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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.




Early concerns about confidentiality in AIDS, and what Jim Monroe had to do with this.

April 23, 2009 Leave a comment

From time to time I will write about some extraordinary people I have worked with. The first of these is Jim Monroe.

Jim worked for the Centers for Disease Control (CDC).  He worked to improve the health of all, but it is people with AIDS who probably derived the greatest benefit from his efforts.

Those who do the most to help others often remain completely unnoticed. Maybe their commitment leaves no room for seeking personal attention; maybe they don’t care about recognition, or actively shun it.

Jim Monroe personally helped many individuals who were in great need.  He was also the person who was probably responsible for first bringing attention to the issue of confidentiality in AIDS in the earliest years of the epidemic.

He most certainly did not care about personal recognition.  Apart from a few friends and colleagues and those who directly benefited from his efforts, he remains largely unknown.

I first met Jim in the late 1970s. I was at that time working for the New York City Health Department, concerned with sexually transmitted infections.  Jim worked in the same field, but for the CDC.  He was based in New York City.  Our places of work were in close proximity and we met through our common interest in the control of sexually transmitted infections.

Jim is probably the person who was responsible for the early attention given to confidentiality in connection with AIDS

Confidentiality in matters of health is of the greatest importance; it is also complex, with some special concerns in connection with sexually transmitted infections.

We have an obvious obligation to respect the trust placed in us by those who seek our care. But there are different and strongly held views on the tensions that can exist between individual rights to privacy and the protection of sexual partners, as well as society at large.

But the context in which Jim brought attention to confidentiality was the concern to protect individuals suffering from this new, untreatable, and as yet unnamed disease.   From the very start, affected individuals frequently had to contend not only with this frightening illness but with irrational and cruel discriminatory acts against them.

Not only was the disease itself associated with stigmatization, particularly in the early years, there was yet another issue requiring attention to confidentiality.  Sexual orientation was revealed with a diagnosis when the disease was thought to be confined to gay men. As other groups of individuals were identified, perhaps only those who acquired the disease from blood products were relatively free from the threat of discriminatory practices that were all too frequently directed against gay men and IV drug users.

Those were the days when HIV infected people in hospitals had to retrieve their meals which had been left outside their doors;  when medical personnel would refuse to care for infected people; when some children were not allowed to be in contact with those known to be infected, and infected children sometimes not allowed to attend school.  Thankfully in the US today children are protected.

http://www.ed.gov/about/offices/list/ocr/docs/hq53e9.html

But despite advances, AIDS is still a disease associated with stigmatization, not only in developing countries but also in the US and other developed nations.

I will describe how Jim started a response intended to assure that those affected by this new disease would be protected by measures to maintain their confidentiality.

A few introductory words are needed.

I started my own research into this new disease in 1981, and received tremendous support from an old colleague in the interferon field, Dr Mathilde Krim.

In 1983, my lawyer, Frank Hoffey with Graham Berry prepared the papers and incorporated the AIDS Medical Foundation (AMF), initially to raise funds to support my research.  Apart from Mathilde’s personal support our work was not funded.  AMF soon broadened its mission to support the work of others as well.

Fundraising during the first year was very difficult and the foundation really owes its survival to the efforts of Dr Krim, who was the chairman of the board.

Concern with confidentiality started with an anxious call from Jim in 1982.  The reason for his extreme agitation was that he knew that a study was to be undertaken on this new disease in the Health Department clinics for sexually transmitted infections. In particular, the clinic on 28th street was known to be the site where large numbers gay men were treated for sexually transmitted infections.   The study would be concerned with people who had “reversed T cell subset ratios”.  A reversal of the normal CD4: CD8 ratio was how we recognized AIDS before the name was coined.

What concerned Jim was that no provision had been made to protect the confidentiality of the study participants. Their names were to be recorded.  I cannot recall if the proposed study was a CDC study or one originating with the Health Department.

