PrEP is an HIV prevention intervention in which antiviral medications are taken to interrupt sexual transmission of the virus. It is now being recommended by the WHO for, it seems all sexually active gay men. Actually it’s not quite that stark – they continue to recommend condom use as well. Despite this, many will probably see this as a recommendation to rely on PrEP as an alternative to condoms.
The WHO recommendation is a population based proposal, a public health recommendation as opposed to recommendations for specific individuals. Recommendations for individuals are different because they take into account individual circumstances, such as the extent to which a specific person is at risk. Population based recommendations are recommendations made across the board, in the case of the WHO, addressed to all men who have sex with men.
While assuring us that the recommendations are evidence based and providing the customary explanation of how the strength of evidence is graded, we learn that the WHO has made a sweeping worldwide population based recommendation on evidence provided by just one randomized study! This was the iPrEx study, which was beset with interpretative difficulties, not least because few took the medication as directed, if at all.
We simply do not know enough about PrEP to make a sweeping population based recommendation. . We have little idea of what adherence to the medication might look like in various populations, we know little about the degree of protection in specific sexual acts. Different sex acts carry different risks, for example, to the receptive or insertive partner in anal sex. Also, how effective is PrEP in situations of exposure to high and low viral loads. In addition we have little idea of the extent to which condom use will be abandoned.
It’s clear that there is a widespread view that PrEP is an alternative to condoms, despite official recommendations stating that PrEP should be part of a comprehensive prevention approach that includes condom use.
A more balanced response would have been a call for more research, and importantly, for a fuller description of those individual situations where PrEP use is a rational preventative intervention at the present time.
The use of PrEP by an individual is very different. The degree of risk to individuals will vary considerably and on an individual basis PrEP use can be a completely appropriate intervention in situations of very high risk, even if we do not have precise information of its efficacy without condom use. The use of PrEP could also be considered when there is an inability to maintain an erection with a condom. It might be an option to enable a fuller sexual expression among what is probably a large number of men whose difficulty with condoms, for whatever reason, stands in the way of satisfactory sex. Medical supervision is also more likely in individual situations. It is important to check for HIV infection and to monitor for sexually transmitted infections and drug toxicities.
Monitoring for sexually transmitted infections is important. Since PrEP alone offers no protection from the transmission of infections that might be interrupted by condoms we might expect an increase in such infections with a wide roll out of PrEP. The current increase in sexually transmitted infections among gay men in some cities is most likely attributable to an increase in unprotected sex. Many sexually transmitted infections facilitate the transmission of HIV which may be another factor that could drive an increase in new HIV infections.
The way PrEP has been promoted during the past few years has surely contributed to the poor support received for prevention education. One way in which this has happened is the shifting of budgets for prevention to those entities, private or government insurers that pay for drugs used in biomedical prevention.
There seems to be a widespread view that prevention education does not work. But we know that it can work. The adoption of safe sex practices including condom use in the early 1980s curbed the spread of the epidemic, although admittedly conditions are not the same today. There is little support for continued condom use, and rather than take the view that condoms don’t work, we might try to understand the obstacles that stand in the way of effective prevention education.
If prevention education has been ineffective it’s be because there has been so little of it, and what little there is has not been properly targeted. The move of the epidemic into African American communities during the 1990s was occurring in plain view yet the federal government was churning out expensive vacuous untargeted prevention messages in the form of “America responds to AIDS,” a futile exercise that helped to discredit prevention education.
I get the sense that some younger gay men feel they have missed out in not experiencing the abandon of the 1970s and see PrEP as a way to make up for this. The real lesson of the 1970s is that sex with multiple different partners on such a vast scale, as occurred in NYC in the 1970s, permits any pathogen that can be transmitted sexually to disseminate widely. That’s what started to happen with amebas and other intestinal parasites and HIV, and is happening with syphilis, gonorrhoea, herpes, hepatitis and many other infections. There surely will be others beyond HIV.
Since we really have very little information about PrEP, and almost none about its use on a population level such a broad recommendation by the WHO is absolutely inappropriate, so maybe faced with increasing HIV infections among gay men, the WHO is simply giving up and proposing an unproved intervention out of desperation. When I say unproven, I mean it is unproven as a viable population based intervention. Looked at this way, it’s a put down – a response that may be no more than gestural to people who continue to harm themselves by refusing to use condoms in sex with partners of unknown sero status.
