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H. Aaron Aronow,MD Neurology and Internal Medicine USC ..
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Date Posted: Sat, May 19 2001, 10:27:06 PDT
INFECTION WITH HEPATITIS C VIRUS (HCV) IS REACHING EPIDEMIC PROPORTIONS IN THE UNITED STATES.
H. Aaron Aronow,MD Associate Professor of Neurology and Internal Medicine USC School of Medicine
Medical Director, Hepatitis C Outreach Project (www.hcop.org)
Elyse J. Singer, MD Associate Professor of Neurology UCLA School of Medicine
Approximately one million Americans are infected with HIV, but nearly four times that number have chronic HCV; worldwide, 40 million are infected with HIV, but 200 million are infected with HCV.1
What is the true rate of HCV infection among people with HIV? A recent study at the University of Cincinnati College of Medicine analyzed two trials sponsored by the ACTG (Adult AIDS Clinical Trials Group) using the quantitative PCR test from Roche Diagnostics to detect HCV RNA. The study found a strong relationship between HCV infection and age in people with HIV.
Patients in their forties were at very high risk; more than 50% of this group tested positive for the virus. HCV infection was also associated with both the immune status and viral load of HIV- positive people. All of those whose CD4 cell count was less than 100 cells per microliter were coinfected with HCV, compared with approximately one-fourth of those with CD4 cell counts exceeding 500 cells per microliter. This study suggests that over a third of HIV-positive patients in the U.S. are probably co-infected with HCV. Kenneth Sherman, MD, the investigator, suggests that these and similar findings are a warning sign. They highlight the need for a new policy of broad-based screening for HCV in HIV-positive patients.2
HIV-treating physicians must become more aware of the high prevalence of HCV in HIV patients. To achieve this goal, more accurate tests for HCV also need to be developed and made available to all primary care physicians as well as HIV-treating physicians. Getting out the word Why are the numbers for HCV infection so high? Many recent studies indicate that part of the problem is the poor response of HIV-treating physicians and others in the medical community to the threat of hepatitis C.
Because screening for HCV is inadequate, few cases receive early or appropriate treatment. However, institutions are beginning to respond to the dramatic increase in rates of coinfection in the U.S. For example, the Consensus Statement of the National Institutes of Health (NIH) has become: “Treat for HIV suppression and HCV eradication.” The Consensus Statement on HCV can be obtained online at: .
In terms of public opinion, the HCV epidemic is in several respects affected by the same problems that hampered HIV diagnosis and treatment in the 1980s, when HIV became stereotyped as a disease of male homosexuals. It took several years before physicians routinely tested for HIV in heterosexuals, women, and other populations. The same thing is happening now with HCV; the stereotype of the intravenous drug user prevents many health professionals from screening rigorously for HCV across other groups.
For several reasons, it makes more sense to use an epidemiology model like that of HIV when viewing the current community health problem posed by HCV than to look at HCV as simply another hepatitis infection.
HCV Compared with HBV Particular features of HCV pathogenesis also contribute to the size of today’s epidemic. Several facts about the hepatitis C virus itself, and its patterns of replication, help to explain why an epidemic of chronically infected people might have been better predicted and planned for—if more attention had been focused on the problem.
