Posted on March 8th, 2009 1 comment
Why treatment of HIV infection must be individualized.
HIV disease is usually a progressive disease. That is, it has a starting point; the time of infection. The disease then progresses, and without treatment will generally end fatally. There are some very fortunate HIV infected individuals who are able to control viral replication and remain disease free. But for most, HIV disease does progress. But, for each individual, the rate at which it progresses varies widely. Disease progression is reflected in the fall in the numbers of CD4 lymphocytes.
So any single CD4 count measurement is really a point on a descending curve, one that does not necessarily proceed in a straight line, and falls at widely differing rates in different individuals.
Recommendations for the treatment of HIV infected individuals are issued periodically by DHHS and bodies such as the International AIDS Society. These recommendations, particularly those concerning when to start antiviral treatment, have always included a particular CD4 count as a signal to start or to consider starting antiviral treatment.
All individuals with a CD4 count of less than 200 should be on therapy. They are in great danger of acquiring a possibly fatal opportunistic infection and evidence derived from clinical studies makes it absolutely clear that antiretroviral treatment is life saving.
But what about people with higher CD4 counts? Here there is uncertainty about when in the course of HIV infection it is best to start treatment. Of course, if the drugs were completely harmless (including cost) it might be less important to have an answer to this question. However the drugs can have significant adverse effects, some of which only become evident after years of use. For people with fewer than 200 CD4 lymphocytes, the benefit of antiviral treatment overwhelmingly outweighs the risks.
For others, a very mixed group, with CD4 cells anywhere from 200 to over 1000, and each with a different rate of disease progression, we cannot, with any security, make a “one size fits all” recommendation as to when it is best to start treatment.
The best way to resolve clinical uncertainty remains randomized prospective clinical trials. By now we might already have obtained reliable evidence as to whether, on average, it is best for infected individuals with more than 200 CD4 lymphocytes, and who have no symptoms, to start antiviral treatment immediately, or to defer it. (A suggestion made in 1997 when the first guidelines were issued: http://aidsperspective.net/articles/guidelines1.pdf )
The current recommendations, regarding people with greater than 200 CD4 lymphocytes, and who are without symptoms, propose a CD4 count of 350 as a point to start treatment ( many believe this number should be 500). This recommendation is made for all individuals – it is a one size fits all approach. This kind of approach is appropriate for some aspects of treatment; for others it is very wrong.
Perhaps the most important example of a recommendation, where its application across the board is problematic, is that which deals with the time when antiretroviral treatment should be started in individuals with greater than 200 CD4 lymphocytes. This recommendation specifies a specific CD4 count at which to start. As noted, for individuals with a CD4 count below 200, there is no doubt that they will benefit from therapy. For others who have no symptoms, specifying a CD4 count for all is mistaken. It is here that individualization is necessary.
The reason is that no two HIV infected people are the same with respect to the rate of disease progression. During the early years of the epidemic, before antiretroviral treatment was introduced, we soon noted that the CD4 count declined at different rates in different people, and not necessarily in a straight line. As noted, at one extreme, there were the few fortunate individuals in whom there seemed to be no disease progression, at the other there were the few people whose CD4 cells fell very rapidly after infection, and who did not survive for more than 2-3 years, but most fitted somewhere between these extremes .
To illustrate this I have considered four possible situations. This is a picture of the possible rates of CD4 decline in four different individuals. . It is true that these pictures are constructs, but they do accurately reflect the observed variability in disease progression; real examples showing this variability would be easily found in my medical records, and of course in those of other physicians during the period between 1981 and about 1993.
The dip in CD4 cells following infection is usually seen when there is an opportunity to observe this. CD4 cells then rebound to a level called the set point, which will be different in relation to the pre infection level in different people. From then on it declines, but at a very variable rate, and can remain steady for varying periods before declining, again at varying rates.
Look at where three of them (A ,B and C) reach a count of 450 CD4 lymphocytes; A (an unusual rapid progressor) gets there in about one year, B in about 3 years, C in 7 years, and D, who is a fortunate non progressor is nowhere close after 18 years.
The arguments for starting early are not only to forestall reaching the dangerous level of 200 CD4 lymphocytes. The continuous deterioration of the immune system and diminished chances of recovery at lower counts are also arguments for an earlier start. There is also the possibility that there is a greater incidence of cancer, – other than lymphoma and Kaposi’s sarcoma, at higher CD4 counts in HIV infected people. If this is so then it remains to be shown how frequently these events occur and whether antiviral therapy can avert them.
Treatment itself, particularly if extended over many years, is not without risks, some of which cannot even be completely known yet, particularly with the newer antiviral agents. We have to do the best we can in making a risk benefit assessment. In order to do this we should attempt to obtain information on the rate of disease progress in any one individual. This may not be entirely possible, as the rate of disease progression in any one individual may not be steady; it may accelerate or slow down. But it is possible to obtain a good, if not perfect, picture of the course of HIV disease in any one person.
