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AIDS pathogenesis: HIV disease and Positive feedback: An additional comment.

August 31, 2010 Leave a comment

 

This blog more or less duplicates that at the aidsperspective.net site, explained in the “about” page above.

HIV Disease and Positive Feedback.  An additional comment.

AUGUST 31ST 2010

A previous post focussed on the positive feedback interaction between HIV replication and immune activation.   HIV replication and immune activation reciprocally enhance each other.

While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it.   In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation.   As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.

Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.

Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients.  We even knew then that interferon alpha and gamma could  induce an enzyme, indole 2,3-dioxygenase  (IDO),  (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of  tryptophan  in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes.   Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.

Since immune activation and its effects, including  inflammation, are harmful if sustained,   there are mechanisms that can  dampen it.

But in HIV disease, immune activation persists with continued deleterious consequences.

The reason I’m revisiting this now is that there is a question that continues to be bothersome.

HIV disease is not the only infection associated with long standing immune activation.

Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation.   In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease.  While individuals with active pulmonary  TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.

Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?

Could the  mechanisms that dampen and check  immune activation be impaired in HIV disease?   These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and  TGF-beta, among others.  Specialized immune system cells can also dampen immune activation.  Tregs, a subset of T lymphocytes, have such a dampening effect.   Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of  these particular T lymphocytes.

This graphic comes from my earlier post on positive feedback characteristics of HIV disease.

In this diagram HIV pathogenesis is represented by a circular process moving in a clockwise direction.  It is started by HIV infection and can be propelled by a positive feedback association  between HIV replication with immune activation.      Immune activation is reinforced by CMV, and in certain settings, by some endemic infections.  This is represented by the + sign in the diagram.      Immune activation is retarded by those influences that dampen the immune response, including anti-inflammatory cytokines and Tregs, represented by the – sign in the diagram.

Here is a revised version of this diagram:

HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses.  Tregs  act as brakes, but HIV can directly make the brakes less effective.

Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be  the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?

I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.

In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it.  Some predictions can be made.

The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression.  The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent  rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case.  There already is  some evidence in support of this possibility.

It’s well established that HIV disease progresses more rapidly with increasing age.  Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation  contributes to the aging process.

HIV disease progresses more rapidly in individuals with active TB.  CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic.  There are but two  examples, but there are many more of  of a more rapid course of HIV disease in the setting of other  infections caused by bacteria, protozoa, viruses and helminthes.  Some are referred to in a previous post.

Are Treg numbers at seroconversion and for a period immediately afterwards  related to subsequent disease progression?

Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?

There already  is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.

The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.

Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection,  provides a useful descriptive framework as well as testable predictions.

We need reliable evidence to justify an earlier start of anti-retroviral therapy. May, 2009


The most recent revision of the US Department of Health and Human Services (DHHS) guidelines for the treatment of HIV/AIDS recommended initiation of anti-retroviral treatment at a CD4 count of 500.

This recommendation was made in the absence of evidence from a prospective randomized clinical trial.   Instead, evidence of inferior quality was relied on.

Much is at stake for HIV infected individuals.  The point in the course of HIV infection when treatment is initiated can affect the duration and quality of life.

Rather than issuing interim guidelines pending the completion of a prospective randomized trial the guidelines committee has jumped the gun, relying on evidence of inferior quality.

In the following article, John Falkenberg reminds us of the harm that has resulted from basing recommendations on observational cohort studies.

—————————————————————————————

John Falkenberg  New York, NY

Doctors and patients always have the right to choose treatment that is not based on data generated from well-designed clinical trials.  However, I worry when treatment guidelines are based on cohort studies or anecdote, and it’s alarming when the city of San Francisco and Project Inform endorse that practice.

No study is cited more often than NA-ACCORD, an observational cohort study, to support early antiretroviral therapy.  Besides the many historical examples of harm caused by treatment guidelines based on observational studies (see the Nurses’ Health Study, below), NA-ACCORD suffers from more than the self selection bias of observational studies:  a large percentage of the deferred treatment group, approximately 45%, did not initiate therapy and/or did not have a decline in CD4 counts.  How can those findings be extrapolated to clinical practice?  In addition, the early treatment group may have had incomparable medical care.  For example, were lipids more carefully monitored in that group resulting in more aggressive use of statins, a class of drug with pleiotropic effects that include improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response.  These drugs have demonstrated morbidity and mortality benefits in clinical settings where lipid levels are normal.

The history of HIV treatment guidelines is an excellent reminder of the risk of formulating guidelines based on observational studies and anecdotal evidence.  However, HIV is not the best example.  There are clinical settings where “more compelling” cohort data using medications considered relatively safe served as the basis for treatment guidelines that ultimately were proven wrong at a significant cost.

I think the best example pertains to the use of hormone replacement therapy (HRT) in postmenopausal women.  There were many anecdotal, observational and retrospective reports of the many benefits of HRT, but the Nurses’ Health Study was the flagship.  The Nurses Heath Study was a case control, observational study of over 120,000 nurses, including over 20,000 who were post menopausal.  As the follow up continued for years, an increasing number of women reached menopause, and various health variables were monitored and reported.  The most striking “conclusion” of this study was that the relative risk of death was 0.63 in HRT users vs. non users.  The risk of major coronary artery disease among HRT users was 0.60 when compared to those who never used HRT.  Both of these findings were statistically significant.  These data were broadly reported in medical journals, and professional meetings.  The data were added to the HRT prescribing information and aggressively promoted by the pharmaceutical industry, particularly the manufacturer of Premarin (American Home Products, renamed Wyeth, recently acquired by Pfizer), the most widely prescribed HRT.

There was huge resistance to conducting a prospective randomized controlled trial in this population.  “It denies the placebo-controlled group the protective heart benefits of HRT.”  “It is unethical to randomize people who would clearly benefit from HRT to placebo.”  “No one would enroll in this trial considering what we already know about the benefits of HRT in this population.”  Despite the criticism, the Women’s Health Initiative, a prospective randomized controlled study of HRT in postmenopausal women was conducted.  In July 2002 the study was halted early due to a statistically significant excess risk of heart attack, stroke and breast cancer in those receiving HRT versus those on placebo; a finding that literally rocked the world of HRT.

More recently, long-term treatment recommendations in diabetes were debunked by results from the first well designed, randomized controlled study (coincidently named ACCORD), with cardiovascular clinical endpoints.  Using multiple medications for intensive glucose lowering and intensive blood pressure reduction did not reduce cardiovascular events but only increased adverse events.  Once again, guidelines formulated without data derived from controlled clinical trials did more harm than good.

There is a lot at stake here and I fear that this is déjà vu all over again.  The NA-ACCORD results are compelling and generate a hypothesis that needs to be tested, but the clinical trial has yet to be performed and the evidence is absent.  I find it difficult to understand why those of us who have lived during decades of this epidemic, who have seen those living with HIV experience a wide range in the rate of disease progression, and who have seen the rise and fall of early antiretroviral therapy, do not demand more.  I’m shocked by both the city of San Francisco and Project Inform.

I cannot claim to know the motivation behind the current push for early treatment without evidence.  However, I do know the pressure felt by the pharmaceutical industry as they approach a patent cliff with little in the advanced research pipeline and significant overcapacity.  It is not coincidental that lobbying efforts have been stepped up in an economic climate where value driven medicine is a new priority.  That lobbying includes an aggressive push to eliminate informed consent for HIV testing and a push for early treatment.  And, here we are with major public health agencies and CBO’s jumping on the bandwagon without the evidence

USPHS guidelines:We need reliable evidence to justify an earlier start of anti-retroviral therapy.


The most recent revision of the US Department of Health and Human Services (DHHS) guidelines for the treatment of HIV/AIDS recommended initiation of anti-retroviral treatment at a CD4 count of 500.

This recommendation was made in the absence of evidence from a prospective randomized clinical trial.   Instead, evidence of inferior quality was relied on.

Much is at stake for HIV infected individuals.  The point in the course of HIV infection when treatment is initiated can affect the duration and quality of life.

Rather than issuing interim guidelines pending the completion of a prospective randomized trial the guidelines committee has jumped the gun, relying on evidence of inferior quality.

In the following article, John Falkenberg reminds us of the harm that has resulted from basing recommendations on observational cohort studies.

—————————————————————————————

John Falkenberg  New York, NY

Doctors and patients always have the right to choose treatment that is not based on data generated from well-designed clinical trials.  However, I worry when treatment guidelines are based on cohort studies or anecdote, and it’s alarming when the city of San Francisco and Project Inform endorse that practice.

No study is cited more often than NA-ACCORD, an observational cohort study, to support early antiretroviral therapy.  Besides the many historical examples of harm caused by treatment guidelines based on observational studies (see the Nurses’ Health Study, below), NA-ACCORD suffers from more than the self selection bias of observational studies:  a large percentage of the deferred treatment group, approximately 45%, did not initiate therapy and/or did not have a decline in CD4 counts.  How can those findings be extrapolated to clinical practice?  In addition, the early treatment group may have had incomparable medical care.  For example, were lipids more carefully monitored in that group resulting in more aggressive use of statins, a class of drug with pleiotropic effects that include improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response.  These drugs have demonstrated morbidity and mortality benefits in clinical settings where lipid levels are normal.

