Monitoring the patient with HIV and chronic hepatitis B virus infection

INTRODUCTION — In the era of potent antiretroviral therapy (ART), end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection remains a leading cause of morbidity and mortality in people living with HIV [1]. Thus, treating and preventing HBV infection are essential in light of the negative impact HIV has on the natural history of chronic hepatitis B infection. Patients with chronic HBV and HIV coinfection should be treated with a regimen that is effective against both HIV and HBV.

However, treatment of HBV in the patient with HIV can be complicated by drug-induced hepatotoxicity, immune constitution syndromes, and toxicity related to medications. Furthermore, regardless of whether the patient is treated, surveillance for development of hepatocellular carcinoma is required.

Monitoring of the patient with HIV/HBV coinfection, regardless of whether the patient is taking antiviral therapy, will be discussed here. The epidemiology, clinical manifestations, diagnosis, management, and prevention of HBV infection are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV" and "Treatment of chronic hepatitis B in patients with HIV" and "Prevention of hepatitis B virus infection in adults with HIV".)

PATIENT MONITORING DURING HBV THERAPY

HBV DNA and aminotransferase monitoring — Laboratory monitoring during hepatitis B virus (HBV) therapy includes serial aminotransferases and assessment of viral suppression. We typically monitor HBV DNA and aminotransferases every three months to confirm the viral load is decreasing appropriately (eg, <500 copies/mL by 6 months), we then reduce the frequency to every six months.

Studies in patients with HBV alone have demonstrated that normalization of aminotransferases and suppression of HBV DNA (with or without HBeAg seroconversion) are associated with improvements in liver histology and lower rates of cirrhosis, hepatic decompensation, and hepatocellular carcinoma [2]. Studies in coinfection suggest similar benefit [3-5].

HBeAg status — Based on results of serologic testing, patients with HBV are classified as having either "HBeAg-positive infection" or "HBeAg-negative infection." Patients with HBeAg-positive infection tend to have higher levels of HBV DNA than patients who are HBeAg negative. A more detailed discussion of the significance of HBeAg is found elsewhere. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection'.)

●Patients who are HBeAg positive should have HBeAg and anti-HBe testing repeated every 6 to 12 months to determine if seroconversion (loss of HBeAg with gain of anti-HBe) has occurred. Seroconversion implies a transition from a more active to a less active disease state. (See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

●No monitoring of HBeAg or anti-HBe is required in HBeAg-negative patients, only HBV DNA. In general, HBeAg-negative patients require chronic HBV therapy for an indefinite period of time, regardless of HIV status, since treatment discontinuation is usually associated with virologic rebound. (See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

Hepatitis B surface antigen — The ultimate goal of HBV therapy is to achieve hepatitis B surface antigen (HBsAg) seroconversion, but this occurs in the minority of patients, regardless of HIV status. Annual testing of HBsAg in patients with ongoing HBV DNA suppression is reasonable. If HBsAg seroconversion occurs and ART needs to be altered, then an anti-HBV drug does not need to be included in the new ART regimen, provided the patient has had 6 to 12 months of anti-HBV therapy after HBsAg seroconversion.

SCREENING FOR HEPATOCELLULAR CARCINOMA — Patients with HIV and chronic hepatitis B infection should be screened for hepatocellular carcinoma (HCC); however, there is no standardized approach. We typically obtain a baseline ultrasound at the time of diagnosis in all patients. We then obtain an ultrasound (with or without alpha fetoprotein [AFP]) every six months in those with evidence of advanced fibrosis or cirrhosis and those over age 40 years. In one study of patients with HIV/HBV coinfection, the incidence of HCC increased in patients in their 40s [6].

A more detailed discussion of HCC screening in patients with chronic HBV is found elsewhere. (See "Surveillance for hepatocellular carcinoma in adults", section on 'Patients with hepatitis B without cirrhosis'.)

MONITORING IN PATIENTS WITH HIV, HBV, AND HCV — In patients with hepatitis B virus (HBV) and coexisting hepatitis C virus (HCV) infection, one virus typically predominates over another. During HBV therapy, it is reasonable to assay for HCV RNA, particularly if aminotransferases rise despite declining HBV DNA levels. However, in one small study of 21 patients with HIV, HBV, and HCV coinfection, re-emergence of the less dominant virus was uncommon [7].

