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  • Treatment as prevention. Another postscript.

    Posted on April 19th, 2009 admin 1 comment

    This additional postscript was prompted by an article that appeared a few days ago in the Washington Post. It was written by Dr Anthony Fauci, who adds his voice to support a policy of universal HIV testing and treatment of all those infected, adding also the treatment of uninfected people at high risk.

    He points to the dire situation in DC, and states that our prevention efforts have been insufficient. That is perfectly true. But he, with all of us, have watched  this terrible situation developing over the past 20 years;  as my first post, AIDS and Minorities  indicates, we did little to prevent it.

    We get Dr Fauci’s point that probably more than 56,000 Americans have been infected with HIV every year for the past decade. But if we look at the graph in my first post we can see that over the years, the proportion of infections in African Americans rose, while it fell in white Americans, although the numbers have levelled in the past 6-7 years.

    So, when we are told that our prevention efforts have been insufficient, are we not really being told that we just neglected or were unable to develop adequate prevention education programs for some populations? Or are we being told that this is inherently an impossible task?

    It is not. Gay men were able to make a significant impact of the spread of AIDS in the early years of the epidemic. Safer sex with the use of condoms did make a difference.

    Safer sex originated in this community without the slightest outside help.  I would also guess that the armies of behavioral psychologists who entered the field found that within this community, essential behavioral modifications had been already learned without much need for their interventions or recommendations.

    We might learn something from this experience.  Empowered communities can respond to threat, and maybe we should be providing  the support communities need to achieve this.

    Dr Fauci’s “three pronged” approach is fraught with danger. Firstly it implies that prevention education cannot work.  This is very unfortunate as it provides an excuse to diminish, rather than intensify our efforts. We absolutely have not exhausted all the potential there is to create persistent and effective highly targeted prevention education programs. It is possible that with adequate support communities can best do this themselves.

    Then there is the problem discussed in an earlier post  “Treatment as Prevention”  that deals with the many implications of providing treatment to individuals for a social good, but where the treated individuals will derive no benefit themselves.

    Infected individuals who do not need treatment will therefore be asked to receive it and thus be exposed to the risks of the drugs but derive no personal benefit from them.

    The first of the three bold approaches suggested is the treatment of uninfected people at high risk; this is called pre-exposure prophylaxis (PrEp).

    This of course includes sexually active gay men, IV drug users, and heterosexual female and male partners to an infected person. If this means intermittent use of PrEp I would agree that this may well be a useful, if as yet unproven approach.  The persistent use of PrEp is another matter as drug toxicity is an issue.

    Here it can certainly be argued that the uninfected  individual taking  antiviral drugs may certainly  benefit from their use, unlike the treatment of healthy HIV infected people with higher CD4 counts who may be slow or even non progressors.

    For the uninfected individual at risk the persistent use of PrEp  is something that individuals should decide on themselves,  given adequate information.  I doubt whether this will make the slightest difference to the state of the epidemic, but may provide individual benefit.

    The multitude of problems associated with the second and third approaches were simply ignored.  I will not repeat the problems that exist in treating people, not for their benefit, but for a social benefit; these are discussed in my previous post.

    It is far from clear – as the article categorically states that benefit will be derived from starting treatment as soon as possible after infection. There is no direct evidence to support this contention. We simply do not know if very prolonged exposure to antiviral drugs will prolong, shorten or have no effect on an individual’s life span.

    As far as toxicity is concerned, it is often stated that the newer drugs are less toxic.  How on earth do we know this with only a few years use? We have enough experience of severe toxic effects only being recognized after years of use.  The drugs that block the HIV co-receptor are particularly worrisome.   CCR5 does not exist on the cell surface for the convenience of HIV. It serves a physiological function and time will tell if blocking its natural function has deleterious effects, and if these outweigh the benefits the drugs confer in inhibiting HIV replication.

    As far as eradication is concerned – which appears to be the third new bold approach, this possibility is so far in the future, if it ever can be achieved, that it is absolutely unrealistic to base any practical policy on its success.  The difficulties in killing all cells that harbour stable integrated HIV DNA, or of excising it from the human genome are enormous.

    Before undertaking such a “three pronged” project we would need some assurance of success; we would need to know, for example what degree of compliance would be necessary for it to work. But these issues are discussed in my previous post.

    At the moment the only winners in this approach will be the drug and testing equipment manufacturers.

    We should renew and redouble our efforts towards producing and persistently disseminating prevention education messages, appropriately targeted to specific populations. We should provide communities with adequate support so that they can craft their own prevention education materials, and disseminate them.