Jim told me that the study was to be submitted for review by New York  City’s Institutional Review Board (IRB) although it was not called an IRB.  I suppose he must have had little confidence that the IRB, which is a body regulated by the FDA and intended to protect human research subjects, would address the confidentiality issue. In view of what transpired he was probably correct.

I also don’t know what he expected I could do. Maybe he just wanted to share his frustration with a person who shared his concerns.

In the event, this call was to actually result in something that would have lasting effects.   I spoke about this to Mathilde, who I knew also shared these concerns about protecting confidentiality.

She immediately said that she knew who could effectively deal with this problem.  Mathilde was associated with and had provided support to the Hastings Center, which was concerned with bioethics, and introduced me to Carol Levine and Ron Bayer.  I conveyed Jim’s concern about the proposed study  and the result was that I attended a meeting at the Health Department with Carol or Ron, or maybe both were there, as well as a lawyer from Lambda Legal Defense Fund, whose name I think was Chris Collins.

As a consequence, because of a lack of provision for confidentiality protection, the study was tabled.

Jim Monroe’s concern to protect individuals with AIDS started this train of events.

It is hardly surprising that not much attention had been given to the issue of confidentiality in 1982. The disease was after all new, and we were just learning of the extremely hostile and irrational responses directed at those who were affected.

Carol and Ron’s interest did not stop.  I think it was Ron Bayer who proposed that a meeting be held on the issue of confidentiality.  This meeting in fact did occur and resulted in the publication of guidelines for confidentiality in research on AIDS.

Lloyd Schloen had worked at Memorial Sloan Kettering Cancer Center as a fund raiser.  Mathilde had introduced us and we had become friends.

Lloyd then became an official at the Charles A. Dana Foundation, and we talked about confidentiality protection.  It is through his efforts that the meeting on confidentiality was funded.

The meeting proceedings were published in the Hastings Center’s own publication, IRB.

http://www.jstor.org/pss/3564421

I believe my memory is correct in recalling that an established medical journal declined to publish the guidelines.

I was editor of a journal devoted to AIDS called AIDS Research and had absolutely no hesitation in publishing the guidelines myself. Some pages are reproduced here.

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Later, the CDC was to publish its own set of guidelines.

The Hastings Center guidelines were not the only publication on confidentiality that preceded the CDC’s recommendations.

As part of my research effort I had become associated with David Purtilo, Chairman of the Pathology and Microbiology Departments at the University of Nebraska’s medical school in Omaha. The reason for this was that David was an expert on the Epstein Barr virus, and I believed that this common herpes virus can play a significant role in the pathogenesis of HIV disease[i].

David’s wife, Ruth Purtilo is a bioethicist. She clearly saw how important confidentiality protection was in research on AIDS. She obtained the perspective of Michael Callen, a patient of mine who was HIV infected. Together we wrote a paper on this issue in 1983.

Confidentiality, informed consent and untoward social consequences in research on a new killer disease (AIDS).

Clinical research, {Clin-Res}, Oct 1983, vol. 31, no. 4, p. 464-72, ISSN: 0009-9279.

Purtilo-R, Sonnabend-J, Purtilo-D-T.[ii]

Unfortunate developments today have made the need for respecting confidentiality as important as was the case when the epidemic began.  Differently worded legislation now exists where criminal law is applied to people who transmit HIV to others, or even who expose others to the risk of transmission. There is absolutely no evidence that such criminalization prevents the spread of this disease.  The following link will provide useful sources of information.

http://data.unaids.org/pub/BaseDocument/2008/20080731_jc1513_policy_criminalization_en.pdf

These laws only increase stigmatization.  The introduction of such legislation in many countries is an important additional reason why concerns about confidentiality protection remain vitally important.

Jim Monroe returned to work at the CDC in Atlanta.  Although he was assigned to work in another field, his interest in AIDS remained. He was the kindest of individuals, personally helping people with AIDS, as well as others in difficulty.

