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The XIV International Conference on AIDS was, as usual, an overwhelming event according
to Andrew Grulich. Andrew reflects on his highlights, while acknowledging that any review of
the conference can only be partial, and reflective of his particular interests.
The headline you won’t read - oral sex really is low risk
Those of us working in HIV transmission studies are familiar with the periodic “scares” over
oral sex. Whenever a researcher purports to find that HIV may be transmitted through oral
sex, media frenzy occurs. After the headlines, worried calls flood in to researchers and
community-based organisations, and there are angry demands for the truth. Researchers
are scrambled and reviews commissioned. Then we all calm down again.
Well, this time, some excellent research was presented at Barcelona on just how remote the
risk of HIV transmission in oral sex really is. Naturally, as it wasn’t exciting or titillating
enough, this research was found in the poster halls.
Jorge Del Romero (Centro Sanitario Regional Health Service) and colleagues followed a
Spanish cohort of 292 discordant heterosexual couples, between 1990 and 2000. There were
135 HIV negative partners (110 were women) who reported no unprotected anal or vaginal
intercourse or condom breakage or slipping. Among these couples, the diligent researchers
documented 9,270 acts of cunnilingus, 6,545 of fellatio with no ejaculation, and 3,501 of
fellatio with ejaculation in the mouth. And, wait for it, there was not a single case of HIV
infection among these couples.
The upper limits of the confidence intervals that I have calculated from these data are 0.6 per
thousand acts of fellatio without ejaculation, and one in a thousand for fellatio with ejaculation.
Now that is a low risk. Further follow up of this cohort will tell us exactly how low the risk is.
Some will argue that gay men do oral sex differently. Kim Page-Schafer (University of
California, San Francisco) studied San Francisco gay men who reported no anal sex during
the last six months. Two hundred and thirty nine gay men who performed receptive oral sex
with an average of three partners each were included. In 35 per cent, they had also
performed oral sex with ejaculation. No cases of HIV transmission occurred.
A note of caution was added by Sydney’s own Juliet Richters (National Centre in HIV Social
Research), of which I was a co-author. Of five individuals who judged oral sex to be a
possible route of HIV transmission, three reported insertive fellatio with a genital piercing.
While based on small numbers, this raises the concern that genital piercing may allow a portal
for the entry of HIV.
Of course, as the findings on oral transmission presented were largely negative, they received
no press coverage. The message on oral sex remains the same. Transmission is rare, but it
may occur. Data from this conference reinforces that in reality it is extremely uncommon.
For many years, educators have said that anything that breaches the integrity of the mouth of
the receptive partner (such as mouth ulcers and sores) is likely to increase the chances of
HIV transmission. Perhaps we should also consider whether breaches of the integrity of the
penis of the insertive partner, such as genital piercings, may also increase the remote risk of
infection.
David Cooper, Director, National Centre in HIV Epidemiology and Clinical Research, gave a
broad overview of the possibilities in this field. He argued that prevention efforts in the socio-
behavioural, vaccine, microbicide, and treatment fields have occurred in parallel, with little
interaction between exponents. It was argued that all the biomedical preventions apart from
treatment-based interventions are years away from implementation.
Of treatment-related prevention techniques, the one we are most familiar with is post-
exposure prophylaxis (PEP). Data at the conference from many studies, including our own
Australian study, show that there have now been a few thousand documented PEP
prescriptions with possibly one HIV seroconversion due to treatment failure documented.
In phase one/two trials of such therapy, increased risk behaviour would have to be one of the
end-points examined. Clearly, if the therapy is less than 100 per cent effective, and it results
in increased risk behaviour, it may do more harm than good. If used in association with
behavioural risk modification, then it might be an important addition to, not a competitor for,
behavioural prevention.
The chances of a microbicide working in reducing HIV transmission in anal sex appear
minimal, as the rectum is not, like the vagina, a blind tube. Coating the whole surface of the
rectum and lower large intestine, where infection is likely to occur, will probably prove
impossible.
