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Hyperbilirubinemia and HIV Antiretroviral Treatment
  Written by Steven McGuire, with Allan W. Wolkoff, MD
Introduction by Jules Levin:
Reyataz, (also called atazanavir) was approved by the Food and Drug Admini-stration and became available in pharmacies a few months ago. It is a protease in-hibitor taken once-a-day that has not been found to raise cholesterol and triglyer-cides in studies; so far they have followed patients for up to 2 years. Similar findings appear to be observed with regards to glucose. There is also data on lipoatrophy in patients taking Reyataz. One study reports on median changes in lipoatrophy (fat loss) by objective testing from the large study comparing Reyataz plus AZT/3TC to efavirenz plus AZT/3TC, and after 1 year follow-up no body changes developed. Longer term followup is required for at least 2 years to better evaluate this question. This does not mean necessarily that some patients did not begin to develop some degree of fat loss. Secondly, in data submitted to the FDA for patients taking Reyataz or nelfinavir plus d4T or d4T/ddI about the same percent of patients developed lipoatrophy, 17%. You can read more details these studies, about Reyataz in general, and about antiviral effectiveness in studies comparing it to efavirenz in the just recently released NATAP HIV newsletter called “NATAP’s Positive+Information”. You can either download the newsletter in pdf or contact NATAP (1-888-26-NATAP; 212 219-0106) for a print copy to be mailed to you.
Click here to download the pdf of “NATAP’s Positive+Information” from the NATAP website.
Click here to download the new edition of NATAP’s “Hepatitis C Review” newsletter.
A side effect of Reyataz can be elevated indirect bilirubin. About 35% of treat-ment-naïve patients in studies of this drug experience >2.5 normal levels of bili-rubin. 5% of patients in studies experience jaundice (yellowing of skin), and 1% experience yellowing of the eyes. About 5% of patients experienced grade 4 ele-vations in bilirubin and modified dosing of Reyataz since that was required by the study protocol, but discontinuations due to jaundice in the studies were uncom-mon. So far in studies these bilirubin elevations appear not to cause any health consequences. Much greater elevations in bilirubin can be harmful but elevations of this magnitude have not been seen in the Reyataz studies. The bilirubin eleva-tions in these studies have not been observed to be associated with effects on the liver. This article is meant to explain this subject and to provide information and education about elevated bilirubin, which is measured by a simple blood test.
The article by begins here.
Changes in physical appearance have caused concern for people with HIV almost from the beginning of the epidemic. Some of these changes may be signs of real health prob-lems, while others may represent basically cosmetic issues. The jaundice that can be caused by a high level of bilirubin in the blood—a condition called hyperbilirubine-mia—may occur during treatment with certain HIV-related medications. However, only a fairly small percentage of people who experience hyperbilirubinemia from using HIV-related medications actually show signs of jaundice.
Bilirubin is a yellowish pigment that can be found in the bile, blood, and urine. It is the product of the breakdown of the hemoglobin in red blood cells, which carry the oxygen that nourishes all of the cells in the body. The liver removes bilirubin from the blood, processes it, and then secretes it into the digestive tract. An average person’s body pro-duces about 260 milligrams (mg) of bilirubin per day—approximately 0.0087 ounces. Your body disposes of almost 99 percent of this bilirubin in the feces, and the other 1 percent in the urine. The most common visible sign of a higher than normal bilirubin level is jaundice—a yellowish coloring of the skin or the whites of the eyes.
An elevated level of bilirubin in the blood may indicate liver disease or drug-induced liver damage. At the same time, however, many cases of hyperbilirubinemia are be-nign—meaning that the elevated bilirubin level is a sign and does not mean you have a dis-ease.
The only adults who develop a high indirect (unconjugated) bilirubin levels on Reyataz are those who genetically lack or are deficient in the enzyme causing inhibition of UDPglucuronosyl transferase (UGT) which is needed to conjugate bilirubin (direct bili-rubin). This hyperbilirubinemia is reversible upon discontinuation of Reyataz.
Crixivan (indinavir), another protease inhibitor is also associated with high bilirubin. The bilirubin may go as high as 20 mg/dL but it is not causing the body harm when it is only the indirect bilirubin itself that is elevated and all other lab tests are normal. The bilirubin is usually monitored along with other liver function enzymes and complete blood counts as part of routine care. When bilirubin is abnormal along with other abnormal lab tests, it may mean there is a liver or gallbladder problem or a blood disorder.
So, usually the real side effect of hyperbilirubinemia is the cosmetic effect of jaundice. . In studies conducted there has been no evidence of liver-related toxicity associated with elevated bilirubin due to Reyataz.
The Food and Drug Administration (FDA) said in their review of Reyataz that Grade 3 - 4 elevations in bilirubin were rarely associated with any Grade 3 - 4 elevations in ALT or AST in studies; only 10 patients out of 660 in 3 large studies (034, 043, and 045) had both Grade 3 - 4 ALT or AST and Grade 3 - 4 total bilirubin elevations. Of these 10 patients, 5 reported hepatitis B/C at baseline, and 6 patients had concurrent Grade 3 - 4 transaminase and total bilirubin elevations. There was no evidence that these elevations in bilirubin were associated with a hepatotoxic process.
For patients with hepatitis C or B there appears to be no indication from studies con-ducted to date that elevated bilirubin was associated with toxicities or other serious side ef-fects.
Testing for bilirubin Bilirubin circulates in the bloodstream in two forms:
  • Indirect (or unconjugated) bilirubin does not dissolve in water. When indirect bilirubin reaches the liver, the liver changes it into a water-soluble form.
  • After the liver has changed indirect bilirubin into the water-soluble form, it is called direct or conjugated bilirubin.