The history of HIV treatment guidelines is an excellent reminder of the risk of formulating guidelines based on observational studies and anecdotal evidence.  However, HIV is not the best example.  There are clinical settings where “more compelling” cohort data using medications considered relatively safe served as the basis for treatment guidelines that ultimately were proven wrong at a significant cost.

I think the best example pertains to the use of hormone replacement therapy (HRT) in postmenopausal women.  There were many anecdotal, observational and retrospective reports of the many benefits of HRT, but the Nurses’ Health Study was the flagship.  The Nurses Heath Study was a case control, observational study of over 120,000 nurses, including over 20,000 who were post menopausal.  As the follow up continued for years, an increasing number of women reached menopause, and various health variables were monitored and reported.  The most striking “conclusion” of this study was that the relative risk of death was 0.63 in HRT users vs. non users.  The risk of major coronary artery disease among HRT users was 0.60 when compared to those who never used HRT.  Both of these findings were statistically significant.  These data were broadly reported in medical journals, and professional meetings.  The data were added to the HRT prescribing information and aggressively promoted by the pharmaceutical industry, particularly the manufacturer of Premarin (American Home Products, renamed Wyeth, recently acquired by Pfizer), the most widely prescribed HRT.

There was huge resistance to conducting a prospective randomized controlled trial in this population.  “It denies the placebo-controlled group the protective heart benefits of HRT.”  “It is unethical to randomize people who would clearly benefit from HRT to placebo.”  “No one would enroll in this trial considering what we already know about the benefits of HRT in this population.”  Despite the criticism, the Women’s Health Initiative, a prospective randomized controlled study of HRT in postmenopausal women was conducted.  In July 2002 the study was halted early due to a statistically significant excess risk of heart attack, stroke and breast cancer in those receiving HRT versus those on placebo; a finding that literally rocked the world of HRT.

More recently, long-term treatment recommendations in diabetes were debunked by results from the first well designed, randomized controlled study (coincidently named ACCORD), with cardiovascular clinical endpoints.  Using multiple medications for intensive glucose lowering and intensive blood pressure reduction did not reduce cardiovascular events but only increased adverse events.  Once again, guidelines formulated without data derived from controlled clinical trials did more harm than good.

There is a lot at stake here and I fear that this is déjà vu all over again.  The NA-ACCORD results are compelling and generate a hypothesis that needs to be tested, but the clinical trial has yet to be performed and the evidence is absent.  I find it difficult to understand why those of us who have lived during decades of this epidemic, who have seen those living with HIV experience a wide range in the rate of disease progression, and who have seen the rise and fall of early antiretroviral therapy, do not demand more.  I’m shocked by both the city of San Francisco and Project Inform.

I cannot claim to know the motivation behind the current push for early treatment without evidence.  However, I do know the pressure felt by the pharmaceutical industry as they approach a patent cliff with little in the advanced research pipeline and significant overcapacity.  It is not coincidental that lobbying efforts have been stepped up in an economic climate where value driven medicine is a new priority.  That lobbying includes an aggressive push to eliminate informed consent for HIV testing and a push for early treatment.  And, here we are with major public health agencies and CBO’s jumping on the bandwagon without the evidence

Treatment of HIV/AIDS. The revised USPHS guidelines. May, 2010


The revised USPHS guidelines for the treatment of HIV/AIDS

Guidelines for the treatment of HIV/AIDS were first issued by the US Department of Health and Human Services (DHHS) in 1998. They have undergone numerous revisions since then; the most recent was in December 2009.

The first guidelines were issued shortly after potent antiviral medications became available.  We knew very little about how best to use these drugs at that time, and with only a few years experience our knowledge of their adverse effects was understandably limited.

Perhaps the only reliable information we then had was that individuals with fewer than 200 CD4 lymphocytes received a life saving benefit from their use.

Despite such limited information the panel that had been convened to write the guidelines made firm recommendations for the use of antiviral drugs in groups of patients for whom evidence of a net benefit was lacking.

Even in the absence of experience with the newer antiviral agents, at least two probable problems associated with their use could have been anticipated in 1997.   The propensity of just about any microorganism to develop resistance to antimicrobial agents was no mystery.  Nor was it a surprise  that adverse reactions to new drugs appeared as they were used for longer periods.

As might have been anticipated  healthier HIV infected individuals  have not infrequently had to deal with  both of these problems.

Why then did the first HIV/AIDS treatment guidelines panel not propose and encourage the conduct of a randomized prospective clinical trial to answer the question of whether immediate or deferred treatment with antiviral drugs could or could not prolong life and improve its quality or made no difference apart from cost?

Since the problems that were to arise  could have been anticipated, if not their extent,  the guidelines committee must have accepted that whatever evidence existed was sufficient to reassure them that there would be a net benefit to starting treatment at 500 CD4 lymphocytes.

The most recent revision of the DHHS guidelines now propose, as the first guidelines did, that treatment be initiated at a CD4 count of 500.   A prospective randomized trial that directly addresses the question of when treatment is best initiated has yet to be completed.  In the absence of information from such a trial the committee has relied on evidence from some large retrospective observational studies.

In the next post John Falkenberg writes about some previous experiences where advice based on results of retrospective analyses of observational data had to be reversed when the results of randomized controlled studies became available.

I believe the biggest mistake made in 1997 by the guidelines committee was in not responding to the very real  possibilities of dangers associated with early treatment initiation  by encouraging the completion of a prospective randomized trial, such as START, that could by now have reliably provided an answer to the question of whether immediate or deferred treatment is better or worse or makes no difference that is, apart from cost.

It’s not the benefits of early treatment that are in question. Of course there are benefits, but the question we need an answer to is when in the course of HIV disease the benefits of treatment outweigh the risks.

Long term exposure to antiretroviral drugs can  have harmful effects.  It can take many years to recognize some of these adverse effects. For example we learned only in the last few months that under certain circumstances neurocognitive function improved in some people who stopped antiviral drugs (ACTG 5170).

So the challenge is to find out how best to use the drugs.  Put another way, we must find ways to safely minimize exposure to the drugs, which until we have drugs without significant adverse effects, is what determining the optimal time to start treatment is all about.  We don’t know if a person deferring treatment until a CD4 count of 350 will or will not live longer with an overall better or worse quality of life than someone starting at 800 or even 500 CD4s.

We do know that at 350 CD4s, benefits of treatment far outweigh risks.   But no matter what NIH guidelines committee members may feel, we do not yet have the most reliable evidence that benefits of treatment will outweigh risks when starting at higher numbers.

The wording of the USPHS guidelines is such that depending on whose vote one goes with, I suppose  might even be interpreted  to mean a recommendation for every HIV positive individual to receive treatment irrespective of CD4 count.

A letter written to the DHHS panel in 1997 suggesting that a randomized prospective trial be encouraged to provide guidance for individuals with greater than 200 CD4 lymphocytes remained unanswered although received.

Sadly the repeated changes to the guidelines since their first appearance in 1998 appear to indicate a retreat from evidence-based recommendations.  Maybe this should be stated as a retreat from attempting to find the most reliable evidence on which to base recommendations.  The guidelines panel go to great lengths to reassure us that their recommendations are indeed evidence based.

But as they recognize, the quality of evidence can vary. They also recognize that evidence of the highest quality is derived from the results of prospective randomized trials.   Yet not only do they not vigorously encourage the completion of such trials, their recommendations actually inhibit enrolment into START which is such a trial.

Unfortunately the DHHS recommendations while not binding have a huge influence.  Remarkably they are even regarded by some  as setting an ethical standard, so that fears have been expressed that enrolment into START  might be considered unethical as the current guidelines revision recommend starting treatment at 500 CD 4 lymphocytes.

Thirteen years after the first guidelines were issued, the DHHS panel has now made revisions that continues to threaten enrolment into a randomized controlled trial that will provide clear guidance to HIV positive individuals and their doctors about when to initiate antiviral therapy.

Surely, when we recognize that reliable evidence is lacking to inform a  very important clinical decision, is it not our obligation to seek the evidence, rather than settle for the  uncertainties  associated with evidence of inferior quality?  This is not only for the benefit of our patients but also to affirm that our stated respect for evidence-based recommendations is more than lip service.

At this time the DHHS guidelines are the only ones that recommend a start to treatment at 500 CD4 lymphocytes.

The DHHS guidelines have been of benefit to people with HIV/AIDS.  But on the issue of when to start antiviral therapy they have not best served the interests of HIV positive individuals.

We need a randomized controlled trial to answer this question, not the votes of a committee.

I believe that many health care providers would welcome the opportunity to be   able to present an option to their patients with greater than 350 CD4s, to enrol in a study such as START.

At the end of the day, determining when it’s best to start is not something you vote on. It’s something so important that you nail it down with a trial such as START.

AIDS Pathogenesis: HIV disease has characteristics of positive feedback systems

April 2, 2010 Leave a comment

2nd April,  2010

There is a similar and slightly extended version of this post on the blog I have on the POZ website. It’s in two parts:

Part 1

Part 2

HIV infection and many other infections caused by a wide variety of microorganisms have a mutually enhancing relationship that is characteristic of positive feedback systems.

Although the reciprocal enhancing effects of HIV and other infections have been frequently described since the late 1980s, it is useful to explicitly recognize these as positive feedback systems as this highlights the implications they have for treatment of individuals and for control of the epidemic.  Explicitly recognizing the positive feedback characteristic of HIV disease also provides a way of looking at pathogenesis that can suggest further studies, both clinical and laboratory, that might advance our understanding of mechanisms of disease acquisition.

