Prevention of hepatitis B virus infection in adults with HIV

INTRODUCTION — It is important to prevent hepatitis B virus (HBV) infection in individuals with HIV. Patients with HIV are at high risk for acquiring HBV due to shared routes of transmission (eg, sexual transmission, injection drug use) [1]. In addition, if acquired, individuals with HIV are less likely to develop a protective immune response with production of hepatitis B surface antibody (anti-HBs) during acute infection. Thus, such patients are at increased risk of developing chronic infection, cirrhosis, and end-stage liver disease compared with patients without HIV [2-4].

This topic will address how to prevent HBV infection in individuals with HIV. The epidemiology, clinical manifestations, evaluation, and treatment of HBV in patients with HIV are discussed elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV" and "Monitoring the patient with HIV and chronic hepatitis B virus infection".)

ASSESSING IMMUNITY — Patients with HIV should be evaluated for evidence of HBV infection [5-7]. Individuals should be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). (See "Initial evaluation of adults with HIV", section on 'Screening for coinfections'.)

The results of serologic testing are used to determine the need for vaccination and additional preventive interventions. As an example, patients who are negative for anti-HBs, anti-HBc, and HBsAg have no evidence of immunity and should be vaccinated. There may also be a role for vaccinating those who have isolated anti-HBc. (See 'Whom to vaccinate' below and 'Patients with isolated anti-HB core antibody' below.)

OVERVIEW OF PREVENTION STRATEGIES — In patients with HIV who do not have evidence of immunity to HBV, there are several strategies to reduce to the risk of infection.

●Vaccination is the best way to prevent HBV infection. Patients with HIV should be vaccinated against HBV if they do not have evidence of protective immunity. Individuals are most likely to develop a protective serologic response if their CD4 count is ≥350 cells/microL and their HIV viral load is undetectable [8-11]. Serologic testing should be performed one to two months after vaccination to confirm that the patient is immune. Repeat vaccination may be needed for some individuals.

●Additional prevention interventions may be needed during the course of vaccination and for those who do not respond to the vaccine. These include behavioral interventions to decrease high-risk behaviors and possibly hepatitis B immune globulin if an exposure occurs. Antiretroviral agents used to treat HIV (eg, tenofovir, lamivudine, emtricitabine) may also provide some protection against HBV infection, but they are not the preferred strategy to prevent HBV infection.

These strategies are reviewed in detail below. (See 'Vaccination' below and 'Avoiding HBV exposure' below and 'Postexposure prophylaxis' below and 'The role of antiretroviral therapy' below.)

VACCINATION

Vaccine formulations — Hepatitis B vaccines are recombinant vaccines. In the United States, yeast-derived vaccines are mainly used. Mammalian cell-derived vaccines are used primarily in Europe.

●Yeast-derived vaccines – The United States Advisory Committee on Immunization Practices recommends the use of any of the following vaccine formulations (table 1) [12,13]:

•Recombinant hepatitis B vaccines (conventional)

-Recombivax HB (10 mcg hepatitis B surface antigen [HBsAg]/mL)

-Engerix-B (20 mcg HBsAg/mL)

•Recombinant hepatitis B vaccine (CpG-adjuvanted)

-Heplisav-B (20 mcg HBsAg/0.5 mL)

•Combined hepatitis A-hepatitis B vaccine

-Twinrix (720 enzyme-linked immunosorbent assay [ELISA] units inactivated hepatitis A virus and 20 mcg of recombinant HBsAg)

Recombivax HB and Engerix-B (referred to as conventional hepatitis B vaccines) became available in 1983 and 1989, respectively [14], and are used worldwide [15]. They use an aluminum adjuvant and typically require three doses over a six-month period to provide protection. These vaccines used to contain very small amounts of thimerosal, but those formulations were discontinued.

In November 2017, a new recombinant hepatitis B vaccine (designated HepB-CpG; sold as Heplisav-B) received approval for use in adults 18 years of age and older [16]. This vaccine consists of recombinant HBsAg with a novel immunostimulatory adjuvant [17,18]. The vaccine is administered as two intramuscular doses given one month apart [19]. HepB-CpG is not approved for use in children, pregnant persons, or patients on hemodialysis.

In general, patients should complete the vaccine series using the same type of vaccine (table 1). If this is not feasible (eg, due to vaccine availability), vaccination should not be deferred. The approach to vaccination in this setting is presented elsewhere. (See "Hepatitis B virus immunization in adults", section on 'Choice of vaccine'.)

