In the last issue, we took a look at the nucleoside analogue ‘backbone’ of anti-HIV treatment, but a strong backbone is only part of the story – it needs something to hold up. This Backgrounder looks at the protease inhibitor class of drugs.

Successful anti-HIV therapy typically requires combining at least three different drugs from at least two different drug classes. For most people, that means taking either a protease inhibitor or a non-nucleoside in combination with two nucleoside drugs.

The arrival of protease inhibitors in the mid-1990s – the ‘protease moment’, as it’s known – was a turning point in HIV medicine. For the first time, it became possible to combine different drugs which targeted the replication of the virus at different stages in its life cycle, something which quickly became known as ‘cocktail’ or ‘combination’ therapy, and which today we refer to as HAART – Highly Active Antiretroviral Therapy.

To say that HAART has changed the treatments outlook for people living with HIV (at least those of us who live in a part of the world where treatments are available) is something of an understatement. But while protease inhibitors are very effective in combating HIV, they have some side effects and have been linked to long-term toxicities. And, as with other drugs, resistance and cross-resistance can mean that not all protease inhibitors will work effectively in a particular individual.

To choose the right PI for the job, you and your doctor need to take account of the differences between the various drugs on offer and your individual situation.

How they work

PIs work by chemically inhibiting (blocking the action of) an enzyme called protease which HIV uses to break up large proteins into smaller pieces as part of its reproductive cycle. The protease enzyme is critical to a stage in the HIV cycle called cleavage where the protein building blocks of new viral particles are prepared.

By interfering with this stage of the process, PIs cause the infected cell to produce defective copies of HIV which are unable to infect other cells. They work inside infected cells, disabling the virus’s reproductive process to prevent other cells from infection.

Like all anti-HIV drugs, PIs are only partially effective by themselves; to fully control the virus, they need to be used in combination with other drugs which attack HIV at a different stage in its cycle.

The protease field

At present, there are seven different PIs available on the PBS in Australia – indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), ritonavir (Norvir), lopinavir (Kaletra), fosamprenavir (Telzir) and atazanavir (Reyataz). In addition, there are two more which are available through clinical trials or via Special Access Programs – tipranavir (Aptivus) and darunavir (also called TMC-114). They all have their pluses and minuses, making choosing which PI is right for you somewhat complex.

The ideal for any treatment regimen is that it should be safe to take with as few side effects as possible, effective in suppressing HIV replication, and convenient for you to take – not requiring too many pills or too-frequent dosing.

Safety and side effects

While all protease inhibitors licensed in Australia are safe to take, they do have particular toxicity problems. While these can usually be managed it’s important to know about them.

The table on this page gives a quick summary of the common side effects associated with each of the PIs. If you’re considering starting treatment, you shouldn’t be disheartened by the large number of side effects listed; the majority of side effects (like nausea, diarrhoea, headache, and rash) tend to occur in the first month or two after starting treatment, after which they tend to subside. Less-common side effects such as liver problems should be monitored for by your doctor while you’re taking the drug, and some can be avoided (kidney stones, a possible side effect of indinavir, can be prevented by maintaining an adequate fluid intake, for example).

The best approach is usually to discuss potential side effects with your doctor before starting a new drug, so you know what to expect and you know what the options are for dealing with them if they arise.

Nearly all protease inhibitors can cause rises in cholesterol and triglycerides. Increased levels of these blood fats are a known risk factor for the development of heart and artery disease, and are thought to also play a part in the development of lipodystrophy, the changes in body fat distribution which affect some people who take anti-HIV treatments over long periods. Atazanavir has a much less pronounced effect on blood fat levels than other PIs.

Effectiveness

Clinical studies have shown that, taken in combination with other anti-HIV drugs, PIs have an excellent track record in suppressing HIV viral load.

Convenience

Most PI-based regimens need to be taken two or three times a day, and many have specific requirements about whether they should be taken with food or on an empty stomach. If you’re considering a PI-based regimen, you and your doctor should consider the dosing requirements of all the drugs in the combination and try to avoid combining drugs with different dietary requirements as this can increase the complexity of your regimen.

The daily pill burden is the total number of pills which must be taken per day, in addition to the other drugs in the combination. If you find it hard to take large numbers of pills, discuss with your doctor the total pill burden for your proposed combination and ask if there are alternative options involving fewer pills.

Boosted proteases

While ritonavir has fallen out of favour as a PI in itself (due to side effects and high pill burden), many PIs are now taken with a small dose of ritonavir to ‘boost’ blood levels of the PI. Ritonavir has an effect in the liver which slows down the removal of some drugs from the bloodstream, so using it in this way has enabled fewer doses and lower pill burdens for other PIs. Boosted regimens usually require taking one or two 100mg capsules of ritonavir along with your PI. Kaletra capsules have the ritonavir already added.

Notes on this table: not all side effects will occur in all people taking a particular drug, and other side effects than those listed here are possible. Dosages shown here are usual adult dosages; in some cases your doctor will prescribe a different dose.