Moderators: Di Gibb, Stefano Vella
Despite a great deal of interest at the moment in STIs as a part of adult care, so far no research has been done into possible use of these strategies in paediatrics. Stefano Vella is involved in a large Italian STI study in adults, and the PENTA group are currently discussing studies for children in Europe.
Di Gibb: We are discussing the possibility of doing structured treatment interruption studies in Europe within PENTA.
Guidelines from the US, for treating children early during primary infection, have been adopted quite widely, but until now we haven't really thought about stopping treatment in these kids. In some of the adult trials the set point was lowered after stopping treatment in primary infection, but we are concerned that children will not develop a similar HIV specific response.
A second point is that, because children's CD4 counts increase better than those in adults during HAART, we may have some room for doing structured treatment interruptions even in chronic infection.
Stefano Vella: I am not a paediatrician but these are interesting points and you are looking at primary infection if you treat children after birth. I don't know how they compare to adults and I'm not sure about when children should stop treatment.
Lisa Frenkel: I think that in support of stopping, all of us have heard cases of tremendous CD4 recovery which have prompted a discontinuation of treatment. And we have several children who have now been off treatment for more than two years and lost hardly any CD4 cells. This may be to do with thymic reserve, which will be much better in kids. Instead of the 4-7 years that adults take to progress to AIDS maybe these kids would take 10 years. This is another reason why they may be room for the trials in children.
Stefano Vella: And the reasons that we have structured treatment interruptions for adults - to do with quality of life issues are even more important in children's lives.
Question: Stefano, why don't you include children in the new Italian STI study?
Stefano Vella: I think we need to have data before we start with kids, and I think it needs to be done by paediatricians.
Di Gibb: It should be in parallel...
Stefano Vella: Maybe,
Stephen Arpadi: I am going to play the sceptic. Franco Lori's experiment in monkeys presented at ICAAC showed significant differences between interruptions in acute versus chronic infection. In acute it works very well, but in chronic it does not.
Another issue is related to informed consent. Do you think you can randomise children into arms that are so different. How do you control for people entering a study who may strongly prefer the interruption arm or into the standard of care?
A third point is that we think that the immune system of children is very naive, and allows a lot of manipulation. But if we think of something as common as PCP - a glycoprotein antigen - if you don't link with a protein you don't induce immunity if you are younger than two years of age. So we have a very plastic immune system with the potential for recovery, but we also have limitations.
Ronald de Groot: I would also like to add a caution. In Europe the number of children available for studies is very low, if you want to study this in a structured way. If we look to the results from current studies, for example from the lopinavir/r trial where 70% - 75% of the children still have viral loads below 50 copies after a year. It may not be very promising prospect to propose a study because there are too few people to study.
I would suggest that we need a different approach. We hear a lot of important clinical observations, yet these observations are not put together in a structured way. I don't think that we are ready to go ahead with this in a paediatric population. I would like to see what the results in the adult population are first.
I would like to see better controls and data on the patients who fail (for whatever reason) and who are not on therapy. We need to know what happens to these patients - we want to know what their CD4 counts are, how their viral load changes, and what are clinical barriers. We should be looking to develop a registry of all kids with HIV - not so much because we are interested in another study, but because we are interested to see how any individual child responds in a situation where they are off therapy.
Di Gibb: I think it would be very hard at this moment to include children in treatment interruption studies because so few children currently get persistently low viral loads. This may make it difficult to know whether increases in viral load are necessarily due to the treatment interruption rather than treatment failure.
Lisa Frenkel: I must emhasise that I am only interested in children in this context who have had an excellent treatment response. I am thinking specifically of children whose CD4 count has increased from under 100 to over 1000 cells/mm3. They have now been successfully treated for a certain period of time. How will they do if they stop? Certain children have stopped and they have done extremely well although we don't understand the immunological basis of the respons
Are there questions from the audience?
Question: This is a comment rather than a question. My first thought about doing these trials in a paediatric setting, is the difficulties we have with adherence in adults and stopping and starting. It can be difficult for adults when they have to restart having stopped - and may this be even worse for children?
Stefano Vella: We had this problem regarding stopping and starting in adults when we talked to our colleagues and community organisations. Many were not so concerned about this as it could actually increase adherence if it is carefully explained. The advantages of a drug holiday are as appealing to children as they are to adults - you can say that if they behave very well in these three or four months - they can then have a period without treatment.
It is important do this in the context that clearly explains they will have to start treatment again later though. Some of the adult patients found it difficult to restart 'lifelong' treatment after they experienced how good it was to stop. If you tell them that they have to start again but then you may also re-stop again later - it is a better perspective and it works. The long-term perspective is to study this over ten or twenty years.
Because the response to therapy has been so effective, we now have to think of treating patients for much longer, and this is a strategy to make this more possible. Because I have heard of data, for example, about the toxicity of therapies that accumulate. Even with the best drugs available, it may not be possible to avoid the accumulative toxicity after even four or five years. I would prefer to have cycles with the good therapies.
