Preventing new infections will not impact the predicted wave of morbidity and mortality from persons already infected.
While better and more affordable treatments are eagerly anticipated, much can be accomplished in the interim.
Affected countries must face the dilemmas at hand and give careful consideration to the array of available options for addressing and minimizing the coming wave of HCV-related liver disease.
Current strategies to reduce the long-term sequelae of chronic HCV infection include identifying infected persons by testing those at high risk and offering counseling, medical evaluation and treatment.
-- J.F. Perz and M.J. Alter
Journal of Hepatology
Hepatitis C virus (HCV) is a serious global health problem. According to the World Health Organization (WHO), which describes HCV as a "viral time bomb," 130 million people have chronic hepatitis C, and 3 to 4 million more become infected each year (WHO 2007). If untreated, or unresponsive to treatment, chronic HCV leads to cirrhosis in 20.30% of people. Each year, ~4% of people with hepatitis C-associated cirrhosis develop liver cancer, and ~6% will experience liver failure (Di Bisceglie 2000). WHO estimates that up to 75% of liver cancer and ~65% of liver transplants occurring in the developed world are attributable to chronic HCV infection (WHO 2007).
The current standard of care for HCV, pegylated interferon and ribavirin, is not effective for approximately half of those who undergo it, and the side effects are often debilitating.
The need for new therapies for hepatitis C virus is more urgent than ever, particularly for a growing population of treatment-experienced people with serious liver damage. Results from HALT-C and SLAM-C -- two interferon maintenance trials for people with advanced liver damage -- were an unexpected disappointment. Both reported that maintenance therapy did not reduce fibrosis progression, hepatic decompensation, or liver-related mortality, leaving no stopgap until new drugs are available (Di Bisceglie 2007; Sherman 2008). Without advances in, and broader access to, HCV treatment, liver-related mortality is expected to rise sharply in the coming years (Davis 2003).
Better HCV treatment is critical for the estimated 4 to 5 million HIV/HCV-coinfected people (Alter 2006). HIV increases the risk for and rate of hepatitis C progression. In fact, end-stage liver disease is now the leading cause of non-AIDS-related death among HIV-positive people in areas where antiretroviral therapy is available (Weber 2006).
HCV treatment is far less effective for HIV/HCV-coinfected people (see Table 1. SVR from Clinical Trials by HCV Genotype and HIV Status [Treatment with PEG-IFN plus ribavirin], below). HIV/HCV-coinfected people tend to have more severe -- often treatment-limiting -- side effects from HCV treatment, and many are not considered eligible for treatment.
It is incredibly ironic that we have dramatically altered the prognosis for HIV -- a currently incurable disease -- only to see coinfected people dying from complications of hepatitis C, a disease that we can cure.
Sponsors need to initiate studies of novel HCV drugs in coinfected people as soon as it is safe to do so, preferably in parallel with phase III. Drug-drug interaction studies with antiretroviral agents and other commonly used medications should be performed as early in development as possible to expedite these important trials.
|Population||SVR, Overall||SVR, Genotype 1||SVR, Genotype 2&3|
Carrat F, Bani-Sadr F, Pol S, et al. ANRS HCO2 RIBAVIC Study Team. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004 Dec 15;292(23):2839.48.
Chung RT, Andersen J, Volberding P, et al. AIDS Clinical Trials Group A5071 Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004 Jul 29;351(5):451.9.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347(13):975.82.
Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004 Sep 18(13):F27.36.
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep 22;358(9286):958.65.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. APRICOT Study Group. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29;351(5):438.50.
2007 was a year of many setbacks. The development of several candidates was halted due to toxicity, insufficient efficacy, and/or financial concerns: NM 283 and HCV-796 (polymerase inhibitor candidates from Idenix and Wyeth/Viropharma); ACH-806 /GS 9132 (an HCV protease inhibitor co-developed by Achillion/Gilead); AVI-4065 (an antisense drug from AVI BioPharma); Actilon (a TLR9 antagonist from Coley pharmaceuticals); and VGX-410 C (an oral IRES inhibitor from VGX Pharmaceuticals). Development of MAXY-alpha (a novel interferon formulation co-developed by Roche and Maxygen) was put on hold and is unlikely to resume. XLT Pharmaceuticals suspended development of XTL-2125, a polymerase inhibitor, and XTL 6865, a monoclonal antibody.
Doses of promising candidates have been modified due to safety issues. Gilead is going with a lower dose of GS 9190, an HCV polymerase inhibitor. During the phase III study of Albuferon (a longer-lasting formulation of interferon being developed by Human Genome Sciences and Novartis), a Data Safety Monitoring Board (DSMB) discontinued the highest dosing arm, due to pulmonary adverse events.
A drastic shift in the HCV treatment paradigm will not occur for several years, since interferon-free regimens are years away, and ribavirin is still a necessary component of HCV treatment. Recent research has underscored its value for preventing viral breakthrough and lowering relapse rates. Given emerging concerns with new therapies -- toxicity, drug-drug interactions, resistance, and adherence -- it is especially disappointing to remain saddled with the current standard of care.
