September 29, 2005
Almost 129 million people -- an estimated 2% of the world's population -- have been infected with the hepatitis C virus (HCV) (Global Burden of Hepatitis C Working Group 2004; United States Census Bureau 2005). Approximately 20% (nearly 26 million people) may be expected to develop cirrhosis over a 20- to 50-year period (Alberti 1999; Dore 2002; Freeman 2001; Freeman 2003; Poynard 1997; Poynard 2001). These statistics indicate the immense need for effective, non-toxic, and affordable treatments for hepatitis C.
In the United States, at least 3.8 million people have been infected with HCV and most have developed chronic infections (Armstrong 2004). HCV-related end-stage liver disease is the leading reason for liver transplantation (CDC 1998). HCV-related mortality increased by 220% from 1993 to 1998 (Vong 2004), and morbidity and mortality from hepatitis C are projected to rise sharply in the next fifteen years as a reflection of the large numbers of hepatitis C infections that occurred during the 1980s (Davis 2003). As many as 10,000 to 12,000 deaths each year are now attributed to complications of hepatitis C (CDC 1998; NIH 2002).
Hepatitis C is also an opportunistic infection of HIV disease. Graham and colleagues reported that HIV coinfection significantly increases the risk of developing serious liver disease, doubles the risk of cirrhosis, and increases the risk of decompensated liver disease by more than six times (Graham 2001). In the HAART era, end-stage liver disease from hepatitis C coinfection has emerged as a leading cause of death among HIV-positive people (Bica 2001; Martin-Carbonero 2001; Rosenthal 2003).
The standard of care therapy for treating hepatitis C virus (HCV) is 24 to 48 weeks with a once-weekly injection of pegylated interferon plus daily ribavirin capsules, tablets, or liquid. Although pegylated interferon is more effective than its predecessor, standard interferon, HCV treatment is far from optimal; substantial limitations to efficacy and tolerability remain. Overall, approximately 50% of treatment-naive people will achieve a sustained virological response (SVR; meaning that there is no detectable hepatitis C virus in the bloodstream six months after completion of therapy). Attaining SVR usually indicates that a person will remain virus-free for years; many consider it a cure.
When response rates are examined more closely, however, a grimmer scenario emerges. SVR rates are significantly lower among certain groups, particularly those who have the greatest need for treatment: people with HCV genotype 1 and a high viral load (who constitute the majority of HCV cases in the United States); African Americans, (the population with the highest-prevalence in the US); individuals with advanced liver damage; HIV/HCV-coinfected persons; previously treated non-responders and relapsers; and liver transplant recipients, virtually all of whom develop recurrent HCV infection.
* Dosing of PEG-IFN and RBV differs across studies.
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Side effects from HCV treatment are daunting, although management strategies continue to evolve. People may suffer from a constellation of adverse events, including fatigue; neuropsychiatric side effects (depression ranging from mild to suicidal, and suicide in <1 to 2% of study participants, irritability, anxiety, and insomnia); hematological toxicities (anemia, neutropenia, and thrombocytopenia) and flulike symptoms (Russo 2003). Poor tolerability of treatment often results in discontinuation of therapy (Aspinall 2004) or dose reduction, which may compromise efficacy (Ong 2004).
Hepatitis C treatment is less effective for coinfected persons than for those with HCV monoinfection (Carrat 2004; Chung 2004; Fried 2002; Hadziyannis 2004; Manns 2001; Torriani 2004). Tolerating HCV treatment is often more difficult for HIV/HCV-coinfected persons and mono- and coinfected liver transplant recipients. Side effects are often more severe and adverse events more frequent, as reflected in the high discontinuation rates in HCV treatment trials involving coinfected persons (Cargnel 2005; Carrat 2004). Concomitant HIV therapy must be selected carefully to avoid interactions with ribavirin; in particular, the interaction between ribavirin and didanosine (ddI; Videx®) can be life-threatening (Bristol Myers Squibb 2004; Fleischer 2003).
Until new therapies become available, research on optimizing efficacy and tolerability of the current HCV treatment regimen must continue in tandem with operational research on delivery of HCV treatment, since it is likely that interferon will continue to be the backbone of future treatment regimens. Strategies for managing interferon-induced depression, which is also a common co-morbidity of hepatitis C and HIV, must be rigorously explored. Models of care for active drug users, among whom HCV is highly prevalent, must be developed and evaluated.