The very last project on which we worked was cut short by his death.

Even then, in the late 1990s, the problem of when it is best to start antiviral therapy was of concern – indeed it had been of concern ever since the introduction of AZT.  We then believed – as many still do today, that the question is most reliably approached by a randomized prospective study.  Most certainly not by the opinions and recommendations of experts, not all of whom could properly be considered qualified to hold that rank.

We thought that those entities that pay for the drugs might be the appropriate sponsors of prospective clinical trials.  They have a clear interest in knowing if it is beneficial or not to start treatment early rather than to defer it, or whether it makes no difference.

It is in their interests; if early treatment provides no benefit – (at least one large retrospective study suggests that there is no benefit to starting treatment above a CD4 count of 400) then paying for an early start to treatment would be pointless. On the other hand if early treatment produced some benefit then the cost would certainly be justified.

Among the entities covering the cost of drugs are government agencies such as Medicare and the VA.   The VA has a history of undertaking studies.  There are also the private insurance companies.

Jim together with a Public health expert at Emory University was attempting to present a proposal to the medical directors of private insurance companies. We had the support of an eminent statistician who had also been involved with me on an earlier unsuccessful attempt to set up a study to compare early and deferred treatment with AZT.

This attempt was brought to an end by Jim’s sudden death, as well as by the illness of another one of us working on the proposal.

One Friday afternoon while seeing patients in a clinic in New York City,  I received a call from a friend of Jim’s in Atlanta. She told me that Jim was severely ill in Chicago. He had collapsed a few days earlier.  On Saturday I travelled to Chicago and found Jim unconscious in a hospital. He was not to recover.

None of us knew that Jim had been ill. He kept this a secret while continuing to work  to improve the health of all people, both in his assigned work but also through his initiatives on behalf of people with AIDS.

Jim’s final project, cut short by his death, is still absolutely relevant.

Some recent suggestions, based on the flimsiest of evidence propose that treatment with antivirals should be started even earlier than the current recommendations.  There are well meaning physicians today who already buy into this nonsense, who state that they would treat all infected people, irrespective of CD4 count. Or they would raise the CD4 threshold above 350, which is the currently recommended level at which to initiate treatment, even in the absence of reliable evidence that their patients will benefit.

It cannot be reliably known from any evidence we  have at present whether such prolonged exposure to  antiviral drugs will increase or decrease survival or be without effect in this respect – of course except for cost.

We do need to really know when it is best to start treatment.  Prospective randomized studies can provide an answer to the question if, on average it is better to start treatment early or to defer it.

Hopefully others will take on Jim’s last project and write a proposal to some of the entities who pay for the drugs, to sponsor  prospective studies,  the only reliable way to answer this question.

Are they wasting money? Are they getting their money’s worth?

Surely the payors, will want to know.


[i] I still believe this to be true,  as further evidence continues to support this idea.  Our work on EBV and HIV was quite productive and will be the topic of another post.

[ii] We were awarded a prize for this article: The Nellie Westerman  Prize for Research in Ethics awarded by the America Federation For Clinical Research.

When is it best to start antiretroviral treatment: an update April 2009

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

But is this confidence justified?

Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

“The early initiation of antiretroviral therapy before the CD4+ count fell below two

prespecified thresholds significantly improved survival, as compared with deferred

therapy

One of these prespecified thresholds was a count 500 CD4 lymphocytes.

This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified.

I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

Here is another serious problem with this study.

Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

This information was not given – at least I was unable to find it.

Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions.

All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

It is the “on average” limitation that needs fine tuning for each individual patient.

Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

A previous post discusses the  issue of individualization of treatment.


If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

Often forgotten, the second pillar is individual clinical judgement.

When is it best to start antiretroviral treatment: an update

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

But is this confidence justified?

Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

“The early initiation of antiretroviral therapy before the CD4+ count fell below two

prespecified thresholds significantly improved survival, as compared with deferred

therapy

One of these prespecified thresholds was a count 500 CD4 lymphocytes.