In the unusual case where a patient with HIV/HBV/HCV tri-infection is not on HBV-active antiretroviral therapy (ART) and receives direct-acting antiviral therapy for HCV, reactivation of HBV may occur. Reactivation has been reported in HBV/HCV-coinfected patients who are either positive only for hepatitis B core antibody (isolated-anti-HBc-positive) or are hepatitis B surface antigen-positive with low or undetectable HBV DNA levels [8]. Thus, if such patients are not started on HBV-active antiretroviral therapy before receiving HCV therapy, these patients should be monitored closely for HBV reactivation. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

ABNORMALITIES OF AMINOTRANSFERASES — Fluctuations in aminotransferases in the patient coinfected with HIV and HBV may be due to:

●Chronic hepatitis B infection

●Immune reconstitution syndrome

●Drug-induced liver injury

●Emergence of HBV drug resistance

●Infection with another hepatitis virus

●Steatotic liver disease

Chronic hepatitis B virus infection — HIV/HBV-coinfected patients may have waxing and waning aminotransferases during untreated infection. Data in patients with HBV alone suggest that serial flares of liver function tests can lead to increased rates of fibrosis progression.

Mild increases in liver function tests may also occur in the setting of HBV treatment, which are often seen incidentally with routine laboratory monitoring.

Immune reconstitution inflammatory syndrome — Immune reconstitution after initiation of antiretroviral therapy (ART) in the coinfected patient can be associated with elevation in aminotransferases, possibly because HBV is primarily an immune-mediated disease. Risk factors for HBV-related immune reconstitution include a high level of HBV viremia and a low CD4 count [9]. (See "Immune reconstitution inflammatory syndrome".)

Patients should be instructed to call their healthcare provider if they should develop symptoms of acute hepatitis with right upper quadrant pain, nausea, vomiting, anorexia, jaundice, or icterus. Close laboratory monitoring of aminotransferases is suggested during the first three months of therapy (eg, every six weeks), particularly in those with low CD4 cell counts.

Most cases of immune reconstitution inflammatory syndrome resolve uneventfully; however, the patient with cirrhosis is at risk for decompensation and should be monitored closely during the first three to six months of therapy. Additional testing for prothrombin time in a cirrhotic patient with marked increases in aminotransferases is prudent. If the patient decompensates, they should be seen in a transplant center as soon as possible. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

Drug-induced liver injury — Patients with HIV and chronic viral hepatitis (either HBV or hepatitis C virus [HCV]) may be at increased risk for drug-induced liver injury [10,11]. Certain older antiretroviral medications have a higher risk of drug-induced liver injury and should be used with caution in the patient with liver disease (eg, tipranavir) [12]. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV", section on 'HBV and risk of drug-induced hepatotoxicity' and "Overview of antiretroviral agents used to treat HIV".)

Emergence of HBV drug resistance — HIV/HBV-coinfected patients may develop HBV drug resistance with subsequent hepatitis flares associated with rebound viremia [13]. The diagnosis of HBV drug resistance is suspected if the patient has attained viral suppression with subsequent detection of viremia or in the patient who has an increase in viral load more than 1 log above the previous value. (See 'HBV drug resistance testing' below.)

The risk of resistance is high in patients who are being treated with an ART regimen that contains emtricitabine or lamivudine as the only agent active against HBV. By contrast, resistance to tenofovir, even when it is the only HBV-active agent in a combination ART regimen, is very rare [14]. A detailed discussion of tenofovir resistance in patients with chronic HBV is presented in a separate topic review. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Risk of resistance'.)

Infection with other hepatitis viruses — Infection with hepatitis D virus (HDV), HCV, or hepatitis A virus (HAV) can lead to a hepatitis flare. In the right epidemiologic setting, testing for these infections should be obtained. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

Steatotic liver disease — Fluctuations in ALT level may be seen in association with weight gain or loss as well as alcohol use. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis" and "Evaluation of the patient with HIV and hepatobiliary complaints", section on 'Hepatic steatosis'.)

HBV DRUG RESISTANCE TESTING — Although preliminary data suggest that resistance testing may have a role in drug selection, there are few published studies in this area.

