Hepatitis C Harm Reduction Project

The real IDEAL: Peg-Intron vs. Pegasys

Schering-Plough recently announced the launch of a major study pitting their pegylated interferon, Peg-Intron, against Roche’s Pegasys. The study is dubbed IDEAL, an inventive acronym for “Individualized Dosing Efficacy vs. flat dosing to Assess optimaL pegylated interferon therapy.” IDEAL will enroll 2,880 adults with hepatitis C at about 100 sites across the United States (see IDEAL web site for study locations). To be eligible for the study, you have to have hepatitis C genotype 1 (the strain most common in the U.S., but least responsive to treatment). Only people who have never been treated before will be included (see inclusion and exclusion criteria).

The study requires that you be “free from substance abuse for the past 2 years” – a more conservative criteria than those recommended in the AASLD clinical practice guidelines [PDF] and the 2002 NIH consensus statement. The study also excludes people co-infected with HIV, who generally do not respond as well overall to hepatitis C treatment.

People enrolled in the study will be randomly assigned to one of three arms, each providing 48 weeks of treatment (study drugs provided for free):

Arm 1: high-dose Peg-Intron (1.5 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants

Arm 2: low-dose Peg-Intron (1.0 μg/kg/week) with weight-based ribavirin (Schering’s Rebetol, at 800-1,400 mg/day) – 960 study participants

Arm 3: Pegasys (180 μg/week) with weight-based ribavirin (Roche’s Copegus, at 1,000-1,200 mg/day) – 960 study participants

The study is designed to see whether there are differences between the three arms in the proportion of study participants achieving a sustained virologic response (SVR), defined as an undetectable hepatitis C viral load 6 months after the end of treatment.

So — assuming that you’re clean and sober and HIV-negative — should you rush off to sign up for this trial? First, it’s worth understanding the reasons for the three-arm design.

Where Are the Hepatitis C Protease Inhibitors? Part 1: The BILN 2061 Story

One of the biggest obstacles to treatment for people with hepatitis C is that the drugs that we have now – pegylated interferon and ribavirin – just aren’t that good. They have a range of potentially severe and even life-threatening side effects that deter a lot of people from seeking treatment, especially people with a history of depression, which can be brought on or worsened by interferon. And they don’t work for everybody: treatment only results in long-term clearance of the virus (a sustained virologic response, where hepatitis C is undetectable six months after ending treatment) about half the time. Chances of success are lower for many groups, including African-Americans, people co-infected with HIV, and those with genotype 1 – the most common strain of hepatitis C in the U.S. (for two good fact sheets explaining hepatitis C genotype see Genotype from the Easy C Facts Series by the Hepatitis C Support Project/HCV Advocate and also HCV genotypes from the Hepatitis C Council of New South Wales in Australia -- both fact sheets are PDF files). Furthermore interferon needs to be injected – a big disincentive for a lot of people, particularly former drug injectors wary of relapse. All of which adds up to a compelling need for new drugs.

That’s why research presented a year and a half ago at the annual meeting of the American Association for the Study of Liver Diseases (AASLD) sent ripples of excitement and hope throughout the hepatitis C community. Researchers from Boehringer Ingelheim (BI) presented dramatic data on a brand new drug, BILN 2061. BILN 2061 is the first drug successfully tested in humans that specifically targets the hepatitis C protease (technically, the NS3 serine protease), an enzyme essential for making new copies of the virus. BILN 2061 is a protease inhibitor: it binds to the active site of the NS3 serine protease, blocking its action and shutting down viral replication.

People in the studies took BILN 2061 for two days and saw their hepatitis C viral load drop by over 100-fold (for instance, from 2 million copies to less than 20,000 copies) before returning to original levels within a week. A couple people saw their hepatitis C viral load fall by 1,000 fold (e.g., from 2 million down to 2,000). These initial results were astonishing; in the words of Dr. Charles Rice, a prominent researcher who directs the Center for the Study of Hepatitis C in New York, “sort of a hush fell over the audience” (quoted in “H.I.V. Lessons Used in Hepatitis C Treatment” by Andrew Pollack, New York Times, 3/11/03, section F, page 6).

A Therapeutic Vaccine for Hepatitis C?

Belgian biotech Innogenetics today announced promising findings in a study of their hepatitis C therapeutic vaccine. Out of 23 study participants with chronic hepatitis C who had received multiple courses of the vaccine, 10 showed improvements in liver fibrosis in the three years since initial vaccination. Another 10 had stable fibrosis. Overall, fibrosis regressed by 0.43 points on the Ishak scale, which stages fibrosis on a scale from 0 (no fibrosis) to 6 (cirrhosis).

Therapeutic vaccines are vaccines that don't prevent an infection, but help people already infected to mount a stronger immune response to their infection. The Innogenetics vaccine is based on a purified version of E1, one of hepatitis C's two envelope proteins (proteins that coat the envelope of the virus and bind to target cells -- i.e. liver cells). In theory, the vaccine would help keep hepatitis C under control by boosting the ability of the immune system to target the virus, preventing further liver damage.

