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Natural History and Treatment of Hepatitis C

Winter 2000

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated.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!

Hepatitis C is a liver disease caused by a virus. The majority of people infected with the hepatitis C virus (HCV) develop chronic hepatitis, which may lead to fibrosis and cirrhosis (scarring) of the liver, liver cancer, and ultimately fatal liver failure. Although the rate of new hepatitis C infections has declined in the past decade, nearly four million Americans are believed to be infected, and many will likely develop liver damage as the effects of this slowly progressing disease become apparent. Because people with HCV often develop symptoms years -- or even decades -- after infection, and because many people are unaware of the disease, hepatitis C has been called "the silent epidemic."

The Hepatitis C Virus

Hepatitis is a general term for inflammation of the liver, which may be caused by viruses, toxins, drugs, or other factors. HCV was first identified in 1989; formerly it was known as non-A, non-B hepatitis. HCV is a member of the Flaviviridae family and is unrelated to other known hepatitis viruses. HCV must enter liver cells to carry out its life cycle; once inside, the virus commandeers the cell's ribosomes to reproduce, eventually killing the host cell.

There are at least six genotypes and numerous subtypes of HCV. Multiple quasispecies may co-exist in a single individual. Different subtypes have different geographical distributions and are associated with different rates of disease progression, severity, and response to treatment. Subtypes 1a and 1b together account for about three-quarters of HCV infections in the U.S.

HCV is an RNA virus that is prone to errors in its replication and mutates rapidly. Because of this rapid mutation, the immune system typically cannot eradicate the virus, and it remains in the bodies of most infected people; estimates of chronic HCV range from 70% to 85%. For reasons that are not well understood, a minority of infected persons are able to clear the virus, although they typically remain HCV antibody positive. In the July 2, 1999 issue of Science, Michael Lai and colleagues from the Howard Hughes Medical Institute reported the discovery of an HCV surface protein called E2 that inhibits the immune system's activity against the virus. The virus' genetic variability also hampers the development of a vaccine.

Until recently, HCV could not be grown in the laboratory, making the study and testing of anti-HCV drugs difficult. This past summer, however, Ralf Bartenschlager and colleagues from the University of Mainz, Germany, reported they had devised a DNA mirror-image "replicon" of HCV's genetic material that could be inserted into human cells to create a laboratory model of HCV infection.

The Epidemiology of HCV

Who Has Hepatitis C?

In recent years, it has become apparent that hepatitis C is quite common in the U.S. population at large, four times more so than HIV. The Centers for Disease Control and Prevention (CDC) estimates that at least 3.9 million people (1.8% of the population) have been infected with HCV as indicated by a positive HCV antibody test; an estimated 2.7 million have chronic hepatitis C. This estimate is based on a study by the CDC's Miriam Alter, Ph.D., and colleagues of serum samples from over 21,000 people who participated in the Third National Health and Nutrition Examination survey between 1988 and 1994; results of this study were reported in the August 19, 1999 issue of the New England Journal of Medicine. This study may have underreported the true rate of HCV infection in the U.S. since certain groups with high HCV rates, including homeless and incarcerated persons, were not included. The World Health Organization (WHO) estimates that 170 million people worldwide are infected with HCV.

According to the Hepatitis Foundation International, about 35,000 people in the U.S. become infected with HCV each year, a dramatic decline from an estimated incidence rate of 180,000 new cases per year in the 1980s. Chronic hepatitis C is responsible for 8,000-10,000 deaths each year, a number that is expected to increase as people infected in the 1970s and 1980s begin to develop liver damage.According to the American Liver Foundation, liver failure due to hepatitis C is currently the most common reason for liver transplants in the U.S.

How Is HCV Transmitted?

In the past, many people contracted HCV through blood transfusions. A test to screen donated blood was developed in 1990, and a more accurate test became widely available in 1992. The U.S. Public Health Service recommends that anyone who received a blood transfusion or organ transplant before 1992 should be tested for HCV. The risk of HCV transmission through donated blood is now very small, estimated at 0.01% or one in 100,000 transfusions. Before 1987, when new methods were developed to treat blood clotting factor preparations, a large number of hemophiliacs were infected with HCV through pooled blood product transfusions.

Today the most common risk factor for HCV infection is the use of shared needles or other equipment to inject drugs, which, by CDC estimates, accounts for 60% of new infections. Drug users often acquire HCV soon after they start to inject, and up to 90% of this group are infected in some communities. Public health officials believe that many people may have acquired HCV in the 1970s and 1980s through occasional experimentation with injection drugs. Past use of cocaine is also a risk factor for HCV infection, possibly due to the presence of small amounts of blood on shared straws used to inhale the drug.

Health-care workers are at some risk of occupational exposure to HCV, primarily through needlestick injuries, which carry an estimated infection rate of 1.8%. Overall, however, the rate of HCV among health-care workers in the U.S. is the same as that of the general population. People who have undergone long-term kidney dialysis (hemodialysis) have high rates of HCV, possibly due to poorly sterilized medical equipment.

Hepatitis C can be transmitted through implements that can transfer blood, including tattooing and piercing equipment, acupuncture needles, razors, manicure tools, and toothbrushes. People who have household contact with HCV-infected persons have higher rates of infection than the population as a whole, but this type of transmission is uncommon. The CDC estimates that these various means of HCV transmission collectively account for about 10% of all cases.

Although HCV can be transmitted sexually, this type of exposure is much less likely to lead to infection than exposure to blood. Studies have shown that HCV is present in semen and vaginal fluid. According to the CDC, up to 20% of HCV infections are attributable to sexual contact. However, this estimate may be high, given that most studies have shown a very low rate of sexual transmission. For example, a 1997 study showed a sexual transmission rate of 1% per year among long-term, monogamous heterosexual couples in which one partner had HCV; analysis of several different studies reveals an average sexual transmission rate of 1.5% among long-term, monogamous partners, although transmission risk increases among individuals with multiple sexual partners.

It is thought that HCV transmission from men to women is more efficient than transmission from women to men. Gay and bisexual men have an HCV prevalence rate similar to that of heterosexuals in most studies, despite the fact that receptive anal intercourse is known to be a more efficient method than receptive vaginal intercourse of transmitting blood-borne viruses. It is unclear why HCV rates are not higher among men who have sex with men, but this fact suggests that HCV is not efficiently transmitted through sexual contact. While there is no evidence that HCV is transmitted through oral sex, theoretically this may occur, particularly if the receptive partner has mouth sores or inflammation.

HCV can be transmitted from mother to child before or during birth, but such transmission is uncommon; the overall rate of vertical transmission is generally estimated to be less than 5%. Several studies have shown that perinatal HCV transmission is more common in women with higher HCV viral loads and those coinfected with HCV and HIV, with rates as high as 14-17%. M. Resti and colleagues from the University of Florence, Italy, reported the results of a study of 442 HCV antibody positive/HIV antibody negative women in the August 15, 1998 issue of the British Medical Journal. They concluded that among women who are not coinfected with HIV, only those with detectable HCV RNA viral loads are at risk of transmitting HCV to their babies.