    We should remove all barriers to testing. This includes the most difficult of undertakings which is to fight the stigmatization still associated with this disease.

    This will entail an avoidance of policies and legislation that have the effect of increasing stigmatization.  Among other disincentives to testing is the lack of assurance of a link to medical care.  The cavalier approach to informed consent recently demonstrated by some providers and community groups is misguided:

    http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=58009

    It is likely that the consequences of “streamlining” the consent process for testing will actually have the effect of dissuading individuals from being tested.

    Those proposing “streamlining” the consent process may think HIV testing is routine.  Those testing positive may soon come to a different conclusion when they learn that HIV disease is serious, can be associated with stigmatization, treatments may not be affordable or available, may have adverse effects, jobs may be lost, and  families may abandon infected individuals.

    Can a test that  opens the door to such difficulties be regarded as routine?

    As long as these consequences of testing remain possible, we absolutely must obtain informed consent for testing so that our patients will know  of the implications of both a negative and positive test.  We all gain from  doing  everything possible to be supportive and retain the trust of our patients.   This will not be achieved by misleading them.

    In conclusion: Providing antiviral drugs to people who do not need them is no substitute for developing a variety of highly targeted prevention education strategies.

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

    Posted on April 13th, 2009 admin 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.

  • Individualization of HIV therapy

    Posted on March 8th, 2009 admin 1 comment

    Why treatment of HIV infection must be individualized.

    HIV disease is usually a progressive disease. That is, it has a starting point; the time of infection. The disease then progresses, and without treatment will generally end fatally. There are some very fortunate HIV infected individuals who are able to control viral replication and remain disease free. But for most, HIV disease does progress. But, for each individual, the rate at which it progresses varies widely. Disease progression is reflected in the fall in the numbers of CD4 lymphocytes.

    So any single CD4 count measurement is really a point on a descending curve, one that does not necessarily proceed in a straight line, and falls at widely differing rates in different individuals.

    Recommendations for the treatment of HIV infected individuals are issued periodically by DHHS and bodies such as the International AIDS Society. These recommendations, particularly those concerning when to start antiviral treatment, have always included a particular CD4 count as a signal to start or to consider starting antiviral treatment.

    All individuals with a CD4 count of less than 200 should be on therapy. They are in great danger of acquiring a possibly fatal opportunistic infection and evidence derived from clinical studies makes it absolutely clear that antiretroviral treatment is life saving.

    But what about people with higher CD4 counts? Here there is uncertainty about when in the course of HIV infection it is best to start treatment. Of course, if the drugs were completely harmless (including cost) it might be less important to have an answer to this question. However the drugs can have significant adverse effects, some of which only become evident after years of use. For people with fewer than 200 CD4 lymphocytes, the benefit of antiviral treatment overwhelmingly outweighs the risks.

    For others, a very mixed group, with CD4 cells anywhere from 200 to over 1000, and each with a different rate of disease progression, we cannot, with any security, make a “one size fits all” recommendation as to when it is best to start treatment.

    The best way to resolve clinical uncertainty remains randomized prospective clinical trials. By now we might already have obtained reliable evidence as to whether, on average, it is best for infected individuals with more than 200 CD4 lymphocytes, and who have no symptoms, to start antiviral treatment immediately, or to defer it. (A suggestion made in 1997 when the first guidelines were issued: http://aidsperspective.net/articles/guidelines1.pdf )

    The current recommendations, regarding people with greater than 200 CD4 lymphocytes, and who are without symptoms, propose a CD4 count of 350 as a point to start treatment ( many believe this number should be 500). This recommendation is made for all individuals – it is a one size fits all approach[1]. This kind of approach is appropriate for some aspects of treatment; for others it is very wrong[2].

    Perhaps the most important  example of a  recommendation, where its application across the board  is problematic,  is that which deals  with the time when antiretroviral treatment should be started in individuals with greater than 200 CD4 lymphocytes.  This recommendation specifies a specific CD4 count at which to start. As noted, for individuals with a CD4 count below 200, there is no doubt that they will benefit from therapy. For others who have no symptoms, specifying a CD4 count for all is mistaken. It is here that individualization is necessary.

    The reason is that no two HIV infected people are the same with respect to the rate of disease progression. During the early years of the epidemic, before antiretroviral treatment was introduced, we soon noted that the CD4 count declined at different rates in different people, and not necessarily in a straight line. As noted, at one extreme, there were the few fortunate individuals in whom there seemed to be no disease progression, at the other there were the few people whose CD4 cells fell very rapidly after infection, and who did not survive for more than 2-3 years, but most fitted somewhere between these extremes .

