Joseph's POZ Blog

Could universal periodic testing for HIV and immediate treatment of all who test positive curb the spread of the epidemic?     

The suggestion that it might do so is based on the well-established relationship between viral load and infectivity.  The idea is that by reducing viral load, treatment will make an infected person less able to transmit the virus and therefore could curtail the spread of the epidemic.

 Also, people who know that they are positive are more likely to take steps to prevent sexual transmission of HIV than those who are unaware of their status.  But this is a benefit of testing rather than of treatment.

"Treatment as prevention" is a term that describes this proposal to treat all infected individuals who test positive.   But it also can refer to the preventative effect of providing treatment only to those known to benefit from it.

Early in 2009 treatment of all infected individuals as prevention received support from an article that appeared in the Lancet, an important weekly medical journal.

 (Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model.  Granich, Reuben M. and others. Lancet 2009 373: 7)

This was an exercise in mathematical modelling.  Having made several assumptions, the authors calculated what might happen if a policy of universal voluntary testing with immediate anti-viral treatment were to be implemented. They concluded that it could result in a dramatic reduction in the transmission of HIV within 10 years. Their calculations indicated that this strategy could achieve an extremely  low overall prevalence of infection by 2050. 

This is an interesting idea deserving of every consideration.

However, there are several obstacles that stand in the way of its implementation. 

Apart from feasibility, the one that seems to me to be the most important arises from the necessity that treatment should only be initiated when the infected person voluntarily decides to do so.  This has been commented on and discussed by some individuals and organizations; there are links to these discussions at the end of this post.

At first sight the need for a voluntary decision may not seem to be a problem at all, because given its availability, any infected person who needs treatment would surely decide to receive it.   

But what about people with very high CD4 numbers or those who have the good fortune to be non- progressors or in whom HIV disease progresses extremely slowly?   In the case of such people, treatment would be used as a tool to prevent infection of others.  It is far from clear that these individuals will themselves benefit.

A "treatment as prevention" proposal that aims to treat everyone who is positive is about a public health intervention on individuals, independent of whether or not it will be of benefit to the individual.  Some will be included who may not themselves derive any benefit from the intervention, but will only be exposed to its risks.

Some of these individuals may choose to receive treatment for altruistic reasons, because of the assumed societal benefit. All agree that the decision to do so must be voluntary.

But what meaning can a voluntary decision have when it is not informed? Or worse, should misleading information be provided.

Before undertaking any intervention, its benefits and risks must be described as best as is possible and then weighed. We want to come out ahead.  For many HIV positive individuals, and virtually all with serious immune system deterioration, the benefits of treatment clearly far outweigh the risks associated with the medications.

But let's continue to consider those individuals with high CD4 numbers or whose disease does not progress, or does so very slowly.   Can we give these individuals reliable information that treatment will benefit them?  There are those who believe that it will, but the evidence for this is far from solid.    On the other hand, it is clear that anti-viral drugs are often associated with significant adverse effects.    

Newer treatments may indeed be associated with fewer and less severe adverse reactions than older ones, but we really cannot yet know the full range of their effects. Very recently the FDA required labelling changes for Prezista (darunavir) to include some less frequent adverse effects seen in the 96 week study data, even though Prezista was approved in  2006.

This is not unusual; it can take many years of observation to recognize and understand the longer term effects of new medications, or even earlier side effects which occur in just a few individuals.  Look at how long we were prescribing Stavudine (Zerit, D4T) before we understood what effect it had on fat distribution.    

  Recognizing adverse drug effects is particularly difficult in conditions such as HIV disease which itself can manifest in so many different ways.  Sorting out what is a drug effect and what is caused by the infection may take a very long time.  Added to this is the difficulty of knowing which drug is responsible for a particular reaction when several different medications are taken at the same time.

It seems likely that when fully informed about what is known and not known about these treatments,  HIV positive individuals with high CD4 counts or who are slow or non- progressors may decline or delay treatment.    As far as the benefit to society is concerned, I'm sure that many will feel that this can be attained by practising safer sex, including the use of condoms, rather than by relying on drugs. 

 The safer behavior of people who test positive has been already observed, and is one important reason to encourage widespread testing.

There is yet something else to think about. 

If we are to ask  people to take a risk for a benefit to others we should be able to tell them that it is probable that the endeavour will be successful; that  they will not be taking a risk for nothing. 

We cannot assure them that there is even a good chance that treatment as prevention, where all infected individuals are treated, will make an impact on the epidemic. Among the many uncertainties is a lack of assurance that enough people will participate, and the problem of developing resistance to the antiviral drugs (that was recently highlighted in several news reports).

Treatment with antiviral medications can thus have two objectives. One is to benefit the infected individual; the other is to limit the spread of the epidemic by preventing infection of others. Both objectives will be met when treatments are offered for the benefit of the infected person. 

In another mathematical model   where treatment would be provided only to those with about 350  CD4 cells, Julio Montaner calculated that two thirds of new infections in British Columbia could be avoided.     In this instance the purpose of treatment is to benefit the infected person, but as a result most new infections may be averted.   

Most people in care in developed nations, with 350 or fewer CD4 cells will receive treatment, and this may well have an impact on preventing new infections.

The type of treatment as prevention, where all HIV positive individuals are offered treatment is much like a clinical trial, which is an exercise of uncertain outcome based on an hypothesis, in this case supported somewhat by mathematical modelling.  It should require informed consent from the participants, as is required for participation in a clinical trial.

I wonder what a consent form would look like.

It is important that we are careful not to exert even subtle coercion on healthier HIV positive people.  This means that we must be clear that for individuals with higher CD4 numbers, unlike people with more advanced disease, the benefits of treatment have not yet been clearly shown to outweigh the risks.

Central to this consideration is the still unanswered question of when, in the course of HIV disease, it is best for healthier HIV positive people to start anti-viral treatment.  

Of course people with higher CD4 numbers may also benefit from treatment, but we don't know this with the same degree of confidence we have regarding people with more advanced disease. We need to be upfront with this information.

It is possible that morbidity not traditionally associated with HIV, perhaps resulting from inflammatory reactions, may prove to be a significant problem in HIV positive individuals, and which could be prevented or treated by antiviral medications.  But again, this has not been firmly established.   

The fact remains that we still do not know when it is best for people with higher CD4 numbers to start treatment.   After almost fifteen years this remains one of the most important issues in HIV medicine waiting to be resolved.   This uncertainty creates, among other difficulties, an ethical problem in implementing treatment as prevention where all positive people would be treated.   As already noted, we have to explain the risks and benefits of treatment to healthier individuals, where the benefits remain conjectural, but the risks of adverse drug effects are known more clearly.

The surest way to obtain the kind of evidence needed to make a decision about when it's best to start is to complete a randomized prospective clinical trial that directly addresses the question.   

Such trials could have started in the late 1990s and by now we could have had evidence of the highest quality to help us make a decision about when it's best to start treatment.

Such trials may  be expensive, and last a long time, but in the end, probably much more time and money is lost by turning to  evidence of inferior quality such as that provided by retrospective analyses like the NA-ACCORD trial that is so frequently relied on to justify an earlier initiation of treatment.  

In retrospective observational studies of this type, past records are examined, and outcomes among people who start treatment early and those who defer it are compared. 

Because people are not randomly assigned to receive treatment early, or to defer it, the causative interpretation of such retrospective observations are difficult because of what are called confounding factors and some are impossible to overcome.

 We don't know why some people choose to start treatment early while others start later. The different decisions may reflect the possibilities that those choosing an earlier start to treatment may have better access to medical care, may receive better care in general, or may be more likely to be people concerned with overall health.     Without randomization, the reasons why a particular course of action was chosen, whatever these may have been, might explain differences in outcome between the groups rather than the effect of the time treatment was initiated. It is impossible to adjust for all the possibilities for confounding that arise when randomization is absent.   

The START study is a prospective randomized "when is it best to start"  trial in people with higher CD4 numbers.

 I wonder how enrolment is proceeding in the face of what seems to be an increasing belief among providers that the answer to the question of when it is best to start treatment is already known.   Some of my colleagues have stated that all HIV infected persons are better off receiving treatment irrespective of their immune status.  They may or may not be right.  

