued on the study because they had at least a 2 log drop in their HCV RNA levels by week 12; all but one were PCR negative for HCV RNA at 48 weeks, and 14 of these 16 patients continued to be PCR negative at 72 weeks. Both African-Americans in our trial failed to respond to therapy, and differences were evident during the induction phase. CONCLUSIONS: This randomized study of induction IFN therapy followed by combination IFN plus ribavirin yielded the highest rate of sustained response (50%) reported to date in chronically HCV-infected patients with genotype 1. The predictive value of the infected cell loss rate needs to be evaluated prospectively in larger studies, particularly in patients receiving pegylated IFN.

Adult↗

PubMed2002

Hepatitis C in the liver transplant recipient: current understanding and treatment.

Hepatitis C virus (HCV)-related liver disease is the leading indication for orthotopic liver transplantation worldwide. Recurrent HCV infection as defined by viremia after transplantation is nearly universal, with histologic evidence of recurrent hepatitis present in the majority. Although short-term survival appears to be similar to that in other causes of liver failure, it has recently been demonstrated that approximately 20-30% of HCV-positive patients develop allograft cirrhosis by 5 years. Therefore, it is possible to define disease outcomes within a relatively short period of follow-up. Identification of patients who are likely to develop progressive HCV-related allograft injury is important to optimize results of current antiviral therapy.

Antiviral Agents↗

PubMed2002

Analysis of sequence configurations of the ISDR, PKR-binding domain, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection.

Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only approximately 40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2alpha phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.

Adult↗