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AIDS Pathogenesis: HIV disease has characteristics of positive feedback systems
2nd April, 2010
There is a similar and slightly extended version of this post on the blog I have on the POZ website. It’s in two parts:
HIV infection and many other infections caused by a wide variety of microorganisms have a mutually enhancing relationship that is characteristic of positive feedback systems.
Although the reciprocal enhancing effects of HIV and other infections have been frequently described since the late 1980s, it is useful to explicitly recognize these as positive feedback systems as this highlights the implications they have for treatment of individuals and for control of the epidemic. Explicitly recognizing the positive feedback characteristic of HIV disease also provides a way of looking at pathogenesis that can suggest further studies, both clinical and laboratory, that might advance our understanding of mechanisms of disease acquisition.
This is an illustration of positive feedback. A stimulates B which in turn stimulates A. In this way the effects of A and B are increased.
The infections associated with the immunological disorders of HIV disease are generally, but not solely, caused by microorganisms that replicate within cells. Many of the organisms that cause these infections survive in healthy people without causing disease, prevented from doing so by a competent immune system. When the immune system fails these infectious agents start to divide. They may then cause disease. An additional effect of some of these active infections is to accelerate the replication of HIV. Several mechanisms are responsible for this effect, which can then result in further immunological deterioration.
In addition, co-infection with many of the pathogens that also affect individuals with intact immune systems can also promote HIV replication.
Not all co- infections result in a more rapid progression of HIV disease. Many have no effect and a few have even been reported to cause a temporary improvement of HIV disease. This may be the case with measles, scrub typhus and a form of transfusion associated hepatitis. But more often, when an effect of a co-infection has been noted, it has been to promote HIV disease progression.
Different co-infections can therefore affect the course of HIV disease in different ways. Some may have no impact on the course of HIV disease; a few may possibly cause a temporary amelioration. Those that are able to accelerate it are highly prevalent in HIV infected individuals.
Worldwide, viruses of the herpes family are probably the most important of the co-infections that interact with HIV in a mutually enhancing fashion. . Virtually all adults are infected with some of these viruses that usually exist in a latent or dormant state. They are readily activated in the setting of HIV infection and then promote further HIV replication by a number of different mechanisms.
In developing nations a range of different endemic infections, depending on geography, may be just as important; many can also accelerate HIV disease progression. Conversely, HIV infection can promote progression of some endemic infections.
Several different mechanisms have been uncovered that can explain the effects of co-infections on promoting HIV replication. With such a wide range of infections, the precise ways in which each do this will vary in detail.
However there is one characteristic possessed by all HIV potentiating infections. This is their ability to add to the immune activation that is a feature of progressive HIV disease.
By now I think it is generally accepted that chronic immune activation not only results from HIV infection but is a major contributor to the pathogenesis of HIV disease. A state of sustained high level immune activation is the basis of the chronic inflammation and immunologic deterioration characteristic of progressive HIV disease.
But what exactly is immune activation?
Immune activation refers to those changes that take place in the immune system when exposed to an infectious agent that allow it to eliminate or control the infection. Essentially, the immune system is activated from a resting state to fight an infection. Generally this process will last for days until the infection is overcome, and usually but not always, is followed by a lifelong immunity to the infectious agent.
However in progressive HIV disease the immune system continues to be activated at a high level and it is this sustained immune activation that eventually results in disease. An activated state of the immune system is characterized by differentiation of precursor immune system cells. Differentiation is the process by which these cells develop specialized functions. Examples of cells that have acquired specialized functions are those that produce specific antibodies, or those with the ability to kill other cells infected with specific microorganisms. Proliferation of immune system cells is an important characteristic of an activated state. This is usually a short-term response subsiding with control of the infection that stimulated it. But in progressive HIV disease, proliferation is sustained, probably with episodic cycles of further accelerations, and this continued proliferation contributes to the loss of immune system cells.
These cellular changes, differentiation and proliferation, are associated with the secretion of a variety of cytokines. Cytokines are molecules that can change the behaviour of cells by binding to specific receptors on their surfaces, for example, causing them to divide. Once released, cytokines not only attach to receptors on other cells but can also come back and attach to the receptors on the cell that produced it.
The cytokines that are released have widespread effects. Importantly, they include those that are associated with inflammatory changes, – the pro-inflammatory cytokines. With respect to positive feedback, pro-inflammatory cytokines including IL-6 and TNF alpha are able to accelerate HIV replication.
A part of the immune system, the innate immune system, responds immediately to infection by recognizing molecular patterns common to different organisms. The more familiar adaptive immune system responds to specific characteristics unique to each organism.
The innate immune system is also activated in untreated HIV infection. Interestingly effects of activation of innate immunity were recognized very early in the epidemic, even before HIV was discovered, and so are among the earliest recognized AIDS related immunological abnormalities. Activated innate immunity is responsible for the large amounts of alpha interferon in the circulation of people with untreated HIV/AIDS, first noted in 1981, the year this disease first came to our attention[i]. At that time the origin of this endogenous interferon was not known. For a period, elevated levels of beta 2- microglobulin were regarded as an adverse prognostic marker. This molecule can be regarded as a surrogate marker for interferon. The association of interferon with abnormalities characteristic of this disease – including low CD4 numbers was also reported in the first 2-3 years of the epidemic[ii]. Over twenty years later mechanisms have been discovered that can explain the participation of interferon in the disease process[iii].
Interferon appearing in the circulation in untreated HIV disease may even be the first marker of immune activation noted, although not recognized as such when first observed
The changes that occur on activation of the immune system are associated with many other markers that can be measured. Different molecules appear on the surface of activated cells. These can be detected and measured, as can the cytokines associated with immune activation.
These measurements can tell us the extent of immune activation. Importantly, the degree of immune activation parallels the rate of HIV disease progression.
Although it is now accepted that the consequences of continued activation and proliferation of immune system cells contribute to the loss of CD4 cells and the development of disease, the precise way it does so is not yet known, although there are a number of different mechanisms that could account for it. The associated inflammation also has adverse effects beyond the immune system. For more detailed information on these mechanisms there are references to two reviews at the end of this article[iv].
Sustained immune activation is therefore at the heart of HIV/AIDS pathogenesis. It is the sustained nature of the activated state that is critical. Short lived states of immune activation are of course beneficial allowing us to recover from infections. But in progressive HIV disease the process continues at variable rates. Understanding what causes continued immune activation is central to an understanding of the pathogenesis of HIV disease.
What causes Immune activation?
While infection with HIV may start the process, other causes of immune activation are almost certainly also necessary to keep it going.
The following all contribute:
1: The immune response to HIV itself. This includes both innate and adaptive immune responses. As noted above, adaptive responses are the familiar specific antibody and cell mediated responses that provide generally lifelong immunity to specific infectious agents. Innate responses depend on recognition of molecular patterns common to several organisms.
Some suggest that HIV contributes directly to immune activation through binding of some of its proteins to immune system cells.
2: Microbial products that can penetrate into the intestinal wall as a result of damage caused by HIV. These microbial products then activate immune system cells.
3: Other infections.
