Smarter combos, longer lives
New protease inhibitors offer hope of suppressing HIV long-term even if we
have drug resistance, reports Robert Fieldhouse
Right
now, the medications we take to suppress HIV and keep our immune systems working
need to be taken for life. The key is taking the drugs exactly as they are
prescribed, at the right time of day, along with the right food or water.
Taking as many of your doses in the right way is the surest way of preventing
the emergence of drug resistance. This tends to occur if your drug levels
are too low because you have missed or been late with doses, or due to drug
interactions, which may decrease the level of medications in the blood.
The ultimate goal of anyone taking antiretroviral therapy is to stay well.
This is best achieved by getting your viral load to ‘undetectable’;
below the limits of the HIV viral load test. It doesn’t matter if you
are on your first combo or are highly treatment-experienced, the goal is the
same. Having an undetectable viral load is the surest way of keeping your
CD4 count high and keeping you infection free.
The emergence of drug resistance (usually signalled by a rise in HIV viral
load) indicates you need to switch your treatment to re-suppress the virus.
Any change in your therapy should be guided by two things; results of drug
resistance testing (to show which remaining drugs are least likely to work
for you) and your treatment history.
Improved life-expectancy
Recent research shows life expectancy for people with HIV is improving due
to the effects of combination therapy. A recent study estimated that people
in their 20s starting therapy today can hope to live 33 years beyond the age
of 25. Life expectancy for people with HIV has improved year on year since
the late 1990s. People with sufficient access to therapy can expect a long,
though maybe not yet completely normal, lifespan.
Managing drug resistance
Drug resistance is a reality for anyone on therapy. The good news is it can
be expertly managed by your health care team and potent new meds that still
work even if you have some drug resistance.
Past guidelines suggested treatment-experienced people add a new class of
drugs to their new combo. But this is not always possible due to the limited
number of new classes available. You may feel happier sticking to drug classes
you are familiar with, in the hope that you will be able to cope best with
them day-to-day.
If you’ve used protease inhibitors in the past, you will know how to
manage any side effects such as altering your diet to manage diarrhoea. Some
people living with HIV have refused to take fusion inhibitors as they are
currently only available as a twice-daily injection.
What
if the virus is detectable?
With so many new drugs becoming available, clinical trials to take part in
and treatment strategies being explored, it is best to speak to your doctor
about your options for a change.
It’s better to change therapy sooner rather than later as the more protease-related
resistant mutations you develop to your current PI, the less likely you will
be to respond well to new protease inhibitors.
There is now evidence that switching when your CD4 cell count is higher and
viral load lower makes it more likely you will achieve an undetectable viral
load. Changing sooner may allow you to keep the fusion inhibitor class in
reserve for later therapy though this will depend on how much resistance you
have already developed.
‘Kitchen-sink’ approach
In the past some patients with difficult-to-treat virus were given a large
number of HIV drugs to try to overwhelm the virus and bring it back under
control.
People taking ‘mega-haart’ combos might have taken eight or ten
drugs, including some they had taken before and some which tests suggested
they had resistance to.
This approach was often complicated by side effects and the need to take handfuls
of tablets each day. With new potent drugs now available, this approach will
hopefully be consigned to history and people facing a treatment change may
be able to just continue with fewer, more potent new drugs.
Less
is more
Doctors adopted the ‘mega-haart’ approach mainly because the first
generation of drugs were not particularly good at being ‘sequenced’,
one regimen after another.
Your doctor has probably explained if you experience treatment failure with
nevirapine, you are unlikely to get a lasting response from the other non-nuke
(NNRTI) efavirenz. And if you start with efavirenz and that fails you are
unlikely to get a good response from nevirapine.
With protease inhibitors it’s not so black and white. The more mutations
or changes you acquire in your protease gene, the less likely some PIs will
work. So your doctor will need to carefully select the new drugs in your combo.
New PIs are now available that are active against PI-resistant virus, making
it more likely doctors can sequence these drugs to suppress HIV long-term
without pill-heavy, or over-complicated combinations.
What if I started with the early PIs?
There was some degree of cross-resistance between all ‘first-generation’
protease inhibitors such as saquinavir or indinavir if taken unboosted by
ritonavir and until they failed. This resistance hurdle was usually overcome
by switching to the co-formulated protease inhibitor lopinavir/ritonavir (Kaletra)
sometimes with the addition of a new class such as a non-nuke (efavirenz or
nevirapine) for second-line treatment.
Third-line therapy
Before HIV fusion inhibitors arrived, people switching to third-line therapy
may have taken two protease inhibitors boosted by ritonavir, plus new nukes
(NRTIs) where possible.
The only fusion inhibitor currently available is taken by twice daily injection.
Some clinicians are reluctant to prescribe an injectable drug, citing patient
inability to self-inject as the major barrier. The drug is also fairly expensive
and this may be an important reason why more patients have not been presented
with this option.
What
can I switch to?
It used to be common for people to stay on failing regimens with a detectable
viral load simply because they had few 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 resistant mutations the
longer we stay on a failing regimen with a detectable viral load.
Researchers gathered information from more than 1,200 people who stayed on
a failing combination with low level virus (average 250 copies). Three out
of four developed new drug resistant mutations over two years. And these mutations
had a negative impact on their viral loads. People tended to develop drug
resistant mutations that affected drugs from all classes, significantly influencing
the effectiveness of their current regimen and their response to future drugs.
This is sometimes called cross-resistance.
Within the SCOPE clinical cohort, 44 per cent of people with HIV whose viral
load averaged 41,000 copies on treatment accumulated at least one new drug
mutation at year one, and 30 per cent lost at least one active drug.
Would a ‘drug holiday’ help?
Many years ago there was a great deal of interest in using structured treatment
interruptions, often referred to as ‘drug holidays’, to enhance
the success of the next regimen and minimise the emergence of new resistance
mutations.
This strategy was based on the idea that we don’t continue to develop
drug resistance when we stop taking drugs, as long as we stop them appropriately.
The problem is we are more likely to get sick.
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, 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 compared with people who
stayed on continuous therapy.
Improving the chance of success
If we use drugs from classes we have previously been exposed to such as the
PIs they need to be as active as possible. Drug resistance testing and our
treatment history can help our doctor identify which drugs are likely to be
most active. The same principle applies to drugs from other families. We need
to use drugs that are most likely to work for us. The fewer drug resistance
mutations we have when we switch to a new combination, the better. Current
treatment guidelines from the British HIV Association state people should
switch to at least two or preferably three active new drugs.
In the past, whether 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. However, recent improvements in our knowledge of HIV treatments demonstrate
we are likely to develop more and more resistance which could undermine the
effectiveness of our next combo, the longer we stay on a failing regimen.
So it is better to switch sooner rather than later.
Everybody on treatment needs to aim for the same goal; undetectable viral
load. If we have experienced treatment failure with at least one boosted PI
in the past, we need to select the most active drugs by using drug resistance
testing. New drugs may be so potent that they are able to overcome high levels
of drug resistance and get you back to undetectable.
• This article was supported by Tibotec
