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Interferon and Beyond: Treating HEP C

Fall 1999

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Treatment for HEP C infection has finally entered the modern era. After eight years of interferon as the only treatment available for HEP C, combination therapy with a new anti-HEP C drug has become a viable option. In addition, a novel form of interferon is slated for approval and several new classes of drugs are expected to enter clinical trials soon. The following is a review of the current options available to people living with both HEP C and HIV, along with a nod to the promising future of HEP C treatment.


The Impact of HAART

While some studies have shown that HIV can cause HEP C to worsen, there has been very little success using highly active antiretroviral therapy (HAART) to control hepatitis. None of the currently available anti-HIV drugs have any impact on HEP C replication. While some researchers suggested that HIV protease inhibitors might have some kind of impact on the HEP C lifecycle, this proved similar to forcing a square peg into a round hole.

This is not to say that protease inhibitors do not have an impact on HEP C. Protease inhibitors, like HEP C, can cause liver function tests (LFTs, including AST and ALT) to increase, a sign that damage to the liver is occurring. In other words, people who are co-infected, taking protease inhibitors -- and, quite possibly, non-nucleoside analogues -- are at greater risk for experiencing liver problems than people only infected with HIV.

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Fortunately, one study conducted at Johns Hopkins University School of Medicine found that the risk of severe liver damage among co-infected people taking protease inhibitors was low. Among people being treated with saquinavir, nelfinavir, or indinavir, the risk of serious liver damage was 6%. In co-infected people taking ritonavir, the risk increases sharply to 18%. And in a study which volunteers took both saquinavir and ritonavir, the risk was 32%.

"It is important to keep in mind, however, that people who "fail" interferon therapy may still benefit from the drug."

However are these liver LFT increases necessarily bad? According to Dr. Douglas Dieterich, a hepatitis specialist in New York City, there may be more to moderate LFT increases than meets the eye. Numerous studies have shown that antiretroviral drugs, especially when used in combination, allow the immune system to "jumpstart" itself once viral replication has been suppressed. With HIV beaten into submission, vital immune system cells in the liver are permitted to proliferate, allowing them to resume their activity against HEP C. As explained by Dr. Dieterich, such immune activity could explain the increase in LFTs.


Interferon Therapy

Interferon (IFN), whether it is used alone or in combination with ribavirin (see below), is the gold standard treatment for HEP C. There are actually two types of IFN (interferon) therapies used to treat HEP C: interferon-alpha (IFNa) and consensus interferon (Infergen). With respect to IFNa, the two most common brands prescribed for the treatment of HEP C are IFNalpha-2a (Roferon-A) and IFNalpha-2b (Intron-A). Both appear to have equal activity against HEP C and are associated with many of the same side effects. Consensus interferon combines several different types of interferon and is somewhat unique in its activity, but is associated with side effects similar to those seen with other IFNs.

There are a number of ways in which responses to interferon therapy can be determined. The first is laboratory results, specifically blood tests such as LFT (liver function test) decrease. The second is by measuring histopathologic responses, a fancy way of saying a liver biopsy, which detect the progression or reversal of physical damage to the liver (for example, cirrhosis, fibrosis, etc.). The third and, perhaps, most important response is a decrease in HEP C viral load, a measurement of how much HEP C virus is in the blood.

With respect to HIV, suppression of viral load is important to keeping T-cell counts high and the body disease free. Some researchers believe that HEP C viral load, if adequately controlled, will allow LFTs to stabilize and the liver to recover from the onslaught of infection. However, to date there is no significant evidence to back up this theory. A liver biopsy is the only sure way to know what is happening in the liver.

In terms of the effects of interferon therapy, approximately 50% of all people treated with IFNa at the standard 3 million units (MU) dose three times weekly -- regardless of whether or not they also have HIV -- will see their HEP C viral load decrease dramatically. However, only 20% will continue to see their HEP C viral load remain below the level of detection after completing a one year course of therapy. But for those who do not see their HEP C viral load creep up within six months of finishing therapy, the chances of HEP C virus ever returning are slim -- the virus has most likely been "eradicated" from the body.

With respect to consensus interferon, clinical trials in HIV-negative study volunteers have yielded slightly better response rates. After six months of therapy, approximately 35% of people receiving standard doses of the drug (9 micrograms three-times weekly) had undetectable HEP C viral loads, compared to 27% receiving IFNalpha-2b. After an additional six months of follow-up after stopping therapy, both drugs appeared equal in terms of sustained undetectable HEP C levels (12% for consensus interferon and 11% for IFNa).