Some like active herpesvirus infections or the more traditional opportunistic infections can be seen as indirect effects of HIV infection.
Others are infections that can cause disease in people with intact immune systems like the endemic infections in developing nations. Some of these can be more severe in the setting of HIV infection.
Infections that can accelerate HIV replication include those caused by bacteria, viruses, protozoa and helminths.
Those that promote HIV disease progression can usefully be described in three categories.
A: Herpes virus infections. These are probably the most important worldwide. Virtually 100% of adults are infected with some of them. They represent infections that are more often latent, but are readily activated in HIV infected individuals.
B: Endemic infections caused by a variety of different microorganisms than promote HIV disease progression and HIV replication. These are important in developing nations.
C: Other infections. These include the opportunistic infections, as well as those that can affect people with intact immune systems. TB may be the most important. HIV infected individuals are much more susceptible to active TB infections than those who are HIV uninfected. HIV transcriptional activity and viral loads have been noted to be higher in people with active TB.
Here is a little more detail about these three classes of infection:
A: Herpesviruses.
There are eight members of the herpesvirus family that can infect humans. Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are perhaps the most familiar. Cytomegalovirus (CMV) and the Epstein-Barr virus (EBV) infect close to 100% of adults. Varicella-Zoster virus (VZV) causes chicken pox on initial infection and shingles when reactivated. Of the three remaining human herpes viruses HHV-6, HHV-7, and HHV-8, the last is associated with Kaposi’s sarcoma.
With all of the herpes viruses, once infected, individuals carry them for the rest of their lives, usually in a dormant or inactive state. All can be periodically reactivated with or without symptoms.
Humans and herpes viruses have co-existed for evolutionary periods and are well adapted to each other. The immune system generally maintains these viruses in a latent sate so that they cause no harm. Reactivation does occur periodically but is generally limited. Virtually 100% of adults will carry some viruses of the herpesvirus family, usually in a dormant or latent state.
The impaired immunity characteristic of HIV disease however results in reactivation of herpes virus infections. In progressive HIV disease these viruses become active and through a variety of mechanisms, including their contribution to immune activation, promote the replication of HIV. Cytomegalovirus (CMV) may be the most important of the herpesviruses that promote HIV disease progression. It can be part of a positive feedback system in its interactions with HIV.
HIV → latent herpes infections →active herpes infections → HIV
It is not only through their contributions to immune activation that herpes viruses promote HIV replication. In addition to the pro-inflammatory cytokines that have this effect, herpes virus gene products can directly activate HIV if a cell is infected with both viruses. This process, called transactivation works both ways; HIV can also activate herpes viruses.
In addition herpes infections cause a receptor (Fc) to appear on cell surfaces that allows HIV to enter it. In this way cells that do not possess CD4 molecules can become infected with HIV. Active CMV infections can also exert a mildly immunosuppressive effect.
Herpesviruses, particularly CMV are singled out because they probably play a significant role in the pathogenesis of HIV disease. CMV infections are so common that it is hard to find HIV infected individuals who are free from it so that they can be compared to those who are not. But as early as 1991 this was done with HIV infected haemophiliac patients, when it was noted that those also infected with CMV had a much more rapid progression of their HIV disease[v].
That CMV may play a role was suggested by many very early in the epidemic. A multifactorial model for the development of this disease published in 1983 before HIV was discovered suggested a major role for CMV and EBV[vi]. The considerable evidence for a role for herpesviruses, particularly for CMV, did not disappear with the discovery of HIV. The interactions of CMV and other herpes viruses with HIV that have been discovered may now explain their role.
Large studies on the effects of acyclovir on the course of HIV infection have provided compelling evidence that active infection with these viruses can be regarded as part of the disease process for most HIV infected individuals. Investigators focussed on HSV-2 undoubtedly because it is the most common cause of genital ulcers. The dose of acyclovir used would also have suppressed HSV-1, which is even more prevalent than HSV-2 and may be more sensitive to acyclovir. HIV viral loads and the rate of HIV disease progression were reduced in individuals receiving acyclovir compared to those receiving placebo. Although genital ulcer recurrences were suppressed by acyclovir, the drug had no effect on the transmission of HIV.
The effects of acyclovir on HIV probably resulted from suppression of active herpes infection. This is entirely consistent with a model that places HIV and herpesviruses in a positive feedback relationship.
EBV and CMV are much more resistant to acyclovir than HSV-1 and 2. But it cannot be excluded that this drug did not have some effect in also diminishing reactivations of CMV and EBV. If samples from the trial have been stored appropriately, this can be looked at. EBV reactivation patterns are easily recognized, CMV virus isolation is possible and even detection and quantification of activated T lymphocytes would tell us something.
B: Endemic infections:
These are singled out because of their high prevalence in some parts of the developing world.
These infections affect significant proportions of the population, they tend to be chronic and persist in the absence of treatment. The specific infections will depend on geography and many are transmitted by insects. Many of these can also accelerate HIV disease progression, and some also progress more rapidly in the setting of HIV infection[vii].
C: Other infections:
On an individual level, some episodic infections can promote HIV replication. An acute febrile illness may increase HIV viral loads, but this is a transient effect lasting for the duration of the infection.
Most of the serious opportunistic infections occur late in the course of HIV disease, and may promote even further disease progression.
TB deserves special consideration because of its high prevalence in HIV infection. Susceptibility to TB is increased even at higher CD4 levels. Active TB can then promote further HIV replication thus becoming a partner with HIV in a positive feedback interaction[viii].
A role for immune activation in a positive feedback system:
One way to look at the process of disease acquisition in HIV infection assigns a central role to immune activation.
Immune activation not only results from HIV infection, it can also promote further replication of HIV.
HIV replicates more efficiently in activated immune system cells. Secondly, the pro-inflammatory cytokines that are associated with an activated immune system can directly stimulate HIV replication. Progressive HIV disease and immune activation are therefore components of a positive feedback system in this way.
HIV disease → Immune activation → HIV disease → Immune activation
The process starts with HIV infection, and is promoted by other infections , some of which are activated by HIV infection.
Whatever is driving immune activation is driving HIV disease.
The following diagram illustrates this.
Looking at the course of HIV infection in this way has a number of implications.
Pathogenesis.
In the above diagram the course of HIV disease is represented by a self perpetuating cycle proceeding in a clockwise direction. In addition to the elements that have positive effects in driving the process, there will also be those that retard the cycle. This is illustrated in the next diagram which focuses for simplicity on the immunological control of HIV infection and of those infections that add to immune activation. Of course there are other mitigating factors, for example, genetic factors conferring varying degrees of resistance resulting from receptor polymorphism.
In the diagram, the connection of HIV with CMV and other herpes viruses is probably constant and indicated by a red arrow. The connection of HIV with endemic and associated infections is indicated by a blue dotted line, because HIV infection does not increase susceptibility to all of them, nor does it accelerate the progression of all.
The positive feedback cycle starts with HIV infection. At least some of the determinants of the rate of disease progression may be found in the conditions that exist at the time of initial infection that promote or retard the cycle.
There is evidence that the degree of immune activation at the time of seroconversion predicts future disease progression.[ix] [x] It may also be an important determinant of what is called the set point. This is the point following initial infection with HIV, from which CD4 numbers decline.
