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Progress and Challenges
Alex Sherman, MD, New
York University Medical Center, New York [Infect
Med 17(9):614,617,618, 2000.
© 2000 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]
The cloning of the hepatitis C virus (HCV) in 1989 was the beginning of an era of rapid advances in the knowledge of this infectious agent that continues to this day. HCV was quickly recognized as the primary causative agent of non-A, non-B hepatitis. The development and refinement of antibody assays during the 1990s provided a reliable means of diagnosis. More recently, the application of sophisticated polymerase chain reaction technology has allowed both the qualitative and quantitative determination of viremia. Thanks to these tools, the diagnosis of hepatitis C is now relatively straightforward.
HCV is an RNA virus of approximately 10,000 nucleotides with remarkable genetic variability. It may exist in several closely related forms, called quasispecies, within a single individual. It has a high mutation rate that allows it to evade host immune surveillance. There are 6 major genotypes and numerous subtypes of the virus. Genotype 1 is the most common type found in the United States, accounting for 70% of cases of HCV infection. Unfortunately, this genotype is the least responsive to therapy. The marked genetic heterogeneity of this elusive virus may very well frustrate attempts to develop a broadly effective vaccine.
That hepatitis C is a public health problem of global significance is not in dispute. Roughly 170 million persons worldwide have been infected. In the United States, approximately 2% of the general population has been exposed and nearly 3 million persons are chronically infected.
Transmission and Carriage
The introduction of blood donor screening for antibodies to HCV has led to the virtual disappearance of transfusion-associated acute hepatitis C. This leaves injection drug use as the most important risk factor for HCV transmission; nearly half of new cases of hepatitis C are related to this mode of acquisition. Other significant risk factors include hemodialysis and intranasal cocaine use. Sexual transmission of the virus is surprisingly inefficient; the prevalence of infection in spouses of those chronically infected is only slightly higher than that in the general population. The vertical transmission of HCV from mother to newborn is also unusual; transmission rates are less than 10% and correlate with high levels of maternal viremia and HIV/ HCV coinfection. (Editorial note: the transmissibility of HCV by sex is controversial. Certainly, the presence of certain risk factors can increase transmission: STDs, HIV, unsafe sex practices, multiple sex partners. In one large Italian study mother-to-child transmission was 5% and 17% when the mother had HIV). The prevalence of HCV infection in health care workers is 1% to 2%, similar to that in the general population.[5,6] The risk of needle-stick transmission is low; it varies from 0% to 7% and is dependent on the prevalence of HCV infection in the background population.[6,7]
After accounting for all recognized modes of transmission, nearly 20% of patients cannot be assigned to a specific risk group. Risk factor determination is notoriously spotty and subjective; many of these "sporadic" cases can with detailed questioning be appropriately assigned to a likely cause of infection. Overall, the incidence of hepatitis C in the United States has declined in the past 20 years. The estimated number of new cases declined from 180,000 in 1984 to 25,000 in 1995. Despite this precipitous decline, the prevalence of HCV carriage is rising, attributable to the remarkable persistence of the virus in infected persons.
HCV liver disease is highly variable in severity. The infection has a marked propensity to become chronic -- chronic infection will develop in nearly 85% of those experiencing acute hepatitis. HCV produces a necroinflammatory and fibrotic process in the liver. In one quarter of patients, hepatic cirrhosis will develop, generally over the course of decades. Those with cirrhosis may experience decompensation, with the development of overt liver failure. HCV is thought to be the most important risk factor for the development of hepatocellular carcinoma, which occurs predominantly in those with established cirrhosis. Nearly 10,000 deaths a year in this country are attributable to the virus; this number is projected to increase several fold as the currently infected cohort ages. HCV is recognized as the single most common indication for liver transplantation in industrialized nations.
Goals and Candidates
What are the goals of therapy? Optimally, eradication of the virus results in virologic "cure." Operationally, this is defined as the absence of viremia 6 months after the end of treatment. This favorable result has been shown to be durable; that is, re-emergence of viremia after virologic cure is distinctly unusual. Secondary goals of treatment are normalization of serum alanine aminotransferase levels and histologic stabilization, presumably with slowing of the process of hepatic destruction. This secondary result can be accomplished despite the persistence of HCV viremia; that is, despite the failure to obtain a "cure."
Once a clear diagnosis of HCV liver disease has been made, how does one decide who is a candidate for treatment? If available treatment were safe, convenient, and universally effective, the issue would be moot -- all patients would be offered treatment. As things now stand, the stratification of patients with HCV infection in terms of histologic severity is critical to a rational treatment decision.
I believe that a liver biopsy is essential in patients contemplating treatment. Examination of a liver biopsy specimen is the most definitive diagnostic tool for assessing patients with chronic hepatitis. The degree of active inflammation and the presence and extent of hepatic fibrosis can be accurately determined.
Those with histologically mild disease have a relatively indolent clinical course. Treatment in these patients may safely be deferred until less onerous and/or more effective treatment regimens become available. Those with significant necroinflammatory activity and/or high-grade hepatic fibrosis on liver biopsy do not have the luxury of waiting; they must be treated immediately with currently available therapies or risk rapid progression to end-stage liver disease. (editorial note: A number of HCV in HCV/HIV coinfected patients show HIV accelerates HCV progression and this appears generally accepted by medical experts. This needs to be considered in making treatment decisions).
