Prevention and Management of Hepatitis B Virus Infection in Adults With HIV

Screening Tests

Clinicians should screen all patients with HIV for HBV risk, vaccination history, and infection upon entry into medical care and perform baseline testing to determine HBV immune status. Initial laboratory testing includes serologic testing for HBsAg, anti-HBc total, and anti-HBs, with results interpreted as detailed in Table 1, below. Patients with anti-HBs levels of ≥10 IU/mL are considered immune to HBV [DHHS 2023]. If a patient with HIV decides against HBV vaccination and remains at risk, annual laboratory screening is recommended (see guideline section HBV Vaccination) [Terrault, et al. 2018].

Diagnosis

For patients with positive HBsAg screening test results, follow-up laboratory testing should be performed to confirm HBV status (see Table 2, below). If a patient with HIV and unknown HBsAg status presents with signs or symptoms of acute hepatitis (i.e., elevated ALT), the clinician should perform HBsAg, anti-HBc IgM, HBeAg, anti-HBe, and HBV DNA testing to confirm a diagnosis.

Table

Abbreviations: anti-HBc, hepatitis B core antibody (IgG or IgM); anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IgG, immunoglobulin G; IgM, (more...)

Acute HBV infection: Following exposure, HBV enters the bloodstream and circulates to the liver. The post-exposure time to the onset of abnormal liver enzymes averages 60 days (range, 40 to 90 days), and the onset of jaundice averages 90 days (range, 60 to 150 days). Acute HBV infection is asymptomatic in approximately 70% of patients, and <1% of patients develop fulminant hepatic failure. When symptoms manifest, they may include anorexia, malaise, nausea, vomiting, arthralgias, and right upper quadrant abdominal pain. Symptoms generally resolve within 4 weeks, with normalization of transaminase levels in 2 to 8 weeks.

Acute HBV infection is diagnosed through the detection of HBsAg and anti-HBc IgM. During the initial phase of infection, HBeAg and HBV DNA are also present (see Figure 1, below). Recovery is marked by the disappearance of HBV DNA and seroconversion of HBeAg to anti-HBe and of HBsAg to anti-HBs [Shiffman 2010].

Figure 1

Typical Serologic Course of Acute Hepatitis B Virus Infection With Recovery [a]. Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBe, antibody to HBeAg; anti-HBs, hepatitis B surface antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B (more...)

The ideal management strategy for symptomatic acute HBV infection in patients with HIV is not clear. Treatment with entecavir (ETV), tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF) outside of a fully active anti-HIV regimen could lead to HIV resistance. For most patients with acute HBV, treatment is mainly supportive. Antiviral therapy is generally not indicated in patients with symptomatic acute HBV because most immunocompetent adults with acute HBV recover spontaneously.

However, antiviral treatment is indicated for patients with acute liver failure or a protracted, severe course of HBV, as indicated by a total bilirubin level >3 mg/dL (or direct bilirubin level >1.5 mg/dL), an international normalized ratio >1.5, encephalopathy, or ascites. ETV, TAF, and TDF are the preferred antiviral agents for these patients given in conjunction with a fully suppressive ART regimen. In some patients, acute liver disease may worsen due to immune reconstitution inflammatory syndrome (IRIS). Treatment should be continued until HBsAg clearance is confirmed or should be continued indefinitely in patients who undergo liver transplantation [Terrault, et al. 2018]. Patients with HIV who are already taking a fully active ART regimen that includes TAF or TDF should continue with the regimen.

If acute HBV infection is confirmed in an asymptomatic patient, the clinician should repeat ALT testing within 2 to 4 weeks to assess for symptoms of liver disease progression and repeat HBsAg, HBeAg, anti-HBe, and HBV DNA testing in 6 months to determine whether infection has cleared. Patients with symptomatic acute HBV require more frequent monitoring tailored to the patient’s condition.

Chronic HBV infection: HBV infection is a dynamic disease, and individuals can transition through the defined clinical phases with variable levels of serum ALT activity, HBV DNA, and HBV antigens. See the guideline sections Assessment Before HBV Treatment and HBV Treatment and Monitoring for recommendations on the management of chronic HBV infection in patients with HIV.

