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Biomedical subjects

M Krajden

Publications and source records attributed to M Krajden.

At least 19 recordsLinked to original sources
PubMed2006

Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.

BACKGROUND: The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. AIMS: We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. PATIENTS: Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. METHODS: Patients were retreated with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators' discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. RESULTS: A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and relapsers were similar although more non-responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. CONCLUSIONS: These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.

Adult↗
PubMed2006

Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice.

BACKGROUND: Pegylated interferon alfa-2a (40 KD) plus ribavirin therapy induces sustained virological response rates up to 63% in randomized-controlled trials. AIM: To conduct a prospective open-label programme to examine the efficacy and safety of this therapy in routine clinical practice. METHODS: Treatment-naive patients with chronic hepatitis C received, at the discretion of the investigator, pegylated interferon alfa-2a 180 microg/week + ribavirin 800 mg/day for 24 or 48 weeks. In total, 508 patients were enrolled [334 non-cirrhotic; 174 cirrhotic (defined as stage F3 and F4)]. RESULTS: In genotype 1 patients treated for 48 weeks, sustained virological response rates were 41% in non-cirrhotics and 34% in cirrhotics. Sustained virological response rates in genotype 2 or 3 non-cirrhotics were 79% (24 weeks) and 72% (48 weeks). Corresponding values for cirrhotic genotype 2/3 were 66% and 44%. The negative predictive value of an early virological response at week 12 was 94%. Predictive factors for sustained virological response on multivariate analysis were genotype (2/3 vs. 1), low viral load and degree of fibrosis. Rates of serious adverse events (<or=5%) and adverse events inducing withdrawal (<or=8%) were comparable with the phase III trials. CONCLUSION: Efficacy and safety of pegylated interferon alfa-2a + ribavirin in clinical practice is comparable with results of randomized-controlled trials.

Adult↗
PubMed2005

Clinical utility of viral load measurements in individuals with chronic hepatitis C infection on antiviral therapy.

SUMMARY: Both absolute viral load and log decline in viral load from baseline were found clinically useful in predicting sustained virological response and lack of sustained virological response (non-sustained virological response, NSVR) to treatment. We assessed the clinical utility of hepatitis C virus (HCV) RNA quantitation and changes in viral load using the VERSANT HCV RNA 3.0 Assay (bDNA) in 351 HCV-infected individuals treated with interferon plus ribavirin. We show that viral load decision thresholds provided negative predictive values (NPVs) of >95% at week 4 using a 100 000 IU/mL cut-off and at weeks 8 and 12 using 10 000 IU/mL cut-offs. A 2-log decline from baseline provided NPVs >95% at weeks 8 and 12. Combinations of absolute viral loads and changes in viral load from baseline did not enhance the performance of the decision rules for predicting NSVR. The positive predictive values (PPVs) at weeks 8 and 12 were 59.1 and 67.3%. This study highlights the critical importance of viral quantitation in gauging therapeutic response in patients with chronic HCV infection on antiviral therapy. Early changes in viral load, measured as absolute viral loads or change in viral load from baseline, are highly predictive of NSVR at 8 and 12 weeks. PPVs are modest but these data may provide encouragement to patients who are in the early phases of treatment when side effects are frequent. Additionally, we demonstrated the need for cautious interpretation of stopping rules when the values are at or near the decision thresholds.

Adult↗
PubMed2001

Detection of hepatitis C virus in the corneas of seropositive donors.

PURPOSE: There have been no reported cases of hepatitis C virus (HCV) transmission by corneal transplantation. Previous studies have also shown no correlation between HCV seropositivity and the presence of HCV RNA in the corneal tissues. This study aims to investigate such correlation and to provide further evidence to the possible transmissibility of HCV via corneal grafts. METHODS: Of the 1,619 potential corneal donors to the Eye Bank of Canada over a 1-year period, 15 tested HCV-positive by the second-generation Abbott HCV enzyme immunoassay (EIA) 2.0 assay. Their sera were further tested with second-generation radio-immunoblot assay (RIBA-II), and their corneas (29 altogether) were processed for identification of HCV RNA using polymerase chain reaction (PCR). RESULTS: Of the 29 corneas from seropositive donors, HCV RNA was detected in 7 (24.1%). CONCLUSION: This is the first study in the literature that demonstrates a significant correlation between HCV seropositivity and the presence of HCV in the corneas. Routine HCV serologic testing for all potential corneal donors and rejection of corneal tissues based on HCV seropositivity is certainly justifiable.

