No other baseline differences, such as HCV RNA-level or ALT, were observed. There were no differences in the treatment adherence rate (as measured by pill and vial count) between Whites and Blacks.

After controlling for genotype, there was no difference in the SR rate between Whites and Blacks (P = 0.24). Similar to the findings by Reddy and colleagues, however, there was a significant difference (after controlling for genotype) between the groups in median viral load decreases by week 24 on therapy. According to McHutchinson, "These observations suggest that there may be inherent host differences among racial groups" (McHutchinson 1999).

Results from both studies are intriguing. These results were from post-hoc subset analyses, and the disproportionate number of Blacks/African Americans to Whites (83 vs. 1,980) makes it difficult to draw accurate conclusions. There appears to be something different in the way Blacks/African Americans with HCV, compared to Whites, respond to IFN. The answer cannot be that Blacks/African Americans are ubiquitously unresponsive to the antiviral effects of IFN. We know this because Blacks/African Americans with HBV have been shown to actually have a better response to IFN than Whites with HBV. Lau and colleagues demonstrated this fact in their long-term follow-up of HBV patients treated with IFN monotherapy (Lau 1997). It may be the genetic make-up of the HCV virus in Blacks/African Americans that is responsible for the poor response to IFN. Further prospective randomized studies (and, of course, better HCV therapies) are needed to understand this racial difference. I agree wholeheartedly with K. Rajender Reddy's concluding remarks on this issue:

The clinical finding of a low response rate to alfa interferon among African- American patients further supports the urgent need for better therapies of this disease and stresses the importance of evaluating new therapies in all categories of patients. Hepatitis C is reported to be 2 to 3 times more common among African Americans than among non-Hispanic whites. For that reason, African Americans should make up a sizeable proportion of patients enrolled in trials of antiviral therapy of this disease. (Reddy 1999)

Patients with Acute HCV
Approximately 15% to 20% of individuals with acute HCV will completely recover from infection (MJ Alter 1992; Shakil 1995; Villano 1999). Because of the high rate of chronicity, IFN has been studied to determine if immediate treatment can arrest development of HCV before it becomes chronic. Numerous IFN monotherapy treatment studies in patients with acute HCV infection (mostly from blood transfusions) have been conducted since 1989. Drawing conclusions from these studies has been difficult for at least four reasons: 1) different doses, administration methods (IV vs. SC), and duration (4, 6, 12, 24 weeks) of IFN were used; 2) only a few studies were randomized and controlled; 3) different response criteria (biochemical and/or virologic) were examined; and 4) small sample size (the average study had ~30 patients) (Esteban 1999).

The most common regimen tested has been 3 MU of IFN for 12 weeks. Poynard and colleagues conducted a meta-analysis and identified four randomized controlled trials that used 3 MU for 12 weeks (Poynard 1996). The biochemical and virologic response rates in these four studies are summarized in the chart that follows:

[chart]

The 1997 NIH Consensus Panel did not discuss the treatment of patients with acute HCV infection in much detail. Only two sentences were written:

Data suggest a benefit from interferon treatment with higher clearance of HCV RNA in patients with acute hepatitis C. In light of these findings, interferon treatment of patients with acute hepatitis C could be recommended. (NIH Consensus Panel 1997)

Just mentioning that treatment "could be recommended" gives treating physicians little guidance. We may never fully know the most efficacious way to treat (dose, schedule, duration) these patients. According to Juan Ignacio Esteban,

Available data are, however, too limited to give definite guidelines as to the optimal dose, duration and timing, and given the practical eradication of transfusion-associated hepatitis C, it is unlikely that further large controlled trials will ever be conducted to clarify these issues. (Esteban 1999)

HCV Patients with Persistently Normal ALT Levels
Approximately 25% of chronic HCV patients have persistently normal ALT levels, and most have no symptoms related to liver disease (Marcellin 1999). Neither the 1999 EASL or 1997 NIH Consensus Panel recommends treatment for HCV patients with persistently normal ALT levels outside a clinical trial (EASL 1999; NIH Consensus Panel 1997). It is recommended that they be monitored every four to six months.

While median HCV RNA levels do not differ between chronic HCV patients with normal and abnormal ALT levels, individuals with persistently normal ALT levels more often have a milder degree of histologic abnormalities. In an analysis of 16 published studies totaling 447 patients with persistently normal ALT levels, Marcellin found: 24% with normal liver of non-specific changes; 54% with chronic persistent hepatitis; 21% with chronic active hepatitis; and only 0.8% with cirrhosis (Marcellin 1999).

IFN monotherapy studies in this population have similar methodological limitations as acute HCV treatment trials. In Marcellin's analysis, only one published study included untreated controls and one reported on liver histology. Silverman and colleagues found none of the IFN- treated patients achieved a virologic SR or documented change in liver histology one year after therapy (Silverman 1997). Sangiovanni and colleagues randomized 31 HCV patients with persistently normal ALT levels to receive either IFN (3 MU tiw) for six months or no treatment (Sangiovanni 1998). At the end of treatment, no difference was seen virologically; 15 of 16 IFN-treated patients and 14 of 15 controls, respectively, were still HCV RNA-detectable. ALT levels flared up in ten IFN patients and only one control (62% vs. 7%; P< 0.005). It is because of these ALT flare-ups on IFN and the lack of virologic control that IFN is not recommended for the treatment of HCV patients with persistently normal ALTs. Many combination IFN/RBV studies in this population are ongoing, yet none has been published.

