For a detailed discussion of the “gold standard” treatment for CHB, reference should be to the latest 2012 EASL guideline6 (http://www.easl.eu).
If there is no response or virological breakthrough, as defined by an increase in the HBV DNA level of >1 log10 IU/mL in comparison with the nadir (lowest value) HBV DNA level during treatment with confirmed compliance, then another agent with the optimal resistance profile—that is, tenofovir or entecavir—should be substituted or added.
The following strategies can be used to prevent resistance:
- For the first-line therapy, choose a potent antiviral drug and/or one with a low incidence of resistance (high genetic barrier) over time (entecavir/tenofovir).
- Emphasize to the patient once again the importance of absolute compliance with therapy.
- The HBV DNA level should be monitored frequently when using drugs with a low barrier to resistance (every 3 to 6 mo) during treatment, and resistance testing (genotyping) should be carried out in case of viral breakthrough or suboptimal viral suppression, to allow genotypic resistance to be detected before clinical consequences develop.
- No drug resistance to interferon has been described, although some individuals do not respond to therapy, in which case it should be stopped. If available, the HBsAg titer can be used to guide interferon therapy (see below).
Recommendations: HBeAg-positive patients with persistent ALT ≥2× the upper limit of normal, and with HBV DNA≥2000 IU/mL, should be considered for treatment.
- It is imperative to check for HIV coinfection before treatment, because all approved nucleoside/nucleotide analogues (NAs) have activity against HIV and will rapidly lead to drug-resistant HIV if used as monotherapy.
- HDV testing should be mandatory in countries with a high prevalence of hepatitis D infection (Romania, Moldavia, former Soviet Central Asian Republics, Russia).
- In patients who have had a liver biopsy, treatment should be started for those with moderate to severe inflammation or significant fibrosis (≥F2).
- Treatment should be initiated in those who have cirrhosis with detectable HBV DNA, even those with a low HBV DNA level, irrespective of the ALT level.
- Any of the approved therapies can be chosen, and the decision regarding the selection of therapy should include an assessment of efficacy, safety, and genetic barriers to resistance. To avoid resistance, entecavir and tenofovir are the preferred choices for NA therapy. It is important to ensure that patients have a secure source of support to pay for medications over the longer term before starting therapy, to avoid abrupt cessations of treatment, which can be dangerous.
- Patients should be monitored regularly during therapy at 3 to 6 monthly intervals, or more frequently if they are receiving interferon-based therapy, to monitor for efficacy, safety, and early evidence of resistance (for NAs).
- Ideally, patients should be monitored with ALT, HBeAg, anti-HBe, and HBV DNA, but this may not be possible in countries in which these tests are not available or are prohibitively expensive, in which case ALT will have to suffice.
- Virologic breakthrough: an increase in HBV DNA >1 log above the nadir after a virologic response has been achieved during continued treatment (for NAs). Before assuming this is resistance, adherence should be discussed with the patient. A continued increase in the HBV DNA titer over time is suggestive of resistance in a patient who is complying with the treatment.
- Patients with resistance should be considered for rescue therapy with nucleosides/nucleotides that do not have a cross-resistant profile (lamivudine, telbivudine, and entecavir have an overlapping resistance profile, so that tenofovir substitution would be preferable—or if unavailable, adefovir add-on therapy).
- Oral agents should be continued until at least 12 months after the end point of HBeAg seroconversion occurs in HBeAg-positive hepatitis, and it may be preferable to continue until HBsAg loss occurs because of the high risk of reactivation after cessation of therapy. Close monitoring is recommended after oral therapy has been stopped or withdrawn, because of the risk of a treatment withdrawal flare.
- Peginterferon-based therapies have the advantage of a fixed duration of therapy. HBeAg seroconversion may take place up to 6 months after discontinuation of interferon. HBeAg loss and seroconversion seem to be much more durable when induced with interferon in comparison with a NA. Interferon is most effective in patients with genotype A infection and least effective in those with genotypes D and C.