Individuals with higher CD4 numbers and who are slow or non-progressors  may want more reliable evidence than such opinions, or that provided by retrospective studies such as NA-ACCORD, in coming to a decision to start or to defer treatment.  A prospective randomized trial can supply such evidence.  

If anti-viral drugs were completely benign we would have no problem, apart from cost in treating every infected individual.  But it is quite possible that a person starting treatment at say, 700 or 500 CD4 cells  who may be a slow progressor,  will remain healthier for longer with a better quality of life if treatment is deferred.

In the early 1990s I was involved in an unsuccessful   attempt to pilot a "when to start" randomized prospective trial using AZT in individuals with higher CD4 numbers.  I do not remember precisely how many providers in New York and California agreed to enrol patients. The endeavour was stopped because of poor enrolment.  

Quite remarkably, almost all the patients who had agreed to be randomized to start treatment immediately, or to defer it came from the practice of one physician in San Jose.  When asked how he was able to enrol so many patients his answer was that he told them that he did not know which course of action was better. There was no difficulty in agreeing to let the toss of a coin determine what to do, particularly since doing this would help provide an answer to the question.   Maybe the other participating providers were either not so uncertain or perhaps found it difficult to admit to being so.  

A randomized prospective trial would give us reliable evidence about when, on average, in the course of HIV disease it is best to start treatment.   Fine tuning will be needed to determine when it is best for each individual to start.   This will include consideration of many different factors, some non-medical ones such as domestic and housing issues,  and some medical ones such as co-morbidities.   

One of the most important medical factors in fine tuning the best time for a particular individual to start treatment is that individual's rate of disease progression.   This can vary  widely from person to person and surely should be considered when making a decision to start.

Individualization of treatment to consider the rate of disease progression for each person seems to be receiving just a little attention now, after so many years of neglect.  It is an important subject and I  will leave a discussion of it for another post.

In conclusion I'm going to add a letter I sent to DHHS almost thirteen years ago regarding this very issue.  This was in a response to a call for comments when the very first treatment guidelines were published.  Evidently not enough people who shared these concerns chose to respond to this invitation to comment.

This letter also asks that an individual's rate of disease progression be taken into account when making a decision to start treatment.

July 16,1997

Regarding the Guidelines for the use of Antiretroviral Agents in HIV-infected adults and adolescents.

The panel convened by the Department of Health and Human Services to develop guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents has performed a valuable service. Their recommendations will undoubtedly be greatly relied on by the many physicians without extensive experience in the management of HIV-infected patients.

The recommendations regarding treatment in more advanced disease (where evidence derived from controlled clinical trials is available), will be of great benefit to patients in this category. However it is far from clear that this will be the case for asymptomatic patients, even some of those with fewer than 500 CD4 lymphocytes / mm3 . The potential risks detailed in Table III are far from trivial. For an individual facing more than 5, or even possibly 3 years free of disease, instigation of combination antiretroviral therapy with agents whose long term toxicity is unknown, may in fact have the net effect of shortening that individuals life. The issue of quality of life is also of concern, as is the likelihood of a failure in compliance over a long period, with the attendant risk of the development of resistance, with the possible consequence that effective therapies may be unavailable at later stages of the disease.

For asymptomatic individuals it is quite possible that the risks of early intervention outlined in Table III will outweigh the benefits. The potential benefits listed in the table are conjectural; the potentially serious risks cannot even be approximately quantified with the little experience accumulated thus far. Faced with such difficulty in recommending when to initiate therapy in asymptomatic individuals, I believe that the panel might have devoted more consideration to the rate of disease progression in individual patients as a factor that should influence the decision as to whether or not to start antiretroviral therapy. Rates of disease progression vary widely, and it might require a 6 to 12 month period of observation to assess this rate in an individual patient.

Given the availability of potent antiretroviral agents and the potential benefit that may be associated with their use, the uncertainty as to when to start therapy with these agents in asymptomatic patients is perhaps the most important issue that needs to be addressed at this time. It was therefore most surprising that the panel did not call for controlled clinical trials to resolve this important question. There is the unfortunate implication that in the area of AIDS medicine, convening a panel to make recommendations on such areas of clinical uncertainty has now replaced clinical studies as a means of guiding treatment decisions.

The recommendations regarding treatment of patients with advanced disease are sound as they are supported by evidence derived from clinical studies. I would suggest that the recommendations regarding treatment of asymptomatic individuals, and treatment of acute HIV infection rather be called interim suggestions pending the results of controlled studies. I hope the department of Health and Human Services will acknowledge the pressing need to obtain a clear answer to the question of whether early intervention is of benefit, is harmful or is without effect, and encourage the development of appropriate studies. Admittedly enrolment in such trials would be difficult at this time - in part because of the availability of recommendations regarding treatment , with the implication that the questions have been answered. It is therefore also to be hoped that the Department of Health and Human Services will help to prepare the ground for such trials by educating patients and providers that there is indeed considerable uncertainty regarding when treatment should begin in asymptomatic individuals, and that the clearest answer to this question can only be obtained through appropriate clinical studies.

JA Sonnabend, MB., FRCPEd

Here are some links to several reports on treatment as prevention that highlight concerns that any decision to participate in such a project should be voluntary.    I am grateful to Sean Strub who has written and spoken on this issue, for bringing my attention to these reports.

http://www.catie.ca/eng/PreventingHIV/PreventioninFocus/Issue1/treatment-as-prevention_interviews.shtml

http://www.cdnaids.ca/web/setup.nsf/ActiveFiles/Microsoft+Word+-+Resolution+Report+2009+-final/$file/Microsoft%20Word%20-%20Resolution%20Report%202009%20-final.pdf

http://74.125.113.132/search?q=cache:FmGEdBOj3HAJ:data.unaids.org/pub/Report/2009/20091128_phdp_mr_lr_en.pdf+%22treatment+as+prevention%22+informed+consent+hiv/aids&cd=23&hl=pt-BR&ct=clnk&gl=br


http://www.aidsmap.com/en/news/C35EF8E0-2F47-4F7B-909C-6D30FB600972.asp

Thirty years have passed since the epidemic began. For about half of this period we have had the means to effectively treat this disease.  In N America and Europe where many HIV infected people were fortunate enough to have access to treatments almost as soon as they became available, most will have had no direct experience of the bewildering and awful early years of the epidemic.

During these first years affected individuals learned that they had to not only deal with the disease itself, but also with threats and attempts to deprive them of their rights.  The right to privacy is one of these.

 This post is about the very early recognition of the need to protect the confidentiality of people with AIDS. I will also write about some extraordinary people I have had the good fortune to have worked with and the person I will write about here is Jim Monroe.  He probably was the first, at least in New York City, to do something about protecting the confidentiality of people with AIDS.

His concern led to the first formulation of guidelines for confidentiality protection in AIDS, and I'll describe how this came about.

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

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

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

As physicians we protect the confidentiality of individuals who seek our care and who participate in research studies. As patients we have every right to expect this protection, and there are legal safeguards to ensure this.    The CDC has extensively considered the issue of confidentiality protection in relation to AIDS and continues to do so.

However there was an earlier community response to confidentiality concerns in New York City in 1982 which started with a telephone call from Jim.   This was at a time before HIV had been isolated and even before the disease was called AIDS.

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

Confidentiality in matters of health is of the greatest importance, it can also be quite complex when transmissible infections are involved.  We cannot avoid considering both the interests of the individual and the need to protect public health.

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

 But the context in which Jim brought attention to confidentiality was the concern to protect individuals suffering from this new, untreatable, and as yet unnamed disease who were asked to participate in research studies.

   From the very start, even before the discovery of HIV, affected individuals frequently had to contend not only with this frightening illness but with irrational and cruel discriminatory acts against them.  

Almost immediately  the disease became associated with  public attitudes and responses that were irrational and hostile. But there were also other issues requiring particular attention to confidentiality.  Sexual orientation was revealed with a diagnosis when the disease was thought to be confined to gay men.

