Hepatitis C Virus and Coinfection with HIV
November 1, 2000
This article on hepatitis C virus (HCV) and HCV/HIV co-infection is based upon an extensive report written by Michael Marco and Jeffrey Schouten, for Treatment Action Group (TAG) of New York. The entire report is available online at www.treatmentactiongroup.org. This article will review some of the major clinical issues in the treatment of HCV and HCV/HIV co-infection.
Epidemiology of HCV Infection
Hepatitis C is an infectious disease that causes inflammation and damage to liver tissue. The primary route of transmission of HCV is blood-to-blood contact. The virus that causes hepatitis C was isolated in 1988. This allowed for diagnostic tests and the screening of blood products, effectively eliminating blood transfusion in the U.S. as a mode of transmission. Since then, the major route of transmission of HCV is needle sharing during drug use.
It is estimated that three million people in the U.S. have chronic HCV infection. Current recommendations do not suggest that monogamous heterosexual couples practice safe sex to prevent HCV transmission if one partner is HCV-infected and the other is not. This is because the rate of heterosexual transmission is so low. However, among MSM, (men-who-have-sex-with-men) the rate appears to be higher; up to 5 to 10% of HCV-positive MSM report no risk behavior besides sex.
HCV is ten times easier to transmit by blood contact than is HIV. Thus, in some major urban HIV clinics such as in Baltimore, the incidence of HCV infection in HIV-positive people is as high as 70%. Other clinics report the incidence to be about 30%. Studies of injection drug users show that up to 70% are HCV-infected, and about 30% are also HIV-positive. Thus, as the HIV epidemic in the U.S. spreads in communities with high rates of injection drug use, more and more people are living with HCV/HIV co-infection.
Natural History of HCV Infection
HCV does not cause any symptoms in most people at the time of initial infection. After becoming infected with HCV, about 10 to 15% of people will clear the virus from their system naturally. The other 85% will not generally develop any symptoms of liver disease for decades. Usually the diagnosis is made through aggressive screening programs in high-risk individuals, through testing of individuals who received blood transfusions prior to 1985, or via testing instigated by abnormal results from liver function blood tests.
Because most people remain without any symptoms for many years after HCV infection and are undiagnosed, there was bias in previous studies of the natural course of HCV infection. This occurred because healthcare providers saw only the people who were getting sick, but did not realize that many other infected people were doing well. About 10% of people with chronic HCV infection will eventually develop cirrhosis, or scarring of the liver, and complications of cirrhosis, such as internal bleeding, liver failure, or infection. About 10% of people with chronic HCV infection will develop liver cancer. Life-threatening complications generally do not develop for 10 to 20 years after infection.
One of the major challenges in determining the rate of progression of HCV infection is that a liver biopsy is necessary to determine the amount of scarring and inflammation in the liver. Neither the liver blood tests (SGOT, SGPT), nor the HCV viral load correlates with the amount of injury to the liver. The following factors are associated with increased risk of progressive liver disease in people chronically infected with HCV: increased age, male gender, and alcohol consumption.
HCV and HIV Co-infection
The parallel epidemics of HCV and HIV infection became intertwined due to intravenous drug use in the populations of people infected with HIV and HCV. It is estimated that up to 240,000 people are co-infected with HCV and HIV in the U.S. The prevalence of HCV infection among injection drug users is much higher than that of HIV infection, but alarming increases in the number of people co-infected with HCV and HIV continue to be reported. Studies of various populations worldwide report co-infection in 23% to 75% of injection drug users. A study of 213 HIV-positive people, of whom 35% were co-infected, determined that people between ages 40 and 49 had the greatest risk of being found HCV-infected. No correlation was found with gender or race.
The presence of HIV infection can diminish the accuracy of HCV antibody assays. There is an increased risk of receiving both false-negative and false-positive results from HCV screening antibody tests in people with HIV infection. Current Public Health Service Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus recommend that positive screening antibody tests for HCV in people with HIV should be confirmed with either the recombinant immunoblot assay (RIBA), or an HCV RNA viral load test. In addition, it is recommended that HIV-positive people with undetectable HCV antibodies, but evidence of unexplained chronic liver disease, should have an HCV RNA test performed.
Multiple studies performed in the pre-antiretroviral therapy era have shown that while the course of HIV infection in people with HCV/HIV co-infection is not changed, the course of HCV infection in people with HIV is more rapid. However, the big unanswered question at this time is what will be the impact of immunologic recovery with highly active antiretroviral therapy (HAART) on the course of HCV infection in co-infected people?
