News (Updated July
10, 2011)
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Michael Carter
Published: 10 July 2011
Couple-based risk
counselling reduces rates of unprotected sex in HIV-negative drug-using couples,
investigators from
Results of the study also
showed that the counselling had a positive impact on drug-using behaviours.
The investigators believe
their findings “provide robust evidence of efficacy of the couple-based HIV
prevention intervention.”
Drug users are a high-risk
group for HIV and other sexually transmitted infections. Injecting drug use
poses the risk of the transmission of HIV and other blood-borne infections, and
rates of unprotected sex are high among drug-using populations.
These risks are especially
prevalent in couples where one or both partners use drugs.
A number of studies have
shown that couple-based counselling can reduce HIV risk behaviours. However, no
study has previously looked at the efficacy of this intervention in HIV-negative
heterosexual drug-using couples.
Therefore, between 2005
and 2010 investigators from
The couples were
randomised into three arms.
Those in the first
received couple-based risk reduction counselling.
Couples in the second arm
also received risk-reduction counselling, but on an individual basis.
The couples in the third
arm acted as a control population and received general health promotion
information, focusing on diet, exercise, access to health services, and
screening for chronic diseases.
Most of the couples were
recruited via street outreach. The interventions consisted of seven sessions
lasting two hours which were delivered on a weekly basis. The impact of the
interventions on unprotected sex and rates of sexually transmitted infections
was assessed immediately after the interventions were completed and then six and
twelve months later.
Participation rates were
high and between 66% and 76% of couples attended all seven counselling sessions.
Moreover, there was a high retention rate with 87% completing the
post-intervention assessment and 76% the twelve-month assessment.
“The high participation,
attendance and retention rates achieved in this trial demonstrate the
feasibility of engaging impoverished street-based drug users, who remain at very
high risk of HIV/STIs in a couple-based behavioral intervention,” comment the
investigators.
There was a high
prevalence of risky behaviour at baseline. Only one partner was required to have
a history of recent drug use for the couple to be eligible to participate in the
study. However, 82% reported that they had used drugs in the month before
enrollment, 16% said they had injected drugs in the previous 90 days, and
one-third of individuals had recently had sex outside their relationship.
Over the entire study
period, there was a 30% reduction in the incidence of unprotected sex reported
by participants who received risk-reduction counselling compared to those to
were in the control arm.
Moreover, rates of
unprotected sex were 29% lower for couples who received couple-based risk
counselling compared to those who had individual risk-reduction counselling.
Risk reduction counselling
had a significant impact on sexual risk behaviour immediately after the
conclusion of the intervention (individual risk reduction [IRR] = 0.58; 95% CI,
0.38-0.88) and six months later (IRR = 0.70; 95% CI, 0.54-0.92).
Analysis was then
restricted to the two risk-reduction arms. This showed that couple-based
counselling had a significant effect on rates of unprotected sex at month six
(30% reduction; IRR = 0.70; 95% CI, 0.51-0.96) and month twelve (41% reduction;
IRR = 0.59; 95% CI, 0.35-0.99).
“These results suggest
that when couples receive the intervention together, they are more likely to
improve and sustain positive predictive behaviors over time compared to when one
partner receives the intervention alone,” write the authors.
There were 23 incident
sexually transmitted infections during the study and only one participant
seroconverted for HIV.
The investigators also
found that risk-reduction counselling had a “promising effect” on rates of
injecting drug use.
“These findings draw
attention to an effective intervention strategy that can be scaled up for
drug-involved couples in harm reduction programs,” conclude the investigators,
“a couple-based approach to primary prevention of HIV that addresses both drug
and sexual risks and targets low income, urban, active drug users may help curb
the HIV epidemic in the US and may have dissemination potential to address the
global HIV epidemic.”
Reference
El-Bassel N et al.