Even though the cause of AIDS was then unknown, it soon became clear that the illness could not be transmitted by casual contact. Despite this, discriminatory practices against people with AIDS were unfortunately all too common Some hospital patients had to retrieve meals left outside the doors to their rooms, some medical personnel refused to care for infected people, some children were not allowed to be in contact with people with AIDS, and affected children sometimes not even allowed to attend school.  

With such irrational responses the need to protect the privacy of affected individuals is quite obvious.

Despite advances, AIDS is still a disease associated with stigmatization, not only in developing countries but also in the US and other developed nations.  Protection of the privacy of HIV infected people is as important today as it was in the earliest years.

 To properly describe how Jim started a response intended to assure that those affected by this new disease would be protected by measures to maintain their confidentiality, a few further introductory words are needed.

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

In 1983, my lawyer, Frank Hoffey, along with Graham Berry prepared the papers and incorporated the AIDS Medical Foundation (AMF), initially to raise funds to support my and my colleagues' research.  Apart from Mathilde's personal support our work had not been funded.  Quite correctly, AMF soon broadened its mission to support the work of others as well. The foundation survived and went on to make very significant contributions to the fight against AIDS, largely due to the determined efforts of Dr Krim who was the chairman of our board.

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

What concerned Jim was that no provision had been made to protect the confidentiality of study participants.

Jim told me that the study was to be submitted for review by the health department's Institutional Review Board (IRB) although I don't think it was called an IRB.

 I suppose he must have had little confidence that the IRB, which is a body regulated by the FDA and intended to protect human research subjects, would address the confidentiality issue. In view of what transpired he was probably correct. 

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

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

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

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

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

 Carol and Ron's interest did not stop. They proposed that a meeting be held on the issue of confidentiality.  This in fact did occur and resulted in the publication of the first guidelines for confidentiality protection in research on AIDS.

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

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

The meeting proceedings were published in the Hastings Center's own publication, IRB.  I believe my memory is correct in recalling that an established medical journal declined to publish the guidelines.

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

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

As part of my research effort I had become associated with David Purtilo, Chairman of the Pathology and Microbiology Departments at the University of Nebraska's medical school in Omaha. The reason for this was that David was an expert on the Epstein Barr virus, and I believed that this common herpes virus can play a significant role in the pathogenesis of HIV disease. (Because of its interactions with HIV, this and other viruses of the herpesvirus family may well play such a role.  I'll describe these interconnections in a future post).

David's wife, Ruth Purtilo is a bioethicist. She clearly saw how important confidentiality protection was in research on AIDS. She obtained the perspective of Michael Callen, a patient of mine who was HIV infected.  Together we published a paper on this issue in 1983.   (For which we were awarded a prize for research in ethics by the American Federation for Clinical Research).

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

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

              Purtilo-R, Sonnabend-J, Purtilo-D-T.

The need for respecting confidentiality is as important today as was the case when the epidemic began.  Differently worded legislation now exists where criminal law is applied to people who transmit HIV to others or even who expose others to the risk of transmission, although there is absolutely no evidence that such criminalization prevents the spread of this disease, and such laws only succeed in increasing stigmatization.

 Criminalization of HIV transmission or of exposure to the risk of HIV transmission has frequently been discussed in the pages of POZ as far back as the 1990s, and POZ continues to bring attention to these irrational and destructive measures.

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

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

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

Jim, together with a public health expert at Emory University, was attempting to present a proposal to the medical directors of private insurance companies to fund a large prospective randomized study to determine if an early or deferred start to antiviral treatment produced a better or worse outcome or was without effect. We had the support of an eminent statistician who had also been involved with me in an earlier unsuccessful attempt to set up a study to compare early and deferred treatment with AZT.  We thought that those entities, such as insurers that pay for drugs might be the appropriate sponsors of such a prospective clinical trial.  They would surely have an interest in knowing how the drugs they pay for should be used most effectively.

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

One Friday afternoon while seeing patients at a New York City HIV clinic I received a call from a friend of Jim's in Atlanta. She told me that Jim was severely ill in Chicago. He had collapsed a few days earlier.   I went to Chicago the next day and found Jim unconscious in intensive care. He was not to recover.  

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

Jim's final project, cut short by his death, is still absolutely relevant. A randomized prospective "when is it best to start" trial has still not been completed.   

We need the most reliable answer to this question, and neither expert opinion nor retrospective observational studies such as the NA-ACCORD study can replace randomized prospective studies in resolving clinical uncertainty.

An article with the striking title "Africa's 32 Cents Solution for HIV/AIDS" was recently published in PLoS Neglected Tropical Diseases.  It can be seen here:

http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000430

This dramatic title refers to the cost of treatment of schistosomiasis with praziquantal. 

Schistosomiasis is an infection caused by parasitic worms, or helminths., of the genus  Schistosoma.    Most of the 200 million cases of schistosomiasis in the world occur in Africa.

The species, Schistosoma haematobium is estimated to infect about 112 million people in sub Saharan Africa.  So its high prevalence puts it in the same class as that of TB, malaria and HIV infection.  It is responsible for a huge burden of morbidity particularly in children and young adults.  S. haematobium infection predominantly involves the urinary tract.  S. mansoni is another species; it affects the intestinal tract.

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.  The disease it causes is commonly called bilharzia. 

I was very conscious of its danger growing up in Zimbabwe, where prominent signs at several small lakes around Bulawayo warned one not to swim in them because of the danger of bilharzia.

There already is a substantial literature that strongly suggests that many endemic infections, not only caused by  helminths, but also by bacteria, protozoa, viruses and even common intestinal worms can accelerate the progression of HIV disease and facilitate transmission of the virus .  Some of the mechanisms underlying these HIV enhancing effects have been understood for many years.  In Europe and N. America the ability of an intercurrent infection to accelerate HIV replication is known from the understanding that viral load testing may show a temporary increase if done during a febrile illness, or even following a vaccination.

The paper cited above, whose lead author is Peter Hotez, 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 not only  has a way in, but will find an accumulation of susceptible CD4 cells at the site of  entry.   But in this case what appears to be so obvious may not be the important connection between schistosomiasis and susceptibility to HIV infection.

In fact in the case of herpes simplex, this seemingly obvious connection between a genital ulcer and a mode of entry for HIV 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, as expected, with a reduction in the number of recurrences of herpetic ulcerations, but also appeared to significantly slow the course of HIV disease progression.  Since the probability of transmitting HIV is related to viral load then it is quite possible that while acyclovir may not prevent acquisition of HIV it may reduce the infectivity of people harbouring both HIV and a herpes virus. 

 There are in fact many interconnections between HIV disease and herpesvirus infections, but I will leave a description of these for another post.

As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant than local effects in enhancing susceptibility to HIV infection.  More recently, in direct experiments, acute infection with S. mansoni was  shown to increase susceptibility to mucosal infection of Rhesus macaques by SHIV (a monkey adapted virus).  Of course, both local and systemic effects may play a role in enhancing HIV transmission. 

There are multiple systemic effects associated with many different infections that can accelerate HIV disease progression.   Schistosomiasis and some other endemic infections are associated with an impairment of virus specific immune responses.  Immune responses may be blunted by several mechanisms.  Immune activation will probably  also increase susceptibility to HIV and promote its replication.  Schistosomiasis and other endemic infectious diseases are also associated with an increased density  on the cell surface of the chemokine co-receptors used by HIV which would increase infectability.  Pro-inlammatory cytokines such as TNF-alpha and IL 6 that appear during the course of many infectious diseases are potent promoters of  HIV replication.  

Thus  highly prevalent endemic infections can enhance HIV replication by multiple mechanisms. It is likely that this association will also be expressed clinically and has implications for the effective control of HIV in populations where these infections are common.

 There have been studies showing that treatment of some of the common endemic  infections can lower HIV levels, although it must also be said that not all of the studies agree on this. 

Controlling these infections includes inexpensive traditional public health interventions such as supplying clean water and sanitation. 