HCV poses a more difficult community health problem than does hepatitis B virus (HBV). While approximately 85% of people with HBV resolve their infection, and only 15% become chronically infected, the facts are just the opposite with HCV: roughly 85% of people with HCV become chronically infected; only 15% are able to clear the infection.1
The immune system has difficulty resolving an HCV infection for several reasons. One factor that makes it difficult for the immune system to easily recognize HCV is the array of HCV genotypic variants. At least six “clades” consisting of 11 genotypes have been identified.1
In the U.S., unfortunately, the vast majority of cases of HCV are of genotype 1, which is the most difficult for the immune system to clear and the most difficult to treat. While microbiologists have identified several other genotypes of HCV, these are generally grouped together as genotype non-1 (see the accompanying sidebar “Coinfection Treatment Issues: Genotyping HCV.”). HCV and HIV—similarities and differences
Both HCV and HIV are single-stranded RNA viruses that produce vast numbers of variants when they multiply—and both viruses replicate at alarmingly high rates. This means the viral target is always changing. The many variants of HCV and HIV create extraordinary challenges in the development of therapeutic agents for treatment and effective vaccinations for prevention. HCV is not a retrovirus like HIV, but a flavivirus. This difference spells good news—it means that the virus does not become integrated with the host’s genome, and this in turn means that HCV can be eradicated with ideal treatment.1,3
There can be long periods in both diseases without symptoms, but individuals infected with HCV are typically without symptoms for 20 years or more. A great deal of damage to the liver can occur before blood tests even detect liver toxicities. While HCV does not destroy the immune system as HIV does, chronic infection leads to liver toxicity and finally to end-stage liver disease. HIV viral loads may be relatively stable over time, but HCV viral loads vary. HCV viral loads are not predictive of long-term disease outcome, nor do they correlate with the degree of hepatitis. HCV viral loads do correlate with response to therapy, which in turn is related to long-term liver disease outcome.4
Progression to liver damage
Liver disease develops slowly over a period of 20 to 30 years or more, although progression can occur in 5 to 10 years among “rapid progressors” with HCV. The percentage of people with hepatocellular carcinoma, or liver cancer, is about 3%, and the annual rate of cirrhosis is 5% to 10%.
Once end-stage liver disease occurs, there is little that can be done to reverse the damage or restore the liver. In fact, liver disease caused by chronic HCV infection is the number one cause of liver transplantation in the United States. Approximately 35% of liver transplants in this country are for end-stage liver disease caused by untreated HCV.4
Transmission
The hepatitis C virus “reaches saturation” in intravenous drug users, as David Patrick, MD described it during a presentation at the 12th World AIDS Conference.6 Although injection is the chief route of transmission for HCV, body piercing and tattooing have also become major risk factors. Since the skin is broken in both piercing and tattooing, infected blood products can be transmitted through needles and other implements. The virus can easily be spread this way. Users of heroin and other drugs who do not inject but who snort drugs should be advised that intranasal transmission of HCV is possible and that sharing straws and other implements should be avoided.
It is generally assumed that HCV is not spread sexually. However, there is now evidence that this conventional thinking may be wrong: HCV may be transmitted sexually among people with more than one partner, and among people who have STDs or who practice anal intercourse.1
It is now recommended that partners of people with HCV be screened. It is also prudent for people to avoid sharing razor blades and toothbrushes, as an extra precaution against possible exposure due to breaking the skin.7–9
Occupational risks of infection are similar in HCV and HIV. In 1998, 800,000 healthcare professionals reported needle-stick injuries; these resulted in 40 cases of HIV and 2000 cases of HCV infection.1
Risk factors are not limited to exposure to blood and blood products, or even mucosal routes of transmission. Studies by the Centers for Disease Control estimated the influence of poverty as well as direct exposure in order to establish risk factors for HCV infection3:
• Intravenous drug use 38%
• Sex with multiple partners or a partner known to have HCV 15%
• Low socioeconomic status 38%
• Other factors 9%
Reducing the risk of HCV in the general population and among those with HIV infection will require extensive community outreach services and patient education programs (see the two accompanying sidebars “Summary Against a Tide of Ignorance” and “Confidential HCV+ Screener”).
HIV/HCV coinfection
Coinfection with HIV and HCV is reaching epidemic proportions in this country and poses a serious treatment challenge. To meet this challenge, an aggressive nationwide program of HCV screening will be required. Widespread screening for HCV is critical because it would permit earlier diagnosis and treatment of HCV. Early treatment is essential for two reasons: First, HCV infection can accelerate HIV progression; second, HCV causes increased liver damage in coinfected people.
Actually HIV and HCV mutually accelerate each other’s effects. There is some controversy over the role of HCV in hastening HIV progression. Studies before the era of HAART did not find enhanced HIV progression in the presence of HCV infection. However, many newer studies indicate that HCV, especially genotype 1 HCV, does cause more rapid progression to AIDS.
