AIDS TREATMENT UPDATE, Issue 42, June 1996
Edward King & Keith Alcorn

Cost issues are an important consideration for clinics. Although saquinavir is currently free, Merck charges clinics about ú3,000 per person per year for indinavir, and Abbott is trying to recover at least a proportion of the costs of ritonavir. However, for people with HIV the more important considerations are questions such as which drug is the most effective and easiest to take.

This article tries to answer those questions. However, new research is emerging rapidly, so any conclusions at this stage must be viewed as provisional.

* Should I take a protease inhibitor now?

AIDS Treatment Update asked a number of British doctors which people with HIV they would currently advise to consider taking one of the protease inhibitors. They all agreed that at present, use of protease inhibitors should be limited to people who have already taken the proven combinations of AZT plus ddI or ddC but who are now experiencing disease progression. Some doctors also recommend their patients to try other unapproved drugs such as 3TC and stavudine before they resort to a protease inhibitor.

Given our incomplete knowledge about the protease inhibitors, it is possible that people who take one today may find themselves less able to benefit from other, possibly more effective drugs in the future. For this reason, several clinicians advised that only people with relatively advanced HIV infection should consider a protease inhibitor now; people in less pressing need of new medical options may be better advised to wait until more trial results are available.

Results from more protease inhibitor trials are due to be announced at the International Conference on AIDS in Vancouver which may change the way clinicians use the drugs. In the USA, many doctors already offer combinations of two nucleoside analogue drugs plus a protease inhibitor as initial treatment for people starting anti-HIV therapy.

* Which one is the most effective?

The three leading protease inhibitors have been tested in clinical trials on their own and in combination with other drugs. However, no trials have directly compared the different protease inhibitors, so there is no clear-cut evidence that one is better than the others.

In their effects on surrogate markers such as CD4 counts and viral load, indinavir or ritonavir have significantly greater effects than saquinavir in its current formulation and dose.

Only two completed trials have assessed the ability of protease inhibitors to delay the development of opportunistic infections and/or prolong life. Differences between the trial designs make it impossible to compare the effectiveness of the different drugs.

- Among AZT-experienced people with CD4 counts below 100, adding ritonavir (as opposed to placebo) to whatever anti-HIV therapy (if any) participants were taking halved the rate of new AIDS-defining events and halved the death rate after an average follow-up of six months.

- Among AZT-experienced people with CD4 counts between 50 and 350, those who switched to ddC plus saquinavir had a two-thirds reduction in death rate after an average of 16 months of treatment, compared with those who switched to ddC monotherapy or saquinavir monotherapy.

* Should they always be taken as part of combination regimens?

The largest reductions in viral load and increases in CD4 count have been seen when protease inhibitors have been given in combination with two nucleoside analogue drugs (such as AZT, ddI, ddC or 3TC).

As yet there are no results from studies looking at the clinical effects of triple combinations, but the saquinavir trial described above found that the combination of saquinavir plus ddC was more effective at delaying clinical progression than saquinavir alone or ddC alone. Previous studies have found that ddC alone has little benefit for AZT-experienced people, and in this trial saquinavir was no better than ddC.

Taking protease inhibitors in combination with nucleosides may also help to delay the emergence of resistant strains of HIV.

Nevertheless, indinavir and ritonavir also appear to have good anti-viral effects when they are given as monotherapy. Monotherapy may still be a pragmatic option for people who are unwilling or unable to take nucleoside analogue drugs.

* Which causes fewest side-effects?

Saquinavir consistently has a very low rate of reported side-effects in trials. However, this may be partly due to the relatively small amounts of the drug that are absorbed into the bloodstream from the gut. It is possible that more side-effects will occur when saquinavir is used at higher doses.

Indinavir initially causes nausea (which can be controlled with anti-nausea drugs) and can temporarily turn the skin yellow. It can also cause kidney stones, although this can generally be avoided by drinking plenty of fluids. Otherwise, it too is well-tolerated.

Ritonavir causes side-effects in a high proportion of recipients, at least for the first few weeks of taking it. Recipients often complain of nausea, vomiting, diarrhoea, weakness, taste abnormalities, loss of appetite and numbness or tingling feelings (especially around the mouth). These side-effects often subside within a month, and may be reduced by starting ritonavir at a low dose and gradually increasing it over the first ten days.

Although saquinavir's safety has been confirmed in trials lasting about 18 months, relatively few people have taken indinavir or ritonavir for over a year so their possible longer-term toxicities remain unknown. There is also no information on the safety of combining different protease inhibitors.

* Which one causes the fewest drug interactions?

There are still important questions about interactions between protease inhibitors and other drugs, including those available over-the-counter from high-street chemists. However, it is clear that all three protease inhibitors can have potentially serious interactions with terfenadine (found in Triludan and Boots anti-histamines), the anti-MAI drug rifabutin and the anti-TB drug rifampicin.

There are no other major drug interactions with saquinavir. However, indinavir can also interact with the anti-fungal ketoconazole and a range of sedatives. Ritonavir also has potentially serious interactions with a host of other drugs, making it the most problematic drug for people who need other medications.

* Which one is easiest to take?

Saquinavir is probably the most convenient to take. It is taken three times a day, ideally with food to boost its absorption. If you have diarrhoea, saquinavir may not be a good option as absorption is likely to be very poor.

Indinavir is also taken three times a day, but must be taken on an empty stomach, or after at most a light, fat-free meal such as dry toast and juice. This may not be too inconvenient if you have three main meals a day and take indinavir at, say, 8.00 am, 4.00 pm and midnight, but may problematic if you prefer to eat small amounts of food throughout the day.

Ritonavir only has to be taken twice daily, ideally with food to increase its absorption. However, it has to be kept refrigerated because the drug breaks down after more than a couple of days at room temperature, making it inconvenient for people who spend significant time without access to a fridge.

* Which one is least likely to limit my future treatment options?

For each of these drugs, the emergence of resistant strains of HIV has been seen. If you become resistant to ritonavir you are very likely also to be resistant to indinavir, and vice versa. The risk of developing resistance grows if you take too low a dose, or miss doses.

However, HIV strains that are resistant to saquinavir may still be sensitive to ritonavir or indinavir, although they may be cross-resistant to other protease inhibitors in development, such as nelfinavir (formerly known as AG1343). Resistance to saquinavir also appears to be relatively slow to emerge; saquinavir may therefore be the least likely to limit your future options.

There are still many unanswered questions about the best way to use protease inhibitors to maximise their effects. A decision to take a protease inhibitor today inevitably carries a risk that you will be less able to benefit from other, possibly even more effective options in the unpredictable future.

SIDEBAR TEXT

* Protease forum

The AIDS Treatment Project (ATP) is organising a public meeting on viral load and protease inhibitors on Saturday June 22nd at 1pm at Westminster Central Hall, SW1. For more details, call 0171-470 8707.

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