HCV Patients with Cirrhosis
The 1997 NIH Consensus Panel and 1999 EASL Consensus Statement both state that HCV patients with clinically decompensated cirrhosis (those with jaundice, ascites, variceal hemorrhage [bleeding from abnormal blood vessels in the esophagus] or hepatic encephalopathy) should not be treated with standard therapy but should be considered for liver transplantation (NIH Consensus Panel 1997; EASL 1999). For patients with compensated cirrhosis, the NIDDK says that therapy "can be offered," and EASL says that they "may be treated." Neither appears convinced by data (mostly Japanese) indicating that IFN reduces the risk of HCC or improves survival. (See the "Experimental Treatments" chapter for a discussion of treatment in cirrhotics.)

Children and the Elderly with HCV
A vast majority of IFN and IFN/RBV studies have excluded individuals with HCV under the age of 18 and over the age of 60; thus, there are scant and incomplete data with which to make recommendations on treating children and the elderly.

Smaller studies employing standard dose IFN in children with HCV have shown that response rates are similar to those seen in adults (Ruiz-Moreno 1992; Balistreri 1995). Neither the NIDDK or EASL makes a firm recommendation to treat or not to treat children except to say that: 1) long-term effects of IFN in children (e.g., growth) are unknown; and 2) if children are treated, it should be with IFN monotherapy because the pediatric dose and safety profile of ribavirin in children has not been established (NIDDK 2000; EASL 1999). Nonetheless, in a New England Journal of Medicine review article, Jay Hoofnagle makes the case that IFN treatment in children with HCV might be beneficial:

In view of the findings that adult patients without cirrhosis had better long-term responses than those with cirrhosis, it seems appropriate to treat children with chronic hepatitis C even if symptoms are absent and histologic features of the liver suggest mild disease, as long as serum aminotransferase concentrations are elevated. (Hoofnagle 1997)

The NIDDK does not recommend treatment for all HCV patients over the age of 60, but suggests they be "managed on an individual basis since the benefit of treatment in these patients has not been well documented and side effects appear worse in older patients." (NIDDK 2000)

HIV/HCV Coinfected Patients (for a detailed discussion, see "HIV/HCV Coinfection" chapter)
The 1997 NIH Consensus Panel, NIDDK, and EASL either state that HIV/HCV coinfected patients "should" or "may" be treated as long as they have established control of their HIV infection (NIH Consensus Panel 1997; EASL 1999; NIDDK 2000). The NIDDK correctly points out that in coinfected patients with minimal immunosuppression (>400 CD4 cells/mL), responses to IFN monotherapy are similar in frequency to those HCV patients not infected with HIV (NIDDK 2000). Almost all U.S. and international hepatologists interviewed for this report say that they first have coinfected patients begin potent HIV antiretroviral therapy (an HIV protease inhibitor or a non-nucleoside reverse transcriptase inhibitor plus two nucleoside reverse transcriptase inhibitors) to control their HIV, and subsequently treat them for HCV as they would their HIV-negative patients.

There is, however, incomplete data on coinfected patients treated with IFN. All coinfected patients were excluded from every study discussed in this chapter. Most treatment studies conducted in coinfected patients over the past eight years have been non-randomized pilot/safety trials using different response criteria, IFN doses, and treatment durations. The largest IFN coinfection treatment study published to date enrolled a total of 119 patients (90 HIV-positive patients and 29 HIV-negative controls) (Sorriano 1996).

Only a handful of coinfection studies using IFN/RBV combination therapy have been conducted. They have been small safety studies and mostly presented as conference abstracts. Weisz and colleagues from New York conducted a small, 21-patient coinfection study to determine if combination therapy with IFN and RBV was safe and more effective than IFN monotherapy in HIV-positive individuals with HCV. The results looked promising for those in the combination group, however, it is unclear whether combination therapy was better than IFN alone in this study because patients were unevenly randomized into the two treatment arms. What can be said about the combination of IFN and RBV is that it appears safe in people with HIV who are also on potent antiretroviral therapy. The side effects, such as depression, flu-like symptoms and anemia were no more prominent in the combination therapy group than in the IFN monotherapy group.

Conclusion
Less than 50% of individuals with HCV on treatment today are able to clear their HCV virus. The ability to clear virus on IFN and RBV varies according to genotype and baseline HCV RNA level (viral load): those with low HCV RNA (< 2 million copies/mL) and genotype non-1 have an ~65% chance of a virologic sustained response (SR), while those with high baseline HCV RNA and genotype 1 achieve only an ~27% chance of a virologic SR.

Further research is needed to better understand the clinical significance of a long-term virologic response and its impact on liver disease progression, hepatocellular carcinoma, and mortality. For some HCV patients, combination therapy may be a "cure," but for the vast majority, more effective and less toxic therapies are needed.