Here is the abstract of an article published in 2006 by W.E.Secor of the CDC, dealing with schistosomiasis, but also applicable to many other infections :

"Interactions between schistosomiasis and infection with HIV-1

In many regions of the world, both schistosomiasis and HIV/AIDS are endemic, resulting in patients harbouring co-infections. Because interaction with host CD4 ⁺ T cells is a characteristic of schistosome as well as HIV-1 infections, bi-directional disease effects may be sufficiently different from sequelae caused by either infectious agent alone to warrant alteration of public health approaches in areas of co-endemnicity. Studies published over the past decade provide useful insights into interactions between schistosomiasis and infection with HIV-1, and overall support the hypothesis that special emphasis on treatment of schistosomiasis in populations with elevated prevalence or risk of HIV-1 infection is justified".

 Schistosomiasis is but one of many infections where there is a bi-directional interaction with HIV, and where the above comments have equal relevance.  

  Peter Hotez  does a great service by continuing to  bring attention to a number of devastating neglected tropical diseases.  Many have been shown to interact with HIV, but  not all by the same mechanisms.   

This important article can be seen in the Lancet of May 2^nd, 2009, (Lancet 2009 373;1570-1575).  I have copied the following table from this article.

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

Many of these infections occur in children and young adults and not only can have an impact on life expectancy, but significantly, are the cause of chronic debility particularly in young people.And again, as noted many of these infections also have an activating effect on HIV replication by some mechanisms that have been understood for well over ten years.  

Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections with HIV, this association  seems to have  been relatively neglected as a target in the fight against HIV.   Of course we do not need to justify efforts to improve the health of populations by attempting to prevent and treat highly prevalent endemic infectious diseases, but because of disease interactions, funds available to fight HIV could  very appropriately be used to combat other infections as well.   We can cure and prevent many of these endemic infections, quite often by means that are relatively inexpensive.

To summarize, 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.  

HIV disease  is not unique in its susceptibility to modification in a host infected with other pathogens. HIV itself can modify the course of other infectious diseases.  It may however be unique in that we probably know much more about the mechanisms by which the course of HIV disease can be modified in a host also infected with other disease causing agents.  We know much more about interactions between pathogenic micro-organisms through the study of HIV.  So this is yet another example of the way HIV research has advanced our general understanding of the pathogenesis of infectious diseases.  

Interestingly there are a few examples where the interaction of other infections may temporarily ameliorate HIV disease. Scrub typhus, measles and  a form of viral hepatitis, may have a very temporary beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.

Why have endemic diseases been so neglected in our attempts to control AIDS, particularly in parts of Africa?     We have known about some of  the interactions  for over twenty years; there is no shortage of publications where they have been described.   Is it possible that one answer may lie  in the lack of effective  communication between the different disciplines engaged in HIV research?  How do public health experts become informed of advances in microbiology particularly when the field of microbiology itself is changing as a result of new knowledge concerning basic mechanisms? A related issue concerns how funders and policy makers receive the technical information they need to make their decisions.  Also, in so far as public opinion can influence policy,  information about the effects of common infections on HIV disease has not been widely reported on. 

About two years ago I used a particular article to invite some discussion about these questions.

The title of this  article is  "Contribution of Immune Activation to the Pathogenesis and transmission of HIV type 1 infection";  the authors are Stephen Lawn, Salvatore Butera and Thomas Folks.   (Clinical Microbiology Reviews. Oct  2001 14; 753-777)

This is an account of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS particularly  in parts of Africa where co-infections are frequent.   The   review explains 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.

Because of the immunological and molecular detail,  I wondered if this review might present some difficulties to those not familiar with the technical terminology and thus the public health implications might not be so evident..  This particular paper  is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.

Here is an illustration from the body of the article: there is much more just like this.  A person with no experience of molecular biology or virology would not be likely to spend much time with it.

However if one turned a few pages the following diagram might be of some interest.

 The part that would be of interest to a public health professional  is contained in the large arrow at the bottom right of the illustration.  In this rather complex and busy diagram it would be quite easy  to be sufficiently distracted so that the bottom right hand corner would be easily missed.

There is a long discussion which is quite technical in nature but at least the authors find space for the following brief comment.

Prevention and Treatment of Coinfections

                The widespread use of HAART in the treatment of HIV-

infected persons in westernized countries has resulted in a

phenomenal decrease in the incidence of opportunistic infec-

tions and has greatly increased survival. For these individuals,

the antiretroviral drugs are the major determinant of prognosis

and the potential cofactor effect of opportunistic infections is

now a more minor consideration. However, the vast majority

(>95%) of the world's HIV-infected people do not currently

have access to antiretroviral drugs. Most of these people live in

developing countries, where the quality and access to health

care is often limited and where there is a high incidence of

endemic infectious diseases such as malaria, TB, and infections

by helminths and waterborne pathogens which may adversely

affect HIV-1 disease progression. Prevention or early treat-

ment of these diseases may therefore represent an important

strategy in addressing the HIV-1 epidemic in developing coun-

tries. 

There is quite a long section on possible ways to reduce the immune activation associated with endemic infections, but the last sentence is the only reference that deals  with treating and preventing these co-infections.   

Clinical Microbiology Reviews where the article appeared is a journal published by the American Society for Microbiology  and presumably read mostly by microbiologists.   How does the information it contains, as well as an assessment of its relevance find its way to those who advise funders and policy makers and  those who inform the public?

 In the above quotation, the authors are overoptimistic in their assertion that the HIV enhancing effect of opportunistic infections is now a more minor consideration  in Europe and N. America.  Valacyclovir, a drug that inhibits the replication of many members of the herpes virus group, but has no direct effect on HIV  (unless it is phosphorylated in a cell infected with both viruses, which is unlikely to be of practical significance) 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  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.   Fortunately this drug is already prescribed quite frequently, but often only to those with evidence of herpesvirus type 2  infections, in order to reduce herpesvirus shedding.  

Thus endemic infections in Africa  have everything to do with HIV/AIDS.  There are numerous preventative and therapeutic measures available to control many of these infections.  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, and his continuing contributions.   He pointed out the relevance of schistosomiasis to AIDS  (and TB) at least 10 years ago. (We share a very long standing interest in the role of alpha interferon in the pathogenesis of HIV disease, also something that I will leave for another post).

The connection of so many endemic infections with AIDS  in Africa is also a connection of poverty with AIDS.  Of course poverty does not cause AIDS, nor ascariasis, schistosomiasis, tuberculosis, nor any infection.    But the acquisition of many endemic infections is facilitated in impoverished populations resulting in lives that are ravaged and shortened.  

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  and reinforce each other.  

If our goal is to improve the health of populations, where multiple  infections commonly co-exist, we cannot adequately manage any one of them without also considering the other infections that may be present, both in the individual and in the community.

House of Numbers is the title of a documentary film which according to its promotional material will "rock the foundations on which all conventional wisdom on HIV/AIDS is based" 

 I have seen the film.  It is completely unable to achieve this grandiose objective.  It is in fact an AIDS denialist film, despite the contention to the contrary by Brent Leung who made it.

  The denialists are a disparate group who remarkably continue to believe that HIV cannot be the causative agent of AIDS either because it is harmless or because it does not exist. There are even those who believe that AIDS itself does not exist as a distinct disease entity.    Of course there is no shortage of people with strange views that fly in the face of solid evidence.  We can mostly just ignore them.  But sometimes these views can be dangerous, and then we really do have to confront and challenge fallacious assertions that can lead to harm.

The Spectator is a weekly UK publication that had arranged a showing of the House of Numbers to be followed by a panel discussion of the film with audience participation. I had agreed to be one of the four panel members together with the filmmaker.  Several people asked me not to participate in this event, probably with the thought that it was wrong to associate in any capacity with individuals who hold such outrageous views.  There was also much activity on  UK blogs,  generally denouncing the Spectator event. It seems that a lot of people just did not want it to happen.

Two of the panel members withdrew so the event has now been cancelled.   This is a pity.  The film is as I said, dangerous.     It is dangerous specifically because it presents antiviral treatments as only toxic with no mention of their benefits.  Therefore it is justified to be very concerned that some people who need treatment may be dissuaded from receiving it after seeing the film.

