Around 10,000 people in the UK have used three or more drug combos and many fear running out of therapy options. But there is hope, says Robert Fieldhouse
Most of us now starting HIV therapy do so with two
nucleosides and one non-nucleoside (usually efavirenz or nevirapine). Or,
we may replace this non-nuke with a ritonavir-boosted protease inhibitor (PI).
These
regimens should be even more successful in the current era, as antiretrovirals
are better tolerated and easier to take than ever before. Ritonavir-boosting
PIs minimises the emergence of protease inhibitor resistance mutations because
they are more potent than the un-boosted drugs of the past.
Nevertheless, a significant group of people living with HIV in the UK who
began therapy before HAART, in the late 1990s, started only with the two nukes
(nucleoside analogues such as AZT or d4T), then switched to an un-boosted
PI. Some of these people may now have drug resistance to these three most
commonly used drug classes due to previously receiving suboptimal treatments.
These people are often referred to as triple-class experienced. Estimates
suggest there are currently more than 27,000 people in the UK on treatment,
and around 10,000 patients currently on their third regimen or beyond. Each
year a third of these people experience virological treatment failure.
How should triple-class experienced patients approach their next combo?
In the past it was common for people to stay on failing regimens with a detectable
viral load simply because they had limited options to switch to. Sometimes,
doctors would allow the virus to become detectable and not change the drugs
while the CD4 count was still high.
But there is a price to pay for leaving us on stable but virologically-failing
regimens: we are likely to accumulate more and more resistance mutations the
longer we stay on a failing regimen with a detectable viral load.
Researchers who gathered information from more than 1,200 patients who stayed
on a failing combination with low level virus (average 250 copies) found three
quarters developed new resistance mutations over two years. And these mutations
had a negative impact on their viral loads. People tended to develop drug
resistant mutations which affected drugs from all classes. These impact significantly
on both the effectiveness of our current regimen and may reduce our response
to other drugs in the future. This is sometimes called cross-resistance.
The fusion inhibitor T-20 (Fuzeon) has been available for over two years now
and we also have access to new drugs such as the protease inhibitors tipranavir
and TMC-114, which can be combined with T-20 to offer the best chance of getting
the virus back to undetectable and raising the CD4 count, even if we have
extensive treatment experience and drug resistance.
Can drug ‘holidays’ help?
Many years ago there was a great deal of interest in using a structured treatment
interruption, a so-called ‘drug holiday’, to enhance the success
of the next regimen and minimise the emergence of new resistance mutations.
This was based on the idea that we don’t continue to develop drug resistance
when we stop the drugs, as long as we stop them appropriately. The problem
is we are more likely to get sick during treatment interruptions (see No Time
to Stop, page 44).
A US study of 280 people living with HIV found no additional virological or
immunological benefit for people on a failing regimen taking a four-month
holiday and then switching regimens, when compared to those who switched therapy
as soon as their drugs began to fail. Those who took a treatment interruption
lost an average of 70 CD4 cells, which took two or three years to recover
when they restarted therapy.
Recently the largest HIV trial ever attempted, the SMART trial, reported disappointing
results. It was halted after two years when researchers found people who took
treatment intermittently were more likely to get sick or die. They were also
more likely to experience heart attacks or strokes when compared to people
who stayed on continuous treatment.
Improving the odds of success in triple-class experienced patients
Any antiretroviral is likely to be most active if it belongs to a class we
have never used before.
If we use drugs from classes we have already used before (such as the PIs),
they need to be as active as possible. Drug resistance testing and our treatment
history can help our doctor to try to identify which drugs are likely to be
most active.
Examining the Fuzeon effect
There have been three large clinical trials in people who are treatment-experienced
which demonstrate similar findings. They have shown you are more likely to
get your viral load undetectable if you use a PI which resistance testing
shows is still likely to be highly active. Adding the fusion inhibitor
T-20 to a potent PI doubles your chance of achieving an undetectable viral
load.
Study one: T-20 plus lopinavir/ritonavir
The TORO studies randomised almost 1,000 people with resistance to drugs from
each of the three main classes and a viral load above 5,000, to receive antiretroviral
therapy consisting of an optimised background
regimen (drugs chosen by resistance testing) with or without T-20.
