study details

• aged between 7 - 22

• CD4 count less than 200 ¥ viral load over 100,000

• nuke, PI and NNRTI-experienced

• previously used nelfinavir and ritonavir for at least 6 weeks

• 8-drugs used together: d4T, ddI, 3TC, nelfinavir, ritonavir, saquinavir and nevirapine in higher than usual doses, and hydroxyurea.

• drug levels will be monitored with regular TDM testing

• drugs will be given once or twice a day.

• first two weeks in hospital and have someone visit them at home each day for the next twelve weeks, twice a day, to give them their medicine at first and then make sure they are taking (and being given) them properly.

• Their parent or guardian must give informed consent ¥ the child must know his/her HIV status and (in states where the law permits), give their assent to participate.

• Children, their parents, and health workers must all believe they can be adherent.

Multi-drug regimens, using more than three drugs, may be even more important for kids than for adults - especially when they have developed resistance to existing drugs. Some of the most innovative and impressive approaches to paediatric care have been developed by Dr Grace Aldrovandi.

Interview by Polly Clayden.

Paediatrician Grace Aldrovandi was described to me as "...a brilliant scientist, compassionate clinician and treats HIV as if it were something that could kill a child (imagine that!)". She works at the University of Alabama and is currently running a trial using mega-HAART in very drug-experienced kids.

This term for intensive multi-drug therapy was first associated with Julio Montaner, who"s strategies for heavily pre-treated adults, she admires; she enthuses "When I heard about what he was doing in Canada, I just wanted to go there and pay homage, at last it"s got a name, it"s respectable..."

Her study is called PACTG 1007 which she says has been a great gift to her critics, "007 - you know what that means? Licence to kill! Well I want to kill this virus! As a virologist I know that strictly speaking you cannot kill viruses as they are not living organisms but emotionally that is what I want to do".

She has tremendous optimism, and uses a word usually approached with caution in HIV (or replaced with David Ho"s rather measured "eradication") - "I use a lot of four letter words in my lab, and one of them"s cure, I think you have to have high hopes and go for gold". It was most refreshing to interview a doctor, not only brilliant and compassionate, but also not afraid to use the C-word...

Before setting up this trial, how long had you been treating kids with multi-drug therapy like this in your regular clinic?

We first began over three years ago. Kids were coming to us very heavily pre-treated and resistant to everything with viral loads in the millions and CD4s of nothing.

So you were troubleshooting well before mega-HAART gained currency as a term?

Yeah, it was pretty similar to what Julio Montaner was doing with adults - he started because his patients forced him to try this as a last resort.

You compare heavily pre-treated children with HIV to multiple-relapsed cancer patients, and therefore use very intensive therapy. Was this considered a very radical approach?

Everybody thought I was joking, but I thought it made sense. I"ve always been intrigued with how leukaemia was cured in the early days. I picked up a lot of standard oncology textbooks, as you can see from the study and tried to learn. I was fascinated by the relationship between DOSE intensity and success.

If you use too few drugs and/or a lower dose of chemo, you still get a similar initial response to treatment, but only for a limited time. For example, children with acute leukaemia who received 94% or less of their chemo were more than five times more likely to become ill again in the future than those who received 99% of the chemo. A similar relationship between dose intensification and long-term success have been seen with breast, colon, ovarian and many other types of cancer.

When lower doses, or fewer drugs, have been used to avoid toxicity rates, there is a drop in the rates of people who are cured.

With HIV, when we get people undetectable, we have got them into a sort of remission. Although some people object to this comparison because they say that people in cancer remission don"t have latent cancer, in many ways they clearly do. And although we don"t understand what governs relapse in cancer we understand more about it (or think we do) than with HIV.

So using the cancer model, given the higher risk for kids" to become ill and that this treatment is probably their last and best chance, it makes sense to use everything you"ve got...

Exactly. It is more difficult to get kids to undetectable levels of viral load anyway - because they have much higher levels to start with, especially if they"ve already used a lot of other drugs. A lot of the data shows thatthe higher your viral load when you begin each treatment, the more difficult it is to become undetectable.

