Evolving Strategies to Attack Hepatitis C
Prior to 1989, what we now characterize as hepatitis C was called either non-A, non-B or transfusion-associated hepatitis. Approximately 4 million Americans are currently infected with HCV, and 8 to 10 thousand Americans die each year due to HCV complications. At current rates of disease progression, these numbers will triple within the next decade. HCV is now the leading cause of hepatocellular carcinoma (liver cancer) and is the most common reason for liver transplants in the U.S. This year, feasible treatment options have become available at last. Providers and patients now have some hope of successfully managing HCV.
Injection drug use is the most common route of HCV transmission in the United States. It results in greater than one-half of the 28,000 annual new cases in the U.S. More than 75% of all new intravenous drug users become seropositive for HCV within one year after beginning drug use. Other commonly identified risk factors are hemodialysis, sexual or household contact with an infected individual, multiple sexual partners, exposure during fetal development and birth, and occupational exposure as a health care provider.
A few years ago, the origin of about half the cases of hepatitis C was unidentified. The latest figures from the Centers for Disease Control and Prevention1 indicate, though, that about 60% of HCV infections are now attributed to injection drug use. Another 10% to 20% arose from sexual relations even though HCV is much less easily transmitted sexually in this way than hepatitis B. Since blood testing has sharply reduced the amount of transfusion-derived HCV, the other risk factors account for just 10% of current hepatitis C. The origin of only about 10%, and maybe as little as 1%, of newly identified hepatitis C remains untraceable.
Course of Disease
The clinical course of HCV disease is extremely variable. Most people are identified as HCV-positive long after their acute infection, and 90% report never remembering an acute illness or jaundice. The few prospective studies that document the beginning of HCV infection found that about one-third of infected patients experience such symptoms as jaundice, fatigue, nausea, anorexia and right upper quadrant pain2 -- the syndrome is similar to hepatitis A but milder.
In 15% of cases, the disease is self-limiting, and HCV viral loads become undetectable. However, these 15% are not protected from future infection by HCV, and it is unclear how or why they were able to clear infection. In the majority of cases, 85% continue on to chronic inflammation of the liver due to continued infection by HCV.3
In contrast, 5% of immune-competent adults who contract hepatitis B virus go on to develop chronic hepatitis. The remaining 95% recover and are then protected from future infection by HBV.
Symptoms of long-term HCV infection include mild abdominal pain, malaise, fever and arthralgia (joint pain). But chronic HCV often progresses silently, with symptoms absent until catastrophic liver damage has occurred.
HCV genes are constructed of ribonucleic acid -- RNA. Chronically infected individuals test positive for this RNA, which indicates ongoing viral replication. On average, a trillion HCV virions are produced per day in the HCV-infected person4 compared to the ten billion HIV virions produced per day by the HIV-infected individual.
This chronic viral assault leads to a number of complications. The liver of an individual with HCV first becomes marked by reversible or irreversible fibrosis (internal scarring) and then by cirrhosis. A cirrhotic liver is hard and multinodular. It is no longer fed by venous blood, which it normally detoxifies.
Complications of cirrhosis include variceal hemorrhage (bleeding from esophagus veins, which causes vomiting), itching, jaundice, ascites (accumulation of abdominal fluid due to low blood albumin), encephelopathy, and in the long term, cancer. Additionally, the immune reactions to HCV's huge viral burden can lead to arthritis, small vessel clogging and kidney damage due to high antibody precipitation (cryoglobulinemia).
The rate of liver damage varies among patients. It can occur in as little as two years, but usually takes 10 to 30 years. In some individuals, progressive liver disease is so slow that there is negligible risk of major symptoms before death from other causes.
Studies have repeatedly found that the clinical course of hepatitis C infection is greatly accelerated in people who regularly drink large quantities of alcohol.5 Consumption of alcohol probably increases the risk of disease progression even in treated patients, so abstinence is advised.
Another issue of concern is coinfection with more than one hepatitis virus. Persons with HCV have a worse prognosis if they acquire HAV or HBV. It is strongly recommended that anyone with HCV be vaccinated against HAV and HBV.