In the vagina, however, there is more hope. Nevertheless, there are few products beyond
phase 1/2 trials, and it is thought that microbicides are very unlikely to be more effective than
condoms. This raises a real dilemma, described by Anna Foss and colleagues from the
London School of Hygiene and Tropical Medicine. If the availability of a microbicide leads to
decreasing condom use, it is highly likely they will do more harm than good. Microbicides are
only likely to help decrease HIV transmission at the population level in populations with very
low current condom use. Information like that provided in the current edition of POZ is likely to
be positively harmful in this respect.
Evidence was presented from diverse sites in the United States and Europe of a resurgent
syphilis epidemic among gay men, at levels not seen since the late 1970s. In cities such as
Amsterdam, major public sexual health clinics have diagnosed hundreds of cases in the last
couple of years, when they would only diagnose a case or two a year before this. Syphilis has
great potential to increase HIV transmission and acquisition, through the characteristic genital
ulceration that it causes.
The influx of thousands of gay men heading to Sydney for the Gay Games later this year,
clearly may provide an opportunity for re-entry of syphilis into Australia’s gay male population.
The UNAIDS report showed that a severe HIV epidemic appears to be now taking off in high
risk populations in Indonesia, as well as the more familiar data on HIV in New Guinea.
Reading the UNAIDS report on the state of the epidemic, and listening to speakers who are
surrounded by devastation, it was easy for an Australian to feel insignificant. Our future
success at controlling HIV is by no means guaranteed. It is important to remember that it is
not just good luck that has kept us insulated from the worst of the epidemic. It has been good
public policy and an active response to HIV/AIDS and this must continue if we are to maintain
this success.
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By Megan Nicholson
Since the emergence of serious, long term toxicities associated with antiretroviral therapy,
many HIV scientists and clinical researchers have turned their attention to the human immune
system. The aim is to stimulate HIV-specific immune responses which will slow HIV disease
progression in those already infected, and to prevent infection in others.
The XIV International AIDS Conference in Barcelona heard many presentations on strategies
and therapies which experts hope will change the course of the HIV epidemic without
inducing harmful side-effects. But the news was not all good.
Despite the advances in antiretrovirals, the sharpest brains are still pondering exactly how
HIV destroys the immune system and how some people manage to control HIV reasonably
well.
HIV preferentially infects HIV-specific CD4 cells and consequently, immune responses which
target HIV are usually poor and often disappear altogether. Even when the immune system
recovers during antiretroviral therapy, HIV-specific immune responses do not return. Only in
long-term non-progressors are HIV-specific cellular immune responses maintained. Given this
scenario, scientists have been trying to protect and stimulate HIV-specific immune responses
as a way of delaying HIV disease progression.
Two years ago at the Durban International AIDS Conference, scientists were hoping that
structured treatment interruption (STI) would help stimulate HIV-specific immune responses.
STI involves suppression of virus with antiretroviral therapy, and then cessation of treatment
for a set period of time or until virus rebounds to detectable levels. This cycle is repeated
several times. The theory is that HIV-specific immune responses can be protected and
stimulated by this process, particularly when deployed during the early phase of HIV infection.
Unfortunately, this approach hasn’t really produced the goods. The most encouraging STI
study, published by Bruce Walker’s team in the journal Nature in 2000, found that five of eight
people treated following HIV infection and prior to full seroconversion managed to control HIV
levels after several cycles of STI[1]. However, in Barcelona, Dr Walker was more circumspect.
Currently, nine of 14 people involved in the STI study[2] are off treatment with low viral loads
but Dr Walker acknowledged there is as yet no evidence that STI produces clinical benefits.
In fact, other studies suggest that STI during primary infection may have little impact on the
immune system’s ability to control HIV. For example, Dr J. Miro of the Idibaps Hospital in
Barcelona presented a study of STI in 12 people who were treated within 90 days of infection.
