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WAITING FOR THE NEXT MIRACLE |
Many doctors complained about the dearth of headline-grabbing
treatment news at the Bangkok conference. The main problem was timing: Bangkok
came along too soon. Results from several fascinating new studies that could
revolutionise the course of HIV prevention and treatment will only start to
trickle out over the next couple of years.
Treatment breaks: right and wrong
Treatment stories that caused the biggest fuss mainly affected people with
HIV in poor countries (see Treatment News). But what news was there for those
of us in the rich world for whom getting the pills is no problem? There was
a lot about simplifying therapy regimes. Structured treatment interruptions
(STIs) can reduce the cost and burden of long-term toxicity of HIV drugs.
An important Thai study of 74 patients highlighted interruptions that may
work, and those that won't. Patients who received week-on week-off therapy
had a high viral failure rate; more than a third had HIV 'rebounds' by the
72nd week of the two-year study. This was enough to prompt Italian doctor
Franco Lori, an early proponent of STIs, to call for a blanket ban on fixed-length
structured treatment interruptions, except in carefully-monitored studies.
But patients who stopped their pills when their CD4 count went above 350 and
restarted when it dipped below 200 did just as well as those on continuous
therapy. These patients took less than half the amount of HIV drugs overall,
with all that implies for long-term toxicity and cost. CD4-guided STIs are
now being investigated by the SMART study, the largest ever HIV drug trial
involving 6,000 patients.
Hope for immune-boosters
The SMART study could be extended to maximise the period off therapy by including
treatment with immune boosters such as interleukin-2 (IL-2). A presentation
of early results from the ESPRIT study using IL-2, the second largest HIV
treatment study ever, showed it boosted CD4 counts by an average of 230, which
could add extra valuable time off therapy. However, people who'd had low CD4
counts also had smaller CD4 rises on IL-2. Some doctors can't see IL-2 catching
on as it requires frequent cycles of injections and has nasty, fluey side
effects. Some bio-techs are in early stages of developing less toxic and longer-lasting
immune boosters.
Simpler regimes
Bangkok heard about others ways to make drug combos simpler and cheaper. GSK's
Trizivir pill (AZT/3TC/abacavir) got a bad press last year in terms of its
potency as a new therapy. But a US study showed that if you'd been undetectable
for a year on Trizivir plus efavirenz, it was safe to switch to a Trizivir-only
regime.
New life for old drugs
Another combo that could be cost-saving, especially in countries not paying
the new, inflated price of ritonavir, involves the oldest protease inhibitor,
hard-gel saquinavir (Invirase). A study called Staccato gave ritonavir-boosted
saquinavir plus d4T and ddI to 167 Thai patients. After the first 24 weeks,
92 per cent had a viral load under 50.
This
was good news as ddI plus d4T is a notoriously toxic duo that normally leads
to high drop out rates. This is the best result ever for an initial three-drug
combination, finally knocking efavirenz-based regimes off the top slot for
potency.
"Patients on CD4-guided structured treatment
interruptions did just as well as those on continuous therapy"
Single drug therapy - the Texas experience
Controlling HIV with a single drug is one of the Holy Grails of HIV research.
A few eyebrows were raised last year when results suggested it might be possible
to use Kaletra (lopinavir boosted with ritonavir) as a sole HIV drug. But
final results from the same study presented at Bangkok confirmed this may
be a viable option, though presenter Dr Joe Gathe was careful to say he wasn't
recommending it as standard. Gathe gave Kaletra as the sole drug (monotherapy)
to 40 patients from his Texas clinic. After 48 weeks, 60 per cent remained
on Kaletra monotherapy with a viral load below 50, and another four kept below
50 by adding in other drugs. Many of the 12 patients counted as 'failures'
were so because of what Gathe called 'situational adherence issues', a medical
euphemism for having to stop their HIV drugs when their health insurance ran
out or (in one case) when they were deported to Africa. Patients' average
viral load was fully 5,000 times lower at the end of the study than at the
start, and this was for a group of patients who started with a very high average
viral load of 262,000. Gathe's study wasn't rigorous, because he was basically
saying 'we kept the majority of patients undetectable on Kaletra alone' rather
than 'Kaletra alone is as good as combination therapy'.
News from the resistance front-line
For people running out of treatment options, there was little new data presented
on T-20 (Fuzeon). Researchers continued to stress that performance of T-20
depends on having at least two other working drugs available to you. Others
hinted that patients who combined T-20 with Boehringer's new 'resistance-proof'
protease inhibitor tipranavir did much better, although data will not appear
until next February. A study presented on tipranavir showed the same. Patients
with very high degrees of drug resistance had viral load drops when given
tipranavir, but the drops did not last, because of the lack of other viable
drugs available. It was also confirmed that tipranavir cannot be combined
with other protease inhibitors as it lowers their levels. So the tipranavir
and T-20 stories show it's no use developing a new kind of HIV drug unless
others arrive in their wake to support them soon after.
New candidates
Further along in the drug pipeline are several new candidates. Schering-Plough
and Pfizer are racing to be the first on the market with a new class of drug,
CCR5 inhibitors, which stop the most frequently transmitted variety of HIV
entering cells. SCH-D and UK 427857 respectively, both produced 10- to 100-fold
drops in viral load after 10 days. Pfizer's drug will go into a large efficacy
trial late this year, and Schering's in early 2005. A completely new class
of drugs is represented by PA-457, a 'maturation inhibitor' that works at
a late stage in the HIV life cycle. New data presented at Bangkok shows it
prevents development of the central dark core of HIV that holds its genetic
material. Although protease inhibitors work in a similar way, PA-457 works
against PI-resistant virus. So far PA-457 has only been given in small safety
studies to HIV negative volunteers, but a phase II dosing study in people
with HIV will start later this year.
Prevention
The general atmosphere around vaccines was gloomy. IAVI, the International
Aids Vaccine Initiative, declared scientists were concentrating too narrowly
on second-generation vaccines that try to generate anti-HIV CD8 cells. A large
Thai trial of the previous generation of vaccines, the gp120 vaccines, was
criticised as unlikely to show positive results and is struggling to recruit.
Merck revealed their second-generation vaccine, which encloses a piece of
HIV protein inside an inactive common-cold virus, will start a rolling programme
of phase II trials next year. This is the most promising candidate so far,
but phase II results won't come out until 2008 and only then can the big efficacy
trials, which need 5,000 to 15,000 volunteers, start. Even Merck say that
if their vaccine works, and it is entirely possible that HIV might develop
resistance to it, they are unlikely to be able to prove its worth until the
first half of the next decade. Experts said antibody vaccines like gp120,
had pretty much reached the end of the road as a concept. CD8 vaccines might
start producing results by 2010. A third generation, combining the CD8 approach
with a new approach that generates much more powerful anti-HIV antibodies,
unlikely to produce results before 2017-20. Pre-exposure prophylaxis (PREP)
using HIV drugs to prevent HIV, is starting trials in Africa, Asia and the
US. An early South African trial using AZT in serodiscordant heterosexual
couples (one HIV positive, one negative) had produced an estimated 80 per
cent reduction in HIV transmission, probably the best that could be expected
from this approach, researchers said. So the general verdict from Bangkok,
in both prevention and treatment, is that in two to four years we may have
potent new weapons to fight HIV, but until then the world's population will
have to rely on the ones we already have.