The prevalence of HCV among HIV-infected persons varies -- 50% to 90% of intravenous drug users with HIV also have HCV. Among HIV-positive hemophiliacs, 60% to 85% have HCV coinfections. Gay men with HIV have a 4% to 8% HCV rate. It appears that the course of HIV infection is not exacerbated by HCV. On the other hand, HIV infection seems to lead to a more rapid development of clinical signs of liver disease. There is greater hepatitis-related mortality in HIV/HCV coinfected individuals.6, 7 HCV replication among those with low CD4 counts is greater, and mother-to-infant HCV transmission is increased.
Left untreated, a greater percentage of people with HIV/HCV still will go on to develop AIDS before developing liver failure. A major concern is the effects of HIV antivirals on an HCV-infected liver. Any medication metabolized by the liver has the potential to cause drug-induced hepatitis, but this does not appear to be happening on a frequent basis. The only current exception is ritonavir, which seems to have a greater ability to cause drug-induced hepatitis than the other currently available anti-HIV medications.
There appears to be a transient increase in HCV RNA after such treatment is initiated. It also appears that immune restoration due to suppressing HIV does not lead to a decrease in HCV viral production. At the 12th World AIDS Conference last summer, some researchers theorized that an increase in liver inflammation and fibrosis may take place in the HIV/HCV coinfected after the immune enhancement resulting from highly active anti-HIV therapy.8
Monitoring HCV Disease Progression
Unlike HIV, where CD4 cell counts and viral load are fairly good predictors of disease progression, nothing as simple exists to predict the development of fibrosis and cirrhosis from HCV infection. The marker traditionally employed to determine disease progression in viral hepatitis has been the alanine aminotransferase, or ALT. Although production of ALT is not limited to the liver, high blood levels are an indication of inflamed or damaged liver tissue.
HCV viral load assays are now entering standard medical practice. Although the implications of HCV viral load have yet to be settled, it seems clear that eliminating HCV from the blood improves patients' prognosis, but unlike HIV, there does not appear to be a strong correlation between viral burden and the time to advanced liver damage. High HCV viral load and ALT levels do not necessarily predict the rapid onset of severe and irreversible complications from HCV.
Before initiating therapy, the HCV viral load test is valuable for confirming infection after a positive test for HCV antibodies. Once therapy begins, it can be used to monitor the completeness of viral suppression and then the durability of viral suppression after terminating treatment. According to Mark Sulkowski, M.D., a liver specialist at Johns Hopkins University, undetectable HCV viral load is highly predictive of a normal ALT at 24 weeks post-therapy.
A liver biopsy (in which a special needle is inserted through the skin and into the liver to extract a small amount of tissue for examination) is the gold standard for evaluating liver damage. It is the only test that tells whether a patient has only mild disease and may reasonably delay treatment. Liver biopsies do carry some risk, but complications are rare when a skilled gastroenterologist or hepatologist performs the biopsy. Some HIV-positive individuals with advanced disease have thrombocytopenia (low platelet counts), as do some individuals with advanced liver disease. For these individuals, who tend to have excessive bleeding, a liver biopsy is often too risky and not an option. HIV-positive individuals overall have no increased risk from liver biopsies.
Another important diagnostic test when weighing treatment is HCV genotype to check an individual's HCV genetic strain. There are six major HCV genotypes along with several subtypes. Approximately 70% of HCV-infected Americans carry genotype 1a HCV. Some researchers hold that one's HCV genotype is associated with risk of disease progression. Although that is not confirmed, it is quite clear that genotype influences the response to short courses of interferon-based therapy. Those with the genotype 1 HCV prevalent in this country often need 48 weeks of therapy to obtain the greatest response, while genotype 2 or 3 HCV (prevalent in other industrialized countries) responds more quickly.
Until recently the only treatment for HCV was monotherapy employing a bioengineered (recombinant) form of the natural antiviral immune modulator alpha interferon. There are currently three commercial versions of alpha interferon licensed in the U.S. for HCV. These are interferon alpha-2b (Schering-Plough's Intron A), interferon alpha-2a (Hoffmann-La Roche's Roferon) and interferon alfacon-1 (Amgen's artificial alpha interferon construct known as Infergen). According to large studies,9, 10 around 10% of individuals infected with genotype 1a will have a sustained virologic response (defined as undetectable HCV viral load) 24 weeks after a 48-week course of alpha interferon monotherapy.
