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# HIV protease inhibitors (PIs)

They block HIV's scissors: without protease, viral proteins are not cut to size and new particles come out immature and non-infectious.

Updated 2026-11-01

## What they are

Peptide-like inhibitors of the HIV aspartyl protease: darunavir, atazanavir, lopinavir and ritonavir. They are almost always 'boosted' with ritonavir (or cobicistat), which slows their metabolism. They have a high genetic barrier and are used mainly in second-line treatment.

## Mechanism of action

HIV protease is a dimer with two catalytic aspartic acids that cuts the Gag and Gag-Pol polyproteins into their working parts. PIs mimic the cleavage point and occupy the active site competitively. Virus is still assembled, but it comes out immature and cannot infect other cells.

Target: HIV-1 aspartyl protease

## Key points

- Low-dose ritonavir inhibits CYP3A4 and 'boosts' the other PI, raising and prolonging its levels.
- Serious CYP3A interactions: simvastatin, lovastatin, certain antiarrhythmics and sedatives, ergot drugs, rifampicin, St John's wort.
- Metabolic effects: higher triglycerides and cholesterol, insulin resistance and fat redistribution.
- Atazanavir: indirect hyperbilirubinaemia (it inhibits UGT1A1) and kidney stones; it needs stomach acid.
- Darunavir has a sulfonamide group: caution with sulfa allergy.

## Drugs in this class

- [**Darunavir** A protease inhibitor with a high genetic barrier. Given boosted with ritonavir (or cobicistat) and with food; the… HIV-1 protease](https://durgical.com/en/pharmacology/darunavir/)
- [**Ritonavir** A protease inhibitor now used mainly as a 'booster': it blocks CYP3A4 and raises other PIs' levels. It has a great… HIV-1 protease](https://durgical.com/en/pharmacology/ritonavir/)
- [**Atazanavir** A once-daily PI. It causes benign jaundice from indirect bilirubin and needs stomach acid, so antacids and acid… HIV-1 protease](https://durgical.com/en/pharmacology/atazanavir/)
- [**Lopinavir/ritonavir** A fixed combination of lopinavir with ritonavir as booster. Widely used in children and second line; causes diarrhoea… HIV-1 protease](https://durgical.com/en/pharmacology/lopinavir-ritonavir/)

## Others in the class

- Cobicistat (booster without antiviral activity)
- Fosamprenavir
- Saquinavir
- Tipranavir

## Test yourself

Think of the answer, then tap the question to see it.

## What happens to a virion made in the presence of a PI?

It leaves the cell, but its Gag and Gag-Pol polyproteins are not cleaved: it stays immature and non-infectious.

## Why is ritonavir added to another PI?

As a booster: it inhibits CYP3A4, raising and prolonging the other PI's concentration.

## A patient on atazanavir is jaundiced with normal transaminases. What is the most likely explanation?

Benign indirect hyperbilirubinaemia: atazanavir inhibits UGT1A1, the enzyme that conjugates bilirubin.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 64 (McGraw Hill, 2023); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=J05AE) (WHO Collaborating Centre for Drug Statistics Methodology, 2026); [DailyMed - RITONAVIR tablet, film coated](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11f757f1-cf48-47a8-925e-918359cbd2d4) (DailyMed (U.S. National Library of Medicine), 2026).

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