So do you usually start children on more than three drugs?

I have started children on three drugs, but increasingly I tend to start with much more. For example, I had a newly-diagnosed two year old and started him on six drugs, he was very sick with a high viral load and I wanted to get him controlled as quickly as I could.

He had had terrible problems with his bone marrow, his kidneys, his heart, his brain and everything was going wrong, so it was a very difficult hospitalisation for the mom who expected every day to be his last. I kept saying to her, "It"s very difficult but don"t worry, stick with me, soon your child will be walking and you"ll have an entirely different baby".

Well, I saw her in the clinic on Monday and she said to me, "Boy were you right, he"s not quite walking but he"s crawling around, being naughty and keeping up with his one year old sister". She was a totally different mom.

All your doses are twice-daily, so that gets round difficulty of taking treatment at school, but do you still have major issues with children and adherence?

Adherence is a big problem, but our children and their families have a lot of problems. HIV-infected children are not born in a vacuum and HIV is not the only problem that they have in their lives.

A lot of them are from families with (what"s the PC term for this?), well they don"t have a lot of financial resources, a lot of them are cared for by single parents or single grandparents who are taking care of a number of children. Also, psychologically, it"s very difficult for a lot of women to have to wrestle with their toddlers (babies are slightly easier), especially on three-times-a-day regimens. You can spend an hour getting them to take their medication and they can then spit them all out again.

The formulations are horrible, so you can"t really blame the children. Plus there is the issue of confidentiality. Unlike a child with diabetes where everyone rallies round to be supportive, a lot of times you don"t want your family or other people to know about HIV, so you have to take them into the bathroom and sneak in the pills.

Some of the liquids have to be refrigerated - so what do you do when you"re out on the holidays or on weekends? And a lot of these kids go to school early in the morning so, in addition to getting your three, four or five children dressed and fed and ready, you have to get a whole handful of pills down them - it"s no fun.

I would love for the schools to be able to give the meds and give the parents a break, but because of confidentiality, it"s not usually possible. Children tend to fight the school much less than they fight their moms. Adherence for children is a big deal, and maybe one of the reasons we have higher rates of detectable viral load in children.

And then, in adolescence...

Not good. Yesterday, I saw an eleven-year-old girl who had been undetectable for over two years and now her viral load is creeping up. When she was young, her mom insisted that she take her meds, but now she"s of a age where she takes, if not full responsibility, then a fair amount of responsibility for taking her meds.

Her mom gives her the meds, but she may or may not take them. It"s very hard for adolescents, they feel that its very unfair, they worry about their friends at school finding out. They feel very isolated because there aren"t that many kids in the same situation and they really resent having to take the medicines. I sat down and graphed out what a viral load does, went through the dangers if it went higher, told her "Oh I wish I could take this away..."

Do you find it helpful when children begin to understand what a viral load is and about resistance etc?

I think that it helps. What I do is measure out one millilitre of water and I show them that they have x number of copies of HIV in that amount of blood. I try to explain it that every time you take a pill it"s like a bomb that will blast the HIV, I try to make it as concrete as I can. Sometimes it works, sometimes it doesn"t, but I continue to try and educate knowing that it sometimes falls on deaf ears. Part of being an adolescent is thinking you"re invincible, and it"s very hard when you feel well to think that there"s a virus inside you that could kill you. So are there any secrets to getting kids to take all those meds? For children, I"ve become more and more convinced that, the thing to do is put in a gastrostomy tube. It can be a psychological barrier for some doctors, but it is much less invasive than a central line which has more complications and which are used routinely.

G-tubes are really not that bad, you can remove the tubing and they"re just like an extra belly button, nobody needs to know and you don"t need to worry about infection complications. If my own child needed to take this many pills I would insist on a G-tube.

Even for the first child on our protocol - he was fine for the first three or four weeks, but as he started feeling better, he just refused to take his medicines or he would vomit them back up. So, the doctor put in a gastrostomy tube that made it so much easier for him, and the mother loves it.