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Experimental Treatments and
New Areas of Research for Hepatitis C Virus (HCV) Infection
by Michael Marco

Introduction: A Plea for More Effective and Less Toxic Therapies
After approximately ten years of experience with interferon (IFN) monotherapy and two years with combination IFN and ribavirin (RBV), less than 50% of individuals with HCV on treatment today are able to clear their HCV. We have learned that the ability to clear virus on IFN and combination therapy varies according to genotype and baseline HCV RNA (viral load); those with low HCV RNA (<2 million copies/mL) and a non-1 genotype have about a 65% chance of achieving a virologic sustained response (SR), whereas those with high baseline HCV RNA and genotype 1 have only about a 27% chance of similar treatment success (McHutchinson 1998; Poynard 1998). This latter group, with only a 1-in-4 chance of responding to combination therapy, describes the majority of HCV-infected individuals in the U.S. Approximately 75% of HCV-positive individuals have genotype 1 (Alter 1998), and the median HCV RNA viral load observed in recent natural history studies is near 5 million copies/mL (Thomas 2000). Because IFN/RBV-with its myriad constitutional side effects and hematologic toxicities-is certainly not going to benefit a majority of the HCV-positive individuals who need it, new, potent, safe, and effective antiviral agents for the treatment of HCV are badly needed.

The prospects for future treatments for HCV, including targeted HCV antivirals such as protease, helicase, and ribozyme inhibitors, are scientifically rich and exciting. However (and unfortunately), the word "future" must be emphasized because only one of these, a ribozyme inhibitor, has begun clinical trials. Until novel targeted antivirals are available, it is imperative that we improve our standard of care by optimizing the use of our available arsenal.

HCV RNA Viral Kinetics and Optimizing IFN Administration
Current HCV clinical trials continue to search for the optimal way to administer IFN. HCV RNA kinetics data, originally from Neumann and colleagues in 1998, demonstrate that continued and adequate HCV viral suppression is usually not achieved when using 3 MU of IFN three times a week (tiw) (Neumann 1998). HCV production can be as high as 1 x 109 virions (one trillion) per day, and the half-life of HCV is about 2.7 days. When IFN is administered, there is a two-phase decay process. The initial phase gives rise to a rapid decrease and inhibition of HCV RNA production; the second phase involves a slower decay. Viral decay is not always sustained, because the 3-MU dose of IFN appears to block viral production for only approximately 36-48 hours. The virus is able to rebound and replicate for 24-36 hours until the next IFN dose is administered.

Daily dosing of IFN has been suggested as a way of preventing the rebound of HCV viral production. Numerous clinical trials around the world are looking at both daily and higher initial doses of IFN (so-called induction therapy), either alone or in combination with RBV. Gonzales and colleagues recently presented results of a study comparing a four-week high- dose IFN induction regimen to a standard IFN regimen (Gonzales 2000). In this 48-week study, 135 untreated patients were randomized to receive 5 MU of IFN alfa-2b daily for four weeks followed by 5 MU tiw or 5 MU of IFN alfa-2b tiw. Seventy-six percent of the patients had HCV genotype 1, and 23% had stage 3-4 fibrosis. A virologic SR rate was observed in 14 of 67 (21%) patients in the induction group and 13 of 68(19%) controls (P = NS). Virologic SR rates were higher in the non-1 genotype group, yet no significant differences were noted between the treatment arms in the respective genotype groups. A trend toward more adverse events requiring IFN discontinuation was documented in the induction group compared to the standard group (34% vs. 20%; P = 0.08).

Recently presented results from an Austrian study using IFN induction therapy in combination with RBV did not show an improvement in virologic SR rates over what has previously been reported in the literature (Ferenci 2000). In tests of several induction regimens (5 MU, 10 MU, QD or Q2D) no statistically significant differences were documented among the three arms, which averaged a 37% virologic SR rate.

HCV treatment studies have also tested the strategy of using four-week high-dose IFN induction therapy before adding RBV. Two recently presented studies observed no significant differences in virologic ETR between patients who started with IFN monotherapy induction regimens and those who received standard dosing of IFN/RBV (Cheng 2000; Flamm 2000).

While based on elegant kinetics data, studies reveal that using IFN in higher doses and more often than tiw does not achieve any additional clinical antiviral benefit. Nonetheless, research on HCV viral kinetics–and the impact of IFN-is still a new field, and work in this area is considered by many to be crucial for understanding the virus.

Another question yet to be answered is: What is the optimal dose of RBV? Schering has refused to conduct large randomized controlled trials to ascertain if lower doses of RBV-600 or 800 mg-are less toxic than, and as effective as, standard doses. Some researchers contend that Schering has this data (and has even commissioned studies), but will not release the results.

Pegylated Interferons
Pegylated interferons are a formulation of IFN alfa in which IFN has been covalently bonded to polyethylene glycol (PEG). This modification allows for a much longer IFN half-life and a minimized peak-trough ratio. PEG interferons can be administered weekly (instead of tiw with standard IFN) at higher doses that produce improved antiviral activity due to more consistent circulating levels of IFN. Phase III data have recently been presented, and new drug applications (NDAs) submitted to the FDA for two different PEG interferon formulations: Hoffmann-LaRoche's 40 kDa branched pegylated IFN-a--2a (PEG-IFN; Pegasys™) and Schering Plough's 12 kDa branched pegylated IFN-a-2b (PEG-Intron). Clinical study results have been presented at major hepatology meetings but are not yet published. Data on both PEG interferons document that they are superior to standard IFN. Since they have not been tested head-to-head, it is not yet possible to tell which PEG interferon is more effective.