The most obvious sign of high bilirubin levels is jaundice. Jaundice can result from the buildup of bilirubin in the blood and skin from liver disease (hepatitis), blood disorders (hemolytic anemia), or blockage of the tubes (bile ducts) that carry bile from the liver to the small intestine.
A test for bilirubin uses a sample of blood taken from a vein in the arm, just as with any typical blood test. The bilirubin test is used to:
  • Evaluate liver function and monitor the development of liver disease (such as hepatitis or cirrhosis) or the effects of medications that can affect the liver.
  • Help determine if the bile ducts are blocked.
  • Diagnose conditions that cause increased destruction of red blood cells (a condition called hemolysis), such as hemolytic anemia or hemolytic disease of the newborn.
  • Determine whether newborn infants with jaundice need treatment.

Results of your bilirubin test The values that are considered normal bilirubin levels can vary, depending on the lab that performs the test. The following are the bilirubin levels that are typically considered normal for adults:
  • Total bilirubin: 0.3–1.0 milligram per deciliter (mg/dL). (A deciliter is one-tenth of a liter, which is slightly larger than a quart.)
  • Direct bilirubin: 0.1–0.3 mg/dL
  • Indirect bilirubin: 0.2–0.7 mg/dL.

High levels of bilirubin in the blood occur for one of two reasons:
  • Either your system is producing too much bilirubin,
  • Or your liver is not eliminating enough bilirubin.

Some infections (such as an infected gallbladder, called cholecystitis) or certain inherited enzyme deficiencies can cause decreased elimination of bilirubin. Gilbert’s syndrome, an inherited condition that affects how the liver processes bilirubin, is a common cause of hyperbilirubinemia. Some people with Gilbert’s syndrome may experience jaundice, but the condition does not appear to be harmful or of serious consequence. Individuals with Gilbert’s have the same enzyme deficiency that is associated with the development of hyperbilirubinemia on Reyataz.
Decreased elimination of bilirubin can also result from liver damage (caused, for example, by hepatitis or cirrhosis) or blockage of the bile ducts (for example, because of gallstones or pancreatic cancer).
Rapid destruction of red blood cells in the blood—which can result from disorders such as sickle cell disease or an allergic reaction to blood from a transfusion—can be another cause of hyperbilirubinemia.
The levels of both direct and indirect bilirubin can help your doctor determine what is causing your hyperbilirubinemia:
  • Excessive breakdown of red blood cells increases indirect more than direct bilirubin levels.
  • Blockage of the bile ducts tends to increase the amount of direct more than in-direct bilirubin.