Viral load went below 400 copies in only one in four (24 per cent) people
whose resistance test showed they would still get a response to the ritonavir-boosted
protease inhibitor lopinavir (Kaletra), if they added this drug to two other
active drugs, as determined by drug resistance testing.
But twice as many (55 per cent) of people who also took T-20 with the PI lopinavir
achieved a viral load below 400 copies.
Study two: tipranavir and T-20
Almost 1,500 people with experience of the three main classes of antiretrovirals
and at least one major protease inhibitor resistance mutation were recruited
to the RESIST
studies, which evaluated the recently-licensed PI tipranavir.
Researchers found tipranavir plus nucleoside analogues and NNRTIs worked well
if people had only one or two major PI mutations from previous treatment failure.
But tipranavir retained little activity among people with three or four major
PI mutations when given with nucleoside analogues and NNRTIs alone.
Clearly, you will get much more activity from tipranavir the earlier you switch
to it rather than staying on your failing PI regimen and acquiring more PI-associated
resistance mutations. Around a quarter of people in these studies also took
T-20 with tipranavir. Those people did better than those who did not take
T-20 with tipranavir, despite being more treatment-experienced and this response
was not affected by the amount of PI resistance they had when they entered
the study.
Over 48 weeks, more than half of those people (54 per cent) who took tipranavir
with T-20 achieved a viral load below 400 copies. This was almost twice as
high as the proportion who achieved an undetectable viral load if they did
not take T-20 (30 per cent).
Study three: TMC-114 and T-20
In total, 458 treatment-experienced people received a 600mg daily dose of
the unlicensed protease inhibitor TMC-114 (boosted with 100mg ritonavir) in
one of the three POWER studies. Participants were already on a PI-based combo,
but with a viral load over 1,000 copies, and had previously used drugs from
the three main classes and had at least one primary PI-resistance mutation.
Over 24 weeks of treatment, an interim analysis showed 67 per cent of highly
treatment-experienced patients achieved a viral load below 50 copies if they
took TMC-114 alongside T-20 and other tablet drugs. This is the best response
yet seen in a group of highly treatment-experienced people with drug resistance.
By comparison, only 37 per cent went below 50 copies if they took TMC-114
without T-20. These results were impressive due to the high proportion under
50 copies even though the average number of PI resistance mutations was eight.
People with ten or more PI drug resistance mutations did not have such a good
response.
Why is T-20 under-prescribed?
T-20 is injected twice a day under the skin. Despite its impressive efficacy
described in the three major trials above, it’s an under-prescribed
medication in the UK. A recent, large study assessing doctor and patient
attitudes found that more than three quarters of patients would be willing
to consider an injectable therapy. Doctors who had never prescribed T-20 were
more likely to believe that offering their patients T-20 would
jeopardise their patients’ trust. They also felt injecting T-20 would
make treatment adherence more difficult.
Clearly there are some disparities between doctor and patient beliefs, and
these may influence how likely your doctor is to offer T-20 to you as an option.
If you feel you may be a good candidate for the drug, because you are highly-treatment
experienced and are looking for a potent new
combination, talk to your doctor about it.
What we know
In the past, whether or not we switched from a failing regimen immediately
or waited, depended on the level of our CD4 count and which options we had
to switch to. We now know we are likely to develop more and more resistance
which may undermine the effectiveness of our next combination, if we stay
on a failing regimen.
When switching therapy, using a new class of drug with at least two other
active drugs offers us the best chance of getting our viral load back to undetectable.
Only time will tell if the new investigational drug classes (the CCR5, integrase
and maturation inhibitors) will offer the same hope to people with triple-class
experience as T-20 does.
We need to take advantage of the drugs we have access to at the moment. If
we have experienced treatment failure with at least one boosted PI in the
past, we need to select the most active background drugs by using resistance
testing. Adding the fusion inhibitor T-20 currently seems the most likely
option to get our viral
load back to undetectable, prevent the emergence of more drug resistance and
maintain our health.