Adult↗
PubMed2001

Antenatal seroprevalence of herpes simplex virus type 2 (HSV-2) in Canadian women: HSV-2 prevalence increases throughout the reproductive years.

BACKGROUND: This study sought to provide the first population estimates of herpes simplex type 2 (HSV-2) seroprevalence in Canada. GOAL: To measure the antenatal seroprevalence of HSV-2 antibodies in reproductive age women. STUDY DESIGN: An anonymous unlinked seroprevalence study used stored sera collected from pregnant women in British Columbia during 1999. Randomized sampling within age strata selected a total of 1215 subjects, ages 15 to 44 years. Serologic testing used the Gull Meridian Test. Overall prevalence was directly standardized to the 1999 Canadian female population. RESULTS: The age-adjusted prevalence for HSV-2 was 17.3% (95% CI, 15.2-19.4). Prevalence ranged from 7.1% (ages, 15-19 years) to 28.1% (ages, 40-44 years), with the largest increases after the age of 24 years. CONCLUSIONS: The HSV-2 seroprevalence among pregnant women in British Columbia is similar to that in the United States and other countries. Seroprevalence continues to rise through the later reproductive years. This observation may relate to continued transmission, an age cohort effect, or both.

Adolescent↗
PubMed2001

Infection with Burkholderia cepacia in cystic fibrosis: outcome following lung transplantation.

As a result of concern over excessive mortality after lung transplantation, many transplant programs refuse to accept cystic fibrosis (CF) patients infected with Burkholderia cepacia. As a significant proportion of patients with CF in our community are infected with this organism, we have continued to provide lung transplantation as an option. A retrospective review was conducted of medical records of all patients with CF transplanted between March 1988 and September 1996. Fifty-six transplant procedures were performed in 53 recipients with CF between March 1988 and September 1996. Twenty-eight had B. cepacia isolated pretransplant and 25 remaining positive post-transplant. Of the 53 recipients, 19 have died (15 of 28 [54%] B. cepacia positive and 4 of 25 [16%] B. cepacia negative). B. cepacia was responsible for or involved in 14 deaths. Nine of the deaths occurred in the first 3 mo post-transplantation. One-year survival was 67% for B. cepacia positive patients and 92% for B. cepacia negative patients. Recent modifications in antimicrobial and immunosuppressive therapy since 1995 have resulted in no deaths early post-transplant in the last five patients transplanted. We conclude that early mortality in patients with CF infected with B. cepacia is significantly higher than in those not infected with B. cepacia. Modifications in post-transplant medical therapy may improve outcome.

Adult↗
PubMed2000

A multicenter study evaluation of the digene hybrid capture II signal amplification technique for detection of hepatitis B virus DNA in serum samples and testing of EUROHEP standards.

We have evaluated the new Digene Hybrid Capture II HBV DNA Test (HCII HBV), which is a 96-well microtiter plate-based signal amplification assay. This test uses hybrid capture technology that specifically detects RNA-DNA hybrids. HCII HBV is able to quantify hepatitis B virus (HBV) DNA at between 1.4 x 10(5) and 1.7 x 10(9) HBV copies per ml in a standard format. By using a modified sample preparation method, which allows the input of 30-fold more serum for an ultrasensitive format, the sensitivity of the assay can be increased reproducibly to approximately 8,000 copies of HBV per ml. By using a combination of these two formats, the assay can quantify over a total range of 6 logs. In our multicenter evaluation study, the mean laboratory-to-laboratory coefficients of variation were 22, 7, and 12% at the three sites, respectively, with a combined specificity of 98.4%. The linearities of both the standard test and the ultrasensitive test were excellent, with Spearman correlation coefficients of 0.997 and 0.999, respectively. Furthermore, the intra-assay reproducibility for the standard assay gave coefficients of variation of from 13 to 33, 9 to 21, and 3 to 8% at the three sites, respectively. HCII HBV was shown to be genotype independent when the EUROHEP standards for genotypes A and D were used. This assay allows the accurate measurement of HBV DNA levels in serum and can be clinically used for the monitoring of responses to antiviral agents for patients chronically infected with HBV.