It is clear that alcohol worsens the amount of liver damage from HCV infection. Most providers recommend that people with HCV infection abstain from alcohol consumption. Also, people with HCV infection should receive vaccinations for hepatitis A and B, if they do not already have immunity to these infections. This is because an acute case of hepatitis A or B can dramatically worsen HCV infection, and even be fatal.
Treatment of HCV
The current treatment options for people with HCV infection are a combination of oral ribavirin with either interferon, or the newer, longer-acting, pegylated-interferon (peg-interferon). Standard interferon is administered three times a week as a shot under the skin, and stays in the body a very short time. It can be accompanied by a flu-like syndrome after each injection, and has been associated with a significant incidence of depression. Peg-interferon is administered only once a week, also as a shot under the skin, and has a similar toxicity profile, but provides a much more sustained level of interferon in the body.
The measure of the effectiveness of HCV therapy is the proportion of people who maintain undetectable for HCV RNA six months after therapy (called a "sustained response"). There is also some evidence to suggest that some people benefit from therapy for HCV even if they do not have a sustained response, based on liver biopsy studies showing slowing of liver scarring. Additionally, people with cirrhosis may benefit from interferon therapy, which is not certain, since they were excluded from most of the major interferon studies. Unfortunately, all of the major HCV therapy trials of interferon plus ribavirin, and peg-interferon plus ribavirin have excluded people who are HIV-positive.
In HIV-negative people, studies of HCV treatment have shown a sustained response rate of up to 60% for people taking peg-interferon plus ribavirin, compared to only about 30% for people taking interferon plus ribavirin. However, much lower sustained response rates are found in people with more advanced liver disease, African Americans, and people with genotype-1 infection. (There are four different HCV genotypes, and the most common type in the U.S. is unfortunately associated with the lowest response to currently available therapies.)
Treatment of HCV in HCV/HIV Co-infection
While there have been reports that people with HCV infection have an increased risk of abnormal results from liver function tests while on HAART, most clinicians agree that both HIV and HCV in the HCV/HIV can be safely treated in a co-infected person. The general recommendation is to first try to treat the HIV, to build a strengthened immune system to help fight the HCV. But some people must be treated for both because the side effects of some anti-HIV drugs are too severe for a liver that has been damaged as a result of HCV. There were also some concerns about potential drug interactions with ribavirin and the anti-HIV nucleoside reverse transcriptase inhibitor (NRTI) class of drugs, but this does not appear to be significant.
Possible reasons HAART may worsen liver function test results There are several reasons why the results of liver function tests may be "abnormal" in people on HAART:
There are also data suggesting that immune system recovery associated with HAART may also improve the ability of the immune system to control HCV replication and the resultant liver damage. Benhamou reported that projected rates of liver scarring decreased significantly when PI therapy was used to treat HIV. It is not at all clear why PI-based HAART regimens would result in less scarring, compared to non-PI-containing HAART regimens, which are equally effective at suppressing HIV RNA and improving CD4 cell counts. Nonetheless, these reports suggest that the treatment of HIV with HAART may reduce HCV progression rates and liver fibrosis.
The exclusion of people with HCV from many HAART trials has resulted in an unacceptable lack of data to address the above issues. There are a number of ways in which people with HCV have been excluded from many HAART trials -- these include unnecessary limitations on pretreatment liver function test abnormalities, unnecessary exclusion of many active substance users/abusers, inaccurate perceptions about the suitability of HCV/HIV co-infected people as study candidates, exclusion of people on methadone, and outright exclusion of people who have HCV infection. As a result of this exclusion, important leads into the immunologic and non-immunologic control of HCV replication, and the ways in which HCV actually causes liver damage and fibrosis, have not been pursued. Unless there is a scientifically valid reason to exclude people with HCV infection from HAART trials, they should be included.
The AIDS Clinical Trials Group (ACTG) is just starting a trial comparing standard interferon to peg-interferon, both with ribavirin, in HCV/HIV co-infected people. There are only a few small trials reported on the efficacy and toxicity of HCV treatment in HIV-positive people. Some of the early trials reported a significant problem with anemia (low red blood cell count) from ribavirin. Consequently, lower doses are now being evaluated and red cell stimulators are being used more routinely to treat this problem. While there is a temporary drop in CD4 cell counts during HCV therapy, they generally return to pretreatment levels after HCV therapy is completed. Unfortunately, most co-infected people have genotype-1, which is the least responsive to therapy with interferon.
At some major HIV clinics, the most common cause of death is liver failure due to HCV infection. Unfortunately, with the exception of one or two transplant centers, people who are HIV-positive are denied liver transplantation. The reason offered is that the potential drug interactions between immunosuppressive drugs and anti-HIV drugs are unknown. But people are dying because they are denied a liver transplant. There is simply no reason to exclude HIV-positive people from liver transplant programs.
This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Ezine.