Marco A. Olivera-Martínez, MD and Sandeep Mukherjee, MD
What are the antiviral actions of interferons?
Interferons are naturally occurring glycoproteins produced by cells in response to a variety of stimuli including viral infection. Interferons have direct antiviral effects postulated to occur through induction of cellular enzymes that interfere with viral synthesis such as up-regulation of the mitogen activated protein kinase (MAPK) that enhances some signaling pathways. Inhibition of viral RNA and DNA transcription and translation is likely but unproven. Interferons are also antiproliferative and might induce suppression of the necro-inflammatory response. In addition, interferons have immunomodulatory properties and may exert antiviral actions through augmentation of cellular immune function.
What is the risk of interferon precipitating autoimmune phenomena?
Hyperthyroidism (5%), hypothyroidism (3%), autoimmune thrombocytopenia (< 1%), erythema multiforme (< 1%), interstitial nephritis (< 1%), interstitial pneumonitis (< 1%), lupus-like syndrome (< 1%), and psoriasis (<1%). Interferon has also been associated with exacerbation of rheumatoid arthritis (< 1%), ulcerative colitis (< 1%), and vasculitis (< 1%).
True/False: It can be challenging to differentiate autoimmune hepatitis from chronic hepatitis C virus (HCV).
True. Low titers of antinuclear antibodies (ANA) occur in 40%–70% of patients with chronic HCV. ANA titers over 1:160 occur in 20% of patients with chronic HCV. Hypergammaglobulinemia is associated with a false-positive enzyme-linked immunosorbent assay (ELISA) test for HCV in 20% (predominantly young women). Steroid therapy in chronic HCV will decrease alanine aminotransferase levels but elevate HCV RNA levels. Severe hepatitis may occur when autoimmune hepatitis is treated with interferon due to its immunomodulatory effect. Unless the diagnosis of HCV infection is supported by the presence of HCV RNA, steroid therapy should be the primary initial treatment choice.
A patient with chronic hepatitis B virus (HBV) develops a rise in aminotransferases 4 weeks after initiation of pegylated interferon therapy. What should be the response of the treating gastroenterologist?
During or immediately after interferon therapy for HBV, patient responders (those that lose HBeAg and HBV DNA) frequently will develop increased alanine aminotransferase (ALT) levels. Continued interferon therapy with close monitoring of the patient and symptomatic treatment of side effects is indicated. Because of the cost, side effects, and toxicity of interferon therapy for chronic HBV, patients selected for therapy should exhibit elevated ALT and low HBV DNA, and have no evidence of decompensated liver disease.
What oral antiviral should be recommended as first choice for the treatment of hepatitis B?
Tenofovir was approved by the FDA in 2008. It is currently recommended as a first-line treatment for chronic hepatitis B. Its efficacy was demonstrated in two double-blind, placebo-controlled trials. In these trials, a higher proportion of patients taking tenofovir showed undetectable HBV DNA when compared to patients receiving adefovir (76% versus 13%, respectively) and similar results were found when ALT and HB surface antigen (HBsAg) were evaluated. No resistance to tenofovir has been detected in patients after 72 weeks of treatment. An alternative first-line treatment is entecavir. Adefovir is now considered a second-line treatment for HBV.
What is the mechanism of the antiviral action of tenofovir in the therapy of chronic HBV?
Tenofovir is an acyclic nucleotide analog that inhibits HBV viral DNA polymerase-reverse transcriptase.
What is the incidence of the appearance of YMDD mutants in HBV patients undergoing therapy with lamivudine?
Fifteen percent to 35% of patients treated with lamivudine (100 mg/day) for 12 months develop escape mutations in the active site of the HBV polymerase gene (YMDD locus). After 5 years of treatment, up to 66% of the patients receiving lamivudine might develop YMDD mutation. This molecular virologic event is associated with an increase in ALT and reappearance of HBV DNA.
What are the possible clinical presentations of acute hepatitis A viral (HAV) infection in adults?