A variety of lifestyle and medical factors can affect the results of your bilirubin test:
  • Many medications can affect blood bilirubin levels either by affecting the liver directly or by interfering with the test method used to measure bilirubin. Drugs that may increase bilirubin levels include many antibiotics, some types of birth control pills, the anti-inflammatory indomethacin (Indocin), the epi-leptic drug phenytoin (Dilantin), the tranquilizer diazepam (Valium), and the sleep aid flurazepam (Dalmane).
  • Certain medications can lower bilirubin levels. These include vitamin C, the sedative phenobarbital (Nembutal), and the asthma treatment theophylline (Elixophyllin).
  • Caffeine can lower bilirubin levels.
  • Not eating for a long time (fasting) normally raises the level of indirect biliru-bin.

HIV medications and hyperbilirubinemia Because so many antiretrovirals (ARVs) and drugs used to treat HIV-related conditions are metabolized by the liver, some of those drugs can harm the liver. When liver injury occurs, the liver enzymes (see sidebar) and bilirubin can show higher than normal values when a lab tests your blood for them.
Antiretrovirals. According to one retrospective study, 10 percent of patients on ARV therapy experienced severe liver toxicity (along with hyperbilirubinemia)—no matter which ARV regimen they were using. In particular, patients taking therapy that includes the non-nucleoside reverse transcriptase inhibitor nevirapine had a relatively high risk of experiencing increases in liver enzymes and bilirubin several times above the upper limit of normal: 9.4 percent. Most of these increases occurred during the first four weeks of treatment. The use of other ARVs can result in elevations in liver enzymes above the up-per limit of normal: full dose ritonavir, but full dose is hardly used any more, as low rito-navir dosing is now used to boost the levels of other protease inhibitors; d4T; most prote-ase inhibitors and NNRTIs can result in increases in liver enzymes above normal levels. Patients with hepatitis B or C are more likely to experience increases of liver enzymes on ARV therapy.
On the other hand, two protease inhibitors (PIs) have been particularly associated with elevated bilirubin levels, though not with any evidence of serious liver toxicity:
  • Indinavir. Indinavir, one of the first PIs to be approved, has long been associ-ated with elevated bilirubin levels. Studies have shown that approximately 12–14 percent of patients taking the standard dose of indinavir experience hy-perbilirubinemia of ≥2.5 mg/dL, which is 2.5 times the upper level of normal. These bilirubin increases due to indinavir are infrequently (<1%) associated with increases in liver enzymes.
  • Atazanavir. Another recently approved PI, atazanavir, has also shown mildly elevated bilirubin levels in 35 percent of participants in clinical trials and the drug’s expanded access program. These elevations are asymptomatic and have not shown any correlation with hepatotoxicity. About 5–6 percent showed signs of jaundice, and 1 percent yellowing of the eyes (called scleral icterus). Fewer than 1 percent discontinued use of atazanavir due to hyperbilirubine-mia. Hyperbilirubinemia can be reversed by discontinuing atazanavir.