This is an illustration of positive feedback.    A stimulates B which in turn stimulates A. In this way the effects of A and B are increased.

The infections associated with the immunological disorders of HIV disease are generally, but not solely, caused by microorganisms that replicate within cells.     Many of the organisms that cause these infections survive in healthy people without causing disease, prevented from doing so by a competent immune system.   When the immune system fails these infectious agents start to divide.   They may then cause disease.  An additional effect of some of these active infections is to accelerate the replication of HIV.  Several mechanisms are responsible for this effect, which can then result in further immunological deterioration.

In addition, co-infection with many of the pathogens that also affect individuals with intact immune systems can also promote HIV replication.

Not all co- infections result in a more rapid progression of HIV disease.  Many have no effect and a few have even been reported to cause a temporary improvement of HIV disease.    This may be the case with measles, scrub typhus and a form of transfusion associated hepatitis.   But more often, when an effect of a co-infection has been noted, it has been to promote HIV disease progression.

Different co-infections can therefore affect the course of HIV disease in different ways.  Some may have no impact on the course of HIV disease; a few may possibly cause a temporary amelioration.   Those that are able to accelerate it are highly prevalent in HIV infected individuals.

Worldwide, viruses of the herpes family are probably the most important of the co-infections that interact with HIV in a mutually enhancing fashion. .    Virtually all adults are infected with some of these viruses that usually exist in a latent or dormant state.  They are readily activated in the setting of HIV infection and then promote further HIV replication by a number of different mechanisms.

In developing nations a range of different endemic infections, depending on geography, may be just as important; many can also accelerate HIV disease progression.  Conversely, HIV infection can promote progression of some  endemic infections.

Several different mechanisms have been uncovered that can explain the effects of co-infections on promoting HIV replication.    With such a wide range of infections, the precise ways in which each do this will vary in detail.

However there is one characteristic possessed by all HIV potentiating infections.  This is their ability to add to the immune activation that is a feature of progressive HIV disease.

By now I think it is generally accepted that chronic immune activation not only results from HIV infection but is a major contributor to the pathogenesis of HIV disease.   A state of sustained high level immune activation is the basis of the chronic inflammation and immunologic deterioration characteristic of progressive   HIV disease.

But what exactly is immune activation?

Immune activation refers to those changes that take place in the immune system when exposed to an infectious agent that allow it to eliminate or control the infection.  Essentially, the immune system is activated from a resting state to fight an infection.   Generally this process will last for days until the infection is overcome, and usually but not always, is followed by a lifelong immunity to the infectious agent.

However in progressive HIV disease the immune system continues to be activated at a high level and it is this sustained immune activation that eventually results in disease.   An activated state of the immune system is characterized by differentiation of precursor immune system cells.  Differentiation is the process by which these cells develop specialized functions.   Examples of cells that have acquired specialized functions are those that produce specific antibodies, or those with the ability to kill other cells infected with specific microorganisms.   Proliferation of immune system cells is an important characteristic of an activated state.  This is usually a short-term response subsiding with control of the infection that stimulated it.  But in progressive HIV disease, proliferation is sustained, probably with episodic cycles of further accelerations, and this continued proliferation contributes to the loss of immune system cells.

These cellular changes, differentiation and proliferation, are associated with the secretion of a variety of cytokines.  Cytokines are molecules that can change the behaviour of cells by binding to specific receptors on their surfaces, for example, causing them to divide.  Once released, cytokines not only attach to receptors on other cells but can also come back and attach to the receptors on the cell that produced it.

The cytokines that are released   have widespread effects.  Importantly, they include those that are associated with inflammatory changes, – the pro-inflammatory cytokines.    With respect to positive feedback, pro-inflammatory cytokines including IL-6 and TNF alpha are able to accelerate HIV replication.

A part of the immune system, the innate immune system, responds immediately to infection by recognizing molecular patterns common to different organisms.  The more familiar adaptive immune system responds to specific characteristics unique to each organism.

The innate immune system is also activated in untreated HIV infection.   Interestingly effects of activation of innate immunity were recognized very early in the epidemic, even before HIV was discovered, and so are among the earliest recognized AIDS related immunological abnormalities.  Activated innate immunity is responsible for the large amounts of alpha interferon in the circulation of people with untreated HIV/AIDS, first noted in 1981, the year this disease first came to our attention[i].   At that time the origin of this endogenous interferon was not known.   For a period, elevated levels of beta 2- microglobulin were regarded as an adverse prognostic marker.  This molecule can be regarded as a surrogate marker for interferon.   The association of interferon with abnormalities characteristic of this disease – including low CD4 numbers was also reported in the first 2-3 years of the epidemic[ii].   Over twenty years later mechanisms have been discovered that can explain the participation of interferon in the disease process[iii].

Interferon appearing in the circulation in untreated HIV disease may even be the first marker of immune activation noted, although not recognized as such when first observed

The changes that occur on activation of the immune system are associated with many other markers that can be measured.    Different molecules appear on the surface of activated cells.  These can be detected and measured, as can the cytokines associated with immune activation.

These measurements can tell us the extent of immune activation.   Importantly, the degree of immune activation parallels the rate of HIV disease progression.

Although it is now accepted that the consequences of continued activation and proliferation of immune system cells contribute to the loss of CD4 cells and the development of disease, the precise way it does so is not yet known, although there  are a number of different mechanisms  that could account for it.  The   associated inflammation also has adverse effects beyond the immune system.   For more detailed information on these mechanisms there are references to two reviews at the end of this article[iv].

Sustained immune activation is therefore at the heart of HIV/AIDS pathogenesis.   It is the sustained nature of the activated state that is critical.  Short lived states of immune activation are of course beneficial allowing us to recover from infections.  But in progressive HIV disease the process continues at variable rates.   Understanding what causes continued immune activation is central to an understanding of the pathogenesis of HIV disease.

What causes Immune activation?

While infection with HIV may start the process, other causes of immune activation are almost certainly also necessary to keep it going.

The following all contribute:

1:            The immune response to HIV itself.   This includes both innate and adaptive immune responses.  As noted above, adaptive responses are the familiar specific antibody and cell mediated responses that provide generally lifelong immunity to specific infectious agents.  Innate responses depend on recognition of molecular patterns common to several organisms.

Some suggest that HIV contributes directly to immune activation through binding of some of its proteins to immune system cells.

2:            Microbial products that can penetrate into the intestinal wall as a result of damage caused by HIV.  These microbial products then activate immune system cells.

3:            Other infections.

Some like active herpesvirus infections or the more traditional opportunistic infections can be seen as indirect effects of HIV infection.

Others are infections that can cause disease in people with intact immune systems like the endemic infections in developing nations. Some of these can be more severe in the setting of HIV infection.

Infections that can accelerate HIV replication include those caused by bacteria, viruses, protozoa and helminths.

Those that promote HIV disease progression can  usefully be  described in three categories.

A:            Herpes virus infections.   These are probably the most important worldwide.  Virtually 100% of adults are infected with some of them.     They represent infections that are more often latent, but are  readily activated  in HIV infected individuals.

B:            Endemic infections caused by a variety of different microorganisms than promote HIV disease progression and HIV replication.   These are important in developing nations.

C:            Other infections.  These include the opportunistic infections, as well as those that can affect people with intact immune systems.  TB may be the most important.  HIV infected individuals are much more susceptible to active TB infections than those who are HIV uninfected.  HIV transcriptional activity and viral loads have been noted to be higher in people with active TB.

Here is a little more detail about these three classes of infection:

A:  Herpesviruses.

There are eight members of the herpesvirus family that can infect humans.   Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are perhaps the most familiar.  Cytomegalovirus (CMV) and the Epstein-Barr virus (EBV) infect close to 100% of adults.   Varicella-Zoster virus (VZV) causes chicken pox on initial infection and shingles when reactivated. Of the three remaining human herpes viruses HHV-6, HHV-7, and HHV-8, the last is associated with Kaposi’s sarcoma.

With all of the herpes viruses, once infected, individuals carry them for the rest of their lives, usually in a dormant or inactive state.  All can be periodically reactivated with or without symptoms.

Humans and herpes viruses have co-existed for evolutionary periods and are well adapted to each other.   The immune system generally maintains these viruses in a latent sate so that they cause no harm.  Reactivation does occur periodically but is generally limited.  Virtually 100% of adults will carry some viruses of the herpesvirus family, usually in a dormant or latent state.

The impaired immunity characteristic of HIV disease however results in reactivation of herpes virus infections. In progressive HIV disease these viruses become active and through a variety of mechanisms, including their contribution to immune activation, promote the replication of HIV.    Cytomegalovirus (CMV) may be the most important of the herpesviruses that promote HIV disease progression.  It can be part of a positive feedback system in its interactions with HIV.

HIV → latent herpes infections  →active herpes infections → HIV

It is not only through their contributions to immune activation that herpes viruses promote HIV replication.   In addition to the pro-inflammatory cytokines that have this effect, herpes virus gene products can directly activate HIV if a cell is infected with both viruses.  This process, called transactivation works both ways; HIV can also activate herpes viruses.

In addition herpes infections cause a receptor (Fc) to appear on cell surfaces that allows HIV to enter it.  In this way cells that do not possess CD4 molecules can become infected with HIV.   Active CMV infections can also exert a mildly immunosuppressive effect.