There is conflicting evidence about whether HCV can be transmitted through breast-feeding. Some studies have shown that HCV is present in the colostrum (breast fluid produced prior to milk production) and breast milk, and that transmission through breast-feeding can occur, especially if the mother has a high HCV viral load; however, such transmission appears to be rare. Neither the CDC nor the American Academy of Pediatrics recommend that HCV-infected mothers should refrain from breast-feeding their infants.

Other factors that may affect rates of HCV include age, gender, income, and education level. Dr. Alter's New England Journal of Medicine study found that HCV rates were higher among those with low incomes or fewer than 12 years of education. The CDC reports that rates of HCV incidence, or new infections, are highest among people aged 20-39, slightly higher among men, and similar among whites and African-Americans, with a somewhat higher rate among Latinos. In terms of prevalence, or total infections, however, rates are highest among people 30-49 years old, considerably higher among men, and substantially higher among African-Americans.

After all the above considerations are taken into account, as many as 10-20% of people with HCV have no identifiable risk factors.

Hepatitis C Diagnosis

Several different tests are used to diagnose hepatitis C. Because people with hepatitis C are often asymptomatic, HCV infection is often detected only during blood donor screening or routine checkups that include laboratory blood tests.

Antibody tests show whether the body has produced antibodies against HCV. The enzyme immunosorbent assay (ELISA or EIA) is the primary test used for blood screening. The test has been known to produce false-positive results, however, especially when used for screening in low-risk populations. If an ELISA test is positive, a second test such as the recombinant immunoblot assay (RIBA, also known as the Western blot) is used to confirm the results. In April 1999, the Food and Drug Administration (FDA) approved an over-the-counter home HCV test; an oral fluid antibody test (OraSure) is also available.

Antibody tests can show if a person has been infected with HCV, but cannot distinguish among acute, chronic, and resolved infections. Antibodies may not be present soon after infection, but usually develop within three months. A person with a compromised immune system may not produce enough antibodies to be detected by these tests, and if HCV and HIV are transmitted together, it may take longer for an HCV antibody test to return a positive result. For high-risk populations (including people with HIV), or if hepatitis C is suspected on the basis of clinical symptoms, an HCV RNA viral load test should be done to confirm the presence of the virus in people with positive HCV antibody tests.

The second type of test detects HCV genetic material in the blood. Two types of viral load test, polymerase chain reaction (PCR) or branched-chain DNA (bDNA), may be used to detect HCV RNA; these tests are currently not approved by the FDA. The PCR test can typically detect HCV genetic material within one to three weeks after infection. A person who was infected in the past and has cleared the virus usually will have a positive antibody test but a negative HCV RNA test. Because HCV viral load levels typically fluctuate over the course of infection, a single negative HCV RNA test does not conclusively indicate that a person is not infected. In addition to determining whether a person is infected with HCV, viral load tests can help predict who is most likely to respond well to treatment and monitor treatment effectiveness.

Liver function tests measure liver enzyme levels. The enzymes alanine transaminase or aminotransferase (ALT, formerly known as SGPT) and aspartate transaminase or aminotransferase (AST, formerly known as SGOT) are released into the blood when liver cells are damaged or die. ALT levels are more often used to detect liver damage; elevated AST levels may also occur with heart, kidney, or muscle damage. As with HCV RNA, liver enzyme levels often fluctuate over the course of disease, and normal liver function tests do not necessarily indicate that liver damage has not occurred.

If HCV antibody, HCV RNA, or liver enzyme tests indicate hepatitis C, a liver biopsy may be done to gauge the extent of liver inflammation and damage. In a biopsy, a small sample of liver tissue is withdrawn using a needle and examined under a microscope. Dead liver cells (necrosis) may be visible. HCV-infected liver cells may be surrounded by inflammatory cells and appear shrunken. If fibrosis or cirrhosis have developed, the cells may be surrounded by fibrous scar tissue.

Physicians may also use other laboratory measurements to evaluate liver damage. Abnormal hyaluronic acid and procollagen-III peptide levels may indicate fibrosis; these tests are not standardized and are not FDA-approved for this indication. Low platelet counts, prolonged prothrombin time (a measure of how long it takes blood to clot), and low serum albumin (a blood protein) levels also suggest liver damage. High levels of alpha-fetoprotein may indicate liver cancer. High blood levels of bilirubin (a pigment released when old red blood cells are broken down) and other metabolic byproducts such as alkaline phosphatase suggest that the liver and bile system are not fulfilling their normal metabolic functions.

The Clinical Course of HCV

The Liver and Its Functions

To understand the effects of chronic hepatitis C, it is useful to examine the liver and its many roles. The liver is the body's largest internal organ; it performs several vital functions. If the liver is unable to carry out its normal activities, serious complications may result that can impact almost every other organ and system of the body.

The liver plays a complex role in metabolism. It produces bile, a compound that helps metabolize certain fats; if the liver is damaged, bile production may be decreased and passage of bile into the gallbladder and intestines may be blocked. If the body cannot digest fats, the absorption of fat-soluble vitamins (A, D, E, and K) is hampered. Stools may appear pale and contain fat. At the same time, excess bile may be excreted in the urine, giving it a dark brown color. The buildup of bile products in tissues may lead to pruritis, or itching. In addition, interrupted bile flow may lead to gallstones and bile duct injury. If the liver cannot process the blood pigment bilirubin, individuals may develop jaundice, a yellowing of the skin and the whites of the eyes.

The liver also regulates the body's use of carbohydrates and sugars, converting carbohydrates into fats, in the form of very low-density lipoprotein (VLDL) cholesterol, and converting fatty acids into ketone bodies that provide emergency fuel during periods of fasting. The liver stabilizes blood glucose levels by storing sugar in the form of glycogen and breaking it down for quick energy. The liver also processes proteins and stores certain vitamins and minerals. In addition, it converts ammonia, a metabolic byproduct of nitrogen, into a less toxic compound called urea that is excreted by the kidneys. When the liver is badly damaged in severe fulminant or end-stage liver disease, the buildup of metabolic byproducts and toxins can lead to brain damage (encephalopathy), characterized by dementia, confusion, personality changes, and memory loss; the ultimate outcome may be coma and death.

The liver produces albumin, a major blood protein that regulates water balance in blood vessels. When albumin levels are reduced due to liver damage, water leaves the vessels and enters the surrounding tissues; this process can lead to swelling of the lower extremities (edema) and abdomen (ascites). The liver also manufactures clotting factors that help the blood coagulate; failure to produce these factors can lead to bruising and prolonged bleeding.

