Archive

Posts Tagged ‘Michael Callen’

Herpes Viruses and HIV: Some early History and a Bit about Safe Sex

May 17, 2009 1 comment

[The relationship between herpes viruses and HIV disease is also discussed in a subsequent post:

http://aidsperspective.net/blog/?p=520 ]

The relationship between herpes simplex virus type 2 and HIV is in the news again.   This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.

This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died.  A reduction in HIV viral load was also observed in those treated with acyclovir.

The concept on which this study was based is absolutely solid.

Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.

The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.

There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.

Herpes viruses – and not just herpes simplex virus,  have an impact on the course of HIV infection.  This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.

Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.

“Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .

(NEJM 2007  356:790)

It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed.  The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.

These assumptions about the reasons for increased HIV transmission may all be mistaken.

We do know with some confidence that transmission of HIV is related to viral load in the infecting partner.  It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.

An individual with higher HIV viral loads  will more easily transmit the infection,  and also experience  more frequent recurrences  herpetic ulcers.  This of course only applies to HIV infected individuals.

As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.

Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.

Sometimes individuals know what provokes a recurrence.  Recurrences can be associated with febrile illnesses.  It is completely reasonable to suggest that the effects of some  intercurrent  infections may cause  both  herpetic recurrences and increase susceptibility to HIV.

Whatever infection  causes the fever may also increase susceptibility to HIV, possibly by an association of the  infection with perturbed immunological function.    Transient immunological perturbations  can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.

For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2.  At least regarding what is reported to the public.

However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.

Cytomegalovirus  (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important.  These viruses are also sensitive to the anti herpes drugs used in these two trials.

Since infections with CMV and EBV  are so widespread how can effects of acyclovir and Valtrex   on reducing  HIV viral loads be attributed to an effect of these drugs  on herpes simplex type2?

I cannot recall that these two other members of the herpes virus family – or even a third, HHV6  were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.

It is entirely possible that suppression of  two viruses,  CMV and EBV, contributed, perhaps to the greatest extent,  to the anti HIV effects seen.

One can only hope that sera from these studies were frozen and stored.  Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.

As an historical comment, acyclovir was tried as a treatment for AIDS in 1987  around the time AZT was introduced.

There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.

AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.

One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.

Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir.  Another retrospective observational study found no benefit.

Nothing much can be made of these contradictory early results.

But now, with newer techniques for measuring HIV activity by viral load assays, we   have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.

With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease,  Unfortunately most of the  emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe,  of even greater importance.

Actually there had been  interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.

I have been involved in AIDS research and  treating patients with this disease from the time it started and so can  provide some historical perspective on the interest in herpes viruses,  that dates to the late 1970s, even before AIDS was described and long before HIV was discovered.   At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.

As another historical interlude,  interest in herpes viruses also provided the basis for safer sex, as it is understood today.  As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV.   Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.

From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.

I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men.   By 1983  over 40% of a cohort of gay men in New York City carried CMV in their semen.   Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections.  (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al.  AIDS Research 1983 1: 59)

At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods,  and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.

But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease.  It was thus possible to propose a way to at least prevent the sexual transmission of CMV.

This formed the basis for the first published recommendations for condom use.

With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.

The appropriate  title  was  coined by Richard.

The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007.    Although it is  in fact a landmark event in the history of the epidemic.

Richard is only now receiving some acknowledgement for this life saving proposal  because a documentary film called Sex Positive has brought attention to  his achievement.

An account of our collaboration in producing the safer sex guidelines can be seen by following this link.

Safer sex recommendations.

Michael Callen is remembered by many for his activism.   There is even a clinic in New York City named for him and Audre Lorde .

I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.

I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.

Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.

As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS.    This is quite apart from their multiple clinical manifestations as opportunistic pathogens.  Both of these viruses almost definitely contribute to pathogenesis.

Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated  for many years.

In fact some evidence for this  was already apparent when AIDS was first described.

This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.

As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.

I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.

Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.

The role of CMV in immune system activation, a major force in driving HIV infection.

The systemic effects of CMV and EBV infections are most probably of great importance in this respect.

Systemic effects resulting in immune system activation and activation of HIV replication may also  accompany reactivated herpes simplex virus infecteions.

Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines.  These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles.  So, this is but one way in which an active herpes virus infections can promote the replication of HIV.  The general mechanisms are described in a previous post..

