The Other Hepatitis: The ABCs of HBV
Hepatitis B has been nothing short of a global-health catastrophe -- approximately two billion people in the world today have, at some point in their lives, been infected with the hepatitis B virus (HBV). Of these, 400 million people have chronic hepatitis B, which remains the leading cause of liver cancer and kills more than one million people around the world each year. Closer to home, the U.S. Centers for Disease Control estimates that 80,000 people were infected with HBV in 1999 (the most recent available data) and that there are more than one million people living with chronic hepatitis B in the U.S., resulting in 5,000 deaths every year from cirrhosis of the liver and/or liver cancer.
The ultimate irony is that hepatitis B is a preventable disease. Vaccines are available and are more than 90% effective in preventing infection. While the number of new HBV infections has decreased in the United States and in other countries where the vaccine is available, there is still much work to be done to prevent what is now the ninth leading cause of death worldwide. At the same time, there is much more to learn about how best to manage and treat people who are infected with HBV, particularly those with chronic infection and those living with both hepatitis B and HIV.
As discussed in this issue of ACRIA Update, hepatitis means inflammation of the liver -- the most common cause being infection with one of five viruses: hepatitis A, B, C, D, or E. All of these viruses can cause short-term (acute) disease with symptoms lasting several weeks. Like the hepatitis C virus (HCV), HBV can also cause long-term (chronic) infection in which the patient never gets rid of the infection. If untreated, chronic HBV or HCV infection can be life-threatening, and the risk of serious liver problems is higher in people who are co-infected with HIV.
Technically speaking, HBV is quite different from HCV. HBV is a hepadnavirus, meaning that it contains DNA. It infects liver cells (hepatocytes) in both humans and animals (HBV is the only hepadnavirus to infect humans). While HCV also infects liver cells, it contains RNA and belongs to the flavivirus family, which includes a few viruses known to cause some unsavory tropical infections, most notably dengue and yellow fever.
HBV is also much easier to transmit than HCV. Whereas HCV is almost always spread through the exchange of blood (i.e., injection drug users who share equipment), HBV can spread through many of the same activities as HIV: unprotected sex (including oral sex); sharing of unsterile needles; from mothers to their babies either before or during delivery; accidental puncture from contaminated needles, broken glass, or other sharps; contact between broken or damaged skin and infected body fluids.
HBV and HCV also differ in the ways they cause liver disease. HCV is a cytopathic virus, which means that it causes direct damage to liver cells. HBV, on the other hand, is a noncytopathic virus, meaning that it does not permanently damage the liver cells it infects. Ironically, it is the immune system, not the HBV itself, that ends up damaging the liver in its efforts to clear the virus from the body.
Chronic hepatitis B is also faster in its progression than chronic hepatitis C. In people with chronic HCV infection, it can take up to 20 years for cirrhosis of the liver to occur and more than 30 years for even more serious complications to develop, such as liver cancer. In people with chronic HBV infection, cirrhosis can occur in as few as four to five years, with a significant risk of cancer occurring within ten years after infection.
After HBV enters the body, it can take six weeks for the acute phase of HBV infection to officially begin and for symptoms to develop. However, HBV does not affect all people in the same way. Approximately 70% of people do not experience any noticeable symptoms of infection. Of the remaining 30%, most experience typical symptoms of hepatitis, which usually last a few weeks but can sometimes take more than a year to subside completely. A very small percentage (0.1% to 0.5%) of people with HBV develop severe (fulminant) hepatitis, which can lead to serious illness and death if not treated immediately.
Among the typical symptoms of acute HBV infection are fatigue, appetite loss, nausea, vomiting, joint and muscle pain, itchy skin, headache, swollen lymph nodes, sensitivity to light, sore throat and a runny nose. Acute HBV can also result in a rash on the face, buttocks, and limbs. After a few weeks of these symptoms, jaundice can occur -- a yellowing of the skin and the whites of the eyes. Urine may also become dark and stools can appear pale. If these symptoms occur, they usually last for at least four to eight weeks.
