How Do I Treat a Patient Who Is Coinfected With Chronic Hepatitis B and C Viruses?
Mitchell L.
Shiffman,
MD
Both the hepatitis B virus (HBV) and hepatitis C virus (HCV) are transmitted via percutaneous exposure and, as a result, it is not surprising that some patients acquire both viruses either simultaneously or sequentially. In general, HBV is far easier to transmit than HCV. This is because the serum level of HBV is on the order of 10-fold to 100-fold greater than HCV and that HBV is also found in high concentrations in many other body fluids. As a result, HBV can be transmitted vertically from mother to infant and also sexually through intimate contact. In contrast, the concentration of HCV in body fluids is significantly lower than in the bloodstream and, as a result, it is uncommon for HCV to be transmitted vertically or through sexual activity except in the case of human immunodeficiency virus (HIV) coinfection (see Questions 14 and 15). Thus, the vast majority of patients who are coinfected with HCV and HBV acquired these viruses by utilizing intravenous drugs or through other high-risk percutaneous exposures.
Evaluation of Patients With Coinfection
Over 90% of adults exposed to HBV develop acute icteric hepatitis, mount an appropriate immune response, spontaneously resolve this virus, and develop anti-hepatitis B surface (anti-HBs). Those patients who develop chronic HBV remain hepatitis B surface antigen (HbsAg) positive. In contrast, most persons exposed to HCV develop an acute hepatitis without becoming icteric and approximately 80 to 85% develop chronic infection. All individuals exposed to HCV, whether they develop chronic infection or resolve this virus, are anti-HCV positive. When individuals become coinfected with HBV and HCV, 1 of 4 scenarios may occur: they may resolve HBV and develop chronic HCV; they may resolve HCV and develop chronic HBV; they may resolve both viruses; or they may develop chronic infection with both HBV and HCV.1 These possibilities can be recognized by serologic and virologic testing for these two viruses, as outlined in Table 13-1.
In some cases of HBV and HCV coinfection, one of the two viruses may inhibit the other.2 This is often because one of the viruses is replicating at a much faster rate and inhibiting the replication of the other. After treatment and eradication of the dominant virus the other virus may then become active. An example of this is provided in Figure 13-1. This patient with E-antigen–negative HBV has high levels of HBV DNA and undetectable HCV RNA at baseline. An oral antiviral agent is initiated for the treatment of HBV, and as the serum level of HBV DNA declines, HCV RNA appears in serum. In some cases, depending upon the treatment utilized (see below), reactivation of the apparently dormant virus may not occur until after the treatment has been discontinued. This is most commonly seen with peginterferon since this agent has activity against both of these viruses. It is therefore important that patients with coinfection be monitored on a regular basis for both viruses during and after treatment, even though one of the viruses may be inactive at the time treatment is initiated.
Figure 13-1. HBV DNA and HCV RNA over time in a patient with serologic evidence of both HBV and HCV infection. At baseline the patient was positive for HB surface antigen, anti-HCV and HBV DNA. However, HCV RNA was undetectable. After treatment with adefovir dipivoxil (ADV) was initiated HBV DNA declined. However, when HBV DNA became undetectable HCV RNA began to rise.
Patients with serologic markers for HBV and HCV may have undetectable HBV DNA and HCV RNA and therefore appear to have resolved both of these viral infections. However, another possible explanation for this finding is that these patients have triple infection with hepatitis D virus (HDV). In this setting, the high replication rate of HDV may suppress both HBV and HCV to levels that are undetectable by current virologic assays. As a result, patients with HBV and HCV coinfection should be tested for HDV.3
Treatment of Patients With Coinfection
The indications, factors to consider, and need for liver biopsy prior to initiating treatment in a patient with HBV and HCV coinfection are basically the same as in patients with only an HCV or HBV infection, as discussed in Questions 3, 9, and 10. However, the role and need for liver biopsy prior to initiating treatment may be more important in patients with coinfection, particularly when one of the two viruses is inactive or dormant. As noted above, in the setting of coinfection, one virus may inhibit the replication of the other. Thus, if the active virus is not causing significant liver injury, as assessed by liver histology, treatment may actually worsen the situation by causing reactivation of the previously dormant virus. Thus, all patients with HBV and HCV coinfection should be thoroughly evaluated and all of the implications of treatment should be carefully weighed before treatment is initiated.
Patients with E-antigen–positive HBV and HCV coinfection are excellent candidates for treatment with peginterferon alfa-2a since this medication is indicated and approved for both viral infections.4 Although ribavirin is not useful in the treatment of HBV, this medication significantly enhances the likelihood that the HCV coinfection will be treated successfully. Such patients should therefore be started on standard doses of combination therapy (peinterferon alfa-2a 180 mcg/wk and ribavirin 1000 to 1200 mg/d). There are currently no data to suggest that coinfection alters the response of either of these viruses to peginterferon. Once treatment is initiated, HCV RNA should be monitored at regular intervals as outlined in Question 4. If the patient with HCV genotype 1 fails to achieve an early virologic response, ribavirin should be stopped and peginterferon continued for another 24 weeks to complete the 48-week treatment course recommended for HBV infection. If HCV RNA responds to treatment and becomes undetectable within 24 weeks of treatment, then both peginterferon and ribavirin should be continued for the appropriate duration of therapy based upon the HCV genotype, as discussed in Question 4. Patients should then be monitored at regular intervals for sustained virologic response or relapse in the case of HCV and for seroconversion in the case of HBV. If seroconversion does not occur within 6 months after discontinuing treatment, then the use of an oral antiviral agent to treat HBV can be considered.
Patients with E-antigen–negative HBV and HCV coinfection should also be treated with peginterferon and ribavirin. Although seroconversion does not occur in patients with E-antigen–negative HBV, approximately 33% of these patients do respond to peginterferon, become HBV DNA undetectable, and remain so for many years after this treatment has been completed. If the HBV infection does not respond to peginterferon or reactivates at some time after this treatment is completed, than the use of an oral antiviral agent for treatment of HBV can be considered.
In patients where HBV is either inactive or dormant, the HCV infection can be treated with peginterferon and ribavirin. Patients with active HBV but dormant or resolved HCV can be treated with either peginterferon or an oral antiviral agent. However, with either scenario, both viruses should be monitored on a regular basis during and after treatment to ensure that reactivation of the previously inactive or dormant virus has not occurred. This is especially important in those patients where the active virus has responded to treatment.
References
1. Squadrito G, Orlando ME, Pollicino T, et al. Virological profiles in patients with chronic hepatitis C and overt or occult HBV infection. Am J Gastroenterol. 2002;97:1518-1523.
2. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med. 1999;341:22-26.
3. Shukla NB, Poles MA. Hepatitis B virus infection: co-infection with hepatitis C virus, hepatitis D virus, and human immunodeficiency virus. Clin Liver Dis. 2004;8:445-460.
4. Urganci N, Gulec S, Dogan S, Nuhoglu A. Interferon and ribavirin treatment results of patients with HBV-HCV co-infection cured of childhood malignancies. Int J Infect Dis. 2006;10:453-457.