starting
HIV therapy
Why are more people living with HIV in the UK starting therapy with a ritonavir-boosted
protease inhibitor?
Words Robert Fieldhouse
Image Antonio Maggi
Protease
inhibitors (PIs) were the first class of drug to really make an impact against
HIV. The first PI, saquinavir, was approved over a decade ago. It seems hardly
believable that it’s almost ten years since the first presentations
to catch global media attention describing the remarkable effects of combining
protease inhibitors with nucleoside analogues, such as AZT or d4T, were made.
For the first time, people
with HIV saw their viral loads decline to extremely low levels and stay there,
their CD4 counts rise, and with this response came the prospect of renewed
life. Initial hopes that a few years of treatment with PIs would cure HIV
soon faded and while the great news is that current treatments should allow
you to live a
normal lifespan, right now, it seems they have to be taken as prescribed for
life.
A decade ago most protease inhibitors had to be taken three times a day, swallowing
handfuls of pills and sticking to demanding food and liquid requirements.
Thankfully, those days are now over and many PIs have been re-formulated to
reduce the number of daily tablets significantly.
What is ritonavir-boosting?
It took a few years before researchers realised that to get the best from
a protease inhibitor, it should be taken with a boosting dose, usually 100mg
or 200mg, of the PI ritonavir. Ritonavir slows down the way the body absorbs
the various PIs meaning that dosing is now reduced from three times to twice
daily. Lots of pharmaceutical companies are currently studying if their PIs
can be safely dosed once daily.
Current UK HIV therapy guidelines
The 2005 HIV treatment guidelines from the British HIV Association (BHIVA)
recommend that anyone who has HIV-related symptoms or a CD4 count below 200
should be offered antiretroviral treatment. Check out www.bhiva.org
for the complete guidelines. Current guidelines recommend starting therapy
with two nucleoside analogues plus either an non-nucleoside reverse transcriptase
inhibitor (NNRTI) (particularly efavirenz) or a ritonavir-boosted protease
inhibitor; particularly lopinavir-ritonavir, though recommended alternatives
include ritonavir-boosted saquinavir in its new 500mg Invirase formulation
and ritonavir-boosted fosamprenavir. The majority of patients starting therapy
do so with an NNRTI-based combination. The most recent BHIVA audit of UK clinic
prescribing found that while around 80 per cent started with either efavirenz
or
nevirapine, an increasing proportion are starting therapy with a ritonavir-boosted
protease inhibitor.
Why start with a ritonavir-boosted PI?
Currently, around a quarter of people newly diagnosed with HIV in the UK have
acquired some drug resistance from the person they caught HIV from. It is
essential you get a drug resistance test before starting therapy to help you
and your doctor decide which drugs are most likely to be effective. Not every
clinic is doing this test; ask for it if you are about to start therapy or
are newly diagnosed.
If you have acquired resistance to either nevirapine or efavirenz (the NNRTIs)
when you became HIV positive, starting therapy with a ritonavir-boosted PI
may be your best option.
Boosted protease inhibitors are a particularly attractive option for women
who may be considering having children, since current advice states they should
not take either efavirenz due to the possibility of birth defects in the unborn
child or nevirapine if their CD4 count is above 250 cells due to an increased
risk of side effects.
Being diagnosed with advanced
HIV progression
Overall, a third of people newly diagnosed with HIV in the UK and Ireland
are diagnosed with a CD4 count below 200. Black Africans and those who are
older are most likely to be diagnosed with a low CD4 count, while gay men
are likely to present for HIV testing when their CD4 count is higher. That
said, a recent report showed a quarter of gay men in 2002, especially those
living outside of London, those who are older or who are not white, were diagnosed
with a CD4 count below 200.
At least 57 per cent of people starting HAART for the first time in 2001 did
so with a CD4 count below 200. It’s not all bad news, though. Studies
have shown that people with advanced HIV infection, those whose CD4 count
has dropped below 200, or with opportunistic infections such as PCP pneumonia,
still benefit from HIV medications. However, when your CD4 count is very low,
some doctors feel more confident
about recommending a ritonavir-boosted protease inhibitor to start treatment.
What
drugs should I start with?
Lopinavir-ritonavir (Kaletra) was the first and remains the only protease
inhibitor formulated with ritonavir in the capsule, avoiding the need to take
additional ritonavir capsules. It was licensed in Europe in April 2001. More
long-term clinical trial data exist for Abbott’s lopinavir-ritonavir
than all other PIs. It is currently taken as three tablets twice daily, or
four twice daily if you are taking it with an NNRTI. Later this year a new
formulation will become more widely available (see Treatment News, pg 38).
The new Meltrex tablet formulation will reduce the number of pills needed
to be taken to four a day (compared with today’s six). Clinical trials
are currently assessing how safe and effective once daily lopinavir-ritonavir
is for people starting therapy.Patients taking lopinavir-ritonavir have been
followed for up to six years in one trial. CD4 rises with the drug are usually
great: over six years, the average increase was 528 cells. Unlike the NNRTIs
efavirenz or nevirapine, lopinavir-ritonavir has been studied in people with
very advanced HIV infection, who may have very low CD4 counts before starting
treatment.
