AIDS TREATMENT NEWS Issue 232, October 6, 1995
Jules Levin

The development of resistance to protease inhibitors, and then cross-resistance to other protease inhibitors, has been controversial and, for the last several months, a major concern to people with AIDS. Hopefully it will be possible to use these drugs in a way which delays or prevents resistance.

The controversy was stirred up by a published article in the scientific journal NATURE, authored by Jon Condra and Emilio Emini of Merck (April 1995). This article was based on only four patients who were using doses of indinavir (the Merck protease inhibitor, trade name Crixivan(TM)) which were significantly lower than the doses used today. It reported that HIV developed resistance to indinavir -- and then was also resistant to all other protease inhibitors tested. It is important to remember that this was a very small study, which used sub-optimal doses (which are known to lead to resistance), and which was using indinavir monotherapy. (It is well known that resistance develops faster with monotherapy than with combination therapy -- see "Caution" section at the end of this article.)

In response, Roche has been releasing information suggesting that their protease inhibitor, saquinavir, does not cause resistance nearly as quickly or as much. They have found that resistant virus develops by one year in their trials -- although this resistance is conveyed by one or two mutations, and these mutations do not seem to cause much cross resistance to the Merck drug.

Merck, Abbott Combination Results

Recently Merck and Abbott released information from their ongoing small studies. Merck is studying the combination of indinavir and AZT; the combination seems to achieve a somewhat better viral load drop than indinavir alone, but -- most importantly -- the antiviral effect lasted longer. Indinavir plus AZT achieved a MAXIMUM drop of 2.6 log (400- fold), vs. 2.3 log (200-fold) for indinavir alone, vs. 0.6 log (4-fold) for AZT alone. But after 24 weeks, the combination was SUSTAINED best, with 2.5 log (315-fold) drop in the amount of virus in the blood, vs. 1.5 log (32-fold) for indinavir alone, and 0.3 log (2-fold) for AZT alone.

Abbott Laboratories released information from their ongoing small open-label French study examining 24 treatment-naive participants using AZT, ddC, and ritonavir. So far they only have data for up to six months, but five study participants' viral load remains undetectable, while the mean viral load level achieved for all study participants at six months is still well sustained at a low level, between 2 and 2.5 logs (100-fold to 320-fold).

These studies imply that optimal multi-drug combination therapy (including an effective protease inhibitor) should delay drug resistance, and therefore cross-resistance. No one knows how long this delay could last. The theory is that adequate suppression of the virus delays the development of mutations which could lead to resistance. This promising theory needs further research and confirmation.

Merck is conducting two small three-drug studies: indinavir with AZT plus ddI, and indinavir with AZT plus 3TC. Data may be available by January 1996. These results may further confirm the theory that one can delay drug resistance by achieving adequate viral suppression, with well-selected, effective multi-drug combinations.

The implications are promising. For example, one might be able to begin with a particular three-drug combination (including a good protease inhibitor), and keep viral activity low enough that resistance does not develop rapidly. Then, before resistance develops, one could switch to a different combination -- without having cross resistance due to one's previous drug use.

Months ago, when the debate surrounding cross resistance was beginning and many of us were confused and discouraged, David Ho, M.D., of the Aaron Diamond AIDS Research Center, predicted that cross resistance would not be as much of a problem as others were claiming. He predicted that sequential use of protease inhibitors would be a useful tool in treatment strategies.

The message to people with HIV or AIDS is, don't be discouraged. These theories will be explored and hopefully confirmed. From this research, improved treatment strategies are likely to emerge.

And there may be other developments which are not yet foreseen. For example, Glaxo Wellcome is developing two new reverse transcriptase inhibitors, one of which may be effective against virus which is resistant to AZT and to other drugs in its class. Those who are already resistant to AZT may be able to switch to new drugs to use in combination with a protease inhibitor.

Another major research area is the combination of two or more protease inhibitors. Roche and Abbott will soon be collaborating on studies exploring the combination of their drugs. These drugs appear to have a unique relationship, since ritonavir (the Abbott drug) greatly increases the blood level of saquinavir (the Roche drug). (Caution: these drugs must not be combined until they have been carefully studied, since the dose of saquinavir must be greatly reduced, probably ten to 100 times or more -- but nobody yet knows what the proportion will be). Also, Merck and Roche may collaborate on a study combining their protease inhibitors. And other protease inhibitors, including Agouron's AG-1343, and the Glaxo Wellcome/Vertex VX-478, are now in earlier human trials.

I am hopeful that useful treatment strategies will emerge from this work.

Caution

In some people being treated with the current protease inhibitors, resistance can emerge, sometimes very quickly. To minimize this problem, it is important that you follow the instructions provided by the doctor or study nurse for administering these medications. There are some precautions anyone being treated with indinavir, ritonavir, saquinavir, or other protease inhibitors can take to help prevent the occurrence of resistance and to maximize the benefit of these drugs to oneself.

There appears to be a relationship between dosing and resistance. You should adhere completely to the dosing instructions. Make sure to take your full dose as instructed, at the appointed time, without delay; waiting 15 minutes may not matter, but a delay of two hours could be relevant. Do not skip taking a dose; if you forget or miss the appointed time, take the dose as soon as possible and then take the next dose at the regular time you were supposed to take it. And follow any other instructions on matters such as food intake, or storage of the drug.

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