Introduction

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.

Table 1 SVR From Clinical Trials by HCV Genotype and HIV Status (Treatment with PEG-IFN plus ribavirin)

Population	SVR, Overall	SVR, Genotype 1	SVR, Genotype 2&3
HIV/HCV coinfected	27%-44%	14%-38%	53%-73%
HCV monoinfected	56%-61%	42%-44%	70%-82%

Sources:

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.

Setbacks

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.

Progress

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.

Lessons Learned

The remarkable successes, complexities, and challenges in HIV research and clinical care offer valuable lessons for HCV drug development, care, and treatment.

Research Issues: Trial Design and Study Populations

• Trials need to be designed to identify therapeutic strategies, as well as to gain approval for a single agent.
• As with HIV, a combination of drugs, targeting different steps in the HCV life cycle, is needed to ward off resistance. Cross-company collaboration on multi-agent trials (involving both approved and experimental drugs) is needed to advance the field. Regulators can facilitate these collaborations by developing regulatory guidance for multi-experimental agent trials.
• Sponsors must study safety, efficacy, and tolerability of new HCV treatments and treatment regimens in clinically relevant populations prior to approval. This means exploring new therapies in populations that are hard to treat and may have urgent, unmet needs, such as: HIV/HCV-coinfected people; African Americans; people with genotype 1 and/or high baseline HCV RNA; transplant candidates and recipients; people with advanced liver damage; current and former drug users; and the rapidly growing population of treatment-experienced people.
• There are practical and financial reasons for sponsors to conduct registration trials in "real-life" populations. From a regulatory perspective, "... it is important that a good sampling of the patients who will receive the drug be part of registration trials" (Dr. Debra Birnkrant, FDA, 2006). More inclusive trials will enroll more quickly and are more feasible, because the number of cherry-picked, otherwise completely healthy, treatment-naive patients available to participate in HCV treatment trials is dwindling. Securing a broader indication facilitates drug sales, since insurers have begun to limit access to off-label use of drugs, and it is likely that restrictions will increase in the future.
• There are specific issues involved in designing re-treatment trials for people who did not respond to pegylated interferon and ribavirin.
• Re-treating these non-responders with an identical regimen has yielded SVR rates of ~3% (Rustgi 2008). Future trials in this group of non-responders should offer more than one novel agent, preferably in a factorial design when possible. Until combinations of drugs are available, these re-treatment trials need to incorporate successful re-treatment strategies into their design -- especially into the control arm -- so that participants have the best possible chance to achieve sustained virological response (SVR; see Terms for Response to HCV Treatment, page 34; see also Table 2, page 11. Re-treatment Trials in Non-Responders to at Least 12 Weeks of PEG-IFN and Ribavirin: Strategies and SVR). These strategies may involve extending the duration of treatment, or using a different formulation of interferon, or a higher dose of ribavirin.

Table 2. Re-treatment Trials in Non-Responders to at Least 12 Weeks of PEG-IFN and Ribavirin: Strategies and SVR

Treatment Strategy	SVR	Comments
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
Low-dose induction 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
High-dose induction 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

Sources:

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.

Care and Treatment Issues: Resistance/Adherence, Appreciating Toxicity, Multidisciplinary Systems, and HCV Treatment Guidelines

• Resistance to HCV protease and polymerase inhibitors can develop rapidly. The first generation of HCV protease inhibitors to reach phase II must be taken three times a day, every eight hours -- a dosing schedule associated with poor adherence (Claxton 2001).
• Liver specialists may be unaccustomed to providing adherence support. Methods that are proven to promote adherence -- such as patient support and education, and pillboxes -- should be incorporated into clinical trials and clinical practice (Peterson 2007; Rueda 2006).
• Liver specialists will need information on the importance and interpretation of resistance testing to optimize HCV treatment outcomes.
• When targeting a virus, the patient often seems to get in the way. It is a mistake to underestimate the importance of tolerability, which is sometimes overlooked by eager researchers in their quest to cure hepatitis C.
• In the United States, the majority of people with chronic hepatitis C are 40 to 59 years old. Many have other chronic health problems, family responsibilities, and demanding jobs that make it difficult or impossible for them to tolerate the current standard of care, resulting in low rates of treatment uptake and completion.
• Therapeutic advances must be accompanied by health-care delivery systems suited to the needs of multiply diagnosed persons. These systems need to be created now to meet current needs and in anticipation of future improvements in HCV treatment.
• It is likely that the standard of care for HCV will become somewhat of a moving target in the coming years. Convening an expert, cross-disciplinary panel to develop and update HCV treatment guidelines will optimize treatment and avert therapeutic chaos.

Community Involvement

• Since the late 1980s, when they demanded to be treated as partners in HIV research, people with HIV/AIDS and treatment activists have become vital participants in HIV drug development. They serve on scientific peer-review committees, protocol teams, regulatory advisory committees, and treatment guidelines panels. Activists work with sponsors of public and private research, and participate in the design and oversight of clinical trials.
• HCV researchers have much to gain by working more closely with activists and community members. Many bring an often-overlooked, practical perspective to areas ranging from drug development to delivery of care and treatment. Continuing to exclude members of the HCV community from contributing as fully respected partners in hepatitis C research is counterproductive and shortsighted.

Access

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:

• Ensure adequate coverage of additional costs associated with HCV care and treatment, such as diagnostic testing and other lab work; nursing and clinic staff time; management of side effects; and mental health care;
• Anticipate future costs, such as resistance testing and adherence support services, and provide funding; and
• Work to develop a reasonable, high-volume, low-profit framework for global pricing of HCV drugs and diagnostics.

Figure 1. Targets for HCV Drugs