An important and interesting  paper that also deals with   EBV and CMV in relation to HIV replication was published by V Appay and colleagues.  It can be seen  by clicking the following link.

HIV ACTIVATION

I am  reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references.  The references can be seen in the complete text seen by following the above link.

“HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”

“In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in

the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained

antigen mediated immune activation occurs in HIV-1-infected

patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.

“CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears

to monopolize a significant fraction of the whole T cell repertoire [97], so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects [98]”.

Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface.  These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.

Transactivation  of HIV by herpes viruses.

In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.

Acyclovir and Valtrex have no direct effect on HIV except under one unusual circumstance,  yet both have been demonstrated to reduce HIV viral loads.

In the early 1980s when we had no effective measures against  this disease I treated my patients with high dose acyclovir.

There then  was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.

In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.

But interestingly,  at that time,  none of these theoretical considerations placed much importance on HSV 2.

The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.

Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.

But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending  interventions.

What I have written of this experience with bactrim in the early years can be seen by following this LINK

In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.


[i]   Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc.   But this drug has a truly remarkable quality.  The cellular enzyme that  adds phosphate to make drugs of this type active,  does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues.   But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears  in herpes virus infected cells  has the ability to add the phosphate group and turn acyclovir into an active drug.  This is the reason why acyclovir is such a safe drug.  It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.

However, if  the same  cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to  terminate  HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.

This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.

Advertisements

Early concerns about confidentiality in AIDS, and what Jim Monroe had to do with this.

April 23, 2009 1 comment

From time to time I will write about some extraordinary people I have worked with. The first of these is Jim Monroe.

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

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

Jim Monroe personally helped many individuals who were in great need.  He was also the person who was probably responsible for first bringing attention to the issue of confidentiality in AIDS in the earliest years of the epidemic.

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

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

Jim is probably the person who was responsible for the early attention given to confidentiality in connection with AIDS

Confidentiality in matters of health is of the greatest importance; it is also complex, with some special concerns in connection with sexually transmitted infections.

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

But the context in which Jim brought attention to confidentiality was the concern to protect individuals suffering from this new, untreatable, and as yet unnamed disease.   From the very start, affected individuals frequently had to contend not only with this frightening illness but with irrational and cruel discriminatory acts against them.

Not only was the disease itself associated with stigmatization, particularly in the early years, there was yet another issue requiring attention to confidentiality.  Sexual orientation was revealed with a diagnosis when the disease was thought to be confined to gay men. As other groups of individuals were identified, perhaps only those who acquired the disease from blood products were relatively free from the threat of discriminatory practices that were all too frequently directed against gay men and IV drug users.

Those were the days when HIV infected people in hospitals had to retrieve their meals which had been left outside their doors;  when medical personnel would refuse to care for infected people; when some children were not allowed to be in contact with those known to be infected, and infected children sometimes not allowed to attend school.  Thankfully in the US today children are protected.

http://www.ed.gov/about/offices/list/ocr/docs/hq53e9.html

But despite advances, AIDS is still a disease associated with stigmatization, not only in developing countries but also in the US and other developed nations.

I will describe how Jim started a response intended to assure that those affected by this new disease would be protected by measures to maintain their confidentiality.

A few introductory words are needed.

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

In 1983, my lawyer, Frank Hoffey with Graham Berry prepared the papers and incorporated the AIDS Medical Foundation (AMF), initially to raise funds to support my research.  Apart from Mathilde’s personal support our work was not funded.  AMF soon broadened its mission to support the work of others as well.

Fundraising during the first year was very difficult and the foundation really owes its survival to the efforts of Dr Krim, who was the chairman of the board.

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

What concerned Jim was that no provision had been made to protect the confidentiality of the study participants. Their names were to be recorded.  I cannot recall if the proposed study was a CDC study or one originating with the Health Department.

Jim told me that the study was to be submitted for review by New York  City’s Institutional Review Board (IRB) although it was not called an IRB.  I suppose he must have had little confidence that the IRB, which is a body regulated by the FDA and intended to protect human research subjects, would address the confidentiality issue. In view of what transpired he was probably correct.

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

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

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

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

Jim Monroe’s concern to protect individuals with AIDS started this train of events.

