Safer sex in a pill

[Guest guest]

19 November 2008 by Clare

New Scientist

As a gay man living in

the US, has seen every kind of AIDS awareness campaign out there. He is

intelligent and well informed, yet sometimes he has unsafe sex. He never plans

to, but he does not always have a condom handy and occasionally, on the spur of

the moment, decides not to use one.

Such behaviour is not

that unusual among gay men, but unlike most, (not his real name) isn't

leaving himself totally exposed. That is because his doctor is willing to do

something most would not countenance - prescribe a medicine that could

lower his risk of catching HIV.

This strategy is called

pre-exposure prophylaxis, or PrEP, and gets it from Marcus Conant, a doctor with a long history of standing up

for gay rights. PrEP has yet to be proven in clinical trials, and Conant will

only prescribe it for a select group of his patients - those who understand the

limitations of this tactic. But if the most optimistic predictions are borne

out, by taking a pill once a day is radically reducing his risk of

infection even if he has condom-free sex with as many people as he likes. It is

more likely that the medicine has a modest effect - perhaps reducing the risk

by around two-thirds - but even so, it significantly improves 's odds in

the dicey game he plays.

For now PrEP is only

available to a select few, but that looks set to change very soon. PrEP is

being tested in several large trials, with the first results due next year. If

it works, PrEP could save millions of lives from the epidemic that is still

raging around the world, infecting an estimated 7000 people every day.

33.2

million people living with HIV

While it sounds like good

news, PrEP is not without its critics. The main fear is that it will lull

people into a false sense of security, encouraging them to have more unsafe sex

and so, paradoxically, spreading the virus further and faster. There is also a

looming firestorm over a drug that apparently gives people licence to have

unprotected sex or inject themselves with illegal drugs.

Yet with vaccine research

in the doldrums, PrEP is seen by a number of leading specialists as a vital

weapon in the fight against HIV. " There's a lot of buzz about PrEP, "

says Fauci, head of the National Institute of Allergy and Infectious

Diseases at the US National Institutes of Health in Bethesda, land.

" There's some cautious optimism that this will work. "

The fact that a strategy

like PrEP is being considered at all is a sad reflection on the painfully slow

progress towards a vaccine against HIV. In the 25 years since the virus was

first identified, only two vaccine candidates have made it to the final stage

of human trials. Both failed. The most recent one, which also seemed the most

promising, flopped just last year (see

" The trouble with vaccines " ).

270

thousand children died from AIDS in 2007

Since then, scientists

have admitted that we still do not know enough about the virus, and that more

basic research is needed before anyone begins further human trials (Science,

vol 321, p 530). " It has been a sobering experience, " says Fauci.

As the problems on the

vaccine front have emerged, interest has grown in other strategies. First came

the idea of microbicides - antiviral drugs used in the vagina or rectum,

usually in the form of a gel applied before sex (New

Scientist, 8 February 2003, p 42). This field has also had its share of

disappointments, however. First a chemical called nonoxynol-9 was found to

irritate the vaginal lining and actually increase the risk of infection. Two

other promising compounds have also fallen by the wayside in the past two

years, for reasons that are unclear.

A couple of other

microbicides are still undergoing clinical trials, and there are more in the

pipeline, but these are still some years away from readiness. " The fact

that it's taking so long is disappointing, " says Alan Stone, a former

chairman of the International Working Group on Microbicides.

The beauty of PrEP is

that it involves drugs already used as a treatment for HIV, known as highly

active antiretroviral therapy, or HAART. These drugs have shelf-loads of safety

data to back them up and could be ready to use as PrEP long before any vaccine

or microbicide goes on sale.

Antiviral drugs work by

suppressing virus replication, thus halting progression to AIDS. The hope is

that when used prophylactically, the drugs will inhibit replication so well

that the immune system can clear out the virus and prevent the infection from

taking hold.

