Viral Hepatitis Treatment & Management
- Author: Adrienne M Buggs, MD, FACEP, FAAEM; Chief Editor: Steven C Dronen, MD, FAAEM more...
No specific emergency department (ED) treatment is indicated, other than supportive care that includes intravenous (IV) rehydration. A liver abscess calls for IV antibiotic therapy directed toward the most likely pathogens and consultation for possible surgical or percutaneous drainage.
Admit patients with hepatitis if they are showing any signs or symptoms suggestive of severe complications. Admit and evaluate for hepatic encephalopathy any patients with altered mental status, agitation, behavior or personality changes, or changes in sleep-wake cycle. Other admission criteria that are suggestive of severe disease include a prothrombin time (PT) longer than 3 seconds, a bilirubin level greater than 30 mg/dL, and hypoglycemia.
Admit any patients with intractable vomiting, significant electrolyte or fluid disturbances, or significant comorbid illness; those who are immunocompromised; and those who are older than 50 years.
Certain patients may benefit from pharmacologic therapy. For chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infections in particular, the goals of therapy are to reduce liver inflammation and fibrosis and to prevent progression to cirrhosis and its complications. Because the treatment regimens for hepatitis are being actively researched, medication recommendations, indications, and dosages are all subject to change. Consultations with a gastroenterologist, hepatologist, or general surgeon may be indicated.
Most patients with viral hepatitis can be monitored on an outpatient basis. Ensure that patients can maintain adequate hydration, and arrange close follow-up care with primary care physicians. Instruct patients to refrain from using any potential hepatotoxins (eg, ethanol or acetaminophen). Advise patients to avoid prolonged or vigorous physical exertion until their symptoms improve. Patients who are found subsequently to have HBV or HCV should be referred to a gastroenterologist or a hepatologist for further evaluation and treatment.
Acute Hepatitis A
Treatment for acute hepatitis caused by hepatitis A virus (HAV) is necessarily supportive in nature, because no antiviral therapy is available. Hospitalization is warranted for patients whose nausea and vomiting places them at risk for dehydration. Patients with acute liver failure require close monitoring to ensure they do not develop fulminant hepatic failure (FHF), which is defined as acute liver failure that is complicated by hepatic encephalopathy.
Acute Hepatitis B
As is the case for acute HAV infection, no well-established antiviral therapy is available for acute HBV infection. Supportive treatment recommendations are the same for acute hepatitis B as for acute hepatitis A. Lamivudine, adefovir dipivoxil, and other antiviral therapies appear to have a positive impact on the natural history of severe cases of acute HBV infection. A study by Schmilovitz-Weiss described a rapid clinical and biochemical response in 13 of 15 patients with severe acute hepatitis B who received lamivudine.
Chronic Hepatitis B
Ideally, treatment of chronic hepatitis B would routinely achieve loss of hepatitis B surface antigen (HBsAg). Indeed, loss of HBsAg is associated with a decreased incidence of hepatocellular carcinoma (HCC) and a decreased incidence of liver-related death in patients with HBV-induced cirrhosis. However, loss of HBsAg is only achieved in relatively small percentages of patients with chronic hepatitis B: 3-7% of those treated with pegylated interferon (PEG-IFN)[36, 37, 38] and 0-5% of those treated with oral nucleosides or nucleotides.
At present, the key goal of antiviral treatment of HBV is the inhibition of viral replication. This is marked by the loss of hepatitis B e antigen (HBeAg) in patients with HBeAg-positive chronic hepatitis B and by the suppression of HBV DNA levels. Secondary aims are to reduce symptoms, if any, and prevent or delay the progression of chronic hepatitis to cirrhosis or HCC.
Agents currently used to treat hepatitis B include PEG-IFN alfa-2a and the oral nucleoside or nucleotide analogues. Typically, PEG-IFN treatment is continued for 48 weeks for both HBeAg-positive and HBeAg-negative chronic hepatitis. Oral agents may be used for as little as 1-2 years; however, most HBeAg-positive chronic hepatitis patients and almost all HBeAg-negative chronic hepatitis patients require indefinite therapy with these agents. Withdrawal of oral nucleoside/nucleotide analogue therapy in these individuals usually results in virologic relapse.
Candidates for antiviral therapy must have evidence of active HBV infection. Before therapy is started, patients should undergo testing with a polymerase chain reaction (PCR)-based assay for HBV DNA. Viral loads may range from undetectable to hundreds of millions of IU/mL. At present, the typical threshold for treatment is a viral load of 2 × 104 IU/mL or more for patients with HBeAg-positive chronic hepatitis, 2 × 103 IU/mL or more for patients with HBeAg-negative chronic hepatitis, and 200 IU/mL or more for patients with decompensated cirrhosis.
Patients with chronic hepatitis tend to have abnormal liver chemistry findings. Treatment may be offered to patients with a normal alanine aminotransferase (ALT) level, but it may be less efficacious. Although liver biopsy is not mandatory before treatment, the author recommends it. Liver biopsy is helpful for confirming the clinical diagnosis of chronic hepatitis B and for documenting the severity of liver disease. Detailed treatment recommendations and practice guidelines have been published.
Lactic acidosis and severe hepatomegaly with steatosis have been reported rarely in patients undergoing treatment with lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. Severe acute exacerbations of hepatitis have been reported infrequently in patients who discontinue antiviral therapy. Thus, patients continuing treatment and patients who discontinue treatment require careful monitoring.
IFNs have both antiviral and immunomodulatory effects. Treatment with IFN alfa is appropriate for some patients with chronic hepatitis B.
In the 1990s, the most commonly used interferon was IFN alfa-2b. The medication was dosed at 5 million U subcutaneously (SC) every day for at least 16 weeks or 10 million U SC 3 times per week for at least 16 weeks. An elevation in the ALT level was common 8-12 weeks after the start of therapy. This change may have represented IFN-induced activation of the cell-mediated immune system.