The hyperbilirubinemia that can occur when using indinavir or atazanavir is similar to that of the inherited condition called Gilbert’s syndrome, which can affect as much as 10 percent of some Caucasian population groups. People with Gilbert’s syndrome have a defect in how their livers process bilirubin. This means that they do not break down and excrete bilirubin in the normal way. Your doctor can request a blood test from the labo-ratory for you to test for Gilbert’s syndrome before prescribing Reyataz.
The one significant symptom of hyperbilirubinemia of this type is jaundice, although most people with the syndrome never experience that. This jaundice may come and go throughout the life of a person with Gilbert’s syndrome. However, health problems or disease processes have not been shown to be associated with either the hyperbilirubine-mia or the jaundice that may come with Gilbert’s syndrome.
Researchers and clinicians have not identified clinical manifestations of serious conse-quence resulting from the bilirubin increases associated with ARVs like indinavir and atazanavir. Extremely high indirect bilirubin levels—for example, 25 times the upper level of normal—may cause a type of encephalopathy. However, that has not been seen at all with atazanavir or any of the other drugs. Nor have clinicians seen it in practice in pa-tients who have chronic or even acute hepatitis.
HIV-related medications. A number of other medications commonly used to treat HIV-related conditions have shown marked effects on the liver in some patients, bringing the possibility of hyperbilirubinemia. These medications include:
  • Amphotericin B, used to treat serious fungal infections, like cryptococcal meningitis.
  • Dapsone, an antibiotic sometimes used to prevent and treat pneumocystis pneumonia.
  • Isoniazid, used to treat tuberculosis (TB).
  • Ketoconazole, used to treat a broad range of fungal infections, including can-didiasis.
  • Pyrazinamide, used to treat TB.
  • Rifampin, used to treat TB.
  • Sulfonamide, a type of antibiotic that is part of the drug TMP/SMX com-monly used to prevent and treat pneumocystis pneumonia.
  • Taxol, an anticancer drug that is sometimes used to treat Kaposi’s sarcoma.

People who use these medicines should make sure that their health care providers do regular checks of their bilirubin and liver enzyme levels.
A concern but no cause for alarm People living with HIV have more reason than most others to be concerned about the health of their liver, largely because so many HIV-related medications are processed by the liver and have some potential to cause adverse effects on it. In addition, a significant number of HIV-positive individuals are dealing with one or more of the types of hepatitis. This, of course, means that anyone on an antiretroviral regimen should be sure that her or his liver enzymes and bilirubin levels—the standard indicators of the liver’s health—are tested regularly.
Higher than normal bilirubin levels in the blood—hyperbilirubinemia—tend to occur with two anti-HIV drugs in particular: the protease inhibitors indinavir and atazanavir. But even in those individuals who do experience hyperbilirubinemia, only a small percentage show signs of jaundice, such as a yellow coloration of the skin or whites of the eyes.
Disturbing as jaundice may seem, researchers and clinicians have found no association between the hyperbilirubinemia that causes it in some people using these PIs and health problems or disease processes. In other words, so far in following patients taking these drugs in studies it has not been observed that the high blood level of bilirubin that may occur appear to pose a health threat. And the jaundice that a small percentage of indi-viduals may experience represents a cosmetic, rather than a health, issue. In fact, some practitioners may even suggest that spending a little time in the sun can help diminish the appearance of jaundice. However, if you should develop jaundice as a result of taking antiretroviral therapy, you should consult with your health care provider about what, if anything, you should do about it.
Your Liver
What your liver does for you
Because the liver and its health play such a central role in processing bilirubin, under-standing how the liver works is important to understanding what bilirubin levels may mean to your overall health.
The liver is the largest organ in the abdomen and is located in its upper-right area, just above the bottom of your rib cage. The liver performs a range of vital jobs to keep your body working at its best:
Digestion. The liver helps to process the food you eat. After the stomach and intestines have broken food down into small particles that are absorbed by the bloodstream, these small particles go to the liver for processing, or “metabolizing,” into even smaller parti-cles. Then the liver converts the particles into the basic building blocks needed for all of your body’s activities.
The liver uses some foods right away for energy needed by the rest of your body’s or-gans, muscles, and other tissues. Other foods it stores as fats that it can later convert into energy. In other words, the liver makes it possible for your body to have a continuous supply of energy without your having to eat continuously.
Waste disposal. The liver disposes of many substances to help keep you healthy. These include the waste products of your body’s different processes, toxins like alcohol, and medicines.
One of these natural waste products is bilirubin. Most of your body’s cells are constantly being replaced, and red blood cells are among the most important. Red blood cells live about 120 days before they need to be replaced. When a red blood cell wears out, the he-moglobin inside it is broken down into bilirubin, and the bloodstream carries the bilirubin to the liver. The liver takes the bilirubin, processes it for disposal, and sends it to the in-testines through the same bile ducts that carry bile to the intestines to dissolve fat. The bilirubin then goes on to become part of a bowel movement.
Another natural waste product that your liver gets rid of is ammonia. Cells make tiny amounts of ammonia as part of their life cycle. Your liver gets rid of this ammonia right away because it is toxic.
Detoxification. One definition of “toxin” is anything that the body does not need for nourishment or that is potentially harmful to it. Even the ammonia mentioned above can be considered a toxin. Generally, however, “toxin” refers to a foreign substance.
The liver detoxifies your bloodstream, meaning that it gets rid of any toxins in it. The liver does this the same way it metabolizes (processes) food—by breaking down the toxins into smaller particles. These particles are then in a form that is either less harmful or that your body can get rid of more easily.
The liver eliminates some medicines using the same mechanisms it uses to break down foods and toxins. Once the liver has processed the medicine, the body has two ways to get rid of the waste:
  • The liver can dispose of the processed medicine in the bile.
  • The liver can send the medicine back into the blood so that the kidneys can get rid of it in the urine.