PEG-IFN (Pegasys^™): Hoffmann-LaRoche
Roche conducted a sound and thorough development plan for its PEG-IFN. Four efficacy studies were conducted totaling ~1,600 patients with ~1,000 receiving PEG-IFN. In Roche NV15489, a phase II dose-ranging study conducted by Shiffman and colleagues, a dose of 180 micrograms (mcg) once weekly was determined to be the most effective (Shiffman 1999). The virologic SR rates are listed below:

The 180 mcg dose was chosen for use in the three registrational PEG-IFN studies. The first of these studies was conducted in HCV patients with cirrhosis. Standard dose IFN monotherapy in cirrhotics has been shown to be relatively ineffective in producing sustained virologic suppression (~10%), and its ability to prevent hepatocellular carcinoma (HCC) and improve survival is debatable (Schalm 1997). In light of these data, U.S. and European HCV treatment guidelines do not universally recommend that cirrhotics receive therapy, yet say they "can" or "may" be treated (NIDDK 2000, EASL 1999). Roche was bold and conducted study NV15495, a 271-patient phase II/III trial comparing two doses of PEG-IFN (90 and 180 mcg) with standard IFN therapy for 48 weeks (Heathcote 1999; Ballart 2000). This is the largest prospective randomized study in cirrhotics ever conducted. The baseline demographics and disease characteristics and study results are listed on the next page:

Never before had a prospective, randomized HCV clinical trial in cirrhotics documented a 30% virologic SR or 54% histologic improvement. Likewise, ~34% of PEG-IFN patients who did not achieve a virologic SR had documented histologic improvement. In many patients with cirrhosis, any decrease in histologic activity is needed and welcome. Response rates were not inflated by the 22% of patients with transition to cirrhosis. In fact, in the 180-mcg arm, the cirrhotics achieved a 32% virologic SR compared to 22% in the transition-to-cirrhosis patients.

As impressive as these results appear, there continues to be a marked difference in response rates between those with genotype 1 and non-1. In the 180-mcg arm, the genotype-1 patients achieved a 13% virologic SR compared to 53% in patients with genotype non-1. The response rates, documented in the chart on the next page, are further splayed when analyzed according to good viral prognostic factors (genotype non-1 & HCV RNA <2 million copies/mL) vs. poor viral prognostic factors (genotype 1 & HCV RNA > million):

Roche next conducted U.S. and European phase III randomized controlled trials of PEG-IFN vs. IFN. Study NV15497, the 531-patient phase III European trial, was recently presented by Zeuzem and colleagues (Zeuzem 2000). This study compared PEG-IFN 180 mcg weekly vs. 6 MU tiw of IFN . Baseline demographics and disease characteristics, as well as study results, are detailed below:

When analyzing the results based on genotype and baseline HCV RNA, the sustained responses are markedly different. The chart below details the 72-week virologic SR rates according to patient's genotype and viral load:

A 28% SR on PEG-IFN is the highest response recorded for genotype-1 patients treated with monotherapy and coincidentally identical to the virologic SR in genotype-1 patients on the IFN/RBV arm of the U.S. phase III IFN/RBV registrational study (McHutchinson 1998).

Roche has not publicly released the results of its U.S. phase III trial (study 15496) and will not until the fall. Study 15496 is a three-arm trial of ~650 untreated HCV patients randomized to receive IFN 3 MU, or PEG-IFN at 135 mcg or 180 mcg. Roche submitted its PEG-IFN NDA to the FDA on 22 May 2000. In a press release Roche contends:

In rigorous intent-to-treat analyses of three pivotal clinical studies involving a total of more than 1,400 patients, those treated with 180 mcg. of PEGASYS had overall sustained virologic responses of 35 percent in patients without cirrhosis and 30 percent in patients with cirrhosis. (Roche Press Release, 5/22/00)

Because the press release reveals a 35% virologic SR in non-cirrhotics, it is obvious they are discussing the results of the 180 mcg arms in the two phase III trials. With a 39% virologic SR in the 180-mcg arm of the European study (15497), the SR in ~215 patients in the 180-mcg arm of the U.S. study must be between 28% and 30% to mathematically achieve an overall 35% virologic SR.

The data from the three studies presented demonstrate that PEG-IFN is significantly more effective than IFN (all P-values were < 0.001). For those in whom ribavirin is contraindicated and cannot initiate combination therapy, PEG-IFN is an excellent alternative and will likely be considered first-line for HCV monotherapy.

