The Burden of Disease and the Evolving Landscape in Hepatitis C Therapy (REALLY LONG)

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The Burden of Disease and the Evolving Landscape in Hepatitis C Therapy

Introduction: Prevalence and Incidence

Chronic active hepatitis C is currently a leading worldwide cause of liver-related morbidity and mortality. Globally, 3% of the population, or 170 million people, are infected with this bloodborne infection,[1] including nearly 5 million in the United States, 85% of whom have chronic disease.[2-4]

Prevalence

Before measures were implemented to screen for the hepatitis C virus (HCV), thousands of individuals were exposed. Initially, US estimates of HCV prevalence were based on data obtained from the Third National Health and Nutrition Examination Survey (NHANES III) which sampled 21,000 noninstitutionalized civilian people between 1988 and 1994;[5] 1.8% of this population had antibodies to HCV and 74% had detectable HCV RNA.[5] These numbers, when projected to the entire US population, suggested that nearly 4 million individuals in the United States were infected. These data also identified demographic, ethnic, and geographic variations. Non-Hispanic blacks and men were most likely to have been exposed, and 65% of all HCV antibody-positive persons were between the ages of 30 and 49 years. It is now known that this survey of the general population severely underestimated the actual disease prevalence because it excluded several populations with known high-risk behaviors. A survey of 1032 outpatient veterans found that 18% had evidence of HCV exposure,[6] whereas in a screening of homeless veterans, 40% were found to have evidence of HCV exposure.[7] Screening in the prison systems has shown even higher rates of HCV exposure, with a prevalence of 39% among 6536 male inmates and 54% among 977 female inmates in the California correction system.[8] Although a current accurate prevalence estimate does not exist, it is likely higher than the 1.8% suggested by the NHANES data or the 1.6% estimated by a more recent 1999-2002 population survey (Table 1).[2]

Table 1. Incidence and Prevalence of HCV Infection by Specific Population[2,5,82,83]

Rate of New Cases of HCV/Year (Incidence)*

Total Population With Anti-HCV (Prevalence) 1994

Total Population With Anti-HCV (Prevalence) 2002

Most Prevalent Age Range (1994)

Most Prevalent Age Range (2002)

Metabolic Syndrome Prevalence

US: total general population

1992: 2.4/100,0002005: 0.2/100,000

1.8%

1.6%

3.9% 30-39 yrs

4.3% 40-49 yrs

21.8%

Non-Hispanic whites

****

1.5%

1.5

3.2% 30-39 yrs

3.8% 40-49 yrs

23.8%

Non-Hispanic blacks

****

3.2

3.0

6.3% 40-49 yrs

9.4% 40-49 yrs

21.6%

Hispanic

****

2.1***

1.3***

6.0% 50-59 yrs

** 50-59 yrs in men

31.9%

Male

0.26/100,000

2.5

2.1

**40-49 yrs

24%

Female

0.21/100,000

1.2

1.1

**40-49 yrs

23.4%

*2005 unless otherwise specified** Data presented in table form; prevalence not quantified in article***Peak in prevalence among Mexican Americans 50-59 years may not reflect true prevalence due to the small numbers of subjects in this age group, and also likely explains the discrepancy between the 1994 and 2002 reports****Incidence not quantified; article states no significant difference between ethnicities

Incidence

After the identification of the virus in 1989 and the recognition of potential risk factors for exposure, implementation of universal precautions, screening of blood products, and educational and needle-exchange programs led to a dramatic decrease in the incidence of hepatitis C. The Centers for Disease Control and Prevention estimates that the annual incidence of acute HCV infection has decreased from 240,000 new cases per year in the United States in the 1980s to 26,000 in 2004.[4]

This decrease in disease acquisition will unfortunately not translate to a decrease in disease burden for decades. In most individuals, the disease is clinically silent, remaining unrecognized for 20 years or more while significant hepatic injury occurs, resulting in clinical manifestations. Thus, although the prevalence of HCV infection peaked in the 1990s, the prevalence of liver disease caused by HCV is not expected to peak until after the year 2030 and to plateau around 2040.[9]

Natural History

As indicated previously, hepatitis C is a major public health problem. It is currently both the leading cause of liver disease-related death and the most common indication for liver transplantation in the United States.[9-12] Hepatitis C is also one of the leading causes of hepatocellular carcinoma (HCC). A population-based study of cancer epidemiology (the Surveillance, Epidemiology and End-Results [sEER] program) has revealed that over the last 10 years in the United States, the incidence of liver cancer has increased more than that of any other malignancy, with HCV directly responsible for the majority of cases.[13] This increase is also expected to continue to rise as the burden of HCV-related disease increases.[14]

HCC risk is highest in individuals with HCV infection and cirrhosis, with estimates of annual incidence ranging between 1% and 7%.[15,16] However, not every patient chronically infected with HCV develops significant fibrosis. A retrospective study of chronic hepatitis C acquired through blood transfusion found that the mean time to the onset of cirrhosis was 18 years after exposure.[17] It has been postulated that approximately 20% of HCV-infected patients develop cirrhosis after 20 years.[18] Male sex, older age at acquisition (> 40 years), concomitant daily alcohol consumption (≥ 50 g per day), and HIV or HBV coinfection independently increase the risk for disease progression.[19,20] Studies also suggest that the degree of hepatic inflammation determines the development of fibrosis. One study found that up to one third of HCV-infected patients had severe hepatic inflammation on biopsy and thus risk rapid progression to cirrhosis in 20-30 years, whereas those with mild disease on liver biopsy did not develop the same degree of fibrosis over the same time interval.[21] Another study by Yano and colleagues[22] found that aggressive histology was associated with a 50% chance of progression to cirrhosis in less than 10 years.

The rate of fibrosis progression is not necessarily linear, with documented cases of mild stable histology followed by rapid accelerated progression. Poynard and colleagues[20] applied mathematic modeling to a large cross-sectional study of HCV-infected patients with known histology. They found that after acquiring disease, fibrosis did progress linearly but at different rates over different time periods. There was minimal progression during the first 10 years after infection, although disease progression accelerated during each subsequent decade, with the most rapid phase occurring in the last 5 of 40 years.[20] Disease was significantly more virulent in those patients who acquired hepatitis C after the age of 50. Once acquired, cirrhosis is generally well tolerated, with excellent survival until symptoms of decompensation begin to occur. This may include the onset of ascites, muscle wasting, variceal bleeding, cholestasis, coagulopathy, and encephalopathy. Approximately 4% of compensated cirrhotic patients decompensate per year, and this drastically affects survival. Once complications arise there is more than a 50% chance of succumbing to disease manifestations within 5 years.[23]

Clinical decisions, including the selection of patients to receive therapy for viral hepatitis, require appraisal of both therapeutic risk and benefit. Current American Association for the Study of Liver Diseases guidelines state that treatment is widely accepted for adults (at least 18 years of age) with an abnormal ALT and well-compensated liver disease in whom liver biopsy demonstrates significant fibrosis, defined as more than portal fibrosis (Metavir score ≥ 2; Ishak score ≥ 3). Uncontrolled depression, organ transplantation, autoimmune disease including autoimmune hepatitis, severe concurrent disease, pregnancy, and untreated hyperthyroidism are therapeutic contraindications. Individuals falling outside of these parameters should be considered for treatment on a case-by-case basis.[24]

Current Treatment Paradigm

The goal of treatment is to prevent disease complications. This is best accomplished through disease eradication, defined as sustained virologic response (SVR; undetectable HCV RNA by a sensitive polymerase chain reaction [PCR]-based assay 24 weeks after discontinuation of treatment). Therapeutic options for hepatitis C have changed significantly since the introduction of interferon monotherapy. The current standard of care is combination pegylated interferon (PEG) and weight-based ribavirin (RBV). This regimen doubled the SVR compared with interferon monotherapy, but still leaves much to be desired. Three pivotal trials helped determine the optimal dose and duration of these drugs.[25-27] These trials also established the differences in therapeutic efficacy of this regimen for treating patients infected with HCV genotype 1 vs HCV genotypes 2 and 3. Overall, 42% to 46% of patients infected with HCV genotype 1 achieve an SVR with 48 weeks of treatment with the current standard of care, whereas 76% to 82% of patients infected with genotype 2 or 3 respond with only 24 weeks of PEG-RBV.[25-27] Additionally, baseline patient characteristics can increase pretreatment predictions for response. Genotype 1, high viral load (greater than approx. 400,000 IU/mL), increasing fibrosis, male sex, African-derived race, age over 40, insulin resistance, hepatic steatosis, renal failure, and high body mass index (BMI) portend suboptimal outcome.[28,29] The expectation of achieving an SVR in some of these subgroups is less than 20%.[28,29]

Monitoring of On-Treatment Response

In the majority of patients, PEG-RBV therapy is associated with side effects (flu-like symptoms, hemolytic anemia, irritability, and depression), some of which may result in dose adjustments or discontinuation. It would be ideal to administer the appropriate amount of medication for the shortest effective duration to minimize toxicity. Integral to this strategy is the ability to recognize patients who are most likely to respond as well as those who are least likely to respond, so that adherence can be encouraged or treatment can be stopped.

End-of-treatment response (EOTR; defined as undetectable virus by PCR at the end of a full therapeutic course) is essential but does not predict SVR, as patients may still relapse. The first recognized litmus test for on-treatment response was early virologic response (EVR; defined as at least a 2-log decline over baseline in viral burden at treatment week 12). This measure is the most accurate predictor of not achieving an SVR (ie, a negative predictor of SVR).[26,30,31] Treatment is discontinued in patients who do not meet this treatment goal, as expectations for SVR are essentially zero. Rapid virologic response (RVR; defined as undetectable HCV RNA by sensitive PCR-based assay at treatment week 4) was found to be a highly accurate predictor of SVR but a very poor negative predictor.[32,33] RVR may also help guide treatment duration. In the post-hoc analysis, 24% of genotype 1 patients in the 24-week treatment arms attained RVR, of which 89% also achieved SVR.[33] Most genotype 2 and 3 patients respond well to treatment with the current standard of care, as reflected by the high SVR rates seen in studies. It is becoming increasingly apparent that predictive rules will also apply to these more favorable patient subsets. Genotype 2/3 patients who achieve RVR may also be able to truncate therapy, albeit at an increased risk for relapse. Several studies suggest that short-course (12-16 weeks) therapy is highly effective, with 79% to 85% of patients with HCV genotype 2 or 3 achieving SVR. Relapse rates varied between 10% and 12%.[34-38] More important, those genotype 2/3 patients who do not achieve RVR are at higher risk for suboptimal response. These same trials confirmed that patients who did not have RVR reached SVR only 36% to 64% of the time, despite standard 24-week treatment.[35,37]

Nonresponse

Nonresponders (defined as less than a 2-log decline in viral load at week 12 of treatment with the current standard of care [PEG-RBV]) comprise approximately 30% of all treated patients and encompass the greatest treatment challenge. At this time, options are extremely limited for this patient subgroup. Re-treatment with PEG-RBV results in an SVR in less than 5% of patients, and is thus not advocated unless the first treatment course was compromised by suboptimal drug dosing or nonadherence.[39] This was further validated in the recently presented and highly publicized REPEAT (REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy) study, which enrolled nearly 1000 nonresponders to the current standard of care who were then treated with: (1) higher-dose PEG (360 mcg/week plus RBV for the first 12 weeks followed by PEG-RBV for 36 weeks); (2) longer-duration therapy (PEG 180 mcg/week plus RBV 1000/1200 for 72 weeks); (3) both higher-dose PEG and longer-duration therapy (PEG 360 mcg/week +RBV for 12 weeks followed by PEG-RBV for 60 weeks); or (4) repeat standard of care. Although 28% to 33% of patients achieved EOTR, only 7% to 16% achieved SVR.[40] In the nonresponder population, the outcome achieved by treatment with consensus interferon (currently licensed for the treatment of naive HCV infection) with RBV has also been disappointing. The recent DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial reported SVR in only 2% to 11% of null responders (those who failed to reduce their viral load by more than 1 log at 12 weeks).[41] As will be addressed later in this clinical review, future treatment options for this subset are also less likely to offer benefit and may even compromise the efficacy of other forthcoming therapies.

Liver Transplantation

Liver transplantation is the best option for an individual with hepatic decompensation due to end-stage liver disease or early HCC. Currently there are 17,227 people actively waiting for approximately 7000 expected deceased liver donations per year.[42] Hepatitis C is already the most common indication for liver transplantation. If projections are correct, the number of new patients with cirrhosis may double by the year 2020.[9] Obviously, this increased burden will be impossible to meet given an already limited supply of organs. In addition, hepatitis C universally recurs post transplant for HCV infection, with reinfection at the time of hepatic reperfusion.[43] By the fourth day post transplant, the viral load has reached pretransplant levels, peaking 1-3 months after surgery at levels that are frequently 10-100 times greater than the original baseline.[44]

Although not predictable, posttransplant hepatitis C is generally more cytotoxic, with the median interval from hepatic replacement to development of cirrhosis of only 10 years.[45] Thirty percent of patients will develop cirrhosis 5 years after transplantation, and the time to manifesting symptoms of decompensation and death is significantly shorter than in immunocompetent hosts.[46] Up to one fourth of patients transplanted with hepatitis C will die or require retransplantation within 5 years.[47] Ideally, HCV should be eradicated prior to transplantation. However, very few patients are able to tolerate the therapy without dose reductions or interruptions, and therefore few clear virus or achieve SVR. By carefully selecting a subset of pretransplant patients with stable cirrhosis and initiating low-dose therapy with subsequent dose escalation, investigators from the University of Colorado were able to achieve SVR in only 22% of a heterogeneous group of treated individuals.[48] HCV genotype 2/3 and the ability to tolerate full-dose therapy were associated with a more favorable response. These patients also remained virus-free after transplant.[48]

Statistically, the majority of individuals with HCV infection awaiting orthotopic liver transplantation will not tolerate therapy with the current standard of care or achieve SVR if treated. As expected, HCV treatment after liver replacement is just as challenging as pretransplant treatment. Several strategies exist for management of HCV post transplantation. Some advocate for preemptive HCV therapy as soon as the patient is clinically able to tolerate treatment. Ideally, this would eliminate disease while the viral load is still low and prior to histologic damage. Unfortunately, therapy immediately post liver transplant is poorly tolerated, with only 10% to 25% achieving SVR.[49] Few would debate that those patients with recurrent disease and evidence of at least stage 2 fibrosis should be considered for combination PEG-RBV therapy. This approach post transplant is particularly challenging because it requires serial protocol liver biopsies to identify patients with progressive fibrosis, and results remain suboptimal, with SVR rates ranging between 9% and 45% in case series.[50] Although therapy was tolerated poorly, these investigations failed to demonstrate any increased risk for cellular rejection, which is a theoretical concern with immune-modulating interferon-based therapy.[46]

Evolving Therapeutic Options: New Strategies With "Old" Drugs**

Given the limitations associated with the current standard-of-care therapy for HCV infection, the development of novel therapeutic strategies is paramount. Numerous compounds are in development but remain elusive to the practitioner outside of highly regulated research trials. This has resulted in even more creative use of our available agents and a more critical appraisal of our patients.

Old Drugs New Ways: "À la Carte"

As evidenced by the importance of baseline patient and viral factors as well as the various on-treatment "mile markers," not all patients are identical. Thus, it is logical that therapy should be tailored to the individual. Treatment dose and duration are already modified by HCV genotype, but it is likely that other factors will also play a prominent role in transforming choices to achieve optimal outcomes. The recent recognition of the importance of complete EVR (cEVR; defined as aviremic by sensitive PCR-based assay at week 12) supports the concept of "à la carte" therapy or treatment tailored to the individual. Ad-hoc analysis of the PEG-RBV registration trials confirmed that 74% of patients with cEVR achieved an SVR, whereas SVR was reached by only 16% of those patients with at least a 2-log decline in viral load but residual viremia (EVR).[51] Other studies also support these findings and further suggest that without cEVR, significantly fewer patients achieve EOTR. Of those who attain EOTR, there is a relapse rate as high as 50% to 79%.[52] Considering viral kinetics, it seems rational that patients who clear virus later in their treatment course receive less consolidation therapy or less drug exposure after the virus is undetectable.

The next reasonable step is to treat slow responders with extended duration therapy. Unfortunately, this strategy has not proven universally effective. Berg and colleagues[53] randomized 455 genotype 1 patients to 48 vs 72 weeks of PEG coupled with only 800 mg/day of RBV. Treatment duration did not change outcomes, with SVR achieved in 54% and 53% of patients at week 48 and 72, respectively. However, these patients were randomized a priori, not by achieved response. The TeraViC-4 study enrolled 510 mixed genotype HCV-infected patients and randomized them by their response at 4 weeks. Those who still had detectable virus (no RVR) received either 72 weeks, or the standard 48 weeks, of treatment with PEG + RBV 800 mg/day. Although EOTR was identical at 61%, relapse was more common with the shorter-duration therapy. In the final analysis, the 72-week arm did significantly better, with an SVR rate of 45% compared with only 32% in the 48-week arm. The 48-week arm had a 48% relapse rate (vs 26% after 72 weeks).[54] This high degree of relapse in both arms likely reflects suboptimal RBV dosing, as data presented at the 2007 American Association for the Study of the Liver meeting support significantly less relapse and thus higher SVRs with 72-week extended therapy in slow responders.[55]

Dose modifications may also increase anticipated SVR rates. It is well established that patients with a BMI > 30 kg/m2 are significantly less likely to achieve an SVR when compared with normal or mildly overweight patients.[56] These patients are also at an increased risk for liver disease compared with nonobese patients.[57] Thus, strategies to improve therapeutic outcomes are highly desired. The importance of weight-based RBV dosing is already well established, but the dose plateaus at an upper limit of 1200 mg/day for all patients > 75 kg. PEG-2b is also dosed by body weight: 1.5 mcg/kg/week subcutaneous; but again, the dose peaks at 150 mcg total. Patients who weigh ≥ 100 kg receive the same amount of drug, thus no longer making the dosing truly weight-based in the obese patient. PEG-2a is administered at a fixed dose of 180 mcg/week as a consequence of its large volume of distribution, but this regimen is also less effective in obese patients.[57] SVR can be increased in the obese patient by increasing the RBV dose.

The WIN-R (Weight-Based Dosing of Interferon and Ribavirin) trial was designed to compare the efficacy and safety of flat-dose RBV (800 mg/day) vs weight-based RBV dosing (800-1400 mg/day), both given in combination with PEG.[58] son and colleagues[59] analyzed a subgroup of the WIN-R trial that included 51 severely obese patients weighing at least 125 kg. They found that the outcomes for severely obese patients receiving weight-based (1400 mg/day) RBV were significantly better than for those who received fixed-dose regimens, and that the SVR was then comparable to those who weighed < 125 kg. Fried and colleagues[60] further clarified these dosing controversies by investigating 188 obese high viral load genotype 1 treatment-naive HCV-infected participants. These patients were stratified into 4 treatment groups: standard of care (PEG-2a 180 mcg/week + RBV 1200 mg/day); standard dose 180 mcg PEG-2a with high-dose RBV (1600 mg/day); high-dose PEG-2a (270 mcg/week) + standard dose RBV (1200 mg/day); or high-dose PEG-2a with high-dose RBV. They found that although increasing either the dose of PEG-2a or RBV resulted in a greater reduction in HCV RNA over the first 4 weeks, this effect did not translate into significantly improved EVR. The greatest benefit occurred when PEG-2a and RBV were both given at higher doses -- increasing SVR (46.8% vs 28.3% for standard of care) and RVR over standard (RVR: 2.2% for the 180/1200 regimen, 8.5% for the 180/1600 regimen, 10.6% for 270/1200 regimen, 12.8% for the 270/1600 regimen) dosing as well as decreasing the risk for relapse (19% vs 40% for standard of care). Intensified treatment was associated with more therapy-related side effects as well as treatment withdrawals.[60]

Other investigators have looked at intensified regimens in other HCV-infected populations. A small pilot study involving 10 genotype 1 treatment-naive patients with high viral load treated with PEG and individually titrated RBV dosing to a steady-state concentration of > 15 mcmol/L suggested that high-dose RBV (mean daily dose of 2540 mg) was highly effective. Nine of 10 patients achieved an SVR, although serious side effects were frequent. Despite routine use of growth factors, 20% experienced a decline in hemoglobin to < 8 g/dL and required red blood cell transfusion.[61] This approach is also difficult, as the ability to measure RBV concentration is not routinely available in most laboratories. Both the RENEW (RE-treatment of Non-responders with Escalating Weight-based Therapy) and REPEAT studies suggest that previous suboptimal responders may have improved outcomes with higher dosing of PEG, but again, with more side effects.[40,62]

Old Drugs, Unsuccessful Ways

With the anticipated increase in disease burden as the HCV-infected population ages, strategies to delay disease progression are highly attractive, especially for those patients with significant fibrosis who have failed to achieve an SVR with the current standard of care, PEG-RBV. Unfortunately, the results of the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial do not support the use of long-term low-dose antiviral therapy or maintenance therapy. In this study, 1050 chronically HCV-infected patients with advanced fibrosis and previous nonresponse to PEG-RBV were recruited to receive long-term low-dose (90 mcg/week) PEG-2a (without RBV) vs no treatment. There was no difference in the risk for death, hepatic decompensation, the development of HCC, or fibrosis progression among patients who were treated vs not treated.[63] Further subanalysis of this patient cohort may reveal a subset for which this strategy is beneficial; however, at this time, long-term maintenance therapy with PEG-2a is not clinically justified in HCV-infected individuals with advanced fibrosis who do not respond to a prior course of PEG-RBV.

Evolving Therapeutic Options: New Agents

Given the multitude of patients who need effective HCV therapy, research and development have yielded several attractive molecules that are likely to transform current practice. Unlike interferon, which acts primarily through host immune modulation, the focus of these new therapeutic strategies has been on the development of oral antivirals -- the so-called Specifically Targeted Antiviral Therapies for HCV (STAT-C) agents. These drugs are based on the model of antiretroviral therapy for HIV infection, targeting specific viral enzymes important in the replication of HCV. Two classes of compounds at the forefront of development in this setting are the protease inhibitors and polymerase inhibitors. Although several other treatment strategies are under investigation, such as further modification of interferon, therapeutic vaccinations, and immune manipulation with tiny pieces of interfering RNA, the STAT-C agents are anticipated to temporally be the first to actually affect disease treatment.

Protease Inhibitors

HCV is an enveloped RNA virus; its genome consists of a single-strand, positive-sense piece of RNA with one long open reading frame coding for a large polyprotein that then undergoes cleavage by both host and viral proteases to generate core, structural, and nonstructural (NS) proteins.[64] Several nonstructural proteins, NS2 through NS5, are integral for viral replication. The NS3/NS4A serine protease is essential for replication and is the target of the protease inhibitors. Although several protease inhibitors are in various stages of development, 2 compounds, telaprevir (VX-950) and boceprevir (SCH 503034), have generated considerable excitement as very favorable results from phase 1 and phase 2 trials have been reported.

Telaprevir (VX-950).The lessons learned through the development of telaprevir*, a selective, specific, and potent peptidomimetic inhibitor of the HCV NS3/4A serine protease, are paramount. This agent was initially administered to genotype 1 treatment-naive HCV-infected subjects as a 14-day monotherapy in a phase 1 dose-escalation study.[65] Treatment with telaprevir resulted in dramatic decreases in HCV viral load. The optimal dose, 750 mg every 8 hours, led to a 4- to 4.5-log10 decline in viral load in nearly all patients after 14 days of dosing, with some becoming HCV RNA-undetectable. However, some patients had a rapid decline in viral load followed by viral rebound, offering the first insight into the growing concern of viral resistance.[65]

The efficacy of telaprevir as either monotherapy or in combination with PEG was subsequently assessed in treatment-naive genotype 1 patients without cirrhosis.[66] Again, rapid viral reduction was achieved with telaprevir treatment; this reduction was greatest in the PEG combination (ie, PEG + telaprevir) treatment arm, with a median viral load reduction of 5.5 logs from baseline. Again, some patients receiving telaprevir monotherapy experienced plateau or rebound associated with resistance mutations, and some patients on combination therapy had resistant virus detected, although HCV RNA continued to decline throughout therapy.[66] Even though they are resistant to telaprevir, viral variants remained fully susceptible to subsequent PEG-RBV treatment.[67] The addition of RBV to the combination of PEG and telaprevir offered even more viral suppression. After 28 days of dosing with this triple-therapy regimen, 100% of 12 genotype 1 HCV-infected patients had HCV RNA levels < 10 IU/mL.[68] These data prompted a phase 2 trial of telaprevir given in combination with PEG and RBV (PROVE 1).[69] In this trial, interim analysis found that 88% of patients receiving the triple-combination regimen achieved RVR compared with 16% receiving the current standard of care (ie, PEG + RBV + placebo). However, side effects (primarily pruritus, rash, and gastrointestinal-related) were common and frequently led to treatment discontinuation. Virologic breakthrough was also higher in the telaprevir treatment arms (7% vs 2%), 75% of which occurred in patients who never achieved undetectable HCV RNA.[69] All patients with breakthrough had drug-resistant virus.[70] Among those patients who achieved RVR and discontinued treatment at week 12, two thirds remained HCV RNA-undetectable at week 20 post treatment.[69] However, the SVR rate was superior in patients who received 12 weeks of triple therapy followed by 12 weeks of standard of care (61% compared with 35% in those who received only 12 weeks of triple therapy) primarily due to a difference in relapse rates (Table 2).[70]

Table 2. Summary of PROVE 1 and PROVE 2: Standard of Care vs Telaprevir in Combination With PEG ± RBV for Various Durations in Genotype 1 Treatment-Naive Patients With Hepatitis C[70,71]

PROVE 1

PROVE 2

Response, n(%)

A = SOCN = 8148 weeks

B = TPRN = 8248 weeks

C = TPRN = 8024 weeks

D = TPRN = 2012 weeks

E = SOCN = 8248 weeks

F = TPRN = 8124 weeks

G = TPRN = 8212 weeks

H = TPN = 7812 weeks

SVR

NA

NA

48(61)*

6(35)

NA

65%

59%

29%

EOTR

34(45)

51(65)

NA

NA

RVR

11%

---- 79%----

13%

69%

80%

51%

cEVR

39%

---- 70%----

41%

73%

79%

62%

Resistance/viral breakthrough

2%

---- 6.9%----

1%

---- 2%----

24%

*Interim analysis of all patients (mixed population including early discontinuations) completing 24-week treatmentSOC = standard of care; TPR = telaprevir (TVR)+PEG+RBV; TID = 3 times per day;SVR = sustained virlogic response; EOTR = end-of-treatment response; RVR = rapid virologic response; cEVR = complete early virologic response; PEG = pegylated interferon alfa-2a; RBV = ribavirin; NA = not availableA = standard of care (SOC; PEG2-2a 180 mcg/week + RBV 1000/1200 mg/day for 48 weeks)B = TVR 750 mg TID+PEG+RBV for 12 weeks followed by PEG+RBV for 36 weeksC = TVR 750 mg TID+PEG+RBV for 12 weeks followed by PEG+RBV for 12 weeksD = TVR 750 mg TID+PEG+RBV for 12 weeksE = SOCF = TVR 750 mg TID+PEG+RBV for 12 weeks followed by PEG+RBV for 12 weeksG = TVR 750 mg TID+PEG+RBV for 12 weeksH = TVR 750 mg TID+PEG for 12 weeks

Although data support telaprevir 750 mg every 8 hours as the optimal dose to balance efficacy and side effects, the impact of different combination regimens and the treatment duration are still under investigation. PROVE 2, the European counterpart to PROVE 1, was a phase 2 study of telaprevir in combination with PEG ± RBV in treatment-naive patients with genotype 1 chronic hepatitis C, designed to evaluate the optimal duration of this telaprevir dose in combination with PEG-RBV and to assess the importance of RBV in the treatment paradigm.[71] Genotype 1 treatment-naive subjects were enrolled and randomized into 1 of 4 treatment arms: standard of care (PEG-RBV + placebo) for 48 weeks; triple therapy (telaprevir + PEG + RBV) for 12 weeks followed by 12 weeks of PEG-RBV; triple therapy for 12 weeks; or telaprevir + PEG for 12 weeks. Interim analysis at 36 weeks strongly supported the importance of RBV in the on-treatment antiviral response. Results (Table 2) revealed that among patients in the triple therapy arms, 69% to 80% achieved RVR and 59% to 65% achieved SVR (vs 51% and 29% of patients in the telaprevir + PEG arm who achieved RVR and SVR, respectively).[71] Relapse rates were lower for those patients who received an additional 12 weeks of standard-of-care therapy (PEG-RBV) and were highest for those patients who did not achieve RVR.[71] Certainly, the impact of the addition of RBV on RVR and SVR assure RBV a secure role in future HCV therapy. More important, there was minimal (1%-2%) virologic breakthrough (and therefore viral resistance) in patients in the triple-therapy arms, whereas 24% of patients in the telaprevir + PEG arm experienced breakthrough.[71]

Telaprevir resistance. Four common locations have been identified in the NS3 gene that confer telaprevir resistance: V36, T54, R155, and A156.[72] As expected, a combination of mutations increases the degree of drug resistance by enhancing viral fitness.[72] The first studies involving telaprevir given as monotherapy or in combination with PEG found that for some patients, the viral load would plateau followed by viral rebound.[65,73] Sequencing of the NS3 protease domain in patients who experienced viral breakthrough confirmed selection of virus resistant to telaprevir. Additionally, kinetic studies support the preexistence of telaprevir-resistant-variants that are "uncovered" after the initial decline in wild-type virus.[74] Just as concerning, 3-7 months post treatment, repeat sequencing found that these resistant mutations remained, albeit at lower levels, conferring in-vitro resistance.[73] Follow-up of patients who received subsequent standard-of-care therapy after 2 weeks of telaprevir exposure (both with and without PEG) found that for those patients who relapsed after therapy, the majority continued to have detectable telaprevir resistance mutations.[72]

SCH 503034. SCH 503034 (boceprevir)* is another NS3 serum protease inhibitor. In contrast to the initial investigations with telaprevir, boceprevir was introduced into a prior PEG nonresponder population to assess the safety, antiviral activity, and emergence of resistant strains of this agent when given in combination with PEG.[75] The study design was relatively complicated, with HCV genotype 1 nonresponder patients receiving treatment in 3 stages. Patient subsets received in random sequence: boceprevir monotherapy for 7 days, weight-based PEG-2b for 14 days, or both drugs for 14 days. Crossover among groups occurred between each phase. Boceprevir monotherapy resulted in a less than 3-log decline in viral load in the majority of patients; however, combination treatment (boceprevir + PEG) was significantly more effective, with several patients becoming HCV RNA-negative after 14 days. One patient did develop resistance mutations. Side effects were minimal with boceprevir monotherapy, and in combination were typical of interferon therapy. Results of phase 2 trials of nonresponders and treatment-naive patients are expected to be presented in 2008.

Polymerase Inhibitors

The RNA-dependent RNA polymerase (NS5B) and the 3' end of the infective virus' positive RNA bind to the replication complex, resulting in the synthesis of a complementary negative-strand RNA that serves as a template for the subsequent production of genomic RNA. This process represents an appealing target for antiviral therapy. Recently, investigation of 2 HCV polymerase inhibitors (NM283 and HCV-796) has been halted due to tolerability concerns. Several other compounds in this class are in various stages of development, with patients actively enrolled in phase 2 investigations involving R1626. Given the issues of drug resistance seen with the protease inhibitors, most experts believe that the most effective therapeutic strategies will involve multidrug regimens utilizing PEG-RBV in combination with both protease and polymerase inhibitors.

R1626. R1626* is the prodrug of a nucleoside analogue (R1479) that targets the HCV RNA polymerase. In a phase 1, multicenter, observer-blinded, randomized, placebo-controlled, multiple ascending-dose study, R1626 was administered at doses ranging from 500 mg to 1500 mg twice daily for 14 days in treatment-naive HCV genotype 1 patients.[76] This initial dose-escalation study demonstrated a clinically significant mean 1.2-log decline in HCV RNA with the 1500 mg twice-daily dosing regimen. Additional studies found dose-dependent inhibition, with undetectable HCV RNA, after 15 days in 5 of 9 patients receiving 4500 mg R1626 twice daily. Viral rebound was noted with lower doses of R1626 given as monotherapy, but was not associated with phenotypic or genotypic evidence of resistance.[77] Similar to what has been observed with other STAT-C agents, interim analysis of a 48-week study assessing the efficacy of combination therapy with R1626 + PEG ± RBV in treatment-naive patients with chronic hepatitis C genotype 1 showed that this triple-therapy regimen suppressed virus further: HCV RNA was undetectable at week 4 in 80% of patients treated with triple therapy (using R1626 at a dose of 1500 mg twice daily) vs in only 5% of patients who received the standard of care (PEG + RBV) and in 33% of patients who received the same dose of R1626 (1500 mg twice daily) + PEG but without RBV.[78] R1626 and RBV thus appear to interact synergistically, again emphasizing the continued importance of RBV in the HCV treatment paradigm.