Herpesviruses, particularly CMV are singled out because they probably play a significant role in the pathogenesis of HIV disease.  CMV infections are so common that it is hard to find HIV infected individuals who are free from it so that they can be compared to those who are not.   But as early as 1991 this was done with HIV infected haemophiliac patients, when it was noted that those also infected with CMV had a much more rapid progression of their HIV disease[v].

That CMV may play a role was suggested by many very early in the epidemic.  A multifactorial model for the development of this disease published in 1983 before HIV was discovered suggested a major role for CMV and EBV[vi].    The considerable evidence for a role for herpesviruses, particularly for CMV, did not disappear with the discovery of HIV.   The interactions of CMV and other herpes viruses with HIV that have been discovered may now explain their role.

Large studies on the effects of acyclovir on the course of HIV infection have provided compelling evidence that active infection with these viruses can be regarded as part of the disease process for most HIV infected individuals.    Investigators focussed on HSV-2 undoubtedly because it is the most common cause of genital ulcers.   The dose of acyclovir used would also have suppressed  HSV-1, which is even more prevalent than HSV-2 and may be more sensitive to acyclovir.  HIV viral loads and the rate of HIV disease progression were reduced in individuals receiving acyclovir compared to those receiving placebo.  Although genital ulcer recurrences were suppressed by acyclovir, the drug had no effect on the transmission of HIV.

The effects of acyclovir on HIV probably resulted from suppression of active herpes infection.  This is entirely consistent with a model that places HIV and herpesviruses in a positive feedback relationship.

EBV and CMV are much more resistant to acyclovir than HSV-1 and 2.   But it cannot be excluded that this drug did not have some effect in also diminishing reactivations of CMV and EBV.   If samples from the trial have been stored appropriately, this can be looked at.  EBV reactivation patterns are easily recognized, CMV virus isolation is possible and even detection and quantification of activated T lymphocytes would tell us something.

B:  Endemic infections:

These are singled out because of their high prevalence in some parts of the developing world.

These infections affect significant proportions of the population, they tend to be chronic and persist in the absence of treatment.    The specific infections will depend on geography and many are transmitted by insects.   Many of these can also accelerate   HIV disease progression, and some also progress more rapidly in the setting of HIV infection[vii].

C:   Other infections:

On an individual level, some episodic infections can promote HIV replication.   An acute febrile illness may increase HIV viral loads, but this is a transient effect lasting for the duration of the infection.

Most of the serious opportunistic infections occur late in the course of HIV disease, and may promote even further disease progression.

TB deserves special consideration because of its high prevalence in HIV infection.  Susceptibility to TB is increased even at higher CD4 levels. Active TB can then promote further HIV replication thus becoming a partner with HIV in a positive feedback interaction[viii].

A role for immune activation in a positive feedback system:

One way to look at the process of disease acquisition in HIV infection assigns a central role to immune activation.

Immune activation not only results from HIV infection, it can also promote further replication of HIV.

HIV replicates more efficiently in activated immune system cells.  Secondly, the pro-inflammatory cytokines that are associated with an activated immune system   can directly stimulate HIV replication.   Progressive HIV disease and immune activation are therefore components of a positive feedback system in this way.

HIV disease → Immune activation → HIV disease → Immune activation

The process starts with HIV infection, and is promoted by other infections , some of which are activated by HIV infection.

Whatever is driving immune activation is driving HIV disease.

The following diagram illustrates this.

Looking at the course of HIV infection in this way has a number of implications.

Pathogenesis.

In the above diagram the course of HIV disease is represented by a self perpetuating cycle proceeding in a clockwise direction.   In addition to the elements that have positive effects in driving the process, there will also be those that retard the cycle.  This is illustrated in the next diagram which focuses for simplicity on the immunological control of HIV infection and of those infections that add to immune activation.    Of course there are other mitigating factors, for example, genetic factors conferring varying degrees of resistance resulting from receptor polymorphism.

In the diagram, the connection of HIV with CMV and other herpes viruses is probably constant and indicated by a red arrow.   The connection of HIV with endemic and associated infections is indicated by a blue dotted line, because HIV infection does not increase susceptibility to all of them, nor does it accelerate the progression of all.

The positive feedback cycle starts with HIV infection.  At least some of the determinants of the rate of disease progression may be found in the conditions that exist at the time of initial infection that promote or retard the cycle.

There is evidence that the degree of immune activation at the time of seroconversion predicts future disease progression.[ix] [x] It may also be an important determinant of what is called the set point.  This is the point following initial infection with HIV, from which CD4 numbers decline.

The degree of immune activation at seroconversion thus influences the starting CD4 level; the rate of subsequent decline is influenced by the degree of immune activation  in a system where once started, conditions can exist where  immune activation increases with falling CD4 numbers, in a self perpetuating and accelerating fashion.   Whatever the outcome, it will be the balance of positive and negative influences.

In the earliest years there were reports of EBV reactivation preceding HIV seroconversion[xi].

I have not seen any follow up of this interesting report.   It at least suggests that there might even be   situations in which active herpes infections could sometimes promote seroconversion.  They certainly produce signals that can activate HIV transcription from proviral DNA.

Treatment and prevention.

The role of immune activation in driving HIV disease is generally accepted now.   There are sources of immune activation other than HIV and some of these can be controlled.

Attempts to identify and control additional sources of immune activation may be critical in the fight against HIV/AIDS.

Perhaps the most significant benefit in this respect concerns the developing world, where there are so many additional sources of immune activation. Even ascariasis, infestation with the common intestinal round worm is associated with significant immune activation.   Worldwide prevalence is estimated to be about one billion, with 173 million in sub-Saharan Africa.

Many highly prevalent endemic infections can promote HIV replication.  Controlling these are perfectly appropriate targets in the fight against HIV/AIDS, and of course this would independently improve the lives of millions of individuals.

Measures to control endemic infections include traditional public health interventions, such as the provision of sanitation and clean water and the control of insect vectors. Effective drugs are sometimes inexpensive.  Peter Hotez has written an article entitled “Africa’s 32 cent solution to AIDS”.[xii] This refers to the price of Praziquantel , effective in treating  schistosomiasis as a single dose.

The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.

Recent and ongoing studies will probably lead to the routine use of drugs that are effective against herpes virus infections.       Trials of valacyclovir to reduce HIV viral loads are in progress. Given the ubiquitous nature of herpes infections, the use of acyclovir as adjunctive therapy might be warranted even in the absence of recurrent herpetic ulcers.  Valacyclovir unfortunately is not yet available as a generic medication.

Unfortunately EBV and CMV are much more resistant to these drugs.   The development of agents less toxic than valgancyclovir is important.   Valgancyclovir has already been shown to reduce immune activation in HIV infected individuals as measured by a reduction in activated CD8 lymphocytes.

In summary it is useful to explicitly recognize the positive feedback interactions between HIV and other infections that can promote its replication, some of which are in turn promoted by HIV.    Control of the AIDS epidemic in Africa must include measures to prevent and treat multiple endemic infections that affect hundreds of millions of individuals.


[i] This is of particular interest to me as I was involved in the discovery of large amounts of interferon in the circulation of people with HIV/AIDS in 1981, the year the disease was a first described.

http://aidsperspective.net/articles/Interferon_Vilcek.pdf

https://sonnabendj.files.wordpress.com/2009/03/aids-inf-31.jpg

[ii] http://aidsperspective.net/articles/Interferon-AZT-1991.pdf Fig 1 shows CD4 counts in relation to serum interferon  . Presented 1986 at the 2nd international aids conference in Paris.

[iii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491901/

[iv] Immune activation and inflammation in HIV-1 infection:  causes and consequences.

V.Appay and D. Sauce

J.Pathol. 2008; 214: 231-241

(This is an important  review)

HIV immunopathogenesis and strategies for intervention.

M. Cadogan and A Dalgleish

Lancet Infectious diseases. 2008: 8: 675-84

[v] http://www3.interscience.wiley.com/journal/119316871/abstract?CRETRY=1&SRETRY=0

[vi] http://aidsperspective.net/articles/NYAS.pdf

[vii] Endemic infections in Africa have everything to do with HIV/AIDS:

https://sonnabendj.files.wordpress.com/2009/06/lawn21.jpg

[viii]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905977/

http://www.ncbi.nlm.nih.gov/pubmed/14551885?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=4

http://www.ncbi.nlm.nih.gov/pubmed/12416451?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=5

[ix] http://jvi.asm.org/cgi/content/full/81/16/8838?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=fig&searchid=1&FIRSTINDEX=1440&resourcetype=HWFIG

[x]

http://bloodjournal.hematologylibrary.org/cgi/content/full/104/4/942

[xi]

http://www3.interscience.wiley.com/journal/119342256/abstract?CRETRY=1&SRETRY=0

[xii] http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000430

HIV Treatment as Prevention. March 2010

March 4, 2010 Leave a comment

“Treatment as prevention” is in the news again as part of the media coverage of two conferences in California this month where claims were again made that treatment of virtually all HIV infected individuals could bring an end to the AIDS epidemic.

“Research shows that treatment could end the epidemic in thirty years” is typical of the headlines that enthusiastically announced this proposal to test and treat everybody found to be infected. Sadly, most of the reports I saw failed to comment on the huge practical difficulties that will need to be overcome to make such a project feasible. All ignored a probably insuperable ethical obstacle that will have to be confronted, which may well make the project completely unworkable. Added to these difficulties is the lack of agreement on the soundness of the mathematical model on which the proposal is based.

