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Hepatitis B and HIV Coinfection

Hepatitis B and HIV Coinfection

HIV InSite Knowledge Base Chapter

October 2010

Annie Luetkemeyer, MD, University of California San Francisco

Related Resources
Epidemiology Related Knowledge Base
Chapters
Impact of HIV on the Course of HBV Infection Guidelines and Best
Practices
Policy Reports, Papers,
Impact of HBV on the Course of HIV Disease and Briefs
Presentations, Interviews,
and Roundtable
Natural History of Chronic HBV Infection and Interpretation of Discussions
HBV Serology Online Books and
Chapters
Provider Education and
Diagnosis of HBV in HIV Infection
 Training
Clinician Support Tools
Management of HBV in HIV-Coinfected Individuals
Slide Sets
Patient and Community
Prevention of HBV Transmission Education
Links
HBV Therapy

Indications for treatment of HBV in HIV infection

Treatment of HBV in the setting of ART

Treatment of HBV in the absence of ART

HBV Medications

Interferon

Lamivudine and emtricitabine

Entecavir

Telbivudine

Adefovir

Tenofovir

HBV Resistance

Monitoring on Therapy

HCC Screening
 Immunization against HBV in HIV Infection

Conclusion

References

Figures
Figure 1. Natural History of Chronic HBV Infection

Figure 2. Patterns of Serologic and Molecular Markers in HBV Infection

Tables
Table 1. Interpretation of Acute and Chronic HBV Serologies

Epidemiology

Coinfection with hepatitis B virus (HBV) and HIV is common, with 70-90% of HIV-infected
individuals in the United States having evidence of past or active infection with HBV.(1, 2)
Factors affecting the prevalence of chronic HBV include age at time of infection and mode of
acquisition, which vary geographically. In the United States and Western Europe, HBV often is
acquired in adolescence or adulthood via sexual contact or injection drug use. Although
spontaneous clearance of HBV acquired in adulthood occurs in >90% of immunocompetent
individuals, HIV-infected persons are half as likely as HIV-uninfected persons to spontaneously
clear HBV. Therefore, chronic HBV infection occurs in 5-10% of HIV-infected individuals who
are exposed to HBV, a rate 10 times higher than that for the general population.(3, 4) In the
United States, HIV/HBV coinfection rates are highest among men who have sex with men
(MSM) and injection drug users. In contrast, in Asia and sub-Saharan Africa, where vertical and
early childhood exposure are the most common modes of transmission, respectively, and overall
HBV prevalence is higher, the prevalence of HBV among HIV-infected individuals also is
higher, at an estimated 20-30%.(5, 6)

HBV is a DNA virus that forms stable circular covalently closed (ccc) DNA that can persist in
the liver indefinitely. Individuals with evidence of past infection (core antibody positivity) are at
risk of HBV reactivation, particularly in the setting of severe immunocompromise, prolonged
steroid use, or chemotherapy. There are 8 genotypes of HBV. Genotype G may be predictive of
more severe fibrosis in HIV-coinfected patients,(7) and genotypes C and D may be more
responsive to interferon.(8) However, in general, knowledge of the HBV genotype is not
consistently associated with a response to nucleoside therapy and therefore is not particularly
useful in clinical care of HIV/HBV coinfection, as nucleosides are the mainstays of HBV
treatment.
Impact of HIV on the Course of HBV Infection

The course of acute HBV may be modified in the presence of HIV infection, with a lower
incidence of icteric illness and lower rates of spontaneous clearance of HBV.(9) Persons with
HIV and chronic HBV coinfection have higher levels of HBV DNA and lower rates of clearance
of the hepatitis B e antigen (HBeAg).(10, 11, 12, 13) Serum transaminase levels may be lower in
HIV/HBV-coinfected patients than in HBV-monoinfected patients, but normal transaminase
levels should not be interpreted to mean that there is no underlying hepatic fibrosis.