Rarely, jaundice can persist for weeks to months in adults with HAV. This syndrome is known as prolonged cholestasis and can persist for 3 to 5 months. Relapsing hepatitis can also occur in as many as 10% of HAV patients. This syndrome is characterized by a secondary elevation and peak of aminotransferase levels once they were already trending toward normal and, in some instances, even after they reach the normal range. Cholestatic and relapsing HAV infections do not result in increased mortality.
What is the clinical significance of hepatitis B core antibody (anti-HBc)?
To understand the anti-HBc, it is important to understand first that the core antigen is the only HBV antigen that cannot be quantified in peripheral blood since it is located in the nuclei of infected cells. HBsAg and HBeAg can both be measured in peripheral blood. On the other hand, the antibody directed against the core antigen can be detected in blood. Anti-HBc can be detected in its two forms: IgM and IgG. In acute HBV infection, IgM anti-HBc appears approximately 1 month after HBsAg becomes positive and shortly before the ALT rises. IgM anti-HBc usually indicates acute HBV infection and declines before anti-HBs appears. IgG anti-HBc persists in patients with anti-HBs and patients that develop chronic HBV with HBsAg. The clinical significance of an isolated IgG anti-HBc is unknown; however, affected individuals are not allowed to donate blood, and their organ donation may be associated with transmission of HBV infection.
What is the significance of an HBV precore mutant?
Mutations of HBV DNA replication are not unusual. The precore mutation involving a G to A change at nucleotide 1896 is well described. This mutation prevents synthesis of HBeAg. The presence of the A1896 mutant should be suspected in patients with elevated ALT, presence of HBsAg, absence of HBeAg, and positive anti-HBe. HBV DNA should be present. In other words, the precore mutant confers the possibility to the HBV to achieve replication despite the absence of HBeAg, which was traditionally described as a replication marker. Patients with precore mutant (e antigen negative) have higher risk of developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma compared to patients with HBeAg positive viral infection.
What is the clinical significance of an “HBsAg carrier”?
Classically, in these patients, HBV DNA persists at levels that are undetectable by current technology/assays. HBeAg is negative, no hepatic inflammation is present, and ALT is persistently in the normal range; all this occurs despite the presence of HBsAg. However, if replication increases, then the HBV DNA might become detectable triggering liver tissue inflammation with secondary elevation of ALT.
What percentage of patients with hepatocellular carcinoma have HBV or HCV infection?
The prevalence of HBsAg in patients with hepatocellular carcinoma varies from country to country and ranges from 7% (United States) to 87% (Korea). Over 80% of all hepatocellular carcinoma patients have cirrhosis. In the case of hepatitis B, some patients might develop hepatocellular carcinoma even in the absence of cirrhosis. Nevertheless, cirrhosis is a risk factor for the development of hepatoma when patients have HCV or HBV. Cirrhotic patients with HCV have a 7% risk of hepatoma at 5 years and a 14% at 10 years after diagnosis.
How is chronic hepatitis D prevented and who is at risk of acquiring it?
Hepatitis D (or delta) is caused by a small circular, enveloped RNA, hepatotropic virus. Hepatitis D virus (HDV) is considered a satellite or “incomplete” virus since it requires the presence of HBV to infect and propagate within the host. The single stranded RNA virus has an outer coat conformed by HBsAg. Its pathophysiology is incompletely understood, but it seems that the hepatocyte HBV surface receptor also recognizes the HDV through the HBsAg and this is the same reason for which HBV vaccination protects against HDV infection. The same populations at risk to acquire HBV are also at risk of acquiring HDV.
True/False: Coinfection with hepatitis D and hepatitis B is associated with a better prognosis.
True. Hepatitis D can be acquired as a coinfection (patients infected at the same time with HBV and HDV) and as a superinfection (patients that have chronic hepatitis B and are then infected with hepatitis D). Coinfection is associated with a better prognosis, whereas superinfection is associated with a poorer prognosis.
What is the difference in the natural history of HDV infection between coinfection with HBV versus superinfection of HBV?
Only 2% of coinfections become chronic compared to 90% of superinfected patients.
What subsets of patients with end-stage HBV infection would be expected to have improved survival after liver transplantation?