Advances in Therapy
Dr Emmet Keeffe's concise review elsewhere in this issue outlines the highlights of hepatitis C therapy over the past decade. The interferons, a family of glycoproteins with antiviral and immunomodulatory properties, were first used in the early 1990s. Early trials with interferon monotherapy were disappointing, with sustained virologic clearance in only 10% to 20% of patients. These relatively poor results stimulated a search for new approaches. 1998 was a banner year in the management of hepatitis C virus infection, with the publication of 2 large multicenter trials establishing the superiority of combination therapy with interferon and ribavirin, a nucleoside analogue, to interferon alone.[11,12] Viral eradication was approximately doubled, with 40% of all patients clearing the virus.
Together, the trials have produced a quantum shift in therapeutic expectation; combination therapy is the new "gold standard" against which all future treatments need to be measured. The trials were consistent in establishing the importance of viral genotype in determining treatment response. Patients with genotypes other than 1 had substantially higher HCV clearance rates. In addition, patients with genotype 1 required 48 weeks of combination therapy to achieve full virologic benefit, whereas those carrying non-1 genotypes experienced a maximal response by 6 months. Thus, viral genotype is a critical determinant of treatment duration and response. The HCV genotype assay is commercially available, and the genotype should be determined before the start of treatment in all patients.
Combination therapy by all accounts is arduous. Patients require thrice-weekly injections and multiple oral doses. Side effects are universal. Adverse reactions to interferon have been well chronicled and include a viral-like syndrome, with fever, chills, myalgias, and fatigue; bone marrow depression; thyroid dysfunction; and psychiatric symptoms, which may be severe.
Symptoms caused by ribavirin are additive to those of interferon. The most important side effect is a dose-dependent hemolytic anemia. Severe anemia may result, with a consequent increase in cardiac workload. Consideration should be given to pretreatment screening for coronary artery disease in those with risk factors for atherosclerosis. Ribavirin has been found to be teratogenic in laboratory animals. Both men and women taking the drug should practice contraception during therapy and for at least 6 months after treatment. Given the multiplicity and severity of combination-therapy side effects, this treatment should be administered only by those specialists experienced in the care of patients with this complex infection.
Dr Keeffe has sketched areas of active clinical research and future therapeutic prospects. High-dose interferon therapy, or induction, represents an attempt to rapidly achieve viral clearance. Substantially improved results of such aggressive therapy would be required to justify the severe side effects associated with high-dose interferon. Although initial viral clearance can be achieved, long-term eradication rates are not improved. More promising, perhaps, is a so-called pegylated interferon formulation. The addition of polyethylene glycol (PEG) to the interferon molecule substantially increases its longevity in serum, allowing weekly dosing. Efficacy of the PEG-interferon appears to be greater than that of interferon alone. Results of ongoing clinical trials of combination therapy with PEG-interferon and ribavirin are eagerly anticipated.
Since this article was written reports from pegylated interferon monotherapy studies and combination studies with ribavirin have been reported. The higher and more sustained interferon levels achieved by pegylated interferon show increased response rates compared to standard interferon. Several Pegasys monotherapy studies show sustained virologic response rates of 28-38%. PegIntron SVR was 25% in one study done & reported. The results of combination studies for the teo pegylated interferons have been more unclear with PegIntron+RBV showing 54% SVR, and Pegasys+RBV showing 56%. Schering reported the SVR for PegIntron+RBV increased to 61% when patients were evaluated retrospectively by their weight and the consequent RBV dose per kg of weight. In other words, patients with lighter weight had better response rates and Schering suggested this was due to higher weight-based concentrations of RBV. A prospective study is supposedly being planned to establish if increasing RBV doses based on weight actually increases the response rate and does not increase adverse events disproportionately.
On the near horizon are inhibitors of viral replication and modulators of host immune response. The optimal treatment of HCV infection may ultimately involve a multidrug approach, with pharmacologic interference at various points in the mechanism of HCV pathogenesis.
Patients Who Are Difficult to Treat
The treatment of HCV infection may be particularly difficult in several special situations. Patients with advanced liver disease due to HCV have decreased treatment response rates as well as increased rates of treatment-related side effects. Treatment in this group should be undertaken with heightened caution; early referral of these patients to a liver transplantation center should be strongly considered. Patients with HIV/HCV coinfection are increasingly being seen with advanced liver disease. Several years ago, the prognosis for these patients was considered so poor that therapy for the HCV infection was considered futile.
With the recent remarkable advances in HIV therapy, these patients have an improved overall prognosis but are now being seen with advanced liver disease caused by hepatitis C. Earlier, more aggressive therapy for HCV infection in these patients may forestall the development of end-stage liver disease. Finally, the recurrence of hepatitis C in the transplanted liver is nearly universal. Fortunately, the severity of HCV infection post-transplant tends to be mild in most patients. In some, however, a rapidly progressive course with fibrosing histology may ensue, leading rapidly to hepatic failure and the need for retransplantation. Clinical trials are currently under way to determine the effectiveness of prophylactic treatment with interferon to prevent the emergence of this aggressive subtype in post-transplant patients. Given the immunosuppression required to maintain graft patency, eradication of the virus in this setting may not be achievable.
The current therapy for HCV infection remains ultimately unsatisfactory with optimal eradication rates of only 40%. Thus, more than half of those who complete the difficult treatment regimen fail to clear the pathogen. Despite the exciting advances that have been achieved in the past 10 years, much work remains before a safe, convenient, and effective treatment for this determined pathogen becomes readily available. Given the rapid pace of discovery in HCV research, it can be anticipated that improved treatment regimens will become available in the not-too-distant future.
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