●Mammalian cell-derived vaccines – There are three different manufacturers producing mammalian cell-derived vaccines with pre-S epitopes. Gen Hevac B (Pasteur, France) contains 20 mcg/dose of vaccine, Bio-Hep-B (Bio-Technology General, Israel) contains 2.5 to 10 mcg/dose, while AG-3 (Hepacare; Medeva, United Kingdom; Evans, United Kingdom) contains 10 to 20 mcg/dose of vaccine [20]. The dosing schedule varies with the type of vaccine.

A more detailed discussion on the different vaccine formulations is found elsewhere. (See "Hepatitis B virus immunization in adults", section on 'Dose regimens' and "Hepatitis B virus immunization in adults", section on 'Types of vaccines'.)

Whom to vaccinate — We recommend hepatitis B vaccination for patients without evidence of prior HBV exposure (eg, negative for HBsAg, hepatitis B surface antibody [anti-HBs], and hepatitis B core antibody [anti-HBc]) [7,21]. We also vaccinate certain patients who are only positive for anti-HBc (ie, negative for HBsAg and anti-HBs). (See 'Patients with isolated anti-HB core antibody' below.)

We administer the hepatitis B vaccine to patients, regardless of CD4 count. Although individuals are most likely to develop a protective serologic response with the conventional hepatitis B vaccines if their CD4 count is ≥350 cells/microL, some immunosuppressed individuals will still respond. It is particularly important that vaccination not be deferred in HBV-uninfected patients who are engaging in high-risk behaviors (eg, unprotected sex with a partner with chronic HBV infection, active injection drug use) or who have household members with chronic HBV. Repeat vaccination can be performed for individuals who do not develop protective immunity. (See 'Response to vaccination' below and 'Assessing vaccine response' below and 'Anti-HBs <10 milli-international units/mL after initial series' below.)

Some patients will have anti-HBs levels <10 milli-international units/mL after receiving their initial hepatitis B vaccine series. Such individuals should be revaccinated. The management of patients who do not respond to their initial vaccine series is discussed below. (See 'Anti-HBs <10 milli-international units/mL after initial series' below.)

It is important to vaccinate patients with HIV against HBV, since such patients are at increased risk of developing chronic infection. Persons with HIV who develop chronic HBV are at a higher risk of subsequently developing cirrhosis, hepatocellular carcinoma, and end-stage liver disease compared with patients without HIV. The efficacy of hepatitis B vaccination in preventing HBV in adults was established in the early 1980s using an inactivated plasma-derived hepatitis B vaccine. In a randomized study of 1083 men who have sex with men who were at high risk for HBV infection, the incidence of hepatitis B was reduced more than 90 percent [22]. In addition, subsequent population-based studies have shown a marked reduction in the incidence of HBV in vaccinated populations [23]. The efficacy of hepatitis B vaccination has been found to correlate with an anti-HBs titer of >10 milli-international units/mL, and vaccine-induced seroprotection is considered a surrogate for clinical protection [12]. Thus, most of the studies evaluating the efficacy of hepatitis B vaccination in patients with HIV have assessed the serologic response. (See 'Likelihood of response' below.)

Vaccine strategies — Conventional hepatitis B vaccines (eg, Engerix-B or Recombivax HB) using standard doses and vaccine schedules are used in many patients with HIV. However, the initial immune response to conventional hepatitis B vaccines can be lower in individuals with HIV compared with those who are HIV uninfected. (See 'Likelihood of response' below.)

Certain strategies may help improve the likelihood of responding to vaccination. As an example, hepatitis B vaccine should ideally be administered before the CD4 count declines to <350 cells/microL to improve immunogenicity, although we do not defer vaccination if the CD4 count is less than this. (See 'Whom to vaccinate' above.)

Other strategies include increasing the dose of the vaccine and using formulations with novel adjuvants.

All patients with HIV should be tested for anti-HBs one to two months after completing the vaccine series to make sure they develop a protective immune response. Those who do not develop protective immunity will require additional doses to achieve an adequate serologic response. (See 'Assessing vaccine response' below and 'Anti-HBs <10 milli-international units/mL after initial series' below and 'Waning immunity' below.)

Approach for most patients — Our general approach to hepatitis B vaccination for patients with HIV is reviewed here, and depends in part upon the availability of the different vaccine formulations. Additional considerations for those with ongoing risk for HBV, those who are anti-HBc positive, and pregnant persons are discussed below. (See 'Patients with ongoing risk for acquiring HBV' below and 'Patients with isolated anti-HB core antibody' below and 'Pregnant persons' below.)