The liver also acts as a filter, detoxifying everything an individual eats, inhales, or absorbs through the skin. Exposure to toxic substances -- including alcohol, drugs, and environmental chemicals -- can irreparably damage the liver. The cytochrome P450 system of liver enzymes is responsible for metabolizing drugs and toxins. A damaged liver may not be able to break down drugs properly, which can result in high blood levels and intensified adverse reactions or side effects. Failure to break down hormones can result in high blood levels, which may lead to symptoms such as menstrual abnormalities, erectile dysfunction, gynecomastia (increased breast size in men), and spider angiomas (visible masses of small blood vessels on the surface of the skin).

Acute Symptoms of Hepatitis C

Hepatitis C has an incubation period of 2-26 weeks. During the initial stage of illness, some people develop acute symptoms that may include fever, fatigue, nausea and vomiting, loss of appetite, abdominal tenderness, and muscle or joint pain. Some 20-30% of acutely infected individuals develop jaundice. The majority of people with acute HCV infection, however, have mild symptoms or none at all. Thus, hepatitis C is often not detected during the initial stage, and may become apparent only later -- sometimes decades later -- after substantial liver damage has occurred. Despite the lack of obvious symptoms, nearly all people with HCV infection sustain some degree of liver damage that may be revealed by liver function tests; liver enzyme levels typically increase before clinical symptoms become apparent.

A small number of people experience acute fulminant hepatitis C, which involves rapid death of liver tissue leading to metabolic imbalances, brain damage, and death; this occurs less often with HCV than with other types of viral hepatitis such as hepatitis B. More often, initial symptoms subside within two to 12 weeks, although fatigue and abdominal tenderness may persist for months.

HCV Disease Progression

In most people with HCV, the immune system is unable to eradicate the virus. According to the CDC's recently released data, 70%of people infected with HCV will develop chronic hepatitis, a condition defined as the presence of detectable HCV RNA for six months or longer; previously, this figure was widely believed to be as high as 85%. In contrast, only about 10% of adults with hepatitis B develop chronic disease. The course of chronic hepatitis C progression varies widely among individuals. According to Jay Hoofnagle, M.D., of the National Institutes of Health (NIH), "there are probably multiple typical courses [of hepatitis C progression], from rapidly progressive to slowly progressive to non-progressive."

It is not possible to accurately predict which HCV-infected individuals will go on to develop cirrhosis, liver cancer, or end-stage liver disease. However, several cofactors appear to affect disease progression. The HCV genotype with which a person is infected appears to have an effect on disease severity. In most -- but not all -- studies, HCV subtypes 1a and 1b have been associated with more rapid progression, more extensive liver damage, and reduced response to treatment.

Alcohol consumption is likely the most important external cofactor; excessive alcohol use can damage the liver in the absence of HCV, and the additive effects of the virus plus alcohol can lead to more severe disease. Mary Rinella, M.D., and colleagues from the University of Illinois at Chicago Medical Center showed in a retrospective study that heavy alcohol users with HCV were three times more likely to develop cirrhosis than non-alcoholics with HCV (61% vs. 21%, respectively) after 20 years.

The infected person's age also seems to play a role. Individuals infected with HCV at an older age (especially over age 50) tend to have more rapid progression and more severe symptoms. Research indicates that children are better able than adults to fight HCV; they tend to experience less severe liver damage and have a slower rate of disease progression. Manfred Vogt, M.D., and colleagues studied 67 persons in Munich, Germany, who had acquired HCV through blood transfusions as children (at a mean age of three). When examined 20 years later, nearly half had cleared the virus without treatment. Among those with persistent infection, very few had elevated liver enzymes or other evidence of liver damage. Dr. Vogt's results were reported in the September 16, 1999 issue of the New England Journal of Medicine. Along with age, gender seems to have some effect, as men tend to develop more serious liver disease than women. In addition, persons whose immune systems are compromised -- due to HIV, immunosuppressive drugs, or some other cause -- are more likely to experience rapid HCV disease progression. Finally, disease progression and development of cirrhosis and liver cancer are more likely in persons coinfected with both hepatitis C and hepatitis B viruses.

It is unclear whether liver damage in people with chronic hepatitis C is due primarily to the action of the virus itself or to the effects of the body's immune response. Soon after infection, the immune system mounts nonspecific responses, including activation of natural killer cells that attack and kill HCV-infected liver cells. Over time, the immune system produces antibodies against the virus, and specific aspects of the immune response come into play. The action of HCV-specific cytotoxic T-lymphocytes (CTLs) and the cytokines (chemical messengers) they produce can destroy liver cells and lead to liver inflammation. The fact that HCV-related liver damage is often more severe in immunocompromised persons has led some researchers to hypothesize that the immune system plays a lesser role than the virus itself in causing damage. Other evidence suggests, however, that the immune response does have a significant effect. For example, research by D.R. Nelson and colleagues indicates that the presence of HCV-specific CTL activity is associated with higher liver enzyme levels and lower HCV viral load levels.

Long-Term Pathogenesis

Over time, progressive liver damage may occur in HCV-infected persons as liver cells are destroyed. This process begins with persistent inflammation, and proceeds to fibrosis or fibrinogenesis (the development of fibrous tissue), steatosis (fat accumulation), and cirrhosis of the liver. As normal liver cells are replaced with fibrous tissue, fat, and scar tissue, they are unable to carry out their normal functions of metabolism, protein production, and detoxification. Although estimates vary considerably, it is generally believed that about 20-30% of people infected with HCV will develop cirrhosis over 10-30 years. Of those with cirrhosis, an estimated 25-30% (or up to 5% of all persons initially infected with HCV) will develop end-stage liver disease or liver cancer. It has long been thought that liver damage due to fibrosis and cirrhosis was permanent, but recent research suggests that liver scarring can be halted and possibly reversed with effective treatment.

Physical symptoms and liver enzyme levels often fluctuate over the course of the disease. About 80% of people with chronic HCV experience elevated liver enzyme levels at some point during their illness (about 50% have fluctuating transaminase levels), while about 20% have consistently normal liver function tests, with or without detectable HCV RNA. In general, people with higher liver enzyme levels and higher HCV viral loads are more likely to experience symptoms. However, HCV viral load does not correlate well with degree of liver damage or severity of liver disease.

Some people with chronic hepatitis C experience mild symptoms, which may include fatigue, nausea, loss of appetite, abdominal tenderness, and liver and/or spleen enlargement; others remain asymptomatic until they develop complications of advanced liver disease. Late-stage complications may include jaundice, itching, and bruising, which indicate the liver is not properly carrying out its metabolic functions (a condition known as decompensated cirrhosis). People with late-stage liver disease may also experience upper gastrointestinal tract bleeding and fluid retention in the abdomen and lower extremities, which are indications of portal hypertension. Blood normally enters the liver through the portal vein. When scar tissue is present in the liver, pressure can build up inside this vein and other vessels that lead to it, interfering with blood circulation to the liver. This process may result in stretched and weakened blood vessels (varices) and subsequent breakage and bleeding of vessels in the esophagus and stomach, or hemorrhoids in the rectum. While many complications are common to various types of liver damage, the presence of steatosis, lymphoid aggregates (clusters of immune cells), and bile duct injury appear to be more specifically characteristic of chronic hepatitis C. The ultimate result of liver failure is brain damage, coma, and death, unless the person can obtain a new liver or be temporarily maintained on an experimental artificial liver.