This initiative is also described as “treatment as prevention” although I also saw the term “seek, test and treat” used.

The prevention in “treatment as prevention” results from the reduced ability to transmit HIV that results from treatment with antiviral drugs.

It’s important to note that “treatment as prevention” can refer to two very different situations where infectivity is reduced by treatment. It describes the mathematical model, noted above that was published about a year ago in the Lancet, an influential weekly medical journal, which claims that the AIDS epidemic could be eliminated with regular tests for HIV and the immediate commencement of antiviral treatment of all who are infected. This is the title of the article: “Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model “ (Reuben Granich and colleagues. Lancet 2009 373: 7).

Antiviral therapy according to this model would be given to all infected individuals whether or not the individual needs treatment. It would include lifelong treatment of healthier HIV infected people who have not been shown to benefit from it, such as those with more intact immune systems as well as those fortunate individuals whose disease does not progress. This is the root of the ethical problem; people who themselves are not known to benefit from treatment will be asked to receive it for a societal benefit. The benefits of treatment to such individuals are conjectural but as the drugs are not free from adverse effects, the risks are real. Unlike individuals with more advanced disease where the benefits of treatment vastly outweigh the risks, this cannot be known in the case of healthier HIV infected individuals.

This is very different to the analysis of the reduction in transmission of HIV that results from treating only those HIV infected individuals known to benefit from antiviral drugs. This is also referred to as “treatment as prevention” but unfortunately in none of the reports I saw was the distinction made between treatment only of those who benefit from it and treatment of all infected individuals. These two very different meanings of “treatment as prevention” were almost always conflated by commentators which could quite easily convey a mistaken impression that all HIV infected individuals are known to benefit from treatment.

Treatment must always be voluntary. But a voluntary decision to receive treatment does not mean a great deal if it is uninformed. The decision can most certainly seen to be coerced if misinformation is supplied. HIV infected individuals must be clearly informed about the risks and benefits of the intervention. As already noted, for individuals with more advanced disease, treatment without question provides a net benefit, but this is not known to be the case for HIV infected individuals with more intact immune systems.   There are suggestions that HIV infection may be associated with morbidity resulting from inflammatory reactions.   It is far from firmly established  if this is indeed the case and if it is, whether  it is an inevitable or even common  consequence of HIV infection, or if it can be prevented or treated with antiviral drugs.   It may also prove to be true that, as claimed by some investigators,  the newer antiviral drugs are less toxic than the older ones.  But the full range of their effects, particularly their longer term effects cannot be yet known. HIV disease can manifest in so many different ways that sorting out what is a drug effect from what is an effect of the infection itself may take a long time.

For healthier HIV infected individuals, the benefits of treatment remain conjectural as long as clinical trials have not been completed that are designed to provide a reliable answer to the question of when in the course of HIV disease it is best to start treatment. Quite remarkably, about fifteen years after potent antiviral drugs became available no such trial has been completed.

If a decision about whether or not to receive treatment is fully informed, healthier HIV infected individuals faced with an intervention that is accompanied with very real risks but only conjectural benefits may well choose to remain untreated, at least at that particular time in the course of their disease. The purpose of treatment is to reduce infectivity to others, but many might feel that this can be achieved with greater safety, and even possibly with greater reliability, by the use of condoms.  It should be said though that those researchers who point out the prevention benefits of treatment do not suggest that treatment is an alternative to condoms. On the contrary they recommend that treated individuals continue to use condoms.

Since the objective of treating all infected people is to end the epidemic, this can only be achieved if a large percentage of infected people receive treatment. But faced with a consent form clearly stating what is known about risks and benefits, it is most unlikely that enough healthier HIV infected people will agree to receive treatment. This is but one reason that if a decision to start treatment is properly informed the project is unlikely to enrol enough individuals to achieve its objective. A danger is that treatment of healthier HIV infected people may be claimed to have a net benefit with greater confidence than is warranted with information we presently have.   To succeed, the project also requires a lifetime of adherence to the treatment regimen.  When drugs are taken without confidence that they are of personal benefit, we cannot know how adherence to the regimen will play out.   Failures in this respect will not only diminish the chances that the project will succeed,  they can also result in the emergence of drug resistant strains of HIV which then could limit treatment options when treatment is needed.

There evidently is a belief that all HIV infected individuals, no matter the stage of disease will benefit from treatment. But this remains just that, a belief, as long as there is no firm evidence to support it. The evidence there is that healthier HIV infected individuals would receive a net benefit from treatment is of inferior quality, and therefore remains insecure. It comes from some retrospective observational studies. In such studies medical records are analyzed to compare outcomes in individuals who started treatment earlier with those who started later. Such studies however are beset with interpretative difficulties. Because individuals were not randomly assigned to start treatment early or later, a particular outcome, say improved survival of those starting treatment early, may result from whatever the reasons were that treatment was started at a particular time.

The great benefit of randomly assigning individuals to receive one treatment or another when two are compared is the elimination of interpretative  problems that arise when one or the other course of action is chosen.

The problem of such confounding factors was also discussed in a previous post: http://aidsperspective.net/blog/?p=75

The retrospective analysis most frequently cited in support of an earlier start to antiviral therapy, the NA-ACCORD study is also discussed in that post.

HIV infected individuals and those who advise them surely deserve more reliable evidence to support a decision whether to start or defer treatment than that provided by retrospective observational studies or worse, by mere belief.

Prospective randomized trials remain the best way to achieve this. They minimize bias, and thus misinterpretation, and remain the most reliable way to resolve uncertainty. There is no getting over this. Such trials may be expensive, and last a long time, but in the end, probably more time and money is lost by repeating inconclusive and conflicting retrospective studies. Surely we need to know, and not guess when it is best to start treatment.

START is a large clinical trial designed to provide an answer to the question of whether it is best to start treatment early or to defer it.     Another casualty of the pursuit of treatment as prevention that aims to treat all infected individuals is enrolment in START which may become more difficult. Those promoting treatment of all infected individuals as prevention must evidently feel that they already know the answer to be that an early start is best. How can this belief be reconciled with a respect for evidence based medicine that many of same experts claim to have?

We should rather concentrate our efforts on providing treatment to all HIV positive individuals who are at a stage in their disease where treatment is of unquestionable benefit. The fact that treatment reduces their infectivity to others is an added powerful argument to encourage widespread testing. An additional benefit is that people who know their HIV status are more likely to take steps to prevent infection of others.

The proposal to treat every infected person as a prevention strategy can be criticized on many levels. I have focussed here on the difficulty that arises from including the treatment of individuals not known to benefit from it. This can usefully be linked to support for and encouragement of enrolment in START.

The lack of concern for the ethical problem that arises from treating people not known to benefit from it is puzzling. A headline on the front page of the UK Independent newspaper reporting on the proposal to treat all infected people states: “AIDS: is the end in sight?”  The report quotes the opinion of one scientist that “the problem is that we are using the drugs to save lives, but we are not using them to stop transmission”   This statement  is quite remarkable.   The real problem arises when we administer drugs that can have adverse effects to people for any reason other than for their benefit.   We can only ask individuals to agree to take risks for a societal benefit if we have good reasons to believe that the endeavour has a good chance of success – in this case the grandiose one of ending the epidemic.  For reasons outlined above we cannot provide any confidence that this will be so.  At any rate many may feel that their societal concerns can be more safely met by using condoms, a proven way to reduce transmission of HIV.

I also wrote about this issue for the magazine POZ about a month ago. It can be seen by following this link. http://blogs.poz.com/joseph /archives/2010/02/treatment_of_hiv_dis.html

I also commented on this issue about a year ago. http://aidsperspective.net/blog/?p=152 This post repeats several points that were made then.

HIV Prevention Education and Pre-Exposure Prophylaxis Against HIV. August 2009

August 30, 2009 Leave a comment

Since my last post on this subject I have heard a variety of different views as well as discussed the issue with several  interested individuals.

As a result I have come to see the issue somewhat differently; I suppose I could just amend my last post, but it’s better to leave it as it is and  describe the differences in how I now view PrEP efficacy trials after having heard several different descriptions of  ways in which these are seen.

I listened to presentations at two conferences during the  last few weeks.  A teleconference organized by CHAMP, a community group, and one organized by the Centers for Disease Control (CDC).  These conferences attempted to engage and inform individuals about PrEP.       As a consequence I realize that I was mistaken in stating so categorically that efficacy trials of PrEP,  unlike safety trials, could not be undertaken in human research subjects.   However I do not think that if all the ethical requirements are met, that is to provide condoms, consistent counseling and sterile injecting equipment, a generalizable result will be obtained indicating that it is an effective prevention strategy.  Of course I don’t know this, and was wrong in my view that trials of PrEP efficacy should not proceed.

The most important concern with the way the promotion of PrEP, at least as a concept, is being pursued is the neglect of encouraging  prevention education.

Prevention education remains the most important tool we actually have, as opposed to theoretical and unproven approaches.  The latter include PrEP, and the test and treat every infected person proposal.   We absolutely know that in principle prevention education, including the use of condoms can work.   It worked in curbing the increase in the epidemic among gay men in the late 1980s .

The principle is thus established, admittedly without application to those who have no control over the use of condoms by the male partner.  This group is therefore in need of prevention strategies they can control themselves, and PrEP may be the only realistic possibility.

