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 antibodies directed against hepatitis B surface antigen (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 accounting 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.^10-12

Hepatitis D virus (HDV) requires HBV for its propagation because it uses the HBV surface antigen (HBsAg) to form its envelope. Thus, prevalence of HDV mirrors that of chronic HBV infection with geographic variation. In a European study of 1,556 people with HIV and chronic HBV infection, 15.2% had antibodies to HDV, with the highest prevalence observed among people who inject drugs at 50.5%.¹³

Clinical Manifestation

HBV has an average incubation period of 90 days (range 60–150 days) from exposure to onset of symptoms.14 Acute HBV infection is asymptomatic in approximately 70% of cases, and <1% develop fulminant hepatic failure.^1,15 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.¹⁶

Diagnosis

Centers for Disease Control and Prevention (CDC) recommends universal hepatitis B screening at least once during a lifetime for all people over the age of 18, including those with HIV.¹⁷ Screening should include three serologic tests (triple panel screening): HBsAg, total hepatitis B core antibody (anti-HBc), and anti-HBs.¹⁷

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 most commonly defined as persistent HBsAg or hepatitis B e antigen (HBeAg) detected on two occasions at least 6 months apart.¹ Other less common definitions can be found on CDC’s Case Definitions webpage. 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 detectable serum HBV DNA and persistent or fluctuating alanine transaminase (ALT) elevations, defined as ≥2 times the upper limit of normal (≥33 U/L for males and ≥25 U/L for females).¹ Because people with chronic HBV infection are at risk for coinfection with HDV, anti-HDV should be checked after chronic HBV infection is diagnosed. If positive, then HDV RNA should be obtained to assess for chronic HDV infection.

People whose past infection has resolved are HBsAg negative with positive anti-HBs and anti-HBc.^18,19 In a low-prevalence country—such as the United States—an isolated positive anti-HBc may represent a false-positive result; however, its presence 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 and can be higher in people with underlying hepatitis C virus (HCV) coinfection.^20-26 Among people with HIV who have isolated anti-HBc, HBV viremia typically occurs in 1% to 10% of cases.^20,21,27,28 Because most people with HIV who have isolated anti-HBc are HBV DNA-negative,²⁴ routine HBV DNA testing is not recommended. However, if a tenofovir-sparing HIV regimen is being considered, some experts recommend that HBV DNA be undetectable prior to the switch (CIII) because detectable HBV DNA increases the risk of HBV reactivation (see the Treating Chronic Hepatitis B Virus Infection section below).²⁹

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.³⁰ People with HIV/HBV coinfection are also more likely to have detectable HBeAg,^30,31 lower rates of seroconversion to anti-HBe, and increased risk of HCC and liver-related morbidity and mortality.^32-34

Chronic HBV infection is a dynamic disease with a number of phases (see the American Association for the Study of Liver Diseases/Infectious Diseases Society of America Practice Guideline on the Treatment of Chronic Hepatitis B). 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, then HCV RNA), antibodies to HDV IgG (if positive, then 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^1,35 who are at increased risk of disease progression:

• Males older than age 40 who are from an HBV-endemic country
• Females older than age 50 who are from an HBV-endemic country
• Males older than age 20 who are from sub-Saharan Africa
• People with a first-degree family member with HCC
• People with active HDV coinfection
• People with the 5-year HCC risk score, PAGE-B, score ≥10

In one study of 2,963 people with HIV/HBV coinfection (median age 41 years) on tenofovir-containing antiretroviral therapy (ART), the negative predictive value of a PAGE-B score <10 was 99.4% for HCC development over 5 years.³⁶ People with HIV/HBV coinfection are at increased risk of HCC,^37,38 and some experts recommend ongoing semi-annual HCC surveillance (ultrasound with or without alfa-fetoprotein) for all people aged 40 years and older with HIV/HBV coinfection (BIII).

Preventing Exposure

To reduce exposure to HBV in the general community context, avoid direct contact with blood or bodily fluids, wash hands thoroughly after any potential blood exposure, and avoid sharing personal use household or medical items, such toothbrushes, razors, nail clippers, or glucometers. Existing recommendations to reduce sexual exposure to other sexually transmitted viral infections can be applied to reduce sexual exposure to HBV. For people who inject drugs, existing harm-reduction principles are recommended to reduce exposure to viruses in this context.