PrEP has its roots in an

existing strategy called post-exposure prophylaxis (PEP), in which people who

have come into accidental contact with HIV are given antivirals afterwards. PEP

has been used since antiviral drugs came on the scene in the mid-1980s. At

first it was reserved mainly for babies born to HIV-positive mothers and

healthcare workers who pricked themselves with used needles, but these days

people who have had unsafe sex can also obtain it - if they can find a willing

doctor. PEP reduces mother-to-child transmission by about 60 per cent and

needle transmission by about 80 per cent.

Early antivirals had

nasty side effects and involved taking large numbers of pills in complex

combinations, so they were not appealing for use as PrEP. But in the past few

years more user-friendly drugs with fewer side effects have been developed,

making PrEP possible. One such drug, tenofovir, is just a single daily pill.

The other is a two-in-one daily pill called Truvada, which contains tenofovir

plus a drug called emtricitabine.

6800

newly infected with HIV daily

Animal research suggests

that both tenofovir and Truvada block HIV infection, with Truvada being

slightly more effective. The degree of protection depends on species and dose,

but in some regimens Truvada completely blocks transmission (PLoS

Medicine, vol 5, p e28). " There's reason to believe two drugs

might be more effective than one, " says Lynn Paxton, who heads PrEP

research at the Centers for Disease Control and Prevention in Atlanta, Georgia.

One human trial of

tenofovir has been completed among 936 women in Ghana, Nigeria and Cameroon,

though not enough finished the trial to show clearly whether PrEP cut the

infection rate. There were six infections in the placebo group and only two in

those taking the drug, but the numbers were too small to rule out the

possibility that this was down to chance (PLoS

Clinical Trials, vol 2, p e27).

The good news from this

trial is that side effects appear not to be a problem. Adverse effects from

tenofovir and Truvada - usually diarrhoea, nausea or fatigue - are generally

mild and uncommon, and among the women in the African trial their incidence was

broadly similar in those taking the drug to those taking placebo. Kidney damage

can be a rare side effect of tenofovir, but this was not a problem in the trial

either.

15

million AIDS orphans worldwide

Several large trials

designed to answer the question of effectiveness are ongoing. They involve a

total of 19,000 people at high risk - including gay men, injecting drug users

and sexually active women in HIV hotspots - in various parts of the world (see

" Blocking HIV " ). The first results on tenofovir should be out next

year, with data on Truvada expected in 2010.

Results from animal

research suggest that users might not need to take a pill every day; twice a

week or just for a few days around the time of sex may work. " That reduces

the cost and any toxicity from the drugs, " says Mike Youle, director of

HIV research at the Royal Free Hospital in London, who was one of the first to

lobby for trials of PrEP. " Most people don't have sex every day. "

Conant's patients tend to use the drugs sparingly because of their cost: around

$30 a pill for Truvada in the US. Conant might recommend, for example, that if

someone usually has unsafe sex at the weekend, then they should take a pill on

Friday, Saturday and Sunday.

PrEP will not be a

substitute for a vaccine, however. " No one believes that anything will be

100 per cent effective, " Paxton says. Based on PEP, the best guess is that

the drugs will reduce infections by 60 to 70 per cent. There is also the fear

that it could prove counterproductive by encouraging users to have more unsafe

sex, and so accelerate the spread of HIV. The prospect of " a lot more

people going out and having wild unprotected sex is a big concern " , Paxton

says. " We have to communicate to people that this is not a replacement for

condoms but an addition to condoms. "

Conant, who has perhaps

more experience than anyone of seeing PrEP in the real world, accepts that some

of his patients probably do have more unsafe sex as a result. " I'm fairly

certain that some engage in more high-risk behaviour because they have got

access to the drugs, " he says. " But that's not true of all the

patients. "

However, such

" behavioural disinhibition " did not seem to happen in the African

trial, perhaps because the participants also received free condoms and advice

on safe sex. Bob Grant, who researches HIV prevention at the University of

California, San Francisco, and helped run the African trial, speculates that

some users may even have less unsafe sex. " PrEP might put people in a

different frame of mind, " he says. " When people take a pill a day,

that reminds them that they are at risk of catching HIV. "

Another concern is drug

resistance. HIV easily evolves immunity to antiviral drugs, which is why people

on HAART take three different ones simultaneously: the probability of the virus

acquiring resistance to all three at once is vanishingly small.