HIV increases the risk of cirrhosis and end-stage liver disease in HBV coinfection.(14) Liver-
related disease has emerged as the leading cause of non-HIV-related mortality in parts of the
world where effective antiretroviral therapy (ART) is widely available. In several cohort studies,
the risk of liver-related mortality has been found to be 2-3 times higher in HIV/HBV-coinfected
patients than in HIV-monoinfected patients (14% vs 6%).(15, 16) Lastly, HIV coinfection is
associated with more frequent flares of hepatic transaminases, which can occur with immune
reconstitution inflammatory syndrome (IRIS) owing to ART, interruption of HIV/HBV
treatment, or the development of resistance to HIV/HBV treatment; they also can occur
spontaneously.(17)

Impact of HBV on the Course of HIV Disease

There are conflicting data with respect to the impact of HBV on the disease course of HIV
infection. In the early ART era, some studies showed an increased rate of HIV progression to
AIDS among individuals with markers of exposure to HBV,(18) whereas others did not show
any change in the progression of HIV disease or survival.(12) More recent data have not found
HBV coinfection to have a substantial impact on immunologic or HIV virologic responses to
ART or on the development of AIDS-defining illness or HIV-related death.(19, 20)

Natural History of Chronic HBV Infection and Interpretation of HBV Serology

Understanding the natural history of HBV and knowing how to interpret hepatitis B serologic
studies are keys to evaluating the current stage of HBV infection and determining who may
benefit from HBV treatment. The U.S. National Institutes of Health (NIH) has adopted
consensus terminology to help clarify discussion of the natural history of HBV, as shown in
Figure 1. Although transition through these stages can be a linear path over the course of time, it
is important to recognize that individual patients may revert from inactive carrier status or,
rarely, even from a state of resolved HBV infection to immune active status, particularly in the
setting of immunocompromise, whether as a result of medications, chemotherapy, or advanced
AIDS.(21, 22)

There are 3 main phases of chronic HBV disease (see Figure 1 and Figure 2),(23) as follows:

1. Immune tolerant phase: This phase is characterized by a high level of HBV replication
with little or no evidence of active hepatic inflammation. Hepatic transaminases are
normal and liver biopsy, if performed, would show little or no inflammation. Most
children infected at birth or during early childhood will be immune tolerant and remain in
the immune tolerant phase for years or even decades; however, most eventually will
progress to immune active disease. Given the lack of immune response to HBV,
treatment is not recommended during this period, but individuals should be monitored for
transition to immune active disease as well as for hepatic fibrosis and hepatocellular
carcinoma (HCC) as they age. HBV DNA is detectable, as are HBeAg and hepatitis B
surface antigen (HBsAg). Because of the high level of HBV viremia, this is a highly
infectious phase.
2. Immune active phase: This phase is characterized by elevated liver enzymes and liver
inflammation on biopsy. Individuals infected in adolescence or adulthood, as is
frequently seen in HIV/HBV coinfection in the United States, often begin the disease
course in the immune active phase, and are never immune tolerant. This phase also is
characterized by detectable HBV DNA, HBeAg and HBsAg, and risk of transmission to
others.
3. Inactive carrier phase: During this phase, HBeAg is lost and HBV DNA declines, often
to undetectable levels. Hepatitis B e antibody (HBeAb) seroconversion can occur,
followed by hepatitis B surface antibody (HBsAb) seroconversion, indicating immune
control of HBV infection. A small proportion of people will continue to have detectable
low-level HBV DNA, which may be intermittent and is referred to as "occult" HBV
infection (see below).

