Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV

INTRODUCTION — The era of potent antiretroviral therapy (ART) has led to declining rates of opportunistic infections and a new focus on other leading causes of morbidity, such as end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection [1]. HIV treatment guidelines generally recommend treatment of chronic HBV in all patients with HIV/HBV coinfection [2-4]; ART should include agents with dual activity against HIV and HBV.

The pretreatment evaluation of chronic HBV in patients living with HIV will be reviewed here. The epidemiology, clinical manifestations, diagnosis, treatment, and prevention of HBV infection in patients with HIV are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "Treatment of chronic hepatitis B in patients with HIV" and "Prevention of hepatitis B virus infection in adults with HIV".)

APPROACH TO EVALUATION — Most patients with HIV and chronic HBV will be treated for their HIV and HBV, regardless of the stage of liver disease or their level of immunosuppression (ie, CD4 cell count). (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Rationale for treatment'.)

The pretreatment evaluation of such patients includes obtaining baseline markers of disease activity (used to monitor the response to therapy), information to determine which antiviral agents to use for HBV treatment, and information to assess for other causes of liver injury and complications of advanced liver disease (eg, varices, hepatocellular carcinoma).

Baseline assessments include:

●A detailed history and physical examination to assess for hepatotoxic medications and evidence of advanced liver disease. (See 'Hepatotoxic medications' below and 'Stage of liver disease' below.)

●Laboratory testing to evaluate markers of HBV activity, kidney function, liver function, and coexisting causes of liver disease. (See 'Baseline markers of disease activity' below and 'Information needed for drug selection' below and 'Evaluation for other causes of liver disease' below and 'Screening and prevention' below.)

●Noninvasive assessment of liver disease. (See 'Stage of liver disease' below.)

●Ultrasound-based imaging to screen for evidence of hepatocellular carcinoma. (See 'Hepatocellular carcinoma screening' below.)

The following discussion will review the evaluation of HIV/HBV coinfected patients as it pertains to HBV treatment. A detailed discussion on the initial evaluation of HIV infection is found elsewhere. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy" and "Initial evaluation of adults with HIV".)

BASELINE MARKERS OF DISEASE ACTIVITY — Certain baseline tests are obtained to assess the level of HBV activity, and are also used to monitor response to therapy and/or guide future treatment decisions. These tests include aminotransferase levels, HBV DNA level, hepatitis B e antigen (HBeAg), and hepatitis B e antibody (anti-HBe). (See 'Aminotransferase levels' below and 'HBV DNA' below and 'Hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe)' below.)

Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) are typically obtained prior to the pretreatment evaluation as they are needed to make the diagnosis of chronic or occult HBV. (See "Hepatitis B virus: Screening and diagnosis in adults".)

Aminotransferase levels — The activity of HBV infection is inferred by elevations of aminotransferase levels. Reductions in these levels are suggestive of a treatment response. (See "Monitoring the patient with HIV and chronic hepatitis B virus infection", section on 'Abnormalities of aminotransferases'.)

HBV DNA — HBV DNA is also used to monitor response to therapy. One treatment goal is to achieve an undetectable HBV DNA. Patients who do not achieve an appropriate virologic response may be non-adherent to their medications or may have developed drug-resistant HBV. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Response to therapy' and "Monitoring the patient with HIV and chronic hepatitis B virus infection".)

Hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) — HBeAg is a marker of HBV replication and infectivity. For individuals who are HBeAg positive, seroconversion from HBeAg to anti-HBe is usually associated with declines in serum HBV DNA. A more detailed review of serologic markers for HBV infection is found elsewhere. (See "Hepatitis B virus: Screening and diagnosis in adults", section on 'Hepatitis B e antigen and antibody'.)

INFORMATION NEEDED FOR DRUG SELECTION — Most patients with HIV and HBV coinfection will be treated with an antiretroviral regimen that includes a tenofovir-emtricitabine containing backbone; these agents are considered first-line treatment for both infections. However, the ultimate choice depends upon the patient’s prior treatment history for HIV and/or HBV, as well as their kidney function. The presence of hepatitis D coinfection may also impact treatment. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Approach to treatment'.)

Kidney function — We obtain a baseline serum creatinine and urinalysis prior to starting treatment. The approach to treatment depends in part upon the estimated glomerular filtration rate. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Approach to treatment'.)