Maintenance therapy with pegylated interferon may provide non-responders, relapsers, and cirrhotics with a bridge until better treatments are available. Much remains to be learned about managing interactions among immunosuppressants, antiretroviral therapies, and HCV treatment in coinfected transplant recipients.
Given the drawbacks of current HCV treatment, there is ample room for improvements in the safety, efficacy, and tolerability of HCV therapy. Ideally, new treatments will replace pegylated interferon and ribavirin; at the least, they should augment the current standard of care. Improvements in future therapy options may include:
A combination of drugs will be necessary to treat HCV since, as with HIV, resistance to a single agent is likely to develop eventually. Currently, the most promising areas of HCV drug development involve oral drugs that inhibit hepatitis C's protease and polymerase enzymes -- a strategy that has proven successful as part of suppressive, multidrug therapy for HIV.
Many new anti-HCV agents and other therapeutics are in preclinical development. Some of the mechanisms involve RNA interference, internal ribosomal entry-site inhibition, and dual monoclonal antibodies to prevent recurrence of HCV after liver transplantation. A few companies have candidates entering phase I in the near future. Gilead Sciences, Inc., and Achillion, who share a research and end-licensure agreement for ACH-806, their HCV protease inhibitor, are planning a phase I study for the end of 2005.
Nevertheless, interferon will likely continue to be the backbone of most foreseeable regimens. Different types and formulations of interferon that may mitigate its toxicity are currently in development (as is a more tolerable version of ribavirin). Research on therapies that modulate the immune response to hepatitis C is ongoing as well, though these drugs may not ultimately be as effective for HIV-positive persons and transplant recipients on immunosuppressive drugs.
Interferon-gamma 1-b (Actimune®) has been approved for treatment of chronic granulomatous disease and severe, malignant osteopetrosis. There are several ongoing pilot studies in nonresponders that combine Actimune® with interferon alfacon-1, ribavirin, and pegylated interferon.
Intermune's interferon-alfacon-1 (Infergen®), a synthetic consensus sequence of interferon-alfa subtypes, is approved for HCV treatment in persons with compensated liver disease; it is currently being evaluated with ribavirin in a phase III study of non-responders.
Given what we know about hepatitis C viral kinetics and the relationship between early virological response to treatment and treatment outcome, it is reasonable to develop innovative methods of evaluating the efficacy of these new drugs. An effective and potent combination of oral antiviral drugs could potentially be used as a lead-in for pegylated interferon, hopefully increasing efficacy by rapidly driving down HCV RNA and shortening duration of therapy. Since, as with anti-HIV drugs, the threat of drug resistance is a concern, it will be crucial to determine how quickly HCV drug resistance develops with each new agent and to tailor clinical trials and treatment paradigms accordingly.
Given the increasing mortality rates among HIV/HCV-coinfected persons from end-stage liver disease, and given the accelerated progression of hepatitis C in HIV/HCV-coinfected people, it is crucial that the efficacy and safety of new HCV therapies and potential interactions with antiretroviral agents be evaluated in coinfected persons. Important goals for the HCV and HIV/HCV advocacy communities are:
Companies experienced in working with the HIV/AIDS community have been more receptive to community input than those with no history of community collaboration. Relationships must be built and cultivated with inexperienced companies so that they recognize the value of input from the HCV and HIV communities.
While it certainly is reasonable to offer patients the anticipation of future treatment opportunities, hope is not a particularly effective method of viral eradication.-- Kenneth E. Sherman, Stephen D. Zucker
The HCV treatment pipeline is robust, but it will probably be at least five years until many new therapies become widely available. Several promising compounds have already fallen by the wayside during clinical development. A case in point is BILN-2061, Boehringer Ingelheim's HCV protease inhibitor, which offered exciting proof-of-concept data (Lamarre 2003) but was shelved due to animal toxicity. People living with hepatitis C and HIV/HCV coinfection and their clinicians are eagerly awaiting new therapies. Decisions to defer HCV treatment until better therapies are available must be informed by accurate, up-to-date information on the status of new therapies. This information should be easily accessible and available to all stakeholders.
Special thanks to Daniel Raymond who helped with this article.