A Phase I/II Dose Escalation Trial Assessing Tolerance, Pharmacokinetics, and Antiviral Activity of NM283, a Novel Antiviral Treatment for Hepatitis C

Eliot Godofsky, Nezam H. Afdhal, Vinod Rustgi, Lawton Shick, Lael Duncan, Xiao-Jian Zhou, George Chao, Christopher Fang, Barbara Fielman, Maureen Myers, Nathaniel Brown

 

Background

Current therapy for hepatitis C has many side effects and induces a sustained virologic response in fewer than half of patients infected with hepatitis C virus (HCV) genotype 1, the most common genotype (60-70% of patients) in the USA, Europe and Japan. It isw expected that there will be 800,00 cases of end stage liver disease in the United States in the next decade. NM283, a novel candidate HCV RNA polymerase inhibitor (NS-5 region) prodrug, has anti-flavivirus activity that is highly synergistic with interferon-α in vitro, and suppresses viremia in chimpanzees chronically infected with human-derived HCV-1 (Standring, EASL2003). It has not shown any activity against HIV or other DNA virus. It is also believed that it would have synergistic with interferon therapy.

 

Aim

To report the first clinical data for NM283 in humans.

 

Methods

A phase I/II dose escalation trial is investigating NM283 in the range 50-800 mg/day. Subjects are treatment-nave or experienced adults with HCV-1 associated chronic hepatitis C, with baseline serum HCV RNA >5 log10. For each dose, 12-patient cohorts are randomized 10:2 to receive NM283 or placebo for 15 days with 14 days of follow-up.

All patients were genotype 1 of whom 87% were prior interferon non-responders. No cirrhotic patients were enrolled.

 

Results

Dosing cohorts of 50, 100, 200,400 and 800 mg/day, involving 68 patients, have been completed with once-daily oral dosing. Dose-related decreases in serum HCV RNA at Day 16 were observed, ranging from a mean 0.15 log10 at the lowest dose (50 mg/day) to 0.73 log10 at 400 mg/twice daily with a subset of patients receiving the 400 mg/twice daily. Tolerance of study treatment has been satisfactory, with no serious adverse events, dose-limiting toxicities, or pattern of laboratory abnormalities. At 400 mg/day, some NM283-treated patients experienced transient mild nausea (5/10) or vomiting (2/10) on Day 1, but all patients completed treatment without modification. NM283 is well-absorbed, with dose-proportional plasma exposure.

 

Conclusions

NM283 exhibits consistent antiviral activity with satisfactory tolerance and linear pharmacokinetics in HCV-1 infected chronic hepatitis C patients. Further investigations studies are expected to examine the side effects and in combination with pegylated interferon. Expanded testing of NM283, alone and in combination with peg-interferon, is anticipated.

 

Outcomes of a Large, Point-Source Genotype 3a Hepatitis C Outbreak in an Oncology Clinic

Mark Mailliard, Matthew Hrnicek, Mary Capadano, Richard Gilroy, James Gulizia, John Gollan

 

Background and Methods

Between March, 2000 and June, 2001, at least 95 adults acquired chronic infection with genotype 3a hepatitis C (HCV-3a) in an oncology clinic in Fremont, Nebraska. Infection occurred through the flushing of their intravenous access with HCV-contaminated saline. Following recognition in 2002 of transmission in a health-care setting, screening of 486 at-risk patients revealed 77 with serum HCV antibody/HCV RNA, 18 HCV antibody negative/HCV RNA positive individuals, and four HCV antibody positive/HCV RNA undetectable persons. None of the patients had other risk factors for HCV. At the time of HCV exposure, all but four were being or had recently been treated for malignancy. This HCV-3a cluster is the largest known nosocomial, non-concurrent, point-source transmission of HCV in the United States. We report the clinical outcomes, with and without antiviral treatment, of 55 of the 95 HCV-3a patients.

 

Results

The mean age of our HCV-3a cohort at infection was 58.1 years (range: 19-87), 100% Caucasians, and with slightly more women. The most common malignant diagnoses were colorectal (11) or breast (10) cancer and non-Hodgkins lymphoma (6). Symptoms had occurred in 18% of patients. Liver histology was available for 30 of the HCV-3a patients. The inflammation grade, fibrosis stage, and steatosis grade and distribution were determined. Grade 1 or 2 inflammation was observed in 88%; no patient had severe inflammation. Ten patients (33%) had steatosis present in greater than 30% of hepatocytes. Eight patients (25%) had stage 3 or 4 fibrosis in liver biopsy specimens obtained within two years of HCV-3a acquisition. Of nine patients with clinical evidence of portal hypertension or histologically advanced fibrosis, only one had evidence of a co-factor that predicted liver disease (iron overload). One HCV-3a patient died awaiting liver transplantation. Only one HCV-3a patient has died from pre-existing malignancy (metastatic adenocarcinoma of the prostate).

 

Twenty-two patients received interferon plus ribavirin treatment. Nineteen of the 20 patients who complete treatment achieved a sustained virological response. Forty-five percent of the treated patients required growth factors or dose reductions.

 

Conclusions

The high rate of chronic infection, relative lack of HCV antibody and advanced liver injury indicate that co-factors exist in this HCV-3a cohort that lead to susceptibility to chronicity, atypical immune reponse and rapid progression of fibrosis. In addition to older age; immunosuppression, concurrent malignancy and its associated chemotherapy are potential co-factors that may accelerate the progression of chronic HCV infection.