HBeAg-Negative Chronic Hepatitis: "e antigen negative" chronic hepatitis is a form of immune
active hepatitis in which individuals have undergone loss of eAg and eAb seroconversion but
still have HBV DNA present at fluctuating levels and evidence of active hepatitis with hepatic
inflammation. eAg is not detectable because the HBV has undergone mutations in the precore or
basal core promoter region, resulting in little to no eAg production. Despite the lower levels of
HBV viremia, eAg-negative hepatitis can be difficult to treat, usually requiring indefinite
treatment with nucleoside therapy, rarely transitions to inactive carrier phase, and is associated
with a high risk of progression to fibrosis.(24) Both the eAg-negative and the inactive carrier
phases are characterized by core antibody (cAb)-positive, eAb-positive, eAg-negative, and sAg-
positive serologies. They are distinguished by detection of HBV DNA, measured at serial time
points (every 3 months); evidence of detectable HBV DNA is suggestive of eAg-negative
chronic hepatitis. In addition, eAg-negative disease is characterized by ongoing liver
inflammation and, in most cases, elevated transaminases.

Resolved infection: HBV-infected individuals who have lost eAg and sAg and seroconverted to
eAb and sAb positivity are referred to as having resolved their HBV infection. However, given
the nature of the long-lived cccDNA that resides in hepatocytes during HBV infection, it may be
more appropriate to think of these individuals as immunologically controlled because, in rare
cases, HBV disease can reactivate in the setting of severe immunosuppression.

The interpretations of acute and chronic hepatitis serologies are summarized in Table 1.

Diagnosis of HBV in HIV Infection

Given the elevated rates of HBV among individuals who are infected with HIV and the shared
routes of transmission between the two viruses, all HIV-infected individuals should be screened
for HBV coinfection with HBsAg testing. Patients who do not have evidence of HBsAg should
have HBcAb and HBsAb evaluated to assess for prior HBV infection as well as HBsAb, which
provides evidence of immunologic control of prior infection or vaccination. Because HBV DNA
can persist in the liver indefinitely, persons with cAb positivity are at risk of HBV reactivation
even if they test positive for sAb, particularly if they become severely immunosuppressed (see
Table 1 and Figure 2).

Isolated HBcAb: Some individuals will have isolated HBcAb positivity, in the absence of
HBsAg or HBsAb. That indicates one of the following scenarios:

 "Occult" HBV viremia: HBV viremia may be detected in 4-88% of isolated cAb-
positive patients.(25, 26, 27, 28) The clinical significance of occult viremia is unknown.
However, as even low levels of HBV viremia may increase the risk of liver disease,(29)
these individuals may be at higher risk of hepatic disease and many experts recommend
managing these patients as chronically HBV infected.
 Waned HBsAb response: Loss of sAb can occur over time, particularly with
immunosuppressed patients. In the absence of detectable HBV viremia, these individuals
may respond to a single booster HBV vaccination. However, the rate of anamnestic
response after 1 booster is low (7-16% in 2 studies of isolated cAb-positive patients),(30,
31) suggesting that it may be more efficient to complete a 3-vaccine series before
checking sAb titer to determine response.
 False-positive HBcAb: Individuals who do not respond to a booster of HBV vaccination
may have a false-positive HBcAb result or may have an impaired antibody response to
prior infection. Vaccination with a full series is recommended.

Persons with detectable sAg should be evaluated for HBeAg, HBV DNA viral load, liver
transaminases, prothrombin time/international normalized ratio (PT/INR), and platelets, and they
should have baseline liver imaging to screen for cirrhosis and HCC (see below).

Management of HBV in HIV-Coinfected Individuals

Patients with chronic HBV should be screened for hepatitis C virus (HCV) infection and should
be vaccinated against hepatitis A virus (HAV) if they are not immune. HIV/HBV-coinfected
patients should be counseled to avoid or limit intake of hepatotoxins, including alcohol and high
dosages of acetaminophen.

Prevention of HBV Transmission

All HBsAg-positive patients should be counseled about reducing the risk of HBV transmission to
close contacts. It is important to inform HIV/HBV-coinfected patients that HBV can be more
infectious than HIV and can be transmitted to household contacts via dried blood, open cuts, and
shared toothbrushes or razors. Sex partners, household members, children with close physical
contact, and those who share injection drug equipment with the patient should be screened for
HBV and vaccinated if they are not actively infected (see "Immunization," below). As with HIV
prevention, condom use with sex and avoidance of shared needles and other equipment for
injection drug use are recommended measures for reducing the risk of HBV transmission.