I do accept that it is right to not prohibit individuals from expressing their views, no matter how distasteful.   But when these views carry danger it is particularly important that they be challenged with valid information.   It is absolutely wrong to ignore the film and allow it  a free hand in spreading misinformation.   As I have experienced when I was a member of President Mbeki's panel in S. Africa, it is impossible to argue with those who hold such denialist views.  They are impervious to reason.  It is therefore pointless to engage them in discussion. However, when their position is presented to the public, then it is right to try to expose the fallacy of their views to those who might be influenced by them and thus may come to harm as noted above regarding HIV infected people in need of treatment.

I should explain why this is definitely a denialist film despite the protestations of its director that it is not.

In providing a more or less equal, uncritical  and essentially neutral platform to those holding denialist views together with those who do not,  the filmmaker,  presenting himself as an unbiased observer merely asking  questions,  puts forward the impression that the issue of HIV's role in causation remains unsettled.  Although the film does not explicitly reject HIV as playing a causative role in AIDS, it most certainly leaves one with the impression that this, and even the existence of the virus, is merely conjecture.  This is a misleading presentation of the well established causative   link between HIV and AIDS as something that is just a theory, on a par with the theories of Dr Duesberg or of those who claim that HIV does not exist.

This is absurd and as I explained, also dangerous.

Conventional wisdom is absolutely sound regarding the existence of HIV and of its causal link with AIDS.    However not all conventional wisdom is so secure (in my opinion).   Mr Leung does point to some real controversies in HIV medicine.   But these are conflated with issues that are firmly settled.

I have had a pretty conventional training as a microbiologist and as an infectious diseases physician. 

From this perspective and accepting that AIDS is an infectious disease with HIV as its causative agent, there are several  controversial issues, where scientists and physicians do not speak with one voice.

We have to remember that this disease only came to our attention about thirty years ago.  There are bound to be controversies and disagreements as our knowledge of the disease and of its causative agent increases.   Researchers are not exempt from a perfectly human proclivity to make generalizations based on far from complete information.  In science this is a desirable activity as sometimes these generalizations prove to be fruitful hypotheses that lead to new discoveries.  On the other hand they can just lead to a dead end and may even retard progress.  Understandably, as long as information remains sketchy, such generalizations will be associated with legitimate controversy.   I'll just describe a few of the problems that I see as legitimate.

The film presents several   researchers who have opposing views on the role of co-factors.    Some researchers interviewed are adamant in their insistence that for AIDS to develop, co-factors are required in addition to HIV.  Others are equally confident that they are not needed.   

This may sometimes be a spurious conflict arising from differences in how the term, "co-factor" is understood.

AIDS has accrued its own peculiar terminology not usually seen in other infectious diseases. Co-factor is one example, or an infectious agent referred to as the "sole" cause of a disease.

In all infectious diseases there is an important distinction to be made between infection and disease.  Epidemiologists are concerned with theories of disease causation and recognize this distinction very clearly.  The attack rate is the parameter used to define the proportion of people exposed to an infectious agent who become ill.   The attack rate varies from infection to infection.   Rabies may be the only infectious disease with an attack rate of 100%.   

 We rarely know exactly what will determine the difference between an asymptomatic infection and one that produces overt disease. But we do know the general categories of influences. These concern both the organism and the host.  The virulence of the infecting organism, the size of the infecting dose or the way it is introduced into the body can all influence the outcome.

 Examples of host factors that can play a role in determining whether or not an asymptomatic infection will progress to a disease are the nature of the immune response, genetic characteristics, concurrent infections that affect susceptibility or  exert a synergistic effect.  

 It is the complex interplay of host and microbial factors that determine whether for example, one individual infected with hepatitis B virus will remain completely without symptoms and only know infection had occurred when antibodies to the virus are later detected, while in another individual infection results in fulminant  clinical hepatitis.  

HIV disease which includes AIDS is an infectious disease, resembling other infectious diseases.  In all of them, there are determinants of infection, factors influencing the attack rate which is almost always under 100%, and usually a variable course in disease progression.

The term co-factor when used by some could mean all these usually unknown host factors that influence the attack rate.   To others it may mean something specific - even if as yet unidentified, that is necessary for disease to develop in HIV infected individuals.   Used in the latter sense, it would represent a position close to that of the denialists, because it suggests that HIV is harmless in the absence of these other specific factors.   But when used in the former sense it would represent a more traditional understanding of infectious diseases.   

A closer questioning of those asked about the role of co-factors may reveal that there is in fact no disagreement on this issue.

 Those of us who accept HIV as the cause of AIDS should probably not use the term co-factor at all, and discuss AIDS as we would any infectious disease, where we understand that infection and disease are not synonymous. 

AIDS research is subject to all the pressures and influences that can affect any enterprise conducted by people whose incentives will be varied and complex.  Of course there will be instances of conflicts of interest and examples where legitimate criticism can be levelled at some researchers and commentators.   For example, case estimates have sometimes been presented as real numbers.   It is of course necessary to make such estimates when widespread testing is not feasible, but numbers should be clearly presented as estimates when that is what they are.  

  There are also technical issues where opinions differ.     Such perfectly understandable instances are exploited in this film to question the reliability of some solid achievements in HIV medicine.  We are without doubt able to detect antibodies against HIV. This ability is brought into question as the film would have us believe, because scientists may differ about which of the many tests available, alone or in combination, are the best ones to use in a particular setting.  

But because some researchers and commentators may be open to criticism on some points, it most definitely does not follow that they are mistaken on the general issue of causation.

Finally, I should explain why this film is also offensive to some of us.    There are many individuals who owe their lives to antiviral medications.  I have treated hundreds- into the thousands, of people with this disease since it was noticed in 1981.  I could have introduced many people whose lives have been saved to  Mr. Leung, so that their (or others) testimony might have been included in the film.  

My own experience as a physician is just at odds with the picture presented  concerning antiviral treatments.

  It is hard to adequately convey the feelings of a physician who was able to finally help his patients in the mid 1990s, having lost hundreds to this disease before that time.  By the time these drugs became available about 400 of my patients had succumbed to AIDS, a dreadful rate of mortality.  The effect of these drugs was life saving to those with advanced disease whose survival had been limited before.  The portrayal of these drugs as in effect only toxic is so unfair.  I can say with some dismay that had my patients who needed treatment been dissuaded from receiving it by this film, many would surely have died. So this aspect of the film is deeply offensive. 

When I asked the film-maker why he had not interviewed any HIV infected person who had benefited from treatment, his response was:  Are there people who can tolerate these drugs?   So much for the intrepid reporter merely seeking the truth. 

 The fact that the drugs have toxicities and may not always be used wisely does not detract from their great benefits when used appropriately. This is not different to the treatments of many other diseases.  Also, these anti HIV drugs are able to substantially reduce the transmission of HIV from mother to infant.  This great achievement is not mentioned in the film.

It is notable that the denialist/dissident groups include no physician who is experienced in the treatment of AIDS.   One German physician is interviewed in the film who states that his patients with AIDS are well without treatment.   I believe he does not specialize in treating this disease and may only have very few patients with it, but was not asked about  the extent of his experience.   I too was interviewed for the film.  I can't remember if I was asked about my clinical experience. If I had been, my responses were not used.

It is absolutely correct that Mr Leung should be free to express his particular views on this disease.  However we do have a responsibility to counter the dangerous misinformation in the film - specifically, that antiviral medicines are only toxic, with no mention of their benefits.

 I'm sorry the Spectator event had to be cancelled and so an opportunity to challenge the misinformation in the film was lost.  There is nothing more powerful than the personal testimony of individuals whose lives have been made possible by anti HIV medications, as well as that of the doctor who prescribed them.  Had this event taken place, at least two HIV positive individuals on antiretroviral therapy would have been in the audience and would have spoken about the immense benefits they received from their treatment. 

In my introductory post, I promised to write about some of my experiences in New York City at the very start of the epidemic, from both professional and personal perspectives.

This post is about preventing Pneumocystis pneumonia in AIDS. 

It's a sad largely neglected history.  Many lives were shortened before 1989 when  interventions to prevent this type of pneumonia  were finally recommended by government officials for people with AIDS.

