Hepatitis C and Co-Infection: An Overview
As more people with HIV are living longer, co-infection with hepatitis C virus (HCV) has emerged as a significant concern. Serious illness and death from hepatitis C-related liver disease are increasing in HIV-positive people. In the United States, about one-third of people with HIV are co-infected with HCV; the rates vary by area because up to 90% of people who got HIV through injection drug use are also infected with HCV.
Before the hepatitis C virus was identified in 1988, doctors knew that some people had a type of viral hepatitis that they called non-A, non-B (NANB). Initially, NANB hepatitis wasn't considered a serious health concern, but after many years, some people with NANB hepatitis began to develop serious liver problems. A small RNA virus -- hepatitis C -- turned out to be the culprit in most cases.
Only about three out of ten people have symptoms immediately after infection. These symptoms can include:
About one out of seven people has a strong immune response that clears the infection two to six weeks after infection. Unfortunately, clearing the virus doesn't make you immune to HCV re-infection. If the infection clears, the antibodies to HCV remain in your blood, but the actual virus doesn't. It may be harder for HIV-positive people to clear HCV infection because the immune system isn't as strong.
In 1999, HCV was categorized as an opportunistic infection because of the potentially serious health consequences of living with two chronic viral infections. Due to the overlap in modes of transmission between the two viruses, it is recommended that people with HIV undergo HCV antibody testing. Most people who have been infected with HCV will develop antibodies within three months. If your antibody test is positive, a viral load test can diagnose current HCV infection.
Qualitative viral load testing can confirm whether virus is present in a blood sample. The test will find virus if there's more than 50 to 60 copies in the sample, but it can't tell you the amount of virus in your blood. A quantitative viral load test does measure the amount of virus in a blood sample (the test can find any amount above 600 copies per ml). Qualitative testing is usually used to confirm or rule out chronic HCV infection because it's cheaper and more sensitive. HCV viral load will show up two weeks to six months after infection. If your qualitative viral load test doesn't find any virus, re-testing six months later is recommended to confirm or rule out current HCV infection. If the second viral load test still doesn't detect any HCV, either the antibody test result was a false positive or the initial infection may have cleared.
If the HCV antibody test is negative, many medical providers recommend HCV viral load testing -- either qualitative or quantitative -- as a follow up for people whose immune systems are weak and/or have symptoms of liver disease (persistently high liver enzymes, fatigue or liver pain). A damaged immune system may just be too worn out to make antibodies.
HCV usually progresses very slowly, so a person might not develop any serious liver damage until 10 to 50 years after infection -- if they're going to develop serious damage at all. Most of our information about HCV disease progression comes from studies of people without HIV. Based on those studies, about 25 out of 100 of people with HCV will never have any symptoms or liver problems. Forty to 50 will experience some symptoms and liver damage (mild liver scarring called fibrosis) that will affect their quality of life, the most common symptoms being fatigue and depression. About 20 out of 100 will develop serious liver scarring (cirrhosis), and only 1% to 4% of people with cirrhosis will eventually develop liver cancer. At most, that's one person out of 100.
HCV disease may progress more rapidly in people with HIV. Studies conducted prior to the use of HAART (Highly Active AntiRetroviral Therapy) showed that HIV could speed up HCV disease progression. But HAART's boost to the immune system may help to slow down HCV-related liver damage.
Co-infected people usually have higher HCV viral loads than people with HCV alone, but much controversy remains about HCV disease progression in co-infection. Long-term follow-up is needed to help provide more answers about HIV's role in HCV disease progression. Several other factors also play a role: alcohol consumption, general liver health before HCV and HIV infection, which infection you got first, age, overall immune health, access to care and the quality of care received, drug use, and use of HAART.
A recent Swiss study showed that co-infected people had a higher risk of progression to AIDS and death despite the use of HAART, implying that HCV may be a co-factor in HIV disease progression. Several studies have shown that co-infected people do not gain as many CD4 cells after beginning HIV treatment compared to those with HIV alone. A Spanish study, for example, found that after two years of HAART, co-infected people gained an average of 53 CD4 cells, while those with HIV alone gained an average of 111 CD4 cells. A study at Johns Hopkins followed a group of co-infected people from January of 1996 until June 2000 and saw similar results. In addition, the Hopkins study found that co-infected people with CD4 cell counts between 50 and 200 progressed to death more quickly than those with HIV alone. However, other studies of co-infected people have not seen a difference in survival rates. Since so many factors can contribute to both HIV and HCV disease progression, further research is needed to confirm whether HCV does make HIV disease worse.
Statistics about the chance of developing liver damage from HCV can't give you specific information about your individual HCV disease progression. There are several tests available that provide information about the condition of your liver. While these tests aren't a crystal ball, the results can help you recognize changes over time and make treatment decisions.
