The Challenge of Hepatitis C and HIV Co-Infection
The emergence of hepatitis C virus (HCV) in HIV-positive patients is an increasingly significant problem. The era of highly active antiretroviral therapy (HAART) has dramatically decreased morbidity and mortality from opportunistic diseases. The longer life span in the HIV population, however, has increased the mortality associated with underlying diseases such as HCV infection.
It is estimated that 30% of HIV-infected individuals also have HCV, totaling approximately 300,000 with co-infection in the United States. Among those infected with HIV via injection drug use (IDU), 60-90% are estimated to have HCV.
Several studies suggest that HIV accelerates HCV progression to cirrhosis and end-stage liver disease. In fact, liver disease is the leading cause of hospital admissions and death in HIV-positive patients. Antiretroviral therapy (ART) in co-infected patients increases the risk of liver toxicity. This and the potential for accelerated liver disease make it crucial to consider HCV treatment of patients with HIV. The burden of co-infection prompted the Centers for Disease Control and Prevention (CDC) to issue guidelines for HCV management in 1999.
Before its discovery in 1989, HCV was known as non-A, non-B hepatitis. Today it is the most common blood-borne infection and one of the most important causes of chronic liver disease in the United. States. HCV is the major cause for liver transplantation and accounts for more than 10,000 deaths each year.
Approximately 4 million Americans, or 1.8% of the U.S. population, have antibody to HCV, indicating ongoing or previous infection with the virus. Furthermore, 2.7 million people have chronic hepatitis C. The HCV epidemic peaked during the 1970s and 1980s, prior to identification of the virus and before HCV screening for blood products and organs was set in place.
Injection drug users are the largest group of people infected with HCV. African Americans and Hispanics are affected disproportionately. Individuals aged 30-49 years make up 65% of HCV infections and the majority of people who die from HCV-related disease are between 44 and 54 years of age.
The present incidence of advanced liver disease due to HCV is on the rise, and the number of deaths from HCV is expected to increase during the next 10 to 20 years. Medical costs due to HCV-related morbidity are expected to exceed one billion dollars annually.
Like HIV, HCV is transmitted through blood-to-blood contact. HCV, however, lives outside the body for a much longer time than HIV and therefore spreads more easily. Sharing needles for injection drugs is a very high-risk behavior.
Using sterilized needles for tattoos is very important in guarding against HIV, but it may not be enough to prevent HCV infection. The reason is that when the tattoo artist dips the needle into the ink, a microscopic amount of blood from the person getting the tattoo can get into the ink. If that blood contains HCV, it is the ink and not the needle that poses the danger to the next person who gets a tattoo.
Women can pass HCV to their babies at birth, but the incidence of this is very low. Breast-feeding does not seem to increase the risk of mother-to-child transmission.
The incidence of sexual transmission of HCV seems to be low, but persons who participate in high-risk behaviors such as unprotected anal intercourse and/or those who have multiple sex partners have an increased risk if infection with HCV. At least 20% of new cases are associated with high-risk sexual behavior.
Hepatitis C and the Liver
After initial exposure to HCV, approximately 15% of infected people spontaneously clear the virus. At least 75% of patients with acute hepatitis C ultimately develop chronic infection and most of these have associated liver disease. HCV-associated liver disease develops very slowly. Many people have HCV and never even know that they are infected until it is too late. It works silently over the years causing irreversible liver damage without any signs. The most common symptom associated with hepatitis C is fatigue.
Liver damage from HCV can lead to cirrhosis in 20 years and liver cancer in 30 years. These problems occur at a much faster rate -- perhaps twice as rapidly -- among those who are co-infected with HIV.
"Hepatitis" simply means inflammation of the liver. A virus that mainly infects the liver cells causes the disease. When a hepatitis virus infects a liver cell, spikes on its outer membrane (known as the "envelope") anchor to the outer surface of the liver cell. A core of viral genes is now able to pass from the envelope into the cell. Once inside, the virus can take over the normal function of the liver cell, forcing it to make more viruses. This process causes the cell to die ... but not before thousands of viruses are released to infect healthy cells.
The immune system is designed to fight infection by making proteins called antibodies; a different antibody is produced for each different infection, and each type of antibody attacks only its particular virus or bacterium. Antibodies also help clear infection from the bloodstream. The antibodies our bodies produce against hepatitis C are similar to those we produce against HIV. They usually are less effective in killing off these viruses than other antibodies are in eliminating their target pathogens.
The liver is a versatile organ that plays several different and vital roles. It enables the body to use nutrients and medications and cleanse itself of toxins, acting as the body's filter. Everything we eat, drink, breathe, or inject gets filtered through the liver, which removes waste and poison from the bloodstream.