The fear with PrEP is

that some users will be HIV positive without knowing it, and because PrEP only

involves one or two drugs their virus will evolve resistence. These people then

become a potential source of infection for others on PrEP. The drugs are also

lost to them as a treatment, as well as to anyone that they subsequently infect.

Resistance is less common

for tenofovir and Truvada than for many of the other antiviral drugs, but it

does occur. One solution would be to insist that people on PrEP are regularly

tested for HIV, though this would raise the cost.

Not only does PrEP raise

scientific questions, it also opens a political debate. It is almost certain

that some people will find PrEP morally objectionable and that there will be

acrimonious debates over who should pay for it. In the UK, for example, Viagra

prompted a furore and the National Health Service now rations access to it and

similar drugs. Imagine what could happen with a drug that apparently gives

people a licence to have risky sex and take drugs.

There is also the issue

of cost in poorer countries. Many manufacturers now sell antivirals in these

countries at cost price - about $1 a day in the case of Truvada. Even so, the

drugs only get to about a third of those who need them. Against this

background, providing PrEP to everyone at risk from HIV in the developing world

seems a fantasy.

PrEP is clearly no

panacea, but it could be a crucial stopgap until a vaccine eventually arrives.

" You need as many different options as possible, " says Stone.

" We can't just hang around doing nothing. We have got to keep

trying. "

The trouble with vaccines

Why has the search for an

HIV vaccine hit so many dead ends? Vaccines against other viral infections use

viruses that have been either weakened or killed to trigger an immune response

without causing disease. This approach is acceptable for most diseases but is

seen as too risky with HIV, as a weakened virus could mutate and become lethal

again.The first attempts to create an HIV vaccine involved isolating the main

molecule on the virus surface, called gp120, and injecting it. As expected,

people given gp120 made antibodies to the virus, but unfortunately these were

not potent enough to prevent infection. Researchers have not given up on the

antibody approach, but it is probably at least 10 years away from producing

results. " There are no really good candidates at this point, " says

Dennis Burton, an immunologist at Scripps Research Institute in La Jolla,

California.In the meantime, most vaccine researchers have turned their

attention to a different branch of the immune system: the T-cells. While

antibodies destroy free-floating viruses, T-cells kill other cells that are

infected with virus. This approach was inspired by the discovery of a few rare

individuals whose T-cells apparently made them immune to HIV.T-cell vaccines

involve injecting HIV genes into the bloodstream. The genes are taken up by

cells and used to make HIV proteins. T-cells recognise the proteins as foreign

and learn to attack cells infected with HIV itself.There are more than a dozen

T-cell vaccines in development involving various mixes of HIV genes, but

confidence in this approach took a big knock in late 2007 after the first

large-scale trial ended in failure (New

Scientist, 16 November 2007, p 14).The trial, called STEP, tested a

vaccine made by drug company Merck. It comprised a weakened cold virus carrying

three HIV genes. For reasons still unknown, the vaccine not only failed to

protect against HIV but actually doubled the infection risk in men who already

had some immunity to the cold virus. Vaccine researchers are now reassessing

the whole T-cell approach, and a planned trial of a US National Institutes of

Health (NIH) vaccine very similar to the Merck one was cancelled in July this

year.The failure of the STEP trial could even make it harder to run trials of

any kind of HIV vaccine in future, as volunteers will have to be told that the

Merck vaccine raised the risk of infection for some people. " The warning will

be ramped up, " says Margaret ston, head of HIV vaccine research at the

NIH. It is not exactly a selling point.

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