Patients with fulminant hepatitis (acute liver failure) from HBV, HDV coinfection, or undetectable HBV DNA would have a lower incidence of graft reinfection than patients that are HBeAg positive and have HBV DNA. Patients that have no history of drug resistance to nucleotide or nucleoside analogs also carry a better prognosis than those patients with a positive history of drug resistance. Immunoprophylaxis with a combination of hepatitis B immunoglobulin and oral antivirals (nucleotide or nucleoside analogs) decreases the incidence of HBV graft reinfection and enhances survival in patients with evidence of pretransplant HBV DNA.
Describe the pathological grading and staging scoring system for chronic hepatitis.
One of the most common classifications used in the United Stated is the Ludwig–Batts classification (Mayo Clinic) and is as follows:
Describe the unique clinical manifestations of hepatitis E virus (HEV) infection.
HEV is a single-stranded RNA virus that was originally classified as a Calicivirus and later reclassified. Now it is considered a Hepevirus. The transmission of this virus is through the fecal-oral route and the symptoms are very similar to those of hepatitis A. This virus, like HAV, only causes acute hepatitis. There are no reported cases of chronic hepatitis E. Fulminant hepatitis may occur in as many as 1%–2% and there is a remarkable increase in mortality for infected pregnant women in the third trimester.
What percentage of patients with infectious mononucleosis have liver involvement?
Approximately 50%–80% have aminotransferase elevations while 5% become icteric.
Describe the clinical spectrum of cytomegalovirus (CMV) hepatitis.
In general, 50%–80% of individuals have serum antibodies to CMV by age 35. CMV hepatitis in healthy children and adults is usually asymptomatic and subclinical. Neonates may develop jaundice and liver failure. Primary and secondary (reactivation) CMV infections may occur in immunosuppressed patients. The diagnosis of CMV hepatitis used to require IgM antibody or a rise in IgG titer and a liver biopsy. Currently, more accurate biological markers include a CMV quantitative viral load, which specifically measures the viral DNA (obtained by polymerase chain reaction [PCR]). Liver pathology classically shows giant cells with intranuclear inclusions. The virus may be identified from culture of liver tissue or body fluid.
What populations are at risk of developing fulminant herpes simplex hepatitis?
Neonates, pregnant women in the third trimester, and immunocompromised patients.
What are the possible extrahepatic manifestations of HCV infection?
What are the most common genotypes of HCV infection in the United States?
HCV has a high mutation rate during replication. The accumulation of mutations during the evolution of HCV worldwide has led to genetic heterogeneity among isolates and at least six major genotypes (1 to 6).
The most common genotypes infecting patients in North America (about 70% of the cases) are genotype 1a and less commonly 1b. Genotype 1 is considered “hard to treat” since it requires 48 weeks of treatment with pegylated interferon and ribavirin.
What are the major etiologies of chronic liver disease in the United States?
How is hepatitis A transmitted and what is its prevalence in the United States?
Although the primary route is fecal-oral, through contaminated food or water, and in endemic areas by contaminated food handlers, transmission of HAV has been documented by parenteral and sexual means via blood transfusion and homosexual activity, respectively. The parenteral and sexual transmission of HAV takes place when the blood donor or the sexual partner is actively (acutely) infected since there is no chronic form of hepatitis A. The prevalence of IgG antibody to HAV is 10% in children and 37% in adults.
True/False: The standard therapy of hepatitis A is supportive/symptomatic.
True. Other than supportive symptomatic therapy, there is no defined protocol. There is no evidence that corticosteroids are helpful. Postexposure prophylaxis is accomplished by serum immunoglobulin (0.02 mL/kg) administered by intramuscular injection. There is also evidence to suggest that immediate HAV vaccination, by itself, may be effective in the setting of postexposure prophylaxis.
What are the phases of perinatally acquired chronic HBV?
Initial phase: Immune tolerance—HBeAg positive, high HBV DNA level, normal ALT.
Second phase: Immune clearance—between the ages of 15 and 35, HBeAg clearance, elevated ALT, mostly asymptomatic, rare hepatic failure, or cirrhosis.
Third phase: Nonreplicating—HBsAg negative, loss of or very low HBV DNA, normal ALT.