This unwise WHO recommendation may also have the effect of increasing new HIV infections if it results in an increase in unprotected sex where adherence is inadequate.
I hope there will be a critical look at the WHO panel and funders responsible for producing such unhelpful recommendations.
Treatment as Prevention
Protecting patient autonomy
Patient autonomy is just a particular instance of individual autonomy, a term that may sound pretty dry and academic but if we used the term individual freedom we would essentially be talking about the same thing.
Respect for the autonomy of the individual may be the most important of the principles that form the foundation of medical ethics. (1)
One attribute of personal autonomy is: “the capacity to be one’s own person, to live one’s life according to reasons and motives that are taken as one’s own and not the product of manipulative or distorting external forces.” (2)
There is no disagreement about the importance of respect for individual autonomy but as I’ll explain, it seems that its pre-eminence is being questioned in some proposals to use antiretroviral treatment to prevent transmission of HIV.
The recent demonstration that antiretroviral treatment can prevent transmission of HIV among serodiscordant heterosexual couples is great news. However, when the person offered treatment has not yet been shown to personally benefit from it, an ethical issue needs to be addressed. It has not yet been reliably demonstrated that for people with greater than 350 CD4 lymphocytes, starting treatment immediately rather than deferring it confers a net benefit; indeed, it may even prove to be harmful. A randomized controlled trial now enrolling will provide needed information, but we will have to wait several years for its results.
The issue isn’t whether or not people with greater than 350 CD4 lymphocytes should receive treatment. A respect for their autonomy requires that the decision whether or not to do so is made by them and is made free from coercion.
A recent issue of the Journal, Public Health Ethics (3) is devoted to ethical issues associated with the proposal that a program of universal testing and treatment of infected individuals could bring an end to the HIV/AIDS epidemic. Such a proposal would involve the treatment of healthier HIV infected individuals not at this time known to personally benefit from antiviral medications which could even harm them.
In an article in the journal referred to above, public health ethics is said to require an approach where respect for individual autonomy is not paramount; a commitment to the supremacy of individual autonomy could have no place where the “primacy of collective wellbeing is the starting point”.
In that case I wonder just how desirable a collective wellbeing would be where individual rights were subservient to whatever was defined as the collective good.
I can only hope that this goes nowhere, as abandoning the pre-eminence of respect for individual autonomy opens the door to tyranny, paternalistic or otherwise. Individual freedoms have been hard won, and we should always be aware of harms that have been perpetrated in the name of the public good, even leaving alone the problem of who defines what constitutes the public good.
In public health, medical research and medical practice, concern for individual autonomy remains paramount. The only commonly agreed acceptable exemption is the restriction of personal freedoms to prevent harm to others such as limiting the movement of individuals with highly communicable diseases where the harm that may be done to others is considerable. That is, outside the criminal justice system, among individuals who are free.
People have the right to make decisions about their treatment, their participation in a research study, or in a public health intervention, free from coercion.
Providing misleading information is a form of coercion; withholding information may also be coercive.
Providers of health care have an obligation to provide patients with honest information to inform their decisions. This must include information about what is known about the risks and benefits of treatment, as well as what remains conjectural.
Information and the strength of the evidence upon which it rests:
It’s not enough to simply provide individuals with information concerning the benefits and risks of a particular treatment. In order for the information to be useful we must also indicate the strength of the evidence on which the information rests. (4)
The most reliable evidence regarding the effects of a particular treatment is provided by results of randomized controlled clinical trials. This is because the treatment in question has been put to the test in a protocol that minimizes bias; we can therefore have a greater degree of confidence that effects observed are in fact caused by the treatment.
Unfortunately information derived from randomized controlled trials is often unavailable. The clinical trial may not yet have been completed, or for whatever reasons the trial cannot be undertaken.
When this is the case we have to consider evidence of inferior quality, for example, evidence derived from reviews of patient records or observational studies, and the opinion of experts.
Observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention. The particular reasons why participants were selected for study may influence the outcome rather than the effects of the intervention.
In all the systems I have seen that grade the quality of different kinds of evidence, expert opinion is at the bottom of the list. But expert opinion can be valuable to an individual in coming to a treatment decision when evidence of the highest quality is not available.
Respect for patient autonomy means that patients make their own decisions free from coercion. As noted, supplying misleading information is a form of coercion. To state that something is known to be the case, when it is only an opinion is misleading.
HPTN 052 is the study which demonstrated the efficacy of antiretroviral treatment in preventing transmission of HIV among serodiscordant heterosexual couples. Although the result was not unexpected it is nonetheless significant because it was obtained from a randomized controlled clinical trial.
We now know that the uninfected partners of individuals with greater than 350 CD4 lymphocytes will benefit from treatment of the HIV positive partner. At this time we can only have an opinion about whether starting treatment immediately or deferring it will benefit or harm the infected partner with greater than 350 CD4s or be without effect – apart from cost.
Most of the jubilant reports of the results of HPTN 052 do not mention the problem facing the healthier HIV positive partner in coming to a decision. Do the commentators just assume that it’s been established that all infected individuals receive a net benefit from treatment irrespective of CD4 numbers? Or do they not believe it to be important that patients make their own decisions regarding their treatment?
I wish I could say I was startled to read in one newsletter that “For treatment as prevention to work….. people need to be convinced that early treatment is in their interest.”
Convincing people to take a possibly perilous course of action based merely on opinion and evidence of inferior quality is a step on a road that ends with enforcement.
A respect for individual autonomy means that we respect the right of individuals to make decisions on their own behalf, free from even subtle coercion. Our obligation as providers of health care information is to not only provide information, but also an indication of the quality of the evidence supporting it.
At this time we do not know that individuals with greater than 350 CD4 lymphocytes receive a net benefit from antiviral treatment. There is evidence that they may, but until this is put to the test in a randomized controlled trial such as START, we must not mislead them by trying to convince them that “early treatment is in their interest”.
Given adequate information, a person with greater than 500 CD4 lymphocytes may reasonably decide to take antiretroviral drugs to lessen the risk of infecting a partner even knowing that there may be no personal benefit or that there is a possibility of harm.
Whenever treatment is offered for any reason other than for a person’s benefit, and where it has not yet been reliably demonstrated that there will be a net benefit, a consent process should be required. I doubt though that this will happen.
At the end of the day what’s of central importance is that we respect our patient’s right to make choices about his or her treatment, and provide honest information to inform that choice, recognizing the difference between expert opinion and established fact.
(1) Ever since Beauchamp and Childress published the first edition of their classic text, Principles of Biomedical Ethics, in 1979 it’s been commonly accepted that beneficence, nonmaleficence, justice and respect for autonomy, are four principles that should guide medical ethics.
The Four Principles are general guides:
Respect for autonomy: respecting the decision-making capacities of autonomous persons; enabling individuals to make reasoned informed choices.
Beneficence: this considers the balancing of benefits of treatment against the risks and costs; the healthcare professional should act in a way that benefits the patient
Non maleficence: avoiding the causation of harm; the healthcare professional should not harm the patient. All treatment involves some harm, even if minimal, but the harm should not be disproportionate to the benefits of treatment.
Justice: distributing benefits, risks and costs fairly; the notion that patients in similar positions should be treated in a similar manner.
Beauchamp and Childress; Principles Biomedical Ethics, OUP, 5th edition
(2) Christman, J, 2001″Autonomy in Moral and Political Philosophy”, The Stanford Encyclopedia of Philosophy (Fall 2007 Edition) , Edward N. Zalta (ed.), URL = <http://plato.stanford.edu/archives/fall2007/entries/autonomy-moral/>.
(4) Several systems have been devised to grade the quality of evidence.For example: http://www.cebm.net/index.aspx?o=1025 The GRADE working group has been working on assessing the quality of evidence since 2000. http://www.gradeworkinggroup.org/index.htm
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:
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.
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.
[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.
[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
[vii] Endemic infections in Africa have everything to do with HIV/AIDS:
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:
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-
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.