Among those individuals receiving tenofovir, serum creatinine and urinalysis should be monitored. (See "Patient monitoring during HIV antiretroviral therapy", section on 'ART-associated toxicity'.)

Treatment history — A careful treatment history should be obtained to determine whether or not the patient has received prior lamivudine (which may also be used to treat HIV infection). Entecavir, one of the agents used to treat HBV, is less likely to suppress HBV DNA in patients with lamivudine-resistant HBV.

HBV resistance testing in some patients — A baseline HBV resistance panel is sometimes obtained in patients with prior exposure to lamivudine/emtricitabine since HBV resistance has been reported in patients using these agents (especially if they were used as monotherapy). Reasons for and against resistance testing are described below:

●Some experts assume that patients with prior lamivudine/emtricitabine treatment have lamivudine-resistant virus and treat accordingly, without obtaining a baseline resistance panel.

●Other providers feel that a baseline resistance panel can help guide treatment decisions, particularly in patients who have reduced kidney function or who are at risk of developing renal insufficiency on treatment.

Hepatitis D antibody — Patients should be tested for antibody to hepatitis D virus (HDV), which can only cause infection in patients with chronic HBV and may accelerate liver disease progression. This virus requires HBsAg to complete replication in the hepatocyte. In some cases, HDV infection is treated with interferon. The diagnosis and treatment of hepatitis D virus infection are discussed elsewhere. (See "Treatment and prevention of hepatitis D virus infection" and "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

EVALUATION FOR OTHER CAUSES OF LIVER DISEASE — Patients with chronic HBV infection should be evaluated for concurrent causes of liver disease. Many of these can be addressed, which may help prevent progression to end-stage liver disease. More detailed discussions of the evaluation of abnormal liver function tests, as well as hepatobiliary disease in individuals with HIV, are found elsewhere. (See "Approach to the patient with abnormal liver biochemical and function tests" and "Evaluation of the patient with HIV and hepatobiliary complaints".)

As examples, we assess all patients with HIV for the following:

Hepatitis C — All patients with chronic HBV should be evaluated for hepatitis C virus (HCV) infection (eg, hepatitis C antibody). Approximately one-third of all patients with HIV have serologic evidence of HCV exposure, and the vast majority of such patients have chronic infection. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

Hepatic steatosis — Patients with HIV may be at increased risk for hepatic steatosis compared with those who do not have HIV, and this may be associated with abnormal aminotransferase levels. Hepatic steatosis may be suggested on ultrasound, which is also used to screen for hepatocellular carcinoma. It may also be suggested from transient elastography if a controlled attenuation parameter score is also obtained. (See 'Hepatocellular carcinoma screening' below and "Management of nonalcoholic fatty liver disease in adults".)

Hepatotoxic medications — Patients should be evaluated to determine whether or not they are using hepatotoxic agents (eg, acetaminophen, alcohol). This is particularly important for those with advanced liver disease. Such patients should be instructed to avoid these agents. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Avoidance of hepatotoxins'.)

SCREENING AND PREVENTION — In addition to evaluation for other causes of liver disease, patients coinfected with HIV and HBV should be evaluated for the following:

●Cirrhosis

●Hepatocellular carcinoma

●Osteoporosis

●Immunity to hepatitis A virus

The results of this testing may prompt additional tests and/or treatments.

Stage of liver disease — Patients should be assessed for their stage of liver disease to determine the need for further evaluation/management of portal hypertension. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

A detailed discussion of how to assess patients for evidence of cirrhosis is found elsewhere (see "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis"). Briefly:

●History – Patients should be asked about easy bruisability, jaundice, dark urine, light stools, history of gastrointestinal bleeding (eg, hematemesis or melena), signs associated with hypogonadism (eg, impotence, infertility), and pruritus. In addition, insomnia, altered sleep patterns, and recent automobile accidents may suggest the presence of early hepatic encephalopathy. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Symptoms'.)

●Physical examination – Patients should have a physical examination to determine if there are any stigmata of advanced liver disease (eg, spider angiomata, splenomegaly, palmar erythema, asterixis). Decompensated liver disease is likely if ascites and/or encephalopathy are present. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Physical examination'.)

