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AIDS Treatment Update
RESISTANCE QUESTIONS: What are the practical implications of drug-resistant HIV strains?
Edward King
April 1, 1996
AIDS Treatment Update, Issue 40, April 1996

Resistance to anti-HIV drugs is thought to occur due to evolutionary pressures. When HIV reproduces mutations often occur so that the new viruses that are produced have small changes in their structure. Some of these mutations occur in the enzymes that are targeted by anti-HIV drugs, such as reverse transcriptase or protease, andescan result in virus strains that are less susceptible to the drugs. Over the last year it has become clear that very high rates of HIV reproduction are taking place in the body all the time, even in asymptomatic people with high CD4 counts. This means that mutant strains that are resistant to drugs can emerge very rapidly.

When somebody starts to take an anti-HIV drug such as AZT, HIV strains that are highly susceptible to the drug are rapidly killed. This leaves behind strains that are naturally less susceptible to the drug.

Often these drug-resistant strains are less 'fit' than the 'wild-type' strains of HIV, so they tend to die out in people who are not taking anti-HIV drugs. However, in people who are taking drug treatments, the drug-resistant strains have the best chance of surviving. When they reproduce they produce more of the resistant viruses, so that over time the 'pool' of viruses in the body has fewer drug-susceptible strains and more resistant ones.

Increasingly, doctors and people with HIV are debating the practical implications of resistance for day-to-day treatment decisions. AIDS Treatment Update spoke to several doctors and researchers to try to provide answers to the commonest questions asked by people with HIV.

* I've been taking AZT monotherapy. If I've become resistant does this mean I am no longer benefiting from the drug so should stop taking it? No, it's not that simple. First, levels of resistance can vary. People who develop high-level resistance are likely to have HIV strains that are hardly inhibited by AZT at all. On the other hand, AZT may still have a significant impact on people with HIV strains that are only mildly resistant.

Secondly, if highly resistant strains have emerged in your body, there are likely to be other strains that are only mildly resistant and some that are not resistant at all. If HIV in the blood is resistant to AZT, HIV in other parts of the body (e.g. the brain) may still be sensitive. Thirdly, AZT is synergistic with several other anti-HIV drugs, meaning that it enhances their anti-viral effects. Some doctors therefore argue that it may be worthwhile continuing AZT and adding a second treatment. Others think it's likely to be better to switch to new drugs that you have not taken before.

* If I have AZT-resistant virus, will it regain sensitivity if I stop taking AZT? This is unclear. Studies have found that in some cases AZT-resistant strains persist in the body for one year or longer after you stop taking AZT or switch to another therapy. However, inother cases the AZT- resistant virus quickly disappears from the body after you stop taking AZT.

In some trials, adding or switching to 3TC has resulted in a virus that appears to be less resistant to AZT. But in fact it is more common for the virus strains to retain their resistance to AZT and also become resistant to 3TC.

* If I have AZT-resistant virus, will it reduce the benefits I can get from other drugs such as ddI, ddC and stavudine? This too is unclear. Test-tube studies have suggested that AZT-resistant strains may also be less susceptible to ddI, ddC and stavudine (d4T). However, there has been little research to test whether this observation holds true in real people. One recent study did find that when people who had been taking AZT for some time added ddC, those who had AZT-resistant HIV strains were less likely to experience a fall in viral load than those who had AZT-sensitive strains.

Nevertheless, trials such as Delta and ACTG 175 found that even people who had taken AZT for a long time and probably had resistant virus still experienced clinical benefits from adding ddI.

* If I do have AZT-resistant virus, what are my best treatment options? Because of the doubts about the significance of AZT resistance, you should still consider the whole range of current anti-HIV treatments as options. However, trials have consistently found that people who have already taken AZT respond less well to combination therapy with AZT plus ddI or ddC than those who start with two drugs.

Combination therapy regimens that include a protease inhibitor have reported the best treatment responses in AZT-treated people to date. However, in the UK protease inhibitors are currently only available to a restricted few (see the article on the front page).

* Can HIV become resistant to ddI and ddC? Is cross-resistance a problem with these drugs? Yes, resistance to ddI and ddC doesoccur, but less frequently and more slowly than resistance to AZT, especially when they are taken in combination with AZT.

Strains that are resistant to ddI are also resistant to ddC. However, the reverse is not usually the case - strains that are resistant to ddC are usually still sensitive to ddI.

* Is it true that 3TC works by blocking or reversing AZT resistance? This is one theory, and it does seem to occur in some cases. However, researchers now doubt that this is 3TC's main means of action. Trials have suggested that combination therapy with AZT plus 3TC has much greater anti-HIV effects than AZT alone, even though the vast majority of people develop resistance to 3TC within a matter of weeks. The most popular theory at the moment is that HIV strains that have become resistant to 3TC are disabled or slow-growing, and so cause less damage to the immune system. 3TC-resistant strains may also be less capable of developing resistance to other anti-HIV drugs.

* Is 3TC-resistant HIV also resistant to other drugs? Yes. 3TC-resistant strains are also less susceptible to ddI and ddC.

* If I start treatment with combination therapy, am I less like to develop resistance? Not necessarily - it may depend on the combination you choose. AZT resistance appears to develop just as quickly in people who take AZT in combination with ddI or ddC as in people who take AZT on its own - although the combinations are more effective at suppressing viral load and reducing disease progression than AZT alone. However, AZT resistance appears to be delayed in people who take AZT in combination with 3TC, saquinavir or indinavir.

Likewise, the emergence of resistance tosaquinavir, ddC or ddI appears to be delayed if you take AZT as well, as compared with taking any of these drugs on its own.

It is possible for HIV to become resistant to several drugs simultaneously, but such multi-drug resistance is generally slow to develop.

* Can HIV develop resistance to protease inhibitors? Are there any ways I can delay the emergence of resistance? Yes, HIV can develop resistance to any of the protease inhibitors. The risk of developing resistance appears to be greatest if you take too low a dose of the protease inhibitor or if you miss doses. Doctors advise people who are suffering side-effects from a protease inhibitor tostotaking the drug altogether rather than to miss or reduce doses.

Preliminary research suggests that the emergence of resistance may be delayed among people who have the greatest decreases in viral load on treatment. From the limited evidence to date, the best way of achieving such a fall in viral load appears to be by combining the protease inhibitor with two other anti-HIV drugs. The best results have been seen when people take combinations of several drugs that they haven't taken previously.

* If I take a protease inhibitor now, am I running the risk of becoming cross-resistant to a range of other protease inhibitors too? Yes, but it depends to some extent on the drug in question. HIV strains that are resistant to indinavir appear to be cross-resistant to all the other leading protease inhibitors. It's very likely that the same applies to strains that are resistant to ritonavir. However, if you take saquinavir and develop resistance, you are likely to be cross-resistant to nelfinavir (Agouron's protease inhibitor, previously known as AG1343), but not to indinavir or ritonavir.