After several cycles of treatment interruption, only four participants had viral load below 5,000
copies/ml. Seven people had HIV-specific CD4 responses but these were generally weak and
transitory and seven also had HIV-specific CD8 responses.
Dr Marty Markowitz, a former advocate of ‘hit hard, hit early’ from the Aaron Diamond Institute
in New York, also presented a study suggesting that STI has little affect on HIV[3]. He told a
debate session on STI that HIV is a very difficult target because it escapes from the control of
cytotoxic cells.
The failure of STI to stimulate immunological control of HIV in all but a few people has led to
renewed interest in therapeutic vaccines and immune-based therapies as a way of controlling
HIV disease.
Ongoing trials are attempting to find particular therapeutic vaccines which can stimulate
cytotoxic T-cell and helper T-cell responses to limit HIV disease progression. A number of
studies published this year showed that various therapeutic vaccines have failed to block HIV
or SIV[4] [5] [6] [7]. However, several studies of therapeutic vaccines and immune-based
therapies presented in Barcelona reported more encouraging results.
One of the most exciting presentations at Barcelona indicated that a therapeutic vaccine
could help suppress viral load. Dr Juliana Lisziewicz of the Research Institute for Genetic and
Human Therapy tested a topical vaccine called DermaVir in SIV-infected monkeys[8]. She
randomised 26 macaques (monkeys) with chronic infection and 10 with AIDS to STI (three
weeks on, three weeks off HIV treatment), or STI and DermaVir vaccine, or DermaVir alone.
The asymptomatic monkeys treated with STI and DermaVir had their average viral load fall
from approximately 33,000 to less than 200 copies/ml, while the monkeys with AIDS had their
median viral load drop from over four million to undetectable levels. Monkeys treated with
DermaVir alone had stable viral load and survived for longer than untreated monkeys.
Virological control was associated with improved SIV-specific CD4 and CD8 responses, as
measured by levels of an immune cell messenger called interferon gamma. Long-term non-
progressors have higher levels of CD8 cells which express interferon gamma than
progressors[9].
Other studies reported in Barcelona also suggested that therapeutic vaccines can assist HIV-
specific immune responses and impact on viral replication. For example, the final results of a
placebo-controlled study of antiretroviral therapy with or without the therapeutic vaccine
known as Remune found that people randomised to Remune were less likely to experience
virological failure.[10] Another study reported that use of interleukin-2 and Remune in people
on antiretroviral therapy produced transient regeneration of HIV-specific immune responses[11
These findings provide enough evidence for ongoing research into therapeutic vaccines for
the treatment of HIV infection.
Preventive vaccines
Despite some impressive spin doctoring about vaccine trials and some encouraging
preliminary findings, no one has yet shown that a HIV vaccine can prevent infection in
humans. Based on encouraging animal studies, HIV vaccines trials in human are ongoing in
the UK, Uganda, Australia, Thailand, and the USA. At the Barcelona Conference, a new
vaccine trial involving 16,000 people to be conducted in Thailand was announced.
The bad news of the Conference came from Dr Bruce Walker’s team at the Harvard Medical
School[12]. He reported a case study of a man who was treated during primary HIV infection
and exposed to three cycles of STI. He had sustained immunological control of his virus for
some time off treatment, but then “viral breakthrough” occurred. When Walker’s team
investigated, they found that the supposed “breakthrough virus” was in fact a new clade B
virus. The man reported an instance of unprotected sex.
Superinfection had occurred despite that fact that the man's immune system had been
containing replication of the first virus. In addition to the implications for safe sex practices of
HIV positive people, this finding has profound implications for vaccine research because
much vaccine research is based on the assumption that a strong cellular immune response to
a HIV vaccine will prevent HIV infection with a range of viral variations. Walker’s case study
suggests that this may not be true.
Dr Stephen Kent, head of the HIV Vaccines Laboratory at the University of Melbourne who
helped develop the Australian HIV vaccine currently being trialled, told HIV Australia that the
case study was, “Not good news”. However, Dr Kent cautioned that “Isolated cases... are
difficult to interpret.”