HBV Therapy

The goal of HBV treatment for persons with HIV coinfection is to suppress HBV viral
replication and minimize ongoing hepatic damage. Loss of sAg and seroconversion to sAb
indicating resolution of active HBV disease are uncommon in HIV/HBV coinfection; therefore,
indefinite treatment of HBV for coinfected patients often is required.(32)

Indications for treatment of HBV in HIV infection

HBV therapy is recommended for all HIV/HBV-coinfected patients with abnormal alanine
aminotransferase (ALT) values or HBV DNA levels of >2,000 IU/mL. Some guidelines cite
>20,000 IU/mL as the threshold for treatment of eAg-positive patients (33); however, many
experts recommend treatment of HBV for all HIV-coinfected patients in whom any HBV
replication is present. If HBV viremia is low level (<2,000 IU/mL) and the ALT value is normal,
a liver biopsy may be considered for patients who are not on HIV therapy, as those with no or
limited fibrosis may not require HBV treatment. It is important to note that significant liver
fibrosis may be present in persons with normal transaminases. If HBV treatment is deferred,
transaminases and HBV DNA values should be monitored closely.

Treatment of HBV in the setting of ART

As most HIV treatment contains one or more HBV-active agents (eg, lamivudine [3TC],
emtricitabine [FTC], tenofovir [TDF]), patients with an indication for HBV treatment should be
started on fully active ART that contains HBV-active nucleoside/nucleotide analogues,
regardless of the CD4 cell count, to ensure that HIV is not partially treated.(34) Similarly, any
HIV/HBV-coinfected patient with an indication for ART should be started on HIV treatment that
includes effective anti-HBV treatment. The combination of TDF with 3TC or FTC is
recommended as a highly effective first-line treatment for HBV.(34) Individuals who cannot take
TDF because of renal insufficiency or other intolerance may consider entecavir treatment
(renally dosed if necessary) for HBV in lieu of TDF. Treatment with 3TC or FTC as the only
HBV-active agent in ART (ie, HBV monotherapy) is not recommended owing to a high risk of
developing HBV drug resistance over time.(35)

Treatment of HBV in the absence of ART

The current U.S. Department of Health and Human Services guidelines recommend fully active
ART for HIV/HBV-coinfected patients who require HBV treatment, even if they do not have a
current indication for HIV treatment.(36) However, in some circumstances, an individual may
not tolerate HIV therapy or may wish to defer treatment for HIV. Treatment with HIV/HBV-
active agents that are insufficient to fully suppress HIV should be avoided. Entecavir and
telbivudine have been shown to have anti-HIV activity and to contribute to HIV drug resistance,
(37, 38) as have traditional HIV-active agents used for HBV treatment (eg, 3TC, FTC, TDF).
Whereas adefovir may be an option for treatment of HBV only, there is a concern that even low-
dose adefovir used for HBV could have anti-HIV activity. Pegylated interferon (IFN) is an
option in this scenario, but there are limited efficacy and safety data in HIV coinfection, and
long-term treatment with IFN is not feasible because of toxicity and poor tolerability.

HBV Medications

Interferon

IFN is most effective for HBV treatment in patients with low levels of viremia and elevated
transaminases, and it therefore may be less useful in patients with HIV/HBV coinfection than in
those with HBV alone. In coinfected patients, IFN has been associated with lower rates of HBV
treatment success and increased toxicity.(39) It cannot be used for patients with decompensated
cirrhosis and is not feasible as a long-term treatment, owing to adverse events and tolerability
issues. There are no data for use of pegylated IFN in HIV/HBV coinfection.