Ronald de Groot: One of the core issues with treating children is adherence - and it is an area that I don't think we are doing very well. Although in the Netherlands we see children every week, or even more frequently when they start treatment, we then go to a regimen where we might see them only once every three months.
After a year or two we increasingly see kids who, despite all the efforts of the physician and the HIV nurse and the social worker are still not adherent. We use pill boxes and other support material but still we don't do well, and we need to pay much more attention to the social science aspects of HIV care. We need to be able to estimate which children are at risk of non-adherence. For example, we use questionnaires before starting treatment with these kids to get an idea of their social background and social support in the family. We hope that this will give us information, which we can link to failure in the long term so we can know which populations need special approaches.
Maybe one visit every three months is not sufficient, maybe we need to see them every four or six weeks. One home visit is not enough for many people, maybe we need more intensive consultation with parents and children. I think that this is a major factor behind the results and we need to deal with adherence before even talking about triple therapy or quadruple therapy or treatment interruptions.
Question: We can measure glucose levels quite quickly in blood with a 'pinprick' test - how far do you think we are away from this for measuring drug levels?
Ronald de Groot: I think we are still far away from that. We use HPLC methods that we developed ourselves. There is not one commercial company that is developing immuno-assays, so unfortunately I think we are many years away from that.
Question: Is it possible that children may do better with adherence than adults because their mother gives them the drugs, and also with treatment interruptions?
Di Gibb: There are a lot of complicated issues related to adherence in kids. For example, if mothers are HIV-positive themselves, it depends which treatments they are on and what they think of their own treatment. They are certainly not going to want to give something to their children that makes them feel dreadful.
Children also are getting older - in the US now almost a quarter of kids are going into adolescence and we are not that far behind in Europe. You then have all the issues of adolescents starting to take their own therapies, which involves developing new approaches again.
For structured treatment interruptions we need some parallel trials in children. If we wait until we get adult results, everyone will be doing it in a chaotic way anyway. Also, the answers may well be different in kids because of their developing immune system. Maybe we can think of situations where we stop for longer periods of time and restart based on falling below a certain CD4 count. That might be a useful trial design.
This could help adherence because you can explain 'if, your CD4 count has dropped below this level you need to restart'. So it is not just stop and start in a vacuum and I think that would be a good idea for kids.
Question: Could you address the particular issue of hypersensitivity reactions, and using drugs that require dose escalation regimes in structured treatment interruptions.
Stefano Vella: This is a good question. We don't include patients on 'triple nucleoside' therapy because this invariably includes abacavir and this is a risk. We might also need to exclude abacavir, even in terms of background nucleoside therapy. There is a risk of the person stopping treatment while they are having a mild hypersensitivity reaction that hasn't been noticed. Restarting with abacavir is contraindicated and can be very dangerous. It is a question of being very careful in monitoring patients while they are on therapy to catch any early signs.
Question: I think there is a place for structured treatment interruptions in children and perhaps this will lead to a better response. I am wondering about the immune activation when you have viral rebound. Are there any approaches to suppress immune activation during a period without drugs?
Stefano Vella: It may be possible to do something during the interruption or just before. At the beginning, for example, one possibility would be to decrease immune activation and so incur less damage. Another strategy could be to use IL-2 before stopping - but we didn't want to add this complexity to the trial. If you have a large viral rebound and a greater number of CD4 cells ready to be infected, this could lead to further damage - although I know that this is an approach in the UK.
Octavio Ramilo: I would like to raise the issue of salvage therapy in people who have very high viral load and resistance to existing drugs - and the risk of having large drops in CD4. I know two people - one adult and one child - who then had practically no CD4 count left after a long treatment interruption. It was very hard for them to maintain the new therapy when they restarted althoughI am pleased to say that after several months they saw the CD4s increase again.
Stefano Vella: In some patients it works but I am scared that it may only work for a short time. When wild type virus returns it drives the CD4 decrease but I also think that resistant virus will return later, possibly in only a few weeks, although we don't have data from sufficient studies
Lisa Frenkel: This is definitely an area where we need trials. The treatment results presented by Veronica Miller who used mega-HAART after a treatment interruption, and the data from Julio Montaner who used mega-HAART with no interruption, both look very similar to me.
I think you get a CD4 loss with the treatment interruption, but the exact mechanism from the benefit of mega-HAART is not known. Because there can be so many different sub-populations the virus that is resistant to all the different therapies may only be minimal. It is the people who don't have viruses with good fitness that are resistant to all the different elements of mega-HAART that I think are the main responders. There are diverse and strident opinions about the use of STI for re-sensitisation of the virus to previously resistant drugs, but I, like Stefano, don't think that is the mechanism.
Di Gibb: Are you suggesting we should be doing trials in heavily pre-treated children, like the one that Octavio was describing, because I don't agree with this. You may stop treatment for a while for other reasons - because they are so fed up , or you think that a break will improve adherence in the subsequent regimen, but I am not sure I want to randomise them to stop and watch and wait for some response.
Lisa Frenkel: I would like to see the people who are believers in treatment interruption for re-sensitisation look at it in a more objective way and there is therefore theoretical room for trials.