Viral Hepatitis in Hawai‘i – Differing Perspectives
V. The Future of Hepatitis in Hawai‘i
C. The Future of Hepatitis Therapy:
C. Bradley Hare MD and Carroll Leevy MD
pp. 16-18
Hepatitis B
In the last decade, therapeutic options for treatment of hepatitis B have improved significantly. Despite these advances, the treatment options are not optimal. It was originally thought that hepatitis B had three sequential phases: immune tolerant, which is characterized by the detection of the hepatitis B ‘e’ antigen (HBeAg) with no evidence of anti-HBe antibodies (anti-HBe), immune active or chronic phase in which the host immune system recognizes the HBeAg and anti-HBe appears, and a non-replicative phase, or inactive HBsAg carrier. However, these groups are in fact interchangeable and reactivation can occur as long as an individual has HBeAg surface antigen present. One of the primary goals of HBV therapy is to suppress HBV replication and reduce DNA to undetectable levels, as incidence of hepatocellular carcinoma and cirrhosis increases with increasing HBV DNA baseline viral levels.39 Because the natural course of the disease is typically asymptomatic, detecting HBV in patients who need treatment is crucial. Indications for treatment are based on serum ALT levels, serum HBV DNA levels, and histological grade and stage of fibrosis.40
There are two distinct patient populations targeted for antiviral and immunomodulatory therapies. In HBeAg-positive (wild-type) patients, therapy is aimed at suppressing DNA to low or undetectable levels. Data indicating discontinuation of therapy after seroconversion and ALT normalization is strongest following treatment with interferons; however, because there is less data available to support discontinuation of therapy following treatment with newer, safer nucleoside and nucleotide analogs, experts are beginning to consider longer, even indefinite durations of treatment rather than complete discontinuation.
For HBeAg-negative patients, therapy is indicated for an unending period of time, as seroconversion does not represent an endpoint. Characteristics of HBeAg-negative chronic hepatitis B, which has an increasing prevalence, include: more common in Asian immigrants, with liver disease that is typically advanced; more common in males in the 36-45 year age range; fluctuations in ALT and viremia levels; severe liver necroinflammation; and progressive fibrosis with a poor prognosis.41-42
In terms of need for long term therapy, recognition of naturally occurring and treatment-induced genotypic HBV mutations is a key component to drug development and application. While these mutations are spontaneous and are capable of reverting back to the wild-type, when drugs are targeting and selecting against the wild-type, mutations and resistance are able to take hold. Although some HBV treatment and management leaders recommend using pegylated interferon alfa-2a as a first course of treatment due to its efficacy in getting rid of the virus, in reality it only works successfully in less than 50% of patients and has the potential to produce serious adverse side effects, and is not cost effective. Factors associated with choosing interferon as initial therapy include favorable genotypic predictors of response, low baseline HBV DNA levels, high baseline ALT, younger patient demographics, no co-infection with HIV, and concomitant HCV infection.
On the other hand, oral antivirals are often better tolerated and more convenient to administer, but are prone to the development of resistance. The primary drugs recommended as the first lines of therapy include tenofovir and entecavir. Although lamivudine, a well-tolerated oral L-nucleoside analogue that interferes with HBV DNA polymerase activity and inhibits replication, has similar results to peginterferon with minimal side effects, it has the least favorable resistance profile with up to 70% of patients becoming resistant within 36-48 months. Because of this, lamivudine monotherapy is not currently recommended as a first line of treatment. Entecavir has reduced activity against lamivudine-resistant HBV when compared to wild-type HBV, and as such, tenofovir is recommended for use by the vast pool of lamivudine experienced patients.
Several other agents in development but not currently approved for use in the United States include clevudine and emtricitabine in combination with FDA approved tenofovir, although resistance, side effects, and efficacy data from phase III clinical trials vary.43-45 Phase II investigational trials for pradefovir, valtorcitabine, amdoxovir, ANA 380, and racivir are also underway. Nucleoside and nucleotide therapies are generally designated for patients with low baseline HBV DNA, high ALT, older patient demographics, concomitant HIV infection, and no HCV co-infection. For patients with HIV co-infection, the HBV-active drugs lamivudine, tenofovir, and adefovir (as well as emtricitabine) have activity against the HIV virus as well and should be used as part of a fully suppressive HIV regimen.