Lamivudine and emtricitabine

These nucleoside analogues have similar activity against both HIV and HBV and they are
commonly used components for HIV/HBV cotreatment. However, HIV-infected individuals
should not receive 3TC or FTC monotherapy for HBV infection because resistance to those
drugs develops in up to 90% of patients within 4 years of single-drug treatment.(35) Resistance
to 3TC and FTC is characterized by the development of mutations at HBV rtM204 (also known
as YMDD mutations). Once 3TC resistance has developed, HBV medications such as
telbivudine will no longer have activity against HBV, and agents such as entecavir may be less
efficacious and more prone to development of HBV resistance.(40) As with other agents that
have activity against HIV, 3TC and FTC should be used only for patients on fully suppressive
ART.

Entecavir
Entecavir is a guanosine analogue that appears to be more potent than either 3TC or adefovir.
Entecavir resistance requires the development of several resistance mutations, including the
rtM204 mutation that confers resistance to 3TC. In the presence of 3TC resistance, entecavir
usually is active but may be more vulnerable to the development of further resistance (see
above). Although entecavir initially was thought to have no anti-HIV activity, it has been
demonstrated to select for the M184V mutation (37) and should not be used in the absence of
combination ART with full suppression of HIV viremia.

Telbivudine

Telbivudine is a thymidine analogue that also selects for the HBV rtM204 mutation, which leads
to 3TC cross-resistance, and should not be used after 3TC or FTC failure. Telbivudine also may
have anti-HIV activity (38) and is not recommended for use without fully suppressive ART.

Adefovir

Adefovir initially was formulated as an anti-HIV agent but was not developed for that purpose,
owing to an association with renal toxicity. At lower dosages, adefovir suppresses HBV
replication but is less potent than telbivudine or tenofovir. Adefovir appears to be active against
3TC-resistant HBV.(41) The use of adefovir largely has been supplanted in favor of treatment
with tenofovir, a related but more potent agent and one that is active against HIV. At the dosage
used to treat HBV, adefovir does not appear to be active against HIV and has not been associated
convincingly with the development of HIV resistance mutations such as K65R.(42) Adefovir is
an option for HBV treatment in HIV-infected patients who decline or cannot take ART, but it
should be used with caution.

Tenofovir

TDF is related to adefovir but it has more potent HBV activity and also can be used for HIV
treatment. As with other agents that have activity against HIV, TDF should be used only for
patients who are on fully suppressive ART. It usually is used in combination with 3TC or FTC as
first-line therapy. HBV that is resistant to 3TC or adefovir can be treated effectively with TDF
therapy.(43, 44)

HBV Resistance

HBV resistance can develop after long-term exposure to oral nucleoside and nucleotide
analogues, particularly in the setting of 3TC or FTC monotherapy. However, TDF can be used
effectively despite the presence of 3TC or adefovir resistance.(44)

HBV genotyping is not recommended for HBV treatment-naive individuals, but may be
considered for those who have failed to suppress HBV DNA on treatment, who have had
significant 3TC monotherapy, or who have experienced a rebound in HBV DNA levels despite
continued HBV treatment.

Monitoring on Therapy

The goal of therapy is suppression of HBV below the assay level of detection. For patients on
treatment, HBV DNA should be monitored at 3-6 month intervals, along with transaminases and
eAg. Virologic response is defined as a ≥2 log10 copies/mL decrease from baseline HBV DNA
after 6 months of therapy. TDF-based HBV treatment will fully suppress HBV replication for the
majority of patients, but that could take several years to accomplish. Development of TDF
resistance despite ongoing viremia has not been documented; it is unclear whether there is a role
for additional anti-HBV agents such as entecavir for patients in whom HBV replication has not
been suppressed after a year or more of therapy. It is important to note that HBsAg and eAg may
remain detectable for years despite HBV DNA suppression, and in some cases indefinitely.