This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified[i].

I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

Here is another serious problem with this study.

Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

This information was not given – at least I was unable to find it.

Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions[ii].

All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

It is the “on average” limitation that needs fine tuning for each individual patient.

Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

A previous post discusses the  issue of individualization of treatment.


[i] If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

[ii] Often forgotten, the second pillar is individual clinical judgement.

HIV Infection in HIV Antibody Negative Individuals

April 1, 2009 2 comments
  • HIV infection in HIV antibody negative individuals

The possibility that there are individuals who are infected with HIV but who are negative on the test for HIV antibodies has always been theoretically possible. Considerable evidence has accumulated for many years that there are indeed such individuals. Despite the importance of this phenomenon, it receives relatively little comment.

It sometimes seemed to me ever since I first tried to discuss this possibility in the mid 1980s that there was a wilful discouragement of any discussion of this topic.

In 1989 David Imagawa reported that that 31 of 133 HIV antibody negative men showed the presence of HIV.

In 27 of them this persisted for 36 months despite remaining seronegative  [1]. This resulted in a vigorous response culminating in what almost looked like a retraction by the authors. At that time many unsuccessful attempts to replicate these results were reported, and the findings of David Imagawa were generally presented as due to technical errors, such as incorrect specimen labelling. In view of many subsequent findings, the likelihood is that David Imagawa and his colleagues were correct. The furious response to Imagawa’s paper is an indication of how non rational considerations can influence the progress of science. This is of course nothing new.

Curiously in a recent book, Imagawa’s findings are included in a list of what are stated to be errors and controversies in the HIV/AIDS epidemic that impeded scientific progress [2]

What in fact impeded progress was a rigid adherence to what was only a hypothetical, not an empirical model of the course of HIV infection.

David Imagawa died shortly after this controversy, and sadly did not live to see that his initial conclusions were absolutely consistent with what has been learned of the complexity and diversity of individual responses to HIV infection.

I certainly experienced considerable resistance and disbelief when I raised the possibility of silent HIV infections. In the late 1980s I took part in a NPR program, and was quite abruptly dismissed by another scientist (I have forgotten who) when I raised the absolutely reasonable theoretical possibility of persistent latent infections in antibody negative individuals.

Apart from very few exceptions there was an almost complete lack of interest in HIV seronegative, but infected individuals, by science writers; there was no shortage of community commentators who also seemed to be oblivious or uncaring of this phenomenon.

To be sure there were occasional reports of seronegative but infected individuals. Gus Cairns, a UK journalist wrote about this in the UK magazine, Positive nation. I wrote something about this as a result of an interview with him in 2000, which he published. I have scanned the article. I was unable to make a perfect copy, but a legible version can be seen by clicking HERE.

In the US reports confirming the existence of seronegative infected people continued to receive very little comment; what little there was was generally quite hostile..

Today this issue was again brought to my attention by an article I saw reporting the presence of HIV proteins and HIV RNA in cervical biopsies from women who were persistently HIV seronegative , at least for the duration of the study which was one year [3]. They did not have antibodies to HIV despite being infected; of course it is possible that they are in an unusually long “window period” and will eventually seroconvert.  If we use “window period” in this sense then we  can speak of a distribution of window periods of different lengths, including an indefinite one.

I expect that, as is usual this report will provoke little or absolutely no interest.

But it is enormously interesting; (just one of many questions: can these women infect their male partners?)

Seeing this article is the reason why I decided to make this issue the subject of this post.

It was no great surprise when evidence appeared that there were some individuals who were HIV infected but remained negative on the HIV antibody test. It must be said that there were probably more papers in the early years in which silent HIV infections in HIV antibody negative individuals was not observed.