HIV also accelerates HCV, leading the U.S. Public Health Service in 1999 to call HCV the newest opportunistic infection of HIV. HCV viral loads increase after HIV infection. HIV infection also leads to more rapid liver damage in people with HCV. For example, having HCV alone means being about 16 times more likely to die from end-stage liver disease, while being coinfected means the odds of fatal liver disease increase 100-fold.1
Without treatment of HCV, liver damage is clearly associated with death in many coinfected people. In attempting to explain why, Dove and colleagues from the University of California at San Francisco studied the pathogenesis of this complex virus. They determined that HCV species sustain more mutations (diversity or variation) when the person’s CD4 count is less than 200 cells per microliter. The greater number of mutations may be associated with a more virulent species of virus. The researchers conclude that the immune compromise caused by HIV may promote the selection of new HCV viral species, and this could contribute to persistent infection and progression of liver disease in coinfected people.10
Other researchers have found that HIV/HCV coinfection is increasing at an alarming rate and is leading to earlier, often fatal, liver damage. Because coinfection with HIV is associated with more potent viremia, it may accelerate the progression to liver damage in HCV5:
· HCV levels are significantly higher in coinfected individuals than in those with HCV alone.22
· Coinfected individuals have a significantly higher incidence of genotype 1 than do those infected with HCV alone.12
Alcohol abuse or heavy drinking is a widely recognized cofactor in progression to liver disease and is an undisputed risk factor in fibrosis. Other predictors of progression to cirrhosis are age and immune status (CD4+ count) at time of HCV infection.13 Since the goal of treating HCV is to avoid liver disease, it is important to obtain liver biopsies to accurately assess baseline liver disease and to select treatments based on that.3,5
According to McGovern, who conducted a study with her colleagues at the Lemuel Shattuck Hospital in Jamaica Plain, Massachusetts, 1. End-stage liver disease due to underlying HCV/HBV [infection] is now the leading cause of death in patients with underlying HIV at our institution…Patients with co-infection with HCV and/or HBV need careful assessment of the possibility of underlying liver disease prior to initiation of antiretroviral therapy.14
McGovern’s study of coinfected patients found high and increasing risks of liver damage and end stage liver disease. In this study, many patients taking HAART therapy lowered their viral loads to undetectable or low levels and raised their CD4 counts to greater than 200 cells per microliter. Yet an increasing number of these coinfected patients died from liver complications. Many had accelerated progression to liver cirrhosis (scarring) and end-stage liver disease. McGovern found that over half of the patients who died in the Massachusetts study had an undetectable HIV RNA viral load, with CD4 counts greater than 200 cells per microliter, within one year prior to death. Also, one out of three in the study group had to discontinue HAART due to liver toxicity.14
In another recent hospital study in Pennsylvania, Gupta found an alarming rise in the rate of coinfection between 1996 and 1998—from under 10% to over 50%.15 A frequent concern today is whether highly active antiretroviral therapy (HAART) leads to liver damage in coinfected people. Selik, who has also examined trends connecting HAART treatment and liver disease in coinfected patients, confirms the association between HAART and liver disease, but emphasizes that no report has yet proved a cause-and-effect relationship. A number of factors could explain the trend of increased deaths due to liver disease in HIV patients16:
· Increased use of tests for HCV that were first FDA- approved in 1990
· Fewer deaths now due to AIDS-related opportunistic infections (because of improved immunity from HAART and/or effects from preventive antibiotic therapy)
· Other drugs in HAART regimens that might cause liver toxicity.
The “cohort effect” from the late 70s (if people who were later to become infected with HIV actually became infected with HCV in the late 70s, then many liver-related deaths could be accounted for by the normal delay of 20 to thirty years before liver complications are detected)
Whatever the underlying cause of the HAART–liver deaths connection, the reports all show that, at least in 1997, liver disease became fatal for a tenth of HIV-positive people. This percentage is expected to increase, and will certainly do so if better screening for HCV is not forthcoming.16
Since research shows HAART to be associated with liver disease so regularly, HAART treatment has become an independent risk factor for liver toxicity. Although estimates vary, it is clear that at roughly 15% of HAART patients will develop hepatotoxicity. While there is some controversy about when to treat with HAART in coinfected individuals, after HCV treatment or right away, it is generally recognized that rigorous drug monitoring for liver toxicity is extremely important.