HBV treatment in HIV-infected individuals can be associated with hepatic decompensation and
transaminase flares caused by immune responses to HBV infection; however, other causes of
decompensation or increased transaminases must be considered, including drug toxicity, viral
hepatitis coinfection, medication nonadherence, and development of viral resistance to current
HBV treatment. Coinfected patients should be cautioned against interruption of HIV and HBV
therapy, as treatment interruption can be associated with HBV viral rebound and hepatic
decompensation. As a sustained loss of HBsAg is uncommon among HIV-coinfected patients,
most of these individuals require indefinite HBV treatment with nucleosides or nucleotides,
which are given as a component of HIV treatment, if possible.

HCC Screening

HBV infection is associated with development of HCC even in the absence of cirrhosis. The
2010 American Association for the Study of Liver Disease guidelines recommend screening for
HCC every 6-12 months with alpha-fetoprotein (AFP) and with ultrasound in groups at risk of
HCC, including patients with chronic HBV who are >40 years of age and those of African
American ethnicity.(45) The guidelines also recommend ongoing HCC screening for patients
with evidence of cirrhosis, regardless of age or other risk factors. The benefit of surveillance in
patients with chronic HBV who are <40 years of age is not well established. However, given that
liver disease progresses more rapidly in HIV/HBV-coinfected patients and that HCC may be
more aggressive in HIV coinfection,(46) many experts recommend HCC surveillance for all
HIV-infected patients with chronic sAg-positive HBV disease.

Immunization against HBV in HIV Infection

All HIV-infected patients who lack sAb and do not have sAg positivity or occult HBV should be
vaccinated against HBV. Although transient HIV viremia has been reported after vaccination in
some studies, it does not appear to be clinically relevant. Patients with HIV infection are less
likely to develop protective sAb after HBV vaccination, with a response rate of 18-71%,
compared with >90% for HIV-uninfected adults.(47, 48) Lower seroconversion rates are
associated with lower CD4 cell counts, detectable HIV RNA, and HCV coinfection.(49, 50) HIV
infection also is associated with lower mean HBV sAb titers and faster decline of sAb levels over
time.(51) Administration of a higher dose of HBV vaccine ("double" or "renally" dosed at 40
mcg) has been associated with a trend toward increased effectiveness compared with the
standard 20 mcg dose (47% vs 34%), an effect that was strongest in patients with CD4 counts of
>350 cells/µL.(49) Those data have prompted some clinics to adopt 40 mcg dosing of HBV
vaccine for all HIV-infected individuals, although data to support that practice are limited.

Although low CD4 cell counts are associated with an impaired response to vaccination, HBV
vaccination should not be deferred for patients with advanced HIV, as some individuals do
develop protective antibody titers despite low CD4 cell counts. Postvaccination sAb levels
should be checked 1-2 months after the vaccination series is completed to ensure titers of ≥10
IU/L.(52) Revaccination should be considered for patients who have not attained protective
titers, and use of the higher dose (40 mcg) vaccine for repeat vaccination should be considered.
(34) Several studies have reported that a second vaccination series, with 2 studies reporting a 40
mcg dosing for HBV vaccination, resulted in seroconversion rates of 50-76%.(53, 54, 55)
Adjuvants such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and CpG 7909
(Vaximmune) have shown promise in boosting responses to the HBV vaccine, but are in use only
for research purposes at the present time.(48, 56) For persons who develop sAb in response to
vaccination, some experts recommend annual testing to ensure sAb titers remain adequate,
extrapolating from recommendations for dialysis patients, in whom loss of protective antibody is
associated with reduced protection against HBV.(34)

Conclusion

Markers of HBV exposure are present in a high proportion of HIV-infected individuals. HIV
affects HBV viral replication and clearance, accelerates the development of liver disease, and
contributes significantly to hepatic morbidity and mortality in HIV infection. HBV coinfection
does not appear to influence the rate of HIV progression but may be a surrogate for factors
associated with HIV seroconversion. Patients receiving HIV treatment should receive fully active
HBV treatment as well, avoiding 3TC or FTC monotherapy. Conversely, it is preferred to give
fully active ART in conjunction with HBV therapy, as there are limited options for effective
HBV treatment that lack anti-HIV activity.

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