Dr Walker himself expressed similar sentiments after his presentation in Barcelona. “I don’t
want to draw too many conclusions from a single case,” he said. “But he was definitely
controlling one of the viruses and not the other”.
The second B clade virus was only 12 per cent different to the original virus and the man had
maintained his original CD8 responses. However, half of the epitopes (the ‘flags’ expressed
by human cells which signal that they are infected) of the second virus were less well
recognised by the pre-existing CD8 responses. Although new CD8 responses to the second
virus were produced, these failed to control viral replication. Despite the similarity of the two
viruses, the original immune response was not enough to prevent superinfection or control
replication of the second virus.
While the case study seems to have implications for preventive vaccines, superinfection of a
person with an impaired immune system is a different scenario to the infection of a vaccinated
person. However, the results do concur with a vaccine study in monkeys, which found that
SIV-specific immune responses did not prevent infection[13].
No one is writing off vaccine research on the basis of one case study. Nevertheless, as
leading Parisian researcher Dr Brigitte Autran exclaimed following Dr Walker’s presentation,
“It is terrible news”.
Some experts have acknowledged the shortcomings of the cellular approach to vaccine
research. For instance, Dr Lawrence Corey of the HIV Vaccine Trials Network in the US told
the conference, “T-cell-based vaccine are approaching the immunogenicity that we feel is
needed for effectiveness.... They have the potential to significantly impact the epidemic if they
are shown to reduce the infectiousness of infected individuals for a prolonged period of time.
However, in animal models they do not appear to completely block infection, so traditional
prevention strategies are likely to be needed for the foreseeable future.”
As a result of the limitations of HIV specific immune responses to control or prevent HIV
infection, vaccine researchers are now returning to an interest in antibodies to HIV. During the
Barcelona Conference, the International AIDS Vaccine Initiative in collaboration with the US
National Institutes of Health’s Vaccine Research Centre announced the creation of a
Neutralising Antibody Consortium. The Consortium will search for broadly neutralising
antibodies against HIV which may contribute to the development of a successful HIV vaccine.
Megan Nicholson attended the Barcelona Conference as a reporter for www.aidsmap.com
[1]
Rosenberg ES et al. Nature 407:523-526, 2000.
[2]
Walker B et al. Abstract ThOrB259, 14th International AIDS Conference, Barcelona, 2002.
[3]
Markowitz M et al. Abstract ThOrB260, 14th International AIDS Conference, Barcelona, 2002.
[4]
Barouch DH et al. Nature 415(6869):272-273, 2002.
[5]
Allen TM et al. Journal of Virology 76(8):4108-4112, 2002.
[6]
Lindenburg CE et al. Vaccine 20(17-18):2343-2347, 2002.
[7]
Amara RR et al. Journal of Virology 76(12):6138-6146, 2002.
[8]
Lisziewicz J et al. Abstract LbOr11, 14th International AIDS Conference, Barcelona, 2002.
[9]
Autran B et al. Abstract WeOrA199, 14th International AIDS Conference, Barcelona, 2002.
[10]
Moreno S et al. Abstract LbPeA9004, 14th International AIDS Conference, Barcelona, 2002.
[11]
Gotch FM et al. Abstract ThOrA1483, 14th International AIDS Conference, Barcelona, 2002.
[12]
Walker B et al. Abstract WeOrA197, 14th International AIDS Conference, Barcelona, 2002.
[13]
Horton H et al. Journal of Virology 76(14):187-202, 2002.
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Vaccine news
Grant Davies and Andy Quan take a look at the vaccines news from Barcelona.
Discussion on AIDS vaccines got off to a start before the official proceedings at the Barcelona
World AIDS Conference. Two satellite sessions on 5 and 6 July turned the spotlight on
vaccines trials, treatment access and advocacy.