HCV treatment uptake will not increase significantly until combinations of more effective, less toxic, more affordable drugs are available, particularly for people who are unlikely to respond to, or unable to tolerate, the current standard of care. According to Data Monitor, in 2006, sales of pegylated interferon and ribavirin -- the current standard of care for HCV -- reached $2.5 billion in the U.S. and Europe; but sales are projected to increase by only $1.5 billion by 2010, reflecting the limitations of the current treatment. Better HCV drugs will be a jackpot for the pharmaceutical industry.
The efficacy of HCV treatment improved with the advent of pegylated interferon-based regimens, and there has been additional progress since then. A steady parade of new agents is moving forward into preclinical and clinical development; researchers toil in state-of-the-art laboratories, developing new drugs, attempting to identify correlates of spontaneous viral clearance and response to HCV treatment, and characterizing resistance to new HCV antiviral drugs. Activists are working with regulators, researchers, and industry to develop guidance for swift, strategic, and inclusive drug development.
More effective, shorter-course HCV treatment is on the horizon. The pipeline is full of second-generation candidates and new approaches, such as RNA interference, to thwart HCV replication. Promising results have been reported from phase II studies of Vertex's HCV protease inhibitor, telaprevir, and from Romark's phase II study of nitazoxanide, an approved anti-protozoal agent. Data are flowing in from phase I studies of protease and polymerase inhibitors. In the future, coformulated versions of these oral drugs may be possible.
The remarkable successes, complexities, and challenges in HIV research and clinical care offer valuable lessons for HCV drug development, care, and treatment.
|REPEAT ~90% HCV Genotype 1|
|Double Dose Induction, Standard Duration|
360µg PEG-IFN for 12 weeks, followed by
180µg PEG-IFN + RBV for 36 weeks
|11/156 (7%)||Induction dosing did not make a significant difference in SVR 14/156 (9%) experienced serious adverse events 7/156 (4%) discontinued for safety|
|Double Dose Induction, Extended Duration|
360µg PEG-IFN for 12 weeks, followed by
180µg PEG-IFN + RBV for 60 weeks
|52/317 (16%)||Extending duration of treatment increased SVR, lowered relapse rate|
33/317 (10%) experienced serious adverse events
37/317 (12%) discontinued for safety
|Standard Dose, Standard Duration|
180µg PEG-IFN + RBV for 48 weeks
|27/313 (9%)||33/313 (11%) experienced serious adverse events|
20/313 (6%) discontinued for safety
|Standard Dose, Extended Duration|
180µg PEG-IFN + RBV for 72 weeks
|22/156 (14%)||28/156 (18%) experienced serious adverse events|
18/156 (12%) discontinued for safety
|DIRECT (Daily Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) ~95% HCV genotype 1|
|Control: no treatment after lead-in||SVR 12 = 0%||Participants in the control arm eligible for roll-over study|
|Interferon alfacon 9µg/day + RBV for 48 weeks||SVR 12 = 5.3%||14% discontinued for adverse events|
|Interferon alfacon 15µg/day + RBV for 48 weeks||SVR 12 = 9.5%||14% discontinued for adverse events|
|The German Consensus Interferon Multicenter Study (Interim Results) 96% HCV genotype 1|
9/9 Interferon alfacon 9µg/day for 16 weeks, followed by Interferon alfacon 9µg/day + weight-based RBV for 32-56 weeks
|13%||SVR differed by original regimen:|
13% for PEG-alfa 2b vs. 19% for PEG alfa-2a
27/18/9 Interferon alfacon 27µg/day for 4 weeks, followed by Interferon alfacon 18µg/day for 12 weeks, followed by Interferon alfacon 9µg/day + weight-based RBV for 32-56 weeks
|19%||SVR differed by original regimen:|
19% for PEG-alfa 2b vs. 27% for PEG alfa-2a Although treatment discontinuation did not differ by treatment arm, the high-dose induction was less tolerable
Jensen DM, Freilich B, Andreone P, et al. (abstract LB4) Pegylated interferon alfa-2a (40KD) plus ribavirin (RBV) in prior non-responders to pegylated interferon alfa-2b (12KD)/RBV: final efficacy and safety outcomes of the REPEAT study. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
Bacon B, Regev A, Ghalib RH, et al. (abstract 168) The DIRECT trial (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy): treatment of non-responders to previous pegylated interferon plus ribavirin: sustained virologic response data. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
Kaiser S, Boecher W, Schlaak JF, et al. (abstract 1306) Treatment of Peginterferon/Ribavirin Nonresponders with Daily Dosing of Consensus Interferon and Ribavirin - Preliminary Results of the German Consensus Interferon Multicenter Study. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
Our challenge is to ensure that advances in HCV treatment are available to all who need them, since a majority of people with hepatitis C live in poverty. Hepatitis C is a disease that reflects and magnifies global social and economic inequality. Limited -- or the complete lack of -- access to HCV prevention, care, and treatment render these virtually useless to millions of people with chronic hepatitis C. We can decrease HCV-related morbidity and mortality if we: