New Therapeutic Developments

After a decade of disappointment with interferon- therapy caused by frequent lack of response or relapse after this therapy is discontinued, specialists who treat patients with chronic hepatitis C have been encouraged in the past year by several pivotal developments. The first of these is the demonstration of the durability of HCV RNA clearance in patients (albeit less than 50%) who respond to 6 to 12 months of interferon- monotherapy [2]. Second, the addition of a nucleoside analogue, ribavirin, to interferon- has been shown to greatly improve the sustained virologic response rate in patients who have never been treated [3, 4] and patients who have had relapse after a course of interferon monotherapy [5]. Consensus interferon, a new synthetic type 1 interferon, is the only drug other than interferon- that is approved by the U.S. Food and Drug Administration for the treatment of chronic hepatitis C, and it may be as helpful as interferon- monotherapy for patients who have had relapse after a course of interferon [6]. Results such as these account for a major change in our perception of the benefits of antiviral therapy for chronic hepatitis C.

The recent National Institutes of Health (NIH) Consensus Development Conference solidified an approach to the treatment of hepatitis C and gave us a road map with which to navigate the myriad therapeutic options for this disease. One key finding endorsed by the Conference Panel [7] was the ability to predict, early in the course of therapy, which patients have a chance for a sustained response with prolonged treatment. Failure to clear viral load, as measured by sensitive HCV RNA assays within the first 12 weeks of treatment, indicates that sustained response is unlikely and that continuation of treatment is essentially futile. Others [8] have chipped away at the 12-week decision point and have found that viral clearance as early as 4 weeks after the start of therapy may predict long-term response. Factors that have previously been associated with poor response to interferon, such as the presence of cirrhosis, high pretreatment viral burden, and genotype 1, were predictive only in certain therapeutic settings (standard interferon doses, 6-month treatment periods, or naive patients compared with patients who have had relapse or nonresponders) that reflect the circumstances in which the data were generated and may be less important as generic predictors, particularly if newer therapeutic approaches produce higher rates of sustained viral clearance. Prognostic factors may remain important but will require repeated reassessment in different patient groups receiving emerging therapies.

The Debate about Whom To Treat

It is often more appealing to treat a chronic disease, such as hepatitis C, with currently approved medication immediately after diagnosis than it is to wait for confirmation of potentially better therapies being evaluated in large clinical trials. The high public profile of hepatitis and the easy access we have to anecdotal information on the Internet adds to the sense of urgency about "doing something." Because of the breakneck pace of recent therapeutic advances, decision making has never been more in flux. In my own unscientific poll conducted at national meetings and in the practice community, I have found that many of my colleagues are tempted to treat "all-comers" with an initial short course of interferon monotherapy in an attempt to eradicate HCV RNA, regardless of the presence or absence of predictive factors. Their argument is bolstered by the fact that such treatment may ultimately cut costs by distinguishing potential responders from nonresponders, allowing cessation of prolonged interferon therapy in the latter and reducing the incidence of interferon-associated side effects. Moreover, patients with mild hepatitis are more likely than those with more advanced histopathologic disease to respond to early treatment with viral clearance. A recent report [9] of the use of decision modeling techniques in such patients showed an extension of life expectancy at reasonable cost. However, as Koff points out [10], this report assumed that HCV RNA negativity at only 6 months of follow-up represents "cure" and restoration of life expectancy, which may not be the case. Further, the NIH Consensus Development Conference Panel report [7] contradicts such decision-modeling logic; the Panel recognized that patients who have the greatest risk for progression to cirrhosis and most deserve treatment have evidence on biopsy of either portal or bridging fibrosis or moderate degrees of inflammation and necrosis rather than mild hepatitis. The Panel recommends that decisions about treatment for mild hepatitis be made in consultation with each patient [7].

My interest in the natural history of chronic hepatitis C and the importance of initial histopathologic findings was rekindled after more than 10 years of observation of some asymptomatic patients whom I studied in 1970 [11]. These patients had persistently elevated serum alanine aminotransferase (ALT) levels and subsequent HCV RNA positivity and negative findings on serologic tests for hepatitis B virus. Typical of such patients is a man, followed for 25 years, whose liver biopsy specimens at approximately 5-year intervals showed stable mild inflammation without significant fibrosis, or what is now considered grade 1-stage 1 disease. This new histologic classification of chronic hepatitis C [12] based on grading (extent of necroinflammatory activity) and staging (extent of fibrosis) is widely accepted and provides insight that can aid in decision making. If patients do not have significant fibrosis [13], the likelihood of progression to cirrhosis is remote. Predictions of stable disease can be made more confidently if the initial biopsy is done more than 10 years after onset of disease and shows no significant fibrosis-under these circumstances, subsequent fibrosis is unlikely to occur. The overall time to the appearance of cirrhosis (if it appears at all) in the absence of significant fibrosis on the initial biopsy specimen may be 20 to 50 years [13, 14]. For patients with grade 1 hepatitis and no unusual circumstances, I would wait for future therapies because of this condition's virtual lack of progression and the toxicity and relative lack of efficacy of the current therapy. If the first biopsy shows interface or lobular hepatitis (grade 2 disease), it may be more difficult to decide not to treat because few prospective studies have correlated clinical course with grade 2 disease. Clinical acumen may aid in decision making in such patients. If the patient has a palpable or firm liver (usually in the left lobe) or thump tenderness over the liver, I believe that a poor prognosis is more likely; if a liver biopsy specimen in that patient shows grade 2 disease, I am prone to strongly recommend therapy. Grade 3 and grade 4 hepatitis are most likely to progress to cirrhosis [14] and should be treated in the absence of contraindications.

Another reason to postpone therapy is the current difficulty in quantifying histologic improvement in treated patients with mild hepatitis. This measurement is rendered difficult because the principal criterion for meaningful improvement after therapy in most trials is a change of only two histologic activity points. However, histologic activity in biopsy specimens from these patients is in a narrow range of 0 to 4 points, leaving little room for measurable improvement. Interobserver error is also greatest when change is measured in scores of less than two points. This limitation is only important in grade 1 and grade 2 hepatitis without significant fibrosis, but it emphasizes the difficulty involved in interpreting histologic outcomes and highlights our need to rely solely on virologic markers in such patients.

The Patient with Persistently Normal Alanine Aminotransferase Levels

What do we do about the 25% of the population of HCV-infected patients who have detectable HCV RNA; persistently normal ALT levels; and, with few exceptions, minimal to mild hepatitis? Interferon monotherapy in these patients usually fails to produce sustained virologic clearance and may even be associated with an elevation in ALT levels that persists after treatment [15, 16]. Patients with persistently normal ALT levels have a slow rate of fibrosis progression; the expected median time to cirrhosis is 80 years [17]. It has been postulated that nondrinking women younger than 40 years of age may be the "normal ALT" patients who are more responsive to interferon [18] because heavy alcohol intake, usually in men, seems to have a synergistic, deleterious effect on patients with this disease. The answer may come from an international study designed to determine the response rate in patients with repeatedly normal serum ALT levels who either receive no treatment or receive interferon for 12 months [18]. Therapeutic experience is limited in patients with serum ALT levels less than 1.5 times the upper limit of normal [16] because these patients have been excluded from most other clinical trials. For both of these cohorts that rarely progress to cirrhosis, I would delay monotherapy, except in the context of a formal clinical trial. In rare circumstances, treatment decisions can be made solely to eliminate viral infection per se, regardless of histologic findings (for example, to meet the desires of an active surgeon or a mother-to-be).

Future Therapeutic Options

New interferon regimens in the early 12-week induction period that have been or are being evaluated are higher-dose and daily dose therapy and, after induction, de-escalation and maintenance therapy. Consensus interferon reportedly causes greater reductions in HCV RNA levels in patients with higher pretreatment viral loads [19], but this effect has yet to be confirmed. A variant mode of interferon delivery that has been touted to improve interferon's efficacy is pegylation using conjugated polyethylene glycol. Pegylation may augment the drug's duration of action by controlling the rate of absorption from the injection site, allowing less frequent injection (for example, only one injection per week). Because the NIH Consensus Development Conference Panel's recommendation to extend monotherapy from 6 to 12 months for early virologic responders [7] will probably result in a more durable sustained virologic response and because the likelihood of gains from other permutations may be less than that from prolonged treatment, I have little enthusiasm for pursuing the other proposed regimens for mild hepatitis. To elucidate the possible deleterious role of increased hepatic iron levels (especially iron levels in portal tract cells [20]) on therapeutic response to interferon in chronic hepatitis C, iron reduction therapy plus interferon (compared with interferon alone) is being studied in two multicenter, randomized, controlled trials. Preliminary results from one of these important studies [21] showed significant improvement in serum ALT levels but only a slight decrease in serum HCV RNA levels. Final results should be available soon.

The limited success of vaccine strategies [7] has stimulated the search for adjunct therapies and antiviral medications that inhibit viral entry, replication, and assembly. Ribavirin has a synergistic effect with interferon; increases sustained virologic response two- to threefold; reduces relapse rates; and is being evaluated in controlled, randomized trials of therapy-naive patients. Another interesting approach is to correct deficiencies in the host immune response. Using interleukin-10 [22], other cytokines, thymosin- 1, and nonsteroidal anti-inflammatory drugs for their immunomodulatory effects has been suggested.

Interfering with the function of serine protease by using combination therapy for HIV infection may provide an important model for the treatment of chronic hepatitis C. In many ways, HIV and HCV RNA are similar, although we do not know exactly how much of the experience with HIV therapy will eventually apply to HCV. Inhibition of serine protease, helicase, or RNA polymerase activity may be the most promising approach for antiviral treatment of HCV infection. The nonstructural 3/4A serine protease of HCV RNA is especially well characterized [23]. It is required for viral replication and is the first molecular target for which new antiviral agents are being developed. A protease inhibitor would be likely to block both the establishment of viral infection and viral production in chronically infected cells. Several candidate protease inhibitors are currently under intense preclinical study, and it would not be surprising if one or more of these prove to be clinically effective.

More speculative molecular strategies aim to block viral gene expression or function with antisense oligonucleotides and ribozymes (ribonucleic acid enzymes). Several of these interventions may eventually be both effective and well tolerated. Antisense nucleic acids for HCV RNA therapy could be designed to inhibit a specific RNA, resulting in the formation of RNA-DNA (antisense DNA) or RNA-RNA hybrids (antisense RNA) with an arrest of RNA replication or messenger translation. Ribozymes have been reported to eliminate HCV RNA in infected hepatocytes, and antisense drugs have reduced expression of HCV core protein in cell culture [24] and have inhibited HCV-directed protein synthesis in hepatocytes [25].

The Elusive "Cure" for Patients with Mild Histopathologic Findings

I believe that most patients with mild histopathologic findings and a concomitantly longer duration of disease (if that can be determined at the time of diagnosis) tend to have little progression. Delayed initiation of interferon monotherapy allows them to avoid the adverse effects and expense of therapy and the discouragement that can accompany treatment failure, which is frequent. For patients with borderline or mild grade 2 hepatitis and disconcerting clinical markers, as well as patients with more advanced histologic disease who do not respond to interferon, I support the NIH recommendation [7] that they consider entering ongoing trials of combination therapy with ribavirin or other prospective antiviral agents and immunomodulators (with the caveat, of course, that the results of such trials could prove disappointing). On the basis of treatment experience with HCV, which resists eradication, the criteria for "cure" must certainly be extended beyond the usual 6-month definition of a sustained virologic response. Because HCV RNA has been found to recur even years after successful therapy [26], patients should ideally be followed and observed for at least one or two decades, although 2 to 5 years is more feasible in practice. "Cure" for chronic hepatitis C may prove to be elusive and, depending on the patient's viral replication and immune balance, treatment may ultimately mimic that for other chronic viral infections, such as herpes simplex, cytomegalovirus infection, and HIV infection.

Conclusions

We cannot yet confidently identify the patients most likely to benefit from interferon, but we do have tools for detecting nonresponse to this therapy (failure to clear HCV RNA early in the course of treatment) and nonprogression of disease (a liver biopsy specimen that shows no significant fibrosis). The lessons learned from therapy for HIV infection suggest that most patients may be successfully treated with combination therapy directed against HCV. For now, it is the informed patient, after discussion with his or her physician, who should decide on the timing and type of therapy. I will continue to advise a tincture of time for most of my patients with histologically mild chronic hepatitis C, both because I do not believe that their prognosis is as daunting as is often stated and because the outlook for new and more effective therapies is promising.