In a large European study comparing lopinavir-ritonavir with saquinavir-ritonavir,
people who took lopinavir-ritonavir for 48 weeks were less likely to develop
opportunistic infections or see their viral load rise and were more likely
to stay on the treatment than those who were given saquinavir-ritonavir.
Saquinavir-ritonavir (Invirase)
Saquinavir has undergone three re-formulations to get to its current format
of two 500mg tablets plus one 100mg ritonavir twice daily. Clinical trials
showed it better than the most widely prescribed PI of the mid-late 1990s
(indinavir) but viral load returned to detectable levels more quickly among
those treated with ritonavir-boosted saquinavir compared with those treated
with lopinavir-ritonavir. The new formulation is more tolerable; with diarrhoea
rates in particular being lower.
Fosamprenavir-ritonavir (Telzir)
Fosamprenavir is a more potent version of an older
protease inhibitor called amprenavir. It can be taken once-daily but is licenced
for twice-daily dosing: one tablet in the morning and one in the evening alongside
ritonavir. In a clinical trial it showed itself to better than nelfinavir,
but since this is the only protease inhibitor not boosted by ritonavir, this
is not surprising.
How HIV drugs work: HIV (shown in green) infects CD4 T-cells (in brown). Fusion
inhibitors like T-20 stop HIV from getting into the CD4 cell.
HIV uses two enzymes called reverse transcriptase and protease to reproduce
itself. Nucleoside analogues such as AZT, nucleotide analogues such as tenofovir
and NNRTIs such as nevirapine, inhibit reverse transcriptase. After HIV has
integrated the newly formed DNA with the cell’s DNA, the cell produces
a string of protein. The protease enzyme cuts this protein into smaller proteins
that make new viral particles. Protease inhibitors such as lopinavir-ritonavir
block the protease enzyme and help prevent an infected cell from producing
new infectious virus.
Other protease inhibitors:
atazanavir/nelfinavir/indinavir/tipranavir
There are no trials providing information on the safety and efficiency of
using atazanavir in people who have never used therapy before, but many doctors
and patients prescribe atazanavir to patients starting therapy, as it is dosed
once-daily and does not elevate blood fats such as cholesterol or triglycerides
in the same way as some of the other protease inhibitors, and this may mean
it is less likely to lead to lipodystrophy.
Nelfinavir is the only protease inhibitor which is not taken boosted with
ritonavir. Therefore it is not a preferred drug according to the BHIVA therapy
guidelines.Few people are now prescribed indinavir, one of the oldest of the
protease inhibitors, as it causes side effects more frequently than alternatives.
Tipranavir will receive European approval later this year (see Treatment News,
pg 40), but is most likely to be licensed (at least in the first instance)
to people who have already developed resistance to existing
protease inhibitors.
How do they compare on potency and tolerability?
Lopinavir-ritonavir appears more potent than alternative boosted protease
inhibitors. Studies show that blood fats (lipids) such as cholesterol and
triglycerides rise more with lopinavir-ritonavir than with alternative protease
inhibitors. If you have high lipids before you begin therapy you are more
likely to have high lipids during treatment with lopinavir-ritonavir. The
lipid effect may have something to do with the fact that some people get very
high levels of lopinavir-ritonavir from the licensed dose; a blood test known
as ‘therapeutic drug level monitoring’ can see if this is the
case and your doctor may be able to reduce your dose.
In fact, in the trial which compared lopinavir-ritonavir to saquinavir-ritonavir,
more people stopped saquinavir-ritonavir due to side effects (though the saquinavir
formulation has subsequently been improved). And another study found that
lipid rises were actually greater among
people treated with indinavir-ritonavir than with lopinavir-ritonavir.
What about body fat changes?
Soon after the approval of several protease inhibitors in the late 1990s,
people taking the new drugs began to notice quite distinctive changes in body
fat and blood fats. Initially protease inhibitors were blamed for the syndrome
entirely, but it soon became clear that many other factors were playing a
part: long-term HIV infection, your lowest ever CD4 count before you started
therapy and which nucleoside analogues (AZT or d4T) you were taking alongside
the protease inhibitor are now known to be important too.
Anxiety about the development of lipodystrophy was one of the reasons that
a shift in doctors prescribing practice occurred in the late 1990s (with more
people starting therapy with NNRTIs).
One key advantage of not beginning therapy with efavirenz is that the protease
inhibitors do not cause central nervous system side effects, which some
who use efavirenz find difficult to manage.
Resistance
Another advantage to starting with a boosted protease inhibitor is that it’s
more difficult for HIV to develop resistance to this class of drug than to
NNRTIs. It takes multiple mutations or changes in the virus for a PI to become
completely ineffective, but just a single change to lose efavirenz or nevirapine.
This resistance advantage seems to provide some protection against the development
of resistance to nucleoside analogues too. Therefore the hope is that combinations
including boosted protease inhibitors will last for many years.Taking protease
inhibitors nowadays is a very different experience from how it used to be.
We are certain of their potency, and the new formulations are better tolerated
and involve taking fewer pills than the old versions, making them a much more
attractive option than a decade ago.