When FDA approved, PEG-IFN is expected to be used in combination with RBV. Roche only needs to demonstrate superiority over standard IFN in order for initial FDA approval. In expectation of promising results as combination therapy, and out of the desire to compete with Schering for its share of the HCV market, Roche is conducting a series of studies testing PEG- IFN with RBV. Sulkowski and colleagues recently presented 24-week follow-up data on a small, 20-patient open-label study of PEG-IFN plus RBV (Sulkowski 2000). Study NV15800 administered 180 mcg of PEG-IFN plus RBV (1,000-1,200 mg) to 16 genotype-1 patients for 48 weeks and to 4 genotype-2 patients for 24 weeks. Study results are listed below:

Safety Profile of PEG-IFN
PEG-IFN appears to have a similar toxicity profile as conventional IFNs. While PEG-IFN offers more convenient dosing and better efficacy, it does not offer fewer or milder side effects. Included on the next page are the integrated safety data from 604 patients receiving PEG-IFN: 323 on IFN 3 MU, and 261 on IFN 6 MU from four studies: NV15489, NV15495, NV15496, and NV15497:

The genotype-1 patients in the 1.0 and 1.5 mcg/kg PEG-Intron arms achieve only a 14% virologic SR. While it is difficult and unwise to make cross-study comparisons, it is interesting that genotype-1 patients in Roche's European phase III study achieved a 28% virologic SR, exactly twice that achieved in Schering's PEG-Intron trial. The response rate in the 1 mcg/kg arm dropped to 8% for those patients with both genotype 1 and a baseline HCV RNA of >2 million copies/mL.

While not a PEG-Intron registrational study, Schering conducted a small-to-medium-sized multi- armed pharmacokinetics (PK), safety, and "efficacy" (Schering's term) study of three doses of PEG-Intron in combination with three doses of RBV compared to PEG-Intron monotherapy (Glue 1999). In this 72-patient study, it appears that patients received at least six different doses of two treatments: PEG-Intron 0.35 mcg/kg, 0.7 mcg/kg, or 1.4 mcg/kg; alone or in combination with RBV 600 mg, 800 mg, or 1,000-1,200 mg. There were 35 men and 37 women ranging from 20 to 68 years of age, and ~50% were infected with genotype 1. PK results demonstrated that "RBV did not alter the PK profile of PEG-Intron", and "PEG-Intron dose-dependently augmented the antiviral activity of RBV." It is difficult to make anything out of the "efficacy" results, and Schering's Paul Glue, during his presentation, said that there was no difference observed in RBV doses, so results were collapsed. The virologic SR rates listed in the chart below are as Schering presented them:

Schering's PEG-Intron development plan was mediocre in demonstrating the efficacy of the 1.0- mcg/kg dose over IFN. The 1.0-mcg/kg dose, which is planned for marketing, was studied in 297 patients and found to be superior to IFN in its only phase II/III dose-ranging study. In contrast, Roche's PEG-IFN 180-mcg dose was used in ~600 patients and found to be superior to IFN in four separate studies. Nonetheless, on 31 May 2000, the European Union granted approval to Schering's PEG-Intron for treatment of patients with HCV. The PEG-Intron NDA was submitted to the FDA on 23 December 2000, approximately five months ahead of Roche's PEG-IFN. It is expected that both will be eventually approved by FDA, which has 12 months to review the applications. Whether the FDA will approve both pegylated interferon NDAs in the order they were received or at the same time (so as to not show favoritism) is anybody's guess. Nonetheless, PEG-IFN has the distinct advantage (at least in the scientific community) of better-documented efficacy and safety data in HCV patients with and without cirrhosis.

Pegylated IFN-a-2b (PEG-Intron): Schering-Plough
Schering's PEG-Intron is a 12 kDa branched pegylated IFN- -2a; 28 kDa less than Roche's PEG-IFN. The development plan for PEG-Intron was less rigorous than that for PEG-IFN. Instead of conducting a traditional phase II study to identify the appropriate dose, Schering collapsed the phase and made it part of their registrational phase III study. The study, which randomized 1,219 HCV untreated patients to receive three doses of PEG-Intron or IFN for 48 weeks, was recently presented by Trepo and colleagues (Trepo 2000). There were no significant differences in baseline demographics and disease characteristics among the four arms. The mean age was 43 years; 63% were male; 91% were white; 70% had genotype 1; 74% had an HCV RNA of >2 million copies/mL; and 9% had Metavir grade 3 or 4 fibrosis. Virologic SR rates are documented below:

All PEG-Intron arms were found to be significantly more effective at achieving sustained viral suppression than IFN monotherapy. When stratifying by genotype, SR rates decreased by ~40% in genotype-1 patients and doubled for those with non-1. Likewise, the patients with high baseline viral loads (HCV RNA >2 million copies/mL) did significantly worse than those with low viral loads. The chart below documents the virologic SR rates for all arms according to genotype. PEG-Intron 1 mcg/kg is the dose Schering has submitted in its NDA to the FDA.

The NIH's NIDDK recently gave a thumbs-up to Roche when it chose PEG-IFN as the pegylated interferon it will use in the randomized monotherapy phase of its HALT-C trial. The HALT-C trial (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) is a planned eight- year, 28-million-dollar study of 1,350 IFN or IFN/RBV relapsers with stage 3 fibrosis. At nine selected sites, all will be retreated with IFN/RBV for five months. Those patients not achieving a virologic response will be randomized to receive PEG-Intron or no treatment for another ~3 years to determine if continuing antiviral therapy will decrease the incidence of HCC and increase survival.