The liver is also the warehouse of the body. It stores sugar and vitamins for the body to use when necessary. The liver takes nutrients and sends them into the bloodstream so that they can be distributed to the cells that need them. The liver also helps digest and store fat, which makes it possible to keep going all day without eating each time your body needs more energy. The liver changes medicine into a form the body can handle; without the liver, medicines can't work properly. It makes proteins to build muscle, clotting factors to prevent hemorrhage, and bile to absorb nutrients and vitamins.
Left untreated, HCV goes on to cause damage in the form of fibrosis (scarring of the liver), cirrhosis, cancer, and liver failure. Cirrhosis can cause varices, varicose veins in the esophagus that can cause bleeding. It can lead to fluid buildup (ascites) in the abdomen. Hepatic encephalopathy (dementia) is an abnormal change in mental status caused by liver failure. Liver cancer (hepatocellular carcinoma) occurs in people with HCV in the presence of cirrhosis.
Liver enzymes are proteins, and persistent elevations of these enzymes indicate liver inflammation. But almost half -- over 45 percent -- of those infected with HCV have normal liver enzymes. Liver enzymes have no direct relationship to the condition of the liver or to serum HCV levels. Therefore, people known to be HCV-infected who have normal liver enzymes are encouraged to undergo liver biopsies to determine the exact amount of damage there is in the liver.
Liver function tests include tests for the levels of albumin, bilirubin, and platelets. Albumin is a component of blood that helps prevent swelling. Platelets aid in the clotting of blood. Bilirubin is a yellow substance that builds up in your blood as red blood cells age and break down. The liver is responsible for the breakdown of bilirubin. When the liver does not function properly and bilirubin builds up, the result is jaundice -- the yellow skin that is characteristic of liver problems. Lab tests often show normal albumin, bilirubin, and platelet levels, leading to a missed HCV diagnosis.
The most reliable way to diagnose hepatitis C is through an HCV antibody test. Who should be tested? Anyone who has ever shared a needle, even one time, is at risk for infection. If you received a blood transfusion or an organ transplant before universal testing of the blood supply was initiated in 1992 you are at risk, as are people who have had long-term hemodialysis. Others at risk for infection are persons with body piercing or tattoos; healthcare workers who have been stuck with blood-contaminated needles; persons who have shared paraphernalia to snort cocaine or any other substance; persons who have shared razor blades or toothbrushes; persons who have had manicures or pedicures; and persons who have undergone electrolysis or acupuncture. Any blood on the outside of a syringe, on a tourniquet, on any surface at all, may increase your risk of exposure. So who should be tested? Just about everyone.
When you get a hepatitis C antibody test, you should be tested for hepatitis A and B (HAV and HBV) at the same time. If you test negative for antibodies to HAV and HBV, you have no protection against these infections. Ask your healthcare provider to vaccinate you against these viruses. Hepatitis A is spread through oral/fecal contact. You get it by putting something in your mouth that is contaminated with feces. It can be transmitted if someone with the virus, who doesn't wash his or her hands after going to the bathroom, touches your food. HAV is also transmitted from unclean seafood, or when water is not filtered properly. It is sexually transmitted through "rimming," or anal/oral sex. Hepatitis A can be fatal when you have HCV. HBV is transmitted sexually in much the same ways as HIV.
If you test positive for HCV, a viral load should be done to measure the amount of virus in your blood. Unlike HIV, which is measured in the thousands, HCV is measured in the hundreds of thousands to millions. Liver enzymes are measured but, as discussed above, may be normal; even if they measure five to ten times greater than normal they may still not indicate liver damage. A liver biopsy is the most effective way of diagnosing liver damage, but it is not necessary to receive treatment. You can still be treated even if your liver biopsy shows cirrhosis.
The genotype is the genetic variety of the virus. There are 6 known HCV genotypes, 1 through 6, and their relative prevalence varies by geographic location. In the United States, 75% of infected individuals have genotype 1. Patients with genotype 2 or 3 are more likely to sustain a response to therapy. Therefore it is important to know a patient's genotype in order to make recommendations about treatment.
There is no vaccine for hepatitis C, as there are for hepatitis A and B. Effective treatment is available, however, that can help reduce the severity of this disease and decrease the death toll.
The therapy for chronic hepatitis C has advanced significantly in the last ten years. Presently, the standard of care is a 24- or 48-week course of the combination of pegylated alpha interferon (peg-interferon) and ribavirin. Interferon is a natural substance that the body makes to help defend itself against infection. It helps the body's immune response against virus and infected cells.
Ribavirin is a nucleoside analogue similar to AZT that has no independent effect against the hepatitis C virus. It essentially enables the body to utilize interferon more effectively and thereby increases the response rate by two- to three-fold. The dose of ribavirin depends on body weight. Ribavirin can cause a specific type of anemia. Individuals who are anemic may be treated before they start therapy with erythropoietin (Procrit), a drug that stimulates the bone marrow to make red blood cells.
