A turning tide
A great debate is raging about when we should start HIV therapy Robert
Fieldhouse reports
Illustration Antonio Maggi
You
may think doctors know for sure the best time for us to start HIV treatments.
But readers may be surprised to hear that evidence behind guidelines on starting
therapy have never been ‘proven’ by any randomised controlled
clinical trial.
As a result, when to start therapy, remains one of the most important of HIV
medicine’s many unanswered questions.
Right now the world’s leading HIV clinicians are debating this very
question - spurred by newer HIV drugs with simpler dosing schedules and fewer
side effects that can be used in hundreds of different combinations.
Changes
When HIV therapies first arrived, the prevailing wisdom (particularly in the
US) was ‘hit hard, hit early’ with drugs to prevent damage to
the immune system and reduce HIV-related illness.
But with fading hopes of therapy eradicating HIV, doctors became more concerned
about the long-term side effects of HAART. Thus treatment guidelines around
the world became more conservative.
Researchers argued the clinical benefits of starting treatment before disease
onset were unproven. Combined evidence from a number of cohort studies showed
no advantage to starting treatment with a CD4 count greater than 350 cells
over waiting for the CD4 count to drop as low as 200. However, cohort studies,
which follow groups of people, may be subject to bias and that is why a trial
is needed
Weighing risks
Latest draft treatment guidelines from the British HIV Association (BHIVA)
say decisions about when a person should start therapy should be based on
your risk of getting sick if treatment is not started versus the potential
risks of starting treatment earlier. The risks of starting earlier include
short- and long-term side effects and the possibility of the developing drug
resistance.
While the guidelines say you should consider HIV therapy if your CD4 cell
count falls to 350, therapy is only currently strongly recommended when your
CD4 count has fallen to between 250 and 200, or if you are ill because of
HIV.
People with CD4 counts below 200 are more prone to HIV-related and Aids-defining
illnesses. This is why everyone with a CD4 count at this level should take
medicines to prevent opportunistic infections and look seriously at starting
HAART.
Some people with a CD4 count below 200 say they don’t feel sick enough
from HIV to risk common drug side effects like diarrhoea or nausea. And some
hold off starting because they fear the long-term effect of meds. These concerns
were more valid when HAART combos were harder to tolerate.
BHIVA’s draft guidelines urge doctors to consider the risk of disease
progression without therapy in people with CD4 counts above 350. In these
patients, the guidelines say start therapy if the patient wishes to start
and if they have a high risk of disease progression in the medium term (a
2 to 4 per cent chance of disease progression in the next six months) and
the risk of harm from drug side effects or resistant virus is low.
“This is likely to continue to mean that the majority of patients with
CD4 counts greater than 350 should continue to defer treatment,” the
draft guidelines currently state.
Rewrite on cards
These guidelines were written last year, and are still at draft stage. It
is possible, when they are finally presented, we will witness a change in
attitude about the best time to start therapy.
As the draft guidelines stand, combination therapy would only be offered to
you when your CD4 cell count was above 350 cells if you had symptoms of HIV-related
disease; if you were older, had a higher viral load or were co-infected with
hepatitis B or C.
Resistance
Studies that follow groups of patients over time tell us the risk of developing
drug resistance is about 25 per cent over two to three years. But critics
argue this applies only to combos no longer recommended for people’s
first therapy. Certainly, today’s therapies appear more robust in the
face of resistance than those of old.
Boosted protease inhibitors are more resistant-proof than the earliest PIs.
And taking a boosted PI seems to give some protection against developing resistance
to nukes in your combo too. As well as this, clinical trials have shown that
newer nuke combo pills such as Truvada (tenofovir/FTC) lead to less drug resistance
than older combo tablets such as Combivir (AZT/3TC).
Your risk of disease progression is largely determined by your CD4 count and
viral load, as well as your age. These issues, as well as any competing health
concerns, should underpin any discussion you have with your health care team.
Co-infection with hep C
Researchers from Massachusetts General Hospital recently suggested therapy
should start sooner in people co-infected with hep C.
They argued starting treatment with a CD4 count above 300 maintains a range
of ‘hep C specific’ CD4 cells, increasing the chance people will
spontaneously control hep C.
An estimated 15-30 per cent of HIV negative people spontaneously control hep
C after exposure. The rate is lower in people living with HIV and dependent
upon CD4 cells specifically targeted against the hep C virus.
Researchers found people’s lowest ever CD4 cell count prior to starting
therapy was the factor most strongly associated with controlling hep C.
T-cell responses sufficient to control hep C were not seen in people whose
lowest ever CD4 count was below 300, regardless of their level of immune recovery
since starting HIV treatment. A clinical trial is currently enrolling in the
US to see if earlier HIV therapy could help co-infected people control hep
C.
SMART start
Recently, a large clinical trial called SMART randomly selected patients to
take either continual or intermittent therapy. It found patients who took
therapy in cycles with breaks were more likely to develop HIV-related disease
and die compared to those who stayed on treatment continually over 16 months.
The benefit to staying on treatment was seen in people with a range of CD4
cell counts, not just in those with lowest ever CD4 counts below 350. Experts
interpreted these findings as evidence HIV therapy should be started earlier
than currently recommended, ie above 200.
People who took breaks were also more likely to develop heart, kidney and
liver disease than those who stuck with treatment. This prompted observers
to suggest treatment should be started earlier, as the higher rate of these
complications may be due to high levels of HIV in the body typically seen
when people are off treatment.