DNA, Viral↗
PubMed2000

Successful treatment of juvenile laryngeal papillomatosis-related multicystic lung disease with cidofovir: case report and review of the literature.

Cidofovir, a nucleoside analog antiviral agent, has been used with moderate success in the treatment of juvenile laryngeal papillomatosis (JLP) by direct intralesional injection. We report the first case where IV cidofovir was used successfully to treat a rare but lethal multicystic lung disease complicating JLP. A 35-year-old woman with a history of JLP requiring multiple laser ablations of laryngeal papillomata each year presented with hemoptysis and was found on CT scan to have bilateral, multiple pulmonary nodules and cysts. The results of BAL fluid analysis demonstrated no evidence of malignancy, and cultures were negative for fungi and mycobacteria. Molecular DNA typing of a biopsy specimen obtained from a laryngeal papilloma confirmed infection with human papilloma virus type 11. She received 12 months of treatment with IV cidofovir followed by 9 months of combined treatmentwith IV cidofovir and subcutaneous interferon-alpha-2A. This therapeutic regime resulted in a markedly decreased requirement for surgical removal of laryngeal papillomata, and CT scanning documented the regression of the lesions in the lung parenchyma that persisted after the discontinuation of therapy. The results of this case demonstrate that cidofovir may be used successfully to treat JLP-related lung disease and suggest that further studies are warranted.

Adult↗
PubMed1999

Clinical utility of quantitative cytomegalovirus viral load determination for predicting cytomegalovirus disease in liver transplant recipients.

BACKGROUND: The early detection of cytomegalovirus (CMV) after liver transplantation may form the basis of a preemptive strategy for prevention of active CMV disease. METHODS: We prospectively analyzed the clinical use of weekly quantitative polymerase chain reaction-(PCR) based plasma viral load determinations and the antigenemia assay for predicting the development of active CMV disease in 97 consecutive liver transplant recipients. RESULTS: CMV disease occurred in 21/97 patients. Using a positive cut-off of >400 copies/ml plasma, PCR had a sensitivity of 100%, specificity 47.4%, positive predictive value 34.4% and negative predictive value 100% for prediction of CMV disease. Respective values for a positive antigenemia (>0 positive cells/slide) were 95.2, 55.3, 37.0, and 97.7%. Different cut-off points for a positive test were analyzed using receiver-operating characteristic (ROC) curves. The optimal cut-off for viral load was in the range of 2000-5000 copies/ml (sensitivity 85.7%, specificity 86.8%, PPV 64.3%, NPV 95.7% for >5000 copies/ml). The optimal cut-off for antigenemia was in the range of four to six positive cells/slide. Mean peak viral load in symptomatic patients was 73,715 copies per/ml versus 3615 copies/ml in patients with asymptomatic CMV reactivation (P<0.001). In a multivariate logistic regression analysis of risk factors for CMV disease (CMV serostatus, acute rejection, and induction immunosuppression), peak viral load and peak antigenemia emerged as the only significant independent predictors of CMV disease (for PCR, odds ratio=1.40/1000 copy/ml increase in viral load, P=0.0001; for antigenemia odds ratio=1.17/1 positive cell/slide). CONCLUSIONS: Plasma viral load by quantitative PCR is useful for predicting CMV disease and could be used in a preemptive strategy.

Adolescent↗
PubMed1999

Outcome of long-term ribavirin therapy for recurrent hepatitis C after liver transplantation.

