Investigational Therapies
In last month’s HCV Advocate I reported on the data from three new therapies to treat hepatitis C – viramidine, valopicitabine (NM 283) and albuferon. Viramidine (in combination with pegylated interferon) is a prodrug of ribavirin. The data on the effectiveness of viramidine was similar to the group that was treated with ribavirin (in combination with pegylated interferon). Valopicitabine is an oral nucleoside analog – a new class of drugs that directly inhibit the hepatitis C RNA polymerase. The preliminary results from the 24 week data found that there was a 99.0% decrease in HCV RNA (viral load). Albuferon is a form of time released interferon that was found to produce a 99.9% decrease in HCV RNA (viral load) with 23% of the same patients remaining HCV RNA negative. The information from EASL on these new therapies and possibly improved therapies to treat hepatitis C seemed very promising. Building on the positive news from EASL, there was even more information on new HCV drugs presented at DDW. The highlight of the conference was information about VX-950, a new HCV polymerase inhibitor.

VX-950
VX-950 is an oral protease inhibitor of the hepatitis C virus discovered by Vertex Pharmaceuticals. The mechanism of action of VX-950 is to inhibit an enzyme of the hepatitis C virus responsible for viral replication. If the hepatitis C virus can not make additional copies it can possibly be eradicated.

In this study, a total of 8 healthy volunteers and 34 HCV patients were treated with VX-950 in three different dosing arms – 450 mg every 8 hours, 1250 mg every 12 hours or 750 mg every 8 hours or placebo for 5 and 14 days. All patients in the HCV positive group genotype 1 (the most difficult to treat) were either previous non-responders to HCV treatment or patients who had never been treated. It was reported that VX-950 was well- tolerated with no serious side effects that required discontinuation of therapy. It was also noted that there were no elevations of ALT or AST liver enzymes in the treated patients. Across all of the treatment arms patients achieved at least a 1,000-fold reduction of hepatitis C RNA (viral load). The dosing arm that was most effective was the 750 mg arm which achieved a median viral load reduction of 25,000 fold in 4 out of 8 patients. Two patients achieved viral load reductions below the level of detection.

Vertex reported that based on these positive results they are planning further studies using VX-950 monotherapy as well using it in combination with currently approved medications to treat hepatitis C.

Actilon
Actilon (CPG 10101) is a member of a new class of drugs that induces the body’s natural types of interferon to help restore immune function. The data on two randomized, placebo-controlled dose escalation (5 different doses injected subcutaneously) studies of 42 HCV positive people who were non-responders to a previous course of HCV therapy were reported. The greatest decline in viral load was seen in the group receiving the 20 mg dose. Five of the six patients receiving the 20 mg dose twice weekly achieved a 96% reduction in HCV viral load in 4 weeks. While on the therapy five of the six patients in this arm achieved at least a 90% reduction in HCV viral load. The drug was generally well-tolerated. The side effects reported were injection site reactions and mild flu-like symptoms. The authors concluded “early antiviral activity has been demonstrated with CPG 10101” and “safety results suggest that higher doses for a longer treatment period are tolerable.” Further studies examining CPG 10101 both as monotherapy and in combination with interferon plus ribavirin therapy are being planned.

PEG-alfacon
Data from a phase 1 clinical trial of PEG-alfacon (pegylated IFN alfacon 1 – a time released form of consensus interferon) was presented at DDW which showed that PEG-alfacon was safe and well-tolerated in healthy individuals and that further studies are warranted in patients with hepatitis C.

InterMune’s HCV Protease Inhibitors
Information from pre-clinical studies was presented on InterMune’s two HCV protease inhibitors currently under development. It was found that in vitro (in a test tube) these two drugs were stable and targeted the liver in the preclinical models. Additional testing of these compounds is being planned.

The results of all of these studies are very encouraging. The dramatic reduction in HCV RNA (viral load) in the VX-950 study and the NM 283 study reported last month show great promise for future HCV treatments. However, all of these drugs are in early clinical development and the effectiveness and tolerability of these new drugs will not be known until larger clinical trials are enrolled, conducted and completed – which could take as long as 5 to 15 years depending on the current stage of clinical development.

The bottom line is that people should not delay or stop therapy based on these results because the odds of any new drug moving from clinical development to FDA marketing approval for treating any disease is very low.

Treatment – Patients with Decompensated Cirrhosis
Treating people who are in end-stage disease (decompensated cirrhosis) can be difficult because current HCV medications can accelerate the decompensation or the disease progression process. However, people with decompensated cirrhosis are the ones who are in the most need for treatment to help delay or stop further deterioration of the liver. Previous studies have found that people with decompensated liver disease can be successfully treated in research settings under careful observation. In addition, it has been found that even in this difficult to treat population that some people will achieve a sustained virological response (SVR-HCV undetectable during and six months post treatment) and improvement in liver health.