Reactivation: Chronic HBV can resolve in some patients, and tests will indicate a sustained loss of HBsAg, undetectable serum HBV DNA levels, and absence of clinical or histologic evidence of active viral infection. However, reactivation of HBV replication, characterized by the reappearance of HBeAg and HBsAg and a rise in serum HBV DNA, can occur. Reactivation is usually seen in patients taking immunosuppressive therapy for a concurrent medical condition; in rare instances, patients with prior resolved HBV infection who are anti-HBs-positive can have reactivation of HBV during subsequent immunosuppressive therapy. For a list of medications associated with increased risk for HBV reactivation, see Medscape > Hepatitis B Treatment & Management. Reactivation of HBV can also occur in individuals with HIV, including those who experience immune reconstitution after initiation of ART. HBV reactivation may result in severe hepatitis and should be considered a potential cause of hepatitis in patients with previously resolved HBV infection. During reactivation, serum ALT levels will be elevated, and patients who were HBeAg- or HBsAg-negative may become both HBeAg- and HBsAg-positive. HBV reactivation can vary from mild and asymptomatic to severe with possible fulminant hepatic failure.

Occult HBV infection is defined as detectable HBV DNA in HBsAg-negative patients. Most patients with occult HBV have very low or undetectable serum levels, but HBV DNA is often detected in the liver. Patients with occult infection are at risk of HBV reactivation if they receive potent immunosuppressive therapy or chemotherapy. Occult HBV infection has been associated with chronic liver disease and increased risk of hepatocellular carcinoma [Raimondo, et al. 2007].

Transmission Prevention

HBV is significantly more transmissible through exposure to blood and body fluid than HIV and requires more frequent assessment for behaviors that increase HIV/HBV transmission risk. Barrier protection, including latex or polyurethane condoms, should be recommended to decrease the risk of sexual transmission [Smith, et al. 2015; Weller and Davis 2002], and sexual partners should be vaccinated if possible. It is important to advise patients that household contacts should be vaccinated against HBV and that they should avoid sharing any objects that may be contaminated with blood, such as razors or toothbrushes. Patients with chronic HBV should also be advised that there is a still a risk of HBV transmission even in the setting of low or undetectable HBV viral load.

All active injection drug users should be prescribed clean syringes and needles and offered referrals to substance use treatment, such as opioid substitution. Referral to needle-exchange programs should also be offered (see NYSDOH Drug Use Resources). Injection drug users should also receive information about safe disposal and storage of needles/syringes and safer injection techniques.

Figure 2

Algorithm for HBV Screening and Vaccination in Patients With HIV. Abbreviations: anti-HBc, hepatitis B core antibody; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. Notes:

Primary Vaccination Strategies

The single-antigen HBV vaccines currently approved by the U.S. Food and Drug Administration (FDA) for individuals ≥18 years old are Heplisav-B, Engerix-B, and Recombivax HB. Prehevbrio, a new 3-antigen recombinant HBV vaccine, was approved in 2021 by the FDA for use for individuals ≥18 years old [FDA 2021], but experience regarding its use in patients with HIV is lacking at this time.

The level of immune response to HBV vaccination in individuals with HIV can be lower than in adults who are HIV seronegative [Mast, et al. 2006; Rey, et al. 2000; Tayal and Sankar 1994; Loke, et al. 1990]. Many studies have shown that the presence of detectable HIV RNA [Overton, et al. 2005; Tedaldi, et al. 2004] and low CD4 cell counts [Veiga, et al. 2006; Fonseca, et al. 2005; Tedaldi, et al. 2004; Keet, et al. 1992] correlates with a poor immune response to vaccination. Ideally, based on the data, the HBV vaccine should be administered before a patient’s CD4 count declines to <350 cells/mm³ to improve immunogenicity; however, vaccination should not be deferred in patients who have CD4 counts <350 cells/mm³.