●Preferred approach – For most patients, we suggest hepatitis B vaccination using conventional recombinant hepatitis B vaccines (eg, Engerix-B or Recombivax HB) rather than HepB-CpG (Heplisav-B), a vaccine that uses a novel immunostimulatory adjuvant (see 'Vaccine formulations' above). Although HepB-CpG is more immunogenic in healthy adults than conventional vaccines, data are limited in persons with HIV, and the optimal dosing schedule has not been determined. By contrast, there is extensive experience with conventional vaccines demonstrating safety, and more than half of individuals with a CD4 count >500 cells/microL will respond to the initial vaccine series. (See 'Likelihood of response' below.)

The hepatitis B vaccine series using conventional hepatitis B vaccines consists of three doses, administered intramuscularly at zero, one, and six months. Although some studies have evaluated a four-dose series, there is insufficient evidence to suggest this regimen over the standard three-dose regimen [24].

When using the conventional hepatitis B vaccine, we suggest starting with a double dose of the vaccine (eg, Engerix-B vaccine at 40 rather than 20 mcg/mL). In a meta-analysis of 10 studies, the double dose had better response rates in patients with HIV compared with the standard dose at four to six weeks (odds ratio [OR] 1.76, 95 % CI 1.36-2.29) and at >12 months (OR 2.28, 95% CI 1.73-3.01) after vaccine completion [24]. However, the standard dose of vaccine continues to be used in many settings. When this occurs, the higher dose can be used if the patient did not respond to the initial vaccine series. (See 'Anti-HBs <10 milli-international units/mL after initial series' below.)

●Alternative approach – HepB-CpG is a reasonable alternative when the vaccine formulation is dictated by availability. However, HepB-CpG is not approved for use in children, pregnant persons, or patients on hemodialysis.

The HepB-CpG vaccine series is administered as two doses separated by at least four weeks. The dose is the same, regardless of HIV status. In one retrospective study of 64 persons with HIV who received Heplisav-B, the seroprotective rate was 79 percent among HBV vaccine-naïve patients [25]. A detailed discussion of the efficacy and safety of HepB-CpG in healthy adults is presented elsewhere. (See "Hepatitis B virus immunization in adults", section on 'Yeast-derived' and "Hepatitis B virus immunization in adults", section on 'Adverse reactions'.)

Ideally, the vaccine series should be completed using the same formulation for all doses. However, if this is not feasible (eg, due to vaccine availability), vaccination should not be deferred. The single-antigen vaccines can be used interchangeably, except that a two-dose vaccine series should only be used when both doses consist of HepB-CpG [13]. Vaccine series that consist of a combination of a dose of HepB-CpG and a dose of another HBV vaccine should consist of three total vaccine doses: the interval between dose 1 and dose 2 should be at least 4 weeks; the interval between dose 2 and dose 3 should be at least 8 weeks; and the interval between dose 1 to dose 3 should be at least 16 weeks.

Patients with ongoing risk for acquiring HBV — For most patients with ongoing risk for HBV infection (eg, injection drug users, those with sexual partners who have chronic HBV) we initiate a three-dose series using a double dose of the conventional hepatitis B vaccine, as described above. (See 'Approach for most patients' above.)

However, the two-dose series using HepB-CpG may be preferred for those with ongoing risk if there is concern that the patient is unlikely to complete a three dose series at 0, 1, and 6 months using the conventional recombinant hepatitis B vaccine. Several studies have described low completion rates among those who initiate the hepatitis B vaccine series [1,26].

An accelerated dosing schedule of conventional hepatitis B vaccine (eg, Engerix-B or Recombivax HB), using standard doses at zero, one, and three weeks, has also been evaluated but may not be as effective, especially for patients with CD4 count counts <500 cells/microL [27]. In a study that evaluated this accelerated HBV immunization schedule in 761 patients with HIV with a range of CD4 counts (<200 cells/microL, 200 to 500 cells/microL, and >500 cells/microL) [27], adherence was better in the accelerated-vaccination arm, but overall seroconversion rates were lower in the group that received the accelerated series compared with those who received the standard dosing regimen (39 versus 50 percent). The response varied significantly by CD4 count, and the accelerated schedule was inferior in all patients, except those with a CD4 count >500 cells/microL. In this study, anti-HBs titers were only assessed at week 28; thus, no long-term data are available on decay of antibody titers.