The development of peg-interferon revolutionized treatment of HCV. Prior to peg-interferons, standard interferons were used to treat the virus. Standard interferon was given several times weekly and provided fluctuating levels of the drug throughout the week. Peg-interferon is standard interferon that has been changed chemically by addition of a large inactive molecule of polyethylene glycol. This large molecule prolongs the life of interferon in the body. Peg-interferon is given once weekly and provides a constant level of interferon in the blood. It is an injection administered subcutaneously (under the skin). More importantly, because of constant levels in the blood, peg-interferon is more active against hepatitis C and produces higher rates of sustained response. Two forms of peg-interferon have been developed and studied in large clinical trials. Peg-interferon alfa-2a (Pegasys) and peg-interferon alfa-2b (Peg-Intron) are both approved by the Food and Drug Administration (FDA). It is unknown whether these pegylated interferons differ in efficacy and tolerability, although a head-to-head comparative trial is underway.
Patients with HCV mono-infection and genotypes 2 or 3 can be treated for 24 weeks. Patients with genotype 1 need 48 weeks therapy. Studies have shown that in mono-infected patients a sustained viral response or SVR (undetectable viral load 6 months after the end of treatment) with peg-interferon and ribavirin are above 50% overall, about 80% in those with genotype 2/3, and about 45% in those with genotype one.
A number of studies have shown that interferon use in patients with cirrhosis and who are non-responders to therapy can slow disease progression. The National Institutes of Health (NIH) is sponsoring the HALT-C trial. This study is examining whether low-dose Pegasys therapy can slow or reverse disease progression for these patients.
HIV and HCV
The two viruses have many similarities and a few important differences. Both are blood-borne diseases, that is, they enter the body directly through the blood. It is much easier to get HCV through blood than HIV. Antibody screening is the backbone of screening for both viruses. The antibody to each virus is ineffective, providing no immunity to the disease caused by the virus.
Both are RNA viruses. They produce astronomical amounts of virus each day; HIV produces approximately 10 billion new viral particles per day and HCV about 10 trillion each day. The amount of both viruses is measured by viral load. The mutation rate is much faster in HIV -- 10,000 variants daily compared to 1,000 for HCV. Prior to seroconversion HCV, like HIV, is associated with extremely high viral concentrations. After seroconversion HCV concentrations are reduced, sometimes to undetectable levels. One big difference is that HIV, so far, is not curable. HCV is curable and treatment can totally eradicate this virus from the body.
In HIV-positive individuals HCV infection progresses at a faster rate than in mono-infected persons because the hepatitis C virus multiplies faster. HCV does not, on the other hand, make HIV multiply faster. The more controlled an individual's HCV is, the less strain there is on the liver and the better the prospects for effective HIV treatment. If the body can't absorb HIV medication, a possible consequence of HCV infection, then the HIV virus will start to replicate and impaired immune function will develop more rapidly.
Past studies of co-infected patients show they do not respond as well to interferon-based therapy as mono-infected patients. Co-infected patients with genotype 2 or 3 have a 40-60% sustained viral response, while those with genotype 1 have less than a 25% sustained viral response. Furthermore, there is no evidence that co-infected patients should receive less than 48 weeks of therapy. It has been suggested that a longer duration of therapy may improve response rates. There is an ongoing 18-month therapy trial sponsored by Hepatitis Resource Network (HRN) to study duration of treatment in co-infected individuals.
The results of three studies of pegylated interferon and ribavirin therapy in co-infected patients were presented at the 11th annual Conference on Retroviruses and Opportunistic Infections (CROI). APRICOT (AIDS Pegasys Ribavirin International Co-infection Trial) was the largest study of its kind to date and included 868 patients from 19 countries. Overall, 40% of the patients treated with Pegasys/ribavirin achieved a sustained response. This is the highest response rate ever seen in co-infected subjects. The American AIDS Clinical Trials Group (ACTG) also reported results from its much smaller study using Pegasys and ribavirin. This is the first study to compare the safety and efficacy of pegylated interferon/ribavirin with standard interferon/ribavirin in co-infected individuals. The sustained viral response with pegylated interferon/ribavirin was 27% overall versus 12% with standard interferon/ribavirin.
Finally, RIBAVIC was a study conducted in multiple centers in France using Peg-Intron and ribavirin. Overall, 27% of patients on Peg-Intron/ribavirin achieved a sustained response. Differences in rates of sustained response can be attributed to different study populations and different initial doses of ribavirin. Also, the size of the population studied affects the statistical analyses; and both the ACTG and RIBAVIC studies were much smaller than APRICOT.
There have been questions about the use of ribavirin in HIV-positive individuals on HAART. An old study (from 1987, when ribavirin was being evaluated for its HIV effect) showed that ribavirin inhibited the effects of AZT in vitro (in a test tube). In current studies, however, it appears that ribavirin does not inhibit AZT or d4T (Zerit). HIV-RNA levels did not change when ribavirin was introduced into combination therapy in the treatment of HIV, while HCV levels dropped dramatically when ribavirin was used with interferon for the treatment of HCV.
