Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Epidemiology

After acquiring hepatitis B virus (HBV) infection, many adults spontaneously recover and develop protective hepatitis B surface antibodies (anti-HBs). However, some progress to chronic hepatitis B, which is a leading cause of chronic liver disease worldwide.^1-6 Globally and in North America, approximately 8% of people with HIV have evidence of chronic HBV infection, but this varies by region of the world.⁷

Transmission routes vary geographically, with perinatal and early-childhood exposures responsible for most HBV transmission in higher-prevalence regions.⁸ In low-prevalence regions—such as Europe and North America—a large proportion of transmission is through sexual contact and injection drug use, but perinatal transmission also occurs.⁹ Although the general modes of transmission are similar to those of HIV, HBV is transmitted more efficiently than HIV.^4,6 People with HIV are at increased risk for developing chronic HBV infection.¹⁰ Ten genotypes of HBV (A–J) have been identified, and their geographic distributions differ,¹¹ with genotype A being most common in North America and Western Europe, genotypes B and C in Asia, and genotypes A, D, and E in sub-Saharan Africa in people with HBV infection.^12,13

Approximately 5% of people with chronic HBV infection are coinfected with hepatitis D virus (HDV), which requires HBV for its propagation since it uses the hepatitis B surface antigen as its envelope.¹⁴ Thus, prevalence of HDV mirrors that of chronic HBV infection.

Clinical Manifestations

HBV has an average incubation period of 90 days (range 60–150 days) from exposure to onset of symptoms.¹⁵ Acute HBV infection is asymptomatic in approximately 70% and <1% develop fulminant hepatic failure.^1,16 When symptoms manifest, they may include right upper quadrant abdominal pain, nausea, vomiting, fever, and arthralgias with or without jaundice. Most people with chronic HBV infection are asymptomatic or have nonspecific symptoms, such as fatigue. Between 15% and 40% of people with chronic HBV infection will eventually develop cirrhosis, hepatocellular carcinoma (HCC), or liver failure, and up to 25% of people will die prematurely from complications of chronic HBV infection.¹⁷

Diagnosis

Centers for Disease Control and Prevention (CDC) recommends testing all people over the age of 18, including those with HIV, for chronic HBV infection.¹⁸ Initial testing should include a triple screening panel of serologic testing for HBV surface antigen (HBsAg), hepatitis B core antibody (anti-HBc total), and anti-HBs.¹⁸ In acute infection, HBsAg can be detected 4 weeks (range 1–9 weeks) after exposure, and anti-HBc immunoglobulin M (IgM) is usually detectable at the onset of symptoms. See CDC’s Clinical Testing and Diagnosis for Hepatitis B for information on how to interpret laboratory results.

Chronic HBV infection is defined as persistent HBsAg detected on two occasions at least 6 months apart.¹ People with chronic HBV infection should be tested further for HBV e antigen (HBeAg), antibody to HBeAg (anti-HBe), and HBV DNA. “Active” disease, which can be HBeAg negative or HBeAg positive, can be distinguished from inactive disease by the presence of both serum HBV DNA and persistent or fluctuating alanine transaminase (ALT) elevations, defined as ≥2 times the upper limit of normal (≥70 U/L for males and ≥50 U/L for females).¹ Because people with chronic HBV infection are at risk for coinfection with HDV, anti-HDV should be checked once chronic HBV infection is diagnosed. If positive, then HDV RNA should be obtained to look for chronic infection.

In a low-prevalence country—such as the United States—isolated anti-HBc also may represent a false-positive result. However, the presence of an isolated positive anti-HBc test result can signify infection with HBV in the past with subsequent loss of anti-HBs. Isolated anti-HBc occurs in 7% to 19% of people with HIV.^19-22 Frequency of HBV viremia among people with HIV and isolated anti-HBc typically ranges from 1% to 10%.^19,20,23,24 Because most people with HIV with isolated anti-HBc are HBV DNA negative,²⁵ routinely checking HBV DNA is not recommended. The clinical significance of isolated anti-HBc is unknown,^19,22,26-28 but in people with HIV, it may indicate chronic or, more likely, resolved HBV infection.²⁹ People with HIV—particularly those with underlying hepatitis C virus (HCV) coinfection—have a higher frequency of isolated anti-HBc.^21,25,30,31 

People whose past infection has resolved are HBsAg negative with positive anti-HBs and anti-HBc.^1,32

Diagnosing HBV Disease Progression and the Role of Assessing Liver Fibrosis

Compared with people with HBV mono-infection, those with HIV/HBV coinfection have higher levels of HBV viremia and lower likelihood of resolved infection following acute HBV infection.³³ People with HIV/HBV are also more likely to have detectable HBeAg,^33,34 lower rates of seroconversion to anti-HBe, and increased risk of HCC and liver-related mortality and morbidity.^35-37

Chronic HBV infection is a dynamic disease with a number of phases (see the American Association for the Study of Liver Diseases’ 2018 Hepatitis B Guidance). In HIV/HBV coinfection, monitoring and treatment are focused on the simultaneous and immediate treatment of both viruses regardless of HBV phase.