It is important to keep in mind, however, that people who "fail" interferon therapy may still be benefiting from the drug. According to two papers published in the journal Hepatology, interferon therapy -- regardless of whether or not biochemical, histopathological, or virological responses are seen -- helps correct the ways in which the immune system responds to HEP C. This, in turn, may delay problems like cirrhosis, fibrosis, and quite possibly cancer of the liver.

According to Dr. Dieterich, there are a number of factors that may work to the advantage of co-infected people considering treatment with interferon. These include: a T-cell count above 200, a HEP C viral load less than 2 million copies low or normal body weight, a limited amount of liver fibrosis, and HEP C types other than 1a or 1b. While very few people have such favorable factors, they do suggest that regular checkups -- including important blood tests -- can be advantageous in terms of figuring out when to start therapy.

Another possible factor to consider when starting therapy is the dose of interferon being used. Presently, the United States Public Health Service recommends interferon treatment for patients with increased LFTs, detectable HEP C viral load, and signs of liver damage using standard doses of IFNa (3 MU, three times weekly) or consensus interferon (9 micrograms, three times weekly). However, several studies conducted since these drugs were first approved for the treatment of HEP C seem to suggest that higher doses of interferon -- or by administering the drug five or more times a week -- are necessary in order to increase the likelihood of responding to treatment.

Higher doses? Don’t fret. Most researchers and healthcare providers realize that there is only so high a dose of interferon before side effects become unbearable. The answer may lie in new "pegylated" formulations of the drug.


Pegylated Interferon

Pegylated interferons (Pegasys; Peg-Intron) is created by attaching a microscpopic water-soluble, waxy solid called polythylene glycol to the interferon molecules. This allows the drug to remain in the body for longer periods of time, thereby increasing the activity of interferon on HEP C. This is great news for interferon users, as it decreases the frequency of drug injections, from three-times weekly to one-time weekly.

As with HIV, researchers are rushing to develop new drugs that are unique in the way they treat HEP C infection with potentially fewer side effects.

While researchers originally hoped that pegylated versions of interferon would reduce the number and severity of side effects, this has not turned out to be the case. However, side effects associated with pegylated interferon do not appear to be any worse than those experienced by people taking standard doses of IFNa and may in fact be slightly better.

But does it actually work better than standard IFNa? Yes, according to one recent study conducted by Hoffmann-La Roche. The research showed that pegylated interferon reduced HEP C viral load to undetectable levels in 76% of HEP C-positive (but not HIV-positive) study volunteers within three months of treatment. After an additional six months of not taking the drug, 36% of patients maintained undetectable levels. Among those treated with standard interferon, 17% experienced undetectable levels of HEP C within three months of treatment and 3% maintained undetectable levels for six months following completion of therapy.

Additional trials of pegylated interferons are currently underway in the United States. FDA approval of at least one brand is expected soon.


Combination Therapy

As in HIV therapy, it only seems logical to challenge HEP C’s high replication and mutation rates using combination therapy. While there really haven’t been any reports concluding that HEP C can become resistant to interferon, the possibility remains. As explained in the CRIA Update article "Co-infection with HIV and HEP C: Beyond the Basics", HEP C -- like HIV -- replicates and mutates quickly. This, in turn, makes drug resistance a likely scenario.

A new treatment option is ribavirin (Rebetol), a nucleoside analog active against several viruses. Used alone, the drug is of no benefit to people with HEP C. When used in combination with interferon, however, the true benefit of ribavirin becomes apparent.

Results of two clinical trials of ribavirin in combination with IFN, both involving HIV-negative patients who had never been treated with interferon before were published in late 1998. In the first study, 832 HEP C-positive people received either standard doses of IFNa in combination with ribavirin for either 24 or 48 weeks or IFNa alone. Patients who took both drugs for a year did the best; after stopping the combination, 43% had undetectable HEP C viral loads after six months follow-up. Among those who received only IFNa monotherapy for a year, 19% were still undetectable after six months of being off the drugs. As for the patients who only took the combination for six months, 35% had undetectable HEP C viral loads after six months being off therapy, compared to 8% among patients who received IFNa alone.

Similar results occurred in the second study. Approximately 38% of patients who took IFNa in combination with ribavirin for one year had undetectable HEP C viral loads after six months off the drugs. In those who only took the combination for six months, 31% maintained undetectable HEP C viral loads for at least six months after stopping the drugs.

