Grace Aldrovandi interviewed by Polly Clayden
Multi-drug regimens, using more than three drugs, may be even more important for children than for adults - especially when they have developed resistance to existing drugs. Grace Aldrovandi is currently running a trial using mega-HAART in very drug-experienced kids - PACTG 1007.
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?
Yes, it was pretty similar to what 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 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%. A similar relationship between dose intensification and long-term success has 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 these 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 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 that the higher your viral load when you begin each treatment, the more difficult it is to become undetectable.
All your doses are BID, so that gets round difficulty of taking treatment at school, but do you still have major issues with children and adherence?
HIV-infected children are not born in a vacuum and HIV is not the only problem that they and their families have in their lives.
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.
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, they may or may not take their meds. 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 sit-down and graph out what a viral load does, go through the dangers if it went higher, tell them '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?
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. If my own child needed to take this many pills I would insist on a G-tube.
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...
You've had to make amendments to your protocol because of the pancreatitis risk, what are they?
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 kids with sickle cell disease already use hydroxyurea.
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's 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 counts of under 200 and who have failed as many drugs as these children have.
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 at all times in treatment though, not just in salvage,
Are you seeing lipodystrophy with your kids and other stuff that we're concerned about with adults?
Yes, children on HAART can develop lipodystrophy, lipid abnormalities, and diabetes. The PACTG 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.
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.
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 approach so 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 children to all the toxicity associated with this strategy. 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 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...
Study summary
Entry criteria
aged between 7 - 22
CD4 count less than 200
viral load over 100,000
nucleoside, PI and NNRTI-experienced
previously used nelfinavir and ritonavir for at least 6 weeks
Protocol
For 8-drugs to be 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.
Full article first published in Postive Treatment News Issue 7, Jan 2000 and DrFax #80.
 |
 |
 |
 |