Complete recovery from acute hepatitis B infection depends on the ability of the immune system to control the virus. If it is successful, HBV antigens -- proteins produced by the virus, such as HBsAg and HBeAg -- eventually become undetectable in the bloodstream and are replaced by specific antibodies produced by the immune system: anti-HBs and anti-HBe. Once these antibodies appear, the virus can no longer be detected in the body and the liver eventually normalizes. (Note: A third antigen, HbcAg [the "core" antigen], can only be detected in liver cells and always results in the production of anti-HBc core antibodies, which are detectable in the blood.)
Most adults with healthy immune systems are capable of clearing the HBV virus within six months after the infection first establishes itself. There are, however, the unfortunate few who simply aren't able to mount the immune response needed to eliminate the infection -- approximately 5% of healthy adults who are infected with the virus go on to experience chronic hepatitis B. In children and individuals with compromised immune systems -- such as the elderly and HIV-positive people -- chronic infection rates are much higher. More than 90% of babies infected with the virus at birth, because their mothers had HBV, go on to develop chronic hepatitis B. Children who are infected with the virus between the ages of one and five have a 25% to 50% chance of developing chronic hepatitis B.
So what is chronic hepatitis B? For diagnostic purposes, chronic hepatitis B simply means that HbsAg -- the HBV surface antigen -- has overstayed its welcome, lingering in the bloodstream for longer than six months after infection. This indicates that the virus is still present in the liver. Most people with chronic hepatitis B also have detectable amounts of the HBeAg antigen in their blood, which often means that HBV is not only present, but actively reproducing in liver cells. This can spell trouble on two levels. First, active HBV replication can provoke the immune system to cause greater damage to the liver in its efforts to keep hepatitis B viral load in check. Second, it means that the person harboring the virus is extremely infectious and can easily transmit the virus to others.
As mentioned above, it is the immune system -- not the virus itself -- that causes inflammation of the liver. Simply put, the immune system recognizes the virus as foreign and will attempt to do everything in its power to rid the body of the infection. This results in "flares" of the immune system - brief periods of intense immune activity to prevent HBV from reproducing and to kill liver cells that have either been infected or damaged by the virus. A person with chronic hepatitis B often has between two and four flares a year, which usually last several days to a few weeks. These flares are often effective against the virus, resulting over time in the loss of the HBeAg antigen and the gain of the anti-HBe antibody. However, it can take many flares over the course of several years for this crucial antigen-to-antibody shift to occur. It is during these flares that the immune system causes the greatest amount of damage to the liver.
Most people with chronic hepatitis B infection have no symptoms in the early stages. The most common early symptoms include fatigue and right upper abdominal discomfort. Occasionally, during flares, there may be symptoms similar to those seen during acute hepatitis B. People who have developed cirrhosis are more likely to have symptoms. As liver disease progresses, complications of cirrhosis and liver failure may occur, including jaundice, ascites (accumulation of fluid in the abdomen), variceal bleeding (bleeding from blood vessels in the esophagus, stomach, or intestines), leg edema, and encephalopathy (mental confusion due to the accumulation of toxic metabolic products that cannot be cleared by the liver).
It's estimated that 20% to 35% of patients with chronic hepatitis B will go on to develop cirrhosis of the liver. However, the most accurate way to interpret the risk of cirrhosis is on an annual basis. According to one Italian study, for every year that the HBeAg antigen remains positive in the bloodstream, there is a 6% chance of developing cirrhosis (rates in other studies have varied from 2% to 12%). In other words, after five years of chronic hepatitis B infection, provided that HBeAg remains positive, the risk of developing cirrhosis would be approximately 30%. After ten years, the risk would increase to 60%, and so on.