In another approach, reports started to appear that HIV antibody negative individuals had T lymphocyte responses to HIV which means that they were exposed to the virus, not necessarily that they were infected – although that is quite a real possibility. Some early papers, before 2000, including those showing T cell responses can be seen by clicking HERE . There was quite an extensive literature at that time, but most, as mentioned reported that there was no such thing as a silent antibody negative infection, apart from the short window period following infection.

Why has the possibility of prolonged latency always been theoretically possible?

As part of its life cycle HIV is turned into DNA and is then incorporated into the host genome. In infected cells it effectively becomes part of our genetic material. Once inserted into human DNA, it must be activated to start the process of making new virus particles. Cellular signals that start the process of activating HIV DNA include cytokines, which are messenger molecules produced and released by cells, which can then act on other cells to evoke a variety of responses. Amongst these HIV activating cytokines are those that are called proinflammatory cytokines.  These appear during the course of many different infections.  Once HIV DNA is activated, and at least some of its proteins made, these then mediate further activation.

There are some other factors that can activate HIV DNA.

Alloantigens are antigens expressed on foreign cells. When these antigens are in contact with a cell containing integrated HIV DNA, activation occurs; HIV DNA is transcribed and new viral particles made. In earlier days HIV was isolated from infected lymphocytes in this way. Latently infected lymphocytes were induced to produce HIV by culturing them together with lymphocytes from an uninfected donor.

It is the nature of HIV infection that it is frequently acquired in situations which involve exposure to foreign cells (to alloantigens). This may be exposure to semen in sexual transmission, or blood cells in the case of infection by shared needles, or by blood transfusion.

Herpes viruses have the ability to activate HIV if a cell is infected with both viruses. I suppose this must happen but I imagine doubly infected cells may not be found  too frequently. Of course active herpetic infections in non HIV infected cells may be associated with the production of pro inflammatory cytokines, which circulate and can activate HIV DNA in a cell at a distance.

There is absolutely no reason not to expect that in some circumstances incorporation of HIV DNA into human DNA will result in a state of stable integration. This means that HIV DNA remains in the genome, it is not activated, and no virus is produced. Since antibodies are made as a response to viral proteins, and as none are made, the HIV antibody test will be negative.

So it was no surprise when such individuals were again reported in 1999 [4]. These individuals remained in good health and were reported to be antibody negative as long as they were observed [5].

We cannot know if these individuals may seroconvert (or maybe already have), but what is established is that stable integration of HIV DNA without seroconversion can occur. In such individuals limited expression of HIV can occur, at least sufficient to induce, if not antibodies, a cellular immune response.

The presence of such cellular immune responses in HIV antibody negative individuals is further evidence consistent with HIV DNA persistence, but in itself does not indicate this.

Demonstration of cell mediated immunity to HIV:

Apart from the identification of antibodies, specific immunity to HIV can also be detected by a much more elaborate test that measures cellular immunity rather than immunity determined by detecting specific anti HIV antibodies. In this case what is measured is the ability of lymphocytes to recognize HIV. They will do so only if they have been exposed to the virus, which would obviously be the case if they were taken from an infected individual.

The detection of such lymphocyte responses in the mid 1990s was one of the first indications that there may be infected people who don’t make antibodies. Other interpretations are that the infection was overcome, or that that the individual was infected with defective virus.

Gene Shearer was I believe the first to report this phenomenon. HIV antibody negative sexual partners of HIV positive people, as well as individuals who had occupational contact with HIV were among those showing these responses.

It is unknown how widespread this phenomenon of silent HIV infection is. It may be exceedingly rare. It is also unknown if this condition of stable integration is really just a prolonged “window” period that always follows all HIV infections.

But it is entirely possible that there are individuals in whom the ability to control HIV is such that they will remain healthy and HIV negative.

A number of different  outcomes of HIV infection are possible:

Some of the factors that influence this:


Host genetic factors.

Size of the inoculum – the amount of infecting virus.

Route of infection

The particular virus strain.

