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HIV Treatment: There is a role for intermittent therapy. July, 2009

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 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.

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.

Kuller 2

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.

http://content.nejm.org/cgi/content/full/355/22/2283

———————————————————————————————————————–

Refs

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

The not so SMART study: a very short postscript

June 12, 2009 Leave a comment

I believe the SMART study team have submitted a response to Justin Stebbing and Angus Dalgleish’s comments in the Lancet Infectious Diseases, that was referred to in a previous post:

The not so SMART study.

The explanation that the huge discrepancy in the number of deaths in the US and non US sites was due to the fact that non US sites started to enrol participants 2-3 years later than   US sites,  was addressed in the comments in the Lancet Infectious Diseases.

Here is the relevant part:

“Whereas most non-US sites commenced patient recruitment 2—3 years after the US sites, it is unlikely that longer protocol exposure could account for this difference. We are told that there were 38 deaths in the first year and 47 deaths thereafter. Hence, assuming that all six non-US deaths occurred in the first year, there remain 32 deaths (38 minus six) in the USA from the first year of the study—about five-fold more than expected based on the non-US mortality rate”.

Whatever explanation is to be offered by the SMART team, even if turns out to be consistent with their conclusions, the following questions remain.

Why was information on the distribution of deaths withheld for so many years?

Why was this information, when it did appear in the article by Kuller et al in PLoS last year,  ignored by community commentators  to whom HIV infected people and their advocates look to for help.?

Did they not notice it? (I did not).

Did they think it was of no significance?

Hopefully the SMART team’s response will put an end to this mystery of why, with more or less the same number of participants in US and  non US sites,   79  people died  at  US sites while there were only 6 deaths at sites  outside the US.

The Not So SMART Study

April 27, 2009 2 comments

I have borrowed this title from a comment in the journal, Lancet Infectious Diseases, entitled “Not so Smart?” by Justin Stebbing and Angus Dalgleish.

The SMART study as many will recall was a randomized comparison of two antiretroviral treatment strategies.

HIV infected individuals were randomized to receive either  continuous antiviral treatment or to receive it intermittently while the CD4 count had fallen below 250. This trial received a tremendous amount of publicity.  Deaths from all causes – including those that were not obviously related to HIV infection, were significantly increased in the group that were treated intermittently.  This seemed to dampen enthusiasm for treatment interruptions and brought attention to a possible relationship between HIV infection and deaths from causes previously not associated with it.

5,472 patients participated in this study at 318 sites in 33 countries.

There were a total of 85 deaths in the study.

79 of these 85 deaths occurred in the US where 55% of the patients were randomized.

There were only 6 deaths among the 45% of patients randomized in countries outside the US.

.

It would seem that treatment interruptions are quite safe, as long as they occur in countries outside the US.

Did I miss this information in the original report of the study published in 2006?

There were numerous discussions of the SMART study on websites and newsletters addressed to HIV infected people and their health care providers.  Did I miss those that reported on the fact that only 6 of the 85 deaths occurred in countries outside the US?

Of course I looked at the original report again but could not find this information – perhaps it was buried in a supplementary appendix?

For some reason, it seems that the authors of the report on the SMART study did not feel it necessary to draw attention to this information – at least not with the prominence that it deserved, if it was mentioned at all.

Most of the deaths on the study were not from AIDS associated opportunistic infections or malignancies.

With a presumption (maybe this  suggestion is too harsh) that despite this, the deaths were indeed related to HIV,  a possible relationship with this virus was sought. One obvious possibility of connecting these deaths with HIV was by linking them with the inflammation that is associated with HIV disease.

Thus, as a follow up to the SMART study, various markers of inflammation were looked at in both groups, and not surprisingly these were increased in the group with the most deaths, those receiving intermittent treatment rather than continuous treatment. As mentioned almost all of these deaths were confined to the US.

So, what we have is the observation that people who were to die within a relatively short period had increases in markers of inflammation. Of these, D-dimer, CRP and IL 6 had already been associated with all cause mortality, even in people not infected with HIV.

