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Hepatitis C Virus and HIV Co-Infection

Winter 1998/1999

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 As a result, parts of this article may be outdated.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!

Since its discovery, AIDS has been marked by the development of opportunistic infections, which cause significant illness and death. Recently, advances in prophylactic and antiretroviral therapies have dramatically reduced the incidence of these diseases and their impact on AIDS mortality. However, obscured by the headlines announcing reductions in AIDS deaths, is the increasing importance of chronic hepatitis C virus (HCV) infection among HIV-infected persons.

Due to shared routes of transmission, HCV and HIV co-infection is common, affecting 60-95% of those with blood exposures, such as injection drug users and recipients of transfused blood products. Sexual transmission of HCV is less common, but may be facilitated by concurrent HIV infection. As a result, the HCV disease burden among HIV-infected adults is substantial, particularly in urban settings where injection drug use is common. For example, one-half of all patients followed in Baltimore, Maryland at the Johns Hopkins HIV clinic are infected with HCV.

Similar to HIV, most persons do not experience symptoms during HCV infection, and have a long, period of clinically silent infection. However, natural history studies show that HCV infection can cause progressive hepatic (liver) inflammation and scarring (fibrosis), which may lead to cirrhosis, liver cancer, and liver failure in up to 25% of persons over a period of 20 to 30 years. Among HIV-infected persons, the progression of HCV-related liver disease may be quite rapid (<10 years), particularly in those with advanced immunodeficiency. Several studies have shown the synergistic effect of HIV infection on the development of HCV-related liver disease and emphasize the emerging risk of death due to liver disease among HIV/HCV co-infected persons. Among HCV-infected hemophiliacs in the United Kingdom, liver-related deaths were almost 20 times higher than the general population among men with only HCV infection, and an astounding 94 times higher among men with both HIV and HCV infection. This and other studies demonstrate the increasing importance of HCV co-infection as deaths from AIDS and other opportunistic diseases decline, and underscore the need to develop effective HCV treatment strategies.

"Among HCV-infected hemophiliacs in the United Kingdom, liver-related deaths were almost 20 times higher than the general population among men with only HCV infection and an astounding 94 times higher among men with both HIV and HCV."


Today's Treatment Strategies

As with HIV, successful treatment strategies will be based on an understanding of the virus itself. Hepatitis C is an RNA virus with a very rapid replication rate; each day about 367 billion hepatitis C virions are produced and survive in the blood about 8 hours before being replaced by new virus. HCV does not have "proof-reading" capabilities and is prone to make frequent errors or mutations during replication, which may lead to rapid resistance to anti-viral drugs.

An understanding of such viral dynamics led to the development of successful, multi-drug "cocktails" against HIV, and these same principles will guide the development of new anti-HCV drugs.

Viral mutations or diversity may also explain some of the shortcomings of currently available treatments. Alfa interferon is the only FDA-approved drug with anti-HCV activity. Interferon, administered as a single dose, can result in dramatic decreases in HCV blood levels within 24 hours, and administered over longer periods of time, such as 12-18 months, can result in the eradication of hepatitis C virus from the blood. However, sustained virologic response, defined as a undetectable plasma hepatitis C viral load six months after the discontinuation of therapy, is achieved in only 20-30% of patients with interferon monotherapy.

Among HIV-infected patients, interferon therapy may be less effective, but few well designed studies of alfa interferon for the treatment of HCV among HIV-infected persons have been performed. The largest published study, conducted by the Hepatitis-HIV Spanish Study Group, reported sustained virologic responses in 20% of HIV-infected patients who took interferon injections three times a week for 12 months. Patients with CD4 cell counts >500 cells/mm3 were more likely to respond to treatment. Moreover, for patients who fail to respond virologically, interferon therapy may have beneficial effects on the liver. Most clinical trials have found decreased hepatic inflammation by liver biopsy after interferon therapy, and several studies have shown that interferon therapy can delay progression to liver cancer or failure.

New Approaches

Recently, therapy with the combination of interferon with ribavirin has been shown to improve the rate of sustained virologic response. The combination is marketed in the United States as Rebetron®, and may lead to sustained virologic response in up to 50% of patients. While clearly an advance in the treatment of HCV-infection, this may not represent true "combination" therapy. Ribavirin alone has no anti-HCV effect, and viral inhibition studies show no synergy between interferon and ribavirin. The mechanism of action of ribavirin is not known, but it appears to prevent the recurrence of HCV in the blood when therapy is stopped in patients who initially respond to treatment. No studies have been published on the use of this combination for the treatment of HCV in HIV-infected patients; AmFAR is currently sponsoring a multicenter clinical trial to evaluate its safety and effectiveness in co-infected persons.