People with HIV and chronic HBV should be linked to care and have a complete history and physical examination for signs of cirrhosis or HCC. HBV serologic and quantitative nucleic acid testing (HBeAg/anti-HBe and HBV DNA) and other laboratory testing—complete blood count, ALT, aspartate aminotransferase (AST), albumin, total bilirubin, alkaline phosphatase, international normalized ratio (INR), hepatitis A virus (HAV) immunoglobulin G (IgG) (to determine the need for vaccination), HCV IgG (if positive, HCV viral load), antibodies to hepatitis D virus IgG (if positive, HDV RNA), abdominal ultrasound, and liver fibrosis assessments (transient elastography or serum markers e.g. Fibrosure)—should be performed at the initial visit.¹ The decision to perform a liver biopsy should be individualized, but the procedure is rarely necessary.¹ People with chronic HBV infection are at increased risk of HCC; therefore, HCC surveillance every 6 months (ultrasound with or without alfa fetoprotein) is required for people who have cirrhosis and for people in the following groups who are at increased risk of disease progression: Asian males older than age 40, Asian females older than age 50, and males older than age 20 who are from sub-Saharan Africa.¹ People with HIV/HBV coinfection are at increased risk of HCC,^38,39 and some experts recommend ongoing semi-annual HCC surveillance for all people aged 40 years and older with HIV/HBV coinfection (BIII).

Preventing Disease

See the Hepatitis B Virus row of the Recommended Adult Immunization Schedule by Medical Condition and Other Indications table in the Immunizations for Preventable Diseases in Adults and Adolescents With HIV chapter for a summary of HBV vaccination recommendations. The evidence summary in this section will be moved to the Immunizations chapter in the next update.

All family members and sexual contacts of people with chronic HBV infection should be tested, and all susceptible household and sexual contacts should receive hepatitis B (HepB) vaccine regardless of whether they have HIV (AII). All people with HIV who are not immune to HBV infection (anti-HBc and anti-HBs negative) and do not have chronic HBV, as well as those who have failed a prior HBV vaccine series, should receive HepB vaccination with one of the available vaccines (AII).

Available adult single-antigen HepB vaccines in the United States that have been studied in people with HIV include two recombinant HBsAg vaccines (Engerix-B and Recombivax HB) and a recombinant HBsAg vaccine conjugated to a cytosine phosphoguanine oligonucleotide adjuvant (HepBCpG), which is a toll-like receptor 9 agonist (Heplisav-B).

The preferred vaccine in previously unvaccinated patients is Heplisav-B given at 0 and 4 weeks (AII). A single-arm study in 68 people with HIV, who were naive to HepB vaccine, and received Heplisav-B at 0, 4, and 24 weeks demonstrated a seropositivity rate (anti-HBs >10 mIU/mL) at 4 weeks and 20 weeks after the second dose of 87% and 98.5%, respectively.⁴⁰ The seropositivity rate 4 weeks after the third dose was 100%.

A two-dose Heplisav-B is appropriate only when both doses are Heplisav-B. In other situations, three total doses of vaccine should be given (AI). If Heplisav-B is not available, then vaccinate either with double-dose vaccine Engerix-B or double-dose Recombivax HB as the primary three-dose series (AII), or combined HepA and HepB (i.e., Twinrix) as a three-dose series (AII). A meta-analysis of 10 studies of people with HIV demonstrated that compared to a single dose, a double dose of Engerix-B or Recombivax HB had better response rates at 4 to 6 weeks (odds ratio [OR] 1.76; 95% confidence interval [CI], 1.36–2.29) and at >12 months (OR 2.28; 95% CI, 1.73–3.01) after vaccine completion.⁴¹ A double dose of Engerix-B is 40 mcg (two injections of the 20-mcg dose). A double dose of Recombivax HB is 20 mcg (two injections of the 10-mcg dose).

The magnitude and duration of immunogenicity to HepB vaccination with the two recombinant vaccines (Engerix-B, Recombivax HB) in adults with HIV are significantly lower than in healthy adults who are HIV seronegative.^42-44 Factors associated with poor response to these two recombinant vaccines include low CD4 T lymphocyte (CD4) cell counts,^42,45-50 presence of detectable HIV RNA,^46,50,51 coinfection with HCV, occult HBV infection, and the general health status of the host.^20,25,52-56 Although vaccine response to the two recombinant vaccines is better when CD4 counts are >350 cells/mm3, vaccination should not be deferred until CD4 counts increase to >350 cells/mm³ in those at high risk for HBV infection because some people with HIV with CD4 counts ≤350 cells/mm³ do respond to vaccination (AII).

Response to HepB vaccination, defined as anti-HBs ≥10 mIU/mL, should be documented 4 weeks after the last dose of vaccine (AII). In an observational study of 409 people with HIV who received the HepB vaccine, those with anti-HBs ≥10 mIU/mL were less likely to develop breakthrough HBV infection compared to those who did not achieve that level.⁵⁷ In addition, among those with a breakthrough HBV infection, 0% of those with anti-HBs ≥10 mIU/mL developed chronic infection compared to 35% of those with anti-HBs <10 mIU/mL (P = 0.02).

