St John's wort causes dangerous reduction in indinavir levels; implications for other HAART drugs too

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A popular herbal remedy being used as an anti-depressant has the potential to reduce blood levels of indinavir by 50-80%, according to research in HIV-negative volunteers. Researchers from the US National Institute of Allergy and Infectious Diseases warn that people taking indinavir as their sole protease inhibitor should avoid taking St John's Wort, and people taking other protease inhibitors (particularly saquinavir or nelfinavir alone) should also beware.

The researchers treated 8 HIV-negative volunteers with 300mg of St John's Wort three times daily for 14 days and then gave 800mg of indinavir three times a day for one day, followed by a final dose of 800mg of indinavir. Blood levels of indinavir were then tested and compared with blood levels that had been established prior to St John's Wort treatment.

On average, the total exposure to indinavir (AUC) had fallen by 57%, and the 8 hour trough level (the lowest level reached before the next dose) had fallen by an average of 81%.

Glossary

trough level

The lowest point to which levels of a drug fall in the blood between doses.

 

depression

A mental health problem causing long-lasting low mood that interferes with everyday life.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

When used as the sole protease inhibitor, indinavir is a very `fragile' drug, because the trough level declines to a point only slightly above the minimum required to inhibit HIV replication by 50%. Anything which reduces blood levels of indinavir in such a serious fashion is likely to provoke the emergence of resistance, or viral load rebound without resistance.

"I'd also be concerned about interactions with saquinavir or nelfinavir" said Prof. David Back of Liverpool University's HIV Pharmacology Unit. "To a lesser extent use with efavirenz is also a concern, although you have a greater margin of safety with that drug. I would be interested to see whether ritonavir would counteract the effect when dosed with saquinavir or indinavir".

In the past year it has become more common to dose indinavir with a drug that can slow down the metabolism of indinavir, such as ritonavir.

St John's Wort reduces indinavir levels dramatically because it is an inducer of the cytochrome p450 system, through which protease inhibitors and NNRTIs are metabolised.

St John's Wort has become popular in recent years as an anti-depressant following the publication of a meta-analysis of several studies which showed benefits compared with placebo in the treatment of depression. These studies are discussed in more detail in the Hypericin entry in Drugs used by people with HIV.

Reference

Piscitelli SC et al. Indinavir concentrations and St John's wort. The Lancet 355: 9203, Feb 12 2000.