●Laboratory testing – Patients should have laboratory testing that includes a complete blood cell count, as well as measurements of albumin and the prothrombin time. A low albumin and/or an elevated prothrombin time are suggestive of advanced liver disease with hepatic decompensation. Leukopenia and thrombocytopenia may heighten suspicion of portal hypertension. Although certain findings are suggestive of advanced liver disease, they may also be a result of HIV infection. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Laboratory findings' and "The natural history and clinical features of HIV infection in adults and adolescents", section on 'AIDS and advanced HIV infection'.)

●Evaluation for fibrosis – Patients should also be assessed for fibrosis through the use of a noninvasive method (eg, biomarkers, such as fibrosis marker panels; calculated scores, such as AST to platelet ratio index; or ultrasound-based technology, such as liver elastography). Some centers can provide magnetic resonance elastography (MRE), which is highly accurate but relative expensive. Increasing data support the use of noninvasive methods rather than liver biopsy to evaluate liver stage. As an example, a meta-analysis of 2772 Asian patients with chronic HBV found that the sensitivity and specificity of transient elastography for cirrhosis was 84.6 and 81.5 percent, respectively [5]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

However, a biopsy can help determine the true degree of hepatic fibrosis when laboratory evaluations suggest the presence of portal hypertension and noninvasive markers indicate mild liver disease. (See "Histologic scoring systems for chronic liver disease".)

Hepatocellular carcinoma screening — All patients with HIV and chronic HBV infection should have a baseline ultrasound to screen for hepatocellular carcinoma (HCC). Patients with obesity may require biphasic or triphasic computed tomography (CT) or enhanced magnetic resonance imaging, since ultrasound may provide an inadequate survey of the liver in such patients. Simple contrast CT is not recommended for HCC screening. A discussion on how to monitor patients with HBV for HCC is found elsewhere. (See "Surveillance for hepatocellular carcinoma in adults".)

Hepatitis A screening — Patients should be evaluated for prior vaccination to hepatitis A virus (HAV), or for evidence of previous HAV infection by measuring the total hepatitis A antibody. Individuals without evidence of prior HAV vaccination or infection should be vaccinated, since persons with chronic HBV infection are at increased risk for fulminant HAV. (See "Hepatitis A virus infection: Treatment and prevention".)

Bone density screening — We obtain a baseline dual-energy x-ray absorptiometry (DXA) scan in all patients with advanced liver disease (advanced liver disease and tenofovir can both lead to bone loss) [6]. A discussion of bone density screening in patients with HIV is found elsewhere. (See "Bone and calcium disorders in patients with HIV", section on 'Bone mineral density screening'.)

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

SUMMARY AND RECOMMENDATIONS

●General approach – The pretreatment evaluation of patients with HIV and hepatitis B virus (HBV) coinfection typically includes: a detailed history and physical examination to assess for hepatotoxic medications and evidence of advanced liver disease; laboratory testing to evaluate markers of HBV activity, kidney function, liver function, and coexisting causes of liver disease; assessment of liver disease through noninvasive testing; and ultrasound imaging to screen for evidence of hepatocellular carcinoma. (See 'Approach to evaluation' above.)

●Determining HBV disease activity – Certain baseline tests are obtained to assess the level of HBV activity, and are also used to monitor response to therapy and/or guide future treatment decisions. These tests include aminotransferase levels, HBV DNA level, hepatitis B e antigen (HBeAg), and hepatitis B e antibody (anti-HBe). For some patients, HBV resistance testing should also be performed. (See 'Baseline markers of disease activity' above.)

●Considerations for regimen selection – Most patients with HIV/HBV coinfection will be treated with an antiretroviral regimen that includes a tenofovir-emtricitabine containing backbone; these agents are considered first-line treatment for both infections. However, the ultimate choice depends upon the patient’s prior treatment history for HIV and/or HBV, as well as their kidney function. The presence of hepatitis D coinfection may also impact treatment. (See 'Information needed for drug selection' above.)

●Evaluation for other causes of liver disease – Patients with chronic HBV infection should be evaluated for other causes of liver disease. Many of these can be addressed, which may help prevent the progression to end-stage liver disease. (See 'Evaluation for other causes of liver disease' above.)

●Additional testing – Patients should be evaluated for cirrhosis, hepatocellular carcinoma, osteoporosis, and immunity to hepatitis A virus. The results of this evaluation may prompt the need for additional tests and/or treatments that can reduce the risk of future complications. (See 'Screening and prevention' above.)