The data indicate that PEG-IFN alfa-2a is more effective than nonpegylated IFN alfa. In one study of HBeAg-positive chronic hepatitis B, patients received a 48-week course of PEG-IFN alfa-2a 180 µg SC once weekly, and seroconversion from positivity for HBeAg to positivity for antibody to HBeAg (anti-HBe) was seen in 32% of patients. Reduction of serum HBV DNA from a mean of 1010 copies/mL to fewer than 105 copies/mL was seen in 32% of patients. ALT levels normalized in 41% of patients. Liver histology also improved in treated patients.
In HBeAg-negative chronic hepatitis B, a 48-week course of PEG-IFN alfa-2a 180 µg SC once weekly also produced promising results. Reduction of serum HBV DNA from a mean of 107 to fewer than 20,000 copies/mL was seen in 43% of patients. HBV DNA levels were reduced to fewer than 400 copies/mL in 19%. ALT values normalized in 59%. Liver histology improved in a significant number of patients. However, enthusiasm about using PEG-IFN alfa-2a in HBeAg-negative patients is tempered by a relatively high rate of virologic relapse.
Patients with HBV genotypes A and B appear to be good candidates for treatment with PEG-IFN alfa-2a. The drug might also be considered in young patients with a relatively brief history of HBV infection, an ALT level exceeding 100 U/L, and a relatively low serum HBV DNA level. IFN is less effective in patients with lifelong HBV infection, an ALT level below 100 U/L, a high HBV DNA level, end-stage renal disease (ESRD), HIV infection, or a need for immunosuppressive therapy (eg, after organ transplantation).
Adverse effects of IFN are common and lead to discontinuance in about 5-10% of patients. Such effects include flulike symptoms (eg, fatigue, fever, headache, myalgia, and arthralgia), neuropsychiatric symptoms (eg, depression, irritability, and somnolence), hematologic effects (eg, granulocytopenia and thrombocytopenia), and other miscellaneous effects (eg, pain at the injection site, dyspepsia, alopecia, and thyroid function abnormalities).
Because of their relative lack of side effects and their high rate of achieving undetectable HBV DNA levels, the oral nucleoside and nucleotide analogues attractive as potential first-line agents for HBV infection. However, treatment with PEG-IFN alfa-2a offers the hope of a finite course of treatment and the potential for achieving HBsAg negativity. In contrast, the oral agents are often prescribed for indefinite periods and only infrequently produce HBsAg negativity.
Nucleoside/nucleotide analogue therapy
Lamivudine is the negative enantiomer of 2’3’-dideoxy-3’-thiacytidine. This synthetic nucleoside analogue inhibits DNA polymerase–associated reverse transcriptase and can suppress HBV replication.
In patients with HBeAg-positive chronic hepatitis, lamivudine 100 mg/day orally for 1 year resulted in HBeAg seroconversion in about 20% of patients and achieved HBV DNA negativity in 36-44% of patients.[39, 42] In patients with HBeAg-negative chronic hepatitis, this regimen achieved HBV DNA negativity in 60-73% of patients. In both HBeAg-positive and HBeAg-negative patients, ALT levels and liver histology improved significantly. The rate of the development of hepatic fibrosis was reduced in a significant number of patients.
Early studies with lamivudine demonstrated that treatment in patients with HBeAg-positive chronic hepatitis should be continued for at least 6-12 months after seroconversion from HBeAg-positive to anti-HBe positive status. This helped to maximize the odds of maintaining a durable virologic response.
In patients with HBeAg-negative chronic hepatitis, however, it was learned that virologic relapse was almost invariable when treatment was discontinued. This led to the general dictum that patients with HBeAg-negative chronic hepatitis were likely to require indefinite treatment with a nucleoside analogue in order to keep viral loads suppressed.
The advantages of lamivudine over IFN included its ease of application and the virtual absence of adverse effects. Lamivudine was effective in populations whose HBV disease was generally not responsive to older formulations of IFN alfa (eg, persons with high HBV DNA levels). Lamivudine was also successful in some patients with decompensated hepatitis B–induced cirrhosis and some patients with recurrent hepatitis B after liver transplantation.
After December 1998, when the US Food and Drug Administration (FDA) approved lamivudine for the treatment of chronic hepatitis B in adults, problems with lamivudine therapy quickly became apparent. Approximately 24% of patients whose condition initially responded to lamivudine developed drug resistance within the first year of therapy. The incidence of lamivudine resistance increased to 69% after 5 years of therapy.
This finding was explained by the development of a mutation at the YMDD locus in the HBV DNA polymerase gene. The development of lamivudine resistance occasionally led to a reversion of the improvements seen on some liver biopsy specimens.
Adefovir dipivoxil is a synthetic nucleotide analogue that was approved by the FDA for treatment of chronic hepatitis B in adults in September 2002. This agent inhibits HBV DNA polymerase and causes DNA chain termination after its incorporation into viral DNA.
Adefovir dipivoxil is typically dosed at 10 mg orally once daily. Dose adjustments should be made for patients with creatinine clearances below 50 mL/min. Long-term use of adefovir dipivoxil has induced nephrotoxicity, particularly in patients with underlying renal dysfunction. It is recommended that patients undergo monitoring of their serum creatinine and phosphate while under treatment.
Adefovir dipivoxil 10 mg orally once daily for 48 weeks resulted in a mean drop in HBV DNA of 3.52 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and of 3.91 log10 copies/mL in patients with HBeAg-negative chronic hepatitis.
In patients with HBeAg-positive chronic hepatitis, negative HBV DNA findings were achieved in 6% of patients by week 48 of treatment and 46% of patients by week 144 of treatment. In patients with HBeAg-negative chronic hepatitis, negative HBV DNA findings were achieved in 64% of patients by week 48 of treatment and 79% of patients by week 144 of treatment. Most HBeAg-positive and HBeAg-negative patients experienced improvements in both ALT and liver histology results while receiving adefovir dipivoxil.