Interleukins: IL-2, IL-10, and IL-12
Interleukins are cytokines which are responsible for cell-to-cell communication, inflammatory response amplification, and immune response regulation. Cytokines can be produced by multiple cells in the body, including CD4 and CD8 T cells, and macrophages in response to exogenous and endogenous antigens and bacterial products (Peters 1996). Cytokines are polarized, depending on their phenotype, into type 1 and type 2 helper T cells (TH1 and TH2) (Swain 1990; Mosmann 1991). TH1 cells produce IL-2, IFN-gamma, and tumor necrosis factor (TNF) while TH2 cells produce IL-4, IL-6, and IL-10. Individuals who naturally recover from acute HCV infection have been found to have a strong TH1 response (Diepolder 1995); however, progressive liver disease in chronic HCV has been correlated with an increased intrahepatic expression of TH1cytokines (Napoli 1996).

Recombinant IL-2 has been studied in patients with chronic HBV and HCV in the hope that IL-2 can shift T-cell responses towards a predominantly T_H1-like phenotype and thus facilitate clearing of virus without being necroinflammatory. In a 1993 pilot study, recombinant IL-2 (rIL- 2) demonstrated immunomodulatory and antiviral activity in HBV patients (Tilg 1993). RIL-2 was tested a few years later by Pardo and colleagues in 33 IFN-naive HCV patients (Pardo 1997). The 33 patients were randomized to receive three different doses of IL-2 (0.9, 1.8, and 3.6 MU) five times a week for 12 weeks. At 12 weeks, those who responded stopped treatment while non-responders continued with a higher dose of 5.4 MU. Approximately 24% of patients had normalization of their ALT levels at the end of treatment, yet only 8% had an SR on follow- up. No patient's HCV RNA became undetectable, and no histologic improvement was found. Some 24% to 73% of the patients experienced side effects, including flu-like symptoms, nausea, anorexia, and local site irritation.

In mice induced with carbon tetrachloride, IL-10 has been shown to control neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis (Louis 1998). Recombinant human (rHu) IL-10 has demonstrated some activity in HCV patients in two pilot studies. McHutchinson and colleagues conducted a 16-patient pilot study to assess the safety of IL-10 and its ability to normalize ALTs (McHutchinson 1999). Three IFN-naive patients and 13 non-responders received 4 or 8 mcg/kg of IL-10 subcutaneously daily for 28 days. With both IL-10 doses, ALT levels normalized in eight patients at the end of treatment, but returned to pretreatment levels in patients during the four-week follow-up period. There were neither significant increases nor decreases in HCV RNA levels. The only adverse event noted was a transient fall in platelet counts (73,000-63,000) in two patients.

Nelson and colleagues randomized IFN non-responders to receive 4 or 8 mcg/kg of IL-10 for 90 days (Nelson 2000). Nineteen of the 22 patients who completed therapy had a normalization of their ALT levels, yet only four remained normal on follow-up. Hepatic inflamation decreased (>2 decrease in HAI score) in 11 of 22 patients and Ishak fibrosis score decreased in 14 (mean change = 3.6-3.2; P = 0.001). Mild anemia occurred during the first four weeks of therapy in most patients with an average decrease in hemoglobin level of 2.2 g/dl. Side effects, including headache (75%), dry mouth (25%), and insomnia (17%) were more common in the 8 mcg/kg arm.

IL-12, which drives T_H1 responses, has shown minimal antiviral activity in patients with HCV. It is not considered to have a promising future for treating HCV. IL-12 was originally studied for its demonstrated ability to mount an effective cellular response directed towards intracellular pathogens (Scott 1993). In a multinational, Roche-sponsored phase I/II study, Zeuzem and colleagues randomized 60 HCV patients to receive four doses of IL-12 for ten consecutive weeks: 16, 14, 15, and 15 patients at .03, 0.1, 0.25, and 0.5 mcg/kg, respectively (Zeuzem 1999). Mean age was 41 years; 42 patients were male; 24 had previously received IFN; 39 had genotype 1; and median HCV RNA was 480,000 copies/mL.

No patients achieved a virologic end of treatment response, but 20 of the 60 patients did have a >50% decrease in their baseline HCV RNA: 3, 3, 6, and 8 patients on the .03, 0.1, 0.25, and 0.5 mcg/kg doses, respectively. At the end of follow-up, only 5 of 60 patients had a normalization of their ALT levels and significant anti-rHuIL-12 antibody titers were not detectable in any patients. The most common adverse events on IL-12 were: headache (67%); fatigue (32%); rhinitis (28%); fever (28%); and chills (12%). The most frequent laboratory abnormalities were transient decreases in leukocytes in (31 patients; grade I and II) and transient increases in ALT levels (32 patients) and bilirubin (7 patients), most of which returned to baseline.

Because of their limited activity and side-effect profile, cytokines as monotherapy do not appear to be promising for HCV. As adjuvants to HCV antivirals, cytokines may prove to be beneficial. More research will need to be done in this area.