The use of antiretroviral therapy (ART) regimens that include tenofovir-emtricitabine may also provide protection against HBV. (See 'The role of antiretroviral therapy' below.)

Patients with isolated anti-HB core antibody — Some patients have evidence of prior HBV infection (anti-HBc) but do not have detectable HBsAg (evidence of chronic infection) or anti-HBs (evidence of immunity). These patients may have lost their anti-HBs over time or have occult HBV infection (as evidenced by presence of HBV DNA in serum). (See "Hepatitis B virus: Screening and diagnosis in adults".)

●Whom to vaccinate – Guidelines recommend that all patients with HIV who have isolated anti-HBc be vaccinated followed by anti-HBs testing [7]. While some UpToDate authors agree with these guidelines, other experts check HBV DNA in patients with isolated anti-HBc and only vaccinate individuals if the HBV DNA is not detected. Patients with a detectable HBV DNA will not respond, regardless of dose, and these individuals should receive ART that is active against both HIV and HBV instead of vaccination. (See "Treatment of chronic hepatitis B in patients with HIV".)

Vaccinating patients with isolated anti-HBc protects those who have a false-positive test and may theoretically boost immunity in those who recovered from a prior infection and lost their anti-HBs. There have been anecdotal reports of clinically apparent HBV due to reinfection in patients with HIV who have isolated anti-HBc [28].

●Approach to vaccination – Once the decision to immunize is made, there are several approaches to vaccination; however, there is no consensus, since data are limited.

•One approach to vaccination in patients with isolated anti-HB core antibody is to administer one standard dose or double dose of a conventional hepatitis vaccine and then check anti-HBs titers one to two months after the dose. If the anti-HBs titer is ≥100 milli-international units/mL, no further vaccination is needed; but if the titer is <100 milli-international units/mL, the HBV vaccine series should be completed [7].

Developing a protective antibody response (≥10 milli-international units/mL) after a single booster dose is typically considered consistent with an anamnestic response from prior infection [29]. However, in persons with HIV, guidelines recommend completing the vaccine series if the titer is <100 milli-international units/mL, since available data suggest this approach enhances the durability of the response, as described in the study below [30].

•Another approach is to administer the full hepatitis B vaccine series using a standard or double dose of a conventional hepatitis vaccine. Many labs do not report titers, so this may be the only option in certain settings. (See 'Approach for most patients' above.)

Administering two doses of the recombinant hepatitis B vaccine that uses a novel immunostimulatory adjuvant (Heplisav-B, HepB-CpG) is also reasonable; however, the safety and optimal use of this vaccine in patients with HIV are still to be determined.

For patients who receive a complete vaccine series, anti-HBs should be checked one to two months later. If the anti-HBs is ≥10 milli-international units/mL, annual anti-HBs should be obtained in those with ongoing risk, and revaccination should occur if the anti-HBs becomes negative, as discussed below. (See 'Waning immunity' below.)

In patients with isolated anti-HBc who do not respond to the initial vaccine series, additional or higher doses of vaccine may result in protective anti-HBs titers in some patients. However, we first check HBV DNA to exclude occult HBV, if not done previously, unless the patient is receiving an ART regimen that contains tenofovir (patients on tenofovir are unlikely to have HBV DNA detected). The approach to revaccination and the need for additional prevention strategies in those who fail to respond to vaccination are the same as those for patients who are anti-HBc negative. (See 'Anti-HBs <10 milli-international units/mL after initial series' below and 'Anti-HBs <10 milli-international units/mL after repeat vaccination' below.)

Studies evaluating hepatitis B vaccination in patients with HIV and an isolated anti-HBc have demonstrated that most patients will develop an anti-HBs level >10 milli-international units/mL after completing three or four doses of the vaccine [30,31]. In one study of 54 patients with HIV, isolated anti-HBc, and an undetectable HIV RNA, individuals received one 20 mcg dose of recombinant HBV vaccine, and those with anti-HBs <10 milli-international units/mL four weeks after the first vaccine received three additional 40 mcg doses at weeks 5, 9, and 24 [30]. At week 4, 25 patients (46 percent) had anti-HBs ≥10 milli-international units/mL; those who achieved a titer of ≥100 milli-international units/mL after a single booster dose maintained anti-HBs level of ≥10 milli-international units/mL for more than 18 months, compared with only 23 percent of those who achieved a titer between 10 and 100 milli-international units/mL. Among the nonresponders at week 4 who received additional vaccine, 81 percent had anti-HBs ≥10 milli-international units/mL at month 18. In a subsequent study, patients who received standard doses of vaccine (rather than high-dose vaccine) had a similar response [31].