Alpha interferon's serious side effects (see below) and meager benefit make monotherapy hardly worth the effort. But the advent of combination therapy -- alpha interferon plus the nucleoside analog ribavirin -- has doubled or tripled the number of sustained virologic responders.
Even more important than virologic response is histologic response (improvement in liver tissue structure). On repeat biopsy, a significantly greater percentage of those who receive combination therapy display a decrease in liver inflammation than those who receive monotherapy. The decrease in histologic inflammation is greatest among virologic responders. If someone's HCV viral load is undetectable 24 weeks after completing combination therapy, then one can expect a decreased amount of inflammation and scarring. Other parameters predictive of better histology at the end of follow-up are female gender, low baseline HCV viral load, low fibrosis stage at initial biopsy, and HCV with genotype 2 or 3.
The landmark combination therapy studies, published in The Lancet11 and New England Journal of Medicine12 excluded HIV-positive individuals. Past studies on alpha interferon monotherapy offer hope for those with HIV because they essentially showed no difference in response in HIV-positive and -negative volunteers. One caveat is that persons with high CD4 counts had better responses to monotherapy with alpha interferon than those with low CD4 counts. A study sponsored by the American Foundation for AIDS Research (AmFAR) now underway in the U.S. will compare alpha interferon monotherapy to combination therapy in persons with HIV.
The common side effects from alpha interferon are flu-like symptoms such as fever, chills, and headache, myalgia (muscle pain) and arthralgia. These tend to diminish over the first few days of treatment. More significant toxicities include bone marrow suppression leading to pancytopenia (low blood cells) and mental disturbances such as depression, insomnia, cognitive impairment, and irritability.
Individuals often must decrease their dose of alpha interferon or discontinue therapy prematurely due to these adverse reactions, but clinicians are able to treat and alleviate many of them in various ways. Alpha interferon can be injected at night so that some of the symptoms can be slept through. Prior to the interferon injection, Tylenol or a nonsteroidal anti-inflammatory drug (NSAID) can be taken. An increase in fluids and a reduction in caffeine also help with the flu-like side effects. The mental effects require professional evaluation. Antidepressants and physical exercise have been effective for many patients.
Some rare side effects of alpha interferon are hyperthyroidism, which is followed by thyroid collapse and hypothyroidism leading to hormone replacement therapy for life; alopecia (hair loss), which is reversible once the interferon is stopped; and severe depression, which has led to some suicides.
Ribavirin is dosed at 1,000 to 1,200 mg per day, depending on the patient's weight, when combined with alpha interferon. Its main drawback is that it leads to a reversible hemolytic anemia (destruction of red blood cells, which can interfere with pulmonary and cardiac function). Hemoglobin, the oxygen-transporting component of red blood cells, drops by an average of 3 grams per deciliter of blood. The fall in hemoglobin concentrations begins by week one and stabilizes by week four of therapy. Rather than discontinue the drug, doctors reduce the ribavirin dose to 600 mg/day when mild anemia occurs. Whether lessening the dose of ribavirin can have the same therapeutic effect while reducing the incidence of anemia is under investigation.
Physicians also have tried to lessen or prevent the hemolytic anemia by administering injections of epoetin alpha (Epogen or Procrit), 40,000 units/week, prior to and/or during ribavirin therapy. (Natural epoetin -- erythropoietin -- regulates red blood cell production in the body.) This therapy reportedly raises hemoglobin an average of 2.0 g/dl. Large phase II trials to measure epoetin alpha's effectiveness in this setting are scheduled to begin soon.
Ribavirin has been found to cause significant structural birth defects and embryo death in all animal species studied (rats, rabbits and monkeys), even at low doses. Use of two forms of birth control is recommended. A woman on ribavirin should not become pregnant until six months after therapy has ended because ribavirin persists in the body for a long time. The potential for harm is so great that men receiving ribavirin should use condoms with female partners of child-bearing potential, pregnant or not, again until six months post-therapy.