- If HBsAg titers are available, they can be used to guide interferon-based therapy. Discontinuation of interferon therapy is indicated in all patients with HBsAg>20,000 IU/mL at week 24, irrespective of the HBV genotype.25 Alternatively, those with no decline in the HBsAg titer at 12 weeks should also stop therapy. Stopping rules improve the cost-effectiveness of peginterferon therapy.26
HBeAg-negative CHB represents a late phase in the course of CHB infection.
- The patient should be considered for treatment if:
- HBV DNA ≥20,000 IU/mL and serum ALT >2×ULN.
- Liver biopsy or other forms of fibrosis assessment should be considered in patients with:
- HBV DNA ≥20,000 IU/mL and serum ALT<2×ULN.
- HBV DNA ≥2000 IU/mL and/or serum ALT >ULN.
- Treatment should be administered if the liver biopsy shows moderate/severe necroinflammation or significant fibrosis (≥F2).
- Treat any patient with cirrhosis who has detectable HBV DNA.
Recommendations for treatment:
- It is imperative to check for HIV coinfection before treatment, as all approved NAs have activity against HIV and will rapidly lead to drug-resistant HIV if used as monotherapy.
- The treatment regimen can be conventional interferon, peginterferon-α, or NAs. Interferon-based therapy must not be used in the presence of liver failure.
- In patients with contraindications to interferon, such as decompensated cirrhosis or autoimmune disease, oral NAs are recommended.
- The duration of interferon or peginterferon therapy is 1 year. If by week 12 HBsAg has not dropped, combined with a <2 log decline in HBV DNA, interferon therapy should be stopped, as a response is unlikely.25,27
- For oral antiviral therapy, agents with a low resistance rate such as entecavir or tenofovir are preferred, particularly in patients with cirrhosis. However, where economic constraints are a consideration, therapy can be started with lamivudine (or telbivudine), with early adefovir add-on therapy or a switch to tenofovir when drug resistance is detected or when HBV DNA remains at ≥2000 IU/mL at week 24 of therapy.
- The optimal duration of antiviral therapy for HBeAg-negative CHB is not known, but long-term therapy is required—possibly lifelong, or until loss of HBsAg.
- Monitoring both biochemistry and HBV DNA every 3 to 6 months is recommended for assessing the treatment response and for early detection of drug resistance.
- A drug with a nonoverlapping resistance profile should be added (adefovir for lamivudine resistance) when drug resistance is detected.
- If ALT is elevated and HBV DNA levels are low (<2000 IU/mL), other causes of inflammation (fatty liver, medication, coinfection with HDV and HCV) should be excluded. HDV inhibits HBV replication, and HDV-coinfected patients are therefore typically HBeAg negative, with low or even undetectable levels of HBV DNA but persistently high ALT levels, often with evidence of advanced fibrosis/cirrhosis.
HDV is a defective virus with a circular RNA genome and a single structured protein, the hepatitis δ antigen. The virus requires HBV surface antigen to serve as an envelope for its δ antigen. This helper function of HBV is required for HDV assembly and propagation.
- Up to 5% of the world’s population is infected with HBV, and probably 5% of those chronically infected with HBV have HDV infection.
- However, some endemic areas in the developing world may have much higher rates (Horn of Africa, Eastern Europe, Amazon Basin). The virus simultaneously coinfects with HBV, or superinfects in someone already chronically infected with HBV.
- Coinfection evolves to chronicity in only 2% of cases, but is associated with a higher chance of fulminant acute infection, whereas superinfection leads to progressive disease and cirrhosis in >80% of cases.
- Cirrhosis develops at a younger age than in patients with CHB monoinfection.
- Universal HBV vaccination should be implemented to prevent HDV infection in the community and thereby decrease its prevalence.
- HBsAg-positive patients should be evaluated to rule out HDV infection, particularly if hepatitis is present in the face of little or no HBV viral replication (ie, a low HBV DNA), or if they come from an HDV-endemic region or have acquired HBV through injection drug use.
- HDV infection can be diagnosed by detection of HDV RNA in serum by polymerase chain reaction, or indirectly by detection of antibodies against hepatitis D antigen (anti-HDV) of the IgG and IgM classes.