Hepatitis B virus (HBV) has a high replication rate, with an estimated 10¹² viruses being produced daily in the treatment-naive host [15]. During replication, HBV mutations arise at a frequency of 1 per 10⁴ to 10⁵ nucleotides [16]. The combination of these two factors leads to a swarm of viral variants called "quasispecies," similar to that described for HIV and hepatitis C viruses (HCV). However, despite the high HBV mutation rate, the emergence of drug resistance occurs more slowly for HBV than for HIV or HCV. This may be related to several factors, including slow turnover of covalently closed circular DNA in chronically infected hepatocytes, the constraints on HBV evolution imposed by its overlapping reading frames, and the effect of the host immune response [17].

Drug resistance is inferred when a ≥1 log(10) international units/mL increase in viral load from nadir is documented on two consecutive serum samples collected at least one month apart in patients who initially responded to and are compliant with therapy [18]. Identification of antiviral resistance involves the detection of mutations in the HBV genome (typically polymerase) that have been selected during treatment [18]. Many clinical laboratories now combine resistance testing with genotyping. (See "Clinical significance of hepatitis B virus genotypes".)

Drug resistance is most common in patients who had or have a detectable HBV DNA while on antiretroviral therapy with lamivudine as the only HBV-active agent. Some experts recommend drug resistance testing, especially if the addition of entecavir is being considered, since entecavir has overlapping resistance patterns with lamivudine. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'When entecavir is used'.)

MONITORING FOR DRUG SIDE EFFECTS — HIV/HBV-coinfected patients typically receive a tenofovir-containing antiretroviral therapy (ART) regimen. We check routine laboratory studies (eg, serum creatinine, urinalysis) based upon guideline recommendations for monitoring patients with HIV receiving ART [19]; these are discussed in detail elsewhere. (See "Patient monitoring during HIV antiretroviral therapy".)

Tenofovir is available in two preparations, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). On occasion, TDF can lead to renal impairment, and the TAF formulation is associated with less renal toxicity. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

A more detailed discussion of the side effects associated with the agents used to treat HBV and the approach to patients who develop renal insufficiency on tenofovir are presented elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Antiviral Medications for HBV' and "Treatment of chronic hepatitis B in patients with HIV", section on 'Renal insufficiency on tenofovir'.)

DURATION OF HBV THERAPY — Most patients with HIV and hepatitis B virus (HBV) coinfection will receive indefinite treatment for HIV and HBV. This is based upon the chronic nature of HBV infection and that patients with HIV require lifelong antiretroviral therapy. A more detailed discussion of the duration of therapy is found elsewhere. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'Duration of therapy'.)

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

SUMMARY AND RECOMMENDATIONS

●Laboratory monitoring – Laboratory monitoring during HBV therapy includes serial aminotransferases and assessment of viral suppression.

We typically monitor HBV DNA and aminotransferases every three months to confirm the viral load is decreasing appropriately (eg, <500 copies/mL by six months); we then reduce the frequency to every six months. (See 'Patient monitoring during HBV therapy' above.)

●Monitoring for hepatocellular carcinoma – Patients with chronic HBV infection should be screened at baseline for the presence of hepatocellular carcinoma. We then obtain an ultrasound (with or without alpha fetoprotein [AFP]) every six months in those with evidence of advanced fibrosis or cirrhosis and in those over age 40 years. (See 'Screening for hepatocellular carcinoma' above.)

●Patients with elevated aminotransferase levels – Fluctuations in aminotransferases in patients with HIV/HBV coinfection may be due to chronic HBV infection, drug toxicity, immune reconstitution inflammatory syndrome, inadequate adherence, the emergence of HBV drug resistance, infection with another hepatitis virus, or steatotic liver disease. (See 'Abnormalities of aminotransferases' above.)

●Role of resistance testing – HBV drug resistance testing may be useful in select patients (eg, those who received lamivudine or emtricitabine without tenofovir), especially if treatment with entecavir is being considered. (See 'HBV drug resistance testing' above.)

●Patients who are taking tenofovir disoproxil fumarate (TDF) as part of their antiretroviral therapy regimen should have routine laboratory monitoring (eg, serum creatinine and a urinalysis) to evaluate for drug-related side effects. (See 'Monitoring for drug side effects' above and "Patient monitoring during HIV antiretroviral therapy".)