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 25th, 2009 1 comment
February 24th 2009
AIDS and Minorities
In the US, African Americans constitute 12% of the population, yet almost half of the total number of AIDS cases in the country occurs among them. This disaster is only now being generally recognized, with the leadership of the Federal AIDS response finally turning their attention to this tragedy, at least publicly.
This is a tragedy that has been developing in full view for more than twenty years. One only has to look at statistics provided by the Centers for Disease Control (CDC) since the epidemic started to know, as early as 1987 that without intervention a preventable disease was inexorably moving into African American communities.
Firstly, take a look at the situation in 2006 (data from the Kaiser family Foundation).
Now take a look at this picture that clearly tells a horrible story that words cannot match.
In the light of this devastating evidence how is one to understand the comments of Dr Fauci, who can be regarded as the head of the Federal scientific and medical response to AIDS?
He noted that these “shocking statistics would be tragic anywhere but are particularly inexcusable in a wealthy country such as the United States.”
His complete statement can be seen here: http://www3.niaid.nih.gov/about/directors/news/BAAID_09.htm
Look at the above picture again. Cases in African Americans started to exceed those in white Americans in 1994, but the trends were quite evident long before this. We knew in 1988-1989 what was coming. So, one must wonder why it took all of twenty years to announce only in 2009, that these statistics are shocking.
A preventable tragedy was taking shape in full view of the Federal AIDS leadership, who rather than fund a vigorous prevention education campaign directed towards those most in danger, instead chose to support a wasteful, vacuous untargeted prevention education program in the form of “America Responds to AIDS”.
It is not only the federal AIDS leadership that failed to respond to warning signals flashing brightly right in front of them. In the early days of the epidemic there was a vigorous and exemplary community activist response. This was a terrific example of people dealing with a deadly disease taking action on their own behalf, fighting for the best medical and scientific response and against the all too frequent shameful stigmatization of HIV infected individuals.
The flowering of AIDS activism in the late 1980s and early 1990s achieved a great deal. All people dealing with serious illness have benefitted from the precedent that was set. Yet, in recognizing this achievement, we must also wonder why many of these experienced advocates, who no doubt were aware of the demographic trends shown above, seemed generally less willing to at least try to avert the disaster threatening their fellow citizens? Of course some tried, and maybe were overwhelmed by massive indifference.
Whatever the reasons, the advocacy of US activists abroad, particularly in Southern Africa, proved to be more effective than anything they were able to achieve in their own country for their fellow African American citizens. There are also other groups where AIDS has been, and continues to be a growing problem, but have been relatively neglected.
Not for profit organizations, that raise funds to help and advocate for people with AIDS were also aware of what was developing, but if there were any efforts devoted to preventing a calamity visibly descending on the largest community at greatest risk, these clearly were of little benefit.
What is almost, but not quite, as shocking as the neglect of a disaster developing in front of our eyes, is the complete absence of any sense of contrition, let alone a simple acknowledgment of failure, on the part of those who might have helped to prevent it.
If justice includes the notion of equity then prevention resources should be distributed in proportion to the needs of different communities. This clearly has not happened and it might be helpful to give some thought as to why this has been the case.
We need to know and admit what it is that we did unsuccessfully, or failed to do, to stop a preventable disaster, so that we can get it right in the future.
Instead we have a wringing of hands by those who could have done something, but did nothing, to stop this.
A similar article was posted on a health related web site in December of last year. There was no response to the issue I raised.
This post can be seen here.
Take yet another look at the picture showing the changes in the proportion of AIDS cases according to racial/ethnic group over the past 20 years. It tells the whole story; no comment is really needed.