In those who failed a prior vaccine series with Engerix-B or Recombivax HB, Heplisav-B at 0 and 4 weeks is recommended (AI), and a third dose at 24 weeks can be considered since three doses results in higher anti-HBs titers (BIII). In a study of 561 people with HIV and prior nonresponse to Engerix-B or Recombivax HB, they were randomized to either Heplisav-B at 0 and 4 weeks, Heplisav-B at 0, 4, and 24 weeks, or Engerix-B at 0, 4, 24 weeks. Participants had CD4 counts >100 cells/mm³ (median 635 cells/mm³) and HIV RNA <1,000 copies/mL (94% <40 copies/mL). Four weeks after the last dose, the proportion with anti-HBs >10 mIU/mL (positive) was 93.1%, 99.4%, and 80.6% in two-dose Heplisav-B, three-dose Heplisav-B, and three-dose Engerix-B, respectively (P < 0.05). Of note, 96% of those who received the three-dose Heplisav-B had anti-HBs titers >100 IU/mL compared to 70% of those who received the two-dose Heplisav-B and 63% who received Engerix-B.⁵⁸ These data suggest that a third dose may be beneficial to provide more durable immunity but further follow-up is needed.

Because of waning immunity, some experts would check anti-HBs annually and give a booster dose if levels fall below 10 mIU/mL, particularly if a person has ongoing risk factors for acquiring HBV and is not receiving tenofovir (CIII).⁵⁹ Waning immunity is typically seen in people with low CD4 cell counts (<350 cells/mm³) and may be a consequence of the height of the initial antibody response after immunization. In a study of people with HIV who had antibody titers assessed 4 weeks after completing the three-dose hepatitis B vaccine series, those who had a titer <100 mIU/mL were significantly more likely to have waning immunity over the next 5 years compared with individuals who had higher titers after vaccination.⁶⁰

People with isolated anti-HBc should be vaccinated with one standard dose of HepB vaccine (one dose of Heplisav-B, or Engerix-B, or Recombivax HB), and anti-HBs titers should be checked 1 to 2 months after vaccination (BII). If the anti-HBs titer is ≥100 mIU/mL, no further vaccination is needed, but if the titer is <100 mIU/mL, a complete series of the same HepB vaccine should be completed and followed by anti-HBs testing (BII).⁶¹ The cutoff of 100 mIU/mL is used in this situation because one study demonstrated that 100% of people with isolated anti-HBc who achieved a titer of 100 mIU/mL after a booster dose maintained an anti-HBs response for >18 months compared with only 23% of those who achieved a titer of 10 to 100 mIU/mL.⁶¹ If anti-HBs quantitative titers are not available, then the complete series of HepB vaccine should be completed followed by qualitative anti-HBs testing (BII).

HBV-active ART (includes tenofovir with lamivudine [3TC] or emtricitabine [FTC]) decreases the risk for acute HBV infection, but it does not eliminate the risk, so taking ART alone is not a recommended strategy to prevent HBV infection. Therefore, HepB vaccine is recommended even if receiving an HBV-active ART regimen (AIII). In a study that evaluated HBV incidence in 591 males who have sex with men (MSM) with HIV, the HBV incidence rate for men not on HBV-active ART was 23.8 per 1,000 person-years (PYs) compared to 2.6 per 1,000 PYs for men on HBV-active ART with HIV RNA <400 copies/mL.⁶² The protective effect against incident HBV was similar in those taking lamivudine- or tenofovir-containing ART regimens. In another report of 354 people 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 acquired HBV were taking lamivudine, and some acquired lamivudine-resistant virus.⁶³ The potential benefit of a tenofovir- versus lamivudine-containing regimen in preventing HBV infection was examined in a study of 381 males with HIV and found HBV incidence rates to be 2.85, 1.36, and 0.14 cases per 100 PYs among those taking ART without hepatitis B virus antibody (anti-HBV) activity, lamivudine without tenofovir, and tenofovir, respectively.⁶⁴ In another study of 786 MSM on pre-exposure prophylaxis (PrEP), there were fewer incident HBV infections in persons who took tenofovir-based PrEP compared to those who did not take PrEP (3.8% vs. 0.8%, P = 0.02).⁶⁵

Preventing Other Liver Diseases

Hepatitis A vaccination is recommended for all people with HIV, including pregnant people, who are HAV total (IgG plus IgM) antibody negative (AIII). Among people with HIV with CD4 counts <200 cells/mm³, responses to the hepatitis A vaccine are reduced.^66,67 Antibody response should be assessed at least 1 month after vaccination is complete. If total HAV antibody (anti-HAV) immunoglobulin (IgG and IgM) is negative, people should be revaccinated when their CD4 count is >200 cells/mm³ (BIII). People with chronic HBV infection should be advised to avoid alcohol consumption (AIII).

Treating Hepatitis B Virus Infection

Preferred Regimens

The ultimate treatment goals in HIV/HBV coinfection are the same as for HBV mono-infection: to prevent disease progression and to reduce HBV-related morbidity and mortality. All people with HIV/HBV coinfection (HBsAg positive), including pregnant people, regardless of CD4 count and HBV DNA level (AII), should be treated with an antiretroviral (ART) regimen that includes drugs active against both HIV and HBV infections (AII).

