AIDS TREATMENT UPDATE, Issue 29, May 1995
Edward King

Protease (or proteinase) is the name of the enzyme that HIV uses when it replicates within a cell to break down large viral proteins into smaller functional ones from which new virus particles can be made. Protease inhibitors block this process.

The protease inhibitor about which most is known is saquinavir, manufactured by Roche. Trials have shown that it can boost recipients' CD4 count and reduce the amount of HIV detectable in their blood. These effects are increased when it is taken in combination with AZT, or in combination with both AZT and ddC. British clinics are taking part in a trial comparing saquinavir, the double combination of AZT plus saquinavir and the triple combination of AZT plus ddC plus saquinavir.

Other protease inhibitors that are now in trials include:

- ABT-538, made by Abbott. A trial of this drug was due to start soon at the Kobler Centre, but has been cancelled. For more details, see AIDS Treatment Update issue 28, and page 10 of this issue. - AG1343, made by Agouron. The first trial of this drug in people with HIV is well underway at the Kobler Centre. For further information, see AIDS Treatment Update issue 27 - MK-639, previously known as L-735, 524, made by Merck. No trials of this drug are taking place in the UK.

Other drugs being tested in the USA include XM-323 and DMP-450, both made by Dupont-Merck, Searle's S-338, Upjohn's U-104,904, Bristol-Myers Squibb's BMS 186318, and VX-478 which is being developed by Vertex and Wellcome in partnership. Some experimental protease inhibitors have already fallen by the wayside, such as Searle's SC-52151.

RESISTANCE

Resistance to anti-HIV drugs seems to occur due to a kind of 'natural selection'. When somebody starts to take an anti-HIV drug such as AZT, HIV that is highly susceptible to the drug is rapidly killed. This leaves behind strains that are naturally less susceptible to the drug. Moreover, when HIV reproduces the new viruses that are produced often have small changes or mutations in their structure. Some of these mutations occur in the HIV enzymes that are targeted by anti-HIV drugs, such as reverse transcriptase or protease. Particular mutations can result in virus strains that are less susceptible to the drugs, and these strains are the most likely to survive within the body of the treated person. Over time, the 'pool' of viruses has fewer and fewer drug-susceptible strains and more and more resistant ones.

As with other anti-HIV drugs, the development of mutant HIV strains that are resistant to the protease inhibitor drugs has been seen. However, in laboratory tests there also seems to be a significant degree of cross-resistance between the drugs. Cross-resistance is caused by a single mutation or set of mutations producing resistance to several different drugs. This means that somebody who has taken one protease inhibitor and become resistant to it may then also be resistant to certain other protease inhibitors even though he has not taken them. This raises new issues for people making treatment decisions, as cross-resistance has not been a substantial problem with previous anti-HIV drugs such as AZT, ddI and ddC.

IMPLICATIONS

The significance of the development of resistance to anti-HIV drugs is not clear even for drugs that have been studied for years, such as AZT. There is still no agreement about the extent to which the development of resistance is the explanation for the gradual loss of effectiveness of AZT, even after several years of intensive research. Studies have shown that people taking long-term AZT may begin to experience increases in levels of HIV in their blood or other signs of disease progression before they have developed high levels of resistance to AZT.

The implications of protease resistance and cross-resistance are even more unclear. For a start, no-one knows how much of a problem cross-resistance will be in real people, as opposed to lab tests in which cells are exposed to high levels of the drugs for long periods. The only drug about which there is a substantial amount of resistance data in humans is saquinavir. Studies have shown that while resistance develops to saquinavir, it does so at a slow and moderate rate, and HIV continues to be susceptible to the drug.

Some researchers point out that resistance mutations can sometimes present positive new possibilities for treatment. For example, when AZT-resistant strains of HIV are exposed to one of the non-nucleoside anti-HIV drugs such as nevirapine, the development of resistance to the second drug seems to make the virus more susceptible to AZT again. This reversal of AZT resistance is also thought to explain the dramatic results seen recently with the combination of AZT plus 3TC. It is possible that the development of resistance to one or several protease inhibitors may also leave the virus more vulnerable to attack by other drugs. Another positive possibility is that the mutations that make HIV strains resistant to certain treatments may also damage the virus' ability to reproduce in the body.

Cross-resistance may have important implications for the development of combination therapy using two or more protease inhibitors. Researchers will probably avoid cross-resistant combinations, such as saquinavir plus AG-1343, but may test combinations that are not thought to be cross-resistant such as saquinavir plus ABT-538. However, researchers from Merck reported last month that a proportion of people treated with MK-639 developed HIV strains that were cross-resistant to no less than five other protease inhibitors, including ones with chemical structures that are quite different from MK-639. The possibility remains that HIV strains that are resistant to all protease inhibitors currently in clinical trials could occur after treatment with only one of them.

For the time being, however, protease inhibitor cross-resistance is something of an unknown quantity. Trials are investigating whether the onset of resistance to a protease inhibitor can be prevented or delayed by taking it in combination with AZT; an early trials of saquinavir found that it took longer for HIV to develop resistance to saquinavir when the drug was given in combination with AZT rather than as monotherapy.

Until this is known, some people may be reluctant to join trials in which protease inhibitors are given as monotherapy. On the other hand, some people may want to join those trials in order to get access to these promising drugs as quickly as possible.

TABLE - Resistance to selected protease inhibitors

Drug - ABT-538 Resistance in humans - Moderate-to-high level develops quite quickly Cross resistance - Multiple cross-resistance to all protease inhibitors except S-338 and U-104,904 reported in test-tube

Drug - AG1343 Resistance in humans - Not known Cross resistance - Multiple cross-resistance to all protease inhibitors except S-338 and U-104,904 reported in test-tube

Drug - MK-639 Resistance in humans - High level develops rapidly Cross-resistance - Multiple cross-resistance to A-80987, saquinavir, SC-52151, XM-323 and VX-478 reported in humans

Drug - Saquinavir Resistance in humans - Develops slowly and at low level Cross-resistance - Cross-resistant to AG-1343 and SC-52151 in test-tube

REFERENCE

The data on cross-resistance to MK-639 was published as:

Condra JH et al. "In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors". Nature 374:569-571, 6th April 1995.

There is an accompanying comment by Dr Doug Richman on page 494.

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