The recommended initial option for HBV vaccination is Heplisav-B, a 2-dose (4 weeks apart) recombinant HBsAg vaccine with a novel adjuvant, available for individuals ≥18 years old [FDA 2024]. In 3 randomized controlled trials among individuals without HIV, administration of 2 doses of Heplisav-B was associated with a higher seroprotection rate than 3 doses of Engerix-B [FDA 2024]. In a multicenter, open-label study in 68 participants with HIV who were not previously vaccinated against HBV, 3 doses of Heplisav-B vaccine (0, 4, and 24 weeks) conferred seroprotective titers in all participants; before administration of the third dose, 94.4% of participants had seroprotective titers at week 12 and 98.5% had seroprotective titers at week 24 [Marks, et al. 2023].

A retrospective cohort study among individuals with HIV found seroprotection rates were increased with the Heplisav-B vaccine compared with other previously used HBV vaccines [Schnittman, et al. 2021]. A 2-dose series may increase adherence because it requires fewer follow-up visits and a shorter wait time between doses than the 3-dose vaccines. A modeling study found that use of a 2-dose instead of a 3-dose HBV vaccine would increase the number of adults fully seroprotected at 1 year by 275,000 per million persons beginning immunization series [Oster, et al. 2022]. A second modeling study determined that use of Heplisav-B among individuals with HIV results in lower costs and increased benefits compared with Engerix-B [Rosenthal, et al. 2020]. No data are available to support use of other recombinant vaccines for the second dose if Heplisav-B is used for the initial dose.

Other options include vaccination with conventional HBV vaccines (Engerix-B, Recombivax HB) that are typically administered intramuscularly as 3 standard doses at 0, 4, and 24 weeks (see Table 3, below). Whether patients with HIV should receive a standard or double dose of these vaccines is still being debated. This committee and the DHHS Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV recommend administering the standard 3-dose regimen.

Combined HBV and hepatitis A virus (HAV) vaccine: Twinrix is a combination vaccine that includes recombinant HBV and HAV vaccines; it is approved by the FDA for use in individuals ≥18 years old in the United States. For individuals with HIV who are not immune to both HAV and HBV, Twinrix may be considered and administered as an initial series and administered in 3 doses at 0, 4, and 24 weeks. However, this committee prefers separate vaccination for HBV and HAV given the data for better immunogenicity with Heplisav-B in patients with HIV. No data are available to support the administration of this vaccine as a double-dose or 4-dose series, so these strategies are not recommended in patients with HIV.

Table

2 IM injections at weeks 0 and 4 Patients with ESRD: Standard dosing [Awad, et al. 2021]

Double-dose and 4-dose strategies: Other vaccination approaches are to administer a double dose of vaccine on a standard 3-dose schedule or to add a fourth dose at 2 months to a 3-dose vaccine series. Several studies have shown improved immune response to double-dose vaccinations given in a 3-dose schedule [Psevdos, et al. 2010; de Vries-Sluijs, et al. 2008; Fonseca, et al. 2005]. A 2013 meta-analysis (5 studies, n=883) found that increasing the vaccine dosage may significantly improve immune responses in participants with HIV [Ni, et al. 2013].

An RCT conducted in 2013 compared the immunogenicity and safety of 4 standard doses and 4 double doses with 3 standard doses of HBV vaccination in adults with HIV [Chaiklang, et al. 2013]. Response rates were higher in the 4-dose group than in the standard 3-dose group, but the difference was not statistically significant. Local adverse effects were more common with increased frequency and dosage of vaccine, but systemic and serious adverse effects were extremely rare [Chaiklang, et al. 2013]. Based on these data, an HBV vaccination approach with a 3- or 4-injection double-dose vaccine series in patients with HIV can be considered. There are no trial studies comparing Heplisav to 3- or 4-injection double-dose vaccine series, and this committee recommends vaccination with Heplisav over double dose vaccine series.

Accelerated vaccination: An RCT using the standard-dose HBV vaccine compared an accelerated schedule (0, 1, and 3 weeks) with the standard schedule (0, 4, and 24 weeks) and demonstrated a noninferior response rate for participants with CD4 counts >500 cells/mm³; this schedule may increase patient adherence to the full vaccine series [de Vries-Sluijs, et al. 2011]. However, the accelerated schedule was inferior in patients with CD4 counts of 200 to 500 cells/mm³. Because of the low number of participants with CD4 counts <200 cells/mm³, the results were inconclusive for this population.