The Adult and Adolescent Antiretroviral Guidelines recommend the fixed-dose coformulations of tenofovir disoproxil fumarate (TDF)/(FTC or 3TC), TAF/FTC, abacavir/3TC, or 3TC alone (with dolutegravir) as nucleoside reverse transcriptase inhibitor (NRTI) regimen backbones for ART-naive people regardless of CD4 count.⁶⁸ Because both components of the tenofovir combinations (tenofovir and either FTC or 3TC) have anti-HBV activity, they are also the treatment of choice for people with HIV/HBV coinfection (AII) regardless of CD4 count (AI) and HBV DNA level (AII) (see Hepatitis B Virus/HIV Coinfection in the Adult and Adolescent Antiretroviral Guidelines). TDF and TAF are both active against wild-type and 3TC-resistant HBV strains. Studies among people with HIV/HBV coinfection (most of them carrying 3TC-resistant HBV) have shown, on average, 4 log₁₀ declines in HBV DNA levels.^69-74 TDF and TAF have a high genetic barrier for development of resistance mutations.1,75 For people with isolated anti-HBc positivity, some experts recommend tenofovir-based ART because of the potential risk for HBV reactivation, but the precise risk is unknown (see the Nucleos(t)ide-Sparing Regimens section below) (CIII). However, a regimen without TDF or TAF can be considered if the HBV DNA is undetectable and the benefits outweigh the risk of HBV reactivation (CIII).

The decision to use TAF/FTC versus TDF/FTC should be based upon creatinine clearance (CrCl) and an assessment of risk for nephrotoxicity and risk for acceleration of bone loss.

• Among people with CrCl ≥60 mL/min, either TAF/(FTC or 3TC) or TDF/(FTC or 3TC) can be considered.
• Among people with a CrCl 30 to 59 mL/min, a TAF/FTC regimen is preferred.
• Currently approved fixed-dose combination TAF/FTC-containing regimens for the treatment of HIV are not recommended for use among people with CrCl <30 mL/min who are not on hemodialysis. For these people, renally dosed entecavir with a fully suppressive ART regimen is recommended since entecavir without suppressive ART can lead to emergence of the HIV M184V mutation (AIII). Renally dosed TDF and FTC or 3TC also can be used if recovery of renal function is unlikely (AIII). If renally dosed TDF is used, then the CrCl needs to be monitored carefully. In people with CrCl ≥15 to 29 mL/min, ART with TAF (as a single agent) and renally dosed FTC or 3TC may be used (AIII). Of note, some clinicians may choose to continue full-dose FTC to allow for people with CrCl 15 to 29 mL/min to remain on fixed-dose TAF/FTC products.
• In people receiving hemodialysis, ART with either renally dosed TDF plus (FTC or 3TC) (AII) or TAF/FTC (AII) may be used. TAF and FTC do not require dose adjustment in patients receiving hemodialysis; co-formulated full-dose products may be continued and given after dialysis on the day of hemodialysis. Refer to What to Start: Nucleoside Reverse Transcriptase Inhibitor Options as Part of Initial Therapy and Appendix B, Table 12. Antiretroviral Dosing Recommendations in Adults With Renal or Hepatic Insufficiency in the Adult and Adolescent Antiretroviral Guidelines for more information.

Among people with HIV/HBV coinfection, switching from a primarily TDF-based ART regimen to single-tablet TAF/FTC/elvitegravir/cobicistat maintained or achieved HBV suppression, with improved estimated glomerular filtration rate (eGFR) and bone turnover markers.⁷⁶ Among people with HBV mono-infection, TAF 25 mg was non-inferior to TDF 300 mg based on the percentage of people with HBV DNA levels <29 IU/mL at 48 weeks of therapy (94% for TAF vs. 93% for TDF; P = 0.47). People on TAF also experienced significantly smaller mean percentage decreases from baseline in hip and spine bone mineral density at 48 weeks than people receiving TDF (P < 0.0001). Furthermore, the median change in eGFR from baseline to 48 weeks also favored TAF (P = 0.004).^77,78 In a randomized placebo-controlled study of HIV/HBV coinfected people (mainly Asians), TAF/FTC/bictegravir (BIC) was superior to TDF/FTC/DTG in achieving HBV DNA <29 IU/ml (63% vs. 43%, respectively; P = 0.002) at 48 weeks but was similar at 96 weeks (75% vs 70%, respectively; P = 0.64).⁷⁹ Those receiving TAF/FTC/BIC had higher HBeAg seroconversion at 96 weeks (32% vs. 15%; P = 0.008) and HBsAg loss was not statistically different (23% vs. 14%; P = 0.07). Although the data are intriguing, whether these responses are related to ethnicity, HBV genotype, or other HIV-related factors still needs to be determined.

Chronic administration of 3TC or FTC as the only active drug against HBV is not recommended because of the high rate of selection of HBV drug-resistance mutations (AI).

People receiving ART should continue HBV therapy indefinitely (AIII) because relapses after response can occur, particularly in those with lower CD4 counts.¹ Additionally, discontinuation of nucleos(t)ide analog therapy is associated with an HBV reactivation in approximately 30% of cases,^80,81 as well as possible decompensation of liver disease and even death.^42,82-84 If anti-HBV therapy and ART must be discontinued for people with chronic HBV, serum transaminase levels and HBV DNA should be monitored every 6 weeks for 3 months and every 3 months thereafter while off anti-HBV agents (AIII). If a flare occurs, anti-HBV therapy and ART should be reinstituted and can be potentially lifesaving (AIII).