Preventing Hepatitis B and Other Liver Diseases

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 HIV status (AII). 

All people with HIV without chronic HBV infection and without immunity to HBV (negative HBsAg, anti-HBc, and anti-HBs), as well as those who have failed a prior HepB vaccine series, should receive HepB vaccination (AII). Vaccination should not be deferred because of low CD4 T lymphocyte (CD4) cell counts in people who are at increased risk of HBV infection.

Hepatitis A (HepA) vaccination is recommended for all people with HIV, including those who are pregnant, who are negative for HAV total antibodies (IgG plus IgM) (AII).

Refer to the Hepatitis B Vaccine section and the Hepatitis A Vaccine section in the Immunizations for Preventable Diseases in Adults and Adolescents With HIV chapter for information on available vaccines and detailed HepB and HepA vaccination recommendations. 

People with chronic HBV infection should be advised to avoid alcohol consumption since alcohol can accelerate liver disease from chronic HBV (AII).

Treating Chronic 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), regardless of CD4 count and HBV DNA level (AII), should be treated with an 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)/emtricitabine or lamivudine (FTC or 3TC), tenofovir alafenamide (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.³⁹ 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) receiving tenofovir have shown, on average, 4 log₁₀ declines in HBV DNA levels.^40-45 TDF and TAF have a high genetic barrier for development of resistance mutations.^1,46

There are limited data suggesting that TAF may be superior to TDF in people with HIV/HBV coinfection. In a randomized, placebo-controlled study of people with HIV/HBV coinfection (predominantly Asian participants), TAF/FTC/bictegravir (BIC) was superior to TDF/FTC/dolutegravir (DTG) in achieving HBV DNA <29 IU/mL at 48 weeks (63% vs. 43%, respectively; P = 0.002), but efficacy was similar at 96 weeks (75% vs. 70%, respectively; P = 0.64).⁴⁷ At 96 weeks, participants receiving TAF/FTC/BIC had higher rates of HBeAg seroconversion (32% vs. 15%; P = 0.008), while rates of HBsAg loss did not differ significantly between groups (23% vs. 14%; P = 0.07). Although the data are intriguing, it remains undetermined whether these responses are related to ethnicity, HBV genotype, or other HIV-related factors.

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

• Among people with CrCl ≥60 mL/min, TAF/FTC or TAF plus 3TC or TDF/(FTC or 3TC) can be considered (AII).
• Among people with a CrCl 30 to 59 mL/min, either TAF/FTC or TAF plus 3TC is preferred (AII).
• In people with CrCl <30 mL/min who are not on hemodialysis, renally dosed entecavir with a fully suppressive ART regimen is recommended because entecavir without suppressive ART can lead to emergence of the HIV M184V mutation (AIII).⁴⁸ 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 renally dosed 3TC) (AII) or TAF/FTC (AII) may be used. TAF and FTC do not require dose adjustment in patients receiving hemodialysis; coformulated 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.

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 with HIV/HBV coinfection who are receiving ART should continue HBV therapy indefinitely if they remain HBsAg positive (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,^49,50 as well as possible decompensation of liver disease and even death.^51-54 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 hepatic 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,^55-57 treatment for both HBV and HCV should be initiated (AII). 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).^58-61 See the Hepatitis C Virus chapter for information on HCV treatment.

For information regarding drug–drug interactions, such as with tenofovir products and certain antimycobacterial, anti-HCV, or anti-seizure therapies, see the Liverpool HEP Drug Interaction Checker.

Considerations When Using Tenofovir-Sparing Regimens

With increasing use of tenofovir-sparing regimens, HBV status must be considered before such a switch. The Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV (the Panel) recommends checking HBsAg, anti-HBc, and anti-HBs within 3 months of changing to a tenofovir-sparing regimen to avoid reactivation of an unrecognized chronic HBV infection (AIII). In people who are not immune (anti-HBc and anti-HBs negative), completing a vaccination series and checking anti-HBs prior to starting a tenofovir-sparing regimen is recommended (AI). In people with prior receipt of the HepB vaccine, anti-HBs should be rechecked prior to switching to a tenofovir-sparing regimen because incident infections have been reported in such situations (AIII).⁶²

In people with chronic HBV infection, switching to the one-pill regimen of DTG/3TC should be avoided because 3TC is then the only active drug against HBV (AII). Further, switching to a tenofovir-sparing regimen such as 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 recovery from a past HBV infection (anti-HBc positive, anti-HBs positive), DTG/3TC or a tenofovir-sparing regimen without additional anti-HBV agents is appropriate because the risk of HBV reactivation is low (AIII).⁶³ ALT monitoring every 3 months for the first 6 months and then every 6 months thereafter post-switch is recommended (BIII). If ALT elevations occur, then checking HBV DNA is recommended.