With respect to the cardiovascular deaths in the study, here is a quotation from PM Ridker:  “In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis”.

IL-6 is a pro inflammatory cytokine and levels were increased in those receiving intermittent therapy.  IL-6 promotes HIV replication,  and can be produced by HIV infected cells but also by many other stimuli.

So IL 6, which is associated with atherogenesis,  also directly increases the replication of HIV.  IL 6 secretion is increased by numerous and diverse factors. For example bacterial toxins induce IL 1 which in turn stimulates IL 6 release and  hepatitis C virus core proteins induce IL 6.  HIV infected cells can also release IL 6.

But with so many different agents able to do this it is difficult to attribute IL 6 production to HIV.  This is of course muddied by the fact that whatever stimulates IL 6 secretion, IL 6 itself will accelerate the replication of HIV.

But possibly the most intriguing feature of the report of this follow up study  is the first sentence of the Results section:

“Most of the deaths (79 of 85) occurred in the US”.

Having made this rather startling statement, the authors never return to it.  It remains undiscussed,  as if it is of no consequence!

Are we to believe that intermittent therapy with antiviral agents  promotes inflammation with its lethal consequences only in the US?

The outcome measurement of the SMART study included death from all causes. Only 8% were the result of opportunistic disease.

There were 16 deaths from cancer ( 11 in the intermittent therapy(IT) group and 5 in the continuous therapy group(CT)), 11 deaths from cardiovascular   disease  (7, IT, 4,  CT);

8 people died from substance abuse, 7 from violence.

18 deaths were from causes that could not be determined. Of these 18, 15 occurred in those on intermittent treatment and only 3 in those receiving continuous treatment.  This last rather large difference leads one to ask if it is possible that the two groups were treated differently. At least, in the US, where almost all the deaths occurred.

This may seem like an outrageous question. But unintentional bias in unblinded studies cannot be ignored and I will return to this.

Many of the deaths reported –  certainly far from all, were caused by  conditions that might have been ameliorated by appropriate medical care ( this does not only mean from the point of view of the physician. The patient is also involved – for example, were medical visits made? Did the patient pay attention to symptoms? Was there compliance with prescribed treatment?)

With almost all of the mortality confined to the US,  it looks like something else must be at play here, something other than the antiretroviral treatment strategies, and the first place to look is the overall quality of medical care – which,as mentioned, includes issues that may entirely be related to the patient – such as poor compliance with recommendations, despite adequate support.

There are two distinct  questions to be asked.

Firstly,  why was there such  a difference  in  the trial outcomes between US and non US sites?

Secondly, in the US can we reliably attribute the differences in outcomes in the two treatment arms to the differences in the antiviral treatment strategies?

The first two questions one would ask in trying to explain the difference between 6 deaths and 79 deaths is related to the quality of general medical care in the US as compared to the non US countries, and then to possible differences in the patient populations.   The patient populations may have differed for example in the extent of co- morbidities,  and in the degree of compliance with recommended treatments.

But  I don’t know that one can come up with an answer about the quality of medical care.   We must assume that there were probably no great differences.  However there was some information on co- morbidities such as Hepatitis b and C,  but not enough to attribute the differences in the number of deaths to this factor.  [Note`added on April 4 2010. The difference in co-morbidities is in fact probably  the reason for the striking difference in mortality between US and non US sites. Here is a link to a later post where a table is reproduced  from the paper describing the mortality difference referenced below. The population enrolled in US sites, where most of  the deaths occurred,  were much more likely to suffer from non HIV related health problems than those enrolled in non US sites.  Here are two sentences from the later post:  ”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:

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”. This current entry on the SMART study, which I’m leaving unchanged,  should be looked at in conjunction with my subsequent post. LINK TO LATER POST ]

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.

I doubt if information on compliance is available.

Even if one could show differences between the US and non US sites ,  how would  this  affect the study outcome?  More people died in the intermittent treatment arm compared to those receiving continuous treatment. So this is the second question.