The presence of associated systemic infections.

these provide signals activating HIV proviral DNA. In the case of some tropical infections there may be cytokines (IL 10) that blunt immune responses.

Sexually transmitted infections with genital ulcers.

Double infection of a cell with HIV and herpes viruses – probably an unusual occurrence.

Exposure to alloantigens; a theoretical possibility.

These are some of the known influences.

Maybe the most common outcome is a productive infection where viral DNA is activated within a few weeks.

But this scenario is also possible:

Infection is followed by insertion of HIV DNA into cellular nuclear DNA. Possibly with small inoculums, and in the absence of strong or sustained activation signals, the proviral DNA remains silent. This has been observed.

Or this one:

There is a limited burst of viral production, not sufficient to elicit an antibody response but enough to induce a cell mediated response with the generation of lymphocytes that recognize HIV antigens and can kill HIV infected cells. HIV seronegative individuals with such specific lymphocyte responses have certainly been observed. In this case if there is an incipient burst of HIV production, the producing cells are promptly killed. Each time this happens the cellular immune response is primed and strengthened. Such a mechanism has been well studied in EBV infections. This common virus is totally unlike HIV, but it does similar things. It remains present in B lymphocytes rather than T lymphocytes for life. The mechanism of persistence is quite different – EBV is not a retrovirus. But the majority of individuals carry this virus – which in rare situations can have lethal effects, in their B lymphocytes for life. We have evolved many mechanisms to keep this virus in check. The ability of some types of lymphocytes to kill EBV infected cells which start to make virus is well understood. Similar mechanisms must exist for HIV – but obviously for most, are insufficiently effective. But in those with very limited HIV production these killer lymphocytes may actually be what allows such rare fortunate individuals to remain HIV seronegative.

With this outcome, one can view the infection as actually having an immunizing effect.

If there were not yet enough reason to study the phenomenon of persistently seronegative HIV infection, this is an important one. What are the circumstances that produce this outcome?

So, for many reasons individuals who are seronegative but have lymphocyte responses to HIV are of great interest.

Yet another scenario is one of stable integration, but where some HIV proteins, but not complete virus, are produced. Maybe the women referred to whose cervical biopsies contained HIV antigens might be in this category. This is a strange situation as antigens were detected but these women apparently did not develop antibodies.

Another very early observation that can be explained by the prior presence of integrated HIV  DNA that is only activated by a subsequent non HIV  infection is the finding that  episodes  of EBV reactivation may precede HIV seroconversion. [6].  This raises the possibility that at least some illnesses associated with primary HIV infection are nothing of the sort. They instead may represent rather non specific viral infections that activate already present integrated HIV DNA, and thus  followed by HIV seroconversion. This is a completely plausible scenario. Of course self reported sexual histories may sometimes  not be too reliable, but nontheless, I well recall an older gay male patient of mine who told me that he had had no sexual contact for years, he had several negative HIV tests over a period of a few years, and then tested positive.  I wondered  then if he may possibly have been infected years before, that he carried latent HIV DNA and this was subsequently activated by some febrile illness. I know this is only an anecdote, and that individuals can be guarded about their sexual histories.  I wonder if others have had similar experiences?

I think around 1996  a description of the course of infection was produced. Everyone interested in this disease will have seen this picture: Here it is again:

hivaids_9_fig-53

This may represent a typical course of infection.  But HIV disease is probably so variable in the course it can take that there may well not be such a thing as a typical infection.

This depiction does however give the impression that there is,  and discourages an appreciation of the probably  immense variations in the course of  HIV disease.  The notion of a “standard” course of HIV disease has  had implications for treatment.  Recommendations are made that take no account of  individual  rates of disease progression;  a one size fits all approach has been adopted.

The  rapid acceptance that there is a typical – or an  average  course of HIV infection is particularly odd as not only is the disease new – we have no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease are themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea then of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced as the epidemic is proceeding.