It is known that HCV infection can lead to primary hepatocellular carcinoma, a type of liver cancer, but it is not clear why. Although liver cancer may develop as soon as five years after HCV infection, an interval of 25-30 years is more common; hepatocellular carcinoma typically develops only after cirrhosis is present. Some researchers believe that damage and regeneration of infected liver cells leads to development of mutant cells that grow in an uncontrolled manner. Unlike the hepatitis B virus (HBV), HCV does not integrate itself into the host cell's genome; liver cancer is more common in persons coinfected with both HCV and HBV. Randy Jirtle, M.D., and colleagues from Duke University Medical Center reported in the September 16, 1999 issue of the Proceedings of the National Academy of Sciences that once HCV infection takes hold, liver cells have already lost one of two copies of a protective tumor suppressor gene called mannose 6 -- phosphate/insulin -- like growth factor 2 receptor (M6P/IGF2R). If one copy is lost, the other can compensate, but as cells sustain additional damage, the second copy may be lost as well; without the tumor suppressor gene, liver cells can become cancerous.

Chronic hepatitis C is less commonly associated with several non-hepatic (outside the liver) manifestations, including glomerulonephritis (inflammation of the filtering structures in the kidneys), cutaneous vasculitis (damage to blood vessels in the skin), lichen planus (a type of skin lesion), porphyria cutanea tarda (a metabolic disturbance that leads to photosensitivity and skin damage), keratoconjunctivitis (eye inflammation), arthritis (joint inflammation and damage), and essential mixed cryoglobulinemia (high levels of a type of blood protein, resulting in fatigue and weakness, muscle and joint aches, skin rash, and sensitivity to cold). These complications are believed to be associated with an autoimmune or overactive immune response.

Despite this grim picture, it should be remembered that end-stage liver damage and liver failure occur in a minority of people with chronic hepatitis C. Many more do not sustain serious damage and may live without symptoms for decades. Others experience only mild symptoms such as intermittent fatigue, nausea, and muscle aches.

HCV and HIV Coinfection

Because HIV and HCV are transmitted by similar means, coinfection with the two viruses is common. Experts estimate that as many as 30-40% of HIV positive people in the U.S. are coinfected with HCV, although the rate varies widely among different HIV-infected populations.

Since HIV affects the immune system, it can influence the body's response to other infections. Several studies suggest that hepatitis C progresses more rapidly and is more likely to lead to severe liver damage and liver cancer in people with HIV. For example, Javier Garcia-Samaniego and colleagues from the Instituto de Salud Carlos III in Madrid reported in the July 1997 issue of the American Journal of Gastroenterology that people coinfected with HCV and HIV experience more aggressive hepatitis and more extensive liver damage than those without HIV. Yves Benhamou reported in the October 1999 issue of Hepatology that HIV/HCV coinfected persons, especially those with fewer than 200 CD4 cells/mm3, experience a faster rate of fibrosis progression. Studies have shown that people with both HCV and HIV tend to have higher HCV viral loads than those with HCV alone. An estimated 25-50% of HIV/HCV coinfected persons develop liver cirrhosis compared to 20-30% of those with only HCV, and some research indicates that coinfected persons are at greater risk for liver cancer. Other research suggests, however, that because some HCV-related liver damage is due to the body's immune response, those with compromised immune systems may experience reduced liver inflammation and injury.

The evidence is less clear about the effect of HCV on the progression of HIV disease. At the September 1997 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Henri Portier, M.D., presented evidence showing that coinfection with HIV and HCV accelerates HIV disease progression. Arvind Gupta of Lehigh Valley Hospital in Allentown, PA, presented similar results.

In contrast, researchers from the Veterans Affairs Medical Center in Decatur, GA, reported in the July 1999 issue of Clinical Infectious Diseases that HIV/HCV coinfection appears to have little or no effect on the progression of HIV disease or survival. David Rimland, M.D., and colleagues examined the medical records of 350 HIV positive persons treated at the center between January 1992 and May 1997; one-third were also infected with HCV. According to Dr. Rimland, "The bottom line is that in the three ways that we looked at survival -- from HIV diagnosis to AIDS diagnosis, from HIV diagnosis to death, and from AIDS diagnosis to death -- there was absolutely no difference between [persons] who had HIV alone and those who had both [HIV and HCV]."

Coinfection with HIV appears to increase the likelihood that HCV will be perinatally transmitted from mother to infant, and may also increase the risk of sexual transmission of HCV; enhanced HCV transmission may be related to higher HCV viral loads in people who also have HIV. Coinfection also increases the risk of perinatal HIV transmission. Researchers from the Women and Infants Transmission Study reported in the August 1997 issue of the Journal of Infectious Diseases that vertical transmission of HIV occurred in 26% of HIV/HCV coinfected mothers compared to 16% of HIV positive mothers without HCV; however, the rate of HIV transmission in this study was higher than that found in most recent research and may not reflect the full effect of new treatment regimens designed to reduce perinatal HIV transmission.

Hepatitis C Treatment

Wellness Measures

The liver plays many important physiological roles, and damage to the organ may lead to general ill health. Wellness measures including a healthy diet, avoidance of harmful substances, and sufficient rest are even more important for people with chronic hepatitis C than for the population as a whole. In addition, it is recommended that people with chronic HCV receive vaccinations against hepatitis A and B, since these viruses can lead to more severe illness and death in people with damaged livers.

People with HCV should not drink alcohol, which has a detrimental effect on the liver. It is thought that even moderate alcohol consumption can be harmful for people whose liver is already damaged; the NIH recommends that people with chronic hepatitis consume no more than one alcoholic drink per day. People with HCV should avoid chemical fumes and other environmental toxins such as solvents and pesticides as much as possible. Drugs -- both recreational and medicinal -- and certain herbs can be dangerous in people whose livers are not able to metabolize foreign substances adequately. People with chronic hepatitis C should consult a qualified medical practitioner before starting any new drug or herb.

A healthy diet is beneficial for people with chronic HCV. Although diet modification is no longer considered the mainstay of chronic hepatitis treatment that it once was, diet changes in late-stage disease may be beneficial. Many nutritionists recommend a diet rich in whole grains, fruits, and vegetables, with a minimum of chemical additives. For people with cirrhosis, a low-fat diet may put less strain on the reduced metabolic abilities of a damaged liver. Because the breakdown of protein results in byproducts that can be toxic to the brain, it is sometimes recommended that people with liver-related encephalopathy limit their protein consumption.

A damaged liver may not be able to metabolize certain vitamins and minerals properly. Iron supplements should not be used, and intake of iron-rich foods may be limited. People with chronic hepatitis should not take large doses of vitamin A, which can be toxic to the liver. Vitamin E, on the other hand, appears to have a beneficial effect on the liver. Reduced salt consumption can lessen fluid retention and associated swelling. Because some seafood (raw or cooked) may contain toxins, some experts recommend that people with liver damage avoid it.

