How far have we come?
Dr Graeme Moyle speaks to Robert Fieldhouse about recent advances in HIV treatment
and offers insight into the future of HIV therapy
PN: What have we achieved over the past ten years?
GM: We’ve defined a series of therapies which provide
durable efficacy in initial treatment for people with wild type [drug- sensitive]
virus. Most of that work was done in the years 1996 to 2001. In the second
half of the decade we’ve focused more on identifying, from that range
of effective therapies, ones with the lowest risk of short- and long-term
toxicity. We’ve been able to further refine those in terms of convenience
of administration to mean we’ve established greater access to the potential
of durable success with therapy for more and more people.
PN: Which health issues should readers remain concerned about?
GM: First, keeping your HIV well managed because unmanaged HIV is a much more
acute risk for morbidity [disease] or mortality [death] than the majority
of other chronic prevalent conditions of ageing.
If we assume HIV is going to be managed sustainably in the long term, there
are effects directly attributable to drugs, for example morphological changes
such as fat loss and some which are partly related to genetics and ageing
and in part related to drug choice. This would include cardiovascular [heart]
disease, bone disease, renal [kidney] disease, the metabolic syndrome [abnormal
blood lipids] and central fat accumulation.
PN: Let’s focus on body fat changes
GM: Recognition of the lipodystrophy syndrome [body fat changes] was slow
to occur. So if we say d4T (Zerit) is probably the riskiest drug in that regard,
it was seven years after the approval of d4T before the syndrome was recognised.
That was due in part to the fact that it overlapped with other clinical presentations,
like wasting, and also because many people weren’t living long enough
to develop lipoatrophy [fat loss].
The only choices available to us at that time were thymidine analogue- [AZT
and d4T] based regimens. People who developed lipoatrophy at that time got
the best available advice they could have and may only be here today to suffer
the consequences of those drug choices through having had those drug choices
at the time.
When the MITOX study [that found switching from AZT (Retrovir) to abacavir
(Ziagen) was associated with regaining around one kilo of lost limb fat] was
published in 2003, an appreciation that regimens didn’t need a thymidine
analogue backbone began to grow. This is now the preferred approach to therapy,
using initial regimens based on either abacavir (Ziagen, Kivexa) or tenofovir
(Viread, Truvada) with 3TC (Epivir) or FTC (Emtriva).
In the past, we accepted the trade-off that the choice was suffer morbidities
with these medications or die of HIV infection. Now the view is much more:
“I think we can try to absolutely minimise the adverse events associated
with therapy in the long term.”
This is why drugs in the past were once perceived as well-tolerated are now
being re-evaluated. Perhaps we can do better than efavirenz (Sustiva); perhaps
we can do better than lopinavir-ritonavir (Kaletra).
PN: Will we see less lipo in the future?
GM: It’s impossible to rule out the possibility that long-term therapy
will still be associated with lipoatrophy in some people. That possibility
was raised recently in the 5142 study. There was a subset of people who still
appeared to lose fat over the course of therapy. [despite taking newer medications].
In this study a definition of 20 per cent fat loss was used. What we don’t
know is whether those people actually developed any visible changes. However,
I think the incidence of lipoatrophy will decline.
PN: How do you manage body fat changes?
GM: If we focus first on peripheral lipoatrophy. Broadly, the treatments that
have proved most beneficial are those that remove the thymidine analogue from
the regimen. In the MITOX and RAVE studies [where patients switched from AZT
or d4T to either abacavir (MITOX) or abacavir or tenofovir (RAVE)] there was
certainly evidence that people switching away from d4T to either abacavir
or tenofovir saw reasonably good limb fat recovery. And this recovery appeared
to extend beyond one year as if they were heading back to normal over time.
But still the majority of people entering those studies had such low limb
fat that the amount of time it would take for it to recover was a prolonged
- five to seven years from the estimates suggested by their initial fat recovery.
So switching followed by long periods of patience is important. Many people
who have lipoatrophy have a normal BMI and a normal weight; it’s just
that the distribution of the fat is abnormal.
PN: And focusing on heart disease?
GM: Certainly evidence from the D:A:D and other studies supports the idea
that people with HIV on therapy have a somewhat greater risk of cardiovascular
disease than the general population. It suggests they also have a greater
risk of not only myocardial infarction [heart attack] but stroke and diabetes.
Therefore we need to consider treating at least as aggressively as we would
do in the general population. Probably the minimum standard of care for that
would be to do one fasted lipid and glucose per year that included a breakdown
of HDL and LDL cholesterol, encouragement to stop smoking and dietary advice
around following a Mediterranean style diet.
PN: HIV therapy is getting better all the time though?
GM: The quality of CD4 count rise with both abacavir and tenofovir regimens
appears superior to AZT. We don’t know what that means from a functional
immunity standpoint but that may be valuable in terms of people spending relatively
less times at lower CD4 counts and therefore ultimately having better immune
surveillance against a range of cancers in the long term. There is a question
about whether relatively earlier commencement of therapy, as well as more
rapid CD4 recovery with therapy, will reduce the excess risk of cancer that
exists in the HIV population.
PN: And the future of HIV therapy?
GM: In terms of treatment experienced patients, the increasing availability
of a large number of new oral medications is going to result in more people
who are treatment experienced achieving success without the need for an injectable
therapy.
In terms of success with second-line therapy, there will be some improvements
in that we will probably see more nuke-sparing regimens by 2010 where it will
be increasingly routine to see integrase inhibitor plus boosted protease inhibitor
(PI), or CCR5 antagonist plus boosted PI or even the potential to look at
ritonavir-sparing therapies to avoid the toxicity of ritonavir over time.
There’s been some narrowing of the impression that there are big differences
in the effectiveness of protease inhibitors particularly when using them for
the first time.
PN: How can we stay fully informed about our treatment choices?
GM: In the UK we are very fortunate having a number of good patient-oriented
magazines that provide unbiased education.
The majority of physicians looking after people with HIV are enthusiastic
about having informed, challenging individuals to look after who have an intellectual
buy-in about the therapies they are going to take and who are aware of the
side effects that may occur and are vigilant to them.
Take an interest in your disease, in the same way in medicine that we would
encourage others with a range of chronic diseases to have an intellectual
understanding of their disease. People with HIV have got to live with HIV
for the rest of their lives and the rest of those lives are going to be 40
or 50 years long and so therefore it makes good sense to get informed about
the disease and contribute to the decision-making process.
If you understand what you are taking and why you are taking it, you are more
likely to take it.
• Dr Graeme Moyle is director of HIV research strategy at Chelsea and
Westminster Hospital in London
• This article was supported by an educational grant from GlaxoSmithKline
HIV/ART/07/30349/1