A model was constructed before sufficient evidence was available to justify it.  It really had no empirical basis; moreover it seemed to utterly ignore what we knew of other chronic viral diseases.  For example, hepatitis B and Hepatitis C can both have very variable courses.  These can range from clearing the infection, running a fulminant course ending fatally  to the establishment of a chronic active state which may progress at varying rates.  If we were to construct a model of the course of HIV disease only about  12 to 15 years after the disease was first seen, why on earth did we not consider the precedents of other chronic viral diseases?   Thus we might have  included the real possibility that some exposures may result in infections that may be cleared , as well as the now demonstrated situation where silent antibody negative infections occur.    The picture shown above – and presented in every text on HIV disease may indeed represent the most common course of HIV infection. But even this is not  known.

HIV infection, like other chronic viral infections  can progress in different ways. If we were more open to this there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. This has obvious therapeutic implications  -  for example as proinflammatory cytokines promote HIV replication, the control of endemic infections in some areas where they are highly prevalent is absolutely relevant to the control of HIV infection.  Steps as simple as the provision of sanitation and clean water may well have an impact on the control of HIV infection in some geographical areas.  Had we not been so tied to the notion of  a fixed course of HIV infection, we might have placed importance on the individualization of therapy, not only considering a fixed CD4 count as a signal to start therapy, but also considering each individuals rate of disease progression.

HIV disease is in this sense like  every other infectious disease, the course of which  to a greater or lesser extent can be influenced by many different factors , including host factors, factors related to the pathogen, the particular variant , the size of the infecting dose, the route of infection amongst many others.

I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease  does not necessarily  take the course  shown above.

In conclusion, the study of prolonged HIV seronegativity in infected people is important. Some reasons are:

1. There are obvious implications for vaccine development.

2. Seroprevalence may significantly underestimate the prevalence of HIV infection.

3. Understanding the phenomenon will advance our understanding of the pathogenesis of this disease, which in turn will open new therapeutic approaches.

4. There are instances of infected people remaining seronegative and in good health.

[1]

Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al..

Human immunod­eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods.

New England Journal of Medicine 1989 320:1458-1462.

[2]

Scientific Errors and Controversies in the U.S. HIV/AIDS Epidemic: How They Slowed Advances and Were Resolved

By Scott D. Holmberg

Published by Greenwood Publishing Group, 2008

[3]

Human Immunodeficiency Virus (HIV) Antigens and RNA in HIV-Seronegative Women with Cervical Intraepithelial Neoplasia
Jayasri Basu, Seymour L. Romney, Ruth H. Angeletti, Sten H. Vermund, Edward Nieves, Anna S. Kadish, Magdy S. Mikhail, and George A. Orr

The publisher of this journal kindly sends me the contents of each issue as I started this journal around 1983 and was its first editor, seeing it through its first two volumes. It was then simply called AIDS Research.

[4]

Zhu T, Corey L, Akridge R, Change Y, Feng F, Kim J, Alef C, Mcelroy J, Mullins J, Mcelrath J.

Evidence for HIV-1 latent infection in exposed seronegative individuals.

Abstract No.8, 6th Conference on Retroviruses and Opportunistic Infections. Chicago. 1999.

[5]

Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

Journal of virology, {J-Virol}, Jun 2003, vol. 77, no. 11, p. 6108-16,

Zhu-Tuofu, Corey-Lawrence, Hwangbo-Yon, Lee-Jean-M, Learn-Gerald-H, Mullins-James-I, McElrath-M-Juliana.

Abstract

Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specific cytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence for HIV-1 infection in ES individuals below the detection limit of standard assays, suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1 strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection.

[6]
Schattner, A, Hanuka N, Sarov B, Sarov I, Handzel Z, Bentwich Z.

Sequential serological studies of homosexual men with and without HIV infection. Epstein-Barr virus activation preceding and following HIV seroconversion.

Clin Exp Immunol 1991; 85: 209-13.

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