Pregnant persons — Conventional hepatitis B vaccines (Engerix-B or Recombivax HB) should be used for persons who are pregnant. These hepatitis B vaccines have no known teratogenic effects and have been shown to be safe during pregnancy. By contrast, HepB-CpG is not approved for use in pregnant persons since there are no studies evaluating HepB-CpG in this population. A more detailed discussion of immunization in pregnancy is presented elsewhere. (See "Immunizations during pregnancy", section on 'Hepatitis B'.)

Missed doses — Patients who miss doses of their primary series can resume the series at any time. Anti-HBs titers should be checked approximately four weeks after the last vaccine dose has been administered. (See 'Assessing vaccine response' below.)

Safety and adverse events — In general, the safety and adverse events of the conventional hepatitis B vaccines are the same in those who are HIV infected and those who are uninfected. The most common side effect is discomfort at the injection site [32]. There are insufficient data to evaluate the adverse events associated with HepB-CpG in patients with HIV, although studies are underway. A more detailed discussion of adverse reactions associated with the different hepatitis B vaccines is found elsewhere. (See "Hepatitis B virus immunization in adults", section on 'Adverse reactions'.)

Among patients with HIV, transient small increases in HIV RNA (eg, viral blips) have been reported with hepatitis B vaccine and other general immunizations, such as influenza and pneumococcus [33]. However, we do not withhold HBV vaccination for this reason, since isolated viral blips are not associated with adverse HIV outcomes. A more detailed discussion on viral blips is found elsewhere. (See "Patient monitoring during HIV antiretroviral therapy", section on 'Approach to viral blips and persistent low-level viremia'.)

Response to vaccination

Assessing vaccine response — Patients with HIV should have serologic testing (ie, anti-HBs) to confirm the presence of a protective serologic response to vaccination (anti-HBs >10 milli-international units/mL). This testing should be done four weeks after they complete their vaccine series [7]. This differs from patients without HIV, renal dialysis, or other forms of immunosuppression, for whom such testing is not routinely recommended. (See "Hepatitis B virus immunization in adults", section on 'Postvaccination testing'.)

An anti-HBs >10 milli-international units/mL is generally accepted as the level at which protection against HBV occurs. This was supported in an observational study of 626 patients with HIV who received the hepatitis B vaccine [34]. Among 409 vaccinees with anti-HBs <10 milli-international units/mL, 46 (11 percent) developed acute HBV infection compared with 11 of 217 (5 percent) vaccinees with anti-HBs ≥10 milli-international units/mL (hazard ratio 0.51; 95% CI 0.3-1.0). In addition, among the participants who acquired acute HBV infection, 16 of 46 (35 percent) with anti-HBs levels <10 milli-international units/mL developed chronic infection compared with 0 of 11 who had anti-HBs levels >10 milli-international units/mL.

After completing the hepatitis B vaccine series, subsequent management depends upon the anti-HBs level. (See 'Management based upon vaccine response' below.)

Likelihood of response — Among patients with HIV, the immunogenicity of conventional hepatitis B vaccines (eg, Engerix-B or Recombivax HB) ranges from 18 to 80 percent [35-39]. This is lower than what is seen in patients without HIV, in whom seroconversion rates of >90 percent have been reported (see "Hepatitis B virus immunization in adults", section on 'Types of vaccines'). In addition, patients with HIV have faster rates of antibody declines after immunization [8,36,40,41]. (See 'Waning immunity' below.)

Several factors can impact the patient's ability to develop a protective immune response. Patients with ongoing HIV viremia and CD4 counts <350 cells/microL have lower seroconversion rates compared with individuals who have CD4 counts above this threshold and/or HIV RNA suppression [9,35,39,40]. However, some immunosuppressed individuals will still respond [7].

The patient's age and hepatitis C virus (HCV) status can also affect the response to vaccination [9,40,42,43]. As an example, in a study of 437 patients with HIV, the risk of not responding to the vaccine increased by 30 percent for every 10-year increase in age [9]. In another study, patients who had evidence of HCV infection (positive HCV antibody or a positive HCV RNA) had lower rates of seroconversion and lower geometric mean titers of anti-HBs after receiving the HBV vaccine compared with those who were not coinfected with HCV [42,43]. In patients with HCV monoinfection, the degree of liver disease is also an independent factor in vaccine response [44]. This is likely to be true in coinfection with HIV as well, but the response is not as well characterized in this group.