Amantadine (Symmetrel^®; Endo) & Rimantadine (Flumadine^®; Forest)
Amantadine and its analog, rimantadine, are antiviral agents FDA-approved for the treatment and prophylaxis of influenza A virus. Amantadine is also indicated for the treatment of idiopathic Parkinson's disease and drug-induced extrapyramidal reactions (PDR 2000). Both drugs appear to block the viral membrane matrix protein, M2, which plays a central role in virus replication and assembly (Duff 1992). In a recently published in vitro study, amantadine and rimantadine were shown to have no direct inhibitory effects against HCV viral protease, helicase, ATPase, polymerase, and internal ribosomal entry site-mediated translation (Jubin 2000).

In a 1997 pilot study, amantadine monotherapy demonstrated improvement in biochemical and virologic markers for some patient with HCV (Smith 1997). Two later clinical studies of amantadine monotherapy failed to support HCV antiviral effects shown previously (Lynch 1998; Senturk 1998). Results have been mixed in amantadine combination therapy studies. Khalili and colleagues randomized 29 IFN non-responders to receive IFN/RBV (N = 14) or IFN plus amantadine for 24 weeks (Khalili 2000). At the end of follow-up, 2 of 13 (15%) patients on IFN/RBV compared to none of the IFN plus amantadine patients achieved a virologic and biochemical SR. In an Italian triple-combination therapy study, Brillanti and colleagues randomized 20 IFN non-responders to receive IFN/RBV or IFN/RBV plus amantadine for 24 weeks (Brillanti 1999). At the end of the 24 week follow-up period, one of the dual therapy patients had a biochemical SR compared to four triple-therapy patients. Virological SR was achieved in none of the dual-therapy patients and in three on triple therapy.

Amantadine is not without its side effects. Two of 22 (9%) had to discontinue therapy due to cardiovascular adverse events in the original monotherapy study. In other HCV amantadine studies, cardiovascular side effects were only 0.1% to 1% (Younossi 1999). Central nervous system and psychiatric side effects (headache, depression, psychosis, and convulsions) have averaged <5%. Other side effects observed include nausea, vomiting, and diarrhea (5-10%).

Rimantadine monotherapy has proven poor as a treatment for HCV. In two recently published pilot studies (one in IFN non-responders, the other in liver-transplant recipients), no patients achieved a biochemical or virologic response (Fong 1999; Sherman 1999).

It is apparent that neither amantadine nor rimantadine is effective as monotherapy. Because the studies have been so small, there is little that can be said about amantadine's effectiveness in combination therapy regimens. Nevertheless, amantadine in combination with IFN/RBV warrants further investigation in larger studies of untreated and pretreated HCV patients.

Agents in Preclinical and Early-stage Clinical Development

IMPDH Inhibitor: VX-497 (Vertex)
Inosine monophosphate dehydrogenase (IMPDH) is a cellular enzyme that is essential for production of guanine nucleotides, the building blocks of RNA and DNA. Inhibiting IMPDH and thus stopping nucleotide synthesis may be effective in blocking the growth of lymphocytes and virus replication. Ribavirin (RBV) is an IMPDH inhibitor and FDA-approved for the treatment of respiratory syncytial virus infection (in an aerosol) and orally in combination with IFN for treating HCV (PDR 2000). In early HCV studies, RBV monotherapy was shown to decrease ALT levels, yet it had no HCV antiviral activity (Bodenheimer 1997). While it has a synergistic effect with IFN, its exact mechanism of action remains incompletely understood.

VX-497, a new oral antiviral, is a potent IMPDH inhibitor. In vitro studies suggest that VX-497 has increased synergy with IFN and greater activity than that of RBV against DNA and RNA viruses, including HBV, respiratory syncytial virus, and bovine diarrhea virus (Markland 1999). A phase II randomized double-blind placebo-controlled study investigating the PK, safety and antiviral activity of VX-497 was recently presented by Wright and colleagues (Wright 1999). Thirty IFN non-responders were randomized to receive VX-497 at doses of 100, 200, or 400 mg every eight hours or placebo for 28 days. The 200- and 400-mg doses, but not the 100-mg dose, had a mean reduction in ALT levels of 25% and 21%, respectively, compared to placebo (P = 0.01 & 0.04). No significant change in HCV RNA was observed. Studies of VX-497 in combination with IFN are currently being conducted.

Hammerhead Ribozymes: LY466700 (Ribozyme Pharmaceuticals & Eli Lilly)
Ribozymes (ribonucleic acid enzymes) are catalytic RNA molecules that are synthetically engineered to act as molecular scissors capable of cleaving specific RNA sequences. Hammerhead ribozymes contain a conserved catalytic site flanked by engineered antisense sequences which mediate site-specific binding to the target RNA. By cleaving a highly conserved region of the HCV gene (cutting the HCV), the virus is unable to produce more virus, then dies.