Thankfully, with the widespread use of antiretroviral drugs, many people may not be too familiar with this opportunistic infection.  It most certainly has not gone away, but in the 1980s Pneumocystis pneumonia was what most commonly killed people with AIDS.

  It's now almost 30 years since the epidemic was first officially recognized in 1981.  It was in the June 5^th, 1981 edition of the Morbidity and Mortality Weekly Report (MMWR) published by The Centers for Disease Control (CDC), that the first cases of Pneumocystis carinii pneumonia (PCP) were first  described.  Click on this link to see an account of the first official report of AIDS, and the CDCs earliest responses.  First report of AIDS.   

In fact, this CDC report was not the first public mention of AIDS.   The first time the as-yet unnamed disease was noted in the media  was about three weeks earlier, on May 18^th in the New York Native, a gay weekly newspaper in New York City.  Larry Mass was the author of this report.   As noted by Gabriel Rotello, it was the gay community in New York City that first brought the epidemic to public attention. 

Many of us taking care of gay men in the late 1970s became aware that our patients were showing a number of unexplained signs and symptoms.    I was one of these physicians and so  I suppose I should have  started these accounts of the early days  at the beginning - at least, the beginning for me, as I became aware around 1979 that something very unusual was affecting so many of my patients, and  realized that there was a developing problem with potentially immense implications.  But I will leave this "pre-AIDS" account for another post.

 In this post I address the preventable opportunistic infection,  PCP that was the major cause of death among people with AIDS in the first decade of the epidemic.   

Because there are a number of immunological disorders that result in a susceptibility to similar opportunistic infections that are characteristic of AIDS, PCP had been well studied before AIDS appeared.  When the epidemic began we knew how to diagnose this particular opportunistic infection, we knew how to treat it and we also knew how to prevent it.   

 As early as 1977 it had been well established that PCP could be prevented by an inexpensive medication, yet official recommendations for the use of this and other interventions as prophylactic agents against PCP in people with AIDS did not appear until 1989. 

This long delay is a strange episode in the history of medicine, although it is barely remembered today.   But anyone who experienced the first decade of the epidemic in the US will remember the scourge that was PCP.

Attempts to bring this effective prophylactic measure to attention had been made by individuals in the gay community  well before its formal introduction in 1989, most notably by Michael Callen, an early AIDS activist who has since died. 

First a few words about PCP.  Thanks to antiretroviral medications this infection is now relatively uncommon.  But it most certainly has not gone away.    Although the name of the causative organism has been changed to Pneumocystis jiroveki from Pneumocystis carinii, we still recognize the pneumonia associated with it as PCP.   The organisms interfere with the diffusion of oxygen into the blood, and untreated, the infection is almost always fatal, in effect causing death by suffocation.

To get an idea of the extent of the fatalities this pneumonia caused,   Michael Callen asked a CDC statistician in 1989 how many AIDS related PCP deaths had occurred since the beginning of the epidemic.    As of February 20^th, 1989, 30,534 Americans had died of AIDS-associated PCP.  The year is significant as it was then that the CDC finally issued recommendations for the prevention of PCP, using a drug that had been known to prevent this kind of pneumonia since 1977.

The drug in question is Bactrim, also known as Septra, Septrin or co-trimoxazole. It is actually a combination of two drugs, trimethoprim and sulfamethoxyzole.   It has been available as an inexpensive generic product for many years.

Bactrim was first demonstrated to be an effective prophylactic agent against PCP in children with leukaemia by Walter Hughes in 1977.  What about other immunocompromised conditions associated with a susceptibility to PCP?  Dr Hughes suggested in a 1981 publication that in these other immunocompromised conditions, where a first episode of PCP was known to be followed by a rate of recurrence of about 15%, Bactrim should be prescribed after the first episode.  

In AIDS we soon learned that the rate of recurrence of PCP was about four times higher than the 15% threshold suggested by Walter Hughes as an indication for prophylaxis.   By 1984, if not sooner, we knew that one episode of AIDS -related PCP was followed by another within a year in at least 60% of those initially affected.  I don't know if Walter Hughes made any proposals that PCP prophylaxis in this new disease should be considered differently to his 1981 recommendations regarding the use of bactrim in immunocompromised conditions other than childhood leukaemia.   He was a member of the CDC committee that recommended the use of Bactrim to prevent PCP in AIDS in 1989.

It is true that people with AIDS have a higher frequency of adverse reactions to Bactrim than those not infected with HIV.  These are mostly hypersensitivity reactions including fever and rashes.  But we soon learned that these reactions could be frequently avoided by a desensitizing process, involving a gradual increase in dose.  We also learned that the initial dose proposed by Dr. Hughes in the 1970s and by the CDC committee in 1989, which was two double strength tablets a day, was much higher than needed.  Bactrim given only three times a week is equally effective.

It is worth quoting the following passage from the CDC recommendations.

"In 1989, the United States Public Health Service convened a Task Force of experts to consider the expanding knowledge base about prevention of Pneumocystis carinii pneumonia (PCP) among adults and adolescents (greater than or equal to 13 years of age) with human immunodeficiency virus (HIV) infection. This Task Force concluded that the morbidity, mortality, and cost due to PCP could be substantially reduced by appropriate use of antipneumocystis prophylaxis in subgroups of HIV-infected patients known to be at high risk, and developed recommendations for the administration of prophylactic regimens. "

At this time 30,534 people in the US had already died of PCP.

Michael Callen was a patient of mine.   He was tireless in his advocacy that recommendations be promoted  to use measures to prevent PCP in people with AIDS.    Michael was also one of the authors of the Denver Principles, which in his words essentially state "People with AIDS should have a say in any decision-making process that will  affect our lives".   He tried to do this with respect to PCP prophylaxis. 

Michael with other activists met Dr Fauci in May of 1987, Michael was insistent in asking for recommendations to prevent PCP in people with AIDS.   Michael wrote the following in relation to this meeting:

"It is particularly galling to me that 16,929 of the 30,534 unneccessary PCP deaths occurred since May of 1987, the date on which I and other AIDS activists met with Dr. Anthony Fauci (the closest person we have to an AIDS czar) to ask him - no, to beg him - to issue interim guidelines  urging physicians to prophylax those patients deemed at high risk for PCP.  He steadfastly refused to issue such guidelines. His reason? No data. As a result many more people died of PCP who didn't have to".

Dr Fauci wanted data from a clinical trial of Bactrim for PCP prophylaxis in AIDS before he would recommend its use.  But people were dying of PCP at a terrifying rate; I and some other physicians could not wait for these recommendations.  I was routinely prescribing  Bactrim, or another drug, dapsone to patients  I deemed to be  at risk for PCP.

I was fortunate in that I had some experience in the 1970s  dealing with infections in people who had received kidney transplants. These individuals are intentionally immunosuppressed, to avoid rejection of the transplanted kidney, and because of that immunosuppression, they experience a number of the same opportunistic infections seen in AIDS, including PCP. They also can sometimes get Kaposi's sarcoma.   As an infectious diseases specialist, with some experience in the transplantation field,  I was familiar from the beginning of the epidemic  with the use of Bactrim to prevent PCP. 

I found it  remarkable that at some transplant centers patients received PCP prophylaxis without the need for a trial while people with AIDS were denied this intervention.  There had been several trials of PCP prophylaxis in different transplant populations at various times.  But after  Walter Hughes demonstrated the efficacy of bactrim in 1977, the need for these trials is debatable.   I don't know if anyone has written a history of the use of PCP prophylaxis following Dr Hughes 1977 trial.   I feel fairly certain that in groups at risk for PCP other than the  leukaemic children studied by Dr Hughes, Bactrim use has been erratic, with some receiving the intervention, maybe just following the criteria suggested by Dr Hughes himself  in 1981 (where the PCP  recurrence rate is at least 15%), while other groups had to wait for the results of trials before receiving the benefit.

In the case of AIDS a trial of Bactrim prophylaxis was finally conducted by Margaret Fischl in patients with Kaposi's sarcoma, using two double strength tablets a day.  At this dose adverse reactions were seen, but only 5 (17%) of patients had to discontinue treatment.  As already noted we soon learned how to reduce the frequency of these reactions by desensitization procedures and  using a much reduced dose.