For everyone else, the sexual transmission of HIV can be controlled by the use of condoms, even if not with 100% efficacy.  We have a powerful tool in our hands, and if there are new infections, this is certainly not an indication that it does not work well enough.   It indicates that it is an activity that receives insufficient support, or  it may well be that some of those doing it are just not very good at it.  Maybe there is little societal support for HIV prevention education, even little support from individuals at risk who could use condoms but would like not to.

Unfortunately, from what I have experienced, the several groups supporting and promoting PrEP seemed to have given little thought to prevention education in presenting this intervention to stakeholders. .  They may be diligent in the context of efficacy trials, in ensuring the availability of condoms and counselling to participants.

But what seems to be missed is this:  Unless the promotion of PrEP is accompanied by very clear advocacy of prevention education with condom use,  PrEP can be seen as an alternative to safer sex practices as now recommended.

This cannot be the intention, but from comments I have heard after the CHAMP and CDC conferences this seems to be a dangerous conclusion that some have drawn.

The explanation of the utility of PrEP must be accompanied by a strengthening of prevention education to avoid this unfortunate misinterpretation. The very promotion of the concept of PrEP in the way it has so far been done can actually be seen as an undermining of condom use.  A possible alternative to condoms is presented. One can only hope that in the absence of accompanying prevention education there will not be instances sex with available antiretroviral drugs rather than with condoms.

Prevention education is in a dismal state as it is, and we should be aware of any activity that can undermine it further, unless care is taken in how it is presented.

I have commented in other posts that in HIV medicine a one-size-fits-all approach seems to be the norm.  Admittedly it’s cheaper to deal with populations rather than individuals. A single size that fits everybody is even cheaper  than providing  small, medium or large varieties, let alone customizing the size to fit individual needs.

So in HIV medicine, treatment recommendations have been made for all infected individuals, without considering the rate of disease progression, and many other characteristics applicable to any given person.

So it is with PrEP.  Its relevance is different to different constituencies.

At one extreme, for those who have no power to control the use of a condom by their male partner, PrEP may be the only realistic possibility of avoiding infection with HIV.  PrEP to these individuals is obviously of vital importance.

In fact it is so important that it would be useful even if its efficacy, if this can be demonstrated, proves to be inferior to the consistent use of condoms.   Such individuals have no alternative.

The situation of people who are perfectly capable of consistent condom use is different.

The power of the receptive partner in this case is the power to say no. No condom, no sex.   Both partners have an effective means of preventing the sexual transmission of HIV.  There is no need for PrEP to prevent infection, except that some may welcome an additional layer of protection.

There are others whose hopes for PrEP are different.  The desire to conceive is one.

Yet others hope that PrEP will make sex without condoms safe with respect to HIV transmission.   In this case the efficacy of PrEP would have to be known to be at least equal to the consistent use of condoms (and free from toxicity and affordable).   Of course  individuals decide to take risks that involve danger to  themselves only, but full information should be available, and certainly we should take care not to disseminate material that can  mislead, even if only by implication.   We do not have full information on the efficacy of PrEP, and I can see no way of testing its efficacy without the use of condoms.   But it is here that we need to take great care not to mislead, even by implication, that PrEP is as safe as using condoms unless in the unlikely event, it is actually  proven to be so.

Even a modest degree of efficacy is better than nothing for those who are unable to avoid sex with a partner who cannot be relied on to use a condom. There actually is nothing else to protect them.

A modest degree of efficacy is insufficient for those who are well able to refuse to have sex if a condom is not used.   That’s my opinion, and I would believe that of many others, but as  always risking  harm to oneself only,  is an individual choice;  our obligation is not to mislead, and ensure  that full and accurate information is available.

So, PrEP is of undoubted importance to individuals who have no control over the use of a condom by their male partner.  Apart from the female condom, it is the insertive partner who has to use a condom.  All the receptive partner has as protection now,  is the ability to just say no.  We recognize that there are situations when this is not possible, and no practical remedy is available to change this.

Of course there are other situations when it is possible to attempt a change.  If an individual just cannot say no to a partner who cannot be relied on to use a condom because he or she is ignorant of safer sex practices this is something we must try to remedy with intensive prevention education.  This will include imparting the knowledge of the lapses in judgement that can accompany the use of drugs or alcohol.

Getting away from the one-size-fits-all approach, there probably will be some individual situations in which PrEP, even if less effective than consistent condom use may be considered.  An example noted by one commentator is when condom use may be associated with sexual dysfunction.

Prevention education with consistent condom use is the best available means we have to prevent the transmission of HIV.   Prevention education should be strengthened and care taken not to undermine it.

Where individuals have no control over the use of a condom by their male partners  we should do what we can to provide them with the means to protect themselves, and PrEP may be all we have to work on at present.

Others may look to PrEP as a means to avoid the use of condoms.  The price of failure seems to be an extraordinary high one, considering that condom use is known to be highly effective in preventing HIV transmission.

There are people who need PrEP. There are also people perfectly able to use condoms but who want PrEP.

In promoting PrEP studies we must take great care not to undermine efforts at prevention education, even by implication.  Promotion of PrEP must go hand in hand with promotion of HIV prevention education.

PrEP: Pre exposure prophylaxis to prevent HIV infection. August 2009

August 11, 2009 Leave a comment

Pre exposure prophylaxis in relation to HIV infection refers to the administration of anti HIV medications to uninfected people as a means of protecting them from becoming infected with HIV.     It is not known if this intervention will succeed in achieving its goal.   Several trials have been underway to test it for safety and efficacy, and many more are planned worldwide.

I have paid little attention to these initiatives but was prompted to do so by notices of a meeting to discuss pre exposure prophylaxis – now known as PrEP – in the coming weeks.   The wording of this notice is quite vague, but the notice suggests that it is urgent to start planning for the implementation of PrEP as the analysis of initial safety and efficacy trials are expected within the next year.

This is quite startling in its implication that PrEP actually works and presumably is safe.  The actual words of the notice are:

“Results and analyses of initial safety and efficacy trials are expected within the next year, which highlights the urgency to beginning to plan now for how PrEP might be used to maximize its public health impact”.

This is a convoluted statement, to the point of being quite unintelligible. It can be misleading in the implication that can easily be drawn from it that PrEP works. Why else begin to plan for how to use it?

I had not been aware of just how extensive the PrEP initiative has been.   To get some idea of the many trials that are underway or planned, take a look at this website:

http://www.prepwatch.org/

Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).

http://www.fhi.org/en/Topics/preexposure_prophylaxis.htm

FHI has produced a set of slides listing PrEP trials.

http://www.prepwatch.org/pdf/Meetings/Cates_TDF_slides_May.2006.pdf

Among the “research consortia” listed as involved in PrEP research are the Bill and Melinda Gates Foundation, Gilead Sciences, the Centers for Disease Control (CDC), The National Institutes of Health (NIH),  and UCSF. These trials are conducted  in many countries, including Peru, Botswana, Thailand, the US and Malawi.

Organizations listed under “community consortia” are GMHC,  AVAC, Global Campaign for Microbicides, CHAMP, and the IAS.

The websites of these organizations contain information about PrEP.

AVAC :   http://www.avac.org/

Global Campaign for Microbicides:  http://www.global-campaign.org/

CHAMP:  http://www.champnetwork.org/about

The International AIDS Society:  www.iasociety.org

All the trials use a once daily drug, tenofovir, with or without emtricitabine (FTC). Tenofovir is manufactured by Gilead in the US although I believe a generic version is produced in India.

The trials vary in design.   Some require daily tenofovir, some are used intermittently or specifically before sexual intercourse. Some use a gel formulation.

Previous trials had run into difficulties; several were stopped for different reasons.  For example a trial in Cameroon was stopped amid allegations that those who seroconverted did not receive adequate treatment.  A trial in Nigeria was stopped because of inadequate standards in laboratory testing.

A trial of PrEP among Cambodian sex workers was stopped in 2004 by the Cambodian government.  This was perhaps the most publicized of the several PrEP trials that were stopped, because several activist groups brought attention to it at the XV International AIDS Conference in Bakgkok.   Among the many reasons stated for pressure by activist groups to stop the trial were poor HIV prevention counselling, and a lack of medical services to those who seroconverted.    Act Up-Paris was active in stopping PrEP trials both in Cambodia and Cameroon, although it is reported that this organization is supportive of tenofovir trials in general.

These events are described in an article entitled “The Abandoned Trials of Pre-Exposure Prophylaxis for HIV: What Went Wrong?”  The authors are Jerome Singh and Edward Mills.  It can be seen here.

http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020234

For reasons I will describe I do believe that there is no way to design a trial of the efficacy of PrEP that can meet acceptable ethical standards.   On the other hand, it is perfectly possible to conduct trials to determine the safety of tenofovir for pre exposure prophylaxis.

So maybe an answer to Drs Singh and Mills as to what went wrong with the abandoned trials of pre exposure prophylaxis is that the question of efficacy, unlike that of safety, cannot and should not be tested on human research subjects.

Here are the reasons why this cannot be done, at least regarding the use of tenofovir to prevent sexual transmission of HIV.

No ethically designed and conducted trial can definitely prove that PrEP works.  Definite proof of course may be an unattainable goal, but even credible evidence regarding efficacy  would not be found if the trial were to be conducted in an ethical manner, simply because with the availability of condoms, and the imperative to provide counselling  that they be consistently  used,  such  a trial could not answer the question asked of it. This is essentially because the consistent use of condoms will ensure that insufficient seroconversions occur in participants receiving  placebo.