Liver cancer, technically called hepatocellular carcinoma, is more likely to occur in men with chronic HBV infection (as opposed to women) and develops in approximately 25% of all patients with cirrhosis. But liver cancer can also occur in patients with chronic hepatitis B who don't develop cirrhosis. In one study conducted in Asia, approximately 15% of patients with chronic hepatitis B without cirrhosis went on to develop liver cancer. And in a study conducted in Africa, roughly 40% of noncirrhotic chronic hepatitis B patients developed liver cancer, usually within one or two decades of becoming infected with the virus.
Until recently, there has been little information -- and very little research -- regarding the effects and treatment of HBV in HIV-positive people. This should come as no surprise, given that HIV-associated deaths were most commonly tied to "classic" AIDS-related complications rather than chronic HBV disease. Thus, for many years chronic hepatitis B was of little concern. But with the significant survival gains ushered in by combination antiretroviral therapy, fewer HIV-positive people are dying of typical AIDS diseases, such as MAC or PCP. Many are now living long enough to see their slow-brewing liver disease become a major health concern.
Although only a small percentage of otherwise healthy adults infected with HBV go on to experience chronic hepatitis B, this is not the case in HIV-positive adults: roughly 25% of HIV/HBV-co-infected patients develop chronic infection. What's more, a number of reports have suggested that as HIV disease progresses, the immune response to HBV gradually decreases or is sometimes lost. Some patients experience a relapse of infection, marked by the loss of anti-HBs and the return of HBsAg positivity. Other co-infected patients experience gradual declines in anti-HBs activity, sometimes at the expense of increased hepatitis B viral load and HBeAg levels.
It is not entirely understood what impact HIV has on the severity of chronic HBV infection. There have been a number of reports demonstrating that patients infected with both viruses have higher HBV viral loads and more cirrhosis, regardless of immune system status. There are also data from studies suggesting that HIV-positive people with chronic hepatitis B are more than twice as likely as their HIV-negative counterparts to experience liver failure, thus requiring a liver transplant -- a life-saving treatment option that is not without controversy (see "Is Transplant An Option?").
While it is usually not necessary to treat acute hepatitis B -- taking it easy and avoiding alcohol remain the best possible remedies -- it is often necessary for patients with chronic hepatitis B to consider treatment.
It's safe to say that neither of the currently available treatments for chronic HBV infection -- interferon-alfa (Intron A) and lamivudine (Epivir-HBV) -- are perfect. Interferon-alfa has been approved for more than a decade. At doses of 5 million units (MU) every day or 10 MU three times a week for six months -- doses that are much higher than those used to treat chronic hepatitis C -- using interferon alone is associated with HBeAg clearance in up to 40% of otherwise healthy HIV-negative patients and HBsAg clearance in up to 15% of patients. However, the drug is associated with significant side effects including fever, muscle aches, thyroid problems, bone marrow damage, and a litany of psychiatric symptoms. What's more, the drug must be used cautiously in patients with cirrhosis, as it may heighten the immune response to the virus and lead to severe liver damage. For patients co-infected with HIV and HBV, interferon has been disappointing. Many do not respond to therapy and, given the increased risk of side effects in this group of patients, interferon is a less-than-ideal choice. (Pegylated interferon, an approved treatment for chronic hepatitis C, has not yet been studied for the treatment of chronic hepatitis B.)
GlaxoSmithKline's lamivudine (Epivir), first approved for the treatment of HIV in the mid-1990s, was awarded a second FDA approval for the treatment of chronic HBV infection in December 1998. The dose of lamivudine typically used to treat chronic HBV is 100 mg once a day, compared to the 150 mg twice a day schedule used for HIV.
Unlike interferon, lamivudine has no direct effect on the immune response to HBV. It does, however, have a profound impact on HBV viral load and, in three randomized phase III studies, was associated with a loss of HBeAg after a year of therapy in 17% to 33% of chronically infected patients. Moreover, progression of cirrhosis decreased in all patients who received lamivudine.