Not surprisingly, combination therapy in clinical trials was associated with many of the same side effects reported in studies of interferon alone. With the addition of ribavirin, there is an increased risk of developing hemolytic anemia, a condition in which red blood cells are destroyed in the bloodstream. Hemolytic anemia is most likely to occur during the first four weeks of therapy.

Emerging Therapies for Chronic Hepatitis C Virus Infection and Estimated Date of Availability
DRUG CLASS MECHANISM OF ACTION DATE
Pegylated-interferon+ribavirin Interferon chemically bound to polyethyleneglycol (PEG); allows for the slow, continuous release of interferon 1999
Helicase inhibitors Prevents unwinding of double-stranded viral RNA during HCV replication 2001-2003
Protease inhibitors Prevents cleavage of large viral protein into smaller segments 2001-2003
RNA-dependent RNA polymerase inhibitors Prevents replication or copying of the HCV genome 2001-2003
IRES (internal ribozomal entry site) inhibitors Prevents the expression of viral proteins 2001-2003
Antisense nucleotides Bind to interferon resistance sites 2008
DNA vaccines Stimulate cytotoxic T-cell activity 2008
Dominant negative mutants Block viral protein production 2008

Extreme caution should be used by women of childbearing years, as the drug can cause serious birth defects, especially if it is taken during the first three months of pregnancy. Women who are either pregnant or unwilling to use birth control should avoid ribavirin.

Of unique concern to HIV/HEP C co-infected patients is the fact that ribavirin may alter the ways in which AZT (Retrovir) and d4T (Zerit) are processed in the body. At least one test tube study has shown that ribavirin can reduce the activity of AZT and d4T and, interestingly, may increase the activity of ddI (Videx).

Given that ribavirin does not work by itself, it must be used in combination with interferon. Schering-Plough, the maker of ribavirin and Intron-A, currently sells them together in a boxed kit (Rebetron). While this may make a lot of sense, a number of community activists and physicians are weary of the "bundled" kit, as it prevents people with HEP C from using the ribavirin in combination with interferon types other than Intron-A. Schering-Plough’s position is that since ribavirin was studied with Intron-A only, using other forms of interferon poses a safety issue. A process known as compounding, where a pharmacy can take a drug that is available on the international market and sell it for special cases, has gained a lot of attention recently. Compounding of ribavirin is currently being done, but only by a few pharmacies in the country and third party payers may not reimburse for it. The Food and Drug Administration regulates compounding and it is unclear how they will view this particular issue.


Side Effects of Interferon / Ribavirin Therapy

Chances are, if you ask someone about interferon therapy, their first response will be: "Isn’t that the drug with terrible side effects?" The fact is that interferon does cause side effects. In clinical trials, some of the most common side effects -- occurring in more than 10% of study participants -- include: fatigue, muscle aches, headaches, nausea and vomiting, skin irritation at the site of injection, low-grade fever, weight loss, irritability, depression, mild-bone marrow suppression (low white and red blood cells), and reversible hair loss.

Most of these side effects are mild to moderate in severity and can often be managed. They are worse during the first few weeks of treatment, especially after the first injection, but usually diminish over time. Side effects such as fatigue and depression can actually escalate over time, prompting between 5% and 15% of people to drastically reduce their interferon dose or stop therapy altogether. The nocturnal (night time) administration of interferon may lessen the side effects since they will be occuring during sleep. Using aspirin and acetaminophen before the dose of interferon can lessen some of the side effects, but always consult your healthcare provider before changing your medication dose time or taking any medication to control side effects. In many cases, antidepressants can be prescribed to help control persistent depression.

With the addition of ribavirin, there is an increased risk of fatigue and irritability. Some of the more distinct side effects that can be directly related to ribavirin include; anemia, itching, skin rash, nasal stuffiness, and cough. Of greatest concern is anemia, as ribavirin in combination with interferon can cause levels of hemoglobin -- a protein used by red blood cells to transport oxygen from the lungs to the rest of the body -- to decrease significantly. In some cases, this has led to heart attack and stroke. In turn, patients with a history of anemia should think twice about starting therapy with ribavirin. Under the advice of a physician, drugs used to treat anemia may be initiated to increase the red blood cells.