Some people with HIV/HBV coinfection also have chronic HCV infection. Scant information is available on the treatment of HBV/HCV/HIV coinfection. Because people with HBV/HCV/HIV coinfection appear to have accelerated progression of liver fibrosis, higher risk of HCC, and increased mortality,^85-87 attempts should be made to treat both hepatitis viruses, if feasible. Because HBV reactivation can occur during treatment for HCV infection with direct-acting antivirals in the absence of anti-HBV therapy, all people with HIV/HBV coinfection who will be treated for HCV infection should be on HBV-active ART at the time of HCV treatment initiation (AIII).^88-91 See the Hepatitis C Virus chapter for more information.

Considerations When Using Nucleos(t)ide-Sparing Regimens

With increasing use of nucleos(t)ide-sparing regimens, HBV status must be considered before such a switch. We recommend checking HBsAg, anti-HBc, and anti-HBs prior to changing to a nucleos(t)ide-sparing regimen to avoid reactivation of an unrecognized chronic HBV infection unless evaluated within the last 3 months (AIII). In people with a chronic HBV infection, switching to the one-pill regimen of dolutegravir (DTG)/3TC should be avoided because 3TC is then the only active drug against HBV (AIII). Further, switching to long-acting cabotegravir/rilpivirine (RPV) or DTG/RPV without addition of an anti-HBV drug (TAF, TDF, or entecavir) should be avoided (AIII).

In people with isolated anti-HBc positivity, some experts would recommend not switching to DTG/3TC or a nucleos(t)ide-sparing regimen because there is a small risk of reactivation, but this could be considered if the benefits outweigh the risk (CIII).⁹² In a study using data from the Veterans Aging Cohort Study, HBV reactivation occurred in 1.6% of individuals who were anti-HBc positive and HBsAg negative after switching to a nucleos(t)ide-sparing regimen.⁹² The risk was 20.2% in people with a remote positive HBsAg compared to 1.0% in those without a prior positive HBsAg. In people with recovery from a past HBV infection (anti-HBc positive, anti-HBs positive), DTG/3TC or a nucleos(t)ide-sparing regimen is an option provided they maintain undetectable HIV RNA levels (AIII).⁹² In people with prior receipt of the HBV vaccine, anti-HBs should be rechecked prior to switching to a nucleos(t)ide-sparing regimen because incident infections have been reported in such situations (AIII).⁹³

Alternative Treatment of HBV Infection Among People With HIV Who Are Not Receiving HBV-Active ART

All people with HIV should receive ART. Among people with HIV/HBV coinfection, co-treatment is essential and recommended.⁶⁸ Pegylated interferon (IFN)-α-2a (or 2b) monotherapy is approved for HBV treatment, but it should only be used in rare cases with consultation of an expert.

Regimens That Are Not Recommended

Tenofovir (TDF and TAF), entecavir, 3TC, and FTC should not be used alone in the absence of a fully HIV-suppressive ART regimen because of the potential for development of HIV drug-resistance mutations (AI).^94,95 Other anti-HBV treatment regimens include adefovir in combination with 3TC or FTC in addition to a fully suppressive ART regimen^74,96,97; however, data on this regimen among people with HIV/HBV coinfection are limited. In addition, compared with TDF or TAF or entecavir, adefovir is associated with higher incidence of toxicity, including renal disease, as well as higher rates of HBV treatment failure. Therefore, the Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV (the Panel) does not recommend an adefovir-containing regimen for people with HIV/HBV coinfection (AI).

Monitoring of Response to Therapy and Adverse Events

To evaluate response, HBV DNA should be monitored at 6-month intervals (AII). Treatment responses are slower than responses to HIV therapy and are defined as the following for nucleos(t)ide analog therapy:

• Virologic response: undetectable HBV DNA (<10 IU/mL) by real-time polymerase chain reaction⁹⁸
• Partial virologic response: HBV DNA ≥1 log₁₀ decline, but still detectable HBV DNA at 12 months⁹⁸
• Primary nonresponse: HBV DNA <1 log₁₀ decline after 3 months⁹⁹

See the Managing Treatment Failure section below for information on managing partial virologic response.

For people who are HBeAg positive, loss of HBeAg is also a measure of virologic response. Other markers that indicate treatment success include improvement in liver histology based on biopsy, transient elastography or other noninvasive tests; normalization of serum aminotransferases; and, in those with loss of HBeAg, the development of anti-HBe. Sustained loss of HBsAg is considered by some to be a complete response or functional cure; however, this desirable serologic response is uncommon (<1% of HBsAg-positive people without HIV per year).¹ Interestingly, after ART initiation, in some studies people coinfected with HIV and HBV have up to 20% chance of loss of HBsAg especially in the first 1 to 2 years.^100,101 For this reason, HBsAg should be checked yearly after ART initiation (AIII). If HBsAg loss occurs and there is a desire to switch to a nucleos(t)ide-sparing regimen, this option may be considered as long as HIV RNA suppression is maintained.