Based on these findings, the accelerated schedule may be considered for patients with CD4 counts ≥500 cells/mm³ but is not recommended for patients with CD4 counts <500 cells/mm³ [de Vries-Sluijs, et al. 2011]. If an accelerated HBV vaccination schedule is used, the patient should also receive a fourth-dose booster at least 6 months after initiation of the vaccine series.

Pregnancy: Clinicians should not defer initial vaccination or revaccination in pregnant patients with HIV who do not have immunity to HBV. There are no well-controlled studies designed to evaluate the recommended anti-HBV vaccines during pregnancy. However, available data do not suggest an increased risk of miscarriage or major congenital disabilities in individuals who received Engerix-B, Twinrix, Recombivax HB, or Heplisav-B vaccines during pregnancy compared with individuals in the general U.S. population who were not vaccinated during pregnancy [FDA 2024; FDA(a) 2023; FDA(b) 2023; FDA 2018].

Isolated anti-HBc positivity: Defined as having negative HBsAg, negative anti-HBs, and positive anti-HBc test results, isolated anti-HBc positivity has been reported in 0.4% to 1.7% of blood donors in low prevalence areas and 10% to 20% of the population in endemic countries [Lok, et al. 1988]. It has been estimated that 17% to 41% of patients with HIV have isolated anti-HBc positivity [Bhattacharya, et al. 2016; Witt, et al. 2013; Neau, et al. 2005]. As shown in Table 1: Interpretation of HBV Screening Test Results, there are 4 possible interpretations of this result: resolved HBV infection with waning anti-HBs titers, false-positive result, occult HBV infection, or resolving acute HBV infection [Mast, et al. 2006].

Most patients with HIV and isolated anti-HBc positivity are HBV DNA-negative, not immune to HBV [Gandhi, et al. 2005], and routinely checking HBV DNA is no longer recommended. Clinicians should offer patients with HIV and isolated anti-HBc a single standard dose of Heplisav-B [DHHS 2023]. Anti-HBs testing should be performed 8 weeks after the first dose. If the anti-HBs titer is <100 mIU/mL, the remaining vaccine in the series should be administered, and anti-HBs testing should be repeated at least 8 weeks after the vaccine series is complete [DHHS 2023; Piroth, et al. 2016]. In a prospective study of 54 patients with HIV and isolated anti-HBc, 46% responded to a single dose of vaccine. Of those who did not respond to a single dose, 89% developed immunity after a 3-dose series of double-dose vaccine [Piroth, et al. 2016]. For patients with an anti-HBs titer ≥100 mIU/mL, clinicians may opt to discontinue the vaccine series. There are few data to guide the optimal number of vaccine doses for these patients but no evidence of harm in completing the full vaccination series.

However, if patients with HIV and isolated anti-HBc refuse vaccination or if post-vaccination anti-HBs testing cannot be assured, then a reasonable approach is to perform HBV DNA testing [Chang, et al. 2018]. HBV DNA testing may also be performed in patients with isolated anti-HBc who do not respond to the full vaccine series. A positive HBV DNA test result in a patient with isolated anti-HBc test results indicates occult HBV infection (see guideline section HBV Screening and Diagnosis > Diagnosis > Reactivation).

Follow-up Testing

Clinicians should repeat anti-HBs testing 4 to 16 weeks, based on the patient’s visit schedule, after vaccination to ensure immunity [Rubin, et al. 2014]. If the anti-HBs titer is ≥10 mIU/mL, the patient is considered immune to HBV. If the anti-HBs titer is <10 mIU/mL, the patient may have primary nonresponse to the vaccine and require revaccination, or the patient may have chronic HBV infection. HBV DNA testing may be used to detect chronic HBV.

Table

Patient education regarding HBV vaccination is important to ensure awareness of the continued risk of acquiring and subsequently transmitting HBV until adequate anti-HBs response is confirmed.

Revaccination

Individuals with HIV who do not respond (anti-HBs <10 mIU/mL) to the primary HBV vaccine series should be revaccinated. In patients who do not respond to an initial 2-dose Heplisav-B vaccine series, clinicians should administer a third dose of Heplisav-B. If Heplisav-B was not administered as the initial HBV vaccination series, clinicians should revaccinate with a 2-dose series of Heplisav-B. In a retrospective, cross-sectional study among individuals with HIV who failed to seroconvert after vaccination (HBsAg- and anti-HBs-negative) with Engerix-B or Recombivax HB, revaccination with Heplisav-B was highly effective in achieving seroprotection [Khaimova, et al. 2021]. If patients have contraindications to Heplisav-B, revaccination with a double dose of Engerix-B or Recombivax HB, given as a 4-dose series, is recommended.

