Chronic hepatitis B (CHB) infection affects approximately 240 million persons worldwide and 800,000 to 1.4 million persons in the United States.1, 2 Due to shared modes of transmission, patients with CHB may also have concomitant infection with hepatitis delta virus (HDV), human immunodeficiency virus (HIV), and/or hepatitis C virus (HCV). Patients who are diagnosed with CHB therefore should be tested for the presence of coinfections, as the prognosis and management of coexisting disease is variable.3 Once a coinfected patient is identified, testing for virus-specific genotype, RNA/DNA levels, replication markers, and markers for hepatic synthetic function should be obtained to determine the need for intervention and liver biopsy.
The unique aspects of managing the coinfected patient lie in understanding the interactions between the specific viruses and how the presence of one virus may suppress or enhance the activity of the other virus and vice versa. This interaction is dependent on the order of virus acquisition (simultaneously or separately), and whether the virus is acquired early or later (i.e., HIV patients with compromised immune function). The decision to initiate therapy ultimately depends on disease severity, which virus predominates, and patient tolerance.
chronic hepatitis B
chronic hepatitis D
highly active antiretroviral therapy
hepatitis C virus
hepatitis delta virus
human immunodeficiency virus
Hepatitis B Virus and HDV
HDV is an RNA virus that depends on the presence of hepatitis B virus (HBV) surface antigen for binding to hepatocytes and virion assembly. Approximately 15 to 20 million persons (5%-8% of HBsAg carriers) worldwide are coinfected with HDV.4 In North America, coinfection is mainly observed among intravenous drug users and immigrants from HDV prevalent nations. The presence of coinfection can be confirmed by testing for HDV RNA, immunoglobulin M anti-HDV, or staining liver tissue for HDV antigen. However, total (immunoglobulin G and M) anti-HDV is the most widely available laboratory test in the United States, while HDV RNA can be used to assess efficacy of treatment.
There are two major patterns of HDV acquisition: (1) simultaneous exposure to both HBV and HDV, or (2) HDV superinfection in the setting of preexisting CHB. Among adult patients exposed to both HDV and HBV, recovery and viral clearance is highly likely, and only 2% of patients progress to chronic HDV. In contrast, superinfection with HDV among patients with CHB almost always results in progression to chronic hepatitis D (CHD). In most CHD coinfection, HBV is spontaneously repressed; however, some patients (during later stages) may have HBV dominance. The four HDV genotypes may vary in clinical course; however, the degree of viremia does not necessarily correlate with degree of liver injury. Approximately half of CHD patients develop cirrhosis within 2 to 14 years and adverse outcomes within 11 years. The risk for development of hepatocellular carcinoma (HCC) is high but ill defined. CHD patients are at increased risk for the development of hepatic decompensation and death.
CHD is difficult to treat and there continues to be a lack of randomized controlled trials to determine the ideal treatment regimen. Management options remain sparse as only standard interferon (IFN)-α and pegylated IFN (Peg-IFN)-α are available. The primary endpoint is to suppress HDV replication, but the only true reliable marker of HDV clearance is loss of HBsAg. Response rates remain poor. Among patients who received standard IFN for 1 year, 10% to 25% achieved disease remission, but with high relapse rates. Peg-IFN response rates range from 17% to 43%.5 Parameters for predicting response are unknown, and the duration of treatment prior to considering patients as nonresponders is not clear. Data regarding the benefits of therapy (histological improvement, survival) are also conflicting. Therefore, given the relatively severe course of disease, therapy with Peg-IFN for a minimum of 1 year should be considered for those with active disease demonstrated by elevated liver enzymes and chronic hepatitis on liver biopsy.
HBV and HIV
Approximately 34.2 million persons worldwide are infected with HIV with an estimated 6% to 13% of those coinfected with HBV.3, 6 HIV-positive patients are more likely to develop CHB compared with HIV-negative patients (25% versus 5%).7 Coinfected patients are also more likely to develop “occult HBV” infection defined as positive HBV DNA, positive anti-HBc, but negative HBsAg. Therefore, HIV patients should be screened with both HBsAg and anti-HBc (positive in 10%-15% of HIV patients).
Much of the natural history of HBV and HIV coinfection has changed with the development of highly active antiretroviral therapy (HAART). Prior to effective HAART, the majority of the morbidity and mortality were HIV-related. Currently, well-managed HIV patients have longer life expectancy, which has resulted in an increased incidence of liver-related mortality, decompensation, and HCC.8 Liver-related mortality rates are significantly higher among CHB/HIV patients compared with patients with HBV or HIV monoinfection (14.2 per 1,000 HBV/HIV-infected persons compared with 1.7 per 1,000 HIV-infected persons and 0.8 per 1,000 HBV-infected persons).9 Data regarding progression to cirrhosis and HCC are unclear, as patients do not routinely require liver biopsy prior to initiation of HBV/HIV therapy.