Adverse Events

Renal toxicity with TDF, including increased serum creatinine or renal tubular dysfunction, has been observed; both increased serum creatinine and renal tubular dysfunction are more frequent among people with HIV who have underlying renal insufficiency, are older, or have been treated with TDF for prolonged periods.¹⁰² These biochemical changes are usually reversible when TDF is discontinued or changed to TAF.¹⁰³

Electrolytes and serum creatinine levels should be evaluated at baseline and every 6 months. Because renal toxicity may be reversible, alternative anti-HBV therapy should be used if renal toxicity occurs (AI). If TDF is used among people with baseline renal insufficiency, either a dose adjustment as noted in the package insert or a change to TAF with appropriate dose adjustment is required.¹⁰³ See Table 6. Dosing Recommendations in People With Renal Insufficiency for more information. 

TDF has been associated with a decrease in bone mineral density (BMD). TAF is associated with less of a decrease in BMD than TDF in studies of hepatitis B treatment.¹⁰⁴ TAF also has been associated with early weight gain among people with HIV although the long-term consequences of this are unclear.¹⁰⁵

See Considerations for Antiretroviral Use in Patients With Coinfection: Hepatitis B Virus/HIV Coinfection in the Adult and Adolescent Antiretroviral Guidelines for more information on adverse events related to TAF and TDF. 

Entecavir-associated lactic acidosis is uncommon but has been reported among people with HBV mono-infection with advanced cirrhosis.^106-108

Immune Reconstitution Inflammatory Syndrome

Return of immune competence after ART (or after steroid withdrawal or chemotherapy) can lead to reactivation of HBV-associated liver disease. Any immune reconstitution can lead to a rise in serum aminotransferases, so-called “hepatitis flare,”¹⁰⁹ which constitutes immune reconstitution inflammatory syndrome (IRIS) among people with HIV/HBV coinfection. IRIS may manifest when serum aminotransferase levels dramatically increase as CD4 counts rise within the first 6 to 12 weeks after ART is started, with signs and symptoms characteristic of acute hepatitis and without another cause for the flare.^110,111 After introduction of ART, serum ALT levels should be monitored closely; some experts recommend ALT testing at 6 and 12 weeks, then every 3 to 6 months thereafter. Any association between abnormal aminotransferases and clinical jaundice or synthetic dysfunction (elevated INR and low serum albumin) should prompt consultation with a hepatologist (CI).¹⁰³

Flares are worse among people with more severe liver disease, especially those with cirrhosis.¹¹² Distinguishing between drug-induced liver injury, HBV drug resistance, HBeAg seroconversion, or other causes of hepatitis (i.e., acute hepatitis caused by HAV, HCV, HDV, hepatitis E virus, Epstein-Barr virus, herpes simplex virus, or cytomegalovirus infection) and IRIS may be difficult. ART-associated hepatotoxicity may be dose dependent or idiosyncratic. Among people with HIV, the risk of ART-associated hepatotoxicity has been associated consistently with elevated pre-ART aminotransferases (ALT, AST) and the presence of HBV or HCV coinfection. In HIV/HBV coinfection, baseline elevated HBV DNA levels are predictive of hepatotoxicity.^113-116 Despite this increased risk of hepatotoxicity in the setting of HCV or HBV coinfection, most (90%) people with HIV/HBV coinfection do not have ART-associated hepatotoxicity,¹¹⁷ and clinically significant hepatotoxicity (elevated direct bilirubin and INR) is rare. Aminotransferase levels return to baseline in most cases, even if the offending medication is continued.^118,119 Therefore, discontinuing ART usually is not necessary in the presence of hepatotoxicity unless the following symptoms are observed: hypersensitivity (e.g., fever, lymphadenopathy, rash), symptomatic hepatitis (i.e., nausea, vomiting, abdominal pain, or jaundice), or elevations in serum aminotransferase levels >10 times the upper limit of normal (AIII).¹²⁰ Liver histology also may help to differentiate drug toxicity (e.g., increased eosinophils) from viral hepatitis (e.g., portal inflammation). If aminotransferases increase >2 times the baseline level, the Panel recommends monitoring aminotransferases weekly and also obtaining bilirubin and INR until the aminotransferases begin declining (AIII).

Other noninfectious causes of abnormal liver tests that should be considered include use of drugs or alcohol and steatotic liver disease.¹²¹

Managing Treatment Failure

HBV treatment failure on nucleos(t)ide analogs is defined as primary nonresponse (HBV DNA <1 log₁₀ decline) after 3 months of therapy among people who consistently adhere to HBV therapy or an increase in HBV DNA levels >1 log₁₀ above nadir. In either situation, treatment failure generally is due to either drug-resistant HBV if the person is on 3TC/FTC monotherapy or to nonadherence to therapy.¹ If drug-resistant HBV is present, a change in treatment is needed (AII). Distinct resistance patterns exist with the different groups of anti-HBV drugs: the L-nucleosides (telbivudine, 3TC/FTC); acyclic phosphonates/nucleotides (adefovir and tenofovir); and D-cyclopentane (entecavir), which shares some resistance mutations with the L-nucleosides. Many experts will obtain HBV-resistance testing because it has value in distinguishing between nonadherence and drug resistance, evaluating people with unclear prior drug history, assessing different adefovir-resistance pathways, and predicting the level of resistance to entecavir.¹²² However, TDF is associated infrequently with clinical resistance, although slow response has been noted, as discussed above. Addition of entecavir has led to suppression of HBV DNA among people whose response to TDF is slow.¹²³