Given that lamivudine has far fewer side effects than interferon, healthcare providers have come to depend heavily on this drug. But it's important to use it cautiously. If the drug is stopped abruptly or not taken correctly, HBV viral load can rebound and cause a flare of the immune system. This can cause a person with chronic hepatitis B to become ill and, as discussed above, may result in liver damage.
As in HIV, HBV resistance to lamivudine can and does occur. Used as monotherapy, approximately 40% of people taking lamivudine develop HBV resistance to the drug within one year. After four years of lamivudine use, approximately 70% have HBV strains resistant to the drug. While these findings suggest that lamivudine monotherapy is somewhat limited, they also suggest that HBV resistance to lamivudine develops much more slowly than it does with HIV. And even when HBV resistance to lamivudine does occur, the drug still appears to be helpful in keeping HBV viral load low and in slowing the progression of liver disease.
The threats of flares and lamivudine resistance are particularly important for HIV-positive people to consider. When the time comes to use lamivudine to treat both HIV and HBV, it is necessary for patients with chronic hepatitis B and their healthcare providers to remember both viruses when making treatment decisions. For example, if a drug-resistance test shows that lamivudine is no longer working against HIV -- which would usually prompt someone to switch the drug -- it may be useful to continue using lamivudine to treat chronic hepatitis B. Stopping the drug early may not only result in a flare, but could prematurely end lamivudine's anti-HBV benefits.
Researchers evaluating treatments for chronic hepatitis B have learned a valuable lesson from those studying anti-HIV therapies: that combination therapy is likely the best approach, given the impact of drug resistance. Unfortunately, the results of two-drug anti-HBV combinations in clinical trials have been mixed. In one international trial combining lamivudine with interferon-alfa in chronically infected patients who had already attempted interferon monotherapy, those who received the dual regimen responded similarly to those who received lamivudine monotherapy. However, in two other studies, HbeAg seroconversions to anti-HBe after a year of treatment were much more common in patients receiving a combination of interferon-alfa and lamivudine (29%), compared to those receiving either interferon monotherapy (19%) or lamivudine monotherapy (18%).
The next step is to evaluate three-drug regimens in clinical trials. At the present time, however, this is something of a problem, given that only two drugs are currently approved for the treatment of chronic hepatitis B. New drugs must be developed and approved if three-drug regimens are to become feasible options.
There are a number of drugs in various stages of development, including several nucleoside/nucleotide analogues that target HBV's DNA polymerase protein, which is similar to HIV's reverse transcriptase enzyme. Three of the nucleoside analogues furthest along in development are famciclovir (GlaxoSmithKline), which is already approved for the treatment of herpes, entecavir (Bristol-Myers Squibb), and emtricitabine (Triangle Pharmaceuticals). There is also adefovir dipivoxil (Gilead Sciences), the nucleotide analogue that did not pan out as a treatment for HIV, but is enjoying a good showing in clinical trials involving patients with chronic hepatitis B. Tenofovir dipovoxil, another nucleotide analogue from Gilead Sciences that is approved for the treatment of HIV, also has activity against HBV and is expected to enter clinical trials soon.
These new agents -- and there are several more of them in earlier stages of development -- are being studied as monotherapy and in various combinations, both with each other and with approved therapies (interferon-alfa and lamivudine). Unfortunately, it is still too early to tell how safe and effective anti-HBV regimens containing three (or more) drugs are for patients with chronic hepatitis B. Even if these drug combinations prove to be more effective than currently available options, the question remains of when to initiate treatment, and for how long, in order to achieve the best possible outcome with the fewest side effects possible. This is especially true for patients co-infected with both HIV and HBV who may face the daunting task of combining two different combinations of drugs -- this could easily exceed six antiviral drugs being taken at one time -- to effectively battle both viral infections. Thus, amid the hope of emerging options, there are numerous fundamental questions that have yet to be addressed.
Tim Horn is Executive Editor of The PRN Notebook, published by Physicians' Research Network in New York. He is also the head medical writer for AIDSmeds.com.
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.