Resistance mutations developed in fewer than 2% of patients receiving long-term therapy with adefovir dipivoxil. The drug was also useful in patients who had previously developed resistance to lamivudine. Substitution of adefovir dipivoxil for lamivudine in such patients produced a 3-log10 drop in the number of HBV DNA copies/mL. Treatment with adefovir dipivoxil costs approximately $5300/y, compared with approximately $1700/y for lamivudine.
Entecavir is a deoxyguanine nucleoside analogue that inhibits priming of HBV DNA polymerase with a resulting decrease in HBV replication. It was approved by the FDA for treatment of chronic hepatitis B in adults in March 2005.
Entecavir is dosed at 0.5 mg orally once daily in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. In patients with a history of lamivudine-resistant chronic hepatitis B, it is dosed at 1 mg orally once per day. As with adefovir dipivoxil, dose adjustments should be made for patients with creatinine clearances below 50 mL/min and for patients receiving dialysis.
Entecavir 0.5 mg orally once daily for 48 weeks resulted in a mean drop in HBV DNA of 6.98 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and 5.20 log10 copies/mL in patients with HBeAg-negative chronic hepatitis. By 48 weeks, a negative HBV DNA was achieved in 69% of HBeAg-positive patients and 91% of HBeAg-negative patients. These results were superior to those seen with lamivudine 100 mg once daily for 48 weeks. Entecavir is currently regarded as a first-line oral therapy for chronic hepatitis B.
Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It received FDA approval in 2006.
By 52 weeks, treatment with telbivudine 600 mg/day reduced HBV DNA by 6.45 log10 copies/mL in patients with HBeAg-positive chronic hepatitis and 5.23 log10 copies/mL in patients with HBeAg-negative chronic hepatitis. A negative HBV DNA was achieved in 75% of patients with HBeAg-positive chronic hepatitis and 88% of patients with HBeAg-negative chronic hepatitis. Drug resistance was reported in 8-21% of patients.
Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate received FDA approval for the treatment of hepatitis B in 2008. Previously, this agent had received approval for use in HIV infection. Like adefovir, tenofovir is an oral nucleotide analogue and has been associated with nephrotoxicity; accordingly, renal function should be monitored in patients under treatment. Like entecavir, tenofovir is considered a first-line oral agent for the treatment of chronic hepatitis B.
Marcellin et al published their results comparing tenofovir to adefovir in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients were randomized to receive either tenofovir 300 mg or adefovir 10 mg (ratio, 2:1) once daily for 48 weeks.
At week 48 in HBeAg-positive patients, a serum HBV DNA below 69 IU/mL (400 copies/mL) was achieved in 76% of patients randomized to tenofovir and in 13% of those randomized to adefovir. At week 48 in HBeAg-negative patients, a serum HBV DNA below 69 IU/mL (400 copies/mL) was achieved in 93% of patients randomized to tenofovir and in 63% of those randomized to adefovir.
Patients underwent liver biopsy before treatment and at 48 weeks of therapy. A histologic response—defined as a reduction in liver inflammation without worsening fibrosis—was seen in approximately 70% of patients treated with either tenofovir or adefovir. Drug resistance was not reported in any of the patients under treatment with tenofovir.
Current data do not support the use of either a combination of interferon and a nucleoside analogue or a combination of 2 nucleoside analogues as first-line therapy for patients with chronic hepatitis B.
After the initiation of treatment with a nucleoside or nucleotide analogue, viral loads are typically followed every 3-6 months by means of PCR assay. Combination therapy may be appropriate either for patients who exhibit a suboptimal response to first-line therapy or those who show evidence of virologic breakthrough, defined as a 10-fold increase from the nadir HBV DNA level in a patient undergoing treatment.
Virologic breakthrough is often the hallmark of the development of virologic resistance to drug therapy. Such an event might necessitate either a switch to a new oral analogue with no cross-resistance to the first drug or the addition of a second oral agent to the original regimen. The optimal use of combination therapy remains to be determined. Recommendations for the management of drug-resistant HBV infection have been offered by the American Association for the Study of Liver Diseases and by Keeffe et al.
Management of HBV carriers undergoing chemotherapy or immunosuppression
Reactivation of HBV infection is a common event in HBV carriers who undergo either chemotherapy or immunosuppression for another indication. Typically, such reactivation is described in patients who are already HBsAg-positive; however, it is also described in patients who are negative for HBsAg and positive for anti-HBc and anti-HBs. In these circumstances, HBV reactivation has the potential to be severe or even life-threatening.
The practice guidelines of the American Association for the Study of Liver Diseases recommend that HBV carriers with a baseline HBV DNA below 2000 IU/mL undergo prophylactic antiviral therapy during their treatment and for 6 months after the conclusion of chemotherapy or a finite course of immunosuppressive therapy. Patients with a higher baseline HBV DNA should be treated until “they reach treatment endpoints as in immunocompetent patients.”
Acute Hepatitis C
Acute hepatitis C is detected infrequently. When it is identified, early IFN therapy should be considered. In one study, 44 patients with acute hepatitis C were treated with IFN alfa-2b at 5 million U/day SC for 4 weeks and then 3 times per week for another 20 weeks. About 98% of patients developed a sustained virologic response (SVR), defined as an undetectable level of serum HCV RNA 6 months after completion of antiviral treatment. Most experts now equate achievement of an SVR with viral eradication or cure of HCV infection.[48, 49]
Chronic Hepatitis C
Patients who are infected with HCV genotype 1 or 4 typically undergo treatment for 48 weeks. Those who are infected with HCV genotype 2 or 3 typically undergo treatment for 24 weeks. HCV RNA levels are usually rechecked 1 month and 3 months after treatment is started and every 3 months thereafter.
In HCV genotype 1 cases, patients who achieve viral load negativity 1 month into treatment (ie, a rapid virologic response [RVR]) have a greater than 90% likelihood of achieving an SVR. More typically, patients remain HCV RNA–positive at 1 and 3 months. If treatment cannot induce a 2-log10 drop in the viral load from baseline by week 12, the likelihood that the patient will achieve a SVR is less than 3%. Many physicians advise discontinuance of therapy in patients who do not manifest an early virologic response.