The first satellite session, Putting Third First, organised by the Canadian HIV/AIDS Legal
Network focussed on vaccines and treatments. David Gold of the International AIDS Vaccine
Initiative (IAVA) started by saying AIDS had surpassed the Black Plague in the number of
deaths. He asked participants to consider where advocacy in vaccine development needs to
go to arrest this devastating death toll.
A crucial objective of Putting Third First was how to make links between treatment access and
vaccine advocacy. Conference organisers suggested a framework for a right of access to
health care. This translates to people at risk of HIV having the right to prevention technologies
such as HIV vaccines and people living with HIV/AIDS (PLWHAs) having the right to access
treatment.
“There is a right of access to health care and the violation of that right is killing people,” said
Mark Heywood of the South African AIDS Law Project.
The 100 participants decided that much more interaction is needed between vaccine
development and treatment access, and that there is a need for better and broader
partnerships. There is a crossover between many issues. For example, a campaign for
voluntary licenses would be useful for greater distribution of treatments and vaccines since a
recent patent review by the AIDS Vaccine Advocacy Coalition found that the 13 leading
vaccines involved more than 1,000 patents. More, it was seen that vaccine advocates have
much to learn from the treatment advocacy movement which is much more advanced and
active.
South Africa’s Justice Edwin Cameron, by far the most impassioned speaker, challenged
national leaders, stakeholders, the World Trade Organisation and the World Health
Organisation to re-think the patent protections on drugs and to demonstrate principled
leadership. He challenged the audience to recapture the ‘angry activism’ of past times to
motivate the crucial political will towards access to treatments.
Words of caution were also issued. Wanjiku Kamau of the National AIDS Trust responded
when asked about developments in treatment access and vaccine development, “I was
shocked by how much has changed and how little has changed as well. We talked about
developments such as the Global Fund and UNGASS but on the ground, for the end-user, not
much has happened.”
The satellite also described the importance of national plans for vaccines like those
developed in Brazil, Thailand, Uganda and Nigeria. Australian efforts in HIV vaccine
development are focused on the National Institute of Health funded program to develop a HIV
preventative DNA-Fowlpox vaccine. Does this mean that we are neglecting more strategic
and significant contributions to HIV vaccine development globally?
Steve Wakefield, US HIV Vaccine Trials Network (HVTN), spoke about community
involvement in clinical trials. He discussed the HVTN’s Community Advisory Boards, which
build relationships, provide an avenue for community education prior to and during trials,
enable community ‘buy-in’ and allow for consultation with target populations. The Community
Advisory Boards can provide advice and are reliant on funding through other bodies (like
universities), he explained.
Chris Collins of the AIDS Vaccine Advocacy Coalition (AVAC) pointed to developments in the
HVTN of a Bill of Rights for trial participants built around respect for persons, beneficence and
justice. On questioning, he said that the Bill is only an in-principle agreement of HVTN
member organisations and is not enforceable.
Paisan Tan-Ud from Population Services International/Asia in Thailand, raised controversy
when commenting on the current Phase III trial with Thailand’s the injecting drug use (IDU)
community. He said that despite claims to the contrary, the community was not being properly
informed about the trial and offers to be involved have been rejected. The means of recruiting
volunteers posed difficulties because the volunteers feared that if they said no, they would be
refused access to methadone services. Paisan said the community must be part of every
important decision during a trial, and asked, “Who does the vaccine belongs to?” he asked.
On the morning of the second satellite, a full day discussion organised by the IAVI in
collaboration with a number of co-sponsors, the morning news reported on an epidemic of
measles in Naples. Only 60 per cent of the population were vaccinated as the vaccinations
are not compulsory in the area. The news sounded as a warning of the challenges we would
face even if a successful HIV vaccine is developed.
The IAVI session covered key concepts of vaccine development and delivery, state-of-the-art
updates on products in development, clinical trials and community involvement, and advocacy
and access policy issues.
Of particular interest was Supachai Rerks Ngarm of the Thai Ministry of Public Health, who
outlined Thailand’s prime-boost vaccine Phase III trial. He described community
representative involvement as useful for community education, access points for knowledge
about the community and as a means of explaining the consent process. The importance of
ethical issues was raised, although he did not elaborate on what those issues might be.
