Q&A: Darunavir
PN’s treatment editor Robert Fieldhouse
answers your
questions about darunavir, a powerful, recently licensed
protease inhibitor
A
new protease inhibitor was launched across Europe last month with little fanfare.
The drug in question, darunavir, seems effective, so why hasn’t there
been more fuss? Perhaps when the data are this good, the results can do the
talking.
A lot of what we’ve learnt about darunavir has been gleaned from presentations
at medical conferences and reports on the internet. Now the study results
that led to its licensing have finally been published in The Lancet, a respected,
peer-reviewed medical journal. Here’s PN’s take on darunavir’s
data so far.
Q: What’s so special about this drug?
A: From the outset this drug was designed to work against
HIV resistant to other protease inhibitor (PIs). Researchers at a Belgian
pharma firm spent years identifying compounds promising for treating treatment-experienced
people who had developed drug resistance.
If you took indinavir or saquinavir ten years ago and developed some resistance
to them, switched to a non-nuke (NNRTI) like efavirenz (Sustiva) or nevirapine
(Viramune) and have since taken a ritonavir boosted PI like lopinavir/ritonavir
(Kaletra), darunavir may be particularly interesting to you.
Q: What’s the name again?
A: During development this drug was called TMC-114. Now it’s
licensed you’re likely to hear it called darunavir. Its brand name is
Prezista.
Q: What’s the dose?
A: You need to take two 300mg tablets twice daily with food.
Q: Is it taken with ritonavir?
A: Yes, like all protease inhibitors, excluding nelfinavir,
you take it with a small dose of ritonavir to further boost darunavir levels.
Darunavir needs to be taken with a 100mg capsule of ritonavir twice daily.
Q: Is that all you take?
A: You need to take it alongside other HIV drugs, typically
two others that are ‘active’. That means your virus is still susceptible
to them. In the published studies it was taken alongside optimised background
therapy where researchers used drug resistance testing to select drugs still
likely to work, despite participants’ treatment experience.
In these studies some people also took the fusion inhibitor T-20. Adding T-20
(Fuzeon) to darunavir in treatment-experienced patients produced a "substantial
effect”.
Q: Where have the data come from?
A: Results of the two studies, POWER 1 and POWER 2, were
recently published. Because the way they were designed and what they were
looking into were so similar the authors combined the 48 week safety and efficacy
data for participants on the dose of darunavir/r finally licensed (600/100mg)
and compared to people receiving other PIs in both the studies.
All other PIs available at the time were used in this trial excluding tipranavir
(Aptivus). So darunavir was compared with lopinavir/ritonavir (45 patients);
saquinavir (Invirase) (43); amprenavir or fosamprenavir (Telzir) (42); atazanavir
(21), indinavir (Crixivan) (three) and nelfinavir (Viracept) (one).
Across the two trials, 131 people received the 600/100mg dose of darunavir/r
and 124 people received an already licensed PI. In these trials, 23 per cent
of patients taking comparator protease inhibitors used two PI’s boosted
by ritonavir.
Trial results
Q: What was darunavir’s effect on CD4 cells?
A: CD4 count gains on darunavir were far superior to those
in people taking older PIs. Average CD4 cell increases over 48 weeks was 102
cells with darunavir/r compared with 19 cells with comparator PIs.
Q: What does that mean?
A: Researchers suggested it was likely participants who took darunavir/r might
experience slower disease progression than those taking the older PIs. This
is because the CD4 cell increases correlate with a decrease in getting Aids
or dying.
Q: What did darunavir do to viral load?
A: At week 48, 67 of 110 darunavir/r patients compared with 18 of 120 of control
PI patients experienced HIV viral load reductions of one log or greater.
Q: Isn’t the aim of therapy to be under 50?
A: That’s what the treatment guidelines say. In the
past, this has been difficult for some people with high levels of drug resistance.
That seems to be changing now with potent drugs like darunavir available.
Fifty-three per cent of patients in POWER 1 and 39 per cent in POWER 2 achieved
a viral load below 50 compared to 18 per cent and just seven per cent respectively
in people taking any of the comparator PIs.
Q: What happened when people took T-20 alongside darunavir?
A: Forty-four per cent taking darunavir also took T-20. People
who had never used T-20, and who included the drug as part of their optimised
background regimen, were significantly more likely to experience a viral load
reduction of at least one log by week 48. In total 81 per cent taking T-20
versus 23 per cent taking darunavir without T-20 achieved a one log drop at
week 48.
People who took T-20 were also significantly more likely to have viral load
below 50 copies at week 48; 58 per cent taking T-20 compared to 11 per cent
without T-20 had a viral load below 50 at week 48.
Q: What does that mean?