How might we obtain some information about a given individual’s rate of disease progression? Apart from obvious exceptions, and in people below 200 CD4 cells, there are no emergencies in HIV medicine. For each person we generally will have time to observe the CD4 count and viral load over a period of 6 to 12 months and obtain some idea of the rate of progress. A rapid fall in CD4 count might result in a decision to start in less than six months of observation. Or a consistent fall in CD4 count might lead to a decision to start treatment at CD4 numbers higher than even 500. This is far from perfect, as changes in CD4 cell numbers do not necessarily follow a straight line. But it is far better than basing a decision on a snapshot – which is what the experts are telling us to do.
Individualization involves more than considering the rate of disease progression. There are other factors, such as associated diseases, domestic and social circumstances such as a lack of housing, as well as mental health issues, and many other considerations that are involved in individualization. Observing people also provides the time to establish a doctor patient relationship and for the physician to become familiar with the patients particular circumstances.
The natural history of untreated HIV disease is relevant to the “when to start treatment” issue and will be the topic of the next post.
 Evidence supporting the recommendation is derived in part from retrospective observations. The reasons why these are unreliable guides are outlined in the previous post. It is critical to as far as possible, eliminate bias in study designs because this increases the probability that a particular outcome can be interpreted as indeed resulting from a particular intervention. In this case it would be that improved survival is due to an earlier start of antiviral therapy and that the medications mediate the effect – and not for example, from simply being under the supervision of a physician. Retrospective observations, that is, looking back at information already gathered cannot be free of confounding factors as described in the previous post. In a prospective study people would be randomly assigned to receive immediate treatment or to defer it. This will give us the most reliable answer to the question of which approach is better on average.
Examples of measures that should be taken in the treatment of every HIV infected person, irrespective of the rate of disease progression are the types of tests that are performed on the initial assessment of an infected person. For example, the initial assessment of an HIV infected person should always include not only CD4 counts and HIV viral load measurements, but also tests for hepatitis, toxoplasmosis, and many other investigations. Another example of an intervention that is appropriate for categories of infected people is treatment to prevent Pneumocystis pneumonia in people with less than 200 CD4 cells. And of course, people in this category must always be offered antiretroviral therapy.
Posted on February 26th, 2009 1 comment
When is it best to start antiretroviral treatment?
The issue of when it is best for asymptomatic HIV infected people with more than 350 CD4 cells to start treatment with antiretroviral drugs has received renewed attention lately. Reports at recent conferences and discussions of these reports on several websites all seem to favour an earlier start than at a CD4 count of 350. There is absolutely no reliable evidence to support this recommendation. The evidence that is presented derives mostly from retrospective observations. Such retrospective studies cannot provide reliable evidence that improved clinical outcomes in those starting treatment earlier are actually caused by the antiretroviral drugs. That this is so can only be an hypothesis, a theory to be tested by prospective studies. Such a prospective study would essentially follow people who are randomly assigned to start treatment immediately or to defer it.
Some of the problems associated with interpreting retrospective observations are outlined at the end of this post1.
The “when to start” issue of course only applies to infected persons who are not symptomatic and have a CD4 count above 200. For those with fewer CD4 cells there is no doubt at all that such individuals should be on therapy.
If the antiviral drugs were completely harmless, with no toxicity, we would have no problem at all, apart, of course from the financial toxicity. However the drugs are not without problems, particularly if we are dealing with taking the medicines for a life time. The newer drugs are touted as being less toxic. However it takes years for some toxicities to become manifest. How many years were people taking Zerit, (D4T,stavudine) before we knew about its effects on fat distribution? Another example of toxic effects only becoming apparent after years of use is thinning of bones caused by some antiviral drugs.
When potent antiretroviral agents were introduced in the 1990s their impact on reducing mortality was unequivocally demonstrated in persons with more advanced disease. This immediately left us with a question regarding the effect of starting these drugs in individuals with less advanced disease.
Rather than admitting that the answer to this question was unknown, and required to be studied in a prospective fashion, the Department of Health and Human Services issued a set of guidelines. It is understandable that issuing guidelines, in the face of uncertainty is reasonable, but they must be regarded as interim, pending the outcome of studies.
In 1997 I wrote a letter in response to the publication of these guidelines; it was received by the Guidelines Committee, but I was sent absolutely no response. The letter can be seen here: http://aidsperspective.net/articles/guidelines1.pdf
Despite attempts to rely on retrospective observations to resolve clinical uncertainty, – such as uncertainty about when to start antiviral treatment, prospective randomized trials remain the best way to achieve this. They minimize bias, and thus misinterpretation, and are therefore the most reliable way to resolve uncertainty. There is no getting over this. Such trials may be expensive, and last a long time, but in the end, probably more time and money is lost by repeating inconclusive and conflicting retrospective studies.