    To illustrate this I have considered four possible situations. This is a picture of the possible rates of CD4 decline in four different individuals. . It is true that these pictures are constructs, but they do accurately reflect the observed variability in disease progression; real examples showing this variability would be easily found in my medical records, and of course in those of other physicians during the period between 1981 and about 1993.

    The dip in CD4 cells following infection is usually seen when there is an opportunity to observe this. CD4 cells then rebound to a level called the set point, which will be different in relation to the pre infection level in different people. From then on it declines, but at a very variable rate, and can remain steady for varying periods before declining, again at varying rates.

    img049

    Look at where three of them (A ,B and C) reach a count of 450 CD4 lymphocytes; A (an unusual rapid progressor) gets there in about one year, B in about 3 years, C in 7 years, and D, who is a fortunate non progressor is nowhere close after 18 years.

    The arguments for starting early are not only to forestall reaching the dangerous level of 200 CD4 lymphocytes. The continuous deterioration of the immune system and diminished chances of recovery at lower counts are also arguments for an earlier start. There is also the possibility that there is a greater incidence of cancer, – other than lymphoma and Kaposi’s sarcoma, at higher CD4 counts in HIV infected people. If this is so then it remains to be shown how frequently these events occur and whether antiviral therapy can avert them.

    Treatment itself, particularly if extended over many years, is not without risks, some of which cannot even be completely known yet, particularly with the newer antiviral agents. We have to do the best we can in making a risk benefit assessment. In order to do this we should attempt to obtain information on the rate of disease progress in any one individual. This may not be entirely possible, as the rate of disease progression in any one individual may not be steady; it may accelerate or slow down. But it is possible to obtain a good, if not perfect, picture of the course of HIV disease in any one person.

    How might we obtain some information about a given individual’s rate of disease progression? Apart from obvious exceptions, and in people below 200 CD4 cells, there are no emergencies in HIV medicine. For each person we generally will have time to observe the CD4 count and viral load over a period of 6 to 12 months and obtain some idea of the rate of progress. A rapid fall in CD4 count might result in a decision to start in less than six months of observation. Or a consistent fall in CD4 count might lead to a decision to start treatment at CD4 numbers higher than even 500. This is far from perfect, as changes in CD4 cell numbers do not necessarily follow a straight line. But it is far better than basing a decision on a snapshot – which is what the experts are telling us to do.

    Individualization involves more than considering the rate of disease progression. There are other factors, such as associated diseases, domestic and social circumstances such as a lack of housing, as well as mental health issues, and many other considerations that are involved in individualization. Observing people also provides the time to establish a doctor patient relationship and for the physician to become familiar with the patients particular circumstances.

    The natural history of untreated HIV disease is relevant to the “when to start treatment” issue and will be the topic of the next post.


    [1] Evidence supporting the recommendation is derived in part from retrospective observations. The reasons why these are unreliable guides are outlined in the previous post. It is critical to as far as possible, eliminate bias in study designs because this increases the probability that a particular outcome can be interpreted as indeed resulting from a particular intervention. In this case it would be that improved survival is due to an earlier start of antiviral therapy and that the medications mediate the effect – and not for example, from simply being under the supervision of a physician. Retrospective observations, that is, looking back at information already gathered cannot be free of confounding factors as described in the previous post. In a prospective study people would be randomly assigned to receive immediate treatment or to defer it. This will give us the most reliable answer to the question of which approach is better on average.

    [2]Examples of measures that should be taken in the treatment of every HIV infected person, irrespective of the rate of disease progression are the types of tests that are performed on the initial assessment of an infected person. For example, the initial assessment of an HIV infected person should always include not only CD4 counts and HIV viral load measurements, but also tests for hepatitis, toxoplasmosis, and many other investigations. Another example of an intervention that is appropriate for categories of infected people is treatment to prevent Pneumocystis pneumonia in people with less than 200 CD4 cells. And of course, people in this category must always be offered antiretroviral therapy.

  • AIDSPERSPECTIVE

    Posted on February 4th, 2009 admin 1 comment

    Why another AIDS blog?

    In order to just get started on this blog, the various reasons for creating it will be described on my web site: aidsperspective.net One of these reasons, which I suppose is self evident, is to bring some attention to the web site, where I am attempting to create a record of various AIDS related activities I have been involved with since the epidemic was first recognized in 1981. I have more or less learned how to construct a web site – at least to the extent that I am able to post legible material, and I am gradually adding to its content.

    Another reason for creating this blog is to provide an opportunity for comment on contemporary HIV/AIDS related events.

    With that I can start with the first post on this blog.

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