Liver Fibrosis in HIV-Infected Patients With Elevated Liver Enzymes on Antiretroviral Therapy

At present, there are no clear guidelines as to when antiretroviral therapy for human
immunodeficiency virus (HIV) infection should be stopped in the setting of elevated liver
enzymes. In large part, this is due to a limited understanding of the natural history of
antiretroviral-related hepatotoxicity. Although several antiretrovirals have been reported to
cause fatal acute hepatitis, more often they cause an asymptomatic elevation in transaminase
levels, the optimal management of which is uncertain. This pilot study seeks to create a
foundation for research on the impact of antiretroviral-induced liver injury by providing an
estimate of the prevalence of hepatic fibrosis in a cohort of sixty HIV-infected patients who
have chronically elevated transaminases while on antiretroviral therapy in the absence of
chronic hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens will be evaluated
for fibrosis by microscopic examination, the current gold standard for assessing the nature
and severity of liver disease.[1] The presence of fibrosis, as well as other histopathology,
will be described using a validated scoring system. Primarily, this will be a crosssectional
study, but subjects will be offered the opportunity to participate in an extended follow-up
period and undergo another liver biopsy. Individuals will not be excluded on the basis of
alcohol abuse, insulin resistance, or lipodystrophy, but data will be collected on these
potentially confounding variables. Noninvasive measures, such as transient elastography (an
ultrasonic technique), will be assessed for their ability to predict fibrosis in this
population. Correlations will also be sought with laboratory markers of fibrosis. The
identification of fibrosis (and its precursors) in association with antiretroviral therapy
may be very clinically relevant as it may slowly regress with cessation of the causal
agent(s). If the causal agent is continued, however, cirrhosis may develop, the reversal of
which is thought to be rare.

- INCLUSION CRITERIA:

Age 18 years or older.

Ability to understand and willingness to provide written informed consent.

Willingness to undergo liver biopsy.

Willingness to comply with study requirements and procedures including storage of blood and
liver tissue samples for use in future studies of HIV, AIDS, immune function, hepatic
diseases, or other related diseases.

Established HIV diagnosis (documentation of HIV-1 infection by licensed ELISA testing and
confirmed by Western Blot).

For the antiretroviral cohort on combination antiretroviral therapy for at least 12 months
with stable regimen for at least 3 months prior to enrollment.

Chronically elevated transaminases for at least 6 months documented by an elevated AST
and/or ALT on the following 3 occasions within the 12 months prior to enrollment:

1. Screening;

2. Less than 6 months (24 weeks) prior to enrollment (distinct from screening);

3. More than 6 months prior to enrollment.

Note: Occasions must be at least 8 weeks apart.

Specific screening lab criteria:

- AST and/or ALT greater than upper limit of normal;

- Absolute neutrophil count greater than 750/mm(3);

- PT/PTT within normal range;

- Platelets greater than 50,000/uL;

- Hemoglobin greater than or equal to 10 mg/dL;

- Creatinine less than or equal to 2.0 mg/dL;

- Negative serum or urine pregnancy test for females of childbearing potential.

Willingness to avoid medications that contain aspirin for 7 days PRIOR to liver biopsy
and nonsteroidal anti-inflammatory drugs for 3 days PRIOR to liver biopsy.

Willingness to avoid medications that contain aspirin for a week AFTER liver biopsy.

Willingness to avoid other medications or herbal supplements (e.g., gingko biloba)
which may increase the risk of bleeding before and after liver biopsy, as directed by
the study team.

Willingness to restrict activity for 72 hours after liver biopsy.

Have a primary care physician.

HIV monoinfected individuals who have had a previous liver biopsy to evaluate
chronically elevated transaminases on antiretroviral therapy or for another indication
may be allowed to enroll in the study for the purposes of obtaining additional
information on predictors of liver disease and to observe the natural history. In such
instances, investigators will attempt to access this tissue for review.

EXCLUSION CRITERIA:

Chronic hepatitis B infection (defined as positive HBsAg or hepatitis B viral load
greater than 10,000 copies/ml).

Hepatitis C infection (defined as positive HCV viral load) or history of treatment for
chronic hepatitis C.

Acute Hepatitis A infection (defined as HAV IgM positive).

Suspected rhabdomyolysis (e.g., markedly elevated AST with elevated CPK).

Known or suspected autoimmune hepatitis.

Known or suspected biliary diseases, such as primary biliary cirrhosis or sclerosing
cholangitis.

Known or suspected Wilson's disease, alpha-1-antitrypsin deficiency, celiac disease.

History of primary hemochromatosis, glycogen storage disease, amyloidosis, or cystic
fibrosis.

Clinical evidence of decompensated liver disease (e.g., jaundice, ascites, esophageal
varices, or hepatic encephalopathy).

Active clinical pancreatitis.

Chronic renal disease.

Morbid obesity (BMI greater than or equal to 40), if judged to be a contradiction to
percutaneous liver biopsy

AFP greater than or equal to 100 ng/mL.

Hepatoma or hepatocellular carcinoma.

Pregnancy.

Active opportunistic infection (except oral thrush) or neoplasm (except Kaposi's
sarcoma, skin cancer, or cancer of the cervix or anus, unless known or suspected liver
metastasis).

Severe psychiatric disorder that would interfere with adherence to protocol
requirements. Individuals who have a stable psychiatric condition may be eligible.

Decompensated cardiac or pulmonary disease limiting physical activity (e.g., New York
Heart Association Heart Failure Class 2 or higher).

History of unexplained bleeding.

Allergy to lidocaine.

Current use or a history of treatment with interleukin-2, interferon-alpha or other
investigational agent(s) within 6 months of protocol screening. However,
antiretroviral medication obtained through expanded access programs are permitted.

Current use or a history of treatment with a systemic corticosteroid,
immunosuppressive or cytotoxic agent within 90 days of protocol screening. However,
volunteers receiving no more than one day of corticosteroid therapy in the 90 days
prior to screening will be eligible.

Any medical condition for which an investigator believes liver biopsy may be
contraindicated.