An important debate was the relevance of subtypes (clades) to vaccine development. One of
the main pressures against testing vaccines that don’t match local clades has been political,
arising from the idea that populations in developing countries are being used as “guinea pigs”
to test vaccines designed for clades prevalent in rich countries. For example, the South
African vaccine program has made a decision to only test new vaccines based on subtype C
viruses.
However, this was called into question at the satellite. At this point, the relevance of clades is
not really known and it won’t be know without further tests. Some preliminary clinical research
has shown “cross-reactivity”, an immune response to a single HIV gene sequence from a
subtype B virus that can destroy cells of other HIV subtypes. Dr. Jose Esparza, who leads the
HIV vaccine work at the World Health Organisation, said that the idea of “national vaccines” is
threatening to become an obstacle in the development and future widespread use of an
effective vaccine.
Is Australia’s development of a clade A/E vaccine for use in Thailand the wrong approach
then? Not according to Bonnie Matheson of the National Institutes of Health who pointed out
that the envelope region of clade E is the only clade that is not cross-reactive for neutralising
antibody, and that the South East Asian region may be the world’s only strong argument for
clade specificity. In addition, if successful, the vaccine may be useful for parts of Africa where
clade A is prevalent.
During the Conference itself, there was little new on HIV vaccines. The main focus was in
relation to the basic science and preliminary results of current and proposed candidates. The
same presentations given at ICAAP 6 on Thai trials (ALVAC and VaxGen) were repeated.
Some new vaccine approaches are entering trials and look hopeful.
Harriet Robinson, from the US Emory University Vaccine Centre, presented interesting results
of animal studies of their prime-boost vaccine, a multi-clade DNA-MVA vaccine, saying that
with the prime-boost model, viral control improves over time and the ENV aspect of the
vaccine is important. She did present some disturbing data that suggested the introduction of
a GP 120 boost worsened viral control, thereby decreasing protection.
Without any major vaccines news, IAVI president Seth Berkley was left to announce, “We
have always known that AIDS vaccine development would be a marathon, not a sprint.”
During the conference, there was also little discussion on ethics generally and the ethical
implications of vaccine development. One opportunity to explore ethical issues outside of the
main program occurred in an additional meeting organised by the AIDS vaccine Advocacy
Coalition (AVAC). Gathering together around 100 people, it was similar to the community
focussed meeting held during the International Congress on AIDS in Asia and the Pacific in
Melbourne 2001. Participants brainstormed issues surrounding advocacy and involvement in
vaccine development.
Discrete working groups were identified including a group dealing with community
participation in vaccine trials. The key point from this group was that what constitutes
participation varies according to the perspective you bring to it. Researchers have a very
different view to community advocates of what participation means in terms of when to
engage the community in the process and what their role might be.
This raised some challenges over who speaks for community and what is the role of the
community in the informed consent process. While exploring this issue, it was observed that
the UNAIDS guidance document, Ethical considerations in HIV preventive vaccine research,
was not mentioned once throughout the conference. Participants called for a review of this
document to make it a more meaningful and useful and called on an independent body to
auspice a meeting to further this aim. The results of this and the other working groups will be
included on the AVAC website[i].
The overall message on vaccine development was that it is too early to tell how efficacious
some of the current Phase III trials will be and what is known is not encouraging.
The presented and informal reports that Community Advisory Boards throughout the US and
the world fail to adequately address the legitimate concerns of the community within which
vaccines are being trailled was of equal concern. Australia has a different view and a more
appropriate model, but must remain committed to finding appropriate ways to engage their
community in ‘meaningful and full partnership’.
[i]
http://www.avac.org/
Andy Quan is the International Policy Officer at AFAO. Grant Davies is a PhD candidate at
the University of Melbourne researching community participation in HIV vaccine research.
This article written with the assistance of Julian Meldrum, international editor, aidsmap.com
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