Hepatobiliary Complications of HIV

The seroprevalence of antibody to hepatitis A virus (HAV) is high among HIV-infected persons, with a range of 40% to 70%.

The annual cumulative frequency of HAV infection is reported to be 5.8% per year among HIV-positive persons.

HAV viremia is prolonged in HIV-infected persons, and the level of HAV viremia is higher compared with those without HIV infection, even with relatively high CD4+ T lymphocyte counts.

No evidence indicates that ART has a detrimental effect on the course of HAV infection.

Hepatitis A vaccination is recommended for all HIV-positive/HAV-seronegative persons, with standard doses given 6 to 12 months apart. Immune response is excellent (overall response rate, 78% to 94%), even in persons with CD4+ cell counts <200/mm ³ (response rate 64%).

Worldwide, 10% of HIV-infected persons are chronically infected with hepatitis B virus (HBV).

HIV adversely affects the natural history of HBV infection. Compared with those infected with HBV alone, HIV-coinfected persons have a higher rate of progression from acute to chronic HBV infection, higher serum HBV DNA levels, lower rates of spontaneous hepatitis B e antigen (HBeAg) to antibody to HBeAg (anti-HBe) seroconversion, increased frequency of reactivation episodes, faster progression to hepatic cirrhosis, and earlier development of, and more aggressive, hepatocellular carcinoma (HCC).

HIV coinfection may accelerate progression of hepatitis D virus (HDV)–associated liver disease.

All HIV/HBV-coinfected patients with active HBV replication should be considered for HBV antiviral therapy, which can potentially prevent the development of liver-related complications and reduce HBV transmission.

The goals of HBV treatment in HIV-infected persons are suppression of HBV DNA to an undetectable level (as for persons without HIV infection), return of serum aminotransferase levels to normal, HBeAg seroconversion (not applicable to HBeAg-negative chronic hepatitis B), and improvement in liver histology.

Several antiviral medications have been approved in the United States for chronic HBV treatment, and some of these have also been approved for HIV treatment ( Box 27.1 ).

Combination oral nucleoside or nucleotide therapy (tenofovir disoproxil fumarate 300 mg daily or tenofovir alafenamide 25 mg daily plus either emtricitabine 200 mg daily or lamivudine 300 mg daily) is the regimen of choice. The preferred form of tenofovir is tenofovir alafenamide, which is not known to have the renal toxicity or decrease in bone mineral density associated with tenofovir. Because replication of both viruses depends on reverse transcription, dual HIV/HBV therapy can include the same reverse transcriptase-inhibiting agents to treat both viruses.

In the absence of ART, entecavir can reduce HIV RNA levels and select for HIV-resistance mutations; therefore, it should not be used in an HIV-infected person without ART.

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  Telbivudine does not have intrinsic activity against HIV in vitro, but it has been associated with declines in HIV RNA levels and can select for lamivudine-resistance mutations. It is not a recommended treatment for the HIV/HBV-coinfected patient.

Frequent toxicities and low rates of therapeutic success have limited peginterferon alfa-2a use as HBV therapy in HIV-infected persons.

Because lamivudine resistance occurs at a rate of 15% to 25% per year, lamivudine resistance may be present in HIV-infected patients who previously received lamivudine as part of an ART regimen. Tenofovir remains active in patients with lamivudine-resistant HBV infection and can suppress HBV DNA to undetectable levels, because of the potency of tenofovir and the lack of cross-resistance between lamivudine and tenofovir.

For patients receiving combination tenofovir plus emtricitabine (or lamivudine) who fail to suppress HBV DNA by 96 weeks, entecavir 1 mg daily may be added.

Because HCC can occur at any stage of chronic HBV infection, screening with abdominal ultrasonography and alpha fetoprotein testing is recommended every 6 to 12 months (see Chapter 29 ).

HBV vaccination is recommended in all HIV-positive hepatitis B surface antibody (anti-HBs)–negative persons. The presence in serum of isolated hepatitis B core antibody (anti-HBc) with no other HBV markers most likely reflects previous exposure and recovery, rather than a false-positive result, but not necessarily.

Anti-HBs titers should be assessed after HBV vaccination in HIV-infected persons. Immune reactivity to the HBV vaccine is frequently suboptimal in these persons in terms of rate of response, antibody titers, and durability. A CD4+ cell count >500/mm ³ and an HIV viral load <1000 copies/mL promote optimal vaccine responses. Revaccination should be instituted if the anti-HBs titer is <10 mIU/mL.

30% of HIV-infected persons are chronically coinfected with HCV.

The natural history of HCV infection is adversely influenced by HIV coinfection. Compared with persons infected with HCV alone, HIV-coinfected persons more commonly progress to chronic HCV infection; have higher HCV RNA levels; are at higher risk of cirrhosis, hepatic decompensation, and liver-related death; and have a shorter survival once end-stage liver disease develops.

HCV-related liver disease is now a leading cause of death in the HIV-infected population.

HIV/HCV coinfection increases the risk of HCC compared with HIV monoinfection but not with HCV monoinfection.

Available data suggest that ART favorably affects the course of HIV disease in HIV-infected patients, decreases mortality from liver disease, and should not be withheld from HIV/HCV-coinfected persons on account of potential toxicity.

The stage of hepatic fibrosis can help guide HCV treatment decisions in HIV/HCV patients. The incidence rate of hepatic decompensation events or death is higher in coinfected patients with more advanced fibrosis at the time of staging.

The timing of HCV therapy depends on the need for HIV treatment. HCV treatment should be considered first if liver disease is advanced and HIV infection is at an early stage. If HIV infection requires treatment, ART should be initiated first, and once the HIV infection is controlled, HCV therapy can be considered.

Given accelerated progression to end-stage liver disease among HIV/HCV-infected patients, treatment of chronic HCV infection should be considered in all coinfected patients who do not have decompensated cirrhosis or other contraindications. DAAs are currently the standard of care. Options include PRoD (paritaprevir [that is ritonavir-boosted], ombitasvir, and dasabuvir); ledipasvir and sofosbuvir; daclatasvir and sofosbuvir ± ribavirin; grazoprevir and elbasvir plus ribavirin; and velpatasvir and sofosbuvir. The main goals of treatment are viral eradication (i.e., sustained virologic response) and reduction in the risk of liver-related complications.

Drug-drug interaction is common in persons on DAAs. Therefore careful attention to drug-drug interactions is necessary before consideration of HCV therapy in persons with HCV/HIV coinfection (see Chapter 10 ).

Acute infection with HIV may manifest with hepatitis as part of a mononucleosis-like illness with fever, malaise, and myalgia; hepatosplenomegaly on physical examination; and elevations of serum aminotransferase and alkaline phosphatase (ALP) levels. This presentation is referred to as the acute retroviral syndrome.

Several other common viral infections can secondarily affect the liver and cause acute hepatitis. Adenovirus, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and varicella-zoster virus are rare causes of acute viral hepatitis in HIV-infected persons.

Hepatitis E virus (HEV) infection has been described in HIV-infected persons. HEV genotype 3–related chronic infection can lead to cirrhosis. The seroprevalence of HEV antibodies in those with HIV infection ranges from 1.5% to 29%. HEV infection needs to be excluded in patients with an acute hepatitis-like illness. HEV infection may also mimic drug-induced liver injury.

The designation MAC refers to infections caused by one of two nontuberculous mycobacterial species, either Mycobacterium avium or M. intracellulare.