An effective therapeutic vaccine for hepatitis C would be a major advance in therapy. Such a vaccine could delay the need for treatment with interferon and ribavirin, and help people who do not respond to current treatment (most of the Innogenetics study participants are people who did not respond to interferon-based therapy). But therapeutic vaccines are in some ways more difficult to develop than traditional preventative vaccines. Dozens of companies are working on therapeutic vaccines for a variety of conditions, most notably cancer, but also infectious diseases like hepatitis C, hepatitis B, and HIV. So far, no therapeutic vaccines have been approved to treat any of these conditions.

(For a good, readable survey of therapeutic vaccine development in HIV, see this recent article by Simon Noble from the International AIDS Vaccine Initiative [IAVI]. See also this review of therapeutic vaccines for infectious diseases [abstract; email me for the full article] from the journal Current Opinion in Microbiology.)

So does the Innogenetics vaccine really work? Here are some caveats:

- So far we only have a press release. It's hard to evaluate the data fully until it comes out in a reputable, peer-reviewed journal.

- The reduction in fibrosis score is impressive, but relatively small and could in theory be due to chance. In a commentary on earlier data from this study published in Hepatology (Nevens et al., abstract here), Marc Ghany and David Kleiner of the National Institutes of Health discussed the challenges of evaluating improvement in fibrosis, noting another study showing that 20% of people who do not receive any treatment (or therapeutic vaccination) showed a regression of fibrosis by a full point on the Ishak scale over an average interval of 44 months (commentary in Hepatology here [email me if you want the PDF], abstract for cited study from Gastroenterology here). So it's possible that the observed reversion in fibrosis could be a statistical fluke, especially given the limitations of liver biopsies (sampling error, intraobserver variation) discussed in the previous post. It's also possible that if the vaccine makes a difference, it will take longer (5-10 years) to really show the impact.

- If the Innogenetics therapeutic vaccine works, you'd expect to see a reduction in hepatitis C viral load, since the immune system would presumably be controlling the virus better. With this vaccine, that doesn't seem to happen, raising the question of how it might actually be working to reduce fibrosis.

- There were only 23 study participants described in the press release, all of whom received vaccinations. A true demonstration of effectiveness would require a comparison group who did not receive the vaccine. Innogenetics is currently conducting a larger study of 164 people with hepatitis C, where some participants receive vaccinations and some receive placebo.

The study described in the press release is considered a phase 2a study -- drug development proceeds through 3 phases before a drug (or vaccine) will be considered for approval. It will take several years to demonstrate whether Innogenetics' therapeutic vaccine works to the satisfaction of regulatory bodies (e.g., the Food and Drugs Administration [FDA]). In the meantime, studies are on-going in Europe.

The take-home message? This news offers some hope, but real science isn't advanced by press releases. And even the most encouraging preliminary results often don't end up panning out. To quote from the title of Ghany and Kleiner's commentary, "all that glitters is not gold."

But keep in mind that other companies, like Chiron and Austria's Intercell, are also trying to develop therapeutic vaccines for hepatitis C. Sooner or later, someone's going to get it right.

Alcohol: How much is too much? (part 1)

The negative effects of heavy drinking on the liver health and survival of people with hepatitis C are well-documented. Heavy drinking increases damage to the liver, leading to greater risk of cirrhosis and liver cancer (hepatocellular carcinoma).

But research on the effects of light or moderate drinking on hepatitis C disease progression have been less conclusive (download full article as a PDF file here). In the absence of clear answers, many doctors, educators, and people with hepatitis C advise total abstinence from alcohol if you have hepatitis C.

Yet veterans of the War on Drugs are instinctively wary of absolute, "Just Say No" messages. Harm reduction theory and practice originated in part from a recognition that total abstinence from substances was not always possible, necessary, or even perhaps desirable for many people. Is harm reduction an appropriate model for thinking about alcohol and hepatitis C? That depends on how you interpret the research.

A new study published in the March issue of Hepatology examines how different amounts of alcohol affect the progression of hepatitis C liver disease. The study compared the biopsy results of 800 people with hepatitis C to their reported histories of alcohol consumption, measured as average grams/day (with one drink containing 10 grams of alcohol). People were divided into four categories:

Non-drinkers -- no alcohol
Light drinkers -- up to 2 drinks per day
Moderate drinkers -- between 2 and 5 drinks per day
Heavy drinkers -- greater than 5 drinks per day

As expected, heavy drinkers had more fibrosis overall. There was a general trend showing greater fibrosis with increased amounts of alcohol, but these results were only considered statistically significant for heavy drinkers -- specifically, men who consumed on average over eight drinks a day. There was a substantial range of fibrosis within each category of alcohol consumption, and nearly half of heavy drinkers had little or no fibrosis. When all factors were considered, the most significant predictors of fibrosis were age (strongly associated with duration of hepatitis C infection, which averaged over 20 years), liver inflammation (as measured on biopsy), and ALT levels.

So what does this mean for people with hepatitis C? The headlines of two articles discussing the study reflect different interpretations:

from WebMD: "Bad Mix: Alcohol and Hepatitis C -- No Safe Alcohol Levels if You're Infected"

from HIVandHepatitis.com: "Light and Moderate Alcohol Intake May Have Minimal or No Effect on Fibrosis Development in HCV Infection"

Both perspectives are valid, and supported by the research. But they only tell part of the story. It seems that the effects of alcohol on hepatitis C progression can vary considerably, and in some cases other factors may be more important in determining fibrosis.

Coming next: translating research on alcohol into harm reduction.