As always, you can’t beat the truth. Regarding the “when to start” question, the truth was and still is that the answer to the question is unknown. Again, if the drugs were harmless there would be no problem. But it is quite possible that a person starting treatment at say 700 CD4 cells, even 500 CD4 cells, who may be a slow progressor may well have his or her life shortened by long exposure to the medications.
If, for whatever reason one presumes to favour a particular answer one can always select snippets of data to support one’s bias. Many would like to believe that it is better to start early. I have even read on one web site, that a New York physician stated that he would start any infected person on treatment no matter what the CD4 count was. I suppose this physician, and those who share this view are happy to practice with only their unsupported beliefs as a guide. This is as reliable as using a crystal ball and sick people deserve more from their health care advisers. In this respect the writers reporting such nonsense generally make no comment on the danger of views based only on belief, thereby adding credibility to these statements of faith. The practice of medicine is not a faith based activity.
The scientists who attach unwarranted importance to retrospective studies are also doing a disservice to clinical research. Some at the recent CROI meeting did admit that a prospective randomized trial was the best way to obtain reliable evidence on the issue of when to start. But as reported on one web site:
“Professor Doug Richman of the University of California San Diego questioned whether a ‘when to start’ trial was worth the expense. “Rather than spend millions on a trial, given that most people aren’t diagnosed until much later, why not use all that money to identify people who have the higher risk?” he asked”.
“He [Bartlett] also believes that the field is not willing to wait the 5 to 10 years necessary to generate an answer on when to start therapy.”
Discovering what is in the best interests of the infected person is not worth the expense? Waiting 5 to 10 years to find out is unacceptable?
So if we dispense with the truth to inform our actions, what could it be that guides us? Whatever it is, it is certainly no more reliable than consulting a palm reader.
Interpretations of associations found in retrospective studies presented as reliable indicators of a cause and effect relationship, rather than possibly suggestive of such a relationship, have as much meaning as the interpretations of an astrologer. Of course such data may be useful in suggesting hypotheses.
At a recent ICAAC meeting Dr Kitahata presented an analysis of a large retrospective study comparing outcomes among people starting at a higher as compared to a lower CD4 count. There was little meaningful criticism of the interpretation that the improved outcome in those starting treatment earlier was actually due to medications taken. Dr Kitahata felt that it was possible by some statistical magic for retrospective observations to mimic a randomized prospective study.
Here is an illustration of the interpretive pitfalls in such studies; it is a comment I sent to the web site reporting the results and conclusions of retrospective studies. I used the name James Mello, and pointed out that, as an example people who started treatment earlier were more likely to be under medical care than those who started later, and this might have contributed to their better survival. Another possibility is that most of the mortality might have occurred in those with the lowest CD4 counts; the examples I gave in my comment were a CD4 count of 1 compared to 349, when in fact the study concentrated on individuals with counts above 350. There are other possible explanations. There was one comment that suggested the possibility that people who choose to start treatment early are more likely to be concerned with their health in general and thus more prudent, and presumably more cautious in risk taking.
This is the comment of James Mello:
Another retrospective study actually showed no survival benefit in people with CD4 counts above 450. Here is a report of this study and that of Dr Kitahata:
Surely we need to know, and not guess when it is best to start treatment.
There are those who favour an earlier start and may have reasonable ideas to support these views. But they remain views – not proven ways to proceed that are in the patient’s best interests.
Let us find out if it is a fact that there is a benefit to starting earlier. All of us – HIV infected people and their advocates should be calling for appropriate prospective studies to guide us. We need to know the truth about when it is best to start.
Even if we were to conduct an appropriate large randomized prospective study we would only know if in asymptomatic HIV infected people with greater than 350 CD4 cells, it is on average better or worse to start treatment early or to defer it or if it makes no difference, of course apart from the expense.
The causative interpretations of retrospective observations are made difficult by what are called confounding factors and some are impossible to overcome. For example we don’t know why people choose or agree to start treatment early or defer it. The different decisions may reflect the possibilities that those choosing an earlier start may have better access to medical care, and receive better care in general, or may be more likely to be people concerned with their overall health.
Here is another example of something that might make interpretation of retrospective observations difficult. A retrospective study comparing mortality in people starting treatment above and below 500 CD4 cells finds that those who start treatment at higher CD4 numbers have a lower risk of risk of death. If, in those who delayed treatment and died, we are not told what the median CD4 count was at the time treatment was started the overall conclusion that antiretroviral drugs improve survival if started above 500 CD4 cells, would be unwarranted. It might well be that those most who died delayed treatment until a CD4 count of 100 or less. Had`they started at 450, 350, or 300 – numbers of course`all below 500, the outcome might have been very different.
The importance of individualized treatment.