The degree of immune activation at seroconversion thus influences the starting CD4 level; the rate of subsequent decline is influenced by the degree of immune activation in a system where once started, conditions can exist where immune activation increases with falling CD4 numbers, in a self perpetuating and accelerating fashion. Whatever the outcome, it will be the balance of positive and negative influences.
In the earliest years there were reports of EBV reactivation preceding HIV seroconversion[xi].
I have not seen any follow up of this interesting report. It at least suggests that there might even be situations in which active herpes infections could sometimes promote seroconversion. They certainly produce signals that can activate HIV transcription from proviral DNA.
Treatment and prevention.
The role of immune activation in driving HIV disease is generally accepted now. There are sources of immune activation other than HIV and some of these can be controlled.
Attempts to identify and control additional sources of immune activation may be critical in the fight against HIV/AIDS.
Perhaps the most significant benefit in this respect concerns the developing world, where there are so many additional sources of immune activation. Even ascariasis, infestation with the common intestinal round worm is associated with significant immune activation. Worldwide prevalence is estimated to be about one billion, with 173 million in sub-Saharan Africa.
Many highly prevalent endemic infections can promote HIV replication. Controlling these are perfectly appropriate targets in the fight against HIV/AIDS, and of course this would independently improve the lives of millions of individuals.
Measures to control endemic infections include traditional public health interventions, such as the provision of sanitation and clean water and the control of insect vectors. Effective drugs are sometimes inexpensive. Peter Hotez has written an article entitled “Africa’s 32 cent solution to AIDS”.[xii] This refers to the price of Praziquantel , effective in treating schistosomiasis as a single dose.
The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause. Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.
Recent and ongoing studies will probably lead to the routine use of drugs that are effective against herpes virus infections. Trials of valacyclovir to reduce HIV viral loads are in progress. Given the ubiquitous nature of herpes infections, the use of acyclovir as adjunctive therapy might be warranted even in the absence of recurrent herpetic ulcers. Valacyclovir unfortunately is not yet available as a generic medication.
Unfortunately EBV and CMV are much more resistant to these drugs. The development of agents less toxic than valgancyclovir is important. Valgancyclovir has already been shown to reduce immune activation in HIV infected individuals as measured by a reduction in activated CD8 lymphocytes.
In summary it is useful to explicitly recognize the positive feedback interactions between HIV and other infections that can promote its replication, some of which are in turn promoted by HIV. Control of the AIDS epidemic in Africa must include measures to prevent and treat multiple endemic infections that affect hundreds of millions of individuals.
[i] This is of particular interest to me as I was involved in the discovery of large amounts of interferon in the circulation of people with HIV/AIDS in 1981, the year the disease was a first described.
http://aidsperspective.net/articles/Interferon_Vilcek.pdf
https://sonnabendj.files.wordpress.com/2009/03/aids-inf-31.jpg
[ii] http://aidsperspective.net/articles/Interferon-AZT-1991.pdf Fig 1 shows CD4 counts in relation to serum interferon . Presented 1986 at the 2nd international aids conference in Paris.
[iii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491901/
[iv] Immune activation and inflammation in HIV-1 infection: causes and consequences.
V.Appay and D. Sauce
J.Pathol. 2008; 214: 231-241
(This is an important review)
HIV immunopathogenesis and strategies for intervention.
M. Cadogan and A Dalgleish
Lancet Infectious diseases. 2008: 8: 675-84
[v] http://www3.interscience.wiley.com/journal/119316871/abstract?CRETRY=1&SRETRY=0
[vi] http://aidsperspective.net/articles/NYAS.pdf
[vii] Endemic infections in Africa have everything to do with HIV/AIDS:
https://sonnabendj.files.wordpress.com/2009/06/lawn21.jpg
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905977/
[ix] http://jvi.asm.org/cgi/content/full/81/16/8838?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=fig&searchid=1&FIRSTINDEX=1440&resourcetype=HWFIG
http://bloodjournal.hematologylibrary.org/cgi/content/full/104/4/942
[xi]
http://www3.interscience.wiley.com/journal/119342256/abstract?CRETRY=1&SRETRY=0
[xii] http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000430
HIV Prevention Education and Pre-Exposure Prophylaxis Against HIV. August 2009
Since my last post on this subject I have heard a variety of different views as well as discussed the issue with several interested individuals.
As a result I have come to see the issue somewhat differently; I suppose I could just amend my last post, but it’s better to leave it as it is and describe the differences in how I now view PrEP efficacy trials after having heard several different descriptions of ways in which these are seen.
I listened to presentations at two conferences during the last few weeks. A teleconference organized by CHAMP, a community group, and one organized by the Centers for Disease Control (CDC). These conferences attempted to engage and inform individuals about PrEP. As a consequence I realize that I was mistaken in stating so categorically that efficacy trials of PrEP, unlike safety trials, could not be undertaken in human research subjects. However I do not think that if all the ethical requirements are met, that is to provide condoms, consistent counseling and sterile injecting equipment, a generalizable result will be obtained indicating that it is an effective prevention strategy. Of course I don’t know this, and was wrong in my view that trials of PrEP efficacy should not proceed.
The most important concern with the way the promotion of PrEP, at least as a concept, is being pursued is the neglect of encouraging prevention education.
Prevention education remains the most important tool we actually have, as opposed to theoretical and unproven approaches. The latter include PrEP, and the test and treat every infected person proposal. We absolutely know that in principle prevention education, including the use of condoms can work. It worked in curbing the increase in the epidemic among gay men in the late 1980s .
The principle is thus established, admittedly without application to those who have no control over the use of condoms by the male partner. This group is therefore in need of prevention strategies they can control themselves, and PrEP may be the only realistic possibility.
For everyone else, the sexual transmission of HIV can be controlled by the use of condoms, even if not with 100% efficacy. We have a powerful tool in our hands, and if there are new infections, this is certainly not an indication that it does not work well enough. It indicates that it is an activity that receives insufficient support, or it may well be that some of those doing it are just not very good at it. Maybe there is little societal support for HIV prevention education, even little support from individuals at risk who could use condoms but would like not to.
Unfortunately, from what I have experienced, the several groups supporting and promoting PrEP seemed to have given little thought to prevention education in presenting this intervention to stakeholders. . They may be diligent in the context of efficacy trials, in ensuring the availability of condoms and counselling to participants.
But what seems to be missed is this: Unless the promotion of PrEP is accompanied by very clear advocacy of prevention education with condom use, PrEP can be seen as an alternative to safer sex practices as now recommended.
This cannot be the intention, but from comments I have heard after the CHAMP and CDC conferences this seems to be a dangerous conclusion that some have drawn.
The explanation of the utility of PrEP must be accompanied by a strengthening of prevention education to avoid this unfortunate misinterpretation. The very promotion of the concept of PrEP in the way it has so far been done can actually be seen as an undermining of condom use. A possible alternative to condoms is presented. One can only hope that in the absence of accompanying prevention education there will not be instances sex with available antiretroviral drugs rather than with condoms.