Couple-based HIV prevention for low-income drug users from
Last month, we looked at
the case of Timothy Ray Brown, a leukaemia patient who became the first person
ever to be cured of HIV infection.1
We explained why this is
so difficult: even under the most intensive current therapy, a silent
‘reservoir’ of a type of CD4 cell called ‘memory cells’ remains infected
with HIV. These are like sleeper cells in a resistance organisation – their
job is to spring into action when a specific infection they are primed to
recognise turns up. In other medical conditions, vaccines work by tricking cells
to ‘recognise’ an infection without actually having had it. The trouble is,
when HIV-infected memory cells spring into action, they start spewing out HIV.
We can flush HIV-infected
memory cells out of hiding by activating them and then kill them: but the burst
of HIV they produce in this process causes more CD4 cells to be infected.
Last month, we explained
how Brown’s doctor, Gero Hütter, got round this by destroying Brown’s CD4
cells and then re-introducing others, via a bone marrow transplant, from a donor
naturally resistant to HIV (missing the CCR5 co-receptor, which HIV grabs on
to). However, a bone marrow transplant, while the standard second-line treatment
for leukaemia, is far too toxic – and expensive – for general use and indeed
nearly killed Brown.
It is, however, proof that
a cure is possible. The most promising approach towards a cure for all is to do
at least one of the two things Dr Hütter did, but in a much more subtle way.
1. Re-engineer CD4 cells
One approach could be to
take bone marrow cells from the patient’s own body, and by means of enzymes
and genetic tools, engineer them to become CCR5-negative, thus protecting them
against further HIV infection. You then re-introduce them into the patient’s
body, in a so-called ‘autologous’ – meaning self-donated – transplant.
The hope is that the
CCR5-negative cells would slowly start to take over from the CCR5-positive cells
and HIV would slowly be starved of the cells it needs in order to reproduce.
Even people on effective
antiretrovirals maintain a viral load averaging three copies/ml and this appears
to contribute to keeping the immune system in a permanently higher state of
activation than in HIV-negative people. This activation kills off some
HIV-infected cells but infects others, keeping the reservoir topped up, or so
the theory goes. If, however, a population of infection-proof cells were
introduced, they would come to predominate as there would be fewer cells to
infect as time went by.
This approach has actually
been trialled successfully, in mice genetically modified to be susceptible to
HIV. Researcher Paula Cannon and her team from the
Many scientists are
sceptical that the reservoir of HIV-infected cells could be replaced by
HIV-proof cells unaided. The CCR5 cells in Cannon’s mice were by no means
eliminated, especially the all-important progenitor cells in the bone marrow.
Steven Deeks, a prominent cure researcher from the
Even if it does work, it
could take a long time for one cell population to replace another: “In mice it
happens in months, in people it could take years,” Deeks told HTU.
Nonetheless Cannon and her
colleague John Zaia are now leading a Phase I trial in patients with lymphoma,
using bone marrow transplants of patients’ own genetically engineered
progenitor cells to try to ensure the growth of a CCR5-negative cell
population.3
2. Delete infected cells
Alternatively, one
approach could be to concentrate more on the immune-destruction part of Timothy
Ray Brown’s therapy instead of the CCR5-deletion bit. The idea would not be to
crudely annihilate all the cells HIV might infect. Instead we could:
‘Purge’. This strategy
involves enticing reservoir cells out of hiding using drugs that ‘switch on’
reservoir cells so they become activated and therefore detectable, while keeping
patients on antiretrovirals so that the activated cells do not go on to seed new
infection. The HIV-infected activated cells would then destroy themselves, and
the idea is that repeated cycles of activation would deplete the reservoir
beyond the point at which it can replenish HIV – a strategy that’s been
called ‘purge’.
Experiments were done more
than five years ago using the drug valproic acid (Depakote). This is a member of
a class of drugs called HDAC inhibitors, which take the genetic brakes off
resting cells. In one study, three out of four subjects given valproic acid
achieved a 70% reduction in the number of HIV-infected reservoir cells.4 It
appears, however, that this reduction may only be temporary: two larger studies
in 2008 showed no long-term reduction in the number of HIV-infected reservoir
cells in other patients.5,6
This may be because
valproic acid is not strong enough. Trials are planned of a stronger HDAC
inhibitor called vorinostat (Zolinza), a cancer drug already used for some types
of lymphoma and which is being trialled for anal cancer.7 “Vorinostat is a
tremendously powerful drug,” says Deeks.