Although the risk of HBV reactivation is low in people with isolated anti-HBc (HBsAg negative, anti-HBc positive, anti-HBs negative), the risk is higher than in those with past HBV infection who are anti-HBs positive. Thus, in people with isolated core positivity, switching to DTG/3TC or a tenofovir-sparing regimen can be considered with ALT monitoring every 3 months for the first 6 months, then every 6 months thereafter post-switch(BIII).⁶⁴ If ALT increases, then checking HBV DNA is recommended. Some experts recommend undetectable HBV DNA prior to such a switch (CIII). Vaccination initiated at the time of such a switch is recommended (AII) (see Vaccination Schedule for People With Isolated Anti-HBc). 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.⁶⁴

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

All people with HIV should receive ART. Among people with HIV/HBV coinfection, cotreatment is essential and recommended.³⁹ 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

TDF, 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).^65,66

Monitoring of Response to Therapy and Adverse Events

To evaluate response, HBV DNA should be monitored at 3 and 6 months after treatment initiation and then 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 reaction⁶⁷
• Partial virologic response: HBV DNA ≥1 log₁₀ IU/mL decline, but still detectable HBV DNA at 12 months⁶⁷
• Primary nonresponse: HBV DNA <1 log₁₀ IU/mL decline after 3 months⁶⁸

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 functional cure; however, this desirable serologic response is uncommon (<1% of HBsAg-positive people without HIV per year).¹ Interestingly, some studies indicate that after ART initiation, people with HIV/HBV coinfection have up to 20% chance of HBsAg loss, most commonly within the first 1 to 2 years of treatment.^69,70 For this reason, HBsAg should be checked yearly after ART initiation in these individuals (AIII). If HBsAg loss occurs and is maintained for at least 6 months and there is a desire to switch to a tenofovir-sparing regimen, this option may be considered as discussed above.

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.⁷¹ These biochemical changes are usually reversible when TDF is discontinued or changed to TAF.⁷²

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 is required or a change to TAF if appropriate based on degree of renal insufficiency.⁷² 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.⁷³ TAF also has been associated with early weight gain among people with HIV, although the long-term consequences of this are unclear.⁷⁴

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.^75-77

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,”⁷⁸ which constitutes immune reconstitution inflammatory syndrome (IRIS) among people with HIV/HBV coinfection. IRIS can 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.^79,80 Flares are more consequential among people with more severe liver disease, especially those with cirrhosis,⁸¹ and it can be difficult to distinguish between IRIS and other causes of hepatitis flare, such as drug-induced liver injury, HBV drug resistance, HBeAg seroconversion, or acute hepatitis caused by infection with HAV, HCV, HDV, hepatitis E virus, Epstein-Barr virus, herpes simplex virus, or cytomegalovirus.

After introduction of ART, serum ALT levels should be monitored closely; some experts recommend ALT testing at 6 and 12 weeks and 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).⁷²

Most (90%) people with HIV/HBV coinfection do not experience ART-associated hepatotoxicity,⁸² and clinically significant hepatotoxicity (elevated direct bilirubin and INR) is rare. 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.^83-86 Nonetheless, aminotransferase levels return to baseline in most cases, even if the ART is continued.^87,88 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).⁸⁹ 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).

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). 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, and predicting the level of resistance to entecavir.⁹⁰ However, TDF/TAF 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/TAF is slow and adherence is confirmed.⁹¹ (see Monitoring of Response to Therapy and Adverse Events)

With 3TC monotherapy for HBV, the rate of developing 3TC-resistance is approximately 20% per year among people with HIV/HBV coinfection, hence it should not be used as monotherapy for HBV.⁹² If 3TC resistance is suspected or documented, TDF or TAF should be added to the ART regimen (AIII).^93-95 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).⁹⁶ If consideration is given to entecavir use in this situation, consultation with an expert in the management of drug-resistant HBV is recommended. 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, then 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).