Could there be an explanation for the differences noted between the study arms (albeit only in the US) other than the antiviral treatment strategies?

There could be a connection with general patient care.

In order to minimize bias in a study, where possible when treatments are compared, participants and those conducting the trial do not know what treatment is being received by particular participants.

The study is blinded, so that as far as it is possible, we can attribute any effects observed to the treatment, not to any anything else.  For example, if patients knew what they were or were not receiving in a treatment trial, they may behave differently, and  in ways that may affect the outcome, which then could not be attributed to the particular treatment being studied.

For example if a patient knew they were receiving a placebo, they may then take other medications that might affect the outcome of the trial, or if doctors knew patients were taking a medicine they believed worked they might treat their patients with greater care or with less care.  We do recognize that some behaviors that may alter the outcome of a study are  certainly not intentional.

It was impossible to blind the SMART study.  So, both participants and physicians knew which arm of the study patients were randomized to.

If the study doctor was also the person who provided  general  care than the specter of bias unfortunately is lurking and may confound interpretations.

This is not to say that differences in general care between both study arms, if indeed there were differences, were intentional.

To put the questions in another way:

1: Can general patient management strategies ( not the strategy of antiviral treatment being studied) have an impact on all cause mortality?  In other words, can the way health care providers manage the general  health of their patients make a difference to survival?

2: Can bias influence the ways physicians take care of their patients?

The answer is of course yes., although we may not like to admit this.    So bias might be a factor in an unblinded study and affect the outcome.

So we are still in the dark regarding regarding the value or danger  of treatment interruptions.

As a postscript, a similar problem hangs over the original AZT study – the study that led to the approval of this drug by the FDA.  Of course the dramatic life saving effect of zidovudine seen in this trial  has never been observed again.

This placebo controlled study was also in effect unblinded. Patients and doctors knew who was receiving placebo or active drug.

Deaths were mostly due to opportunistic infections. Patient management strategies can make the difference between life and death with regard to these infections. Rapid diagnosis, effective treatments obviously make a difference. Can bias influence patient management strategies?

I wrote about this in – I think 1989, and the article can be seen by clicking here.

I suppose that one must conclude that the fact that almost all the deaths in the SMART study occurred in the US was not known to journalists and those who specialize in informing us about issues related to AIDS.  I also missed it when it was  published in 2008 [iii].

The report of Dr Kuller may be the first public mention of this odd result. But it is just mentioned and not discussed at all.

Here is what Justin Stebbing and Angus Dalgleish wrote in the Lancet Infectious diseases about this report:

” The follow-on case-control study by Kuller and colleagues showed that it is apparently safer to be off  HAART outside the USA rather than on HAART within the USA”

As a clinician I don’t know what to make of the SMART results. In the lamentable absence of firm evidence one has to use one’s best judgment in caring for patients.  Numbers of my patients have – at their request and at my recommendation, temporarily interrupted their treatments, using a variety of strategies, with no harm, and with a better quality of life.

I imagine that some will have been persuaded to stop this practice  by their new physicians. But I am still in touch with one, who had a CD4 count of 0 when first seen, who still regularly interrupts his treatment.  He is extremely well, leading an active and productive life.


The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 268 – 269, May 2009

The New England Journal of Medicine [NEJM 355(22): 2283-96 (2006)

PLoS Medicine 5 (10); e203.doi:10.1371/journal.pmed.0050203

Kuller LH, et al. (2008) Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV infection.

HarrisTB et al 1999  Association of elevated IL6 and CRP levels with mortality in the elderly, Am J Med 106: 506

Ridker PM et al 2000 Plasma concentrations of IL 6 and the risk of future myocardial infarction among apparently healthy men.  Circulation  101 1767

Shorr AF et al 2002 D-dimer corerelates with proinflammatory cytokine levels and oycomes in critically ill patients, CHEST 121: 1262

HIV disease is in fact characterized by multiple examples of positive feedback systems – a subject for another post.