STD Series: Hepatitis Coinfection in HIV Patients

I. Introduction
• HBV infection among HIV patients globally
• Need for screening HIV individuals for HBV infection
II. Progression of HBV in stages
III. Impact of HIV on the HBV Infection
• Increased levels of HBV DNA and low clearance rate of e antigen (HBeAg)
• High risk of HBV infection advancing faster to cirrhosis, liver cancer, and end-stage liver disease
• Associated with the frequent flares of hepatic transaminases
IV. Diagnosing hepatitis B in HIV-infected individuals
• HBsAg, HBcAb, and previous HBV vaccination assessment
• ALT level and abnormal liver enzymes
• Determination of HBeAg
• Ultrasound and other evaluations
V. ART in HBV/HIV coinfected patients
• Treatment for HBV and antiretroviral drugs for HIV
• Hepatoxicity associated with antiretroviral medications
• Use of antiretroviral therapy with active agents
• Treatment of HBV with ART
• Treatment of HBV in the absence of ART

Hepatitis B virus (HBV) is a double-stranded DNA multiplying in hepatocytes and is considered one of the common infections among HIV individuals globally. With the increase in the rate of HBV infection among HIV patients and the common routes of transmission, HIV individuals should be screened for HBV infection with HBsAg testing. As the HBV DNA can continue to remain in the liver throughout an individual’s life, those with cAb positivity are at the risk of reactivation of HBV infection even when the sAB test appears positive.

Globally, an estimated 2.6 million HIV individuals are co-infected with HBV and around 25-36% co-infection with HBV occurs in the high endemic parts of the world. According to the Centers for Disease Control and Prevention (CDC), in the United States, around 10% of HIV people also have HBV.

Progression of HBV in stages

Individuals with a weakened immune system such as HIV population will progress to have a chronic infection which is indicated in four stages;

Immune tolerance (stage 1): a short-lived phase among adults where HBV multiplies to a high viral load with the immune system not responding very well.

Active immune response (stage 2): the immune system continues to attack the infected cells in the liver. This phase can last for just a few weeks or continue for years or decades causing liver damage deteriorating over time.

Inactive carriage (stage 3): in a process known as seroconversion, the body develops antibodies against HBV so the virus is not reproduced freely. Individuals are also at the risk of liver cancer.

‘e’-antigen-negative chronic active hepatitis (stage 4): individuals lack the ‘e’-antigen, presenting moderate levels of viral multiplication with inflammation of the liver and presenting a very high risk of cirrhosis and liver cancer.

Impact of HIV on the HBV Infection

Individuals with HIV and chronic HBV co-infection present increased levels of HBV DNA and low clearance rate of e antigen (HBeAg). Co-infected individuals are at high risk of HBV infection advancing faster to cirrhosis, liver cancer and end-stage liver disease than those with only HBV infection. The co-infection also is associated with the frequent flares of hepatic transaminases, that can develop with IRIS (immune reconstitution inflammatory syndrome) because of ART or the development of resistance to HIV/HBV treatment.

Diagnosing hepatitis B in HIV-infected individuals

As the initial assessment, all HIV individuals should be tested for HBsAg, for hepatitis B core antibodies (HBcAb) and assessed for previous HBV vaccination.

ALT level – increased ALT is indicative of liver inflammation and ALT level three times more than normal is associated with cirrhosis risk while abnormal liver enzymes for three months indicates HBV treatment should be initiated.

Determination of HBeAg – Positive HBeAg present high HBV DNA and negative patients also can have a progressive liver disease, however, in both circumstances, measurement of HBV DNA should be done.

Ultrasound and other evaluations – Ultrasound of the liver can detect cirrhosis, steatosis and maybe early hepatocellular carcinoma (HCC), a common type of liver cancer. Individuals with liver cirrhosis can also have serum alpha-fetoprotein (AFP) assessment to identify HCC.

Histological evaluation – liver biopsy may present several advantages such as assessment of necrosis, inflammation and fibrosis.

ART in HBV/HIV coinfected patients

Generally, the treatment for HBV is the antiviral drugs that either stops or delay the effects of liver damage. Several of the antiretroviral drugs as treatment for HIV infection can also slow the progression of the disease by decreasing the viral load. However, some degree of hepatoxicity has been associated with the majority of antiretroviral medications along with the HBV infection, acting as an independent risk factor for the development of hepatoxicity. Also, these co-infected individuals are at risk for HBV immune reconstitution inflammatory syndrome that is characterized by a paradoxical hepatitis flare.

According to a study reported at the 20^th Conference on Retroviruses on Opportunistic Infections, the use of antiretroviral therapy with active agents such as tenofovir, 3TC (lamivudine, Epivir) and FTC (emtricitabine, Emtriva) can act against both HBV and HIV thus reducing the chance of becoming infected with HBV (acting a HBV pre-exposure prophylaxis – PrEP). Hence, the need for vaccination against HBV is also reduced when taking these drugs.

Treatment of HBV with ART

As one or more HBV-active agents are present in most of the HIV treatment (eg, emtricitabine (FTC), tenofovir (TDF), lamivudine (3TC)), an indication for HBV infection should be initiated on fully active ART containing HBV-active nucleoside/nucleotide analogues. Any HIV/HBV co-infected individual with an indication for ART should initiate on HIV treatment that contains effective anti-HBV treatment. As the first-line of effective treatment for HBV, the combination of TDF with 3TC or FTC is recommended. In case TDF cannot be tolerated by the patient, entecavir can be used as the alternative treatment.

Treatment of HBV in the absence of ART

U.S Department of Health and Human Services guidelines recommends that an active ART should be initiated as the treatment for HBV among HIV/HBV co-infected individuals even if they don’t have an indication for HIV treatment. With the adefovir as the treatment for HBV only, even a low-dose could have anti-HIV activity. Pegylated interferon could be an option here, but the long-term treatment is not possible due to poor tolerability and toxicity.

Treatment prospects

Drugs as the treatment of HBV infection among individuals with HIV;

Tenofovir disoproxil fumarate – when used in combination with lamivudine, it is effective in reducing the viral load of both HIV and HBV

Lamivudine – active against HIV and prevents HBV replication in most of the cases

Emtricitabine – similar to lamivudine but when used as monotherapy, HBV resistance can develop rapidly

Entecavir – active against both HIV and HBV but not recommended for treatment of HBV infection among HIV patients not receiving ART

Adefovir dipivoxil – nucleoside analog reverse transcriptase inhibitor active against HBV although a warning was indicated against the use as monotherapy in HIV/HBV co-infected individuals

Interferon-alfa – Interferon-alfa 2a or 2b or Peg IFN-alfa 2a are used for HBV mono-infected individuals. Studies suggest a decrease in the response rate in HIV/HBV co-infected individuals; however, it may be used if an agent not active against HIV is required.

Guidance for treatment of individuals with HBV and HIV co-infection

Initiation of ARVT for all co-infected patients that should include two drugs with activity against HBV regardless of their CD4 count
Those already receiving effecting ART but does not include drug against HBV should change treatment to include TDF and TAF with emtricitabine or lamivudine.
If ART regime is changed, effective drugs used against HBV must not be discontinued without substituting with another drug
Dose adjustment of TDF-emtricitabine-inclusive regimes if creatinine clearance appears <50mL/min

References

STD Series: Hepatitis Coinfection in HIV Patients

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