New NNRTI halted for safety check

Keith Alcorn
Estimated reading time 2 minutes
This article is more than 24 years old.

A non-nucleoside reverse transcriptase inhibitor (NNRTI) called capravirine has been pulled from clinical studies pending safety checks, following the discovery that the drug caused vasculitis (inflammation of blood vessels) in dogs. Vasculitis may cause severe damage to the tissues supplied by inflamed blood vessels, because blood cannot reach the tissues.

So far, no cases of vasculitis have been reported in people taking capravirine, but the US Food and Drug Administration has ordered Agouron/Pfizer to stop several studies of the drug until safety checks can be carried out on all patients receiving the drug. These studies inlcude protocol 504, which has already recruited treatment-naive patients in the UK. However, patients currently receiving capravirine in study 509 who have undetectable viral load will be allowed to continue taking the drug if they wish. This study is comparing background therapy with two nucleoside analogues with or without capravirine in NNRTI-experienced individuals. This study is also recruiting patients in the UK.

If capravirine is found to have unacceptable toxicities, it will remove the only salvage option in this class of drugs for NNRTI-experienced individuals on the near horizon, and bring into sharp focus the need for careful use of NNRTIs in clinical practice in order to maximise the utility of this class of drugs. Failure of one NNRTI leads to cross-resistance to all currently available NNRTIs, and even capravirine is likely to be active only against viruses with resistance to efavirenz. Resistance to nevirapine (usually characterised by a mutation at codon Y181C) would render capravirine useless.

Glossary

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

treatment-naive

A person who has never taken treatment for a condition.

cross resistance

The mechanism by which a virus that has developed resistance to one drug may also be resistant to other drugs from the same class. 

 

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

immune response

The immune response is how your body recognises and defends itself against bacteria, viruses and substances that appear foreign and harmful, and even dysfunctional cells.

For Agouron-Pfizer, this is a depressing development. The company had to scrap development of new protease inhibitor, AG-1776, last year, and a large clinical endpoint study of Remune, the therapeutic vaccine being developed in partnership with Immune Response Corporation, showed no benefit in a controversial study published in the New England Journal of Medicine last year.

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