Fatigue is one of the most common and persistent symptoms of chronic hepatitis C. People with HCV may need to adjust their lifestyles and work schedules to allow for rest when they need it. Taking frequent short naps during the day, and interspersing more demanding activities with those that are less strenuous, may help people maintain their energy levels.

Who Should Be Treated and When?

Several factors influence decisions about whether and when to treat people with chronic hepatitis C. Drugs used to treat the disease are expensive, sometimes have severe side effects, and until recently have not been very effective. Treatment effectiveness depends on many factors, including age, extent of liver damage, immune system status, and HCV viral load. Many practitioners prefer to treat only those who are most likely to progress to more serious liver disease and who are likely to benefit the most from therapy. Another major factor influencing treatment success is HCV genotype. According to Teresa Wright, M.D., of the Veterans Administration Medical Center in San Francisco, "the single strongest predictor of response" to treatment is the presence of an HCV subtype other than 1a or 1b. Recent research suggests that genotype 1 HCV may be harder to treat because it lives longer in the body.

Since many people with chronic hepatitis C do not experience symptoms for decades -- and may never develop serious liver disease -- physicians disagree about the wisdom of treating people who are asymptomatic, have normal liver enzyme levels, and show minimal liver damage. Many physicians believe that for these people, watchful waiting with regular transaminase measurements, HCV viral load monitoring, and liver biopsies may be a better choice; some practitioners also recommend regular blood testing for alpha-fetoprotein, a marker for liver cancer. For people with moderate to severe liver inflammation or fibrosis, or early cirrhosis, most physicians agree that treatment is indicated. A liver biopsy should be done to determine the extent of liver damage. HCV RNA viral load and liver enzyme levels are not reliable markers of disease severity, although they can help guide treatment decisions.

Many experts recommend that persons with severe end-stage liver disease should not receive interferon or antiviral therapy. Interferon kills liver cells infected with HCV, causing further liver damage. People with compensated cirrhosis (no ascites, varices, jaundice, or encephalopathy) should be routinely offered treatment, but those with decompensated cirrhosis should be treated only in experimental studies with close monitoring.

To date, no large studies of treatment of children with chronic hepatitis C have been done, although available data suggest that children respond better than adults treated with interferon monotherapy; there is little data on treatment of children with interferon/ribavirin combination therapy.

Although people with hepatitis C are not often diagnosed during the acute phase of the disease, prompt treatment of those who are so identified is associated with a high rate of sustained HCV clearance.

Approved Pharmaceutical Treatments

Before 1998, the only FDA-approved treatment for chronic hepatitis C was interferon monotherapy. The interferons are a group of naturally occurring messenger proteins with anti-inflammatory and immunomodulating effects. Bioengineered interferon is manufactured by several companies and sold under names such as Intron A and Roferon-A. Interferon treatment is thought to work by inhibiting viral replication and enhancing immune system activity. Interferon-alpha 2a and 2b are approved for HCV treatment; a form known as consensus interferon (Infergen) that combines amino acids from both 2a and 2b may also be used. Interferon-beta has also been studied for treatment of chronic HCV infection, but it has proven less effective.

Interferon monotherapy at approved doses is not very effective in treating chronic hepatitis C; with the approval of interferon/ribavirin combination therapy, interferon monotherapy is now considered substandard treatment. Interferon initially reduces liver enzyme and HCV RNA levels in about 50-60% of treated persons, but sustained viral suppression is seen in only 10-20% of persons treated with interferon monotherapy. Many later relapse and experience viral load rebound, while others experience viral "breakthrough" during treatment. Most relapses occur during the first six months after stopping treatment; if a person maintains viral suppression after a year, later relapse is uncommon.

Studies have shown that treatment with interferon is more effective in people who have a low HCV viral load, are under age 40, are female, have HCV genotypes other than genotype 1, and have not yet sustained extensive liver damage. For unknown reasons, interferon appears to be less effective in African-Americans than in Whites. A typical course of interferon-alpha therapy is three million units administered by injection under the skin three days per week for 6-12 months; many physicians recommend the shorter treatment period for people with HCV genotypes other than subtype 1. Some studies have explored using high-dose interferon induction therapy, as well as using the drug for more days per week or for longer periods of time in persons who do not benefit from the standard regimen; prolonged treatment does not appear to improve the initial response rate, but may decrease the rate of relapse. The NIH recommends that if no improvement is seen after three months of interferon monotherapy, further benefits are unlikely and treatment should be changed or discontinued.

Adverse side effects of interferon-alpha range from flu-like symptoms such as fatigue, headache, nausea, loss of appetite, and muscle and joint pain, to psychological effects such as anxiety and depression, to immune system toxicities such asbone marrow suppression and low blood cell counts; reversible hair loss may also occur. Side effects may diminish over time, and may be relieved by ibuprofen or low-dose acetaminophen (normal doses may be toxic in people with damaged livers), mild tranquilizers, or antidepressants. Injection of interferon at bedtime may allow a person to sleep through the worst symptoms. Nevertheless, approximately 40% of people taking interferon reduce their dose and 15% discontinue therapy due to side effects. Persons with a history of psychiatric disease or thyroid disease should not be treated with interferon.

Several studies have shown that using interferon-alpha in combination with a guanosine analog antiviral drug known as ribavirin (Rebetol) leads to superior results compared with interferon monotherapy. Ribavirin is taken as a capsule twice daily. Side effects include gastrointestinal symptoms and hemolytic anemia; a recent small study suggests that antioxidants (e.g., vitamin C, vitamin E) may reduce hemolysis (the breakdown or destruction of red blood cells). In addition, ribavirin is a teratogenic drug, which means that it may cause miscarriages and birth defects. In June 1999, the FDA mandated that the ribavirin package insert must include a "black box" warning instructing people who take ribavirin and their sexual partners to use two forms of contraception until six months after treatment is stopped.

In June 1998, the FDA approved Rebetron, a prepackaged combination of interferon-alpha 2b (Intron A) and ribavirin manufactured by Schering-Plough (see sidebar). Rebetron was initially approved for those who did not experience a sustained response on interferon monotherapy; in December 1998, the combination was approved as a first-line therapy for treatment-naive persons. Combination therapy with interferon-alpha and ribavirin is now considered standard treatment for chronic hepatitis C.

Approval of the combination was based in part on two randomized, double-blind phase III studies that involved 1,744 HCV-infected participants (912 in the U.S. and 832 in a multinational trial) who had not previously been treated with interferon. The interferon-alpha/ribavirin combination was compared with interferon-alpha plus placebo. After 48 weeks of combination therapy, 38% of participants in the U.S. study and 43% of those in the international trial had an undetectable HCV viral load, versus 13% and 19% (respectively) of those receiving interferon plus placebo. Persons receiving combination therapy also had greater reductions in liver enzyme levels. Treatment response rates were highly dependent on HCV genotype.