If HDAC inhibitors turn
out not to work, there is a second family of drugs called HMT inhibitors, some
of them already in use as cancer drugs, that reawaken latently infected cells in
a different way. They are only just starting to be studied.8
‘Kill’. We don’t yet
know if activating HIV-infected cells would cause so many to commit cellular
suicide that HIV would be purged from the body. Instead of enticing cells out of
hiding by activating them and seeing if they blow themselves up, how about a
more aggressive strategy of directly seeking them out and killing them in their
sanctuary sites? Amazingly, attempts to do this date from as long ago as 1988,
when a group devised a drug ‘missile’ that combined an antibody that locked
on to the CD4 molecule with a cell-killing toxin derived from the pneumonia
bacterium Pseudomonas. It wasn’t taken further because it wasn’t selective
enough, targeting all CD4 cells.9
By 2002, we were able to
make more specific antibodies that only locked on to the memory cells that form
the reservoir, and a team devised a similar cell-missile that eliminated a
proportion of latently HIV-infected cells in the test tube, from blood taken
from patients with HIV. The trouble is that while it cut the number of
HIV-infected reservoir cells by at least 80%, it probably didn’t eliminate
enough, while at the same time picking off rather a lot of non-infected memory
cells.10
‘Shock and kill’. We
still don’t have a way of infallibly identifying only those one-in-a-million
memory cells latently infected with HIV, so we can’t kill them and only them.
So researchers are devising combination drug missiles that would both entice
HIV-infected cells out of hiding and then seek them out actively for
destruction. The idea is to devise a three-component therapy that would combine
an immune stimulant, an antibody that seeks out activated cells, and a toxin to
destroy the targeted cell, a strategy that’s been called ‘shock and kill’.
One of the possible
problems with both ‘purge’ and ‘shock and kill’ is that anything strong
enough to activate enough immune cells might be too toxic to use – as has
already proved to be the case with drugs like IL-2. In particular, some
researchers are concerned that it may cause inflammation in places like the
brain which may have been what happened to Timothy Ray Brown: an opinion piece
warning about this appeared recently in the journal AIDS, recommending that
attempts to deplete the reservoir this way should be started gradually.11
What we really need is a
drug that stops cells from being ‘latent’ and gets them to rejoin the
actively circulating, and therefore visible and vulnerable, force of T-cells
without widespread immune activation. Researcher Robert Siliciano and his team
at
3. Delete resting cells
Another strategy is to try
and find markers that uniquely identify infected reservoir cells while they are
still resting, and kill them without ever having to activate them. Just because
we have found no such markers yet does not mean they don’t exist. Researcher
Rafick-Pierre Sékaly, scientific director of the recently established Vaccine
and Gene Therapy Institute of Florida, is investigating possible chemical
markers, including an enzyme called PDI (protein disulfide isomerase), which
might betray the location of resting HIV-infected cells. Sékaly has identified
a multiplicity of active genes that characterise resting cells and appear to
keep them quiescent, and has also discovered that the presence of another kind
of cell called myeloid dendritic cells may be necessary to keep them that way.13
Equally, HIV may gravitate
towards cells that display particular kinds of biomarkers already, other than
the ones we already know, and we could become able to characterise the subset of
cells that is most likely to become infected with HIV and target just those for
destruction. The cellular receptors CCR4 and CXCR3 have already been found to
characterise immune cells in the gut that are more likely to become infected.14
4. Dry up the reservoir
Cells don’t just
passively stop producing HIV and go into quiescent mode by themselves. The
process through which a small minority of CD4 cells join the reservoir of
resting memory cells is controlled by a complex chemical pathway whereby
specific genes are turned off – just like the lights at bedtime. Instead of
trying to prod the resting cells to come out of hiding, we could keep these
genes active and stop them ever going into hiding in the first place. Protein
disulfide isomerase (PDI) is in a family of enzymes that seem to be involved in
this process, but there are many more.
