Increased bilirubin and jaundice (yellow skin and eyes)

Bilirubin is an orange waste product; Hyper = increased; aemia = ‘in blood’

Associated drugs: atazanavir (Reyataz); Evotaz (atazanavir+cobicistat); indinavir (Crixivan, no longer used).

An increase in bilirubin (called hyperbilirubinaemia) is a common side effect of atazanavir. More than 50% of people who use this protease inhibitor will show increases in a laboratory test, especially when boosted by ritonavir (Norvir) or cobicistat (Tybost).

Small increases are not causing any damage to your body. If levels reach higher than five times the upper range for normal, this is usually the time to change or modify treatment.

These increases are usually mild and less than 10% of people switch to an alternative drug.

When symptoms are noticable, this includes your skin, or the white of the eyes being more yellow. Many people like it because it can look like a light sun tan.

Indinavir can also increase bilirubin, though this drug is rarely used.

What is bilirubin?

Bilirubin is an orange-yellow part of bile. Bile is the bright green fluid secreted by the liver to help digestion.

Bilirubin is mainly formed by the normal breakdown of haemoglobin (the protein in red blood cells that transport oxygen).

Bilirubin normally passes through the liver. It is then excreted as bile through the intestines.

When this process is interrupted, excess bilirubin stains other body tissues yellow. Fatty tissues like skin, eye tissue and blood vessels are most affected.

Two types of bilirubin

There are two types of bilirubin in the blood.

1. Unconjugated (indirect) bilirubin is insoluble in water. This is the bilirubin before it reaches the liver
2. Conjugated (direct) bilirubin has been converted to soluble bilirubin in the liver.  It then goes into the bile to be stored in the gall bladder or sent to the intestines.

Routine blood tests for total bilirubin measure both unconjugated and conjugated bilirubin.

Increases in bilirubin with atazanavir are of unconjugated bilirubin. This is very common with atazanavir.

People who have lower levels of the enzymes responsible for converting bilirubin in the liver will be at a higher risk of increases in bilirubin from atazanavir. This has been linked to genetic factors.

Increases in congugated bilirubin are linked with a range of illnesses and conditions. This includes jaundice associated with hepatitis and cirrhosis, anaemia, Gilbert’s disease and sickle cell disease. Jaundice is common in babies. Very high levels in babies can cause permanent damage.

Normal bilirubin levels and when to change

Normal values might vary between different labs but are within the following ranges.

• Total bilirubin      3 to 17 mmol/L.
• Direct bilirubin     0 to 3 mmol/L.

Jaundice only becomes visible at levels above 40 mmol/L. You need good natural light to see this.

Atazanavir, and the booster are not usually changed (including the doses) unless bilirubin levels increase to five times the upper limit of normal (5xULN). This is at around 60-70 nmol/L.

This yellowish skin can look unusual. When related to atazanavir though it is not causing your body damage.

Less than 10% of people using atazanavir discontinue because of jaundice. If you stop atazanavir, the jaundice reverses within a couple of days.

Using the booster

Just like other protease inhibitors, atazanavir usually needs to be boosted – by ritonavir or cobicistat.

• The booster increases atazanavir levels by around ten times and makes levels more consistent.
• Higher levels of atazanavir at the end of the dose reduces the risk of resistance and might make the drug more active.
• Higher levels also increase the chance of increasing bilirubin.

Key points

• When related to atazanavir, higher billirubin is not damaging your body
• If this is too disturbing then it often disappears by using higher dose atazanavir without a booster.
• Check atazanavir levels with TDM.

Individualising dosing

Some people can use atazanavir without a booster.

High levels of bilirubin might be a marker of high levels of atazanavir. You can’t guess this though–you need to use a test called TDM (see Side Effects and Drug Levels).

In practice, people who get yellow skin or eyes when they use 300 mg/day atazanavir with a booster can often change to unboosted atazanavir (at 400 mg/day). Note that the daily unboosted dose of atazanavir (2 x 200 mg) is a higher dose than the boosted dose (1 x 300 mg capsule).

It is important that your doctor changes the formulation if you don’t use a booster..

Atazanavir is available in four strengths: 100, 150, 200 and 300 mg. This means the dose can be easily adjusted to manage high bilirubin. It is also available as a powder.

Other drugs that affect bilirubin

Other drugs can also increase bilirubin levels. These include anabolic steroids, some antibiotics, anti-malaria drugs, codeine, diuretics, morphine, oral contraceptives, rifampin and sulfonamides.

Drugs that can decrease bilirubin measurements include barbiturates, caffeine and penicillin.

Last updated: 1 March 2023.