Ribavirin therapy was initiated at a median of 181 days after liver transplantation in 18 patients with persistent elevation of alanine aminotransferase values and biopsy-proven hepatitis, and continued for 23 months (12-44 months). All patients had a prompt biochemical response, with alanine aminotransferase decreasing by 69%; complete normalization occurred in 5 (28%). Serum hepatitis C virus RNA levels did not change during therapy. Liver biopsies obtained after 17 months (9-38 months) of therapy showed no improvement in necroinflammation. However, worsening of fibrosis occurred in 12 patients; and cirrhosis developed in 5 patients (28%), with 3 patients progressing to graft failure. Biopsies from 27 untreated patients who did not fulfill treatment criteria (median follow-up, 38 months) and 4 patients who received 3 months of ribavirin (44 months) showed cirrhosis in 11 and 75%, respectively. Patient and graft survival rates for treated and untreated patients were similar. Although ribavirin improves alanine aminotransferase, it does not prevent the development or progression of fibrosis in patients with recurrent hepatitis C virus.

Adult↗
PubMed1999

Detection of occult low-grade b-cell non-Hodgkin's lymphoma in patients with chronic hepatitis C infection and mixed cryoglobulinemia.

Hepatitis C virus (HCV) is both hepatotropic and lymphotropic and has been shown to be associated with the benign lymphoproliferative disorder, mixed cryoglobulinemia (MC). Preliminary studies suggest that there may be an association between chronic hepatitis C, MC, and non-Hodgkin's lymphoma (NHL). The aim of this study was to determine whether patients with chronic HCV and MC have occult bone marrow NHL. Sixteen patients with chronic HCV and clinically active MC underwent bone marrow biopsy and aspiration. Flow cytometry was performed looking for abnormal B-cell lineage. Molecular genetic studies were performed to identify B-cell monoclonality. Nine of 16 patients (56%) had abnormal marrow morphology, 7 (44%) were interpreted as suspicious for lymphoma, and 2 (13%) as consistent with lymphoma. Flow cytometry on 13 patients identified 5 (39%) with increased B-cell populations. Molecular analysis on 13 patients identified 3 (23%) with monoclonal proliferation of the B-cell lineage. All 13 patients tested for Epstein-Barr virus were negative by polymerase chain reaction (PCR). Four of 16 patients (25%) had marrow morphology and evidence of a monoclonal B-cell population by flow cytometry and/or molecular studies, consistent with B-cell NHL. These findings confirm the presence of lymphoproliferative disorders in patients with chronic HCV and MC. Some of these disorders meet the morphological and molecular criteria for the diagnosis of malignant lymphoma.

Adult↗
PubMed1999

No association between hepatitis C and B-cell lymphoma.

Chronic viral infection has been implicated in the pathogenesis of B-cell lymphoma, and hepatitis C virus (HCV) infects lymphocytes. Chronic infection with HCV may result in B-cell proliferation. Individuals infected with hepatitis C are often co-infected with the RNA virus GB virus type C. Studies from Europe where hepatitis C infection is more common than in North America have shown a high prevalence of hepatitis C infection in patients with B-cell lymphoma. The aim of this study was to establish the prevalence of HCV and GBV-C infection in patients with B-cell lymphoma in an area of low HCV prevalence. One hundred patients with B-cell lymphoma (10 high grade, 46 intermediate grade, and 44 low grade) and 100 controls with nonhematological malignancies were studied. Serum was analyzed for HCV antibodies by third generation enzyme-linked immunosorbant assay, and HCV RNA and GBV-C RNA was analyzed by reverse transcriptase PCR. None of the controls or lymphoma patients had antibodies to HCV. HCV RNA was undetected in 60 out of 100 lymphoma patients tested. GBV-C RNA was detected in the serum of 5 out of 100 (5%) of lymphoma patients and in 3 out of 100 (3%) controls. Hepatitis C and GBV-C are, therefore, unlikely to play a major role in the pathogenesis of B-cell lymphoma in North America.

Antibodies, Viral↗
PubMed1999

Long-term follow-up of a randomized trial of interferon therapy for chronic hepatitis B in a predominantly homosexual male population.