In the U.S. trial, nearly three-quarters of the participants were infected with HCV subtype 1; after 24 weeks of therapy, 16% experienced sustained viral suppression, increasing to 28% after 48 weeks. In persons with HCV subtypes 2 or 3, the sustained response rate was significantly higher, at 66%; the response rates at 24 and 48 weeks were similar, suggesting that six months of treatment may be sufficient for those with HCV subtypes other than 1. The results of these studies were reported by John McHutchinson, M.D., and colleagues from the Scripps Clinic in La Jolla, CA, in the November 19, 1998 issue of the New England Journal of Medicine.

Studies have also shown that interferon/ribavirin combination therapy is superior to interferon-alpha monotherapy in persons who had previously been treated with interferon alone. In the same issue of the New England Journal of Medicine, Gary Davis, M.D., and colleagues from the University of Florida at Gainesville published the results of two identical double-blind phase III clinical trials that involved 345 participants with chronic hepatitis C who had relapsed following interferon-alpha monotherapy; relapse was defined as having transaminase levels that normalized after initial treatment, but then increased again within a year after stopping therapy. Interferon/ribavirin combination therapy led to rates of viral suppression ten times higher than those seen in participants receiving interferon alone.

Six months after the end of the 24-week treatment period, 45.7% of the combination therapy recipients had an undetectable HCV viral load, compared with 4.7% of those who received interferon monotherapy. Responses to interferon monotherapy and to interferon/ribavirin combination therapy are better in those who have a low HCV viral load when they start therapy and who have not yet developed cirrhosis. In persons treated with interferon monotherapy, an early response rate predicts sustained response; that is, if a person achieves an undetectable HCV viral load soon after treatment begins, he or she is more likely to experience continued HCV suppression. In persons on combination therapy, this effect is less pronounced, and some who do not respond as quickly may still achieve sustained viral suppression. Research indicates that combination therapy may have a beneficial effect on liver disease progression even if viral load does not become undetectable.

Experimental Treatments

Research continues to produce potential new treatments for chronic hepatitis C. According to a report in the September 15, 1999 issue of the Journal of the American Medical Association, the National Institute of Diabetes and Digestive and Kidney Diseases is launching a $28 million trial of antiviral drugs for the treatment of chronic HCV; the study will take place at nine centers in the U.S. and will last eight years, making it the largest and longest hepatitis C treatment trial ever conducted. Researchers hope this trial will show whether extended antiviral drug treatment can delay or prevent some of the long-term effects of chronic hepatitis C. In addition to antivirals, immunomodulating drugs are also under study. Future treatment options may include therapeutic vaccines and gene therapy, although vaccine development remains challenging due to the genetic variability and rapid mutation of HCV.

One recent addition to the experimental HCV treatment armamentarium is a new, longer-acting form of interferon-alpha called pegylated interferon, which can be administered less frequently. Pegylation is a process whereby the polyethylene glycol (PEG) polymer is attached to interferon, thus protecting it from rapid metabolism in the body. Pegylated interferon has a half-life (the time required for the initial amount to be reduced by half) about ten times longer than standard interferon. Results of a phase II trial in HCV-infected patients without cirrhosis indicated that the use of pegylated interferon monotherapy yields higher sustained rates of undetectable viral load than standard interferon monotherapy (36% vs. 3%).

At the American Association for the Study of Liver Disease (AASLD) conference in Dallas in early November, Jenny Heathcote, M.D., and colleagues reported the results of a phase II/III trial of pegylated interferon monotherapy administered once per week compared to standard interferon monotherapy administered three times per week in HCV-infected persons with cirrhosis. At 72 weeks (24 weeks after the end of a 48-week treatment period), 29% of those receiving pegylated interferon had an undetectable HCV viral load compared to 6% of those receiving standard interferon.

In addition, preliminary results from a small number of patients indicate that combination therapy with pegylated interferon plus ribavirin appears superior to standard interferon/ribavirin combination regimens.Alfredo Alberti, M.D., and colleagues from the University of Padua, Italy, recently presented results showing that up to 80% of those receiving pegylated interferon plus ribavirin had an undetectable HCV viral load after 24 weeks of treatment. Side effects of pegylated interferon are similar to those of standard interferon, but more people taking the pegylated form experience low thrombocyte (platelet) and neutrophil (a type of white blood cell) levels. Roche Laboratories is developing a brand of pegylated interferon called Pegasys; Schering-Plough's experimental pegylated interferon is known as Peg-Intron. The new form of interferon is expected to be approved by the FDA in early 2000.

Another new form of interferon is called lymphoblastoid interferon-alpha n1 (Wellferon). In a study of 1,071 participants conducted by Bruce Bacon, M.D., and colleagues from St. Louis University School of Medicine, participants receiving lymphoblastoid interferon were somewhat more likely to have reduced liver enzyme levels compared to those receiving standard interferon-alpha 2b (32% vs. 20%) and a considerably lower rate of relapse 48 weeks after the end of treatment. The side effects of lymphoblastoid interferon are similar to those of interferon-alpha.

Given the beneficial effects of interferon/ribavirin treatment, many researchers are looking to other combination therapies. Combination treatment with thymosin-alpha 1 (Zadaxin) and interferon-alpha has been shown to confer greater benefits than interferon monotherapy. Thymosin-alpha 1 is a bioengineered version of a naturally occurring chemical messenger produced by the thymus gland that stimulates natural killer cell and T-cell activity. In a trial involving 109 participants, liver enzyme levels normalized in 37% of those in the combination therapy arm and 16% in the interferon monotherapy arm. In terms of viral response, 37% of those in the combination arm and 19% of those in the monotherapy arm achieved an undetectable viral load. In studies to date, thymosin has been associated with few side effects. The drug is not approved by the FDA, but is marketed in several countries in South America and Asia.

Preliminary results from small studies of another immune modulator, interleukin 10 (IL-10) appear promising. At the AASLD conference, Dr. Davis and colleagues reported that IL-10 led to decreased liver enzyme levels and also appeared to reduce liver inflammation and fibrosis. Interleukin 12 (IL-12) has shown less impressive results. A small study of 60 participants in Frankfurt, Germany, suggested that the cytokine does not reduce liver enzyme or HCV viral load levels. The drug appears safe and well tolerated, however, and clinical trials are continuing. As with interferon, side effects of IL-12 include flu-like symptoms.

Two drugs best known as flu treatments have also shown promise as therapies for chronic hepatitis C. Amantadine (Symmetrel) is FDA-approved for treatment of influenza type A; rimantadine (Flumadine) is a related drug. These compounds appear to work by interfering with early viral replication. Side effects of the drugs are similar, and may include depression, anxiety, irritability, insomnia, drowsiness, headaches, gastrointestinal symptoms, and blood pressure abnormalities; drowsiness is less common with rimantidine.