Prevention education is in a dismal state as it is, and we should be aware of any activity that can undermine it further, unless care is taken in how it is presented.
I have commented in other posts that in HIV medicine a one-size-fits-all approach seems to be the norm. Admittedly it’s cheaper to deal with populations rather than individuals. A single size that fits everybody is even cheaper than providing small, medium or large varieties, let alone customizing the size to fit individual needs.
So in HIV medicine, treatment recommendations have been made for all infected individuals, without considering the rate of disease progression, and many other characteristics applicable to any given person.
So it is with PrEP. Its relevance is different to different constituencies.
At one extreme, for those who have no power to control the use of a condom by their male partner, PrEP may be the only realistic possibility of avoiding infection with HIV. PrEP to these individuals is obviously of vital importance.
In fact it is so important that it would be useful even if its efficacy, if this can be demonstrated, proves to be inferior to the consistent use of condoms. Such individuals have no alternative.
The situation of people who are perfectly capable of consistent condom use is different.
The power of the receptive partner in this case is the power to say no. No condom, no sex. Both partners have an effective means of preventing the sexual transmission of HIV. There is no need for PrEP to prevent infection, except that some may welcome an additional layer of protection.
There are others whose hopes for PrEP are different. The desire to conceive is one.
Yet others hope that PrEP will make sex without condoms safe with respect to HIV transmission. In this case the efficacy of PrEP would have to be known to be at least equal to the consistent use of condoms (and free from toxicity and affordable). Of course individuals decide to take risks that involve danger to themselves only, but full information should be available, and certainly we should take care not to disseminate material that can mislead, even if only by implication. We do not have full information on the efficacy of PrEP, and I can see no way of testing its efficacy without the use of condoms. But it is here that we need to take great care not to mislead, even by implication, that PrEP is as safe as using condoms unless in the unlikely event, it is actually proven to be so.
Even a modest degree of efficacy is better than nothing for those who are unable to avoid sex with a partner who cannot be relied on to use a condom. There actually is nothing else to protect them.
A modest degree of efficacy is insufficient for those who are well able to refuse to have sex if a condom is not used. That’s my opinion, and I would believe that of many others, but as always risking harm to oneself only, is an individual choice; our obligation is not to mislead, and ensure that full and accurate information is available.
So, PrEP is of undoubted importance to individuals who have no control over the use of a condom by their male partner. Apart from the female condom, it is the insertive partner who has to use a condom. All the receptive partner has as protection now, is the ability to just say no. We recognize that there are situations when this is not possible, and no practical remedy is available to change this.
Of course there are other situations when it is possible to attempt a change. If an individual just cannot say no to a partner who cannot be relied on to use a condom because he or she is ignorant of safer sex practices this is something we must try to remedy with intensive prevention education. This will include imparting the knowledge of the lapses in judgement that can accompany the use of drugs or alcohol.
Getting away from the one-size-fits-all approach, there probably will be some individual situations in which PrEP, even if less effective than consistent condom use may be considered. An example noted by one commentator is when condom use may be associated with sexual dysfunction.
Prevention education with consistent condom use is the best available means we have to prevent the transmission of HIV. Prevention education should be strengthened and care taken not to undermine it.
Where individuals have no control over the use of a condom by their male partners we should do what we can to provide them with the means to protect themselves, and PrEP may be all we have to work on at present.
Others may look to PrEP as a means to avoid the use of condoms. The price of failure seems to be an extraordinary high one, considering that condom use is known to be highly effective in preventing HIV transmission.
There are people who need PrEP. There are also people perfectly able to use condoms but who want PrEP.
In promoting PrEP studies we must take great care not to undermine efforts at prevention education, even by implication. Promotion of PrEP must go hand in hand with promotion of HIV prevention education.
Despite the SMART study there is a role for intermittent therapy. July, 2009
From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..
The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.
For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.
We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.
One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs. This approach will almost definitely not be possible for all HIV infected people needing treatment. But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.
This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061. SMART is by far the largest study comparing continuous with intermittent therapy. In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.
The negative effect of SMART on the study of intermittent treatment continues. In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought. The most favoured, and almost certainly correct explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.
For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification. The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post. Almost all the deaths in the study occurred at US sites, where in contrast to non-US sites multiple co-morbidities were over represented. As seen in the table below these co morbidities included, among other conditions, hepatitis B and C, a history of heart disease and diabetes. There were even significantly more smokers among those enrolled at US sites. How can one extrapolate interpretations of observations made in such individuals to HIV infected populations free from these co-morbidities?
SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C, hypertension, and a previous history of heart disease Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy. That’s all. The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational literature addressed to physicians.
Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times. But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.
Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART. The Staccato study3, using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.
The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent. Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group). Although pneumonia was more frequent in the STI group. Here is a sentence from the author’s abstract.
“A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.
The finding regarding cardiovascular disease is particularly relevant.
Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study. It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation. There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people. So this needs to be studied. But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.
Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!
There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.
I was shown an invitation to physicians to a free course offered by a distinguished academic institution. Among the descriptions of what those attending the course will learn to do is the following:
“Describe, discuss and apply the data from the SMART study on CHD (coronary heart disease) risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”
What is one to make of this in the light of the LOTTI observations?
This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature. As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.
As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides. They also characteristically had low levels of HDL cholesterol (and of total cholesterol). I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available. We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased. There was, not surprisingly, a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.
So, there may indeed be something in the connection between untreated HIV disease and heart disease. In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease. Increased triglycerides are an independent risk factor for coronary heart disease. There even was a possible mechanism for this that was known in those days that could account for this.
Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted. Such changes have been seen in people with hepatitis C treated with recombinant interferon.
So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle? There are numerous different ways in which intermittent therapy can be structured.
The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit, studies smaller than SMART
Perhaps a clue is to be found in a sentence in the LOTTI study report.
Here it is:
“The mean daily therapeutic cost was 20.29 euros for controls and dropped to 9.07 euros in the STI arm (P<0.0001)”.
This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.
Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes), some form of intermittent therapy will probably be demonstrated to be safe. For individuals with at least 700 CD4 lymphocytes, this is already the case.
Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis. I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts. This desire for treatment interruptions was obviously true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.
Of course for individuals with CD4 counts below 200, this was not a good idea. Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.
There will be many anecdotes accumulated over the years of such experiences of intermittent treatment. I need to stress that these are just anecdotes and most definitely not formal studies. As such they can only lead to hypotheses on which studies can be based.
It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped. This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.
Of my patients who interrupted treatment none have come to harm. There was no established protocol to guide us and strategies used took patient preference into account. An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover. As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment. This approach is now generally considered to be unsafe and CD4 guided strategies are studied. But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.
In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.
“Many of our patients with high CD4 cell counts want to
stop treatment. The LOTTI study does not justify a
recommendation in that regard, but it does give clinicians
useful information that it is probably safe to stop
treatment within the limits of CD4 cell counts of
LOTTI. Continued vigilance is needed so that excellent
adherence is maintained when patients are on HAART
to prevent the emergence of resistance.