Management based upon vaccine response

Anti-HBs ≥10 milli-international units/mL — If the patient has an anti-HBs ≥10 milli-international units/mL, the patient is considered immune. We perform follow-up anti-HBs testing yearly for persons with potential ongoing exposures (eg, patients undergoing dialysis, injection drug users, individuals whose sexual partner has chronic HBV infection) and administer a booster dose to those whose titers drop to <10 milli-international units/mL. This approach is consistent with recommendations from the United States Centers for Disease Control and Prevention [45]. A more detailed discussion of the management of patients with waning immunity is found below. (See 'Waning immunity' below.)

Anti-HBs <10 milli-international units/mL after initial series — Patients who have an anti-HBs <10 milli-international units/mL after the initial vaccine series should receive a second vaccine series. Additional preventive interventions should also be implemented, including behavioral interventions to decrease ongoing risk factors, and possibly hepatitis B immune globulin after an exposure. (See 'Avoiding HBV exposure' below and 'Postexposure prophylaxis' below.)

No vaccination strategy has been consistently effective in patients with HIV who do not respond to their initial series [9,36,46-51]. Our approach to vaccination in nonresponders is as follows:

●We suggest using a double dose of the conventional hepatitis B vaccine, regardless of what the patient received for the initial vaccine series. In a double-blind, randomized trial of 107 patients with HIV comparing standard to double dose of vaccine, those who received the double dose were more likely to have a serologic response (72 versus 51 percent; OR 2.48, 95% CI 1.02-6.10) [52]. The mean anti-HBs titers four to eight weeks after vaccination were also significantly higher in the double-dose versus the standard-dose group (398 milli-international units/mL versus 158.5 milli-international units/mL). There did not appear to be any significant increased risks when the double dose is used.

Another option is to use HepB-CpG (Heplisav-B). Although there are limited data with the use of this vaccine in patients with HIV, it is a reasonable choice for revaccination, especially in patients who received the conventional hepatitis B vaccine.

●For most patients who were vaccinated when their CD4 count was <350 cells/microL, we repeat the vaccination series after they have initiated ART and their CD4 count is ≥350 cells/microL for at least three months. However, certain patients never achieve a CD4 count ≥350 cells/microL, even if the HIV viral load is undetectable. Although there are no data to guide management in this situation, we revaccinate such individuals if they have an undetectable viral load for at least one year.

●Patients should have their anti-HBs measured four weeks after completing the second series to assess immunity. (See 'Assessing vaccine response' above.)

Some vaccine strategies that have been evaluated in patients who do not respond to HBV vaccination include the addition of an immunostimulatory adjuvant to conventional vaccines or the use of an alternative route of administration (eg, intradermal versus intramuscular) [46,47,50].

Anti-HBs <10 milli-international units/mL after repeat vaccination — Patients who have an anti-HBs <10 milli-international units/mL after receiving two complete vaccine series are considered nonresponders. In such patients, we suggest not giving additional doses of HBV vaccine as they are unlikely to respond.

These patients remain at risk for HBV infection. Thus, postexposure prophylaxis with hepatitis B immunoglobulin (HBIG) is typically administered to such patients after a known exposure to HBV. However, some experts may choose not to administer HBIG if the patient's HIV ART regimen is also active against HBV (eg, one that includes tenofovir-emtricitabine). (See 'Postexposure prophylaxis' below.)

In addition, in nonresponders who continue to engage in HBV risk behaviors and who are not already treated with an HBV-active ART regimen, we switch the existing ART regimen to one that includes tenofovir-emtricitabine, if possible. (See 'The role of antiretroviral therapy' below and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Waning immunity — Waning immunity (ie, a decline in antibody titer) can be seen in patients with HIV who initially developed a protective immune response. (See 'Assessing vaccine response' above.)

If there are concerns for ongoing exposure, we administer a single booster dose of the hepatitis B vaccine to patients who were prior responders but whose anti-HBs titer declined to <10 milli-international units/mL. Antibody titers should be rechecked one to two months after a booster dose to determine efficacy. If a level of ≥10 milli-international units/mL is not achieved, they should complete a three-dose series using the standard dose of the vaccine.

Waning immunity is typically seen in patients with low CD4 counts (ie, <350 cells/microL) and may be due, in part, to the height of the initial antibody response after immunization. As an example, in a study of individuals with HIV who had antibody titers assessed 28 weeks after vaccination, those who had a titer <100 milli-international units/mL were significantly more likely to have waning immunity over the next five years compared with individuals who had higher titers after vaccination [53].