With 3TC monotherapy for HBV, the rate of developing 3TC-resistance is approximately 20% per year among people with HIV/HBV coinfection.¹²⁴ If 3TC resistance is suspected or documented, TDF or TAF should be added to the ART regimen (AIII).^125-127 Because people with 3TC-resistant HBV will have cross-resistance to the other L-nucleosides (FTC), and partial resistance to entecavir, those agents should not be used among people found to have 3TC-resistant HBV (AI).¹²⁸ All nucleoside analogs must be dose-adjusted for renal insufficiency per package insert guidelines and Table 6. Dosing Recommendations in People With Renal Insufficiency.

If treatment failure occurs on entecavir, TDF or TAF (with or without FTC) is recommended because of the cross-resistance that occurs with L-nucleosides (3TC, FTC) (AI).

People whose HBV infection initially failed to respond to pegylated IFN-α can be given nucleos(t)ide analog therapy following the recommendations previously described (CIII).

If treatment failure with TDF or TAF occurs, particularly in 3TC- or FTC-experienced people, entecavir may be an active alternative, especially if higher doses of entecavir can be used (CIII).

Declines in HBV DNA levels can be slow, especially when pretherapy HBV DNA levels are very high. HBV DNA levels usually drop quickly among people who are receiving an HBV drug with high potency and a high genetic barrier to resistance—such as tenofovir—but HBV DNA levels may still be detectable for some years.¹ Thus, in a person who is adherent to therapy with a partial virologic response to tenofovir, the drug should be continued with monitoring of HBV DNA levels (BII). Improved virologic response has been reported with the addition of entecavir to TDF; however, whether such “intensification therapy” is required is unclear.¹²⁹

Special Considerations for Treating End-Stage Liver Disease

People with HIV/HBV coinfection who have end-stage liver disease (cirrhosis) should be managed as a person with HBV mono-infection with end-stage liver disease, including referral to a hepatologist (AIII). Among people with HIV/HBV coinfection in end-stage liver disease, IFN-α is contraindicated (AI), but nucleos(t)ide analogs are safe and efficacious (AI).^124,130,131 All people with ascites should undergo paracentesis to exclude spontaneous bacterial peritonitis (SBP).^132,133 Management of ascites includes sodium restriction (<2 g/day) and the recommended diuretic regimen is spironolactone combined with furosemide (ratio of 40 mg furosemide:100 mg spironolactone) (AI). All people who have had SBP and those with ascites total protein <1 g/dL should receive prophylaxis against SBP with administration of oral antibiotics, such as ciprofloxacin (500 mg/day), or trimethoprim-sulfamethoxazole (one double-strength tablet/day) (AI).¹³⁴

Esophagogastroduodenoscopy (EGD or upper endoscopy) should be performed on all people with cirrhosis at the time of diagnosis and then every 1 year to 2 years to identify substantial gastroesophageal varices (see the American Association for the Study of Liver Diseases (AASLD) 2018 Hepatitis B Guidance). People with varices require nonselective beta blockers—such as nadolol or propranolol—that are the mainstay of both primary and secondary prevention of variceal hemorrhage. Esophageal variceal banding is another preventive option, particularly for those who cannot tolerate beta blockers. Hepatic encephalopathy is treated with a 40-g protein diet and the use of nonabsorbable disaccharides—such as lactulose—and/or nonabsorbable antibiotics, such as rifaximin.¹

Because people with HBV-related cirrhosis are at increased risk of HCC,¹³⁵ imaging studies with alpha fetoprotein should be performed every 6 months, as recommended in HBV mono-infection (AI).¹ Choice of imaging (ultrasound, computed tomography, or magnetic resonance imaging) depends upon the expertise of the imaging center. Usually, ultrasound is the initial preferred imaging modality.¹

People with HIV/HBV coinfection with decompensated liver disease and/or early HCC are candidates for liver transplantation. HIV infection is not a contraindication to organ transplantation among people on suppressive ART.¹³⁶ Because transplantation does not cure HBV infection, post-transplant hepatitis B immune globulin (HBIG) and HBV treatment is required (AII). People with HIV who are potential candidates for liver transplantation should be referred to a liver specialist for further evaluation.

Preventing Recurrence

As previously indicated, most people should continue HBV therapy with nucleos(t)ide analogs indefinitely (AIII) because relapses after response can occur, particularly in those with lower CD4 counts, and because reports of hepatitis flares after discontinuation of 3TC in those who have not reached treatment endpoints can be extrapolated to other HBV-active drugs.^82-84

Special Considerations During Immunosuppressive Therapy

With immunosuppressive therapy, both in the context of malignancy and rheumatologic/autoimmune diseases, reactivation of HBV infection can occur. HBV reactivation in people without HIV with HBsAg-positive/anti HBc-positive disease receiving immunomodulatory therapy is well described, especially with anti-CD20 antibodies.^137-139 Even among people with HBsAg-negative/anti-HBc-positive disease, HBV reactivation occurs in up to 18% of people receiving anti-cancer drugs¹⁴⁰ and 1.7% of people receiving rheumatologic disease drugs.¹⁴¹

