Posted on July 9th, 2009 No comments
From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..
The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.
For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.
We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.
One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs. This approach will almost definitely not be possible for all HIV infected people needing treatment. But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.
This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061. SMART is by far the largest study comparing continuous with intermittent therapy. In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.
The negative effect of SMART on the study of intermittent treatment continues. In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought. The most favoured, and almost certainly correct explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.
For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification. The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post. Almost all the deaths in the study occurred at US sites, where in contrast to non-US sites multiple co-morbidities were over represented. As seen in the table below these co morbidities included, among other conditions, hepatitis B and C, a history of heart disease and diabetes. There were even significantly more smokers among those enrolled at US sites. How can one extrapolate interpretations of observations made in such individuals to HIV infected populations free from these co-morbidities?
SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C, hypertension, and a previous history of heart disease Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy. That’s all. The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational literature addressed to physicians.
Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times. But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.
Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART. The Staccato study3, using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.
The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent. Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group). Although pneumonia was more frequent in the STI group. Here is a sentence from the author’s abstract.
“A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.
The finding regarding cardiovascular disease is particularly relevant.
Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study. It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation. There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people. So this needs to be studied. But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.
Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!
There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.
I was shown an invitation to physicians to a free course offered by a distinguished academic institution. Among the descriptions of what those attending the course will learn to do is the following:
“Describe, discuss and apply the data from the SMART study on CHD (coronary heart disease) risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”
What is one to make of this in the light of the LOTTI observations?
This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature. As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.
As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides. They also characteristically had low levels of HDL cholesterol (and of total cholesterol). I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available. We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased. There was, not surprisingly, a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.
So, there may indeed be something in the connection between untreated HIV disease and heart disease. In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease. Increased triglycerides are an independent risk factor for coronary heart disease. There even was a possible mechanism for this that was known in those days that could account for this.
Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted. Such changes have been seen in people with hepatitis C treated with recombinant interferon.
So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle? There are numerous different ways in which intermittent therapy can be structured.
The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit, studies smaller than SMART
Perhaps a clue is to be found in a sentence in the LOTTI study report.
Here it is:
“The mean daily therapeutic cost was 20.29 euros for controls and dropped to 9.07 euros in the STI arm (P<0.0001)”.
This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.
Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes), some form of intermittent therapy will probably be demonstrated to be safe. For individuals with at least 700 CD4 lymphocytes, this is already the case.
Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis. I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts. This desire for treatment interruptions was obviously true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.
Of course for individuals with CD4 counts below 200, this was not a good idea. Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.
There will be many anecdotes accumulated over the years of such experiences of intermittent treatment. I need to stress that these are just anecdotes and most definitely not formal studies. As such they can only lead to hypotheses on which studies can be based.
It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped. This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.
Of my patients who interrupted treatment none have come to harm. There was no established protocol to guide us and strategies used took patient preference into account. An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover. As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment. This approach is now generally considered to be unsafe and CD4 guided strategies are studied. But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.
In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.
“Many of our patients with high CD4 cell counts want to
stop treatment. The LOTTI study does not justify a
recommendation in that regard, but it does give clinicians
useful information that it is probably safe to stop
treatment within the limits of CD4 cell counts of
LOTTI. Continued vigilance is needed so that excellent
adherence is maintained when patients are on HAART
to prevent the emergence of resistance.
The LOTTI study adds important information to the
continued question of whether there is a role for
interrupted therapy. Further study is justified, particularly
with newer combination therapies, which may well
have less toxicity and therefore shift the balance towards
continuous treatment. Clinicians will welcome the
information from LOTTI because it can allay some of
the concerns regarding the safety of treatment interruptions
at high CD4 cell counts”.
In the LOTTI trial, treatment was restarted when the CD4 count dropped to 350 and stopped at a CD4 count of 700. So within these limits we have some reassurance of safety.
So, further study is absolutely warranted.
In the LOTTI study, participants had to have a CD4 count of 700.
What about individuals who have had undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700? Studies with different CD4 criteria should continue and not be deterred by the SMART results.
I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration. That is to get away from the prevailing one size fits all approach to therapy, mainly using a snapshot of just one or two parameters, the CD4 count and viral load to guide one, without considering the rate of change in CD4 numbers.
In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered. As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly. (Of course an individual may be super infected with a drug resistant variant).
It is likely that some form of episodic treatment may be effective in selected individuals. That is, periods on treatment alternating with periods off treatment. Because of its flexibility it is probably best suited to individualization.
As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy. But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5. But other similar studies have shown a high rate of viral rebound6.
However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.
It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.
I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites. At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.
The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented. As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.
Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.
This table shows characteristics of individuals who died compared to those who did not.
The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).
It can be seen that of the people who died, compared to those who did not, 11.8% vs 4.7% had a history of heart disease (p=0.04); 45.9% vs 24.1% were co infected with Hepatitis B or C (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).
Thus the people who died in the SMART study tended to be sick with non HIV related conditions. 64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.
But there is another remarkable figure in this table. 92.9 % of those who died were participants in US sites! I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.
Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle, for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.
The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants. All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm. However the distribution of these characteristics in those who died was not reported in this publication. We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.
I missed seeing this 2008 publication. It seems that most who saw it had little to say. But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8. I did not miss it this time, and have already written about it.
Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible. Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion that the SMART study indicates that treatment interruptions are unsafe for all, into question.
To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.
This lack of interest is really puzzling.
Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.
Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement. There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.
We know with some security from SMART that HIV infected individuals with Hepatitis B and C, hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.
For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all, a form of treatment interruption will be demonstrated to be safe. This can already be said for those meeting the conditions of the participants in the LOTTI trial.
The original report of the SMART study was published in the New England Journal of medicine in 2006.
1: New England Journal of medicine 2006 355:2283-2296
2: Trivacan(ANRS 1269) Lancet 2006 367:1981-1989
3: Staccato Lancet 2006 368: 459-465
4: LOTTI AIDS 2009 23:799-807
5: Proceedings National Academy of Sciences 2001 98: 15161-6
6: AIDS 2003 17:2257-2258
7: Kuller et al. PLoS Oct. 2008 5(10): e203
8: The Lancet Infectious Diseases 2009 Vol 9 Issue 5 268-9