Regardless of CD4 count, current guidelines strongly recommend initiating HAART among all patients with HIV and CHB.10 The type of antiviral regimen depends on whether the patient is amenable to initiating, wishes to defer, or already is on HAART (Fig. 1).3, 11 When HAART is being initiated, antivirals that are both active against HBV and HIV are preferred (Table 1). The suggested starting regimen is tenofovir combined with either emtricitibine or lamivudine. In the event tenofovir cannot be used, entecavir is an alternative. If HAART is already in place, and patients are not on antivirals active against HBV, the regimen may be changed accordingly to include tenofovir, or the addition of entecavir may be considered. In patients who are already on lamivudine, tenofovir should be added or substituted accordingly to account for potential lamivudine resistance. In the rare case when HAART is not initiated, care should be taken to select antivirals that have no activity against HIV in order to prevent the development of resistance. Entecavir and telbivudine should not be used to treat HBV alone without concurrent HAART therapy. These patients may receive Peg-IFN-α or adefovir.12
Table 1. Antiviral Activity
Although it does not target HIV, telbivudine should not be used without concurrent HAART.
Low doses (10 mg) have no HIV activity; however, higher doses do have activity against HIV.
In general, loss of HBsAg is <5% among coinfected patients; consequently, the goal of therapy is to suppress viral replication and prevent progression of liver disease, thus potentially requiring lifelong treatment. The histological outcomes of HBV and or HIV treatment are not well defined, and further studies are necessary to determine the effectiveness of coinfection therapy. Therefore, therapy should be individualized and patients counseled accordingly (Table 2). Hepatitis flares may occur during the course of therapy and may be due to improvement in immune status, patient noncompliance, or provider exchange of an anti-HBV medication for another without HBV activity.13
Table 2. HBV and HIV Coinfection Management
IFN and ribavirin are contraindicated during pregnancy; all pregnant HBV/HIV patients should initiate HAART with tenofovir plus lamivudine or emtricitibine
Ongoing behaviors placing patient at continued risk for superinfection with HDV, HAV, or HCV
Hepatitis A vaccination
Identify and counsel patients regarding safe sexual practices, alcohol cessation, and the need for vaccination
Avoid raw shellfish
Raw shellfish can be associated with vibro infection
Evaluate HBV activity with HBeAg, HBV DNA, prior to and during therapy
Patients with HBV DNA >2,000 IU/L and abnormal liver enzymes should initiate HBV therapy with HAART
Evaluate severity of liver disease with liver transaminases and synthetic function tests
Patients with cirrhosis (classic examination findings) should initiate HBV therapy with HAART; if uncertain of disease severity (i.e., normal enzymes, but with DNA >2,000), a biopsy may be helpful
Screen all coinfected patients for HCC
Review prior HAART therapy and determine potential HBV and HIV drug resistence
Abrupt cessation of therapy may lead to hepatitis flares
Educate patient about medication compliance
HBV/HIV-coinfected patients should receive HAART that includes tenofovir plus lamivudine or emtricitibine
Discuss benefits of HAART that includes anti-HBV activity
HBV and HCV
Approximately 3.9 million people in the United States and 150 million people worldwide are infected with HCV.2 Coinfection with HCV is observed among 10% to 15% of patients with CHB. Coinfected patients have higher rates of development of cirrhosis, HCC, and mortality compared with HBV monoinfection.3 HCV is usually the dominant virus, and standard treatment with Peg-IFN, ribavirin, and a direct-acting antiviral is available for HCV. However, there are no data regarding response rates to triple therapy among HCV/HBV-coinfected patients. The overall rate of sustained virologic response to dual therapy varies depending on many factors, including HCV genotype and the interleukin-28B genotype. Among a Taiwanese HCV/HBV-coinfected population in which the interleukin-28B CC genotype is common, up to 72% of those with genotype 1 and 83% with genotypes 2 and 3 achieved sustained virologic response. In some patients, Peg-IFN may also suppress HBV DNA and result in HBeAg loss or HBeAg seroconversion. The rate of HBsAg seroclearance is up to 11%. Of note, previously undetectable HBV DNA may become detectable with HCV therapy, although not necessarily associated with hepatitis flares.14 Therefore, HBV DNA should be monitored during treatment.
The natural history of CHB coinfection is relatively unclear due to the lack of prospective biopsy data. However, coinfected patients have significantly higher mortality rates compared with their monoinfected counterparts. In HBV/HDV and HBV/HCV coinfection, HDV and HCV typically suppress HBV DNA, and therefore therapy is aimed toward the dominant virus. However, in HBV/HIV coinfection, disease activity is enhanced. Treatment of CHB coinfection unfortunately remains a challenge for providers, and current goals are to prevent progression to cirrhosis and the development of HCC. The choice of which virus to treat reflects the individual markers of viral activity (HBeAg, DNA levels, HCV RNA levels, CD4 count). The key to management is to first identify and subsequently treat the dominant virus with consideration for potential subordinate virus response.