A: A one log drop is a tenfold change in virus, such as a
decline from 100,000 copies to 10,000 copies. It is generally regarded as
evidence of a significant, meaningful change in virus levels.
Q: Can it be used alongside drugs currently in development?
A: Many highly treatment-experienced people may find it difficult
to construct a background regimen of active drugs. In the coming year, it’s
likely drugs from two new classes will become more widely available. The first
CCR5 antagonist up for licensing is maraviroc and first integrase inhibitor
is likely to be raltegravir. After that we’re hopeful of yet another
new class, maturation inhibitors, being licensed. Darunavir may be a good
candidate to be used alongside each of these new drug classes.
A recent study showed that 90 per cent of patients who received raltegravir
with darunavir or T-20 achieved a viral load below 400 after 16 weeks, compared
with 74 per cent who received neither darunavir or T-20. We are still awaiting
an analysis of trials in treatment-experienced people taking the CCR5 antagonist
maraviroc in combination with other HIV drugs.
Q: Who will benefit most from darunavir?
A: In the test tube darunavir inhibited wild type virus (drug
sensitive with no resistance) and virus resistant to the earliest PIs such
as indinavir or saquinavir. In real life it was first studied in people with
resistance to one or more PIs where it appeared to remain active.
Q: And those least likely to benefit?
A: Clearly the more PI drug resistance mutations you have
the less likely you are to benefit from darunavir. HIV needs to accumulate
up to 11 different mutations in its protease enzyme to become resistant to
darunavir.
A Spanish cohort study of 1,021 patients with protease inhibitor failure showed
the risk of cross-resistance to darunavir was highest after the failure of
tipranavir/r or fosamprenavir/r.
At the start of POWER 2, researchers capped the proportion of participants
with three or more major PI drug resistance mutations at 30 per cent. After
11 months, the cap was removed to allow people with a greater degree of drug
resistance to take part.
Side
effects
Q: How many people stopped darunavir
A: Over the 48 weeks of the two studies, divided fairly equally
into two camps; side effects and HIV-related events, and virological failure.
By comparison 81 per cent of people taking one of the comparator protease
inhibitors stopped their treatment, two thirds due to virological failure.
Q: How well did people tolerate darunavir?
A: Twenty per cent of people treated with darunavir/r and
14 per cent treated with the older PIs reported at least one serious side
effect. The majority of serious side effects did not cause people to stop
therapy. No particular serious side effects were identified in people treated
with darunavir/r or comparator PIs.
The most common side effects were diarrhoea (20 per cent); nausea (18 per
cent); headache (15 per cent); blocked sinuses (14 per cent); fatigue (12
per cent), chest infection (12 per cent) and herpes simplex (reported by 12
per cent). Most side effects fell into the least serious categories with a
low rate of more serious side effects in both group.
Triglycerides increased in 15 per cent of darunavir/r, and seven per cent
on the comparator PIs.
A few people in both sections of the trial had increased pancreas activity
but nobody experienced pancreatitis.
Total cholesterol increased to over 7.7 mmol/l in 7 per cent of those taking
darunavir and 2 per cent taking the comparator PIs.
A small percentage taking both darunavir and the other PIs had elevated liver
function but no cases of liver toxicity were reported.
Q: Is it safe if I also have hepatitis?
A: It seems so. No specific safety issues were identified
for people with hepatitis B or C during the 48 weeks of POWER 1. Co-infected
people were excluded from POWER 2.
Q: Anything else happen I should be aware of?
A: People taking darunavir/r were more likely to develop
herpes simplex than people taking the other PIs. About 30 per cent of herpes
cases occurred within the first 12 weeks of therapy as CD4 cell counts were
recovering. Researchers theorised that, similar to other antiretrovirals,
darunavir/r might cause an inflammatory reaction to infections lying dormant.
Q: How many died during the studies?
A: Five (4 per cent) people taking darunavir/r died during
the studies, but researchers judged all deaths unrelated to study drugs.
Q: Are there more studies?
A: Darunavir is now being assessed in patients with less
or no treatment experience in phase III trials. A once daily dose of 800/100mg
is also being studied in people taking HIV therapy for the first time.
Q: How much does darunavir cost?
A: Tibotec has not followed the recent trend of pricing new
HIV therapies higher than other options. In fact, darunavir costs less than
the other medicines approved for use in highly treatment-experienced people
such as tipranavir and T-20. In the UK, darunavir will cost £446.70
per month.
Q: How can I get it?
A: Darunavir was launched across the UK on 16 February except
in Scotland where a decision will hopefully be reached in June.
Q: Will darunavir be available in Africa?
A: Tibotec recently announced a licensing agreement with
South African drug firm Aspen Pharmacare to distribute darunavir across Africa.
If demand proves strong, Aspen will actually manufacture it in South Africa
and sell it at a cost of around $3 a day or less.