Results from several studies suggest that amantadine and rimantadine are not effective as HCV monotherapy. However, they may be useful as part of combination regimens that include interferon-alpha, with or without ribavirin. Early results of a small pilot study suggest that combinations of amantadine or rimantadine plus interferon may be as effective as interferon/ribavirin combination; it is not yet known whether HCV viral suppression will be sustained over time. In trials that have compared a three-drug amantadine/interferon/ribavirin combination regimen to a two-drug interferon/ribavirin regimen, HCV viral clearance and/or normalized liver enzyme levels were initially seen in 60-80% of participants in the three-drug arm; six months after treatment, the response rate fell to about 40%.

Other therapies under study for treatment of chronic hepatitis C -- alone or in combination regimens -- include ursodeoxycholic acid, nonsteroidal anti-inflammatory drugs, corticosteroids, and certain antibiotics. Ribozyme Pharmaceuticals and Eli Lilly are currently collaborating on the development of Heptazyme, a ribozyme that targets HCV; ribozymes are naturally occurring compounds that interfere with RNA production. Treatments that may be developed in the future include protease and helicase inhibitors, RNA polymerase inhibitors, and antisense drugs.

Alternative and Complementary Therapies

A variety of alternative and complementary therapies have been used to treat people with chronic liver disease. Western herbs used as therapy for chronic HCV include milk thistle (silymarin), licorice root (glycyrrhizin), dandelion, and black walnut. Silymarin has been studied in several Western-style clinical trials that have yielded mixed results; such studies have often been conducted in Europe, where herbal therapy is more widely accepted than it is in the U.S. Oriental herbs and herbal formulas used for chronic hepatitis include zhi zi (gardenia), da huang (rhubarb), long dan cho (gentian root), long dan xie gan tang, yin chen hao tang, and sho saiko to. Practitioners of Chinese medicine believe that herbal preparations can help detoxify the liver, reduce inflammation, and improve bile flow.

Chinese methodologies such as herbs and acupuncture may be effective in relieving chronic hepatitis symptoms such as nausea and fatigue. Recent studies suggest that certain alternative therapies, including silymarin and vitamin E, can help lessen or delay the formation of scar tissue in the liver. However, many herbs, including chaparral, comfrey, pennyroyal, germander, mistletoe, and skullcap, are toxic to the liver and should be avoided by those with liver damage. Consult a qualified medical practitioner before beginning any herbal treatment.

HCV Treatment in People with HIV

Some studies suggest that people with HCV/HIV coinfection may not respond as well as non-HIV-infected persons to treatment regimens that include interferon; interferon is intended to boost immune activity, and the immune systems of some HIV-infected individuals may be too damaged to respond. However, people with well-controlled HIV disease and relatively high CD4 cell counts appear to do well on anti-HCV treatment, and most experts recommend that such therapy be offered if indicated. People taking highly active antiretroviral therapy (HAART) for HIV may take anti-HCV drugs as well, but caution should be used when combining medications. People with HIV/HCV coinfection should seek the care of a physician who has experience with both diseases.

Many antiretrovirals used to treat HIV disease are processed by the liver, and some (in particular, ritonavir) have been associated with liver toxicity. Many studies have shown elevated liver enzyme levels in people using anti-HIV combination therapies that include a protease inhibitor. Some people experience a "flare" of hepatitis when they begin an effective HAART regimen; this may be due to improved immune system activity as HIV is suppressed. Existing liver damage due to chronic hepatitis may affect how anti-HIV drugs work. Because a damaged liver cannot metabolize drugs as effectively, there is a risk that blood levels of the drugs will become too high and lead to intensified adverse side effects. Some people with severe liver damage may need to have their doses of anti-HIV medications reduced, or they may not be able to take protease inhibitors or other anti-HIV drugs at all.

Clinical trials to study interactions between anti-HIV and anti-HCV drugs have been few, and none have followed participants over a long period of time. Some laboratory studies indicate that AZT (Retrovir) and d4T (Zerit) may interfere with ribavirin, and physicians have tended to avoid using these drugs together. At the 39th ICAAC this past September, however, Douglas Dieterich, M.D., and colleagues from New York University School of Medicine reported interim results from a small study that suggested that these drugs may be used in combination. In this study, HIV positive participants who were taking HAART and who had an undetectable HIV viral load were also given combination interferon-alpha/ribavirin therapy for HCV. After three months, HIV viral loads remained undetectable and HCV viral loads decreased; long-term follow-up is ongoing, and larger studies are recommended.

Dr. Dieterich decried the reluctance of many practitioners to treat HIV/HCV coinfected persons, stating, "Although it is doubtful that there will be many [HCV] virological cures in people with HIV, even in so-called failures interferon therapy decreases fibrosis, increases T-cell responsiveness to hepatitis C antigens, and decreases the rate of fatal hepatomas [liver cancer] -- lowering the [HCV] viral load can only help the ultimate outcome of the liver disease, and may permit [the coinfected person] to take protease inhibitors that will certainly prolong life."

Therapies for Symptoms and Complications

In addition to treatments specifically intended to boost the immune system or attack HCV directly, many therapies are used to relieve symptoms and manage complications in people with chronic hepatitis C.

Nausea, a common symptom of both acute and chronic hepatitis, may be ameliorated by antiemetic drugs. Medicinal cannabis or dronabinol (Marinol) may both relieve nausea and stimulate the appetite. Ondansetron (Zofran) may help relieve chronic fatigue associated with HCV. A case report of this indication was presented by E. Anthony Jones in the July 31, 1999 issue of the Lancet; ondansetron is also effective against nausea. Pruritis caused by the buildup of toxins may be relieved by drugs such as cholestyramine (Questran). Diuretic drugs may be used to reduce fluid buildup leading to edema and ascites. Beta blockers, which are used to treat generalized high blood pressure, may also be used to reduce portal hypertension; beta blockers that are not metabolized by the liver, such as atenolol (Tenormin) and nadolol (Corgard), are preferred over those that are cleared by the liver, such as propranolol (Inderal) and metoprolol (Lopressor).

Surgical treatments for decompensated cirrhosis include paracentesis (fluid withdrawal from the abdomen) for treatment of ascites; persons undergoing this procedure may require a plasma extender such as albumin to prevent circulatory complications. Endoscopic surgery may be performed to tie off varices in the esophagus and stomach (ligation), or sclerosing agents may be used to harden the varices in an effort to reduce the risk of bleeding (sclerotherapy). A portacaval shunt may also be used to reroute excess blood flow around the liver.

Two treatment options for hepatocellular carcinoma are currently used. In a partial liver resection, cancerous tissue is surgically removed; this is possible because the liver is usually able to regenerate. The second option is total liver removal (hepatectomy) followed by a transplant. If untreated, liver cancer is typically fatal within three to six months. No accepted systemic chemotherapy exists for this type of cancer.

