Leading US HIV doctor Edwin DeJesus talks to PN about the differences in UK and US treatment, the future of AZT and the promising drugs pipeline
Words Robert Fieldhouse
Images Jay Eff
America;
where the documented history of Aids began. A country where an estimated 1.2
million people live with HIV, where new infections disproportionately affect
people of colour, women and the young. Yet it’s also a place of cutting-edge
research into HIV treatment and where drugs can become widely available, months
if not years before they appear in the UK.
During his brief visit to the UK, PN caught up with one of the USA’s
leading HIV clinicians, Dr Edwin DeJesus, medical director of Florida’s
Orlando Immunology Centre. His centre has 3,000 patients, largely from Hispanic
communities who, like African-Americans, are disproportionately affected by
HIV. Florida has the second highest HIV rate among women and children of any
US state. Additionally, about 60 per cent of Edwin’s patients are men
who have sex with men.
Treatments: the first decade. What have we learnt?
“Since the mid 1990s, when we embraced the term HAART (highly active
antiretroviral therapy) as being two nucleoside analogues and a third drug,
nearly all successful regimens have included that formula.
As a nucleoside backbone, most regimens included the use of a thymidine analogue,
either AZT (zidovudine, Retrovir) or d4T (stavudine, Zerit). The third drug
consisted of a protease inhibitor (boosted or unboosted), an NNRTI or a third
nucleoside.
Two things have happened since that era.
“Firstly, we learnt that we should avoid the use of a triple nucleoside
analogue such as Trizivir (AZT/3TC/abacavir) to treat our naïve patients,
and that a boosted protease inhibitor (PI) as a third drug performs better
than a non-boosted PI.
“Secondly, we learnt we should be cautious using a thymidine analogue
as part of that initial regimen. Several studies have documented the long-term
toxicity of d4T (stavudine), in particular its role in body fat changes, which
is unfortunate given its excellent short-term tolerability. Increasingly we
are recognising that the long-term use of AZT may cause similar problems.”
Key differences in US and UK HIV treatment guidelines
“There is a fundamental distinction between the US Department of Health
and Human Services [DHHS] HIV treatment guidelines and the British guidelines.
The DHHS recommends by regimen, but the British HIV Association (BHIVA) and
International Aids Society (IAS) guidelines make recommendations by specific
component drugs.
“In DHHS guidelines, an abacavir-containing regimen is not preferred,
but is an alternative for most patients. This has to do with the hypersensitivity
reaction (HSR) seen in a proportion of people starting abacavir.”
When you combine abacavir with the NNRTIs efavirenz or nevirapine, there is
a possibility that diagnosis of hypersensitivity may be compromised by some
degree of allergic reaction to the NNRTI. People treated with NNRTIs may develop
side effects such as a rash, which doctors may mistake for a symptom of HSR.
Impact of the availability of generic medications in the US
AZT, the first, most studied antiretroviral, lost its patent protection in
the UK a few weeks ago. Its US patent expired last September, allowing other
drug companies to manufacture generic AZT without having to pay GlaxoSmithKline
(GSK) royalties.
The US Food and Drug Administration (FDA) has since approved four generic
forms of AZT for sale in the US. What has been the result? Have prescriptions
of generic AZT increased and can we expect the same to happen in the UK?
“We don’t know what is going to happen with AZT after the introduction
of these AZT-generic formulations. In the US, where most HIV-related treatment
is paid for by private health insurance companies, after ddI (didanosine)
was approved for generic use, the third-party payers immediately substituted
the brand name drug [Videx from Bristol-Myers Squibb] for the generic one.
The same thing will probably happen with Retrovir [brand name of GSK’s
AZT], but the situation with AZT is different because AZT used in the US is
in the form of a fixed-dose co-formulation, such as in Combivir or Trizivir.
“There are two questions on the table; firstly, will physicians prescribing
a brand version containing AZT be forced by third-party payers to break down
these co-formulations into their separate components? For example, for someone
taking Combivir, this would mean they will have to take generic AZT plus Glaxo’s
3TC as separate tablets.
“Despite the complexities of breaking down this co-formulation, the
rationale of doing this is cost. Generic AZT is significantly less expensive
and could result in about a 40 per cent cost saving compared to Combivir.
“I suspect people who buy meds in bulk, such as the US prisons system
and the Aids Drug Assistance Programme, which provides meds to uninsured and
underinsured people living with HIV, probably will benefit from taking this
approach, compromising a little bit of pill burden for price. We have got
the pill burden down so much that it is probably OK to compromise it to some
extent, in the benefit of price.
“The second question is: with the availability of two generic nucleosides,
ddI and AZT, will third-party payers encourage the use of these two generics
together, instead of standard-of-care nucleoside backbone regimens? There
are no data supporting the use of these two drugs together as part of HAART
in adults. It is difficult to coadminister AZT and ddI mainly because of their
dietary restrictions and side effects, so the patient will end up with a three
times a day regimen. So the answer to this second question is likely to be
“no”.
Expensive
new drugs
“Study after study that has looked at the cost effectiveness of expensive
HIV therapies has ended up with the same conclusions: we are better off spending
more money upfront and controlling the illness than allowing disease progression
and have to pay later for the care of patients with advanced disease.
“I think the European and US treatment guidelines have done a very good
job at defining when to use expensive drugs such as T-20 and/or tipranavir.
It’s clear that these drugs need to be saved for third-line therapy,
but when needed, their use and efficacy makes them cost-effective by, in general,
preventing disease progression”.
HIV prevention
“Gay men did a superb job spreading the news about HIV, risk factors
and prevention to their population. But other communities, like the heterosexual
Hispanic population, are very difficult to reach because they don’t
have any peers that they can relate to.
“The same is true in African-American communities. The preventative
message never filtered through all communities in a similar fashion. This
is why the epidemic continues to disproportionately affect some more than
others.
“I’ve heard stories about gay men getting the rapid HIV antibody
tests, and asking their partners to take the test before sex. It sounds very
radical, not that I am encouraging it, but it’s an informed choice those
gay men are making.
“I saw nothing in the news on World Aids Day that indicated the importance
of addressing HIV awareness and prevention. Instead the media concentrated
on avian flu. It’s alarming how little the government
continues to do and how it has allowed the continued spread of HIV by ignoring
the magnitude of this epidemic.
The future of drug development
“Fortunately the pipeline of antiretroviral drug development is very
active. It has continued to produce options for patients who are both naïve
and treatment-experienced. We now have treatments available that are very
simple, compact and tolerable.
“In addition, there are many other
compounds in development, including new classes of drugs, very different from
the ones currently in use, which will expand the range of options we have
available to treat patients with very limited treatment options.
“One of these is an entry inhibitor of the CCR5 inhibitor class, taken
as a pill. The only other entry inhibitor commercially available is T-20 (Fuzeon,
from Roche), which is injected. There are two other promising drugs in development
and they are both integrase inhibitors, preventing the integration of viral
DNA into the host cell DNA.
“The pipeline of ARV development is very exciting. I hope that many
of these drugs can make it to full development, especially to assist patients
with limited options for treatment.”