- Chronic hepatitis D should be treated with interferon (preferably PEG-IFN) for at least 12 months, but the treatment results are suboptimal. Patients with active HBV replication despite HDV coinfection may benefit from treatment with NAs in combination with peginterferon.
Infection with HBV and HCV viruses may occur, as the 2 share similar risk factors and some common modes of transmission. Coinfection is most common in regions highly endemic for both viruses and in individuals who have contracted the infection through injection drug use—because unlike HBV, HCV is poorly transmitted through the sexual or vertical route. For the same reasons, HBV and HCV coinfection—and even triple infection with HBV, HCV, and HIV and potentially quadruple infection (with HDV in addition)—may be observed in high-risk populations.
- The interferons (and PEG-IFNs) are well-established therapeutic agents for both HBV and HCV and represent the treatment of choice for coinfected patients (in the absence of HIV).
- When HCV predominates (with detectable HCV RNA and low or undetectable HBV DNA), HCV therapy, which is rapidly evolving, should be prioritized. IFN-based therapy for HCV may be preferable to control HBV as well, but there are no robust data on this approach to date. New interferon-free therapies for HCV are highly effective and should be considered in HBV/HCV-coinfected patients. Optimal approaches for this population are being evaluated.
- When HBV predominates (with high HBV DNA levels), hepatitis C has often been cleared (ie, undetectable HCV RNA). In such cases, treatment decisions regarding HBV should be made irrespective of the presence of past HCV infection.
- Regular monitoring of ALT and of HCV RNA and HBV DNA during and after therapy is required, as suppression of the dominant virus by antiviral therapy may result in reactivation of the previously suppressed virus.
An estimated 36 million persons throughout the world are infected with HIV. Chronic coinfection with HBV may be present, due to the common modes of transmission of the viruses—parenteral, vertical, and sexual.
- The prevalence of CHB among HIV-infected persons may be 10 times or more higher than that of the background population.
- CHB infection occurs in 5% to 10% of HIV-infected persons in Western Europe and the United States.28
- Progression of CHB to cirrhosis, end-stage liver disease, and/or HCC is more rapid in HIV-infected persons than in persons with CHB alone.29
The absence of controlled trials and the dual activity of some agents complicate the management of CHB infection in patients with HIV coinfection. Treatment regimens depend on the clinical status of both HIV and HBV.
- Many approved NAs with activity against HBV also suppress HIV, and it is therefore critical that monotherapy with any approved oral HBV agents should be avoided, as resistance to HIV and possibly to HBV will rapidly occur. When treatment is indicated, a tenofovir-based regimen is preferred, in combination with other highly active agents for HIV.
- All patients with CHB should therefore always be checked for HIV coinfection before antiviral treatment is initiated.
The principal objectives of anti-HBV treatment are to stop or decrease the progression of liver disease, and to prevent cirrhosis and HCC.
- Prolonged suppression of HBV replication leads to histologic improvement, a significant decrease in or normalization of aminotransferases, and prevention of progression to cirrhosis and end-stage liver disease.
- Sustained viral control requires long-term maintenance therapy.
- Treatment discontinuation in particular may be associated with HBV reactivation and ALT flares.
- The drawback of long-term therapy is the risk of HBV resistance. To reduce drug resistance, most coinfected patients require HBV combination therapy.
The following recommendations are also based on the 2012 EASL guideline6:
- All pregnant women should be screened for HBsAg.
- Before HBV treatment is started, the risk to the fetus in case of pregnancy and the patient’s family planning should be discussed.
- (PEG-)IFN is contraindicated during pregnancy.
- Tenofovir has a better resistance profile and more extensive safety data in pregnant, HBV-positive women than telbivudine (both are pregnancy category B drugs: no risk in animal studies, but unknown in humans).30 The data in HIV-positive pregnant women suggest that the use of lamivudine, emtricitabine, and tenofovir is safe.31,32
- Perinatal HBV transmission mainly occurs at delivery, and prevention focuses on passive and active immunization with hepatitis B immunoglobulin (HBIg) and HBV vaccination, both of which must be given within 12 hours of birth.