Combination therapy leads to improvements in liver enzyme levels and a decrease in viral load. The reason for treating HCV in most cases is to prevent liver damage or keep it to a minimum. Every time your viral load is lowered, your liver has the chance to do some healing thus buying some time. Also, HCV might exacerbate the hepatotoxic effects of HAART, which provides a compelling reason for treating co-infected people aggressively.
There are several things one should know before beginning treatment for HIV/HCV co-infection. First, protease inhibitors can be toxic to the liver; Norvir and Crixivan are the worst offenders. Of the non-nucleoside reverse transcriptase inhibitors (NNRTIs), Viramune poses the greatest threat of liver toxicity. AZT, when used with ribavirin, can increase your risk for anemia. Ribavirin is very teratogenic; that is, it causes severe birth defects. Women who are pregnant should never take the drug. If a woman of childbearing age or her partner is undergoing treatment with ribavirin, the couple must wait at least six months after discontinuing the therapy before attempting to become pregnant. Other diseases such as arthritis, allergies, asthma, or depression may get worse during treatment with ribavirin.
Common side effects of the medications used to treat HCV include depression, irritability, insomnia, body aches, hair thinning, canker sores, abnormal thyroid function, anemia, weight loss, muscle wasting, loss of appetite, changes in taste (which can lead to poor nutrition), increased mucus production, weakness, low-grade temperature, fatigue, concentration problems, nausea, diarrhea, neutropenia (low white blood cell count), and respiratory problems. An individual may suffer from none of these effects ... or from all of them.
Most of these side effects can be managed with good results. If there is a history of depression, the patient should be treated with antidepressants before starting treatment. If the patient already is on antidepressant medication, a dose increase may be necessary while on therapy. Analgesic (acetaminophen/Tylenol) and anti-inflammatory medications (ibuprofen/Advil) can help reduce aches and fever. Appetite stimulants like Marinol are helpful in maintaining and/or gaining weight. If the patient develops anemia, erythropoietin (Procrit) may be used and/or the dose of ribavirin may be decreased accordingly. Vitamin B-12 and fish oil capsules are used to treat fatigue. Inhalers are useful for breathing problems related to bronchospasms caused by interferon.
Treatment with interferon and ribavirin can be very difficult. It is important that the physician who is treating your HCV is familiar with the side effects (see above) and is able to get you through the treatment course. The treatment course for HCV can vary depending on your genotype, viral load, and stage of disease.
Hepatitis C infection is a vast area of investigation and technological advances are opening new avenues for treatment therapies. Other promising agents, including protease and helicase inhibitors, ribozymes, antisense molecules, and therapeutic vaccines are in development and may improve existing therapeutic modalities but these drugs are years away from approval.
Liver transplantation is now an accepted therapy for a number of irreversible diseases of the liver. More than 4,000 liver transplants are performed in the United States annually. However, patients with HIV infection traditionally have been excluded from transplantation.
Recent statistics show that HIV-positive patients on HAART have an increased life expectancy. Therefore, HIV-positive patients with end-stage liver disease are at greater risk of dying from liver failure than from an HIV-related illness. As a result, several institutions in the United States have broadened the spectrum of patients who should be considered for transplantation to include HIV-positive individuals.
The University of Miami and the University of Pittsburgh Medical Center are at the forefront of liver transplantation for patients with HIV disease. In New York City, The Mount Sinai Hospital of Mount Sinai School of Medicine has a protocol for co-infected patients with end-stage liver disease. Patients must have undetectable HIV viral load and a CD4 count greater than 100 to meet criteria for the study.
A study published last year reviewed 16 cases of liver transplantation in HIV-positive patients. The one-year survival rate is 92% overall, equal to that seen in the HIV-negative transplant patients. These results are encouraging and suggest that patients with HIV suffering from end-stage liver disease can benefit from and survive transplantation.
Individuals with HIV are leading longer, healthier lives since the introduction of HAART. However, the significant morbidity related to liver disease in persons co-infected with HIV/HCV impacts on many aspects of their medical care. Clinicians should encourage their patients to undergo proper and timely evaluation, and offer counseling and recommendations about treatment. The advances in HCV therapy and the improved rates of response make treatment a more viable option for many co-infected patients.
The authors are colleagues in the Division of Liver Diseases at the Mount Sinai School of Medicine in Manhattan. Damaris C. Carriero, MS, ANP-C is a nurse practitioner and clinical coordinator; Jennifer Lucas, BSN and Hurdley Freemantle, BS are research coordinators; and Douglas T. Dieterich, MD is Vice Chair and Chief Medical Officer.