Revaccination can be deferred for patients initiating ART until the CD4 count is ≥200 cells/mm³; response rates to vaccination may be higher in patients with CD4 counts ≥200 cells/mm³ than those with lower CD4 cell counts [Gandhi, et al. 2005].

Liver Disease Assessment

Initial assessment of patients with chronic HBV should include a detailed history and physical examination to evaluate for any signs of advanced liver disease, including bruising, jaundice, dark urine, light stools, history of gastrointestinal bleeding, and pruritus. A prior treatment history, including medication history, should be obtained to determine whether the patient has previously taken hepatotoxic medications or lamivudine or emtricitabine, which have been associated with HBV resistance when taken as monotherapy. On examination, identify any stigmata of advanced liver disease, such as spider angiomas, splenomegaly, palmar erythema, and asterixis. The presence of ascites or encephalopathy indicates decompensated liver disease. Baseline laboratory tests include CBC, albumin, bilirubin, alkaline phosphatase, prothrombin time, ALT, and AST. Low albumin levels or elevated prothrombin time may suggest advanced liver disease with hepatic decompensation. Leukopenia and thrombocytopenia may indicate the presence of portal hypertension.

All individuals should be evaluated for liver fibrosis using noninvasive methods, such as transient elastography (FibroScan), serum testing for biomarkers (FibroSure), or AST to platelet ratio index (APRI) calculation. Liver biopsy is no longer preferred because of the risk of complications (e.g., bleeding, infection) and the possibility of a sampling error when only a small portion of the liver is evaluated. All patients with HIV/HBV coinfection should have a baseline ultrasound to screen for HCC [Terrault, et al. 2018], and those with cirrhosis should be referred to a hepatologist to screen for esophageal varices [Garcia-Tsao, et al. 2017; de Franchis 2015].

Results of the liver disease assessment determine the phase of chronic HBV infection. Liver biopsy results are included below as part of the description of each stage. However, liver biopsy is rarely indicated in patients with HIV/HBV. The procedure can be considered in patients who have persistently elevated ALT but persistently low HBV DNA to exclude other causes of liver disease.

• Immune tolerance: Characterized by hepatitis B e antigen (HBeAg) positivity with elevated HBV DNA levels but normal or minimally elevated ALT levels. Liver biopsies are generally benign, without signs of necroinflammation or fibrosis [Tran 2011].
• Immune active: Subdivided into HBeAg-positive and HBeAg-negative. In HBeAg-positive patients, HBV DNA levels are typically >20,000 IU/mL, and serum ALT levels are elevated. In HBeAg-negative patients, HBV DNA levels tend to be lower (2,000 to 20,000 IU/mL) with low to normal serum ALT levels. Liver biopsy often reveals chronic hepatitis with variable signs of necroinflammation or fibrosis [Terrault, et al. 2018].
• Inactive chronic HBV: These patients are HBeAg-negative and antibody to HBeAg-positive. Serum HBV DNA is usually <2,000 IU/mL or undetectable, and ALT levels are normal. Liver biopsy indicates an absence of significant necroinflammation and variable levels of fibrosis [Terrault, et al. 2018].

Alcohol Use Screening and Education

In 2020, there were an estimated 29,000 deaths from alcoholic liver disease and 51,000 deaths from chronic liver disease and cirrhosis in the general U.S. population [CDC(b) 2024; CDC 2023]. Chronic alcohol use in patients with HBV infection results in increased oxidative stress and liver inflammation, which can progress to cirrhosis and lead to the development of HCC [Donato, et al. 1997; Nakanuma and Ohta 1983]. These effects are even more pronounced in patients with HIV/HBV coinfection in whom increased levels of liver inflammation, liver fibrosis, drug-induced hepatotoxicity, liver cirrhosis, and death from liver disease and HCC have been observed [Marcellin, et al. 2008; Poynard, et al. 2003; Núñez, et al. 2001]. Patient education is essential to helping patients understand the effects of alcohol use on the course of HBV infection, as is counseling for patients with underlying liver disease so that patients can make informed decisions regarding alcohol use or abstinence. Studies have shown that individual counseling and peer group education and support can be effective in reducing alcohol use in patients with HIV [Knox, et al. 2013; Velasquez, et al. 2009].