Many people are used to looking at an HIV viral load test as a predictor of disease progression. HCV viral load testing won't provide this information. The amount of virus in your blood can't predict how much liver damage HCV has caused or the likelihood of liver damage in the future. An average HCV viral load ranges between two and five million copies -- much higher than in HIV. This can be scary if you're used to seeing much lower viral load results and associating them with changes in your health. HCV viral load testing is primarily used before and during treatment to determine how likely you are to respond or are responding to HCV medications.
Liver Function Testing
Our liver cells die periodically and are replaced with new ones. When liver cells are damaged or dying, liver enzymes (called AST and ALT) seep into the bloodstream. Liver enzyme levels can be higher than normal for many reasons. This is often a sign that the liver is working hard to break down HIV medications, alcohol, street drugs or other medications. Enzyme levels often go up and down with HCV, and if your liver is damaged, it may be too worn out to make them. Although liver enzyme testing can't predict HCV disease progression, it's a useful tool; it can help you measure your response to HCV treatment and/or changes in your diet and use of alternative or complementary therapies. (See "Keeping Your Liver Healthy" for a discussion of other important measurements of liver function.)
Genotypic testing looks at the genetic makeup of an individual's virus. It identifies which type of HCV you have. There are at least six different HCV genotypes. Genotype 1 is the most common in the United States -- about 75% of people with HCV in the U.S. have genotype 1. Genotype doesn't predict disease progression, but it is the single most important predictor of your response to HCV treatment. Genotypes 2 and 3 respond much better to treatment than genotype 1. Some people with genotypes 2 and 3 may need only six months of HCV treatment, although some medical providers recommend that people with co-infection complete a year of HCV treatment regardless of genotype.
Other Predictors of Treatment Response
Besides your HCV genotype, your immune health may influence your response to HCV treatment. The higher your CD4 cell count, the better your response to HCV treatment is likely to be. HCV treatment is not as effective in people with less than 200 CD4 cells. The condition of your liver can also impact response to HCV treatment. People without cirrhosis tend to have better responses to treatment, although HCV treatment can prevent cirrhosis from worsening. An HCV viral load under 2 million copies and lower body weight or body mass index are also associated with better response to treatment. In addition, people under 40, especially women, have a better response to treatment.
Ultrasound and Biopsy
Ultrasound testing uses sound waves to get a picture of the liver. The test is not invasive, but the information it provides about the condition of your liver is limited.
Liver biopsy, an outpatient procedure, is the most accurate way to identify the extent and cause(s) of liver damage. A needle is inserted quickly through the abdomen, under the ribs on your right side, and a very small liver tissue sample is removed. An ultrasound can be used to guide the biopsy to areas where liver damage is present and to lower the already small risk of puncturing other organs. Liver biopsy can be painful. If you're concerned, ask your doctor about pain management options. In rare cases (less than 1%), a biopsy can cause internal bleeding or death. Results from a liver biopsy are graded between 0 (no fibrosis or inflammation) and 4 (serious scarring that impairs liver function).
Currently, the standard of care for HCV is a combination of two drugs: interferon and ribavirin. Interferon, a protein made in small amounts by the body, literally interferes with a virus's ability to infect cells. HCV therapy uses much larger amounts of synthetic interferon than the body naturally produces. Standard interferon is given as an injection three times a week. Early last year, a new formulation of the drug called pegylated interferon was approved by the Food and Drug Administration. Pegylation is a process that attaches a small molecule to interferon to maintain steady levels in the body for a longer period of time. Pegylated interferon is injected once a week.
Ribavirin capsules are taken twice a day. Like several anti-HIV drugs, ribavirin is a nucleoside analogue, although it has no effect against HIV. Adding ribavirin to interferon produces much better results than interferon alone. Dosing of either or both drugs may need to be adjusted during treatment to help manage side effects. It may be best to try to treat side effects before lowering the dose of either interferon or ribavirin -- if the dose is too low, the treatment won't be as effective. (See sidebar.)
Side effects are different for each person who uses a drug. Both versions of interferon can cause side effects that range from uncomfortable to life threatening. These include flu-like symptoms such as weight loss and fatigue as well as mild hair loss, thyroid problems and low white blood cells and platelets. Interferon can also produce a rapid heartbeat and, in rare cases, heart attacks. Interferon can also cause sleeplessness, mood swings, irritability, and depression -- sometimes resulting in suicidal thoughts or even attempts.
Side effects of ribavirin include shortness of breath, stuffy nose, sinusitis, coughing, itchiness, diarrhea and anemia. There may also be a risk of mitochondrial toxicity (damage to the power plants of cells) if ribavirin is used with other nucleoside analogues. In rare cases, this could lead to a very serious condition called lactic acidosis. (see "Antiretrovirals & Liver Toxicity: How Big A Concern?")
Both interferon and ribavirin can cause serious birth defects. Men and women must wait six months after completing treatment before trying to conceive a child.
