Treatment of HIV/AIDS. The revised USPHS guidelines. May, 2010
The revised USPHS guidelines for the treatment of HIV/AIDS
Guidelines for the treatment of HIV/AIDS were first issued by the US Department of Health and Human Services (DHHS) in 1998. They have undergone numerous revisions since then; the most recent was in December 2009.
The first guidelines were issued shortly after potent antiviral medications became available. We knew very little about how best to use these drugs at that time, and with only a few years experience our knowledge of their adverse effects was understandably limited.
Perhaps the only reliable information we then had was that individuals with fewer than 200 CD4 lymphocytes received a life saving benefit from their use.
Despite such limited information the panel that had been convened to write the guidelines made firm recommendations for the use of antiviral drugs in groups of patients for whom evidence of a net benefit was lacking.
Even in the absence of experience with the newer antiviral agents, at least two probable problems associated with their use could have been anticipated in 1997. The propensity of just about any microorganism to develop resistance to antimicrobial agents was no mystery. Nor was it a surprise that adverse reactions to new drugs appeared as they were used for longer periods.
As might have been anticipated healthier HIV infected individuals have not infrequently had to deal with both of these problems.
Why then did the first HIV/AIDS treatment guidelines panel not propose and encourage the conduct of a randomized prospective clinical trial to answer the question of whether immediate or deferred treatment with antiviral drugs could or could not prolong life and improve its quality or made no difference apart from cost?
Since the problems that were to arise could have been anticipated, if not their extent, the guidelines committee must have accepted that whatever evidence existed was sufficient to reassure them that there would be a net benefit to starting treatment at 500 CD4 lymphocytes.
The most recent revision of the DHHS guidelines now propose, as the first guidelines did, that treatment be initiated at a CD4 count of 500. A prospective randomized trial that directly addresses the question of when treatment is best initiated has yet to be completed. In the absence of information from such a trial the committee has relied on evidence from some large retrospective observational studies.
In the next post John Falkenberg writes about some previous experiences where advice based on results of retrospective analyses of observational data had to be reversed when the results of randomized controlled studies became available.
I believe the biggest mistake made in 1997 by the guidelines committee was in not responding to the very real possibilities of dangers associated with early treatment initiation by encouraging the completion of a prospective randomized trial, such as START, that could by now have reliably provided an answer to the question of whether immediate or deferred treatment is better or worse or makes no difference that is, apart from cost.
It’s not the benefits of early treatment that are in question. Of course there are benefits, but the question we need an answer to is when in the course of HIV disease the benefits of treatment outweigh the risks.
Long term exposure to antiretroviral drugs can have harmful effects. It can take many years to recognize some of these adverse effects. For example we learned only in the last few months that under certain circumstances neurocognitive function improved in some people who stopped antiviral drugs (ACTG 5170).
So the challenge is to find out how best to use the drugs. Put another way, we must find ways to safely minimize exposure to the drugs, which until we have drugs without significant adverse effects, is what determining the optimal time to start treatment is all about. We don’t know if a person deferring treatment until a CD4 count of 350 will or will not live longer with an overall better or worse quality of life than someone starting at 800 or even 500 CD4s.
We do know that at 350 CD4s, benefits of treatment far outweigh risks. But no matter what NIH guidelines committee members may feel, we do not yet have the most reliable evidence that benefits of treatment will outweigh risks when starting at higher numbers.
The wording of the USPHS guidelines is such that depending on whose vote one goes with, I suppose might even be interpreted to mean a recommendation for every HIV positive individual to receive treatment irrespective of CD4 count.
A letter written to the DHHS panel in 1997 suggesting that a randomized prospective trial be encouraged to provide guidance for individuals with greater than 200 CD4 lymphocytes remained unanswered although received.
Sadly the repeated changes to the guidelines since their first appearance in 1998 appear to indicate a retreat from evidence-based recommendations. Maybe this should be stated as a retreat from attempting to find the most reliable evidence on which to base recommendations. The guidelines panel go to great lengths to reassure us that their recommendations are indeed evidence based.
But as they recognize, the quality of evidence can vary. They also recognize that evidence of the highest quality is derived from the results of prospective randomized trials. Yet not only do they not vigorously encourage the completion of such trials, their recommendations actually inhibit enrolment into START which is such a trial.
Unfortunately the DHHS recommendations while not binding have a huge influence. Remarkably they are even regarded by some as setting an ethical standard, so that fears have been expressed that enrolment into START might be considered unethical as the current guidelines revision recommend starting treatment at 500 CD 4 lymphocytes.