The LOTTI study adds important information to the
continued question of whether there is a role for
interrupted therapy. Further study is justified, particularly
with newer combination therapies, which may well
have less toxicity and therefore shift the balance towards
continuous treatment. Clinicians will welcome the
information from LOTTI because it can allay some of
the concerns regarding the safety of treatment interruptions
at high CD4 cell counts”.
In the LOTTI trial, treatment was restarted when the CD4 count dropped to 350 and stopped at a CD4 count of 700. So within these limits we have some reassurance of safety.
So, further study is absolutely warranted.
In the LOTTI study, participants had to have a CD4 count of 700.
What about individuals who have had undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700? Studies with different CD4 criteria should continue and not be deterred by the SMART results.
I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration. That is to get away from the prevailing one size fits all approach to therapy, mainly using a snapshot of just one or two parameters, the CD4 count and viral load to guide one, without considering the rate of change in CD4 numbers.
In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered. As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly. (Of course an individual may be super infected with a drug resistant variant).
It is likely that some form of episodic treatment may be effective in selected individuals. That is, periods on treatment alternating with periods off treatment. Because of its flexibility it is probably best suited to individualization.
As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy. But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5. But other similar studies have shown a high rate of viral rebound6.
However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.
It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.
I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites. At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.
The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented. As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.
Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.
This table shows characteristics of individuals who died compared to those who did not.
The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).
It can be seen that of the people who died, compared to those who did not, 11.8% vs 4.7% had a history of heart disease (p=0.04); 45.9% vs 24.1% were co infected with Hepatitis B or C (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).
Thus the people who died in the SMART study tended to be sick with non HIV related conditions. 64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.
But there is another remarkable figure in this table. 92.9 % of those who died were participants in US sites! I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.
Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle, for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.
The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants. All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm. However the distribution of these characteristics in those who died was not reported in this publication. We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.
I missed seeing this 2008 publication. It seems that most who saw it had little to say. But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8. I did not miss it this time, and have already written about it.
Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible. Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion that the SMART study indicates that treatment interruptions are unsafe for all, into question.
To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.
This lack of interest is really puzzling.
Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.
Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement. There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.
We know with some security from SMART that HIV infected individuals with Hepatitis B and C, hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.
For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all, a form of treatment interruption will be demonstrated to be safe. This can already be said for those meeting the conditions of the participants in the LOTTI trial.
The original report of the SMART study was published in the New England Journal of medicine in 2006.
http://content.nejm.org/cgi/content/full/355/22/2283
———————————————————————————————————————–
Refs
1: New England Journal of medicine 2006 355:2283-2296
2: Trivacan(ANRS 1269) Lancet 2006 367:1981-1989
3: Staccato Lancet 2006 368: 459-465
4: LOTTI AIDS 2009 23:799-807
5: Proceedings National Academy of Sciences 2001 98: 15161-6
6: AIDS 2003 17:2257-2258
7: Kuller et al. PLoS Oct. 2008 5(10): e203
8: The Lancet Infectious Diseases 2009 Vol 9 Issue 5 268-9
HIV Treatment: There is a role for intermittent therapy. July, 2009
From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..
The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.
For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.
We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.
One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs. This approach will almost definitely not be possible for all HIV infected people needing treatment. But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.
This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061. SMART is by far the largest study comparing continuous with intermittent therapy. In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.
The negative effect of SMART on the study of intermittent treatment continues. In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought. The most favoured explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.
For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification. The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post.
SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C, hypertension, and a previous history of heart disease Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy. That’s all. The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational literature addressed to physicians.
Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times. But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.
Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART. The Staccato study3, using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.
The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent. Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group). Although pneumonia was more frequent in the STI group. Here is a sentence from the author’s abstract.
“A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.
The finding regarding cardiovascular disease is particularly relevant.
Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study. It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation. There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people. So this needs to be studied. But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.
Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!
There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.
I was shown an invitation to physicians to a free course offered by a distinguished academic institution. Among the descriptions of what those attending the course will learn to do is the following:
“Describe, discuss and apply the data from the SMART study on CHD (coronary heart disease) risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”
What is one to make of this in the light of the LOTTI observations?
This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature. As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.
As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides. They also characteristically had low levels of HDL cholesterol (and of total cholesterol). I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available. We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased. There was, not surprisingly, a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.
So, there may indeed be something in the connection between untreated HIV disease and heart disease. In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease. Increased triglycerides are an independent risk factor for coronary heart disease. There even was a possible mechanism for this that was known in those days that could account for this.
Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted. Such changes have been seen in people with hepatitis C treated with recombinant interferon.
So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle? There are numerous different ways in which intermittent therapy can be structured.
The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit, studies smaller than SMART
Perhaps a clue is to be found in a sentence in the LOTTI study report.
Here it is:
“The mean daily therapeutic cost was 20.29 euros for controls and dropped to 9.07 euros in the STI arm (P<0.0001)”.
This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.
Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes), some form of intermittent therapy will probably be demonstrated to be safe. For individuals with at least 700 CD4 lymphocytes, this is already the case.
Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis. I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts. This desire for treatment interruptions was obviously true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.
Of course for individuals with CD4 counts below 200, this was not a good idea. Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.
There will be many anecdotes accumulated over the years of such experiences of intermittent treatment. I need to stress that these are just anecdotes and most definitely not formal studies. As such they can only lead to hypotheses on which studies can be based.
It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped. This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.
Of my patients who interrupted treatment none have come to harm. There was no established protocol to guide us and strategies used took patient preference into account. An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover. As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment. This approach is now generally considered to be unsafe and CD4 guided strategies are studied. But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.
In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.
“Many of our patients with high CD4 cell counts want to
stop treatment. The LOTTI study does not justify a
recommendation in that regard, but it does give clinicians
useful information that it is probably safe to stop
treatment within the limits of CD4 cell counts of
LOTTI. Continued vigilance is needed so that excellent
adherence is maintained when patients are on HAART
to prevent the emergence of resistance.
The LOTTI study adds important information to the
continued question of whether there is a role for
interrupted therapy. Further study is justified, particularly
with newer combination therapies, which may well
have less toxicity and therefore shift the balance towards
continuous treatment. Clinicians will welcome the
information from LOTTI because it can allay some of
the concerns regarding the safety of treatment interruptions
at high CD4 cell counts”.
In the LOTTI trial, treatment was restarted when the CD4 count dropped to 350 and stopped at a CD4 count of 700. So within these limits we have some reassurance of safety.
So, further study is absolutely warranted.
In the LOTTI study, participants had to have a CD4 count of 700.
What about individuals who have had undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700? Studies with different CD4 criteria should continue and not be deterred by the SMART results.
I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration. That is to get away from the prevailing one size fits all approach to therapy, mainly using a snapshot of just one or two parameters, the CD4 count and viral load to guide one, without considering the rate of change in CD4 numbers.
In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered. As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly. (Of course an individual may be super infected with a drug resistant variant).
It is likely that some form of episodic treatment may be effective in selected individuals. That is, periods on treatment alternating with periods off treatment. Because of its flexibility it is probably best suited to individualization.
As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy. But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5. But other similar studies have shown a high rate of viral rebound6.
However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.
It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.