AVOIDING HBV EXPOSURE — Patients should be counseled on how to avoid behaviors that put them at risk for acquiring HBV (see "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Transmission of HBV'). As an example, providers should review safe sex and injection drug use practices. Individuals should be reminded to avoid high-risk behaviors even while they are being vaccinated. More detailed discussions on how to reduce high-risk behaviors are found elsewhere. (See "Prevention of sexually transmitted infections" and "Substance use disorder in patients with HIV", section on 'Treatment of substance use disorders in HIV'.)

POSTEXPOSURE PROPHYLAXIS — Postexposure prophylaxis (hepatitis B immunoglobulin [HBIG] and/or hepatitis B vaccine) should generally be administered to individuals who are not immune to HBV (ie, hepatitis B surface antibody [anti-HBs] <10 milli-international units/mL) if they have had a high-risk exposure (eg, unprotected sex, shared needles) with someone who is known to have chronic HBV (ie, hepatitis B surface antigen [HBsAg]-positive) or whose status is unknown.

●Hepatitis B vaccine – All patients without evidence of immunity should receive hepatitis B vaccine if they have not been previously vaccinated or did not respond to the initial vaccine series. (See 'Whom to vaccinate' above and 'Anti-HBs <10 milli-international units/mL after initial series' above.)

●HBIG – In patients with HIV, the decision to administer HBIG to patients who are on an HIV regimen that has activity against HBV (eg, one that includes tenofovir-emtricitabine) must be determined on a case-by-case basis. While some UpToDate authors administer HBIG to all patients without evidence of immunity after an exposure to a source who is HBsAg positive, regardless of their HIV regimen, others only administer HBIG to those who are on a regimen that does not contain tenofovir. Several studies (described below) found a marked reduction in the risk of HBV infection in patients receiving an HBV-active antiretroviral therapy regimen, particularly when tenofovir was used [54-56]. (See 'The role of antiretroviral therapy' below.)

A more detailed discussion of postexposure prophylaxis for HBV is presented elsewhere. (See "Management of nonoccupational exposures to HIV and hepatitis B and C in adults", section on 'Exposure to hepatitis B virus'.)

THE ROLE OF ANTIRETROVIRAL THERAPY — In general, HIV antiretroviral therapy (ART) is not considered a preferred strategy to prevent HBV infection. However, certain agents used to treat HIV (eg, lamivudine, emtricitabine, tenofovir) also treat HBV, and available data suggest that HBV-active ART decreases the risk of HBV acquisition [54-57].

In a study that looked at HBV incidence in 2375 high-risk men who have sex with men, of whom 25 percent were HIV infected, the overall risk of new HBV infection was higher in those with HIV (incidence rate ratio 14.9 versus 7.8 per 1000 person-years) [57]; however, after the introduction of potent ART, the incidence of new HBV infection was similar between those without HIV and those with HIV who had an HIV RNA <400 copies/mL (3.1 and 2.6 per 1000 person-years, respectively). In this study, the protective effect against incident HBV was similar in those taking lamivudine- or tenofovir-containing ART regimens. In another report that evaluated 354 patients with HIV and without prior HBV, the risk of new HBV infection was substantially reduced in those receiving HBV-active ART (hazard ratio 0.11, 95% CI 0.03-0.39); those receiving HBV-active ART who did become infected with HBV were taking lamivudine, and some were infected with lamivudine-resistant virus [56]. The potential benefit of a tenofovir- versus lamivudine-containing regimen in preventing HBV infection was supported in a subsequent study that evaluated 33 incident HBV infections that occurred among 381 males with HIV on potent ART, in which the incidence rates were 2.85, 1.36, and 0.14 cases per 100 patient-years among those taking ART without anti-HBV activity, lamivudine without tenofovir, and tenofovir, respectively [54].

In addition to the potential protective effects of HBV-active ART, the immune recovery associated with treatment of underlying HIV can impact the patient's ability to develop protective immunity after vaccination. This is discussed in greater detail above. (See 'Likelihood of response' above.)

Topic reviews that discuss ART regimen selection for patients with HIV are presented elsewhere. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis B vaccination" and "Society guideline links: Opportunistic infections in adults with HIV".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here is the patient education article that is relevant to this topic. We encourage you to print or e-mail this topic to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Hepatitis B (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Scope of the problem – It is important to prevent hepatitis B virus (HBV) infection in individuals with HIV since they are at increased risk of developing chronic infection, cirrhosis, hepatocellular carcinoma, and end-stage liver disease compared with patients without HIV who acquire HBV. (See 'Introduction' above.)