Longer treatment periods (up to 72 weeks) may be appropriate in patients infected with genotype 1 who are slow responders (ie, patients who achieved a 2-log10 drop in the viral load but did not achieve an undetectable HCV RNA level by week 12). In one study, a 38% SVR rate was seen in slow responders who continued treatment for 72 weeks, in contrast with the 18% SVR rate seen in slow responders who received treatment for the traditional 48 weeks.
Several trials have explored the utility of shortened courses of PEG-IFN and ribavirin for patients with genotypes 2 and 3. Although SVR may be achieved in some patients with as little as 12 to 16 weeks of therapy, overall SVR rates may be diminished. Thus, shortened treatment courses cannot be recommended for patients with genotypes 2 and 3 at this time.
Antiviral therapy has several major goals, including the following:
To decrease viral replication or eradicate HCV
To prevent progression of disease
To decrease the prevalence of cirrhosis
To decrease the frequency of HCC as a complication of cirrhosis
To ameliorate symptoms, such as fatigue and joint pain
To treat extrahepatic complications of HCV infection, such as cryoglobulinemia or glomerulonephritis
IFN has been the drug of choice for the treatment of hepatitis C for more than 2 decades. It is often used in combination with another drug, ribavirin. Successful IFN-based therapy, resulting in an SVR, can improve the natural history of chronic hepatitis C and may reduce the risk of HCC in patients with HCV-induced cirrhosis.[53, 54]
IFN-based therapy appears to reduce the rate of fibrosis progression in patients with HCV infection. One report described regression of cirrhosis in some—but not all—patients who responded well to antiviral therapy. In this study, 96 patients with biopsy-proven HCV-induced cirrhosis were treated with IFN-based therapy.
At a median interval of 17 months after the conclusion of antiviral therapy, patients underwent a second biopsy. 18 patients (19%) had a decrease in fibrosis score on follow-up biopsy, from stage 4 to less than stage 2. SVR had been achieved in 17 of these 18 patients. With a median follow-up of 118 months, these patients were found to have decreased liver-related morbidity and mortality compared with patients who were not histologic responders.
In this study, not all patients who achieved SVR experienced histologic improvements. Thus, it remains important to continue routine surveillance in patients with HCV cirrhosis—even if SVR is achieved through antiviral therapy—in order to rule out the development of HCC as a complication of cirrhosis.
Another report retrospectively assessed 920 patients with HCV-induced cirrhosis who underwent IFN therapy in the 1990s. The mean follow-up period was 96 months (range, 6-167). Achievement of SVR decreased patients’ risk for hepatic decompensation, HCC, and liver-related mortality.
When considering treatment of HCV infection, both the physician and the patient must be clear about the goals of therapy. As an example, in the patient with advanced fibrosis or cirrhosis, the goal of treatment is virologic cure in hopes of preventing progressive liver disease.
Unfortunately, SVR cannot be achieved in everyone. Achievement of SVR, though always desirable, is not always necessary to obtain a desired clinical result. Indeed, partial suppression of HCV through antiviral therapy may be all that is needed to stabilize renal function in a patient with HCV-related glomerulonephritis or to prevent the progression of malignancy in a patient with HCV-related non-Hodgkin lymphoma.
IFNs are a class of naturally occurring compounds that have both antiviral and immunomodulatory effects. They remain the backbone of antiviral strategies used against HCV infection. Agents currently approved by the FDA for the treatment of HCV infection include the following:
Consensus IFN, also known as IFN alfacon-1 (discontinued from market in September 2013)
Ribavirin, which is used in combination with IFN
The addition of a large, inert polyethylene glycol (PEG) molecule to a therapeutic molecule (eg, IFN) can delay the clearance of the therapeutic molecule from the bloodstream. Long-acting PEG-IFN alfa-2b and PEG-IFN alfa-2a are currently the most commonly used medications for hepatitis C therapy in the United States.
Other interferons under study include IFN beta, IFN gamma, and natural interferon. Future medications may target the enzymes responsible for HCV replication. Drugs that have activity against viral helicases, proteases, and polymerases are currently under study, as are ribozymes and antisense oligonucleotides.
Results of clinical trials
IFN alfa-2b, dosed at 3 million U SC 3 times per week, was approved by the FDA in 1991 for the treatment of chronic HCV infection. Patients treated with this agent—and with the subsequently introduced IFN alfa-2a and consensus IFN—had only an 11-12% chance of obtaining a SVR (ie, a persistently undetectable HCV RNA level).
Adding the nucleoside analogue ribavirin to IFN significantly improved patients’ responses to treatment. The SVR after 48 weeks of treatment improved from 13% in patients treated with IFN alfa-2b alone to 38% in patients treated with IFN alfa-2b in combination with ribavirin 1000-1200 mg/day orally. This combination therapy received approval from the FDA in 1998.
In 2000, the FDA approved PEG-IFN alfa-2b in combination with ribavirin. PEG-IFN alfa-2a received FDA approval in 2002. By delaying drug clearance from the bloodstream, pegylation allows each IFN to be administered subcutaneously once per week. Higher IFN blood levels are achieved when PEG-IFN is dosed once per week than when standard IFN is dosed 3 times per week. Typical dosing for PEG-IFN alfa-2b is 1-1.5 µg/kg/wk SC. PEG-IFN alfa-2a is dosed at 180 µg/wk. Typical ribavirin dosing is 800-1200 mg/day in 2 divided doses.
Studies with PEG-IFN alfa-2b and ribavirin showed a 42% SVR rate in patients with genotype 1 who were treated for 48 weeks and an 82% SVR rate in patients with genotypes 2 and 3. Studies with PEG-IFN alfa-2a and ribavirin showed a 46% SVR rate in patients with genotype 1 who were treated for 48 weeks and a 76% SVR rate in patients with genotypes 2 and 3.