I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites. At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.
The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented. As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.
Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.
This table shows characteristics of individuals who died compared to those who did not.
The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).
It can be seen that of the people who died, compared to those who did not, 11.8% vs 4.7% had a history of heart disease (p=0.04); 45.9% vs 24.1% were co infected with Hepatitis B or C (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).
Thus the people who died in the SMART study tended to be sick with non HIV related conditions. 64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.
But there is another remarkable figure in this table. 92.9 % of those who died were participants in US sites! I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.
Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle, for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.
The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants. All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm. However the distribution of these characteristics in those who died was not reported in this publication. We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.
I missed seeing this 2008 publication. It seems that most who saw it had little to say. But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8. I did not miss it this time, and have already written about it.
Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible. Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion that the SMART study indicates that treatment interruptions are unsafe for all, into question.
To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.
This lack of interest is really puzzling.
Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.
Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement. There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.
We know with some security from SMART that HIV infected individuals with Hepatitis B and C, hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.
For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all, a form of treatment interruption will be demonstrated to be safe. This can already be said for those meeting the conditions of the participants in the LOTTI trial.
The original report of the SMART study was published in the New England Journal of medicine in 2006.
http://content.nejm.org/cgi/content/full/355/22/2283
———————————————————————————————————————–
Refs
1: New England Journal of medicine 2006 355:2283-2296
2: Trivacan(ANRS 1269) Lancet 2006 367:1981-1989
3: Staccato Lancet 2006 368: 459-465
4: LOTTI AIDS 2009 23:799-807
5: Proceedings National Academy of Sciences 2001 98: 15161-6
6: AIDS 2003 17:2257-2258
7: Kuller et al. PLoS Oct. 2008 5(10): e203
8: The Lancet Infectious Diseases 2009 Vol 9 Issue 5 268-9
Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.
An article with the striking title “Africa’s 32 Cents Solution for HIV/AIDS” was just published in PLoS Neglected Tropical Diseases. It can be seen here:
http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000430
This dramatic title refers to the cost of treatment of schistosomiasis with praziquantal.
Schistosomiasis is an infection caused by parasitic worms, or helminths., of the genus Schistosoma. Most of the 200 million cases of schistosomiasis in the world occur in Africa.
The species, Schistosoma haematobium is estimated to infect about 112 million people in sub Saharan Africa. So its high prevalence puts it in the same class as that of TB, malaria and HIV. It is responsible for a huge burden of morbidity particularly in children and young adults.
S. haematobium has a complicated life cycle, some of which takes place in snails. People are infected by organisms released by snails living in fresh water. These organisms can penetrate the skin of any body part that is immersed in snail infested water. S. haematobium affects the urinary tract. The disease it causes is commonly called bilharzia.
I was very conscious of its danger as a child growing up in Zimbabwe, with signs at several small lakes around Bulawayo warning one not to swim in them because of the danger of bilharzia.
Peter Hotez and colleagues article is a welcome addition to the already substantial literature that strongly suggests that many endemic infections, not only with helminths, but also with bacteria, protozoa and viruses can increase the transmission of HIV and most probably have a detrimental effect on the course of HIV infection.
This paper concentrates on the local effects of S.haematobium on the female genital tract , where lesions caused by schistosome egg deposition result in mucosal patches, that can bleed during sexual intercourse. The authors state “Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry” and go on to compare this to the process by which herpes simplex ulcers increase susceptibility to HIV.
This does seem obvious – there is a mucosal break, so HIV has a way in.
In fact in the case of herpes simplex, this seemingly obvious connection is probably not correct. The large Partners in Prevention study, recently completed, found that acyclovir, a drug effective in treating herpes does not reduce the risk of HIV transmission. The drug however was associated with a reduction in the number of recurrences of herpetic ulcerations, and significantly slowed HIV disease progression. I have written about this in another post.
As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant, or at least as significant, as local effects in enhancing the transmission of HIV. Of course, both local and systemic effects may play a role in enhancing HIV transmission. The systemic effects include an impairment of virus specific immune responses; immune activation may also increase susceptibility to HIV and promote its replication.
The influence of associated infections on the infectivity of HIV extends far beyond that of schistosomiasis. Peter Hotez (the lead author of the above article) has done a great service by bringing attention to a number of devastating neglected tropical diseases. This important article can be seen in the Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575).
The title of the article is:
“Rescuing the bottom billion through control of neglected tropical diseases”
By Peter J Hotez, Alan Fenwick, Lorenzo Savioli and David Molyneux
I have copied this table from the above article:
These are incredibly huge numbers.
Many of these infections occur in children and young adults and not only have an impact on life expectancy, but significantly are the cause of chronic debility particularly in young people.
Some also have an activating effect on HIV replication by several mechanisms, some of which have been understood for well over ten years. The resulting acceleration of HIV infection, by increasing HIV viral loads, as well as by other mechanisms increases the transmission of this virus.
The health of hundreds of millions of individuals could be improved by efforts to prevent and treat these infections. These infections are also appropriate therapeutic targets in the fight against HIV/AIDS.
Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections and HIV, this association has been inexplicably neglected in providing additional approaches to controlling the epidemic..
I had what might be described as a misfortune to have been a member of President Mbeki’s panel on AIDS, an almost surreal experience I should write about. The following is an excerpt from something I wrote for this panel almost 10 years ago:
“The crucial difference in Africa, as opposed to the US, is the high prevalence of associated infections. These include STDs, TB, malaria and other protozoal infections, helminthic and bacterial infections. Such infections would supply sustained signals, such as IL-1 IL-6 and TNF, known to activate HIV. Some can also upregulate the expression of chemokine co receptors required for HIV entry. Some of these infections are somewhat immunosuppressive themselves, an effect contributed to by the secretion of IL-10.37 Sexual transmission of HIV is also known to be facilitated by a high viral burden.38 This would also be the consequence of the HIV activating effect of frequent associated infections in Africa.”
This was almost 10 years ago, and since then literature has continued to accumulate documenting the detrimental interactions between HIV and multiple infectious agents.
About two years ago I made a presentation at the Prevention Research Center at Berkeley, trying to understand why endemic diseases had been so neglected in our attempts to control AIDS, particularly in Africa. I thought that part of the problem was poor interdisciplinary communication and understanding. Specifically, there might be difficulties in communications between public health experts and microbiologists. Possible public health implications of the findings of microbiologists might not be perceived without additional explanation. I illustrated this with a specific article.
I used an excellent article to illustrate this problem.
The article is called “Contribution of Immune Activation to the Pathogenesis and transmission of HIV type 1 infection” and the authors are Stephen Lawn, Salvatore Butera and Thomas Folks. (Clinical Microbiology Reviews. Oct 2001 14; 753-777)
This is part of what I said in California in trying to illustrate the difficulty in communication:
“Of great interest – because of its implications for disease control was the discovery that other infections, viral, bacterial, protozoal and helminthic, could influence the course of HIV disease. Generally the effect was to enhance HIV replication, but a few seemed to ameliorate – at least temporarily, the course of infection. Scrub typhus, measles and perhaps a form of viral hepatitis, may have a transient beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.