Late is bad, says DAD
The DAD study of HIV treatment side effects, which includes information from
around 25,000 people living with HIV, found people with CD4 cell counts between
200 and 250 cells were at an increased risk of death from certain non-Aids-defining
illnesses, such as heart and liver disease as well as some non-HIV-related
cancers. Because this study is so large, it provides compelling evidence that
HIV therapy should be offered sooner.
View from US
US treatment guidelines and the World Health Organisation recommend therapy
when a person’s CD4 count falls between 350-200. Some US doctors even
believe HAART may best be started at 500. A healthy CD4 count is around 750.
Researchers from one of the leading US HIV treatment centres recently suggested
HIV therapy should be started earlier to give our immune systems the best
chance possible of returning to normal levels.
They cited their six year follow-up of patients at Johns Hopkins University,
Baltimore, which found people who started therapy with a CD4 cell count above
350 cells were more likely to get their CD4 counts back to normal, or near
normal, levels.
They argued: “Commencement of [HIV therapy] at a lower CD4 cell count
will result in a CD4 cell count that does not return to normal levels; this
may be a reason to consider starting [treatment for HIV] before the CD4 cell
count decreases to less than 350.”
What they found
Most (69 per cent) of the 655 patients studied were men; 70 per cent were
African- American. They were divided according to their CD4 count at the time
they started therapy. Researchers looked at CD4 gains each year and found
CD4 counts rose by an average of 274 cells over four years of therapy, peaking
at around 544.
People who started therapy with a CD4 count under 200 typically saw their
CD4 count rise to 493. People who started therapy with counts between 201
and 350 saw them rise to an average of 508 after six years of treatment.
But people who began treatment with a CD4 count of 350 or above got the biggest
rises; typically up to 829 cells over six years.
People aged over 45 experienced significantly lower increases. It did not
seem to make any difference if people started therapy with a protease inhibitor
or a non-nuke (an NNRTI such as nevirapine or efavirenz). Gender, race or
hep C co-infection had no significant impact either way on CD4 gains.
Top UK docs speak out
At the start of this year leading HIV doctors, including Professor Brian Gazzard,
entered the debate.
In the British Medical Journal (BMJ) they called for a revision of current
HIV treatment guidelines to recommend therapy when a person’s CD4 count
falls to 350 cells - as long as the patient is ready.
Current therapy, they said, was now sufficiently potent and well-tolerated
to start sooner than the norm in the recent past when fears over drug toxicity
had prompted a more conservative ‘watch and wait’ approach.
Body fat changes, particularly fat loss, are a key side effect largely associated
with extended use of d4T and AZT. But these drugs tend to be avoided as options
for starting therapy in favour of better tolerated meds such as tenofovir
or abacavir. This is one reason British doctors in the BMJ argue for earlier
treatment.
A higher risk of heart disease is another important complication attributed
to HIV drugs. However some researchers think this raised risk is due to untreated
HIV disease.
The British doctors argued that our understanding of how to avoid and manage
HIV-related cardiovascular complications has also improved. Some drugs are
known to be more ‘lipid-friendly’ and doctors are now more confident
about combining lipid-lowering drugs such as statins and antiretroviral drugs.
Professor Andrew Phillips, of the Royal Free Hospital, London made a strong
clinical argument for earlier treatment:
“We have started to appreciate, albeit with experience only of relatively
short term use, that antiretroviral therapy may permit close to a normal lifespan.
“Given this perspective, a 1.6 per cent six month risk of Aids for a
person with a CD4 count of 350 and viral load of 30,000 begins to not look
so low.”
Massive trial
The US National Institutes of Health is proposing a massive 9,000-strong international
study to work out the best time to start antiretrovirals.
Patients would be split into four groups. Those with CD4 counts above 500
would either begin treatment straight away or wait till their count was between
300 and 350. Those diagnosed later with counts below 500 would either start
immediately or wait till their CD4 counts were between 200 and 250.
Only a long-term study of this kind can begin answer the question about when
to start therapy and determine the trade-off between health benefits of treatments,
quality of life, cost, adherence and long term affects of HAART.
Reaping
benefits
If the pendulum really has swung back to earlier treatment it may result in
less HIV related disease and less HIV transmission (by making people less
infectious).
But to really reap benefits, people would need to be diagnosed earlier and
offered HIV-related care and treatment earlier, assuming they accept.
Right now in the UK some 20,000 people have HIV and do not know it. Getting
these people diagnosed and into care is critical. Many would need HIV treatment
immediately if the starting CD4 cell count is raised.
According to the Health Protection Agency more than a fifth of people with
a CD4 count below 200 in 2005 were not actually taking HIV treatment.
Almost 12,000 of those not taking therapy had CD4 counts above 200 cells.
By current BHIVA guidelines, doctors would consider it OK for this group to
stay off therapy. But if the guidelines changed to recommend earlier therapy,
many in this group will be considered in need of treatment.
Cost
It’s hard to predict how many people this change could affect in the
UK, but it’s likely to mean tens of thousands of people would become
eligible for HIV therapy. HIV therapy costs around £7,000 per patient
per year. London NHS alone spends around £200 million each year on outpatient
HIV care. The increased costs, year on year, of HIV health care are driven
by the increasing number of patients seeking treatment - up by 10 and 15 per
cent across London.
More questions
So where is the extra money going to come from? Will drug companies be encouraged
to lower prices as the number of patients prescribed the pills increases exponentially?
Will people want to take treatment before they feel sick from HIV? What impact
will these developments have on access to care in the developing world? We
may be on our way to answering one of the key questions in HIV but predictably
as we enter the second decade of HAART, we will end up creating many more.