HAV, HCV, and HDV Status

HAV: For information on HAV/HIV coinfection, see the NYSDOH AI guideline Prevention and Management of Hepatitis A Virus Infection in Adults With HIV > Management of HAV/HIV Coinfection.

HCV: HBV/HCV coinfection is associated with higher rates of cirrhosis, increased severity of liver disease, and increased risk of HCC than HBV or HCV monoinfection [Mavilia and Wu 2018]. This is of particular concern in patients with HIV/HBV coinfection; patients with HIV infection have more severe liver disease and higher rates of liver complications than patients without HIV [Bräu, et al. 2007; Thio, et al. 2002]. For information on screening, diagnosis, and treatment of HCV in patients with HIV, see the NYSDOH AI guidelines Hepatitis C Virus Screening, Testing, and Diagnosis in Adults and Treatment of Chronic Hepatitis C Virus Infection in Adults.

HDV: Formerly known as hepatitis delta virus, HDV is a defective satellite RNA virus that requires active HBV infection to replicate. HIV/HBV/HDV tri-infection is associated with more rapid liver disease progression and higher rates of decompensated cirrhosis, HCC, and mortality than HIV/HBV coinfection [Béguelin, et al. 2017; Fernández-Montero, et al. 2014; Castellares, et al. 2008; Sheng, et al. 2007]. HDV infection is uncommon in the United States; it is not a reportable disease, and the prevalence is unknown [Patel, et al. 2019]. The majority of cases occur among people who migrate or travel to the United States from countries with high HDV endemicity (i.e., Eastern Europe, Southern Europe, the Mediterranean region, the Middle East, West and Central Africa, East Asia, and the Amazon River Basin in South America) [CDC(a) 2024].

Existing data indicate that pegylated interferon (PEG-IFN) is the only effective anti-HDV treatment [EASL 2012]. However, fewer than 30% of people without HIV who have HDV achieve sustained HDV suppression when treated with PEG-IFN [Wedemeyer, et al. 2011]. No data are available regarding the efficacy of PEG-IFN therapy in patients with HIV/HBV/HDV tri-infection.

Investigational trials of the newer agent bulevirtide have shown promising results. Bulevirtide, an HDV entry inhibitor, is approved in Europe for treatment of HDV in individuals with compensated liver cirrhosis but is not currently available in the United States [Wedemeyer, et al. 2023]. In an analysis of 38 patients with HIV/HBV/HDV coinfection treated with bulevirtide plus pegylated interferon-α in France, 50% attained virologic response [de Ledinghen, et al. 2024]. Similarly, in a small compassionate use trial in Italy among patients with HBV/HDV-related cirrhosis who were treated with bulevirtide, 66% with HIV and 60% without HIV achieved virologic response and normalization of ALT [Visco Comandini, et al. 2023]. A list of investigational studies of HDV treatment in the United States is available at ClinicalTrials.gov.

Because HDV depends on HBV to replicate, HBsAg seroconversion should be the primary goal for patients with HIV/HBV/HDV tri-infection. In patients with tri-infection, prompt initiation of anti-HBV and anti-HIV therapy should be strongly encouraged. Little guidance is available on optimal monitoring strategies for patients with HIV/HBV coinfection and positive serum anti-HDV total (IgM and IgG) test results. It is reasonable to perform baseline HDV RNA testing and consult with an experienced care provider about ongoing HDV RNA and DNA testing [Farci and Niro 2018].

Treatment

Goals: The goals of treatment for chronic HBV infection in adults with HIV are to reduce liver inflammation (as indicated by normalization of ALT), obtain seroconversion of hepatitis B e antigen (HBeAg) to antibody to HBeAg, and suppress HBV viral replication. These changes will help reduce the risk of hepatic decompensation, halt or reverse liver fibrosis, prevent the development of hepatocellular carcinoma (HCC), and decrease HBV-related mortality [Kim, et al. 2021; Terrault, et al. 2018; Soriano, et al. 2008].