In light of the increasing impact and the availability of effective drugs, many co-infected persons should be considered for anti-HCV therapy. However, interferon with or without ribavirin may not be for everyone. Interferon, given by an injection under the skin, may cause low white blood cell and platelet counts, anemia, depression, hair loss, and thyroid dysfunction. Ribavirin, taken orally, may cause a dose-related anemia during the first 4 weeks of treatment, typically a moderate decrease in the concentration of hemoglobin. In addition, ribavirin is a nucleoside analogue, like zidovudine (AZT) and other antiretroviral drugs, and some preliminary studies of ribavirin and zidovudine (AZT) in a test tube have antagonism between these drugs. However, practical implications, if any, of this laboratory finding are not known. Nonetheless, the limited effectiveness and side effect profile of the current treatment options emphasizes the need for new anti-HCV drugs.

Easier to use, slowly released alfa interferons, bound to polyethylene glycol (PEG), have been developed, and can provide continuous exposure to interferon with a once-weekly injection. Studies evaluating the effectiveness of PEG-interferon and ribavirin are underway. However, novel designer drugs that target specific HCV sites essential for viral replication are urgently needed. As with HIV treatment, these drugs will be used in combination with other drugs, including interferon, to prevent the development of HCV resistance. Several potential targets have been identified within the HCV molecular structure. HCV has a protease, which differs significantly from the HIV protease, but is essential for cleaving large proteins into smaller segments during the virus life cycle. HCV also uses a helicase enzyme, which unwinds the double RNA complex as the virus copies itself. The complex, molecular structures of these targets have been determined, and drugs to inhibit these sites are being developed.

A third enzyme that is critical to HCV replication is an RNA-dependent RNA polymerase, representing another potential target for inhibition. HCV protein production is also dependent on a viral region called the internal ribosomal entry site (IRES), which may be blocked by anti-HCV IRES drugs. In addition, novel approaches, such as the development of antisense molecules, which may prevent the production of HCV proteins and degrade HCV RNA, are being pursued. However, despite aggressive research efforts, progress in the development of these new drugs is impeded by the lack of a cell or animal model that would allow rapid screening of candidate drugs. Current expectations are that some of these new drugs may be available over the next 2 to 5 years for the combination therapy of HCV infection.

Thus, while exciting HCV therapies are under development, the impact of HCV-related liver disease among HIV-infected patients is already being felt in HIV clinical practices around the world. Co-infected patients should be evaluated for significant HCV-related liver disease, which may require a liver biopsy to examine the extent of hepatic disease. The decision to pursue hepatitis C treatment with interferon with or without ribavirin should be addressed on an individual patient basis, taking into account HIV and HCV factors as well as the medication side effect profile. Until the promise of new drugs is realized, more co-infected persons must be treated with interferon or interferon/ribavirin to stem the emerging epidemic of hepatitis C-related deaths among HIV-infected persons.

Dr. Mark Sulkowski is Medical Director of the Johns Hopkins University Center for Viral Hepatitis. He conducts clinical trials and cares for patients with hepatitis C and those with hepatitis C and HIV co-infection.

Emerging Therapies for Chronic Hepatitis C Virus Infection and Estimated Date of Availability
Pegylated-interferon + Ribavirin Interferon chemically bound to polyethyleneglycol (PEG); allows for the slow, continuous release of interferon 1999
Helicase inhibitors Prevents unwinding of double-stranded viral RNA during HCV replication 2001-2003
Protease inhibitors Prevents cleavage of large viral protein into smaller segments 2001-2003
RNA-dependent RNA polymerase inhibitors Prevents replication or copying of the HCV genome 2001-2003
IRES (internal ribosomal entry site) inhibitors Prevents the expression of viral proteins 2001-2003
Antisense nucleotides Bind to interferon resistance sites 2008
DNA vaccines Stimulate cytotoxic T-cell activity 2008
Dominant negative mutants Block viral protein production 2008

Back to the CRIA Update Winter 98/99 Contents Page.

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!

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
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