Protease inhibitors

In contrast to AZT and similar molecules, the protease inhibitors inhibit maturation of HIV proteins. They inhibit a viral enzyme (protease) that cleaves viral protein precursors into their separate components. Protease inhibitors have the disadvantage that a large number of pills have to be taken. There are numerous side-effects. Multiple interactions with other drugs are possible. Lipodystrophia with redistribution of body fat, hypercholesterolaemia, hypertriglyceridaemie and diabetes mellitus can occur. Insulin resistance may occur due to the blockade of certain cellular saccharide transport molecules (glucose transporter 4). There is evidence that protease inhibitors such as indinavir and saquinavir inhibit the development of Kaposi's sarcoma, not only because of their antiviral effect but also by direct interference with the angiogenesis in the tumour.

• Saquinavir (Invirase®, Fortovase®). Invirase® is poorly absorbed from the gastrointestinal tract (bioavailability about 4%). Boosting with ritonavir raises the blood level of saquinavir. Ingestion together with grapefruit juice considerably increases the absorption (see also cytochrome P450). An alternative is Fortovase® 1000 mg twice daily, each time with 100 mg ritonavir as a booster. Fortovase® can be kept for up to 3 months without refrigeration. Invirase 500 mg tablets are expected to become available soon.

• Ritonavir (Norvir®). This is very potent antiviral product, but is frequently poorly tolerated due to gastrointestinal side-effects. Nausea and perioral paraesthesias are frequent. Ritonavir needs to be given only twice per day, preferably with meals. The syrup contains 40% alcohol. The bitter taste can be masked by mixing it with chocolate milk. It is a potent cytochrome P450 (CYP3A4) inhibitor, both in the intestinal wall and liver. This is the most important enzyme for the metabolism of protease inhibitors. There is a substantial first-pass metabolism. There are many interactions with other medications, including, among others, saquinavir and indinavir, so that the dose of these latter substances can be reduced (inhibition of breakdown). It is at present mainly used for its “booster effect” and not so much for its direct antiviral effect. Kaletra® (see further ) is an example of this.

• Indinavir (Crixivan®). This substance is usually tolerated quite well, though 3 doses each of 800 mg (if without Norvir®) are required per day. It should be taken away from meals. Indinavir penetrates into the cerebrospinal fluid and should also play a part in the prevention of AIDS dementia (HIV-encephalopathy). There are many interactions with other medications. If St John’s wort is taken at the same time the blood level falls by 80%. Kidney stones, renal insufficiency and haemolytic anaemia can occur. It is advisable to drink plenty of fluid when taking Crixivan®.

• Nelfinavir (Viracept®). The 250 mg tablets are initially taken in a dose of 750 mg three times a day. Undesirable side-effects of nelfinavir mesylate include gastrointestinal disorders such as diarrhoea. Monitoring liver function is advised. Easier regimens such as five 250 mg tablets twice per day, have been subsequently worked out. Introduction of 625 mg tablets is expected.

• Amprenavir (Agenerase®). This drug is best used in combination with ritonavir. In this way, a reduced number of tablets can be taken (600 mg twice per day instead of 8 x 150 mg capsules twice per day).

• Lopinavir/ritonavir (Kaletra®). Lopinavir is a protease inhibitor. The compound has been marketed in a fixed combination with ritonavir (both drugs in one tablet: Kaletra®). Ritonavir is not actually used here as an antiviral agent as such, but serves to raise the plasma concentration of lopinavir via inhibition of breakdown of the latter. Kaletra® can be kept unrefrigerated for only one month.

• Atazanavir (Reyataz®, earlier name Zrivada). Atazanavir is a novel protease inhibitor that needs to be given only once per day (400 mg). The medicament does not cause any hyperlipidaemia, in contrast to other drugs of the same class. Hyperbilirubinaemia can occasionally occur (without liver function disturbances).

• Tipranavir. Tipranavir is very promising as it shows no cross-resistance with the first protease inhibitors. It is a potent and non-peptidic HIV-1 protease inhibitor, the first of its kind. It can be "boosted" by subtherapeutic levels of ritonavir (e.g. TPV/r 500/200 mg twice per day). The most common side effects are gastrointestinal disturbances (diarrhoea, nausea, vomiting).

Category: Medical Subject Notes , Medicine Notes