- In a meta-analysis of the utility of HBIg given to newborns to prevent mother-to-child transmission of HBV, HBIg and HBV plasma–derived vaccine reduced transmission from 20% to 10% in comparison with plasma vaccine alone (RR=0.49; 95% CI, 0.32-0.74); with HBIg and recombinant HBV vaccine, transmission was reduced from 30.8% to 18.9% (RR=0.61; 95% CI, 0.41-0.92).33
- Women with high concentrations of HBV DNA (serum HBV DNA >106-7 IU/mL, and mostly HBeAg positive) may still have a high risk of mother-to-child transmission despite appropriate vaccination and should be considered for treatment with lamivudine, telbivudine, or tenofovir during the last trimester of pregnancy, in addition to passive and active vaccination with HBIg and HBV vaccination.
- In a meta-analysis of RCTs, lamivudine reduced the transmission of HBV from 25.4% to 12% in comparison with a placebo when it was administered in late pregnancy. In comparison with patients who received HBIg, lamivudine reduced transmission from 20.4% to 6.3%.34 In a meta-analysis of telbivudine treatment in pregnancy, the pooled results were similar to those with lamivudine, but the analysis only included 2 RCTs and 3 non-RCTs.35
- NA therapy given only for the prevention of perinatal transmission may be discontinued within the first 3 months after delivery.
- HBV-infected women should be monitored closely after delivery, as flares may occur.36
HEPATITIS B VACCINATION
A program for universal vaccination of all newborns is a key step toward effective control of HBV infection throughout the world. HBV vaccination has been shown to be highly cost-effective. Vaccination prevents infection with HBV and thus reduces the incidence of chronic hepatitis, cirrhosis, and HCC in the vaccinated population, as well as reducing transmission by limiting the number of susceptible individuals.
Active Vaccination With Hepatitis B Vaccine
HBsAg is the antigen used in the formulation of the hepatitis B vaccine. It is produced from yeast through recombinant DNA technology. It is available as a single-agent preparation or as a fixed combination with other vaccines.
Passive Vaccination With HBIg
HBIg is prepared from the plasma of individuals who have a high concentration of anti-HBs. The standard dose of HBIg is 0.06 mL/kg for all applications in adults or 200 IU in infants. In standard doses, it provides temporary protection (ie, for approximately 3 to 6 mo) against HBV infection. HBIg is administered by intramuscular injection, preferably into the deltoid or gluteal muscle. If it is given with hepatitis B vaccine, the HBIg vaccine should be administered at a different injection site.
A comprehensive strategy for eliminating HBV transmission should start with a preexposure vaccination program. This should include:
- Universal vaccination of all infants at birth; mandatory for infants born to pregnant women who test positive when screened for HBsAg.
- Postexposure immunoprophylaxis for children born to mothers whose HBsAg status is unknown.
- Catch-up vaccination of all children and adolescents who have not previously been vaccinated.
- Vaccination of unvaccinated adults exposed to risks of HBV infection (however, typically “high-risk” individuals frequently do not access health care or inform health care facilities, hence the need for universal infant vaccination).
- Vaccination of those at risk of more severe infection—for example, patients with chronic liver disease.
The combination of prevalence, route of transmission, and viral factors has implications for the vaccination strategy—vaccination of at-risk groups, infant vaccination, or adolescent vaccination.
The vaccine is administered by intramuscular injection into the deltoid muscle (not the gluteal muscle) in adults, or into the anterolateral aspect of the thigh in neonates.
- Studies suggest that universal vaccination at birth is cost-effective in countries with high and moderate prevalence.
- Europe and North America, with very low incidence rates, have implemented either routine infant vaccination or vaccination for newborns of mothers who test positive for HBsAg.
- Routine adolescent vaccination at the age of 10 and catch-up vaccination for at-risk adults (it is difficult to identify and/or access those who are “at risk”) are recommended in some countries, but this will have little effect on the rate of chronic infection.