Studies with PEG-IFN alfa-2b and ribavirin showed a 42% SVR rate in patients with genotype 1 who were treated for 48 weeks and an 82% SVR rate in patients with genotypes 2 and 3. Studies with PEG-IFN alfa-2a and ribavirin showed a 46% SVR rate in patients with genotype 1 who were treated for 48 weeks and a 76% SVR rate in patients with genotypes 2 and 3.
The 2 currently available PEG-IFNs appear to be relatively equivalent in terms of their efficacy and tolerability in patients with HCV genotype 1, as shown by the IDEAL (Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial, which randomized previously untreated patients with HCV genotype 1 to either PEG-IFN alfa-2b or PEG-IFN-alfa 2a in combination with ribavirin.
In the IDEAL trial, treatment with PEG-IFN alfa-2b at a dose of 1.5 µg/kg/wk produced a 40% SVR rate, and treatment with PEG-IFN alfa-2a produced a 41% SVR rate. Surprisingly, treatment with low-dose PEG-IFN alfa-2b at 1 µg/kg/wk produced a 38% SVR rate. These results were not statistically significant.
Factors predictive of an SVR to treatment with PEG-IFN in combination with ribavirin include the following:
Genotype 2 or 3 status
Baseline HCV RNA level < 800,000 IU/mL or < 2 million copies/mL
Compliance with treatment
Absence of cirrhosis
However, patients with well-compensated cirrhosis now have a reasonable likelihood of achieving viral eradication and should be offered IFN therapy, provided no significant contraindication (eg, severe thrombocytopenia) is present. Ideally, HCV eradication in the cirrhotic patient may prevent or forestall the development of progressive hepatic fibrosis and liver decompensation. Patients treated with IFN may also have a decreased risk of HCC.
If a patient ultimately requires liver transplantation for the treatment of complications of cirrhosis, previous eradication of HCV obviates any concerns about potentially severe recurrent hepatitis C after transplantation.
Repeat treatment of nonresponders
Approximately 11% of patients whose HCV disease was nonresponsive to combination therapy with IFN and ribavirin can achieve an SVR when treated with PEG-IFN in conjunction with ribavirin. A more vexing issue is the treatment of patients whose disease was nonresponsive to PEG-IFN combined with ribavirin.
Previously, chronic maintenance therapy with low-dose PEG-IFN was considered for patients with advanced fibrosis who were virologic nonresponders but had achieved some reduction in viral load while under treatment. However, neither the HALT-C trial (utilizing PEG-IFN-alfa-2a) nor the COPILOT trial (utilizing PEG-IFN-alfa-2b) were able to demonstrate any decrease in the incidence of liver decompensation, HCC, or liver-related death in patients undergoing maintenance therapy.
High-dose daily consensus IFN, in combination with ribavirin, has been used in patients with HCV genotype 1 who were nonresponders to standard treatment with PEG-IFN and ribavirin. The results of the DIRECT trial, in which daily consensus IFN (9 or 15 µg) was given with ribavirin to patients who were nonresponders to PEG-IFN treatment, have been reported.
In the DIRECT trial, 11% of the patients in the 15-µg group achieved SVR. However, when patients who had previously achieved a greater than 2-log10 decrease in HCV RNA were assessed, the SVR rate improved to 23% in the 15-µg group. High-dose daily consensus IFN with ribavirin is approved by the FDA for retreatment of patients with chronic hepatitis C who were nonresponders to PEG-IFN plus ribavirin.
Not all patients with chronic hepatitis C are appropriate candidates for therapy with IFN and ribavirin. First, the drugs have well-known adverse effects, which lead to discontinuance in approximately 15% of patients. IFN can induce fatigue, joint pain, emotional irritability, depression, and alopecia. Patients with underlying psychiatric disorders must be carefully screened before they receive a drug that can worsen underlying depression or schizophrenia or that can even induce suicidal ideation.
IFN can also induce the development of thyroid disease or exacerbate an underlying immune-mediated disease (eg, psoriasis or sarcoidosis).
It has long been recognized that adherence to prescribed doses of PEG-IFN and ribavirin will maximize a patient’s ability to achieve an SVR. Missed doses due to lack of patient compliance or to physician-ordered dose reductions (eg, on account of the new onset of anemia or cytopenias) will increase the chance for treatment failure.
Patients invariably need close clinical and laboratory follow-up during treatment. Treatment with PEG-IFN can induce neutropenia. In some patients with IFN-induced neutropenia, granulocyte colony-stimulating factor (G-SCF) must be added to the regimen in order to support a falling white blood cell (WBC) count.
Treatment with PEG-IFN can also induce thrombocytopenia. It was once assumed that most patients (typically cirrhotic) with baseline platelet counts lower then 70,000/µL would be unable to tolerate because of the induction of severe thrombocytopenia. Eltrombopag received FDA approval in November 2008 for the treatment of thrombocytopenia in cases of idiopathic thrombocytopenic purpura (ITP).
Eltrombopag was studied in patients with HCV-induced cirrhosis and platelet counts lower than 70,000/µL. Treatment with eltrombopag 75 mg orally once daily successfully improved platelet counts in 95% of the patients studied, permitting a majority to undergo IFN treatment. However, eltrombopag use has been associated with both venous thromboembolism and drug-induced liver injury. In the United States, the medication is only available through an FDA-mandated restricted-distribution program.
Ribavirin commonly produces rash and hemolytic anemia. Some patients with ribavirin-induced anemia need combination therapy with erythropoietin in order to support a falling hematocrit. In the author’s opinion, patients should undergo baseline cardiac stress testing, given the potential for patients to develop severe anemia.
Both IFN and ribavirin have been associated with a low risk of inducing retinopathy. In the author’s opinion, patients should undergo pretreatment and posttreatment ophthalmologic examinations.
The presence of insulin resistance may reduce the chance of achieving viral eradication with PEG-IFN and ribavirin. Excellent control of diabetes is recommended before patients embark on IFN-based therapy.
In spite of all of the potential concerns related to combination therapy with PEG-IFN and ribavirin, the vast majority of patients are able to tolerate their recommended 24-week (for genotypes 2 and 3) or 48-week (for genotypes 1 and 4) treatment course.