CURRENT TREATMENT OPTIONS FOR HCV
The standard of care for treating HCV is alpha interferon (Intron A, Roferon, and Wellferon) with ribavirin. Ribavirin, a guanosine analog, is an older drug that has been around for 20 to 25 years. It inhibits replication in a range of viruses under test-tube conditions, but its antiviral action against HCV and its effect on the immune response are still poorly understood. Ribavirin produces anemia and other side effects, may interact in complex ways with certain antiretroviral medications, and may be poorly tolerated if kidney disease is present.3,17
Interferons are natural cellular proteins that can protect cells against viruses; the mechanism of action is thought to be immune regulation.3
Interferon alpha must be injected frequently. The pharmacokinetics of interferon alpha are very poor, which means that the agent is cleared from the bloodstream too quickly to be truly effective in fighting HCV. Its half-life—the amount of time it takes until only half of the original concentration of alpha interferon remains—is so short that a person would need to inject it once a day in order to maintain fully therapeutic blood levels. During the last 12 hours of the usual 2-day dosing interval, in fact, the form of interferon alpha that is currently prescribed is not even detectable in the bloodstream. The fact that most patients in the U.S. are taking interferon alpha three times a week, and not once a day, helps to explain why this current standard of care does not lead to widespread eradication of HCV disease.
Currently available alpha interferon is associated with anemia and a higher than 5% decrease in CD4+ counts. Side effects include flulike symptoms such as fatigue, fever, and headache, gastrointestinal symptoms, depression, neutropenia (a decrease in white blood cells called neutrofils), and thrombocytopenia (a decreased number of blood platelets).13 PEGYLATION: IMPROVING THE ACTION OF ALPHA INTERFERON
Newer forms of alpha interferon using “pegylation” have been developed. The term pegylation comes from polyethylene glycol (PEG), a substance that, put very simply, changes the way another substance is metabolized. Attaching PEG to alpha interferon leads to a longer half-life of the interferon because it is cleared more slowly by the kidney. Since pegylation of alpha interferon lengthens the time it takes the body to clear the drug, it results in a more desirable (longer) sustained viral response, or SVR. The goal of this new technology is to attain a better end of treatment (EOT) result. More specifically, the present EOT goal is to eradicate HCV for the year following a 6-month to year-long period of treatment.
The pegylated alfa interferons, soon available from two pharmaceutical companies (Roche and Schering) require only once-weekly subcutaneous injections. The greater convenience should result in much better compliance among people being treated for HCV. Pegylated interferon alpha will also improve outcomes by slowing the metabolism of interferon alpha.
Does alpha interferon hold wider promise as an antiviral treatment? Recently, a physician posed this question to Medscape’s “Ask the Expert…” column: “Is there any role for interferon in HIV management in the absence of hepatitis C coinfection? The medical director of my clinic has decided to add low-dose interferon (approximately 30,000 U SC every week) to the patients’ HAART/IL-2 regimen.” The expert responded that, indeed, some studies have suggested that interferon-alpha has a modest antiretroviral effect, but its limitations—unwanted side effects, inconvenient administration, and attenuation of the CD4+ response—would no doubt prevent it from becoming a mainstay of HIV treatment. However, a role for the pegylated form of IFN-alpha might arise in the future, in particular for patients who are failing HAART.18
Other treatments being considered to treat HCV in coinfected people include HCV protease and helicase inhibitors, antisense oligonucleotides and ribosomes, induction, and liver transplantation.
Treating HCV with standard regimens of alpha interferon alone does not appear to improve the outcomes of coinfected people. People using ribavirin with interferon alpha appear to have better outcomes.
Current treatments for either HIV or HCV cause multiple side effects and drug interactions, and the dosing regimens remain burdensome for most patients. These problems are at least doubled in aggressive treatment of coinfected patients.
As one HIV expert put it,3 It is still not clear…exactly how the determination for treatment should be made. Although there can be substantial toxicities, the potential to eradicate infection would seem to support a very aggressive approach. —William O’Brien, MD
It is hoped that a new awareness of the HCV epidemic will soon lead to more effective and tolerable diagnostic tests and treatments that can be used aggressively and safely to treat the majority of patients coinfected with HIV and HCV.