The CDC recommendations did note that the trial was conducted in patients with Kaposi's sarcoma, and in a typically pedantic and ultimately absurd fashion, warned us that there was no evidence that prophylaxis would be effective in AIDS patients without Kaposi 's sarcoma.  They thankfully stopped short of demanding a trial in AIDS patients without Kaposi's sarcoma.

In the early days of the epidemic we could not know which patients were at risk for PCP. We had to learn that 200 CD4 cells was the dangerous threshold, below which there was a substantial risk of infection.    But well before this we were perfectly able to target a population at great risk for PCP: these were people who had experienced one attack already.  They were almost certainly going to experience another one but their protection was not considered to be a matter of urgency by the federal AIDS medical leadership.   Of course in the absence of effective treatments for HIV disease, preventing PCP would have been a life extending rather than a life saving intervention.

Another curious and indefensible objection to PCP prophylaxis was  raised by Dr Samuel Broder who was then head of the National Cancer Institute.  He felt it justifiable to discourage the use of PCP prophylaxis on the grounds that the introduction of AZT would make this practice redundant!    This objection was raised in the complete absence of any evidence that AZT could prevent PCP in a significant and durable fashion, if at all.

Michael Callen promoted PCP prophylaxis in other ways.

He was the President of the PWA Coalition in New York City (PWAC), and the founding editor of the PWA Newsline.  Michael did what he could to bring attention to the need for PCP prophylaxis in the PWA Newsline.    He also did so in two volumes published by PWAC - Surviving and Thriving with AIDS.

    Around 1987 feeling so frustrated at the wilful neglect of  PCP prophylaxis by so much of the medical establishment, I  wrote a one page article for the Newsline.  I remember the occasion quite well as neglect of PCP prophylaxis was something Michael and I  often discussed.  During one of these discussions, out of frustration, I grabbed a piece of paper at my New York apartment and wrote  about PCP prophylaxis for the PWAC  Newsline.  It  probably  took me  less than ten miniutes  with Michael standing behind me .  It was published unchanged.

Here is a reproduction of that article and also a later one, both  for the PWA Newsline.

The road to PCP prophylaxis was already long and troubled, but had one further detour to make, an expensive distraction with aerosolized pentamidine lasting four to five years.    Pentamidine is another  drug  used to treat PCP for years before the AIDS epidemic was first recognized.   In fact, when it was needed  before AIDS began,  it had to be requested from the CDC where the stocks were kept.  One indication that AIDS cases were appearing at the beginning of the 1980s was awareness at CDC that there were increasing numbers of requests for pentamidine, meaning that there were more cases of PCP.    Pentamidine is given by intravenous injection and has significant toxicity.   It was hoped that this toxicity could be avoided by delivering the drug directly to the lungs by aerosol inhalation.    The droplet size was important if the drug was to reach the parts of the lung where the organism proliferated.  So much time was initially spent in studying nebulizers of different design.  Two types competed - an ultrasonic mechanism for delivering droplets and one in which the aerosol was produced by a nebulizer using compressed air.  Then trials of its safety and efficacy were needed. In 1987 two trials were conducted by two community research organizations.  The Community Consortium in San Francisco provided efficacy data, and the Community Research Initiative (CRI) in New York provided the safety data required by the FDA in the approval process. I wrote the protocol and was the principal investigator for the New York study, which was funded by Lyphomed, the company that manufactured pentamidine for aerosol use.   

Pentamidine for injection was available as a generic preparation.   The formulation for aerosol use however was not and so was costly in the US.  Another organization that Michael Callen, Tom Hannan and I had organized to distribute egg lipids - AL721,  (an interesting topic itself, perhaps  for another post)the PWA Health group, imported a cheaper version from the UK.

A number of physicians treating people with AIDS set up inhalation machines in their offices.

Here is what it looked like. The picture was taken during the CRI trial.

Aerosolized pentamidine proved to be inferior to Bactrim as a prophylactic agent  and was associated with unusual complications.  It presented environmental hazards as other organisms -such as TB could be disseminated, and also resulted in the occurrence of pneumocystis infections in organs other than the lungs.

In all likelihood aerosolized pentamidine was pursued as a possible PCP prophylactic agent because interest in Bactrim was so discouraged by the federal medical leadership.  

 It is not irrelevant to note that unlike pentamidine for use as an aerosol,   Bactrim  was available as an inexpensive generic preparation. 

Should there be interest in a longer and referenced account of this curious episode in the medical response to AIDS, which also tries to find some explanation for the long delay in providing patients with a simple life extending intervention the following link will lead to a more detailed article written in 2006. 

2006 article on PCP prophylaxis

I don't think this is the case.  It is not the only example of the success of prevention education.    In a totally different situation, the number of HIV infections in Uganda fell in the 1990s.  This coincided with the introduction of an intensive prevention education initiative.

Of course the characteristics of the epidemic in the US and Uganda are enormously different; the major means of transmission in Uganda is through heterosexual sexual contact and using this example certainly does not mean that those prevention education measures adopted in Uganda would be appropriate in the US.   The example is an illustration that prevention education can work.
 

With these very different examples we can safely say that in principle, HIV prevention education can be effective.

In the US, in the early years of the epidemic, we had the horrible constant reminder of what we were facing in the frequent deaths of our friends and patients, an experience that younger people are now spared, at least on a daily basis.   It seems absolutely reasonable to accept that these terrible reminders of what HIV infection could do contributed to the success of safer sex campaigns.  Of course there are other differences today, not the least of which is that we have the great benefit of the availability of antiviral drugs. 

The disease is viewed in a different way now, from something that seemed to be uniformly fatal to a "chronic manageable disease".  I have put the term in quotes because it is a misleading message put out by many health departments, and the Centers for Disease Control (CDC), as an explanation why HIV tests should be as routine as having your blood pressure taken.  While there is of course  every reason to test for HIV as widely as possible, it's my opinion that comparing HIV disease to conditions like high blood pressure to promote testing  can have a negative effect on prevention education.

Chronic, so called manageable diseases are in fact not all the same. Some are manageable with great difficulty and sometimes for not very long.   The means used to manage the disease may themselves not be free from problems.

HIV disease has, without question, been transformed by the availability of antiviral drugs.  But it still requires lifelong regular medical supervision, adherence to treatment regimens and, for some, dealing with severe adverse responses to the medicines.  Then there is frequent stigmatization, difficulties in finding care, problems with employment, alienation of family, and a multitude of other difficulties that many people with HIV must face.  No, HIV disease is not like having high blood pressure, diabetes or asthma, as the CDC would have one believe.

Despite this, it is possible that the message that HIV disease is now not so serious that is implicit in the reassuring description of the disease as a chronic manageable one, may have lessened the fear of becoming infected in some individuals.  This is also a possible effect of some advertisements for antiviral drugs that suggest that taking them will transform one into a mountain climber.

But these and other obstacles to effective prevention education programs should be taken into account when designing new strategies.  They can be overcome if there is a will and funding to mount large-scale properly targeted prevention education campaigns.

The most effective prevention education efforts can only have a chance of success if they involve the affected communities at every level.   With a  need for highly targeted prevention education material, various community  groups are best able to craft the messages that are best suited to their needs, if given adequate resources.

The first proposal to use condoms in 1982, came from individuals under threat themselves, not from any organization, and certainly not from a government where the President at that time was unable to even mention the word AIDS or later, one who supported abstinence-only programs.  

In 1982, despite the opposition of organized community groups, I with two of my patients, Michael Callen and Richard Berkowitz, were able to disseminate a booklet suggesting the use of condoms.  This endeavour was made possible, not by a foundation or any other organization, but by an individual, Randall Klose who provided the funds.  Few probably remember Randy Klose, but many should know about him and what he made possible.  Even the foundation that I had incorporated, the AIDS Medical Foundation (which became Amfar) found the explicit words of the booklet a danger to fundraising, and refused financial support. They did help however, by providing fiscal sponsorship of Randy's donation.