- Primary vaccination, consisting of ≥3 intramuscular doses of hepatitis B vaccine administered at 0, 1, and 6 months, results in a positive antibody response in 30% to 55% of adults aged 40 years and below after the first dose, 75% after the second dose, and >90% after the third dose. These response rates decline when the vaccine is given to older individuals (eg, <90% in persons over 40 y old, 75% in those over 60 y old).
- Other innovative vaccination schedules (eg, 0, 1, and 4 mo or 0, 2, and 4 mo or 0, 1, and 2 mo) are able to produce dose-specific and final rates of protection similar to those obtained with the 0-, 1-, 6-month schedule, and may be more practical for newborns.
- Accelerated vaccination schedules for postexposure prophylaxis in adults often ensure compliance with completion of the vaccination schedule.
- Babies born to HBsAg-positive mothers should receive the first dose of vaccine within 12 hours of birth.
- Host factors (eg, smoking, obesity, cirrhosis, genetic factors, immune suppression, renal failure, etc.) are known to result in a decreased vaccine response.
- Individuals who do not mount an anti-HBs response (≥10 mIU/mL) to the primary vaccination schedule should receive a repeat 3-dose vaccination (at 0, 1, and 2 mo). This gives rise to protective antibody levels in 44% to 100% of individuals. Individuals who do not develop protective anti-HBs levels after revaccination can be considered for repeat vaccination (0, 1, and 2 mo, with a 6-mo booster) with double the standard dosage of vaccine.
- For persons 18 years old and above who do not live in an area endemic for hepatitis A, a combined hepatitis A-hepatitis B vaccine (Twinrix) is available.
Postexposure prophylaxis should be considered for individuals who have had recent exposure (either parenteral or sexual) to blood or other body fluids, if it can be carried out in a timely manner.
- Evaluation of the HBsAg status of the infective source and the anti-HBs status of the exposed person should be carried out before the vaccine is administered.
- In countries with a high level of HBV endemicity, HBsAg in the exposed individual should also be checked.
- Individuals without prior vaccination should receive both HBIg and hepatitis B vaccine soon after exposure (preferably within 24 h). Hepatitis B vaccine administered simultaneously with HBIg must be at a different injection site.
- Completion of the hepatitis B vaccine series is again at 0, 1, and 6 months or 0, 1, and 2 months.
Exposed individuals who are in the process of being vaccinated (but who have not completed the vaccine series) should receive the appropriate dose of HBIg and should be advised to complete the hepatitis B vaccination series.
Vaccine responders may maintain protective anti-HBs levels for various lengths of time. Individuals who respond to hepatitis B vaccination are protected for at least 20 years (perhaps lifelong), even if vaccinees lack detectable anti-HBs at the time of a recent exposure. Asymptomatic acute hepatitis B infection can occur in vaccine responders following a decrease in anti-HBs levels, but it is usually self-limited. Occult hepatitis B infection has been recognized in some vaccinated patients, but the clinical significance of this is unclear.37
Thus, immunocompetent persons who are known to have responded to hepatitis B vaccination with anti-HBs concentrations of ≥10 mIU/mL do not require additional passive or active immunization after an HBV exposure. In addition, they do not need further periodic testing to assess anti-HBs concentrations. However, if the previous anti-HBs concentration is not known (not routinely tested) or is <10 mIU/mL, then HBIg and hepatitis B vaccine should be given. If the exposed individual is a known nonresponder, then 2 doses of HBIg, 1 month apart, can be given.
Booster doses are not recommended routinely for immunocompetent individuals, whether they have received the vaccination as infants, adolescents, or adults. Likewise, serologic testing to assess antibody concentrations in any age group is not recommended, except perhaps for individuals at high risk of infection such as household contacts of infected persons or health care workers—for example, a booster dose should be administered when the anti-HBs level is <10 mIU/mL. It is prudent to recommend booster doses to individuals with a clear, ongoing risk of HBV infection (eg, when the sexual partner is HBsAg positive, or in health care personnel).
Pregnancy and Hepatitis B Vaccination
There are no teratogenic or other risks to the fetus if hepatitis B vaccine is administered to pregnant women. There are no contraindications for hepatitis B vaccination or HBIg administration in pregnant or lactating mothers.
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