Treatment of special populations
Chronic renal failure
HCV infection is documented in 10-20% of patients receiving chronic hemodialysis. Anti-HCV therapy is often appropriate for such patients. Attempts to eradicate HCV should be made before renal transplantation is carried out. Indeed, the hepatic histologic abnormalities attributed to HCV infection may worsen dramatically after posttransplant immunosuppressant therapy is started.
Reduced doses of PEG-IFN are typically used. Ribavirin should be avoided in all patients with renal insufficiency and in patients receiving hemodialysis because of the increased risk of severe hemolytic anemia.
Approximately one third of the 1 million Americans infected with HIV are coinfected with HCV. Approximately 10% of all HCV-infected Americans are coinfected with HIV. Therefore, HIV testing should be routine in patients with diagnosed with HCV infection.
HIV-infected individuals appear to have an impaired immune response to HCV infection. This translates into more rapid progression of hepatic fibrosis and higher rates of liver-related death in coinfected patients than in those with only HCV infection. Indeed, HCV-induced cirrhosis is now a major cause of death in the HIV-infected population in the United States.
Accordingly, physicians are now more aggressive than they once were with respect to diagnosing and treating HCV infection in their HIV-infected patients. It also appears that suppression of HCV by means of IFN therapy may improve a patient’s ability to tolerate antiretroviral therapy. Drug-induced hepatotoxicity is common in patients treated with antiretroviral therapy.
Treatment with PEG-IFN and ribavirin is usually offered to patients with a CD4 cell count higher than 200/µL. CD-4 cell counts lower than 200/µL—and certainly those lower than 100/µL—are associated with a poor response to therapy.
In general, HIV-infected patients tolerate treatment well. However, significant neutropenia, thrombocytopenia, and anemia may develop. A few case reports describe mitochondrial toxicity and lactic acidosis when IFN and ribavirin are used in combination with dideoxyinosine, zidovudine, stavudine, and efavirenz. Pancreatitis has been described in patients receiving IFN and dideoxyinosine.
Since the introduction of IFN therapy, patients with HIV-HCV coinfection have generally had a diminished rate of hepatitis C SVR in comparison with patients without HIV infection. However, in a 2004 study of coinfected patients who received PEG-IFN alfa-2a 180 µg SC once weekly and ribavirin 800 mg/day orally, patients with genotype 1 had a 29% SVR rate, and those with genotype 2 or 3 had a 62% SVR rate.
There are multiple reports of liver transplantation being successfully performed to treat decompensated HCV-induced cirrhosis in coinfected patients. Potential candidates for transplantation include patients who have achieved a negative HIV viral load through antiretroviral therapy.
On the whole, however, 2-year posttransplant survival rates are lower in patients coinfected with HIV and HCV than in patients infected with HCV alone. At present, only a small percentage of the more than 100 transplantation programs in the US are performing liver transplantation in HIV-infected patients.
Newer therapeutic agents
It is likely that the ongoing development of direct-acting antiviral drugs (DAAs) will improve treatment options for patients infected with hepatitis C. More than 2 dozen DAAs are being studied in clinical trials. These drugs, previously known as specifically targeted antiviral therapy for HCV drugs (STAT-C drugs), target different aspects of the HCV life cycle and thus fall into different categories, as follows:
Nucleoside NS5B polymerase inhibitors
Nonnucleoside NS5B polymerase inhibitors
Viral entry inhibitors
NS3/4a protease inhibitors, such as telaprevir and boceprevir
Telaprevir and boceprevir inhibit the ability of HCV’s nonstructural 3/4a serine protease to cleave the viral polyprotein into independent HCV proteins. This is an important step in suppressing replication of HCV. It is hoped that these drugs—in combination with PEG-IFN and ribavirin—will produce early virologic suppression, improve SVR rates, and shorten the of duration treatment while causing minimal toxicity.
The clinical trials investigating telaprevir and boceprevir have used different sorts of designs. With telaprevir, the protease inhibitor was employed first, in an effort to produce a rapid reduction in HCV viral load that would increase the chance of SVR when PEG-IFN and ribavirin were added. In the boceprevir trials, PEG-IFN and ribavirin were used in a lead-in phase, in the hope of reducing the HCV viral load and thereby decreasing the odds that a resistance mutation to the protease inhibitor might emerge.
The work being done on DAAs raises hopes that IFN-free regimens for the treatment of HCV infection may become generally available. The ease of administration of an oral HCV treatment regimen might improve patients’ access to therapy and, ultimately, decrease the morbidity and mortality associated with hepatitis C.
Two similar protocols, PROVE1 (Protease Inhibition for Viral Evaluation 1) and PROVE2, assessed the efficacy of telaprevir when it was added to a standard regimen of PEG-IFN alfa-2a plus ribavirin. Both trials studied previously untreated patients infected with HCV genotype 1.
In PROVE1, patients who were randomized to receive telaprevir plus PEG-IFN alfa-2a plus ribavirin for 12 weeks, followed by PEG-IFN alfa-2a plus ribavirin for 36 additional weeks, achieved a 67% SVR rate. This was significantly higher than the 41% SVR rate achieved in patients treated with a standard 48-week course of PEG-IFN alfa-2a plus ribavirin.
In PROVE2, patients who were randomized to receive telaprevir plus PEG-IFNalfa-2a plus ribavirin for 12 weeks, followed by PEG-IFNalfa-2a plus ribavirin for 12 additional weeks, achieved a 69% SVR rate. This was significantly higher than the 46% SVR rate achieved in patients treated with standard PEG-IFN alfa-2a plus ribavirin for 48 weeks.
Rash and pruritus were common adverse events. Severe rash was noted in 11% of telaprevir-treated patients in PROVE1 and 5% of telaprevir-treated patients in PROVE2 but was uncommon in patients treated with standard therapy. Treatment discontinuance rates were also higher in telaprevir-treated patients. Treatment was discontinued because of adverse events in 21% of telaprevir-treated patients in PROVE 1 and 12% of telaprevir-treated patients in PROVE 2 but in only 11% and 7%, respectively, of patients treated with standard therapy.