Beyond Interferon: A Glance at New Therapies in Development

As with HIV, researchers are rushing to develop new drugs that are unique in the way they treat HEP C infection with potentially fewer side effects. While there are numerous drugs being developed, most can be categorized into one of three types:

    1) Drugs to prevent HEP C from binding to liver cells;
    2) Compounds that attack viral enzymes that promote HEP C replication;
    3) Drugs to bolster the immune response to HEP C.
Unfortunately, very little information is available on particular drugs in development. Most are still in the laboratory stages of development and have yet to be tested in humans.


Preventing Cellular Infection

Before the virus can infect a cell, HEP C must first successfully bind to the cell’s membrane. Based on their experiences with other viruses -- including rhinovirus, influenza virus, picornavirus, and, we kid you not, the Semliki Forest virus and the foot and mouth disease virus (FMDV) -- researchers have stumbled upon several possible approaches that may prevent the binding of HEP C to liver cells (hepatocytes). These compounds, which include neutralizing antibodies and fusion inhibitors, are barely out of the test tube, so information about how effective they may be is extremely limited.


Viral Enzyme Targets

Once inside a cell, HEP C uses several of its own enzymes to help itself replicate. Thus, finding drugs that stop these enzymes from functioning is a primary goal for many researchers. It is likely that these drugs will be used in combination, both with interferon and each other, in clinical trials once they are available.

Protease inhibitors, as their name implies, attack the HEP C protease enzyme. Similar to HIV’s protease enzyme, HEP C protease snips large strands of the virus into smaller pieces during the replication process, allowing them to form into new virus. Unfortunately, there has been very little success producing any anti-HEP C protease inhibitors although many researchers are screening possible candidates.

Helicase is another enzyme used by HEP C and is primarily responsible for unwinding the virus’ RNA once it is inside a cell. As this is an important step in the lifecycle of HEP C, helicase inhibitors may prove to be effective treatment. Researchers have recently determined the three-dimensional structure of helicase -- an important discovery for pharmaceutical companies hoping to produce compounds that will work against it.

Three other classes of drugs include replicase inhibitors, antisense molecules, and Ribozomes. Replicase inhibitors are being developed to halt the production of new HEP C RNA. Antisense molecules are receiving much attention, as they have shown to be effective for the treatment of other viral infections, such as CMV. As a potential treatment against HEP C, these drugs prevent the virus from producing necessary proteins and prevent HEP C RNA from functioning properly. Ribozymes do the opposite of protease inhibitors. They cleave RNA at critical places needed by HEP C to replicate.


Immune Therapies

Over the past few years, much has been learned about the role of the immune system and its inability to control HEP C in the majority of people infected with the virus. People who are either able to clear the virus or control HEP C replication for many years have an abundance of "type 1" T-cells (Th1), while people who gradually see their HEP C viral load increase and experience liver damage mostly have "type 2" T-cells (Th2). The difference? Th1 T-cells produce vital proteins, called cytokines and chemokines, which program other immune system cells to seek and destroy HEP C-infected cells. Th2 T-cells, on the other hand, produce antibodies that can prevent necessary immune system cells from doing their job correctly. The reason for this phenomenon is not known, but one thing is for sure: Th1 T-cells are the ones to have.

According to Dr. Dieterich, one of the advantages of interferon therapy is its ability to shift the immune response in people with chronic viral infections from Th2 to Th1. Some of the other immune-based therapies slated for development include cytokine therapies -- particularly those that boost Th1 cytokines, such as interleukin-2 (IL-2) and interleukin-12 (IL-12), and those that block Th2 cytokines, including IL-10 and tumor necrosis factor (TNF) -- and therapeutic vaccines.


Alternative Therapies

As with other diseases that do not have a cure, there are a number of alternative therapies . Unfortunately there have been no formal studies on their effectiveness , and their safety is unknown. Be wary of products that claim a cure. When considering an alternative therapy it is always best to consult your physician. In this issue the article "Liver Health", sheds some light on how to be good to your liver and how diet can be of help.


Conclusion

While interferon therapy is by no means a panacea, there is much to be said for the newest ways in which the drug can be used to achieve HEP C eradication. In combination with ribavirin, or by administering higher doses or pegylated versions of the drug, the likelihood of achieving eradication has increased from a dismal 20% to a more favorable 40%. Still, many patients are not able achieve this desirable outcome. Thanks to recent developments that have helped researchers understand how HEP C causes disease and the tools it uses to do so, new treatments to stop the virus in its tracks are likely to follow soon.


Tim Horn is the executive editor of The PRN Notebook, published by Physicians' Research Network in New York.


A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 
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