Liver Transplants

When cirrhosis becomes severe enough to cause liver failure, a liver transplant may be the only way to save the life of a person with chronic hepatitis C. End-stage liver disease due to HCV is currently the leading reason for liver transplants in the U.S. A severe shortage of transplantable livers, however, means that only about one-quarter of people who require a liver transplant are able to obtain one.

New livers typically become infected with HCV soon after transplantation, and the immunosuppressive drugs used to prevent transplant rejection may lessen the immune system's activity against the virus. Nevertheless, the recurrent infection may be milder, and studies indicate that the survival rate after liver transplants due to HCV is similar to the rate for those undergoing liver transplants for other indications (an average 65% survival rate after five years).

A recent study conducted by Hugo Vargas, M.D., and colleagues at the University of Pittsburgh Medical Center -- one of the country's leading transplant centers -- and published in the July 1999 issue of Gastroenterology suggests that the shortage of donor livers may be relieved by use of livers that are already infected with HCV. This study examined nearly 200 liver transplants performed on recipients with HCV infection between 1992 and 1995; 23 people received HCV-infected livers and 169 received non-infected livers. The survival rate after one year was 89% for recipients of HCV-infected livers and 88% for recipients of non-infected livers; five-year survival rates were 72% and 73%, respectively.

Another possibility for increasing the supply of livers is using liver tissue from living donors, since a healthy liver can typically regenerate even when nearly half of the organ is removed. A related approach involves dividing donated livers in half so that they can be transplanted into two recipients. Further studies are needed to determine if partial liver transplants are feasible in people with liver failure due to chronic hepatitis C. Finally, an experimental artificial liver may temporarily prolong survival in cases of end-stage liver failure.

Most transplant centers will not perform liver transplants on persons with HIV infection, in part due to the belief that the necessary immunosuppressive drugs would further impair a compromised immune system. With new anti-HIV combination therapy, however, many people with HIV are living longer and experiencing less immune system damage. Good results have been seen in some of the few liver transplants done in HIV/HCV coinfected persons who do not have advanced AIDS. Three out of four HIV/HCV positive persons who received a liver or kidney transplant at the University of Pittsburgh in the past two years are doing well and have maintained undetectable viral loads.

Similar results were reported from King's College Hospital in London, where five coinfected liver recipients have remained free of HIV-related illness following transplantation. Recently, the University of California at San Francisco (UCSF) was awarded a $1 million state grant to study liver and kidney transplantation in HIV positive people who have undetectable viral loads and no AIDS-defining illnesses. Activists are working diligently to increase the willingness of transplant surgeons to perform liver transplants in people with HIV and the willingness of health insurers to pay for the procedure.


In the coming decades, the individual and public health implications of chronic hepatitis C will likely increase as people infected in the 1970s and 1980s develop complications related to advanced liver disease. According to former Surgeon General C. Everett Koop, "The hepatitis C epidemic poses one of the most serious public health crises faced in this century -- the threats of which will be even more serious as we enter the next century. Soon after the turn of this century, the hepatitis C virus will take more human lives each year than AIDS." Fortunately, effective blood screening and increased public awareness have greatly reduced the incidence of new HCV infections.

Although current hepatitis C treatment still leaves much to be desired, recent advances have improved the chances of sustained viral suppression. It is becoming increasingly clear that there are several parallels between treatment of HCV and treatment of HIV. First, some people with both diseases appear not to develop symptoms over the course of many years. Second, it appears that for either virus, combination therapy with two, three, or more drugs is more effective than monotherapy. Third, treatment can reduce viral load to undetectable levels in both diseases, but viral replication often rebounds when treatment is stopped (although this is less likely with HCV). Fourth, in the case of both HCV and HIV, treatment appears to work better in people with low viral loads, and is more effective before extensive liver or immune system damage occurs.

Finally, increased knowledge about the virus' life cycles and how they affect the body has led to continual improvements in treatments for both diseases and a greater ability to tailor treatment to an individual's specific needs. With proper care and treatment, many people with HCV and HIV/HCV coinfection can expect to live for many years, often with few or no hepatitis-related symptoms.

Liz Highleyman is a freelance medical writer and a former member of the BETA editorial staff.

Selected Sources

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  3. Buzzelli, G. and others. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB 1016) in chronic active hepatitis. International Journal of Clinical Pharmacology and Therapeutic Toxicology 31: 456-460. September 1993.

  4. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Morbidity and Mortality Weekly Report 47(RR19): 1-39. October 16, 1999.

  5. Cohen, J. The scientific challenge of hepatitis C. Science 285(5424): 26-30. July 2, 1999.

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  7. Dieterich, D. and others. Interferon-alfa and ribavirin therapy for hepatitis C in HIV co-infected patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco. September 26-29, 1999. Abstract 429.

  8. Garcia-Samaniego, J. and others. Influence of HCV genotypes and HIV infection on histological severity of chronic hepatitis C. American Journal of Gastroenterology 92: 1130-1134. July 1997.

  9. Gish, R. Standards of treatment in chronic hepatitis C. Seminars in Liver Disease 19(s1): 35-48. 1999.

  10. Gretch, D. Identifying the sustained responder. Digestive Disease Week 1999 Annual Meeting. Orlando, FL. May 16, 1999.

  11. Gupta, A. and others. Relationship between hepatitis C virus viral load and HIV viral load: a case control study. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto. September 28-October 1, 1997. Abstract I162.

  12. Koff, R. Advances in the treatment of chronic viral hepatitis. Journal of the American Medical Association 282(6): 511-512. August 11, 1999.

  13. McHutchison, J.G. and others. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis. New England Journal of Medicine 339(21): 1485-1492. November 19, 1998.

  14. National Institutes of Health. Management of hepatitis C. Statement of the NIH Consensus Development Conference Panel. March 24-26, 1997.

  15. Resti, M. and others. Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. British Medical Journal 317(7156): 437-441. August 15, 1998.

  16. Sangiovanni, A. and others. Natural history of HCV positive patients with persistently normal transaminases. Digestive Disease Week 1999 Annual Meeting. Abstract L0400.

  17. Sarin, S. and others. Comparison of endoscopic ligation and propranolol for the primary treatment of variceal bleeding. New England Journal of Medicine 340(13): 988-993. April 1, 1999.

  18. Shiffman, M. A controlled, randomized, multicenter descending dose phase II trial of pegylated interferon alfa-2A (PEG) vs. standard interferon alfa-2A (IFN) for treatment of chronic hepatitis C. Digestive Disease Week 1999 Annual Meeting. Abstract L0418.

  19. Taylor, D. and others. Inhibition of the interferon-inducible protein kinase PKR by the HCV E2 protein. Science 285(5424): 107-110. July 2, 1999.

  20. Vargas, H. and others. Outcome of liver transplantation in hepatitis C virus-infected patients who received hepatitis C virus-infected grafts. Gastroenterology 117: 149-153. July 1999.

  21. Vogt, M. and others. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. New England Journal of Medicine 341(12): 866-870. September 16, 1999.

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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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