The available alpha interferons are delivered by subcutaneous injections three times per week, with most Americans needing a 48-week course. Pegylated interferon, under development by Roche and Schering may ease this burden. Pegylated interferon consists of alpha interferon conjugated with polyethylene glycol to shield the molecule from the body's metabolism and deliver more drug to liver cells. Requiring just one subcutaneous injection per week, pegylated interferon does not induce the huge fluctuations of alpha interferon levels seen with the current short-lived formulations. It is also less likely to trigger the creation of anti-interferon antibodies that hobble interferon's effectiveness.
Pegylated interferon achieved a 10 times greater sustained virologic response than standard alpha interferon monotherapy in a Roche phase II study13 that treated noncirrhotic volunteers for 48 weeks. In the trial's high dose cohort (receiving 180 mcg/wk pegylated interferon monotherapy), 37% had undetectable HCV levels 24 weeks after treatment ended. Only 3% of those receiving standard monotherapy attained this status.
Pegylated interferon has yet to show that it is any safer than standard interferon, and tests of its activity when coadminstered with ribavirin are just beginning. Roche nonetheless expects to bring its version (dubbed "Pegasys") to market within the next 18 months.
Other agents in trials include the immune modulator thymosin-alpha1, which, among other things, increases lymphocytes' sensitivity to such signaling molecules as alpha interferon and IL-2 (see Treatment Issues, June 1994, pages 6-12). Several studies have tried thymosin in combination with alpha interferon. In the latest to be reported, 103 volunteers were randomized to receive six months of thymosin plus alpha interferon, alpha interferon alone or placebo. The combination therapy did yield somewhat improved responses over alpha interferon alone, but the researchers concluded that longer treatment and different thymosin doses might be valuable.14 (The trial participants received twice-weekly subcutaneous injections of 1.6 mg of thymosin.) Side effects were similar with either thymosin plus alpha interferon or interferon alone, at least with the present thymosin regimen.
A possibly safer and more effective alternative to alpha interferon is beta interferon, now the subject of a phase I trial sponsored by Serono Laboratories in people who have failed to respond to alpha interferon. IL-12, a natural signaling agent that triggers antiviral response on the part of cytotoxic T-cells and NK (natural killer) cells, also is the subject of continuing trials. Administration of n-acetyl cysteine (NAC) and glutathione to reduce oxidative stress has also been proposed as treatments for hepatitis C.15
Still in the laboratory are agents to inhibit the HCV protease enzyme (which helps construct new virions) and helicase (which packages the HCV genetic material within the virion). Another experimental strategy involves antisense RNA that binds to the HCV RNA within the cell so that the virus is unable to replicate and is broken down by cellular enzymes.
It appears certain that the kinetics of HCV viral production makes combination therapy a necessity. Like HIV, HCV does not have genetic proofreading capabilities, and thus continuously makes errors leading to mutated virus and the rapid evolution of drug resistance.
1. Centers for Disease Control and Prevention. National Center for Infectious Diseases. Hepatitis C Reference Manual. May 28 1998. http://www.cdc.gov/ncidod/diseases/hepatitis/video_c/refmanb.htm
3. Alter MJ et al. New England Journal of Medicine. December 31 1992; 327(27):1899-905.
4. Neumann A et al. Science. October 2 1998; 282(5386):103-7.
7. Darby SC et al. The Lancet. November 15 1997; 350(9089):1425-31.
8. Pialoux G et al. 12th World AIDS Conference. June 28-July 3, 1998. Abstract 22243.
9. McHutchison JG et al. New England Journal of Medicine. Nov 19 1998;339(21):1485-92.
10. Poynard T, et al. Lancet. October 31 1998; 352(9138):1426-32.
12. McHuchison. op cit.
13. Fried MW. Presentation at Hepatitis C satellite symposium of American Association for the Study of Liver Disease 49th Annual Meeting. Nov 6-10 1998.
14. Sherman KE et al. Hepatology. April 1998. 27(4):1128-35.
15. Bonkovsky HL. Hepatology. Sept 1997; 26(3 Suppl 1):143S-51S.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.