Current therapies approved by the FDA are listed in Table 6. While having multiple treatment options for chronic hepatitis B represents a step forward, some clinicians view the expanding array of therapeutic choices as further complicating the challenging process of choosing the appropriate drug for use. There are existing consensus treatment guidelines, but there is insufficient data to identify in whom and when to use them.46 Drugs in the future will need to have better reduction in HBV DNA due to increasing genotypic resistance rates of current HBV antivirals. Avoiding sequential monotherapies and using agents with similar cross-resistance profiles can help prevent drug resistance. In addition, combination therapy is becoming popular by pairing the best nucleoside and the best nucleotide together for treatment. The downside to this potentially bright scenario is that there have been few thorough combination studies done to date, and the necessary clinical trials for FDA approval of dual or triple therapy will likely not be completed for several years.
Hepatitis C
The primary goal for hepatitis C therapy is to eradicate the HCV infection. Secondary goals as outlined by Lindsay et al.47 are to slow the disease progression, improve histology, reduce the risk of hepatocellular carcinoma, and improve health-related quality of life. Although it has been 20 years since the first identification of HCV, therapeutic options remain limited. Treatment of chronic hepatitis C has evolved from interferon alfa (IFN) monotherapy to the current standard as defined by the National Institutes of Health in treatment-naïve patients which is the use of a polyethylene glycol modified form of IFN (pegylated IFN) paired with the nucleoside analogue ribavirin, which leads to a sustained viral response in approximately half of treated patients.22,48-49 Because pegylated IFN has an extended half-life, it can be administered once a week. Treatment duration depends on the HCV genotype and response to antiviral therapy as determined by serum viral load after four and 12 weeks of therapy. Genotypes 1 and 4 are treated for 48 weeks. Genotypes 2 and 3 are treated for 24 weeks, and a 12 week regimen has been shown to be effective in patients who achieved a rapid viral response.50 In the coming decades, hepatitis C treatment will likely be even more tailored depending on the genotype and rapid response. The use of mathematical models and algorithms are increasingly useful in defining the mechanism of action of antivirals, guiding duration of therapy and duration of undetectability, predicting development of resistance, and answering questions regarding pathogenesis. Predictors of response to therapy are primarily dictated by viral genotype and viral load, as well as the HIV status, age, extent of cirrhosis, race, gender, and body weight of the host, among other factors.
The IFN family of cytokines affect the immunoregulatory and antiproliferative properties of target cells, and are capable of inducing intracellular signaling through various pathways, including the Jak-STAT pathway.51 In addition, IFN plays a role in antiviral actions through transcriptional activation of IFN-stimulated genes, which can lead to blocked viral transcription, degradation of viral RNA, and inhibition or interference with viral replication.52 Most effective against genotypes 2 through 6, pegylated interferon is best to use in difficult responders. Ribavirin, when given without IFN shows no antiviral effects; however, its ability to enhance the efficacy of IFN treatment is accepted, although not fully understood. Similarly, the exact mechanisms by which IFNs are effective against HCV remain poorly understood due in part to lack of HCV cell culture and small animal models. Recently, a genetic polymorphism near IL28B which encodes for interferon lambda-3 was found to be strongly correlated with patient sustained viral response when treating with pegIFN/ribavirin in individuals with HCV genotype 1.53 This interferon lambda-3 pathway may constitute a potential novel target for HCV antiviral therapies.
There are new drugs currently being derived against protein targets such as polymerases and protease inhibitors that block HCV replication, although timelines for FDA new drug approval are generally five years or longer. There are currently two HCV NS3-4A protease inhibitors, telaprevir and boceprevir, that are being evaluated in phase III clinical trials,54-55 and it is expected that novel small molecule antiviral compounds, or STAT-C compounds, will eventually be part of standard HCV therapy. STAT-C drugs have been shown to improve the first-phase HCV RNA decline by shutting down virus production, and may yield early viral suppression and improved sustained viral response rates with shorter treatment durations.55-56
Other therapies also under investigation include caspase inhibitors, therapeutic vaccines, longer acting interferons, and a variety of nucleoside analogs. However, the highly replicative nature of HCV infection coupled with error-prone viral RNA synthesis and considerable genome diversity pose challenges to drug development. Although novel therapeutics might shorten the duration of treatment, they will not likely replace the use of pegylated IFN and ribavirin, which will remain a mainstay of therapy for the foreseeable future, or until such time that multiple direct-acting antiviral inhibitors are available and proven to provide a sufficiently high barrier to resistance when used in combination.57 Despite the potential for future advances in therapy, we must have an aggressive approach and treat hepatitis now.