He still takes some of his pills by mouth, but some he just hated, especially the nelfinavir, which made him feel full. It"s hard when you"re having to take forty pills a day, twenty and twenty, for some kids it can take up to an hour at a time to have to sit down and take all this stuff.

He"s OK with the d4T and the saquinavir, but the rest goes in the tube - you just pin them down, push the stuff in, then disconnect them. They go and play, and nobody thinks anything of it - it just takes five minutes.

Most of our children who are that sick are small for their age anyway. So what I tell the moms to do, if anyone notices it in the summer, is just tell them he doesn"t really grow too well because he was premature (or whatever), and it"s just to give them some food at night. I find that quite do-able and that way you save their mouths for feeding.

For adolescents though, it"s a hard-sell, but frankly all these teenagers go around and pierce their belly-buttons (and everything else) - if we could come up with a sexy button for them, maybe we could convince them that it"s the thing to do...

I noticed in your study that there is quite an age- span with a high upper limit - from seven to twenty two years. Why these particular ages?

I tried to be as inclusive as possible, for a lot of studies thirteen or even eighteen is the upper limit. The reason that we chose seven as the minimum age though is that we felt that what they were undertaking was so aggressive that the kids should be of an age when they could, if not consent, at least assent.

They should know about their HIV diagnosis, understand what they"re doing and realise why they are doing it. I also wanted to avoid very young children because then changes in the pharmacokinetics become an issue. I would love to have done this for adults, but I"m a paediatrician.

But by enrolling people up to twenty-two, aren"t you treating some young adults anyhow?

That"s right. Though most of the interest in the study has been for kids who are around seven and eight. The study is actually on hold though for the moment, we can"t enrol anybody, and we"ve had to make a few changes to the study because of the problems with pancreatitis in another adult study.

What amendments have you made?

We lowered the dose of d4T (it was double the standard recommended dose), but we have continued with the ddI and we have now instituted closer monitoring to avoid those risks. We have a bunch of kids waiting to enter in the study when these changes are approved.

I also noticed you are using hydroxyurea...

Yes, so far, but we have to go back to all the regulatory people and of course have very vigilant management and appropriate interventions in cases of any complications. But hydroxyurea is already used by kids with sickle cell disease.

So as soon as these doses are sorted out, will you resume - it does seem important to know the outcome of this study?

Yes, we look forward to restarting to see if this approach works. Our limited experience, and Montaner"s data, would suggest that it does for many but not all.

Our entry criteria are much more stringent than anyone else and we"re taking the children who are the most ill. I don"t know of an adult study that has targeted people with a viral load of over 100,000, CD4 count of under 200 and who have failed as many drugs as these children.

The data from larger adult trials would suggest that if you are NNRTI experienced you are much less likely to respond, but we"ll see. It"s really to see if the principle will work. I know that even within paediatrics, a number of investigators have been moving towards five, six, seven drugs, but I think this is the first children"s study to look at this.

Do you use TDM to check their levels, this seems particularly important with children?

I am fortunate enough that I have a pharmacologist who does tests here for me. It"s not very widely available in the US, but I think it"s something that is essential in treating children with HIV, because the levels of drugs in their bodies change all the time. It needs to be done up-front at all times in treatment though, not just in a salvage setting.

Are you seeing lipodystrophy with your kids and other stuff that we"re concerned about with grown ups?

Yes, HIV-infected children on HAART can develop lipodystrophy and lipid abnormalities, and I"ve even heard of children developing diabetes.

The Paediatric ACTG is developing a study to look at the metabolic effects and the effects on growth of HAART. Anecdotally it appears to occur less than in adults, but it"s hard to really say, there"s so much more adult experience.

I think though, that we may actually get useful answers for adults from the studies in children.

For children that aren"t growing well, do you find they catch up when they use HAART? Have you found growth hormone useful if they don"t?