Thirteen years after the first guidelines were issued, the DHHS panel has now made revisions that continues to threaten enrolment into a randomized controlled trial that will provide clear guidance to HIV positive individuals and their doctors about when to initiate antiviral therapy.
Surely, when we recognize that reliable evidence is lacking to inform a very important clinical decision, is it not our obligation to seek the evidence, rather than settle for the uncertainties associated with evidence of inferior quality? This is not only for the benefit of our patients but also to affirm that our stated respect for evidence-based recommendations is more than lip service.
At this time the DHHS guidelines are the only ones that recommend a start to treatment at 500 CD4 lymphocytes.
The DHHS guidelines have been of benefit to people with HIV/AIDS. But on the issue of when to start antiviral therapy they have not best served the interests of HIV positive individuals.
We need a randomized controlled trial to answer this question, not the votes of a committee.
I believe that many health care providers would welcome the opportunity to be able to present an option to their patients with greater than 350 CD4s, to enrol in a study such as START.
At the end of the day, determining when it’s best to start is not something you vote on. It’s something so important that you nail it down with a trial such as START.
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.
PrEP: Pre exposure prophylaxis to prevent HIV infection. August 2009
Pre exposure prophylaxis in relation to HIV infection refers to the administration of anti HIV medications to uninfected people as a means of protecting them from becoming infected with HIV. It is not known if this intervention will succeed in achieving its goal. Several trials have been underway to test it for safety and efficacy, and many more are planned worldwide.
I have paid little attention to these initiatives but was prompted to do so by notices of a meeting to discuss pre exposure prophylaxis – now known as PrEP – in the coming weeks. The wording of this notice is quite vague, but the notice suggests that it is urgent to start planning for the implementation of PrEP as the analysis of initial safety and efficacy trials are expected within the next year.
This is quite startling in its implication that PrEP actually works and presumably is safe. The actual words of the notice are:
“Results and analyses of initial safety and efficacy trials are expected within the next year, which highlights the urgency to beginning to plan now for how PrEP might be used to maximize its public health impact”.
This is a convoluted statement, to the point of being quite unintelligible. It can be misleading in the implication that can easily be drawn from it that PrEP works. Why else begin to plan for how to use it?
I had not been aware of just how extensive the PrEP initiative has been. To get some idea of the many trials that are underway or planned, take a look at this website:
Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).
http://www.fhi.org/en/Topics/preexposure_prophylaxis.htm
FHI has produced a set of slides listing PrEP trials.
http://www.prepwatch.org/pdf/Meetings/Cates_TDF_slides_May.2006.pdf
Among the “research consortia” listed as involved in PrEP research are the Bill and Melinda Gates Foundation, Gilead Sciences, the Centers for Disease Control (CDC), The National Institutes of Health (NIH), and UCSF. These trials are conducted in many countries, including Peru, Botswana, Thailand, the US and Malawi.
Organizations listed under “community consortia” are GMHC, AVAC, Global Campaign for Microbicides, CHAMP, and the IAS.
The websites of these organizations contain information about PrEP.
AVAC : http://www.avac.org/
Global Campaign for Microbicides: http://www.global-campaign.org/
CHAMP: http://www.champnetwork.org/about
The International AIDS Society: www.iasociety.org
All the trials use a once daily drug, tenofovir, with or without emtricitabine (FTC). Tenofovir is manufactured by Gilead in the US although I believe a generic version is produced in India.
The trials vary in design. Some require daily tenofovir, some are used intermittently or specifically before sexual intercourse. Some use a gel formulation.
Previous trials had run into difficulties; several were stopped for different reasons. For example a trial in Cameroon was stopped amid allegations that those who seroconverted did not receive adequate treatment. A trial in Nigeria was stopped because of inadequate standards in laboratory testing.
A trial of PrEP among Cambodian sex workers was stopped in 2004 by the Cambodian government. This was perhaps the most publicized of the several PrEP trials that were stopped, because several activist groups brought attention to it at the XV International AIDS Conference in Bakgkok. Among the many reasons stated for pressure by activist groups to stop the trial were poor HIV prevention counselling, and a lack of medical services to those who seroconverted. Act Up-Paris was active in stopping PrEP trials both in Cambodia and Cameroon, although it is reported that this organization is supportive of tenofovir trials in general.
These events are described in an article entitled “The Abandoned Trials of Pre-Exposure Prophylaxis for HIV: What Went Wrong?” The authors are Jerome Singh and Edward Mills. It can be seen here.
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020234
For reasons I will describe I do believe that there is no way to design a trial of the efficacy of PrEP that can meet acceptable ethical standards. On the other hand, it is perfectly possible to conduct trials to determine the safety of tenofovir for pre exposure prophylaxis.