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

Carol and Ron’s interest did not stop.  I think it was Ron Bayer who proposed that a meeting be held on the issue of confidentiality.  This meeting in fact did occur and resulted in the publication of guidelines for confidentiality in research on AIDS.

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

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

The meeting proceedings were published in the Hastings Center’s own publication, IRB.

http://www.jstor.org/pss/3564421

I believe my memory is correct in recalling that an established medical journal declined to publish the guidelines.

I was editor of a journal devoted to AIDS called AIDS Research and had absolutely no hesitation in publishing the guidelines myself. Some pages are reproduced here.

img0822

img083

img084

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

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

As part of my research effort I had become associated with David Purtilo, Chairman of the Pathology and Microbiology Departments at the University of Nebraska’s medical school in Omaha. The reason for this was that David was an expert on the Epstein Barr virus, and I believed that this common herpes virus can play a significant role in the pathogenesis of HIV disease[i].

David’s wife, Ruth Purtilo is a bioethicist. She clearly saw how important confidentiality protection was in research on AIDS. She obtained the perspective of Michael Callen, a patient of mine who was HIV infected. Together we wrote a paper on this issue in 1983.

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

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

Purtilo-R, Sonnabend-J, Purtilo-D-T.[ii]

Unfortunate developments today have made the need for respecting confidentiality as important as was the case when the epidemic began.  Differently worded legislation now exists where criminal law is applied to people who transmit HIV to others, or even who expose others to the risk of transmission. There is absolutely no evidence that such criminalization prevents the spread of this disease.  The following link will provide useful sources of information.

http://data.unaids.org/pub/BaseDocument/2008/20080731_jc1513_policy_criminalization_en.pdf

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

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

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

Even then, in the late 1990s, the problem of when it is best to start antiviral therapy was of concern – indeed it had been of concern ever since the introduction of AZT.  We then believed – as many still do today, that the question is most reliably approached by a randomized prospective study.  Most certainly not by the opinions and recommendations of experts, not all of whom could properly be considered qualified to hold that rank.

We thought that those entities that pay for the drugs might be the appropriate sponsors of prospective clinical trials.  They have a clear interest in knowing if it is beneficial or not to start treatment early rather than to defer it, or whether it makes no difference.

It is in their interests; if early treatment provides no benefit – (at least one large retrospective study suggests that there is no benefit to starting treatment above a CD4 count of 400) then paying for an early start to treatment would be pointless. On the other hand if early treatment produced some benefit then the cost would certainly be justified.

Among the entities covering the cost of drugs are government agencies such as Medicare and the VA.   The VA has a history of undertaking studies.  There are also the private insurance companies.

Jim together with a Public health expert at Emory University was attempting to present a proposal to the medical directors of private insurance companies. We had the support of an eminent statistician who had also been involved with me on an earlier unsuccessful attempt to set up a study to compare early and deferred treatment with AZT.

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

One Friday afternoon while seeing patients in a clinic in New York City,  I received a call from a friend of Jim’s in Atlanta. She told me that Jim was severely ill in Chicago. He had collapsed a few days earlier.  On Saturday I travelled to Chicago and found Jim unconscious in a hospital. He was not to recover.

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

Jim’s final project, cut short by his death, is still absolutely relevant.

Some recent suggestions, based on the flimsiest of evidence propose that treatment with antivirals should be started even earlier than the current recommendations.  There are well meaning physicians today who already buy into this nonsense, who state that they would treat all infected people, irrespective of CD4 count. Or they would raise the CD4 threshold above 350, which is the currently recommended level at which to initiate treatment, even in the absence of reliable evidence that their patients will benefit.

It cannot be reliably known from any evidence we  have at present whether such prolonged exposure to  antiviral drugs will increase or decrease survival or be without effect in this respect – of course except for cost.

We do need to really know when it is best to start treatment.  Prospective randomized studies can provide an answer to the question if, on average it is better to start treatment early or to defer it.

Hopefully others will take on Jim’s last project and write a proposal to some of the entities who pay for the drugs, to sponsor  prospective studies,  the only reliable way to answer this question.

Are they wasting money? Are they getting their money’s worth?

Surely the payors, will want to know.


[i] I still believe this to be true,  as further evidence continues to support this idea.  Our work on EBV and HIV was quite productive and will be the topic of another post.

[ii] We were awarded a prize for this article: The Nellie Westerman  Prize for Research in Ethics awarded by the America Federation For Clinical Research.