BACKGROUND/AIMS: Extended follow-up of a previously published therapeutic trial with interferon alfa is now available to further clarify the long-term outcome of HIV-negative and HIV-positive subjects with chronic hepatitis B virus infection after interferon alfa therapy. METHODS: Forty-five subjects with compensated liver disease and chronic hepatitis B infection with evidence of active hepatitis B replication were studied. These subjects were enrolled between 1986 and 1991 and had been randomized, stratified by HIV status, to either receive interferon therapy (10 MU/m2 of lymphoblastoid interferon alfa 3 times per week for 12 weeks) or no treatment. Hepatitis B serology, serum hepatitis B viral DNA and alanine aminotransferase were measured on an annual to biannual basis. CD4-positive T lymphocyte counts and HIV RNA concentration were also obtained. RESULTS: From 9 months post-interferon alfa treatment to the end of the extended follow-up (4 to 9 years), the relative risk of seroconverting to anti-HBe positive for subjects who had received interferon alfa therapy compared to those who did not was not significant in either HIV-negative (p = 0.80) or HIV-positive (p = 0.62) subjects. CONCLUSIONS: Unlike the first 9 months following interferon alfa therapy, the rate of elimination of markers of hepatitis B virus replication, regardless of HIV status, was not increased above the natural rate beyond 9 months following interferon alfa therapy.

Adult↗
PubMed1999

Assessment of hepatitis C virus RNA stability in serum by the Quantiplex branched DNA assay.

OBJECTIVES: Quantification of hepatitis C virus (HCV) RNA in serum is used to assess the probability of treatment response and to monitor antiviral therapy. Since serum specimens often are shipped to central sites for HCV RNA testing, it is important to define conditions that preserve HCV RNA integrity. METHODS: We evaluated the stability of HCV RNA in 25 previously frozen (PF) and 11 fresh, never previously frozen (NPF) specimens subjected to handling and short-term storage conditions that mimic those encountered during interlaboratory shipping. All sera were separated within 4 h of collection. PF samples covering a approximately 3 log10 HCV RNA dynamic range were thawed, divided into aliquots, incubated at 4, 23, and 37 degrees C (+/- 1.5 degrees C) for 24, 48, 72 and 96 h (+/- 2 h), and then refrozen at -70 degrees C prior to testing with the Quantiplex HCV RNA 2.0 assay. Eleven NPF samples were stored at -70, -20, and 4 degrees C (+/- 1.5 degrees C) for up to 1 month prior to testing. RESULTS: Linear regression analysis showed no HCV RNA degradation in PF specimens kept at 4 degrees C over 4 days. However, HCV RNA levels in PF specimens decreased over 4 days by 20 and 105% at 23 and 37 degrees C, respectively. Three independent statistical methods showed that the probability of specimen failure in PF specimens, defined as a loss of 20% or more of HCV RNA, was lowest at 4 degrees C and increased with increasing temperature. The HCV RNA quantification of the 11 NPF specimens stored at 4 degrees C was similar to their frozen controls. CONCLUSION: HCV RNA in separated serum specimens is stable for at least 4 days at 4 degrees C.

DNA, Viral↗
PubMed1999

Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial.

We conducted a phase 1 trial of direct injection of an E1, E3-deleted adenovirus encoding interleukin-2 (AdCAIL-2) into subcutaneous deposits of melanoma or breast cancer. Twenty-three patients were injected at seven dose levels (10(7)-10(10) p.f.u). Local inflammation was observed at the site of injection in 60% of patients, but side-effects were otherwise minor. Incomplete local tumor regression occurred at the site of injection in 24% of patients, but no conventional clinical responses were seen. Circulating CD4 and CD8 counts fell significantly 24 h after injection. Post-injection biopsies demonstrated tumor necrosis and lymphocytic infiltration with the predominant tumor-infiltrating cells both CD3- and CD8-positive. Vector-derived sequences were detected in 14 of 18 biopsies examined 7 days after injection and vector-derived hIL-2 mRNA was detected in 80% of 7-day biopsies processed after injection of 10(8) p.f.u. of AdCAIL-2 or higher. While IL-2 was detectable by ELISA in tumor biopsies at 48 h, no protein was detectable in injected tumors after 7 days and no circulating IL-2 was detectable at any time-point. No Ad5E1 sequences were detected either before or after injection indicating absence of replication-competent virus or endogenous E1-like sequence; furthermore, only rare vector shedding was detected. Anti-adenovirus and neutralizing antibody titers were elevated 1 month after injection in all patients. This trial therefore confirms the safety of use of adenoviral vectors for gene delivery in humans and demonstrates successful transgene expression even in the face of pre-existing immunity to adenovirus.

Adenoviridae↗