Coming Soon to a Clinic near you?
A few new drugs to fight HIV created a buzz
at the World Aids conference in Toronto, and if we’re lucky, they could
be with us within the year. Robert Fieldhouse reports
Illustration: C(Aitch)
Unlike
the Vancouver World Aids Conference ten years ago, it was prevention technologies
like microbicides, rather than HIV drugs themselves, that hogged the limelight
at Toronto this summer. But amid the clamour around the use of antiretroviral
drugs for HIV prevention, we found new studies on new drugs that may shape
the future of HIV therapy. If all goes to plan, you may well see some of these
drugs in your clinic in the coming months or years.
Integrase inhibitors
Integrase is an enzyme which HIV uses to insert its genetic material (DNA)
into the DNA of human cells such as our CD4 cells. Investigational integrase
inhibitors may offer us a way to stymie HIV’s ability to reproduce itself.
The integrase inhibitor furthest along is known rather blandly as MK-0518.
Latest research presented in Toronto shows the drug has potent activity across
a range of doses and is well-tolerated by people starting their first HAART
combo. Those that need this drug most are people who have used all three classes
of HIV drugs (PIs, nukes and non-nukes) and those with drug resistance. Now,
however, the evidence shows it’s also looking good for people starting
therapy for the first time.
Holding back the nukes
MK-0518 appears so potent it may even herald a new approach to HIV treatments;
manufacturer Merck also produces efavirenz (Sustiva), so it’s possible
that in the future MK-0518 may be studied as part of a two drug combo; with
efavirenz-without nukes.
This would allow people to hold back from taking drugs from the nucleoside
analogue family such as AZT or 3TC for second-line therapy. Right now, it’s
being studied as part of a triple combination.
Who they studied
At Toronto, Dr Martin Markowitz of the Aaron Diamond Aids Research Center
in New York presented 24 week data for MK-0518 taken with tenofovir (Viread)
and 3TC (Epivir). This combo was compared with a triple combo of efavirenz
plus tenofovir and 3TC. The team enrolled 198 people who had never used antiretroviral
therapy before, who had a viral load of 5,000 copies or more and who had CD4
cell counts of 100 or over. Most were men, the average age was 36 and one
in three had Aids. MK-0518 was studied at a range of doses (100, 200, 300,
400 or 600mg twice-daily). Efavirenz was given at 600mg once-daily. A total
of 160 patients were put into one of the five MK-0518 treatment groups and
38 people were in the efavirenz group.
Rapid viral suppression
MK-0518 showed potent antiretroviral activity regardless of dose and HIV viral
load fell rapidly between the first and second week of starting therapy for
all people taking the integrase inhibitor. By week 24, 90 per cent of people
receiving any dose of MK-0518 achieved a viral load of less than 400 copies.
Most saw their CD4 counts double by the end of the trial. MK-0518 was very
well tolerated. Most side effects were mild and similar in all groups and
included headache, nausea and dizziness. There were eight serious adverse
events, but none was considered treatment-related.
A phase III study using a 400mg dose of MK-0518 is now underway. Although
this drug is not being studied at any clinical trial sites in the UK, it may
soon be available to those who really need it through a special arrangement
called ‘expanded access’. Merck said it would be made available
within the next few months through an expanded access programme for people
who have exhausted other treatment options and who were at risk of clinical
illness or immunologic decline.
Monoclonal antibodies
TNX-355 is an artificial human antibody that binds to the CD4 receptor, blocking
the path of HIV into host cells such as CD4s. Researchers studied TNX-355
alongside an optimised background regimen (OBR) of other antiretroviral drugs
chosen by drug resistance testing and compared it with an optimised background
therapy plus a placebo drug.
In total, 82 people who had used triple-class antiretroviral therapy were
enrolled. Most were men with an average age of 46. Participants were randomly
assigned to receive either placebo or intravenous TNX-355 in one of two doses.
Twenty-eight received 10mg per kg of body weight once a week for nine doses,
followed by 10mg per kg of body weight every two weeks. Twenty-seven received
15mg per kg of body weight once every two weeks.
After 48 weeks, researchers saw a one-log reduction in viral loads (one-log
is around 90 per cent).
Meanwhile, viral load only fell by 0.14 log in the placebo arm.
It took participants an average of 230-253 days to experience virological
failure in the TNX-355 arms, while those in the placebo arm experienced failure
immediately. CD4 cell increases were greater in the TNX-355 arms (48-51 cells)
compared to the placebo arm (0 cells). No serious side effects, including
injection reactions, were repoted.
The researchers concluded: “TNX-355 in combination with an optimised
background regime results in a statistically significant difference in viral
load reduction compared to placebo plus optimised background regimen at week
48. Treatment with TNX-355 is associated with durable viral load reductions
and clinically meaningful increases in CD4 counts in treatment-experienced
patients."
CCR5 inhibitors
HIV uses the CCR5 co-receptor to enter CD4 cells in up to 85 per cent of people
who have never been on HIV therapy. When people are treatment experienced
with antiretroviral drugs, HIV uses the CCR5 co-receptor approximately 50-60
per cent of the time. HIV can also enter CD4 cells through the CXCR4 co-receptor.
The virus’ tendency to use CCR5 (R5) or CXCR4 (X4), or both, is called
“tropism.” CXCR4-tropic HIV is associated with a more rapid decline
in CD4 cells and more rapid HIV disease progression.
Vicriviroc
Vicriviroc is an investigational CCR5 inhibitor from Schering Plough pharmaceuticals.
Dr Roy Gulick, of Cornell University, New York presented results from a 48-week
study in treatment-experienced patients with R5-topic virus taking ritonavir-containing
HAART with a viral load above 5,000 copies.