We now come to an example of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS in Africa. This example is a review (cited above) explaining in great technical detail how the replication of HIV can be enormously enhanced by concurrent endemic infections, and how this not only accelerates the progression of HIV disease, but also facilitates its transmission. The authors show in molecular detail how many viral, bacterial, protozoan and helminthic infections can affect HIV replication. Included among these are common intestinal worms and water borne bacterial infections, causing severe diarrhea particularly in infants. The discussion is largely concerned with the possible beneficial effect of drugs that might counteract this enhancement of HIV replication. There is one short sentence on public health interventions that might eliminate this problem altogether. It is of particular interest because of its brevity in a rather long article. There is also a curious statement that where antiretroviral drugs are unavailable, measures to control endemic infections may be a useful approach. This comment is reproduced below, and somehow ignores the significance of the implication that control of these endemic infections requires no other justification than as a measure to control AIDS.
This paper, because of its immunological and molecular detail is not too likely to find its way to an epidemiologist or public health expert, but for one trained in these technicalities, I would suppose the public health implications would be immediately evident.
This particular paper also is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.
Below is an illustration from the body of the article: there is much more just like this. A person with no training in molecular biology or virology would not be likely to spend any time with this illustration.
However if one turned a few pages the following diagram may just be of some interest. But again this is unlikely.
The part that would be of interest to a public health professional , if noted, is contained in the large arrow at the bottom right of the illustration. In this rather complex diagram it would be quite easy for the public health expert to be sufficiently distracted so that the bottom right hand corner would be easily missed.
There is a long discussion, quite technical in nature, but at least the authors find space for the following brief comment.
“Prevention and Treatment of Coinfections
The widespread use of HAART in the treatment of HIV-
infected persons in westernized countries has resulted in a
phenomenal decrease in the incidence of opportunistic infec-
tions and has greatly increased survival. For these individuals,
the antiretroviral drugs are the major determinant of prognosis
and the potential cofactor effect of opportunistic infections is
now a more minor consideration. However, the vast majority
(>95%) of the world’s HIV-infected people do not currently
have access to antiretroviral drugs. Most of these people live in
developing countries, where the quality and access to health
care is often limited and where there is a high incidence of
endemic infectious diseases such as malaria, TB, and infections
by helminths and waterborne pathogens which may adversely
affect HIV-1 disease progression. Prevention or early treat-
ment of these diseases may therefore represent an important
strategy in addressing the HIV-1 epidemic in developing coun-
tries”. –
In the above quotation, the authors are overoptimistic in their assertion that the cofactor effect of opportunistic infections is now a more minor consideration in developed countries. Valacyclovir, a drug that inhibits the replication of many members of the herpes virus group, but has no direct effect on HIV was reported to reduce HIV viral loads in the absence of antiretroviral therapy. In the developed world, active herpes virus infections are common in the setting of HIV infection, although most will be asymptomatic. For example, Cytomegalovirus, Epstein Barr Virus and Human herpes virus type 6 are not infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these viruses, and may well find a place in the treatment of HIV infection in developed countries. Indeed it may not be uncommon for experienced physicians here (in the US) to prescribe related anti herpes medications to their HIV infected patients. I certainly do.
There is another aspect, a little more difficult to establish and perhaps altogether conjectural. This is that we are presented with the question of why we need AIDS to justify interventions that have long been established to themselves improve the health of populations. These include the provision of sanitation and clean water, the control of malaria and TB, and something as simple as getting rid of worms. In the public’s assessment of the health needs of developing countries the information that is used is largely to be found in popular media, newspapers, magazines and TV. Those who report in turn receive information from professional sources, and maybe it is here that the interdisciplinary barriers to communication I have been talking about have their effect. Thus the AIDS epidemic is perceived to be the greatest threat to the future of Africa, even though malaria kills more people, and common endemic infections contribute to an abysmal life expectancy. (This was written 2-3 years ago and was probably incorrect even at that time; estimates are that today there are 1.5-2 million deaths from AIDS in Africa, with close to 1 million deaths from malaria. Malaria though is responsible for a greater number of deaths in children under 5 years of age).
It continues to be remarkable that although evidence has existed for years that many of these infections can interact with HIV infection to increase its infectivity and accelerate disease progression, those who advocate for, and allocate funds to fight HIV/AIDS seem oblivious to the relevance and implications of these interactions.
This effort of course needs absolutely no justification, but its funding is small compared to the resources that have been made available to combat HIV/AIDS – but from all that has been described funding for these endemic infections is in fact also funding to fight HIV/AIDS “.
Those were comments made 2-3 years ago.
While malaria and tuberculosis are now receiving attention and are included with AIDS in some programs, many other endemic infections continue to be neglected.
Going back much further in time, interest in the activating effects of associated infections on HIV replication began within the first 10 years of the epidemic. This started with the demonstration that proinflammatory cytokines, TNF alpha or IL 6, for example could greatly accelerate HIV replication.
Of course these cytokines appear in the course of many different infections. When viral load tests became available this effect was well understood by patients and physicians in N America and Europe. It became common wisdom that an HIV infected person who had a febrile illness, or had even received a flu vaccine should delay viral load testing because the infection or vaccination was frequently associated with temporary rises in HIV viral loads.
The implications for geographic areas where the infections were far from temporary seemed to escape notice.
Thus endemic infections in Africa do have everything to do with HIV/AIDS. There are numerous preventative and therapeutic measures available to control many of these infections, and some are inexpensive. Even something as simple as deworming may be useful. Ascaris lumbricoides, the common intestinal round worm also is associated with immune activation and is easily got rid of. There is a report that doing this with a drug called albendazole actually raised CD4 counts. (Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609, 2008).
The person who has been studying immune activation and the association of parasitic infestations and AIDS for the longest time is Zvi Bentwich. I can’t remember when his first publication on this issue appeared but by the mid 1990s he was publishing on this association in Ethiopian immigrants to Israel. Zvi Bentwich deserves the greatest credit for his early recognition of the importance of this association, its significance regarding immune activation and for his continuing contributions. He pointed out the relevance of schistosomiasis to AIDS (and TB) at least 10 years ago.
The connection of so many endemic infections with AIDS in Africa is also a connection of poverty with AIDS. I saw an absurd and instantly forgettable paper entitled something like “Poverty does not cause AIDS” a few years ago. Of course poverty is not the direct cause of ascariasis, schistosomiasis, tuberculosis, or any number of devastating infections. Poverty is a very significant factor in the acquisition of these infections, and as such can certainly be regarded as having a causative role.
The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause. Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other. For example the debility associated with schistosomiasis has an impact on an individual’s productivity, with economic consequences not only for the individual but for the larger community.
Controlling the AIDS epidemic in Africa must also include measures to prevent and treat the multiple endemic infections that affect hundreds of millions of individuals.
To conclude this post I want to recommend a book published about four years ago by Eileen Stillwaggon, a professor of economics. It is called “AIDS and the ecology of poverty” and is published by the Oxford University Press.
Treatment as Prevention: Protecting individual autonomy. May 2010
I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.
This document discusses treatment as prevention at the individual and the population level together.