As indicated in the NYSDOH AI guideline Rapid ART Initiation, clinicians should recommend ART to all patients diagnosed with HIV infection. For patients with HIV/HBV coinfection, the regimen should include medications that suppress both HIV and HBV (see Table 4, below). Optimal treatment for both viruses should be taken simultaneously to prevent the development of HIV and HBV drug resistance. Optimal treatment of both infections may also help reduce the risk of IRIS, which is increased in patients with high levels of HBV viremia (see guideline section Monitoring, below) [Avihingsanon, et al. 2012; Crane, et al. 2009].

Table

A prodrug of the NRTI tenofovir active against HIV and HBV, including 3TC-resistant HBV A preferred agent for chronic HBV treatment because of its high virologic efficacy and low risk of HBV resistance [Terrault, et al. 2018]

Preferred regimen: Because FTC, 3TC, TDF, and TAF all have activity against HIV and HBV, an ART regimen for a patient with HIV/HBV coinfection should include a nucleoside/nucleotide reverse transcriptase inhibitor backbone of either TAF/FTC, TDF/FTC, or TDF/3TC as part of a fully suppressive regimen. TDF or TAF should not be used alone in the absence of a fully suppressive ART regimen because resistance mutations may develop [DHHS 2023; DHHS 2019]. For the use of TDF or TAF in patients with reduced renal function, see the NYSDOH AI guideline Selecting an Initial ART Regimen > ARV Dose Adjustments for Hepatic or Renal Impairment.

Alternative regimen: If patients cannot or choose not to take TDF or TAF, the alternative recommended regimen is ETV in addition to a fully suppressive HIV ART regimen [DHHS 2023; DHHS 2019]. ETV should not be considered part of the HIV ART regimen. The ETV dose should be increased from 0.5 mg per day to 1.0 mg per day in patients with known or suspected 3TC-resistant HBV infection. However, ETV resistance may emerge rapidly in patients with 3TC-resistant HBV infection [Terrault, et al. 2018]. Therefore, ETV should be used with caution in patients with HIV/HBV coinfection who do not take TAF or TDF, and frequent monitoring (every 3 months) of HBV DNA levels should be performed to detect viral breakthrough (see guideline section Monitoring, below).

The anti-HBV activity of 3TC, FTC, TDF, and TAF warrants their continued use whenever possible, even when HIV resistance indicates that they should be discontinued as part of the ART regimen. These agents should be continued after an anti-HBV therapy response has been achieved, even if the ART regimen has to be changed. Patients should be advised against discontinuing HIV or HBV treatment because the cessation of therapy has been associated with reactivation of HBV leading to exacerbations of hepatitis and hepatic failure [DHHS 2023]. Hepatitis flares can occur in patients with HBV monoinfection and those with HIV/HBV coinfection, but the risk of hepatic injury and fulminant hepatic failure is greater in patients with HIV/HBV coinfection [Moreno-Cubero, et al. 2018; Boyd, et al. 2017; Dore, et al. 2010].

Two-drug regimens for HIV: For patients with HIV/HBV coinfection, a 2-drug ART regimen should not be used as initial ART unless combined with an additional agent(s) with activity against HBV (see Table 5, below, for recommended additions). The same is true for patients with controlled HIV/HBV coinfection who switch to a 2-drug regimen for HIV ART—an agent with anti-HBV activity is required. Patients switching to a 2-drug regimen for HIV plus the additional agent(s) to treat HBV should be closely monitored for potential HBV flare (see guideline section Monitoring, below).

Table

Abbreviations: 3TC, lamivudine; ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; ETV, entecavir; FTC, emtricitabine; HBV, hepatitis B virus; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

HBV treatment during pregnancy: Clinicians should offer pregnant patients with HIV/HBV coinfection ART that includes agents active against HIV and HBV. 3TC, FTC, TAF, and TDF can be safely used during pregnancy [DHHS 2023; Terrault, et al. 2018]. The preferred regimen is DTG plus TDF or TAF in combination with either FTC or 3TC. An alternative regimen is ritonavir-boosted darunavir (DRV/r) plus TDF or TAF with FTC or 3TC [DHHS 2023].

