| Conditions: |
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Liver Fibrosis |
| Purpose: |
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This study will provide a basis for research on the impact of liver injury caused by
antiretroviral therapy in HIV-infected patients. Elevated liver enzymes called AST and ALT
are common in HIV-infected patients taking antiretroviral medications and can indicate liver
damage. Although there are a number of possible causes for these elevations, such as
infections with a hepatitis virus, antiretroviral medications alone can lead to the
elevations. The study will focus particularly on evidence of liver fibrosis, which is a sign
of progressive liver damage.
HIV-infected patients 18 and older who 1) have been taking combination antiretroviral
therapy for at least 12 months and have been on a stable regimen for at least 3 months, and
2) have had elevated AST or ALT levels for at least 6 months may be eligible for this study.
Patients who have had liver biopsies performed in the past may be eligible for
participation.
Participants undergo the following tests and procedures over a 12-month period:
- Oral glucose tolerance test: The patient drinks a glucose (sugar) drink. Blood samples
are then drawn over 2 hours through an intravenous (IV) line in the patient's arm. This
test measures how high the patient's blood sugar and insulin levels rise after drinking
a standard glucose load.
- Transient elastography: This ultrasound test uses vibration (sound waves) to measure
liver stiffness (fibrosis). Vibrations move faster through a fibrotic liver.
- Triple-phase CT scan and single slice CT scan of L4-5: Patients fast for 4 hours before
the CT scan. A contrast material is injected through a catheter placed in an arm vein
to improve the visibility of the liver in the specialized X-ray images obtained in the
CT scanner.
- Liver biopsy: This test removes a small sample of liver tissue for microscopic
examination, particularly for evidence of fibrosis. The skin over the biopsy site is
numbed and a needle is passed through the skin and rapidly in and out of the liver.
Patients may be given a sedative for the procedure.
- Follow-up visits. Patients return for follow-up visits 1 to 4 weeks after the liver
biopsy and three more times over the course of the study for a medical history,
physical examination and blood tests.
Patients may participate in an additional 4-year follow-up, during which they have visits
every 3-12 months and are offered the opportunity to repeat the biopsy no sooner than 1 year
after the first biopsy.
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| Study Summary: |
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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 triple-phase computed tomography and transient elastography
(an ultrasonic technique), will be assessed for their ability to predict fibrosis.
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.
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| Criteria: |
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- 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.
Individuals who have had a previous liver biopsy to evaluate chronically elevated
transaminases on antiretroviral therapy may be allowed participation. (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 (i.e., ASMA, anti-SLA, or anti-LKM-1
positive).
Known or suspected biliary diseases, such as primary biliary cirrhosis (i.e.,
positive AMA) and sclerosing cholangitis (i.e., positive p-ANCA).
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).
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.
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| NCT ID: |
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NCT00326482 |
| Primary Contact: |
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Principal Investigator
Caryn G Morse, M.D.
National Institutes of Health Clinical Center (CC)
Mary McLaughlin, R.N.
Phone: (301) 435-8001
Email: mmclaughlin@niaid.nih.gov
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| Backup Contact: |
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Email: cmorse@niaid.nih.gov
Caryn G Morse, M.D.
Phone: (301) 496-9320
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| Location Contact: |
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Bethesda, Maryland 20892
United States
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222
Email: prpl@mail.cc.nih.gov
Site Status: Recruiting |