As paediatricians we"ve always been focused on the whole area of failure to thrive, which has dramatically decreased with HAART, but some children, even children with undetectable viral load, fail to grow.

We haven"t used human growth hormone here but I know of others that have. At UCLA (University College Los Angeles) a group of adolescents with lipodystrophy used it and they responded. There is a study being developed to look at growth hormone and see if it does help. I have not had anyone with bad enough lipodystrophy or who has not developed sufficiently that I would consider using it.

Treatment interruptions (so-called drug holidays) are becoming a popular current strategy for some adults, would you consider this for children, particularly if they were having difficulties with adherence?

Yes, if there are real difficulties with adherence, I have come to the conclusion that no drugs are better than intermittent drugs. At first I was rather scared taking them off treatment, but I have kids off drugs who have maintained stable viral load and CD4 counts. But then I have another kid in hospital that was up and down on his meds and his mom admitted that he wasn"t really taking them so we took him off. He was doing fine, for four for five months, then he shot up to a viral load of three million.

I told his mom we have to treat him. He"s only six so we got him in hospital and tried to teach him to take his pills and he tried really hard, but with the saquinavir soft gel caps (they"re huge), he just couldn"t swallow them. So we put a tube in and we"re waiting for him to respond. I think seeing the numbers rise like that made the mom really understand what we"re up against.

And immune based therapies do you use those with kids?

Oh yes, and we have thought of adding IL-2 to this study, but it"s already so complex as it is.

Do you think that you"ll use this very intensive multi-drug therapy more up-front and not just in a salvage setting?

Yes, I would like to start mega-HAART in kids up-front. People are talking about the whole issue of a latent virus and about intensification but only with one or two drugs.

If you look at the amount of radiation it takes to shrink a tumour... again I think we should learn from the experience of treating cancer... and really aim for what"s maximally tolerated, and then back off. This should be done in the setting of a study though, so we can answer the question properly.

But there"s a lot of toxicity associated with this, we need to answer this rigorously and scientifically.

Back to the 1007, and by way of a conclusion, can you summarise what this trial will show...

That if we throw everything that we possibly, reasonably (reasonably in quotation marks that is) can at the virus in this very, very, very sick population with resistant virus, can we get anywhere?

If we can"t, then we learn that with our present drugs we cannot beat the virus, when it gets to this late stage, and that it"s probably not worth subjecting to all the toxicity associated with this strategy and that we would be better off striving for a palliative approach. However, if we can show effect, it means that our weapons (drugs) can still be used to knock the virus down, even after it has won the first several rounds of the fight.

I have no doubt that we will have to pay a price in terms of side-effects, so that every family will have to decide if the potential benefit is worth the risk. Hopefully this study will provide children and their families with an additional option which because it is collected in a controlled scientific manner, will be supported by data.

What happens next then, can we then go to a maintenance regimen?

That"s what we"ll look at next - daughter of 1007...

The mortality rate for children with a viral load of over 100,000 and less than 15% CD4 cells that have failed on all the available antiretrovirals is over 80%. This study is a last chance for these kids.

glossary: gastrostomy tube (g-tube) - a small tube fixed through the stomach, to give medicines. The tube is not permanent and can be removed later when the child is able to take pills or syrups.

PK (pharmaco-kinetics) how drugs are absorbed in your body

PACTG U.S. Paediatric AIDS Clinical Trials Group

taste is most important...

At Novembers ECAB meeting focussing on paediatrics, Professor Christian Courpotin from Paris presented a kid"s adherence study. They asked a group of 4 to 12 year olds what was the most likely thing to put them off taking their meds. The overwhelming majority answered taste (second and third were pill size and tired of taking drugs), but the most frequently mentioned adult off-putting factor - ie pill count hardly featured at all. Drug companies please note.

"I explain that, every time you take a pill, it"s like a bomb that will blast the HIV..."

"Adherence for children is a big deal, and maybe one of the reasons we have higher rates of detectable viral load..."

Thanks to Body & Soul for drawings