So maybe an answer to Drs Singh and Mills as to what went wrong with the abandoned trials of pre exposure prophylaxis is that the question of efficacy, unlike that of safety, cannot and should not be tested on human research subjects.
Here are the reasons why this cannot be done, at least regarding the use of tenofovir to prevent sexual transmission of HIV.
No ethically designed and conducted trial can definitely prove that PrEP works. Definite proof of course may be an unattainable goal, but even credible evidence regarding efficacy would not be found if the trial were to be conducted in an ethical manner, simply because with the availability of condoms, and the imperative to provide counselling that they be consistently used, such a trial could not answer the question asked of it. This is essentially because the consistent use of condoms will ensure that insufficient seroconversions occur in participants receiving placebo.
In any trial that studies the ability of a new intervention to prevent sexual transmission of HIV, participants must receive persistent counselling about the need to use condoms. These must be provided, with ongoing support for their continued use. This is the ethical requirement.
Quite clearly if great care is taken to meet this requirement there will be few infections in people receiving placebo. The investigators are presented with a conflict of interest that no amount of verbal assurance can resolve. The conflict is that on the one hand the investigator must always be cognisant of the importance of doing all that’s possible to encourage condom use to prevent the sexual transmission of HIV infection, and on the other hand the investigator has an interest in demonstrating an effect of PrEP in preventing it.
It is only when condom use falls below a certain level that the effect of another preventative measure can be assessed. We are obliged to do all we can to ensure that this does not happen.
The Centers for Disease Control (CDC) are sponsoring several trials of PrEP[i]. They are very sensitive to the need to provide risk reduction counselling to participants.
Here is an excerpt from material published by CDC:
“One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that individuals at risk will reduce their use of existing HIV prevention strategies. It will therefore be crucial to reinforce proven behavioral prevention strategies, both within and beyond these trials. All three trials are taking multiple steps to address this issue during the education and enrolment of trial participants and through ongoing participant counselling.
First, it is critical to ensure that participants understand that trial participation may not protect them from HIV infection—either because they may receive a placebo or because they may receive a study drug, the efficacy of which remains unproven. This and other key aspects of the trial, including the potential risks and benefits of participation, are explained to potential volunteers in the language of their choice, prior to their enrolment. To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent. Study participants are also free to withdraw from the trial at any time and for any reason”.
So there is clear recognition that there may be a falling off in the use of proven prevention approaches, importantly, the use of condoms.
Here is another excerpt:
“To assist participants in eliminating or reducing HIV risk behaviours, extensive counselling is provided at each study visit, and more often if needed. This interactive counselling has proven effective in reducing the risk of HIV and other STDs in multiple populations, including past participants of similar HIV prevention trials. Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection”.
If such counselling is effective, the prevention of sexual transmission of HIV particularly through the consistent use of condoms will make it impossible to detect an effect of PrEP. As mentioned the investigators are presented with a conflict that it is not possible to resolve.
PrEP is an experimental approach to prevention, while consistent condom use is an established method to substantially reduce the sexual transmission of HIV.
The argument that may be presented by those who are proponents of PrEP is that condom use is not consistent, and that we need an alternative
The implication of such an argument supporting PrEP is that prevention education, essentially the use of condoms, has not been sufficiently effective. This cannot be known to be true of prevention education in principle.
What is definitely true is that those responsible for prevention education have not been sufficiently effective.
Our efforts should be focussed on improving prevention education and support for the consistent use of condoms,
There is so much more that can be done with persistent, culturally sensitive, highly targeted prevention education. In order to improve our efforts at prevention education we have to first confront the fact that we may have not been too successful in this endeavour, understand why, and absolutely not take the position that the undertaking is an impossible one.
Every new infection today represents a failure, not of prevention education as an undertaking, but a failure to provide it effectively. The introduction of condom use among gay men in the US in the 1980s originated in this community, it was promoted and effectively advocated for by this community and proved to be effective.. In those early years there was certainly no help from the Government which was to spend enormous sums on a vacuous and ineffective untargeted campaign “ America responds to AIDS” which did absolutely nothing to stop the advance of this disease into African American communities , although this was happening in plain sight.
What we can learn from this is that different affected communities are best able to understand the issues specific to their communities that must be emphasized and promote prevention education that is most effective for each of them. Their input is therefore absolutely vital.
The design and implementation of well funded and highly targeted prevention education has been neglected. These initiatives need to be specifically targeted to different groups, the needs of which must be assessed, barriers identified, continuing support provided, as well as some instrument developed to evaluate the success of the programs. . It is an enormous challenge.