If not already performed, people with HIV undergoing immunosuppressive therapy should have HBsAg, anti HBc, and anti-HBs testing. People who are HBsAg positive should receive treatment with TDF or TAF plus 3TC or an FTC-based ART regimen (see Preferred Regimens above) (AII). The optimal approach for those people with HBsAg-negative/anti-HBc positive disease is unknown. However, because TDF or TAF plus FTC or 3TC is a preferred backbone for ART, it is prudent to start or modify ART to include these drugs before initiating immunosuppressive, cytotoxic, or immunomodulatory therapy among people with HBsAg-negative/anti-HBc-positive disease (BIII). If TDF or TAF/FTC or 3TC cannot be used as part of their HIV regimen, these people either could receive entecavir for anti-HBV prophylaxis or could be monitored and given entecavir if signs of HBV reactivation occur (increase in HBV DNA or HBsAg seroreversion) (BIII). The option to give pre-emptive entecavir prophylaxis (in the presence of a fully suppressive ARV regimen) is preferred if HBV DNA is detectable or if immunosuppression is more severe, such as with anti-CD20 antibodies (AII).¹³⁹ No studies have been performed on the appropriate length of therapy, but the Panel agrees with the AASLD 2018 Hepatitis B Guidance recommendation to continue treatment for 6 months after cessation of immunosuppressive therapy and for 12 months in the setting of anti-CD20 antibodies (BIII).¹

Special Considerations During Pregnancy

Pregnant people with HIV should be screened for HBV infection, which may be first diagnosed at this time (AI).⁵⁹ In the interest of completing adult HBV screening, prenatal visits are an opportunity to offer the triple panel to a pregnant person and link the patient to care or vaccinate as needed. People with HIV should be tested for HBsAg during each pregnancy, preferably in the first trimester, even if vaccinated or tested previously.^18,59 Pregnant people with a history of appropriately timed triple panel screening and without subsequent risk for exposure to HBV (i.e., no new HBV exposures since triple panel screening) only need HBsAg screening. Testing pregnant persons known to be chronically infected or immune enables documentation of the HBsAg test result during that pregnancy to ensure timely prophylaxis for exposed infants (see below). Those who are both HBsAg negative and anti-HBs negative should be offered vaccination against HBV (AII). Pregnant people with chronic HBV infection who have not already received the HepA vaccine series should be screened for immunity to HAV infection. Those who screen negative for total anti-HAV should receive the HepA vaccine series (AIII).¹⁴² Treatment of symptomatic acute HBV infection during pregnancy is supportive, with special attention given to maintaining blood glucose levels and normal clotting status. High maternal HBV DNA levels correlate strongly with perinatal HBV transmission, including failures of HBV passive-active immunoprophylaxis.^143-146 See Hepatitis B Virus/HIV Coinfection in the Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States.

ART—including drugs active against both HIV and HBV—is recommended for all people with HIV/HBV coinfection, including pregnant people (AII). TAF or TDF given in combination with 3TC or FTC is the preferred dual-NRTI backbone for pregnant people with chronic HBV infection (AIII).¹⁴² Entecavir has not been well evaluated in pregnancy, with too few exposures to assess overall risk; thus, it is currently not recommended for pregnant people with HBV/HIV coinfection (AIII).¹⁴²

Cases of adverse events during pregnancy related to any of the antiretroviral or anti-HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263 or SM_APR@APRegistry.com). As of June 2024, 5,684 cases of pregnancy outcomes after first-trimester exposures to 3TC have been reported to the Antiretroviral Pregnancy Registry, with no indication of an increased risk of birth defects after exposure (see The Antiretroviral Pregnancy Registry Interim Report). 3TC has been well tolerated by pregnant people and is a recommended NRTI for use in pregnancy (AII).¹⁴⁷ Similarly, no increase in birth defects has been noted in 5,030 cases of first-trimester exposure to FTC. FTC is a recommended NRTI and is used commonly in pregnancy (BII).148 A total of 5,014 cases of first-trimester exposure to TDF and 1,242 cases of first-trimester exposure to TAF have been reported to the Antiretroviral Pregnancy Registry with no increase in birth defects noted.¹⁴⁸

Several large studies have been conducted to evaluate the effect of tenofovir use in pregnancy. No evidence exists that the use of TDF increases the risk of birth defects. Overall, the available evidence does not indicate a link between maternal TDF use and infants who are low birth weight or small for gestational age. Some concern remains regarding a link between maternal TDF use and preterm birth,¹⁴⁹ but the evidence is mixed; the role of concomitant medications and other cofactors and/or confounders requires further investigation.¹⁴⁷

Infants born to people who are HBsAg positive should receive HBIG and HepB vaccine (first dose of three) within 12 hours of delivery (AI). The second and third doses of vaccine should be administered at 1 to 2 months and 6 months of age, respectively (AI). Infants who weigh <2,000 g at birth should receive HBIG and four doses of HepB vaccine; administer one dose of HepB vaccine within 12 hours of delivery and initiate the three-dose HepB vaccine series beginning at age 1 month (four doses total: birth, 1 month, 2–3 months, and 6 months).

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