In the PROVE3 trial, which addressed prior relapsers and nonresponders to PEG-IFN and ribavirin, patients who were randomized to one of the telaprevir arms of the study received telaprevir and PEG-IFN alfa-2a (with or without ribavirin) concurrently for 12-24 weeks. In all, 453 patients with genotype 1 were randomized to 1 of the following 4 regimens:
- T12/PR 24
- T24/P24 without ribavirin
- PR 48 (ie, standard care)
Thirty-eight percent of the patients had bridging fibrosis or cirrhosis. SVR rates for the 4 regimens in prior relapsers were 69%, 76%, 42%, and 20%, respectively. SVR rates for the 4 regimens in prior nonresponders were 39%, 38%, 11%, and 9%, respectively. These results suggest that patients who were previously nonresponders may soon have promising drug therapy available to them. The data also demonstrate the importance of including ribavirin in retreatment regimens.
Preliminary results from the ongoing multinational HEP3002 trial appears to indicate that triple therapy with telaprevir, pegylated-interferon-alpha (PEG-IFNa), and ribavirin is safe and provides effective virologic response in patients with compensated advanced hepatitis C liver fibrosis. Of 1587 patients with HCV-1 infection and bridging fibrosis or compensated cirrhosis who completed 12 weeks of triple therapy followed by 4 weeks of PEG-IFN plus ribavirin, 88% of patients with relapsed disease had nondetectable HCV RNA at 12 weeks, followed by 85% of treatment-naïve patients, 80% of patients with partial treatment response, and 72% of those with null response.
Grade 1-4 anemia occurred in 59% of patients (n=931), of which age and female sex were highly predictive; the anemias were managed with ribavirin dose reduction (40%), administration of erythropoietin (21%), and transfusion (10%). In all, 7 patients died (0.4%), 193 patients required discontinuation of telaprevir owing to adverse events, and 64 patients (12%) developed a grade 3/4 rash.
SPRINT-1 (Serine Protease Inhibitor Therapy-1), a phase II trial that studied boceprevir in combination with PEG-IFN alfa-2b plus ribavirin in previously untreated patients infected with HCV genotype 1, found that concurrent treatment with PEG-IFN alfa-2b, ribavirin, and boceprevir yielded an SVR rate of 54% (58 of 107) in patients treated for 28 weeks. In patients treated with a 4-week lead-in phase of PEG-IFN alfa-2b plus ribavirin, followed by 24 weeks of triple therapy, the SVR was comparable: 56% (58 of 103).
Longer courses of treatment resulted in an improved SVR rate. In patients treated with 48 weeks of triple therapy, the SVR rate was 67% (69 of 103). When a 4-week lead-in phase of PEG-IFN alfa-2b and ribavirin was used, followed by 44 weeks of triple therapy, the SVR rate increased to 75% (77 of 103).
Each of the treatment arms using boceprevir demonstrated a statistically significant improvement in the SVR rate in comparison with the 38% SVR rate seen in the control group receiving standard-of-care PEG-IFN plus ribavirin.
SVR rates also improved for black patients and for patients with cirrhosis. Black patients had an SVR rate of 13% when treated with standard-of-care PEG-IFN plus ribavirin but had SVR rates as high as 53% when treated with PEG-IFN, ribavirin, and boceprevir for 48 weeks. In cirrhotic patients, the SVR rate improved from 25% in patients treated with standard-of-care PEG-IFN plus ribavirin to 67% when a long course of boceprevir was added.
The most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea, dysgeusia, and headache. Treatment was discontinued because of the adverse events in 9-19% of patients receiving boceprevir, compared with 8% of patients receiving standard-of-care PEG-IFN plus ribavirin.
When a subanalysis of the SPRINT-1 data was performed, as many as 55% of patients who had a null response after 4 weeks of treatment with PEG-IFN alfa-2b plus ribavirin actually achieved an SVR when boceprevir was added to the regimen. However, it is not entirely clear to what extent these data can be extrapolated to assess the efficacy of triple therapy in previous nonresponders to PEG-IFN and ribavirin.
RG7128 and danoprevir
In INFORM-1, a trial that studied RG7128 (an oral inhibitor of the HCV NS5B RNA polymerase) and danoprevir (an oral HCV NS3/4A protease inhibitor), the combination of medicines produced up to a 5.2 log10 IU/mL decrease in patients’ HCV RNA viral loads over a 14-day treatment course. Resistance mutations to danoprevir did not emerge during the trial.
Treatment of Hepatitis D and E
Treatment of patients coinfected with HBV and HDV has not been well studied. Multiple small studies have demonstrated that patients with HBV-HDV coinfection are less responsive to IFN therapy than patients with HBV infection alone. Treatment with PEG-IFN alfa-2b produced HDV RNA negativity in only 17-19% of patients.[74, 75] Lamivudine appears to be ineffective against HBV-HDV coinfection.[76, 77]
Treatment of patients infected with HEV is supportive in nature.
Improved sanitation, strict personal hygiene, and hand washing all may help prevent transmission of HAV. The virus is inactivated by household bleach or by heating to 85°C for 1 minute. In addition, travelers to endemic areas should not drink untreated water or ingest raw seafood or shellfish. Fruits and vegetables should not be eaten unless they are cooked or can be peeled.
In 1995, the US Food and Drug Administration (FDA) approved the first vaccine for HAV. Beginning in 1996, the Centers for Disease Control and Prevention (CDC) recommended vaccination against HAV for the following individuals:
People traveling to regions where HAV is endemic
Men who have sex with men
Users of illicit drugs
Beginning in 1999, the CDC recommended vaccination for children living in 17 states with consistently elevated rates of HAV infection. Since 2006, the CDC has recommended vaccination for all children at 1 year of age. It has encouraged “catchup” vaccination programs for unvaccinated children.