Ribozyme Pharmaceuticals, under the direction of Lawrence Blatt (the wunderkind who shepherded Amgen's Infergen through its FDA approval) has developed LY 466700, a nuclease resistant hammerhead ribozyme targeting the 5' untranslated region (UTR) of the HCV genome at site 195. In female C57/B16 mice, the labeled ribozyme is retained in hepatocytes and endothelial cells lining the sinusoid (Lee 1999). It has been shown to inhibit (>90%) replication of a HCV 5' UTR-poliovirus chimera in cell culture (Macejak 2000). A single-dose safety study of LY 466700 was just completed in healthy normals, and additional clinical studies, including PK, safety, and combination therapy trials with IFN are being planned.

Histamine Dihydrochloride (Maxamine, Maxim Pharmaceutical)
Histamine dihydrochloride (Maxamine) is an experimental agent that inhibits phagocyte-derived oxidative stress and inflamation. It is used as an adjunct to cytokine therapy, namely IL-2, as an experimental treatment for metastatic malignant melanoma and acute myelogenous leukemia (AML). Maxamine in combination with IL-2 was found to be more effective than IL-2 alone in a recent phase III malignant melanoma study. In February 2000, the FDA granted Maxim Pharmaceuticals orphan drug status for Maxamine as an adjunct to cytokine therapy for the treatment of metastatic malignant melanoma. An NDA for Maxamine as an adjunct to IL-2 will be filed in the summer of 2000.

Maxamine in combination with IFN is also being studied in HCV patients. A 12-week interim analysis of a phase II dose-ranging study of Maxamine plus IFN was recently presented by Lurie and colleagues (Lurie 2000). One hundred twenty-nine IFN-naive patients were randomized to receive 3, 5, 6, or 10 mg subcutaneously daily plus 3 MU of IFN tiw. All patients received 12 weeks of therapy, and those responding will continue treatment for an additional 36 weeks. Mean age of patients was 30 years; mean HCV RNA level was 6.7 million copies/mL, and 47% had genotype 1. After 12 weeks on therapy, 53-83% of all patients became undetectable (< 1,000 copies of RNA). In those with genotype 1 and high viral loads, 48–77% achieved a virologic response. Side effects included flushing, headache, hypotension, and increased heart rate. Not much can be said about Maxamine until the 72-week data are analyzed. Nonetheless, the company is already planning studies of Maxamine in combination with IFN/RBV.

Antisense Oglionucleotides
Antisense oglionucleotides are designed to bind to specific sequences in the viral RNA, resulting in RNA-RNA hybrids that stop RNA replication, reverse transcription, or mRNA translation (Davis 1999). A number of recent in vitro studies have shown that specific antisense oglionucleotides can successfully inhibit translation of HCV RNA (Alt 1999; Brown-Driver 1999; Wakita 1999). All are in preclinical development. Hepatologist Gary Davis urges caution about the use of antisense oglionucleotides in humans. He writes:

The major drawbacks of antisense oglionucleotides relate to the potential for non-antisense effects, such as destruction of untargetted cellular mRNA, and inappropriate activation of cellular enzymes (2'5' oligoadenylated sythetase, protein kinases, endonuclease RNase L) and upregulation of interferon production of double-stranded RNA in uninfected cells. (Davis 1999)

Inhibition of Viral Replication by Enzyme Inhibition: HCV Protease & Helicase Inhibitors
In 1996, the three-dimensional X-ray crystal structure of the HCV NS3 protease domain was solved by Kim and colleagues from Vertex Pharmaceuticals and Love and colleagues from Agouron Pharmaceuticals (Kim 1996; Love 1996). This was exciting news, and there were high hopes for a potent HCV protease inhibitor that would do for people with HCV what HIV protease inhibitors had for people with HIV/AIDS. Four years later, no company has yet identified a compound that is nearing studies in humans. Many companies, including Schering, Gilead, Roche, Glaxo Wellcome, Merck, Boehringer Ingelheim, and Chiron are believed to be working on identifying an HCV serine protease and/or helicase inhibitor. There are at least three major reasons why research development in this area has been so slow: 1) the lack of reliable and efficient cell culture systems; 2) the lack of a small-animal model (the only animal model is the chimpanzee); and 3) heinous lawsuits from Chiron over patent infringement of HCV technology. According to John Cohen from Science,

The lawsuits involving HCV drug R&D center on efforts to find drugs that block the viral protease enzyme, on which Chiron holds patents. The company [Chiron], arguing that its competitors need this enzyme to screen for compounds that inhibit it, filed suit against Agouron, Gilead, and collaborators Vertex and Eli Lilly to try to force them to pay licensing fees and then royalties if one of their protease inhibitors goes to market. (Cohen 1999)

These patent lawsuits also cover development of an HCV helicase inhibitor. The three- dimensional X-ray crystal structure of the HCV helicase was first solved by Yao and colleagues from Schering in 1997 and later by Kim and colleagues from Vertex in 1998 (Yao 1997; Kim 1998). The lawsuits have not prevented researchers from screening numerous compounds. No one will speak publicly about their development plans for protease or helicase inhibitors or even mention particulars about the lawsuits. One high-profile chemist I recently spoke with was reticent to give me much pertinent information on his company's protease inhibitor drug discovery effort, but when asked if he was bothered that the lawyers were making more money than he was, he laughed, and said, "Yes."

Progress on the vaccine front is also very slow. The EASL Guidelines committee sadly conclude that "A traditional vaccine is unlikely to become available in th