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.

Special Considerations for Treating Cirrhosis and End-Stage Liver Disease

People with HIV/HBV coinfection who have cirrhosis or end-stage liver disease should be managed the same as people with HBV mono-infection with cirrhosis or end-stage liver disease, including referral to a hepatologist (AIII) (see the American Association for the Study of Liver Diseases (AASLD) 2018 Hepatitis B Guidance). Among people with HIV/HBV coinfection with end-stage liver disease, IFN-α is contraindicated (AI), but nucleos(t)ide analogs are safe and efficacious (AI).^92,97,98 In addition, treatment cessation is contraindicated.

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.⁹⁹ Because transplantation does not cure HBV infection, post-transplant hepatitis B immune globulin (HBIG) and HBV treatment are required (AII). People with HIV who are potential candidates for liver transplantation should be referred to a liver specialist for further evaluation.

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.^100-102 Even among people with HBsAg-negative/anti-HBc-positive disease, HBV reactivation occurs in up to 18% of people receiving anti-cancer drugs¹⁰³ and 1.7% of people receiving rheumatologic disease drugs.¹⁰⁴

People with HIV undergoing immunosuppressive therapy should have the triple panel screening performed (HBsAg, anti‑HBc, and anti-HBs) before initiating therapy unless they are known to have chronic HBV. People who are HBsAg positive regardless of HBV DNA level should receive treatment with TDF or TAF plus 3TC or FTC-based ART regimen (see Preferred Regimens above) (AII). For people with HBsAg-negative/anti-HBc-positive disease, the risk of HBV reactivation during immunosuppressive therapy is divided into low (<1%), moderate (1% to 10%), and high (>10%) risk according to the American Gastroenterological Society (AGA).¹⁰⁵ With moderate or high-risk immunosuppression, TDF or TAF plus FTC or 3TC are recommended before initiating immunosuppressive therapy (BII). If TDF or TAF plus FTC or 3TC cannot be used as part of their HIV regimen, these people could receive entecavir for anti-HBV prophylaxis (BII). For people whose ART regimen does not include TDF or TAF plus FTC or 3TC and who will receive low-risk immunosuppression, monitoring with HBV DNA and ALT every 1 to 3 months is recommended (BIII). No studies have been performed on the appropriate length of therapy, but the Panel agrees with the AGA guidance recommendation to continue treatment for a minimum of 6 months after cessation of immunosuppressive therapy or of 12 months in the setting of anti-CD20 antibodies (BIII).

Special Considerations During Pregnancy

Screening for HBV with the triple panel is recommended during pregnancy (AIII), followed by linkage to care or vaccination as needed.¹⁰⁶ HBsAg should be screened during each pregnancy, preferably in the first trimester, even if vaccinated or tested previously.^17,106 If a history of appropriately timed triple panel screening is elicited without subsequent risk for exposure to HBV (i.e., no new HBV exposures since triple panel screening), then only HBsAg screening is needed. Such testing enables documentation of the HBsAg test result during pregnancies with maternal chronic infection or maternal immunity 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). In the context of chronic HBV infection during pregnancy, if the HepA vaccine series has not been previously administered, then screen for immunity to HAV infection. Those who screen negative for total anti-HAV should receive the HepA vaccine series (AIII).¹⁰⁷ Refer to the Hepatitis B Vaccine section and the Hepatitis A Vaccine section in the Immunizations for Preventable Diseases in Adults and Adolescents With HIV chapter for information on available vaccines.

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.^108-111 See Hepatitis B Virus/HIV Coinfection in the Perinatal Guidelines for additional information.

As for all people with HIV/HBV coinfection, ART that includes drugs active against both HIV and HBV should be used during pregnancy (AII). TAF or TDF given in combination with 3TC or FTC is the preferred dual-NRTI backbone (AIII).¹⁰⁷ Entecavir has not been well evaluated in pregnancy, with too few exposures to assess overall risk; thus, it is currently not recommended in the setting of HIV/HBV coinfection during pregnancy (AIII).¹⁰⁷

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 (1-800-258-4263 or [email protected]). TDF, TAF, FTC, and 3TC use during pregnancy has been well tolerated and are recommended for use in pregnancy (AII).¹¹²

Infants born to women who are HBsAg positive should receive HBIG and the first dose of HepB vaccine 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) (AII).

References

References

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