In addition the authors further noted:

     They could not identify cancer therapy as a subset to disease progression

     They could not predict liver disease progression based on lab values ( blood tests)

     They could not really identify a co-factor for disease progression, but the authors suggested that it might be chemo therapy related.

Impaired Allostimulatory Function of Dendritic Cells in Acute Hepatitis C Favors Chronicity

Sanaa M. Kamal, Qi He, Alaa Ismail, Khalifa El Sayed, Sherif Ibrahim, Jens W. Rasenack, Margaret J. Koziel

 

Background/Objectives

The striking feature of hepatitis C (HCV) infection is its high tendency to chronicity. HCV chronic infection is characterized by low or undetectable cellular immune responses against HCV antigens, however the exact mechanism responsible for such alteration is not known. Dendritic cells (DCs) are efficient type of cells involved in antigen presentation (APC) and are capable of inducing a primary immune response. However, dendritic cells are prime targets of persistent viruses such as HCV. We hypothesized that impairment of DC functions during the acute hepatitis C may contribute to viral persistence.

 

Patients/ Methods

Peripheral blood DCs purifaction (magnatic sorting and positive selection), phenotypic analysis, allogeneic stimulatory capacity of DC (S.I.) as well as HCV-specific CD4+ T-cell & cytotoxic responses (ELISpot), cytokine production (IL-12, IL-10) and detection of HCV genomic sequences in DCs (RT-PCR) were prospectively assessed in 28 patients (all genotype 4)with proven acute hepatitis C and the results were correlated to the outcome of acute hepatitis.

 

Results

During acute infection, HCV DCs from HCV infected subjects with chronic evolution (n=21) showed significantly less allostimulatory function as their ability to stimulate proliferation of allogeneic T cells was significantly impaired compared to subjects with spontaneous resolution (n=4;P = 0.001). HCV-DCs also showed less antigen capture capacity but normal morphology and phenotype. HCV sequences were detected in DC cultures from 17/21 subjects with chronic evolution. The same pattern of impaired proliferation was observed in in the form of absent or weak HCV specific CD4+ and cytotoxic CD8+ responses (CTL) were detected in subjects with chronic evolution. In subjects who achieved spontaneous viral clearance, restoration of the allostimulatory function of DCs coincided with the absence of HCV viremia and strong multi-specific HCV specific CD4+Th-1 (IL-12) cell response were maintained. Viral clearance correlated with the DC stimulatory capacity and HCV-specific CD4+ and CD8+ responses.

 

Conclusion

These results indicate that chronic infection by HCV is associated with an allostimulatory defect of peripheral blood dendritic cells leading to inefficient HCV-specific CD4+ and CD8+-T cell responses. There was no big differences between the two types of dendrtic cellsw. These findings have important implications for novel immunotherapeutic strategies.

 

Combination of PegInterferon Alfa-2b and Lamivudine is Superior to Lamivudine Alone in the Treatment of Chronic Hepatitis B Infection

Joseph J. Y. Sung, Henry L. Y. Chan, Alex Y. Hui, Vincent W. S. Wong, Choong-Tsek Liew, Angel M. L. Chim, Francis K. L. Chan, Lawrence C. T. Hung, Yuk-Tong Lee, Nancy W. Y. Leung

 

Background

Treatment of chronic hepatitis B infection is far from ideal and previous studies combining conventional interferon with lamivudine yielded conflicting results.

 

Aim

This prospective randomized study set to evaluate the efficacy and safety of peginterferon alfa-2b and lamivudine combination for chronic hepatitis B infection.

 

Methods

HBeAg-positive treatment-naive patients were randomized to receive either a combination of 32-week peginterferon alfa-2b (1.5mcg/kg/wk, max 100mcg) first than and 52-week lamivudine (100mg daily) or 52-week lamivudine (100mg) monotherapy alone. HBV DNA levels (measured by TaqMan real-time PCR assay), HBeAg status, HBV genotype, drug resistant mutant (INNO-LiPA HBV DR line probe assay), serum transaminase levels were monitored. Pre- and post-treatment liver histology (necro-inflammatory score according to Knodell system and fibrosis score according to Ishak system) were compared. The primary endpoint was sustained virological response (HBeAg seroconversion and HBV DNA <500,000 copies/ml) at 24 weeks after finishing medication. Secondary endpoints include end-of-treatment virological response, reduction in HBV DNA levels, biochemical responses and histologic necro-inflammatory and fibrosis scores.

 

Results

100 patients were randomized into the 2 treatment groups (50 each). Sustained virological response was significantly higher in combination therapy than lamivudine monotherapy (36% vs 14%, p=0.03, adjusted odds ratio=3.74, 95% CI 1.14-12.29). At the end of treatment, patients received combination therapy had a higher rate of virological response (60% vs 28%, p=0.003), had more substantial reduction of log10 HBV DNA (3.91 vs 2.83, p<0.001) and were less likely to have lamivudine resistant mutant (21% vs 40% p=0.045) than those who received lamivudine monotherapy. The median reduction in necro-inflammatory score in the combination group and lamivudine monotherapy group were 2 and 3 respectively (p=0.21). There was no significant change in the median fibrosis score in the two treatment groups.

 

Conclusions

In patients with HBeAg-positive chronic hepatitis B infection, combination of peginterferon alfa-2b and lamivudine yielded significantly better results than lamivudine monotherapy.

 

Editors note:

Unfortunately, there was no study arm for pegylated interferon mono-therapy. Since lamivudine has a high incidence of drug resistance it may not provide an additional treatment benefit over pegylated interferon alone considering the risk of developing lamivudine resistance virus.