Monitoring

Recommended clinical evaluation and laboratory monitoring are described in Table 6, below.

Table

Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus. Notes:

Response to treatment: HBV viral load levels generally decline more slowly after treatment initiation than HIV viral load levels. Anti-HBV treatment responses are defined as follows [DHHS 2023]:

• Primary nonresponse: HBV DNA <1 log₁₀ decline at 12 weeks
• Complete virologic response: Undetectable HBV DNA by polymerase chain reaction assay at 24 to 48 weeks
• Partial virologic response: ≥1 log₁₀ decline but still detectable HBV DNA at 24 weeks
• Maintained virologic response: A response that continues while on therapy
• Sustained virologic response: A virologic response that is still present 6 months after cessation of therapy

Renal toxicity: Renal toxicity with increased creatinine or renal tubular dysfunction has been associated with tenofovir use, and the association is stronger with TDF than TAF [Gupta, et al. 2019]. This renal toxicity may be reversible with dose adjustments of TDF or switching to TAF. Clinicians should evaluate electrolytes, serum creatinine levels, and urinalysis every 6 months [DHHS 2023].

Cirrhosis: Patients with HIV/HBV coinfection and cirrhosis should be referred to a gastroenterologist or hepatologist to assess and manage complications of portal hypertension such as gastroesophageal varices and ascites. Patients with HIV/HBV coinfection and cirrhosis should undergo esophagogastroduodenoscopy at the time of chronic HBV diagnosis and every 1 to 2 years thereafter [DHHS 2023; Terrault, et al. 2018].

Acute flare: If a patient being treated for chronic HBV develops signs or symptoms of acute hepatitis (nausea, vomiting, elevated ALT or bilirubin levels), clinicians should evaluate the patient, rule out HBV IRIS and HDV flare among other potential causes, and consult with an HIV-experienced hepatologist. Hepatic flares are usually mild and self-limited but can result in decompensation in individuals with preexisting cirrhosis [Anderson, et al. 2010; Crane, et al. 2009; Perrella, et al. 2006; Konopnicki, et al. 2005; Drake, et al. 2004].

In patients with HIV, initiation of or a change in ART introduces the potential for IRIS, which may manifest as a worsening of previously diagnosed disease or the appearance of a previously undiagnosed disease. In patients with HIV/HBV coinfection, IRIS can present as an acute flare of HBV disease. It can often be difficult to distinguish HBV IRIS from other causes of an acute HBV flare, such as drug or alcohol hepatotoxicity or other viral infection (hepatitis A, C, D, or E virus, Epstein-Barr virus, herpes simplex virus, or cytomegalovirus). Reviewing medication history and testing for serum HBV DNA, HBeAg, HIV viral load, and CD4 cell count can help distinguish between these possibilities [DHHS 2023].

HBV IRIS is usually detected within the first 6 to 12 weeks after ART is initiated, based on a noticeable rise in ALT levels that coincides with rising CD4 cell counts (immune reconstitution) and signs and symptoms characteristic of acute hepatitis and with no other cause for the flare [DHHS 2023]. Risk factors for HBV IRIS include high HBV viral load, elevated ALT level, and low CD4 cell count at baseline [Singh, et al. 2017].

Ongoing Screening for Hepatocellular Carcinoma

Compared with HBV monoinfection, HIV/HBV coinfection is associated with an increased risk of developing HCC and increased mortality rates [Sun, et al. 2021; Pinato, et al. 2019; Singh, et al. 2017]. Patients with HIV/HBV coinfection and cirrhosis should be screened with ultrasound for HCC every 6 months [Terrault, et al. 2018].

There is no consensus on how frequently to screen for HCC in patients with HIV/HBV coinfection who do not have cirrhosis. In patients with HBV monoinfection, screening is recommended every 6 months for groups at increased risk for developing HCC, including Asian men >40 years old, Asian women >50 years old, Black men >40 years old, individuals with a first-degree family member who has a history of HCC, or individuals with HDV [Terrault, et al. 2018; Sarin, et al. 2016; Zhang, et al. 2004].