Active immunization with HAV vaccine is also recommended for the following individuals:
Persons with an occupational risk of infection (eg, persons working with HAV-infected primates)
Patients who may receive clotting factor concentrates
“Susceptible persons with chronic liver disease” 
“Susceptible persons who are either awaiting or have received liver transplants” 
The third recommendation stemmed from the observation that patients with chronic liver disease, though not at increased risk for exposure to HAV, were at increased risk for fulminant hepatic failure (FHF) if they were infected with the virus. Notably, there are data to suggest that workers exposed to raw sewage do not have a higher prevalence of antibodies to HAV than a comparator population.
The inactivated HAV vaccines Havrix (GlaxoSmithKline, Research Triangle Park, NC) and Vaqta (Merck, Whitehouse Station, NJ) are administered as 1-mL (0.5-mL in children) intramuscular (IM) injections given more than 1 month before anticipated travel. This approach results in a better-than-90% likelihood of stimulating production of immunoglobulin G (IgG) anti-HAV, with resulting immunity against HAV infection.
A booster dose of the vaccine is recommended 6 months after the initial vaccination. Whether HAV vaccine administration should be mandated in children (as HBV vaccination is) remains unclear.
An alternative vaccine, containing inactivated HAV and recombinant HBV vaccines, is Twinrix (GlaxoSmithKline). This product is immunogenic against both HAV and HBV. The FDA has approved its use in adults. Typical administration involves 3 injections of 1 mL given IM on a 0-, 1-, and 6-month schedule. Alternatively, a 4-dose schedule can be used, with Twinrix administered on days 0, 7, and 21-30, followed by a booster dose at month 12.
Passive postexposure immunization with hepatitis A immune globulin (HAIG) is an alternative to active immunization with HAV vaccine. Its effectiveness is highest when it is given within 48 hours of exposure, but it may be helpful when given as far as 2 weeks into the incubation period.
Postexposure prophylaxis with HAIG is appropriate for household and intimate contacts of patients with HAV. It is also recommended for contacts at daycare centers and institutions. Typical dosing of HAIG is 0.02 mL/kg IM as a single dose. Postexposure prophylaxis is not recommended for the casual contacts of patients, such as classmates or coworkers.
For travelers who anticipate spending less than 3 months in an HAV-endemic region, the dose is 0.02 mL/kg IM. Travelers who are planning to spend more than 3 months in a region where HAV is endemic should receive 0.06 mL/kg IM every 4-6 months.
Plasma-derived and recombinant HBV vaccines use HBsAg to stimulate the production of anti-HBs in noninfected individuals. The vaccines are highly effective, with a greater than 95% rate of seroconversion. Vaccine administration is recommended for all infants as part of the usual immunization schedule, as well as for adults at high risk of infection (eg, those receiving dialysis and healthcare workers). Recommendations for hepatitis B vaccination are available from the CDC.
The recommended vaccination schedule for infants consists of an initial vaccination at the time of birth (ie, before hospital discharge), a repeat vaccination at 1-2 months, and another repeat vaccination at 6-18 months. The recommended vaccination schedule for adults consists of an initial vaccination, a repeat vaccination at 1 month, and another repeat vaccination at 6 months. If Twinrix (the combined HAV-HBV vaccine) is used, it is given according to the schedule previously described for hepatitis A.
Because of the nonresponse rate, many recommend that health care workers undergo postvaccination testing to confirm response within 1-2 months of receiving the vaccine. The duration of immunity conferred by the vaccine is not clearly known. Some authors recommend that a booster be given at 5-10 years.
HBV infection is endemic in Taiwan. The institution of universal vaccination for neonates in 1984 reduced the HBsAg carrier rate in children from 9.8% to 0.7% over a period of 15 years. There was a resulting drop in the incidence of HCC in children from 0.54 to 0.20 per 100,000. Follow-up studies are needed to determine whether the overall incidence of HCC in Taiwan decreases as these children enter adulthood.
Hepatitis B immune globulin (HBIG) is derived from plasma. It provides passive immunization for individuals who describe recent exposure to a patient infected with HBV. HBIG is also administered after liver transplantation to persons infected with HBV in order to prevent HBV-induced damage to the liver allograft.
Recommendations for postexposure prophylaxis for contacts of patients positive for HBsAg are as follows:
Perinatal exposure – HBIG plus HBV vaccine at the time of birth (90% effective)
Sexual contact with an acutely infected patient – HBIG plus HBV vaccine
Sexual contact with a chronic carrier – HBV vaccine
Household contact with an acutely infected patient – None
Household contact with an acutely infected person resulting in known exposure – HBIG, with or without HBV vaccine
Infant (< 12 mo) primarily cared for by an acutely infected patient – HBIG, with or without HBV vaccine
Inadvertent percutaneous or permucosal exposure – HBIG, with or without HBV vaccine
No vaccine against HCV is available, and immune globulin is not proven to prevent transmission. In fact, immune globulin administration has been associated with HCV. At present, the major means of preventing transmission of HCV is to prevent infected blood, organs, and semen from entering the donor pools.
Hepatitis D and E
Because HDV can infect patients only when HBV is present, transmission of hepatitis D can be decreased by effectively immunizing patients against HBV. Unfortunately, at this time, no means of preventing HDV superinfection in patients with chronic HBV is known.
No vaccine exists for the prevention of HEV infection. Administration of immune globulin does not prevent the development of clinical disease.
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|Test||CHB HBeAg Positive||CHB HBeAg Negative||Inactive Carrier|
|HBV DNA||>2 × 104 IU/mL*
|>2 × 103 IU/mL
|< 2 × 103 IU/mL
(< 104 copies/mL)
|ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to HBeAg; anti-HBs = antibody to HBsAg; CHB = chronic hepatitis B; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M.
*Increasingly, experts in the field use IU/mL rather than copies/mL.
|Grade||Portal Inflammation||Interface Hepatitis||Lobular Necrosis|
|1 - Minimal||Mild||Scant||None|
|2 - Mild||Mild||Mild||Scant|
|3 - Moderate||Moderate||Moderate||Spotty|
|4 - Severe||Marked||Marked||Confluent|