This was a community triumph.   It arose from affected people themselves, who were not about to wait for some benevolent authority to introduce some way to prevent getting this disease.

When I started this post I pointed to the success of prevention education among groups of gay men in the mid to late 1980s.  I had to say groups because just as cases were declining in white gay men they were increasing in African-American men. 

The neglect of prevention education that is properly targeted to those at risk that is culturally-sensitive and persistently delivered is demonstrated in the most awful way by the current disaster in many African-American communities.  

I, as many of us, have been following demographic trends of the epidemic since its start.  The advance of this disease into African-American communities became quite apparent in the late 1980s, visible to all who cared to look at surveillance data.  By 1993 the percent of diagnoses in African-Americans started to exceed that in white Americans.    Certainly by 1990, we could have had no better evidence to target a group in great need of prevention education, yet "America Responds to AIDS" was the best we could come up with.  For those who did not see this program, it was a vacuous untargeted waste of money and time and an indication of ineptitude or indifference on the part of authorities whose task it was to protect us.

 Take a look at this picture that tells a horrible story that words cannot match.

This represents a tragedy that has been developing in full view for more than twenty years.  We knew as early as 1987, and certainly in 1990, that without intervention a preventable disease would inexorably move into African-American communities.  This picture tells us exactly how America responded to AIDS.

In the light of this evidence, how are we to understand the comments of Dr Fauci , who was appointed as  the AIDS coordinator for the National Institutes of Health in 1985?

In February, 2009 he noted that these "shocking statistics would be tragic anywhere but are particularly inexcusable in a wealthy country such as the United States"

His complete statement can be seen here:

http://www3.niaid.nih.gov/news/newsreleases/2009/BAAID_09.htm
 

But this is only one of endless comments by authorities on a tragedy that was developing before their eyes for twenty years.  The same might be said about the many comments on the dire condition in Washington DC.  

It is not only the federal AIDS leadership that failed to respond to warning signals flashing brightly right in front of them. In the early days of the epidemic there was a vigorous and exemplary community activist response. This was a terrific example of people dealing with a deadly disease taking action on their own behalf, fighting for the best medical and scientific response and against the shameful stigmatization of HIV infected individuals.

The flowering of AIDS activism in the late 1980s and early 1990s achieved a great deal. All people dealing with serious illness have benefitted from the precedent that was set. Yet, in recognizing this achievement, we must also wonder why many of these experienced advocates, who no doubt were aware of the demographic trends shown above, seemed generally less willing to at least try to avert the disaster threatening their fellow citizens? Of course some tried, and maybe were overwhelmed by massive indifference.

Whatever the reasons, the advocacy of US activists abroad, particularly in Southern Africa, proved to be more effective than anything they were able to achieve in their own country for their fellow African American citizens.

There are also other groups where AIDS has been, and continues to be a growing problem, but have been relatively neglected.

To conclude this post I want to explain why HIV prevention education must be closely linked with the promotion of studies on PrEP.

This will also be a response to some comments made following my last post on PrEP, particularly those of Anna Forbes of the Global Campaign for Microbicides  (GCM).  If you click on this link  you will find several papers on ethical issues associated with prevention trials, as well as the links Anna Forbes provided in her response, to in-depth analyses of previous problems in PrEP trials in Cambodia and Cameroon.

I should say that Anna Forbes' presentation at the CHAMP teleconference was extremely good;  she made it quite clear that PrEP was not intended to be a replacement for current recommendations which include the use of condoms.

What I have written above about my involvement with prevention education ever since our booklet "How to have sex in an epidemic: one approach" was written in 1982 should explain the position from which I wrote my last POZ blog post, and why I responded as I did, particularly to the CHAMP flyer.

When I read the flyer I feared that by failing to state that PrEP was not a replacement for current prevention approaches, the interpretation made by some might have been that prevention education is ineffective and that therefore a new prevention strategy was needed.  More people probably saw the flyer or eblasts than participated in the teleconference where the issue was clarified.

It is of course true, as one person stated, that a flyer cannot contain all details. But surely a statement that PrEP is not intended to replace current prevention recommendations including condom use should have been there.

Most of this post has been a defence of HIV prevention education, arguing that it would be quite wrong to conclude that in principle, it is ineffective. The failing has been in the efforts of those responsible for it, a lack of interest or maybe just a belief that the effort would be useless.  As for funding, while the changes shown in the above illustration were steadily progressing in full view, "America Responds to AIDS" was on every TV set in the country.  That must have cost many millions.

As with almost everything in HIV medicine, a one-size-fits-all approach seems to be the norm. It's certainly cheaper to deal with populations rather than customize responses to fit the needs of individuals.  Treatment recommendations are made without concern for individual differences in the rate of disease progression.  At the very least, North America and Europe can afford the expense of individualizing treatment for HIV, as is typical for most other life-threatening conditions.

In the same way there are differences in prevention needs in different communities and differences within these communities. These differences are reflected in differences in what is hoped for from PrEP.

For some women (and some men) PrEP may represent the most practical,  though as yet unproven, way to avoid HIV infection.

For others, both men and women, it may represent an added layer of protection to condom use or other risk reduction measures.

Some may hope that it will provide a safe means to conceive.

Others evidently hope that it may represent a safe way to increase sexual intimacy for people with HIV by dispensing with condoms altogether, although I find it impossible to envisage how safety could ever be tested.

These are all very different situations; the stakeholders are indeed a diverse group. 

Some need PrEP to remain uninfected while others want it, even though there is no insuperable obstacle to following current  HIV prevention recommendations.

The power of men to protect themselves and their partner is the use of a condom.  The only theoretical power available to a woman (apart from the female condom) is the power to say no.  But I say theoretical power, because in real life there are many situations in which this power cannot be exercised. 

It is clear that we need prevention interventions  that are in the control of individuals who are the receptive partners in sexual intercourse.  For these individuals, the study of PrEP is of the greatest importance.

As far as choosing to dispense with condoms is concerned, Swiss investigators have proposed a reasonable set of circumstances when this can be safely done.   These circumstances will apply to very few.  For others where infectivity is realistic, I can think of no way to determine if PrEP would provide a means to safely dispense with condoms.

 Prevention education has been shown to work among men who have sex with men.  And today in America, it is those men--Black, Hispanic, White, Native American, gay men of all ethnicities--who carry the greatest burden of this disease.  So when new strategies are being explored, it is important that it is not even implied that prevention education is  something that cannot work well enough, and therefore new prevention strategies are required. Presenting a new prevention strategy such as PrEP should be accompanied by an encouragement and strengthening of prevention education that we know can be effective. 

As far as my comments on efficacy trials of PrEP are concerned, I believe there is a realistic possibility that a reliable and generalizable result on efficacy may unfortunately be impossible to obtain. There are added, but hopefully not insuperable  potential problems, like  adherence to PrEP and the risk of developing resistance.  Now we also have the troubling news that pre-existing bone density issues among some African men may present a problem in the use of tenofovir as well as growing research indicating the demineralising effect of its long-term use.

It seems better to offer an unproven intervention that has something to support its use, with appropriate testing for infection and toxicity, rather than do nothing. Where conditions permit this, there is a case to be made for presenting this as an informed choice that individuals have every right to make on their own behalf.   This would be the case where, in practice, there is no other intervention available.    In the 1970s I prescribed antibiotics to patients as pre-exposure prophylaxis against gonorrhoea and syphilis, presenting adequate information and follow up testing.  It was a choice I felt they had every right to make.  Despite being chastised by my colleagues, I was able to prevent gonorrhoea and syphilis in some of my patients (of course I have no proof of this, but it is likely that infection was avoided).   HIV infection however is quite a different matter, but still, with full information, making decisions on their own behalf remains the right of an individual.  But we don't yet have full information, and anti-retrovirals are available in many parts of the world.  This is another reason to do what we can to complete efficacy trials of PrEP. 

I certainly had no intention to discourage the study of PrEP; my interest was in strengthening and improving prevention education. This is something that must go hand in hand with the study and promotion of PrEP, not only in trials, where this is happening, but at a community level.