It places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf. I have come to see the issues in a somewhat different way after reading the French document.
This document can be seen here:
http://www.cns.sante.fr/spip.php?article296&lang=en
It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.
At an individual level it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.
The term is also applied at a population level, where the goal of treatment as prevention is the control of the epidemic, even as suggested by some, a means to end it.
The principle underlying the proposals to use treatment as prevention in both of these situations is the same. It is the reduction in infectivity that results from the effect of antiretroviral therapy.
Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.
Treatment as prevention is not the same when applied to individuals as opposed to populations. For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.
To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.
For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.
For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.
Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%. Transmission would be slowed but not reversed with treatment rates below 50%.
Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.
At an extreme, if the stated objective is to end the epidemic, as has been proposed by some, the proportion of infected people who would need to be treated would be so large that it would have to include those who do not need treatment for their own benefit.
I have written about the multitude of problems arising from this situation in previous posts on this topic. Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.
However if, as I believe, an additional goal of treating infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.
Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment. Therefore we must also intensify and improve our efforts at targeted prevention education with the promotion of condom use.
But we will avoid the insuperable problems and threats to personal autonomy associated with treating individuals who do not need to be treated for their own benefit.
The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.
It might be preferable to simply state that the goal is to provide treatment to every individual who needs it. This goal must therefore be coupled with enhanced efforts to facilitate regular testing.
If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.
There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .
When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.
One reason why the French document is so significant is that it stresses the importance of individual autonomy.
It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ coercive measures in the name of the public good. Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.
Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.
” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,
Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.
Instead we should:
Offer treatment to all who need it.
Facilitate testing, identifying and removing barriers that impede it.
Intensify and improve our efforts at targeted prevention education.
Promote condom use and make them available.
There is a final issue.
Who needs to be treated? Certainly everyone with a CD4 count below 200. Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.
Herpes Viruses and HIV: Some early History and a Bit about Safe Sex
[The relationship between herpes viruses and HIV disease is also discussed in a subsequent post:
http://aidsperspective.net/blog/?p=520 ]
The relationship between herpes simplex virus type 2 and HIV is in the news again. This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.
This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died. A reduction in HIV viral load was also observed in those treated with acyclovir.
The concept on which this study was based is absolutely solid.
Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.
The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.
There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.
Herpes viruses – and not just herpes simplex virus, have an impact on the course of HIV infection. This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.
Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.
“Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .
(NEJM 2007 356:790)
It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed. The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.
These assumptions about the reasons for increased HIV transmission may all be mistaken.
We do know with some confidence that transmission of HIV is related to viral load in the infecting partner. It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.
An individual with higher HIV viral loads will more easily transmit the infection, and also experience more frequent recurrences herpetic ulcers. This of course only applies to HIV infected individuals.
As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.
Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.
Sometimes individuals know what provokes a recurrence. Recurrences can be associated with febrile illnesses. It is completely reasonable to suggest that the effects of some intercurrent infections may cause both herpetic recurrences and increase susceptibility to HIV.
Whatever infection causes the fever may also increase susceptibility to HIV, possibly by an association of the infection with perturbed immunological function. Transient immunological perturbations can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.
For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2. At least regarding what is reported to the public.
However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.
Cytomegalovirus (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important. These viruses are also sensitive to the anti herpes drugs used in these two trials.
Since infections with CMV and EBV are so widespread how can effects of acyclovir and Valtrex on reducing HIV viral loads be attributed to an effect of these drugs on herpes simplex type2?
I cannot recall that these two other members of the herpes virus family – or even a third, HHV6 were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.
It is entirely possible that suppression of two viruses, CMV and EBV, contributed, perhaps to the greatest extent, to the anti HIV effects seen.
One can only hope that sera from these studies were frozen and stored. Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.
As an historical comment, acyclovir was tried as a treatment for AIDS in 1987 around the time AZT was introduced.
There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.
AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.
One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.
Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir. Another retrospective observational study found no benefit.
Nothing much can be made of these contradictory early results.
But now, with newer techniques for measuring HIV activity by viral load assays, we have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.
With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease, Unfortunately most of the emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe, of even greater importance.
Actually there had been interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.
I have been involved in AIDS research and treating patients with this disease from the time it started and so can provide some historical perspective on the interest in herpes viruses, that dates to the late 1970s, even before AIDS was described and long before HIV was discovered. At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.
As another historical interlude, interest in herpes viruses also provided the basis for safer sex, as it is understood today. As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV. Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.
From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.
I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men. By 1983 over 40% of a cohort of gay men in New York City carried CMV in their semen. Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections. (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al. AIDS Research 1983 1: 59)
At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods, and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.
But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease. It was thus possible to propose a way to at least prevent the sexual transmission of CMV.
This formed the basis for the first published recommendations for condom use.
With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.
The appropriate title was coined by Richard.
The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007. Although it is in fact a landmark event in the history of the epidemic.
Richard is only now receiving some acknowledgement for this life saving proposal because a documentary film called Sex Positive has brought attention to his achievement.
An account of our collaboration in producing the safer sex guidelines can be seen by following this link.
Michael Callen is remembered by many for his activism. There is even a clinic in New York City named for him and Audre Lorde .
I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.
I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.
Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.
As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS. This is quite apart from their multiple clinical manifestations as opportunistic pathogens. Both of these viruses almost definitely contribute to pathogenesis.
Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated for many years.
In fact some evidence for this was already apparent when AIDS was first described.
This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.
As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.
I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.
Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.
The role of CMV in immune system activation, a major force in driving HIV infection.
The systemic effects of CMV and EBV infections are most probably of great importance in this respect.
Systemic effects resulting in immune system activation and activation of HIV replication may also accompany reactivated herpes simplex virus infecteions.
Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines. These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles. So, this is but one way in which an active herpes virus infections can promote the replication of HIV. The general mechanisms are described in a previous post..
An important and interesting paper that also deals with EBV and CMV in relation to HIV replication was published by V Appay and colleagues. It can be seen by clicking the following link.
I am reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references. The references can be seen in the complete text seen by following the above link.
“HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”
“In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in
the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained
antigen mediated immune activation occurs in HIV-1-infected
patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.
“CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears
to monopolize a significant fraction of the whole T cell repertoire [97], so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects [98]”.
Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface. These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.
Transactivation of HIV by herpes viruses.
In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.
Acyclovir and Valtrex have no direct effect on HIV except under one unusual circumstance, yet both have been demonstrated to reduce HIV viral loads.
In the early 1980s when we had no effective measures against this disease I treated my patients with high dose acyclovir.
There then was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.
In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.
But interestingly, at that time, none of these theoretical considerations placed much importance on HSV 2.
The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.
Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.
But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending interventions.
What I have written of this experience with bactrim in the early years can be seen by following this LINK
In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.
[i] Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc. But this drug has a truly remarkable quality. The cellular enzyme that adds phosphate to make drugs of this type active, does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues. But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears in herpes virus infected cells has the ability to add the phosphate group and turn acyclovir into an active drug. This is the reason why acyclovir is such a safe drug. It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.
However, if the same cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to terminate HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.
This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.
The Not So SMART Study
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.
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.
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.