In any trial that studies the ability of a new intervention to prevent sexual  transmission of HIV, participants must receive persistent counselling about the need to use condoms.  These must be provided, with ongoing support for their continued use.  This is the ethical requirement.

Quite clearly if great care is taken to meet this requirement there will be few infections in people receiving placebo.  The investigators are presented with a conflict of interest that no amount of verbal assurance can resolve.  The conflict is that on the one hand the investigator must always be cognisant of the importance of doing all that’s possible to encourage condom use to prevent the sexual transmission of HIV infection, and on the other hand the investigator has an interest in demonstrating an effect of PrEP in preventing it.

It is only when condom use falls below a certain level that the effect of another preventative measure can be assessed.  We are obliged to do all we can to ensure that this does not happen.

The Centers for Disease Control (CDC) are sponsoring several trials of PrEP[i].  They are very sensitive to the need to provide risk reduction counselling to participants.

Here is an excerpt from material published by CDC:

“One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that individuals at risk will reduce their use of existing HIV prevention strategies. It will therefore be crucial to reinforce proven behavioral prevention strategies, both within and beyond these trials. All three trials are taking multiple steps to address this issue during the education and enrolment of trial participants and through ongoing participant counselling.

First, it is critical to ensure that participants understand that trial participation may not protect them from HIV infection—either because they may receive a placebo or because they may receive a study drug, the efficacy of which remains unproven. This and other key aspects of the trial, including the potential risks and benefits of participation, are explained to potential volunteers in the language of their choice, prior to their enrolment. To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent. Study participants are also free to withdraw from the trial at any time and for any reason”.

So there is clear recognition that there may be a falling off in the use of proven prevention approaches, importantly, the use of condoms.

Here is another excerpt:

“To assist participants in eliminating or reducing HIV risk behaviours, extensive counselling is provided at each study visit, and more often if needed. This interactive counselling has proven effective in reducing the risk of HIV and other STDs in multiple populations, including past participants of similar HIV prevention trials. Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection”.

If such counselling is effective, the prevention of sexual transmission of HIV particularly through the consistent use of condoms will make it impossible to detect an effect of PrEP.   As mentioned the investigators are presented with a conflict that it is not possible to resolve.

PrEP is an experimental approach to prevention, while consistent condom use is an established method to substantially reduce the sexual transmission of HIV.

The argument that may be presented by those who are proponents of PrEP is that condom use is not consistent, and that we need an alternative

The implication of such an argument supporting PrEP is that prevention education, essentially the use of condoms, has not been sufficiently effective.  This cannot be known to be true of prevention education in principle.

What is definitely true is that those responsible for prevention education have not been sufficiently effective.

Our efforts  should be focussed on improving prevention education and support for the consistent use of condoms,

There is so much more that can be done with persistent, culturally sensitive, highly targeted prevention education.  In order to improve our efforts at prevention education we have to first confront the fact that we may have not been too successful in this endeavour, understand why,  and absolutely not take the position that the undertaking is an impossible one.

Every new infection today represents a failure, not of prevention education as an undertaking, but a failure to provide it effectively.  The introduction of condom use among gay men in the US in the 1980s originated in this community, it was promoted and effectively advocated for by this community and proved to be effective..   In those early years there was certainly no help from the Government which was to spend enormous sums on a vacuous and ineffective untargeted campaign “ America responds to AIDS” which did absolutely  nothing to stop the advance of this disease into African American communities , although this was happening in plain sight.

What we can learn from this is that different affected communities are best able to understand the  issues specific to their communities that must be emphasized  and  promote prevention education that is most effective for each of them. Their input is therefore  absolutely vital.

The design and implementation of well funded and highly targeted prevention education has been neglected.   These initiatives need to be specifically targeted to different groups, the needs of which must be assessed,  barriers identified, continuing support provided, as well as some instrument developed to evaluate the success of the programs. .   It is an enormous challenge.

We know that gay men were able to make it work for them before the concept of risk reduction had even been articulated. It can work and this is where our efforts must be concentrated.  Not on trials of the efficacy of PrEP that are impossible to conduct in an ethical fashion.

However It is entirely possible  that PrEP may add an additional layer of safety to condom use during sexual intercourse.  This may be of  particular importance in certain circumstances such as among sex workers.  This is also the case among some women who are unable to rely on the use of a condom by their male partners.   Trials of the safety of once daily tenofovir are absolutely possible and even desirable.  Such trials would be unburdened with the ethical problems that make efficacy trials impossible to conduct.  It will be clear that the trials are to determine the safety of tenofovir when used with condoms to provide an additional level of safety.   It is true that we may never be able to firmly establish its efficacy, but if it proves to be safe, there is sufficient – if far from conclusive evidence to justify its use.

It is clear that all that has been written about concerns the sexual transmission of HIV.    For those in whom the risk of infection  is through intravenous drug use there is an entirely different set of considerations.  The only known prophylactic measure, the reliable provision of sterile injecting equipment is probably just unavailable for most, and efficacy trials are therefore not burdened with the same ethical constraints.

One cannot help but note that at least  in two initiatives, pharmacological rather than behavioural approaches to prevention are now being emphasized.  Of course PrEP to prevent  transmission of HIV is one. The other is the attempt to end the HIV epidemic by testing and treating all HIV infected people, whether or not a particular infected individual needs treatment for his or her benefit.  Both are beset with ethical problems.

The use of condoms can significantly reduce the sexual transmission of HIV.  We know this.   Therefore  our greatest efforts should be placed in improving prevention education.  It is a tremendous challenge given the cultural diversity of the populations involved, and the special difficulties experienced by some. This is particularly true where women are disempowered.

We know that untargeted efforts such as “America Responds to AIDS” do not work.  We need to understand the barriers to effective prevention education.

A denial of  the importance of sexual expression to the human experience, stigmatization of those infected, homophobia, racism, bigotry in general and the fact that unlike the use of drugs, prevention education provides no financial return,  are surely amongst them.


[i] [i]    http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm

Despite the SMART study there is a role for intermittent therapy. July, 2009

From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..

The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.

For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.

We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.

One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs.   This approach will almost definitely not be possible for all HIV infected people needing treatment.  But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.

This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061.  SMART is by far the largest study comparing continuous with intermittent therapy.  In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.

The negative effect of SMART on the study of intermittent treatment continues.   In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought.  The most favoured, and almost certainly correct explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.

For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification.  The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post.    Almost all the deaths in the study occurred at US sites, where in contrast to non-US sites multiple co-morbidities were over represented.  As seen in the table below these co morbidities included, among other conditions,  hepatitis B and C, a history of heart disease and  diabetes.  There were even significantly more smokers among those enrolled at US sites.  How can one extrapolate interpretations of observations made in such  individuals  to HIV infected  populations free from these co-morbidities?

SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where  multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C,  hypertension, and a previous  history of heart disease   Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy.   That’s all.  The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational  literature addressed to physicians.

Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times.  But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.

Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART.  The Staccato study3,  using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.

The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent.  Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group).  Although pneumonia was more frequent in the STI group.    Here is a sentence from the author’s abstract.

A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.

The finding regarding cardiovascular disease is particularly relevant.

Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study.  It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation.   There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people.  So this needs to be studied.  But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.

Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!

There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.

I was shown an invitation to physicians to a free course offered by a distinguished academic institution.   Among the descriptions of what those attending the course will learn to do is the following:

“Describe, discuss and apply the data from the SMART study on CHD  (coronary heart disease)  risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”

What is one to make of this in the light of the LOTTI observations?

This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature.   As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.

As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides.  They also characteristically had low levels of HDL cholesterol (and of total cholesterol).  I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available.  We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased.    There was, not surprisingly,  a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.

So, there may indeed be something in the connection between untreated HIV disease and heart disease.  In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease.   Increased triglycerides are an independent risk factor for coronary heart disease.  There even was a possible mechanism for this that was known in those days that could account for this.

Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted.  Such changes have been seen in people with hepatitis C treated with recombinant interferon.

So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle?   There are numerous different ways in which intermittent therapy can be structured.

The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit,  studies smaller  than SMART

Perhaps a clue is to be found in a sentence in the LOTTI study report.

Here it is:

“The mean daily therapeutic cost was 20.29 euros  for controls and dropped to 9.07 euros  in the STI arm (P<0.0001)”.

This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.

Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes),   some form of intermittent therapy will probably be demonstrated to be safe.  For individuals with at least 700 CD4 lymphocytes, this is already the case.

Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis.  I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts.   This desire for treatment interruptions  was obviously  true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.

Of course for individuals with CD4 counts below 200, this was not a good idea.   Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.

There will be many anecdotes accumulated over the years of such experiences of intermittent treatment.   I need to stress that these are just anecdotes and most definitely not formal studies.  As such they can only lead to hypotheses on which studies can be based.

It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped.  This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.

Of my patients who interrupted treatment none have come to harm.  There was no established protocol to guide us and strategies used took patient preference into account.    An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover.   As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment.  This approach is now generally considered to be unsafe and CD4 guided strategies are studied.   But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.

In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.

“Many of our patients with high CD4 cell counts want to

stop treatment. The LOTTI study does not justify a

recommendation in that regard, but it does give clinicians

useful information that it is probably safe to stop

treatment within the limits of CD4 cell counts of

LOTTI. Continued vigilance is needed so that excellent

adherence is maintained when patients are on HAART

to prevent the emergence of resistance.