●Assessing immunity – All patients with HIV should be evaluated for HBV infection. Patients should be tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) upon HIV diagnosis. (See 'Assessing immunity' above.)

●Indications for hepatitis B vaccination – For patients without evidence of prior HBV (negative for HBsAg, anti-HBs, and anti-HBc), we recommend hepatitis B vaccination (Grade 1B). Vaccination against hepatitis B is safe and effective in reducing the risk of HBV in those who respond. (See 'Whom to vaccinate' above.)

For patients who are only positive for anti-HBc (ie, negative for HBsAg and anti-HBs), we also suggest hepatitis B vaccination (Grade 2C). However, some UpToDate experts only vaccinate individuals if the HBV DNA is negative. Vaccinating patients with isolated anti-HBc may protect those who have a false-positive test and may theoretically boost immunity in those who recovered from a prior infection and lost their anti-HBs. Specific considerations for vaccination in this population are discussed above. (See 'Patients with isolated anti-HB core antibody' above.)

●Initial vaccine series – There are several different hepatitis B vaccines available (table 1). The conventional yeast-derived vaccines (Engerix-B and Recombivax HB) use an aluminum adjuvant and are available worldwide. A recombinant vaccine with a novel immunostimulatory adjuvant (referred to as HepB-CpG, sold as Heplisav-B) is also available in some countries. (See 'Vaccine formulations' above.)

•When both vaccines are available, we suggest using the three dose conventional recombinant hepatitis B vaccines rather than HepB-CpG for most patients (Grade 2C). There is extensive experience with conventional vaccines in persons with HIV, and although the serologic response is lower compared to those without HIV, many individuals will respond. (See 'Approach for most patients' above and 'Likelihood of response' above.)

To increase the immunogenicity of conventional hepatitis B vaccines, we suggest using a double dose rather than the standard dose of the vaccine (Grade 2B). In addition, the vaccine should ideally be administered before the CD4 count declines to <350 cells/microL, although we do not defer vaccination if the CD4 count is less than this.

•HepB-CpG is a reasonable alternative when the vaccine formulation is dictated by availability. In addition, it may be preferred for patients who are at high risk for acquiring HBV and those who are unlikely to complete the conventional hepatitis B vaccine series. Only two doses of HepB-CpG are required to complete the series, and in persons without HIV, it appears to be more immunogenic. However, HepB-CpG is not approved for use in children, pregnant persons, or patients on hemodialysis. (See 'Approach for most patients' above and 'Patients with ongoing risk for acquiring HBV' above.)

●Assessing response to vaccination – Patients should have serologic testing (ie, anti-HBs) one to two months after they complete their vaccine series to confirm the presence of a protective serologic response (anti-HBs ≥10 milli-international units/mL). For patients who develop a protective immune response and have potential ongoing HBV exposures, we perform follow-up anti-HBs testing yearly, since declining antibody titers can be seen in individuals with HIV. (See 'Assessing vaccine response' above and 'Anti-HBs ≥10 milli-international units/mL' above and 'Waning immunity' above.)

●Approach to nonresponders – Patients who do not develop an anti-HBs ≥10 milli-international units/mL after the initial vaccine series should receive a second vaccine series. The conventional recombinant hepatitis B vaccine or HepB-CpG can be used. If the conventional vaccine is administered, we suggest using a double dose (Grade 2C). (See 'Anti-HBs <10 milli-international units/mL after initial series' above.)

Patients who have an anti-HBs <10 milli-international units/mL after receiving two complete vaccine series are considered nonresponders. For such patients, we suggest not giving additional doses of HBV vaccine (Grade 2C). However, these patients remain at risk for HBV infection, and additional prevention strategies are needed. (See 'Anti-HBs <10 milli-international units/mL after repeat vaccination' above.)

●Additional prevention strategies – Additional prevention interventions are needed during the course of vaccination and for those who do not respond to the vaccine. These include behavioral interventions to decrease high-risk behaviors and possibly hepatitis B immune globulin if an exposure occurs. Antiretroviral agents used to treat HIV (eg, tenofovir-emtricitabine) also provide some protection against HBV infection. (See 'Overview of prevention strategies' above and 'Avoiding HBV exposure' above and 'Postexposure prophylaxis' above and 'The role of antiretroviral therapy' above.)