FEATURE REFERENCES
1. Dieterich D. Hepatitis C virus and HIV coinfection: A sleeping giant wakes. Medscape HIV/AIDS: Annual Update 2000. ©2000, Medscape, Inc. Accessed June 6, 2000 at:
2. KE Sherman and others. Hepatitis C prevalence in HIV-infected patients: A cross-sectional analysis of the US adult clinical trials group. Abstract and oral presentation 116. 10th International Symposium on Viral Hepatitis and Liver Disease. April 9–13, 2000. Atlanta, Georgia.
3. O’Brien WA. Hepatitis B and C virus coinfection with HIV. 7th Conference on Retroviruses and Opportunistic Infections. January 31, 2000. ©1994–2000, Medscape Inc. Accessed on Medscape June 6, 2000, at: .
4. Harvey S. Bartnof, reporting on the Co-Infection Seminar for Physicians Held in San Francisco. Speakers: Afdhal NH. Current strategies for the diagnosis and treatment of hepatitis C. Innovations in the Management of Hepatitis C. March 3, 2000, San Francisco, California.
5. Peters M, Sherman K. Coinfection with hepatitis C and HIV. Medscape HIV/AIDS: Annual Update 2000. ©2000 Medscape, Inc.
6. Hepatitis C virus (HCV) and HIV coinfection. J Intl Assoc Physicians in AIDS Care. 12th World AIDS Conference September, 1998.
7. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR. 1998;47 (No. RR-19).
8. Villano SA, Vlahov D, Nelson KE, Lyles CM, Cohn S, Thomas DL. Incidence and risk factors for hepatitus C among injection drug users in Baltimore, Maryland. J Clin Microbiol 1997;35:3274-3277.
9. U.S. Public Health Service. HIV prevention bulletin: Medical advice for persons who inject illicit drugs. May 9, 1997. Rockville, Maryland: CDC, 1997.
10. Dove LM, et al, HCV quasispecies as a mechanism of rapidly progressive liver disease in patients infected with the human immunodeficiency virus. Abstract 1183 at the 50th Annual Meeting of the American Association for the Study of Liver Diseases. Dallas, Texas, November 5–9, 1999. Hepatology. 30(4)(Suppl 2):456A.
11. Sherman KE, et al. Quantitative evaluation of hepatitis C virus in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31(10);2679-2682.
12. Bonacini M, et al., Patients coinfected with human immunodeficiency virus and hepatitis C virus demonstrate higher levels of hepatic HCV RNA. J Viral Hepatol. 1999;6(3):203-208.
13. Youle M. Mangement issues for the millennium—and how we pay for them. 7th European Conference on Clinical Aspects and Treatment of HIV Infection, October 27, 1999. Conference Report. ©2000, Medscape. Accessed June 6, 2000 at :
14. McGovern BH, et al. Increasing mortality from end-stage liver disease secondary to hepatitis C in patients with human immunodeficiency virus infection. Abstract and poster presentation 235 at the 37th Annual Meeting of the Infectious Diseases Society of America (IDSA). November 18–21, 1999, Philadelphia, Pennsylvania.
15. Gupta AK, et al. Increasing incidence of hepatitis C (HCV) and human immunodeficiency virus (HIV)-HCV co-infection: Significance for the future. Abstract and poster presentation 708 at the 37th Annual Meeting of the Infectious Diseases Society of America (IDSA), November 18–21, 1999, Philadelphia, Pa.
16. Selik RM, et al. Increases in the percentage of liver disease among deaths with HIV infection. Abstract and poster presentation F006 at the 10th International Symposium on Viral Hepatitis and Liver Disease, April 9–14, 2000, Atlanta, Ga.
17. Herrine SK. Controversial issues in HCV. American Asociation for the Study of Liver Diseases 50th Annual Meeting. Conference Report. ©1999, Medscape, Inc. Accessed June 6, 2000 at: .
18. From “Ask the Experts on… Antiretroviral Benefit From Interferon?” Reply provided by Jean–Michel Molina, MD, July 7, 2000.
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