The fourth and fifth phases have also been recently described. The fourth phase is called reactivation and might occur in the presence of immunocompromised states such as chemotherapy. The fifth phase is the development of hepatocelluar carcinoma.
How is the diagnosis of acute HCV infection made?
Because anti-HCV by ELISA is often undetectable for 5 or 6 weeks, testing for HCV RNA is necessary.
What is the major side effect of oral ribavirin therapy for HCV?
A dose-dependent hemolytic anemia occurs within 2 to 6 weeks after beginning ribavirin with 15% of hemoglobin tested falling 4 g when 1200 mg/day is administered. Teratogenicity is another important side effect. A patient in the reproductive age receiving ribavirin as part of HCV treatment should practice contraception. If the patient happens to be a male, contraception should be practiced by his sexual partner since ribavirin is secreted in semen.
What is the current state-of-the-art treatment of chronic hepatitis C infection in the United States?
In June 2011, the FDA approved two new drugs (protease inhibitors) to be used in combination with the previous standard of care (pegylated interferon + ribavirin) in the treatment of genotype 1 chronic hepatitis C infection (so-called “triple therapy”):
1. Telaprevir + Pegylated Interferon α 2A + Ribavirin
2. Boceprevir + Pegylated Interferon α 2B + Ribavirin
The other hepatitis C genotypes should continue to be treated with pegylated interferon + ribavirin alone.
What are the most common side effects of telaprevir therapy for HCV?
Cutaneous manifestations (rashes) and pruritus may occur in up to 50% but are usually mild to moderate in severity.
What are potential side effect of oral boceprevir therapy for HCV?
The most common side effects include fatigue, anemia, nausea, headache, and dysgeusia. The addition of boceprevir to peginterferon and ribavirin has been associated with decreases in hemoglobin concentration (and neutropenia and thrombocytopenia also) beyond those with peginterferon and ribavirin alone.
True/False: Individuals at risk of HIV infection are also at risk for HBV and HCV infection.
True. These viruses are blood-borne pathogens that can be transmitted through the same routes: IV drug use, sexual contact, and vertical transmission from mother to child during pregnancy or birth. Coinfection with HBV or HCV has emerged as a major cause of morbidity and mortality among patients with chronic HIV infection receiving highly active antiretroviral therapy (HAART). A recent meta-analysis has demonstrated that HCV––HIV coinfection is more frequent than HBV–HIV coinfection.
How does coinfection with HIV affect hepatitis B infection and its treatment?
Effects of coinfection of HIV with hepatitis B:
• Increased risk of reactivation of hepatitis B.
• Increased development of chronic disease (~20%) after acute infection.
• Attenuation of the severity of biochemical and histological liver disease.
• Immune reconstitution with HAART therapy may cause a flare of the hepatitis B resulting in fulminant hepatic failure.
Effects on hepatitis B treatment:
• Because emtricitabine (FTC), lamivudine (3TC), and tenofovir (TDF) have activity against both HIV and HBV, if HBV or HIV treatment is needed, HAART should be initiated with the combination of TDF + FTC or TDF + 3TC as the nucleoside reverse transcriptase inhibitor (NRTI) backbone of HAART and for treatment of active Hepatitis B.
• If HBV treatment is needed and TDF cannot safely be used, the alternative recommended HBV therapy is entecavir in addition to a fully suppressive HAART regimen. Of importance, entecavir should not be considered to be a part of the HAART.
• Use of entecavir or lamivudine alone leads to rapid development of HIV drug resistance at M184V position of the reverse transcriptase.
How does coinfection with HIV affect hepatitis C disease course and treatment?
Effect on Hepatitis C disease course:
• HCV viral load is much higher than in HIV-negative patients.
• Rapid progress of liver fibrosis and an accelerated progression to cirrhosis, 10 years compared to 20 years in immunocompetent hosts.
• Higher liver-related toxicity rates with antiretroviral therapy.
• HAART is also associated with a rise in HCV RNA and aminotransferases.
• Increases of CD4 cell counts with HAART associated with better hepatic outcomes.
Effect on hepatitis C treatment:
• Lower sustained viral response (SVR) with peg-interferon and ribavirin, 14%–44% in genotype 1 compared to ~55% in normal host.