The LOTTI study adds important information to the

continued question of whether there is a role for

interrupted therapy. Further study is justified, particularly

with newer combination therapies, which may well

have less toxicity and therefore shift the balance towards

continuous treatment. Clinicians will welcome the

information from LOTTI because it can allay some of

the concerns regarding the safety of treatment interruptions

at high CD4 cell counts”.

In the LOTTI trial, treatment was restarted when the CD4 count dropped  to 350 and stopped at a CD4 count of  700.  So within these limits we have some reassurance of safety.

So, further study is absolutely warranted.

In the LOTTI study, participants had to have a CD4 count of 700.

What about individuals who have had  undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700?    Studies with different CD4 criteria should continue and not be deterred by the SMART results.

I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration.   That is to get away from the prevailing  one size fits all approach to therapy,  mainly using a snapshot of just one or two parameters,  the CD4 count and viral load to guide one, without considering the rate of change in  CD4 numbers.

In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered.   As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly.   (Of course an individual may be super infected with a drug resistant variant).

It is likely that some form of episodic treatment may be effective in selected individuals.   That is, periods on treatment alternating with periods off treatment.   Because of its flexibility it is probably best suited to individualization.

As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy.  But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5.   But other similar studies have shown a high rate of viral rebound6.

However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.

It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.

I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.

The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.

Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.

This table shows characteristics of individuals who died compared to those who did not.

Kuller 2

The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).

It can be seen that of the people who died, compared to those who did not, 11.8%  vs  4.7% had a history of heart disease (p=0.04);  45.9% vs 24.1%  were co infected with Hepatitis B or C  (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).

Thus the people who died in the SMART study tended to be sick with non HIV related conditions.  64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.

But there is another remarkable figure in this table.  92.9 % of those who died were participants in US sites!  I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.

Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle,  for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.

The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants.  All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm.   However the distribution of these characteristics in those who died was not reported in this publication.  We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.

I missed seeing this 2008 publication.  It seems that most who saw it had little to say.  But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8.   I did not miss it this time, and have already written about it.

Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible.   Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion  that the SMART study indicates that treatment interruptions are unsafe for all,  into question.

To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.

This lack of interest is really puzzling.

Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.

Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement.  There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.

We know with some security from SMART that HIV infected individuals with Hepatitis B and C,   hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.

For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all,   a form of treatment interruption will be demonstrated to be safe.  This can already be said for those meeting the conditions of the participants in the LOTTI trial.

The original report of the SMART study was published in the New England Journal of medicine in 2006.

http://content.nejm.org/cgi/content/full/355/22/2283

———————————————————————————————————————–

Refs

1:    New England Journal of medicine    2006  355:2283-2296

2:    Trivacan(ANRS 1269)    Lancet  2006  367:1981-1989

3:    Staccato                           Lancet 2006   368: 459-465

4:    LOTTI                                AIDS     2009   23:799-807

5:     Proceedings National Academy of Sciences   2001   98: 15161-6

6:      AIDS  2003    17:2257-2258

7:      Kuller et al.   PLoS  Oct. 2008   5(10): e203

8:      The Lancet Infectious Diseases  2009 Vol 9 Issue 5 268-9

HIV Treatment: There is a role for intermittent therapy. July, 2009

From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..

The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.

For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.

We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.

One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs.   This approach will almost definitely not be possible for all HIV infected people needing treatment.  But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.

This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061.  SMART is by far the largest study comparing continuous with intermittent therapy.  In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.

The negative effect of SMART on the study of intermittent treatment continues.   In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought.  The most favoured explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.

For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification.  The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post.

SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where  multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C,  hypertension, and a previous  history of heart disease   Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy.   That’s all.  The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational  literature addressed to physicians.

Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times.  But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.

Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART.  The Staccato study3,  using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.

The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent.  Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group).  Although pneumonia was more frequent in the STI group.    Here is a sentence from the author’s abstract.

A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.

The finding regarding cardiovascular disease is particularly relevant.

Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study.  It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation.   There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people.  So this needs to be studied.  But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.

Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!

There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.

I was shown an invitation to physicians to a free course offered by a distinguished academic institution.   Among the descriptions of what those attending the course will learn to do is the following:

“Describe, discuss and apply the data from the SMART study on CHD  (coronary heart disease)  risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”

What is one to make of this in the light of the LOTTI observations?

This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature.   As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.

As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides.  They also characteristically had low levels of HDL cholesterol (and of total cholesterol).  I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available.  We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased.    There was, not surprisingly,  a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.

So, there may indeed be something in the connection between untreated HIV disease and heart disease.  In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease.   Increased triglycerides are an independent risk factor for coronary heart disease.  There even was a possible mechanism for this that was known in those days that could account for this.

Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted.  Such changes have been seen in people with hepatitis C treated with recombinant interferon.

So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle?   There are numerous different ways in which intermittent therapy can be structured.

The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit,  studies smaller  than SMART

Perhaps a clue is to be found in a sentence in the LOTTI study report.

Here it is:

“The mean daily therapeutic cost was 20.29 euros  for controls and dropped to 9.07 euros  in the STI arm (P<0.0001)”.

This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.

Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes),   some form of intermittent therapy will probably be demonstrated to be safe.  For individuals with at least 700 CD4 lymphocytes, this is already the case.

Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis.  I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts.   This desire for treatment interruptions  was obviously  true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.

Of course for individuals with CD4 counts below 200, this was not a good idea.   Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.

There will be many anecdotes accumulated over the years of such experiences of intermittent treatment.   I need to stress that these are just anecdotes and most definitely not formal studies.  As such they can only lead to hypotheses on which studies can be based.

It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped.  This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.

Of my patients who interrupted treatment none have come to harm.  There was no established protocol to guide us and strategies used took patient preference into account.    An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover.   As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment.  This approach is now generally considered to be unsafe and CD4 guided strategies are studied.   But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.

In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.

“Many of our patients with high CD4 cell counts want to

stop treatment. The LOTTI study does not justify a

recommendation in that regard, but it does give clinicians

useful information that it is probably safe to stop

treatment within the limits of CD4 cell counts of

LOTTI. Continued vigilance is needed so that excellent

adherence is maintained when patients are on HAART

to prevent the emergence of resistance.

The LOTTI study adds important information to the

continued question of whether there is a role for

interrupted therapy. Further study is justified, particularly

with newer combination therapies, which may well

have less toxicity and therefore shift the balance towards

continuous treatment. Clinicians will welcome the

information from LOTTI because it can allay some of

the concerns regarding the safety of treatment interruptions

at high CD4 cell counts”.

In the LOTTI trial, treatment was restarted when the CD4 count dropped  to 350 and stopped at a CD4 count of  700.  So within these limits we have some reassurance of safety.

So, further study is absolutely warranted.

In the LOTTI study, participants had to have a CD4 count of 700.

What about individuals who have had  undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700?    Studies with different CD4 criteria should continue and not be deterred by the SMART results.

I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration.   That is to get away from the prevailing  one size fits all approach to therapy,  mainly using a snapshot of just one or two parameters,  the CD4 count and viral load to guide one, without considering the rate of change in  CD4 numbers.

In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered.   As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly.   (Of course an individual may be super infected with a drug resistant variant).

It is likely that some form of episodic treatment may be effective in selected individuals.   That is, periods on treatment alternating with periods off treatment.   Because of its flexibility it is probably best suited to individualization.

As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy.  But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5.   But other similar studies have shown a high rate of viral rebound6.

However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.

It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.

I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.

The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.

Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.

This table shows characteristics of individuals who died compared to those who did not.

Kuller 2

The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).

It can be seen that of the people who died, compared to those who did not, 11.8%  vs  4.7% had a history of heart disease (p=0.04);  45.9% vs 24.1%  were co infected with Hepatitis B or C  (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).

Thus the people who died in the SMART study tended to be sick with non HIV related conditions.  64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.

But there is another remarkable figure in this table.  92.9 % of those who died were participants in US sites!  I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.

Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle,  for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.

The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants.  All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm.   However the distribution of these characteristics in those who died was not reported in this publication.  We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.

I missed seeing this 2008 publication.  It seems that most who saw it had little to say.  But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8.   I did not miss it this time, and have already written about it.

Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible.   Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion  that the SMART study indicates that treatment interruptions are unsafe for all,  into question.

To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.

This lack of interest is really puzzling.

Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.

Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement.  There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.

We know with some security from SMART that HIV infected individuals with Hepatitis B and C,   hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.

For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all,   a form of treatment interruption will be demonstrated to be safe.  This can already be said for those meeting the conditions of the participants in the LOTTI trial.

The original report of the SMART study was published in the New England Journal of medicine in 2006.

http://content.nejm.org/cgi/content/full/355/22/2283

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Refs

1:    New England Journal of medicine    2006  355:2283-2296

2:    Trivacan(ANRS 1269)    Lancet  2006  367:1981-1989

3:    Staccato                           Lancet 2006   368: 459-465

4:    LOTTI                                AIDS     2009   23:799-807

5:     Proceedings National Academy of Sciences   2001   98: 15161-6

6:      AIDS  2003    17:2257-2258

7:      Kuller et al.   PLoS  Oct. 2008   5(10): e203

8:      The Lancet Infectious Diseases  2009 Vol 9 Issue 5 268-9