We know that gay men were able to make it work for them before the concept of risk reduction had even been articulated. It can work and this is where our efforts must be concentrated. Not on trials of the efficacy of PrEP that are impossible to conduct in an ethical fashion.
However It is entirely possible that PrEP may add an additional layer of safety to condom use during sexual intercourse. This may be of particular importance in certain circumstances such as among sex workers. This is also the case among some women who are unable to rely on the use of a condom by their male partners. Trials of the safety of once daily tenofovir are absolutely possible and even desirable. Such trials would be unburdened with the ethical problems that make efficacy trials impossible to conduct. It will be clear that the trials are to determine the safety of tenofovir when used with condoms to provide an additional level of safety. It is true that we may never be able to firmly establish its efficacy, but if it proves to be safe, there is sufficient – if far from conclusive evidence to justify its use.
It is clear that all that has been written about concerns the sexual transmission of HIV. For those in whom the risk of infection is through intravenous drug use there is an entirely different set of considerations. The only known prophylactic measure, the reliable provision of sterile injecting equipment is probably just unavailable for most, and efficacy trials are therefore not burdened with the same ethical constraints.
One cannot help but note that at least in two initiatives, pharmacological rather than behavioural approaches to prevention are now being emphasized. Of course PrEP to prevent transmission of HIV is one. The other is the attempt to end the HIV epidemic by testing and treating all HIV infected people, whether or not a particular infected individual needs treatment for his or her benefit. Both are beset with ethical problems.
The use of condoms can significantly reduce the sexual transmission of HIV. We know this. Therefore our greatest efforts should be placed in improving prevention education. It is a tremendous challenge given the cultural diversity of the populations involved, and the special difficulties experienced by some. This is particularly true where women are disempowered.
We know that untargeted efforts such as “America Responds to AIDS” do not work. We need to understand the barriers to effective prevention education.
A denial of the importance of sexual expression to the human experience, stigmatization of those infected, homophobia, racism, bigotry in general and the fact that unlike the use of drugs, prevention education provides no financial return, are surely amongst them.
[i] [i] http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm
AIDS pathogenesis: HIV disease and Positive feedback: An additional comment.
This blog more or less duplicates that at the aidsperspective.net site, explained in the “about” page above.
HIV Disease and Positive Feedback. An additional comment.
AUGUST 31ST 2010
A previous post focussed on the positive feedback interaction between HIV replication and immune activation. HIV replication and immune activation reciprocally enhance each other.
While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it. In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation. As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.
Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.
Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients. We even knew then that interferon alpha and gamma could induce an enzyme, indole 2,3-dioxygenase (IDO), (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of tryptophan in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes. Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.
Since immune activation and its effects, including inflammation, are harmful if sustained, there are mechanisms that can dampen it.
But in HIV disease, immune activation persists with continued deleterious consequences.
The reason I’m revisiting this now is that there is a question that continues to be bothersome.
HIV disease is not the only infection associated with long standing immune activation.
Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation. In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease. While individuals with active pulmonary TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.
Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?
Could the mechanisms that dampen and check immune activation be impaired in HIV disease? These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and TGF-beta, among others. Specialized immune system cells can also dampen immune activation. Tregs, a subset of T lymphocytes, have such a dampening effect. Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of these particular T lymphocytes.
This graphic comes from my earlier post on positive feedback characteristics of HIV disease.
In this diagram HIV pathogenesis is represented by a circular process moving in a clockwise direction. It is started by HIV infection and can be propelled by a positive feedback association between HIV replication with immune activation. Immune activation is reinforced by CMV, and in certain settings, by some endemic infections. This is represented by the + sign in the diagram. Immune activation is retarded by those influences that dampen the immune response, including anti-inflammatory cytokines and Tregs, represented by the – sign in the diagram.
Here is a revised version of this diagram:
HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses. Tregs act as brakes, but HIV can directly make the brakes less effective.
Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?
I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.
In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it. Some predictions can be made.
The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression. The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case. There already is some evidence in support of this possibility.
It’s well established that HIV disease progresses more rapidly with increasing age. Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation contributes to the aging process.
HIV disease progresses more rapidly in individuals with active TB. CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic. There are but two examples, but there are many more of of a more rapid course of HIV disease in the setting of other infections caused by bacteria, protozoa, viruses and helminthes. Some are referred to in a previous post.
Are Treg numbers at seroconversion and for a period immediately afterwards related to subsequent disease progression?
Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?
There already is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.
The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.
Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection, provides a useful descriptive framework as well as testable predictions.