Vicriviroc was given at a range of doses (5, 10, or 15mg daily) or placebo
for 14 days; then background antiretrovirals were chosen. Virologic failure
occurred if their viral load declined by less than 1 log (a tenfold or 90
per cent reduction) after week 16. The object was to suppress the virus within
14 days.
Fast and sustainable
Researchers discontinued the 5mg dose early on following a recommendation
from the study monitoring committee following reports of five malignancies.
The study was unblinded (researchers and patients knew exactly who had been
receiving what) allowing them to do this.
In total, 118 patients were randomised with average viral load of 36,380 copies
and CD4 counts averaging 146 cells. People receiving any of the vicriviroc
doses achieved greater viral load decreases than people receiving placebo.
Two people receiving vicriviroc developed Hodgkin’s disease, two developed
non-Hodgkin’s lymphoma and one developed gastric adenocarcinoma.
The researchers concluded that in treatment-experienced patients, vicriviroc
demonstrated potent 14-day virologic suppression and, following optimisation
of background antiretrovirals, sustained antiretroviral activity over 24 weeks.They
added that the relationship between vicriviroc and malignancy was “uncertain".
Maraviroc
Maraviroc is Pfizer’s investigational CCR5 inhibitor. It works by preventing
the virus from entering CD4 cells by blocking its most common entry route;
the CCR5 co-receptor.
Pfizer conducted a 24-week study to look at the effects of maraviroc in people
whose HIV uses both the R5 and/or X4 co-receptors to infect cells. It is important
to find out whether taking a CCR5 inhibitor may lead HIV to increasingly infect
cells using a different route: the X4 receptor, and whether this leads to
a more rapid CD4 cell count loss. The study recruited 186 treatment-experienced
patients with advanced disease. Pfizer used something called a “trofile”
diagnostic test to select suitable patients which shows which route or routes
a virus is using to infect cells. Patients received the best available combination
plus placebo, or one of two doses of maraviroc once- or twice-daily.
Results showed viral load reduction were fairly similar for those receiving
maraviroc a day (-0.91 log) or placebo (-0.97 log), and slightly greater among
people receiving maraviroc twice a day (-1.20 log). CD4 cell count rises were
higher among people receiving maraviroc (plus 60 cells, once-daily and plus
62 cells, twice-daily) compared to an additional 35 cells for placebo.
Most importantly, researchers identified no evidence of harm by adding CCR5
to the treatment of people with dual/mixed tropic virus. Maraviroc is now
in Phase III studies. Results of this study in dual/mixed-tropic patients
will be evaluated alongside those from ongoing, fully-enrolled, global studies
in both treatment-naïve and treatment-experienced patients with R5-tropic
HIV. These are the populations most likely to show maraviroc’s effectiveness.
Expanded access is likely to begin within the next six months.
Protease inhibitors
Professor Sharon Walmsley, of Toronto General Hospital, reported data from
patients who had reached 48 weeks of treatment in the POWER 1 and POWER 2
studies of TMC 114 (Prezista) taken with ritonavir.
The highest dose studied in this trial (600/100mg twice daily) produced the
best virologic response. The findings shed light on the long-term efficacy
and safety of TMC 114/r against comparator PIs.
In both trials, PI, nuke and NNRTI-experienced individuals, with at least
one primary protease inhibitor drug resistance mutation, were randomised to
receive an optimised background regimen plus one of four TMC 114/r doses or
a boosted comparator PI.
Significant viral load cut
People on TMC114/r were significantly more likely to achieve a one log reduction
in their viral load compared to people in the comparator PI group.
Two thirds of those receiving TMC 114 achieved a one log (90 per cent) or
greater viral load reduction over 48 weeks. This compared with just 15 percent
of the people receiving a comparator PI.
Around half achieved an undetectable viral load (less than 50 copies) compared
with ten percent of those receiving a comparator PI. CD4 cells increased by
an average of 102 cells compared to 19 cells. The most commonly reported side
effects among patients in the TMC 114/r arm vs. control arm were diarrhoea
(20 percent vs 28 pe cent), nausea (18 per cent vs 13 per cent), headache
(15 per cent vs 20 percent) and inflammed nose or throat (14 per cent vs 11
per cent). Seven per cent of the people on TMC 114 stopped due to side effects
compared to five per cent in the control arm.
TMC114/r has demonstrated sustained efficacy in this treatment-experienced
population. Its tolerability profile is similar to that of comparator protease
inhibitors but it seems to cause less diarrhoea.
Non-nukes
We are witnessing the birth of the next generation of non-nukes (non-noculeoside
reverse transcriptase inhibitor (NNRTIs) with TMC125. Data were presented
at Toronto which showed the drug was effective against non nuke resistant
strains. For this study, 199 people with documented non-nuke resistance and
three or more PI drug resistance mutations were randomised to TMC 125 (400mg
or 800mg twice-daily) plus background antiretroviral drugs. These were compared
with 40 others given the best available control combination.
By week 48 the average decline in HIV viral load was -0.88, -1.01 and -0.14
log copies in the TMC125 400mg and 800mg twice-daily and active control groups.
Around one in five in the TMC125 groups reported side effects like diarrhoea
and rashes, more than in the control groups. The researchers said TMC125 showed
high rates of sustained efficacy at 48 weeks in heavily pre-treated patients.
“TMC125 retains activity in the presence of multiple NNRTI mutations
where current NNRTIs, nevirapine or efavirenz, are not expected to be effective."
It’s an exciting time for antiretroviral therapy. Many other drugs were
featured at Toronto and we will bring you news of their development in the
coming months in Treatment News.