Although this drug is administered only twice daily, therapy was well tolerated in doses only up to 3000 mg twice a day, with headaches, anemia, neutropenia, and gastrointestinal side effects more prevalent at the highest doses. In addition, R1626 is active against all HCV genotypes and subtypes.[78] At this time, no emergence of resistance has been detected, even in patients with virologic rebound.[78] However, R1479 resistance mutations have been identified in vitro as S96T or S96T/N142T.[79] Pretreatment and on-treatment samples from patients who experienced either viral rebound or nonresponse while participating in the R1626 trials failed to demonstrate any R1479 resistance mutations or other common substitutions, suggesting that treatment failure was not due to the emergence or preexistence of drug resistance mutations. In addition, patients with viral rebound while on R1626 tended to have low plasma levels of R1479, likely related to dose reductions.

Evolution of the Treatment Paradigm

To date, every STAT-C agent performs best when given in combination with both PEG and RBV, confirming that these agents will continue to be the backbone of HCV therapy for many years. A new dimension, drug resistance, is rapidly becoming part of the therapeutic dialog. Similar to the case for hepatitis B and HIV, concerns now center on not just resistance to a single agent, but also on whether these mutations will lead to cross-resistance, thus compromising several drugs and potentially drug classes. This is especially important for the first phases of STAT-C integration, which will likely involve the addition of a single agent to the standard of care. The studies discussed in the previous section suggest that mutated virus remains sensitive to interferon-based therapy, but only if a person is innately responsive to interferon. This "safety net" does not exist for interferon nonresponders, and resistant virus may persist for months despite treatment discontinuation. This is a concern for the roughly 20% of genotype 1 HCV-infected patients who are nonresponders to standard of care.

The anticipation of newer agents has created debate regarding which patients should be treated with current standard-of-care therapy and which should be "held" for upcoming compounds. Whereas most clinicians agree that patients with advanced HCV disease should be treated immediately, some advocate delaying treatment for patients with minimal histologic injury. Certainly, the rationale behind this is that HCV is, on average, slowly progressive, and this patient subset has time to wait for a more effective therapy. This approach must be carefully weighed against the disadvantages of delaying treatment. In addition to the underlying risk for disease progression, age is associated with other medical conditions, such as obesity, diabetes, heart disease, anemia, depression, alcohol abuse, and malignancies, all of which have a negative impact on treatment response or indeed on the ability to treat at all. The immune system becomes less responsive to immune manipulation, likely as a result of the blunted immune response that occurs with aging.[81] Patients younger than 40 years are approximately 2.5 times more likely to respond to interferon-based therapies as those over age 40.[25,26] Not only does older age affect response to therapy, but it also results in an immune system less capable of controlling hepatitis C. This may explain in part why persons who acquire HCV infection at an older age statistically have more progressive disease, as well as why an increase in fibrosis rate occurs over the age of 50.[20]

Certain subsets of patients have good baseline prognostic factors, with anticipated SVR rates greater than 80%.[25,27] Some clinicians advocate treating only those patients who have good expected outcomes, yet it is important to remember that on-treatment response (RVR and EVR) is the strongest predictor of SVR, especially for a patient infected with HCV genotype 1. Conversely, others would advocate treating only those persons at very high risk for progression, assuming that this subset has the most to gain from therapy. Certainly, as more effective medications come to market, the pool of patients eligible for treatment should also increase, including those patients with minimal fibrosis. It is this group that has the highest potential for achieving SVR, and thus, from an efficacy standpoint, may be the most appealing population to whom therapy could be offered. The goal of therapy will change as the treatment paradigm evolves, namely transitioning from treating only those patients with significant liver disease to also treating those with viremia who have not yet developed liver disease or comorbidities that negatively affect treatment success.

Conclusion

The disease burden of advanced hepatitis C is projected to sharply increase over the next few decades. Transplantation is one of the best options for patients with decompensating cirrhosis or HCC, yet with the growing disparity between supply and demand, this avenue will not be able to accommodate most patients. The therapeutic horizon for HCV infection is rapidly evolving, offering the hope of multiple new agents. However, these new medications are still a few years away, and will involve a learning curve before effective implementation. There will also be several patient subsets with significant need who may not be initially eligible for these agents outside of highly controlled environments, such as those with decompensated disease, renal failure, coinfection, and organ transplantation. The current standard of care is still a valuable therapeutic modality and should be offered to all treatment-eligible patients using the on-treatment viral kinetic predictors of RVR and EVR to optimize response.[80]