Currently, there's one brand of pegylated interferon available, Schering-Plough's PEG-Intron. Hopefully, within a year, the Food and Drug Administration will approve Hoffmann-LaRoche's brand of pegylated interferon, Pegasys. Some states' Medicaid and AIDS Drug Assistance Programs (ADAPs) cover standard interferon and/or pegylated interferon. Schering-Plough offers a Peg-Intron patient assistance program for people who are uninsured and with low incomes. Hopefully, when Roche's Pegasys is approved, it will also be available through a patient assistance program.
There are different ways to measure how a person has responded to HCV treatment. Some differences in treatment response have been seen in co-infected people compared to people who are infected with HCV alone, while other studies have shown similar responses. Treatment usually lasts for one year, although continuing interferon therapy for 18 months is being studied as a possible way to halt or slow down liver damage and improve the condition of a person's liver. Usually, treatment will be discontinued after six months if you continue to have a detectable HCV viral load because you're extremely unlikely to clear the virus even if you continue treatment for a year. Recent studies show that viral load might be used earlier in the course of treatment to predict response. More definitive information about the best time to use HCV viral load testing as a predictor of response to treatment will be helpful to people who are making tough decisions about continuing treatment.
Sometimes HCV treatment is evaluated by measuring the amount of HCV in your blood after you've finished treatment. This is called an end of treatment response (ETR). Unfortunately, an ETR doesn't mean that you'll remain free of HCV. A sustained virologic response (SVR) -- no detectable virus six months after finishing treatment -- is a much more reliable indicator of long-term viral clearance. The likelihood of achieving a SVR after a year of HCV treatment with standard interferon plus ribavirin for mono-infected people with genotype 1 is about 28%. When pegylated interferon is used with ribavirin, SVR rates for mono-infected people with genotype 1 range from 30% to 50%. In mono-infected people with genotypes 2 and 3, after six months to one year of treatment with standard interferon and ribavirin, the SVR rate is about 60%, and the SVR rate rises to about 75% with pegylated interferon and ribavirin.
Even if a person does not achieve an SVR, HCV treatment can improve the condition of the liver tissue by giving the liver a break. Improvements in liver tissue (histological response) can be measured by liver biopsy before and after treatment. People who reduce and maintain low liver enzymes after treatment may have gained benefit from treating HCV.
Although current HCV treatment options are severely limited, several new treatments are in development -- drugs to reduce or slow fibrosis, drugs to boost the effect of ribavirin, a therapeutic vaccine, immunomodulaters, HCV protease inhibitors and several new interferons, both standard and pegylated. Some of these are in very early stages of development; others are further along in the process. Hopefully, within the next three to five years, people will have more treatment options.
Many doctors would treat HCV first in someone with a CD4 count above 500. The rationale behind this is the higher likelihood of a good response to HCV treatment and the possibility of "wiping out" HCV, leaving your liver in better condition to deal with HIV medications, some of which can be hard on the liver.
Other doctors believe that if HIV infection is controlled with HAART, HCV will also remain controlled. Guidelines for when to start HIV treatment in co-infected people don't exist yet. People with less than 200 CD4 cells are at greater risk of developing HCV-related cirrhosis, so keeping your immune system as healthy as possible is an important part of HCV care. Of course many people don't find out that they have HIV until their CD4 cell counts are already low. Unless your liver has been seriously damaged by HCV, most doctors would try to boost the CD4 count above 200 before beginning HCV treatment. Interferon can cause a temporary drop in CD4 cells, which could put people with low counts at risk for developing certain opportunistic infections. A lower CD4 cell count may also add more preventive medications to your drug regimen, increasing the risk of drug interactions and possible stress on the liver.
Part of making the treatment decision that's right for you involves collecting information. Although some HIV doctors may be knowledgeable about HCV, consulting a liver specialist -- a gastroenterologist or hepatologist -- can be very helpful. Different doctors have different philosophies about which tests are most important and about when to treat HCV (and HIV). Having a list of questions for any doctor you consult can help you select one you'll be able to work with well. For example, you might want to try alternative or complementary therapies and check your liver enzymes frequently, while your doctor might be more comfortable offering you a liver biopsy and interferon/ribavirin treatment.
If you're working with more than one doctor, get copies of your lab results and medical records. Make them available to both doctors and do everything in your power to make them talk to each other!
Without long-term follow up information on people with co-infection or treatment guidelines for co-infection, making treatment decisions can be confusing. A conference to revise the out-dated National Institutes of Health 1997 HCV treatment guidelines and add guidelines for co-infection took place in June. (Read the guidelines at http://consensus.nih.gov/cons/116/116cdc_intro.htm) These guidelines will help you and your medical provider begin a discussion about the right treatment strategy for you, including how often you want to monitor your liver enzymes and HCV viral load, whether or not to have a liver biopsy, and all the potential risks and benefits of HCV treatment.
Tracy Swan, an HIV treatment activist, works at ACRIA as a treatment educator.
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.