Vital products of the liver. The liver makes many other proteins that are critical to keeping your body parts in balance, for example:
  • The liver manufactures clotting factors, also called clotting proteins, to help make your blood thicken and coagulate so that bleeding stops.
  • Albumin is another vital protein made by the liver. One of albumin’s functions is to prevent water from leaking out of the blood and into your tissues. With severe liver disease, the liver sometimes cannot make enough albumin, causing parts of the body—often the hands and the feet—to swell up with extra fluid.

Testing the liver Liver function tests are one of the main ways by which doctors can determine the health of your liver. The liver function tests discussed below can be performed at the same time.
The total protein test measures the amount of proteins in the bloodstream. Your doctor may want a total protein test to help diagnose kidney or liver disease, cancers of the blood, malnutrition, or abnormal swelling.
Globulins are proteins made by the liver and the immune system to help fight infections. Globulins are often high in liver disease.
Albumin is a protein made by the liver to help maintain the amount of blood in your veins and arteries. When there is serious liver damage, the liver cannot produce albumin.
Prothrombin is a protein made in the liver that helps blood clot. A prothrombin time test measures how long it takes your blood to clot. A longer than normal prothrombin time can be a risk for excess bleeding and can be caused by serious liver disease, lack of vitamin K, blood-thinning medication, or bleeding disorders.
The liver manufactures the enzymes ALT (alanine aminotransferase) and AST (aspartate aminotransferase) to metabolize amino acids and to make proteins. When the liver is damaged, ALT and AST leak out into the bloodstream. This can be caused by hepatitis, alcoholic liver disease, liver inflammation from medications, fatty liver, liver tumors, or heart failure.
GGT (gamma glutamyltransferase) and ALP (alkaline phosphatase) are cholestatic liver enzymes. Cholestasis means a partial or complete blockage of bile flow. Under this cir-cumstance, GGT or ALP can back up and leak out of the liver and into the bloodstream.
With liver damage, conjugated bilirubin can leak out of the liver and into the blood-stream. A buildup of bilirubin can cause jaundice, darker urine, and light-colored stools. Causes of abnormal bilirubin levels include: hepatitis, blocked bile ducts, other liver dis-eases, or scarring of the liver (cirrhosis). Sometimes a high bilirubin level will not be a sign of any underlying disease process.
Steven McGuire is a Chicago-based writer and consultant specializing in medicine, public policy, and nonprofit issues. Allan W. Wolkoff, MD, is professor of medicine at the Albert Einstein College of Medicine in New York City.
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