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
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
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
* If I do have AZT-resistant virus, what are my best treatment
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
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
* 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
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
* If I take a protease inhibitor now, am I running the risk of
becoming cross-resistant to a range of other protease
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.