A study by Kim et al was presented at DDW on a trial of 32 patients with decompensated cirrhosis. Treatment consisted of pegylated interferon plus ribavirin (78.1% of patients), pegylated mono-therapy (12.5 % of patients) or interferon plus ribavirin (9.4%) for an average of 37.8 weeks. In addition, all of the patients were treated for complications of cirrhosis (ascites and varices) prior to starting HCV therapy to optimize liver function. All of the patients were closely monitored within a major university transplant program for possible complications. Growth factors to manage treatment related side effects were used.

The overall SVR rate reported was 31.3% (genotype 1 – 21.1% SVR; 53.8% SVR in non-genotype 1 patients). As the result of treatment, 5 patients (15.6%) in this study were removed from the transplant listing due to improvements in liver functioning. No patient died as the result of therapy.

A total of 84.4% of patients in this study experienced some form of adverse event with six patients (18.8%) requiring discontinuation of therapy and one patient was required to discontinue therapy due to liver decompensation. The most common side effects included anemia, neutropenia, depression and infections.

The authors concluded that “antiviral therapy appears to be safe and effective in carefully selected patients with decompensated cirrhosis” and that “treatment may result in SVR in nearly one-third of patients.” This is very encouraging news for patients with end-stage disease who currently have very few options other than liver transplantation.

Diabetes and HCV
It is well known that people infected with hepatitis C are at a higher risk for developing Diabetes Mellitus than the general population even though the direct link between the hepatitis C virus and diabetes has not been proven. However, many experts believe that there is either a direct viral mechanism involved or that the hepatitis C virus indirectly causes or increases the likelihood of developing diabetes.

V. Khurana et al reported on a large retrospective study of about a half a million U.S. veterans to investigate the statistical association between HCV and diabetes. Information was collected from October 1998 to June 2004 on 480,306 veterans – 91.7% were males. The average age in this study was 61.1 years. Of these, 103, 256 (21.5%) had diabetes and 14,021(2.92%) had hepatitis C.

After analyzing the data the authors found that in people who are infected with hepatitis C there is a 48% increased risk of diabetes even after controlling for other well known diabetes risk factors – age and body mass index.

Physician Knowledge and HCV
Previous studies have found that among first year residents the knowledge of hepatitis C is very low, with many first year interns misinformed about hepatitis C. What is worrisome about the lack of knowledge is that this group of physicians is the next generation who will identify, evaluate and manage people with hepatitis C.

In a study conducted by J.K. Lim et al, a 1-page survey assessing the knowledge and practices concerning hepatitis C infection was given to 251 internal medicine residents at 8 ACGME-accredited U.S. Training programs. The residents were equally distributed among three post-graduate years. 89.6% were U.S. medical graduates enrolled in traditional (64.9%) or primary care (22.7%) programs and 98% had seen patients with hepatitis C within the past year (60.6% had seen more than 10 patients within this timeframe).

The key findings were:

• Screening for HCV
 w Most screened for hepatitis C in patients with abnormal ALT’s (85.3%), prior needlestick exposure (82.1%), prior injection drug use (80.9%) or HIV infection (77.7%), but many did not screen for other at risk populations, including people with a history of blood transfusion (59.8%), snorting cocaine (26.7%) or incarceration (21.5%)

• Performed a viral load test
 w45.5% performed HCV PCR (viral load) test

• Performed a genotype test
 w36.7% performed a genotype test

• Vaccinated HCV positive individuals against HAV and HBV
 w33.1% vaccinated against HAV
 w61.4% vaccinated against HBV
 w19.5% were familiar with HAV vaccine schedule and 64.5% for HBV vaccine schedule
 wMost alarming was that 20.3% reported that they vaccinated HCV negative individuals with an HCV vaccine.

• HCV and liver transplantation
 w30.7% named HCV as the #1 reason for liver transplantation

• Knowledge about factors that influence HCV disease progression
 wAlcohol (80.5%)
 wHIV (75.3%)
 wHBV (64.1%)

• Knowledge about genotype information
 w25.5% identified genotype 1 as the most common in the U.S.
 w22.3% identified genotype 1 as the least responsive to therapy

• Knowledge about medicines to treat HCV
 w35.5% identified interferon/ribavirin or pegylated interferon/ribavirin therapy as the 1st line of antiviral therapy
 w30.7% incorrectly named lamivudine (used to treat HBV) as a therapy for HCV

• Knowledge about HCV disease progression
 w10.0% correctly estimated the rate of chronic infection after exposure
 w14.7% correctly estimated the risk of developing cirrhosis at 20 years of infection

• Self-knowledge about HCV
 w23.9% reported that they feel adequately trained in HCV management.

The authors concluded that “many internal medicine residents receive inadequate training in the management of chronic HCV infection. Most lack basic knowledge regarding epidemiology, natural history, diagnosis, clinical course and treatment of HCV. Targeted educational interventions are needed to address knowledge deficits among future primary care physicians.”

Hopefully as more and more physicians become educated about hepatitis C, the lack of knowledge or misinformation among some physicians will be reversed. Until then, it is extremely important that all patients educate themselves as much as possible about HCV disease management so that they can receive the best possible medical care when they partner with their medical providers.

http://www.hcvadvocate.org/news/newsLetter/2005/advocate0605.html#1