One old favourite is a
molecule called nuclear factor kappa B (NFκB), a ubiquitous gene activator
that was first investigated as a possible target for HIV drugs 20 years ago.
Aspirin is a NFκB inhibitor, though its effect is far too weak and
non-specific for HIV therapy. Low levels of NFκB are generated during the
low-level viral replication seen in antiretroviral therapy, and these levels
appear to help keep the HIV reservoir replenished. If you could find a drug that
had a much more specific effect on NFκB or one of the other molecules in
the cell suppression/activation pathway, you might be able to stop cells joining
the reservoir. Conversely, if you stimulate NFκB or related molecules with
a stimulant drug like the plant derivative prostratin,15 you turn reservoir
cells into activated ones – another example of the ‘purge’ approach.
However, that also
illustrates a problem: some of these cellular proteins, like NFκB, do
tremendously complex cellular jobs containing many feedback loops. In one
situation they are activators, in another, suppressors, and you may find that
inhibiting them has the opposite effect to the one you want. Scientists are
therefore investigating drugs that inhibit the mechanism whereby the reservoir
gets replenished in other ways. Amongst these is a drug called hexamethylene
bisacetamide (HMBA) which might be able to stimulate HIV-infected reservoir
cells without activating non-infected ones.16
Prostratin is quite an
exciting drug.This is because, while it stimulates cells to come out of hiding
and therefore makes them vulnerable to self-destruction or attack, it also
‘downregulates’ the CCR5 receptor, and indeed another receptor called CXCR4
which some types of HIV use to get into cells. This means that it could be our
best shot yet at a drug that purges infected cells but makes other cells less
likely to be infected. Prostratin itself looks rather toxic and until recently,
has only been available as an expensive extract from the bark of a tree from
The 'combo' cure
We’re used to
combination therapy against HIV and have more recently started talking about
combination prevention. A cure for HIV is also unlikely to involve one ‘magic
bullet’. Any cure is likely to involve several different approaches, used
together or sequentially.
For instance, we don’t
yet know if there is a threshold number of infected cells below which active HIV
replication is very unlikely to restart. It’s like cancer: can we tolerate a
few infected cells in the body, or will the presence of even one eventually lead
to the return of HIV?
We could therefore use
HDAC and NFκB inhibitors to flush out the majority of infected cells, use
engineered CCR5-negative cells to try and replace them, and use a therapeutic
vaccine to mount continued surveillance against whatever small minority of
HIV-infected cells might still remain. Or – since one of the problems with
therapeutic vaccination is that it depends on enhancing an immune response,
which may lead to more infection – use an immune-suppressant drug to ‘lock
down’ the infected remainder.
There have been a number
of attempts already to deliver several HIV eliminators in one package. For
instance, the Australian biotech company Benitec has devised a combination
consisting of an enzyme that snips out CCR5 from CD4 cells, combined with
sections of ‘interfering’ RNA that delete HIV’s reverse transcriptase
enzyme and its Tat protein, the viral toxin that over-excites CD4 cells into an
HIV-receptive state in the first place. This is all wrapped up in a vector, the
shell of an HIV-like virus that infects cells with the genetic products and gets
them to start making them. Zaia’s team at the City of Hope Hospital in
We are only as yet on the
first steps of a journey towards making a cure practicable for all, though in
researching this article I sensed a new confidence amongst researchers that it
might be possible. Many refused to guess at timelines, but Steven Deeks told me
that a usable cure strategy would take “at least ten years”.
Sharon Lewin of
In her keynote address she
said she was encouraged by two major cure-research initiatives now underway:
amfAR’s ARCHE initiative, which had a budget of $1m, and the Martin Delaney
Collaboratory, a public/private partnership of research labs funded to the tune
of $8.5 million by the US National Institutes of Health and named after the late
AIDS activist who founded Project Inform. However, she pointed out that less
than 10% of the current funding for an HIV preventive vaccine is currently
devoted to curing HIV.