• If CD4 counts < 200 cells/mm3, it may be preferable to initiate HAART and delay HCV therapy until CD4 counts increase as a result of HIV treatment.
• Patients receiving or considering therapy with ribavirin should avoid didanosine, stavudine, and zidovudine.
What are the time landmarks used to predict response and determine length of treatment in the management of chronic hepatitis C?
• Rapid viral response (RVR): HCV-RNA is non-detectable at week 4 of treatment.
• Early viral response (EVR): HCV-RNA decreased at least 2 logarithms from the baseline viral load.
• Partial response at 12 weeks is considered the decrease of viral load of less than 2 logarithms.
• Delayed response is a decrease of less than 2 logarithms at week 12 of treatment that is followed by a negative viral load (nondetectable HCV-RNA) at 24 weeks of treatment.
• End of treatment response (ETR): HCV-RNA is non-detectable at the end of the treatment.
• SVR: HCV-RNA is non-detectable, 6 months after the end of the treatment.
• Nonresponder: A nonresponder is the individual that, despite adequate treatment, does not present with decreased viral load during treatment.
• Relapse: A relapse presents as a positive viral load after developing viral response to treatment, most commonly a relapse presents after a partial EVR or a delayed response.
• Recurrence: A recurrence presents as a positive or detectable HCV-RNA after developing ETR.
Among these landmarks, the presence of RVR is the best prognostic factor of an SVR.
What viral factors are associated with an SVR?
Viral factors that are considered prognostic of a poor viral response or nonresponse to antiviral treatment include:
• Genotype: HCV genotypes 1 and 4 are considered “hard to treat.” They require 48 weeks of treatment and the possibilities of SVR are around 50%–60% compared to genotype 2 that requires 24 weeks of treatment and can reach an SVR around 80%.
• Genotype 3 is considered separately since the response to treatment also has a relationship to the amount of steatosis present in the liver. It has been considered that semiquantitative steatosis of less than 30% carries a better prognosis than higher quantitation.
• HCV-RNA: Viral load is an important prognostic factor. The threshold to define a high viral load has changed as the assays to measure viral RNA have evolved. Currently, a viral load of 400,000 IU or less is considered a low viral load and carries a better prognosis to develop SVR than higher viral loads.
• Core and NS5 gene amino-acid substitutions: There is evidence pointing to substitutions in the NS5 and core regions of the virus as involved in the viral response to interferon treatment.
• The presence of interleukin 28B polymorphisms (see next question).
True/False: Interleukin 28B (IL-28B) polymorphisms are associated with response to interferon therapy.
True. The single nucleotide polymorphisms (SNPs) of interleukin 28B are significantly associated with the outcome of interferon treatment of hepatitis C. These SNPs are rs 2979860 and rs 8099917 and are characterized by alleles TT, TG, and GG. SVR is achieved in approximately 14% of patients infected by genotype 1 HCV who carry the TG or GG alleles. Patients with the TT allele carry up to 58% of SVR rate when treated with pegylated interferon and ribavirin.
• • • SUGGESTED READINGS • • •
Marcellin P, Heathcote J, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455.
Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: 1195-1217.
Carneiro de Moura M, Marinho R. Natural history and clinical manifestations of chronic hepatitis B virus. Enferm Infec Microbiol Clin. 2008;26(Suppl)7:11-18.
Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
Berg T, Sarrazin C, Herrmann E, et al. Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy. Hepatology. 2003;37:600-609.
Chen JJ, Yu CB, Du WB, Li LJ. Prevalence of hepatitis B and C in HIV-infected patients: a metaanalysis. Hepatobiliary Pancreat Dis Int. 2011;10:122-127.
National Institutes of Health Consensus development conference statement: Management of hepatitis C: June 10-12, 2002. Hepatology. 2002;36(Suppl)1:S3-S20.
Hayashi K, Katano Y, Honda T, et al. Association of interleukin 28B and mutations in the core NS5A region of hepatitis C virus with response to peg-interferon and ribavirin therapy. Liver International (Web ahead of printing). DOI: 10.1111/j 1478-3231. 2011.02571.x