“Cure research doesn’t
have to be hugely expensive,” she told HTU. “You don’t need the big trials
with tens of thousands of people you need for vaccine and biomedical prevention
studies. The initial discoveries can be made with studies of 100 people. But we
do need large, multidisciplinary consortia like the Martin Delaney project to
ensure that research is co-ordinated and not wasteful.”
The final question,
though, is one only Deeks addressed, among the researchers I talked to. We can
control HIV and the illness caused by it, but it’s becoming apparent we may
never be able to treat everyone because of the massive levels of funding, human
resources and healthcare provision needed. Will the same be true of a cure?
“A cure is going to be
expensive,” he said. “If we were going to do it with aspirin we’d have
done it by now. It may also carry with it a degree of risk, and researchers and
patients may have to ask themselves how much risk they are prepared to tolerate
if the result is going to be elimination of HIV.
“But it’s going to be
a lot more affordable than lifelong antiretrovirals in resource-rich countries.
As to whether it would be scalable for poor countries, though – ah, that’s a
very different question.”
References
Allers K et al. Evidence
for the cure of HIV infection by CCR5Δ32/ Δ32 stem cell
transplantation. Blood, advance online publication December 8, 2010.
Holt N et al. Human
hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted
to CCR5 control HIV-1 in vivo.Nature Biotechnology 28:839-847, 2010.
See Fulmer T CIRM’s
expanding reach. Science Business Exchange 2(44):6-7, 2009.
Lehrman G et al. Depletion
of latent HIV-1 infection in vivo: a proof-of-concept study. The Lancet 366:
549-555, 2005.
Sagot-Lerolle N et al.
Prolonged valproic acid treatment does not reduce the size of latent HIV
reservoir. AIDS 22(10):1125-1129, 2008.
Archin NM et al. Valproic
acid without intensified antiviral therapy has limited impact on persistent HIV
infection of resting CD4+ T cells. AIDS 22(10):1131-1135, 2008.
Archin NM et al.
Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide
hydroxamic acid. AIDS Res Hum Retr 25(2):207-212, 2009.
Shailesh K et al. Curing
HIV: pharmacologic approaches to target HIV-1 latency. Annual review of
Pharmacology and Toxicology 51:397-418, 2011.
Chaudhary VK et al.
Selective killing of HIV-infected cells by recombinant human CD4-Pseudomonas
exotoxin hybrid protein. Nature 335:369-72, 1988.
Saavedra-Lozano J et al.
An anti-CD45RO immunotoxin kills latently infected human immunodeficiency virus
(HIV) CD4 T cells in the blood of HIV-positive persons. J Infect Dis
185(3):306-14, 2002.
Nath A and Clements JE.
Eradication of HIV from the brain: reasons for pause. AIDS
25:DOI:10.1097/QAD.0b013e3283437d2f. Early online publication, 2011.
Yang H-C et al.
Small-molecule screening using a human primary cell model of HIV latency
identifies compounds that reverse latency without cellular activation. J Clin
Invest 119(11):3473-3486, 2009.
Gosselin A et al. The
chemokine receptors CCR4 and CXCR3 are biomarkers for central memory CD4+ T-cell
subsets with increased permissiveness to HIV-1 integration in infected
individuals. 18th International AIDS Conference,
Chan JKL and Greene WC.
NF-κB/Rel: agonist and antagonist roles in HIV-1 latency. Current opinion
in HIV & AIDS 6(1):12-18, 2011.
Biancotto A et al. Dual
role of prostratin in inhibition of infection and reactivation of human
immunodeficiency virus from latency in primary blood lymphocytes and lymphoid
tissue. J Virol 78:10507–15, 2004.
See DiGiusto DL et al.
RNA-Based Gene Therapy for HIV with Lentiviral Vector–Modified CD34+ Cells in
Patients Undergoing Transplantation for AIDS-Related Lymphoma. Sci Transl Med
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See http://www.iasociety.org/Default.aspx?pageId=349