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The not so SMART study: a very short postscript

June 12, 2009 Leave a comment

I believe the SMART study team have submitted a response to Justin Stebbing and Angus Dalgleish’s comments in the Lancet Infectious Diseases, that was referred to in a previous post:

The not so SMART study.

The explanation that the huge discrepancy in the number of deaths in the US and non US sites was due to the fact that non US sites started to enrol participants 2-3 years later than   US sites,  was addressed in the comments in the Lancet Infectious Diseases.

Here is the relevant part:

“Whereas most non-US sites commenced patient recruitment 2—3 years after the US sites, it is unlikely that longer protocol exposure could account for this difference. We are told that there were 38 deaths in the first year and 47 deaths thereafter. Hence, assuming that all six non-US deaths occurred in the first year, there remain 32 deaths (38 minus six) in the USA from the first year of the study—about five-fold more than expected based on the non-US mortality rate”.

Whatever explanation is to be offered by the SMART team, even if turns out to be consistent with their conclusions, the following questions remain.

Why was information on the distribution of deaths withheld for so many years?

Why was this information, when it did appear in the article by Kuller et al in PLoS last year,  ignored by community commentators  to whom HIV infected people and their advocates look to for help.?

Did they not notice it? (I did not).

Did they think it was of no significance?

Hopefully the SMART team’s response will put an end to this mystery of why, with more or less the same number of participants in US and  non US sites,   79  people died  at  US sites while there were only 6 deaths at sites  outside the US.

Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.

June 6, 2009 1 comment

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

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

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

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

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

S. haematobium  has a complicated life cycle, some of which takes place in snails.  People are infected by organisms released by snails living in fresh water. These organisms can penetrate the skin of any body part that is immersed in snail infested water.  S. haematobium affects the urinary tract.  The disease it causes is commonly called bilharzia.

I was very conscious of its danger as a child growing up in Zimbabwe, with signs at several small lakes around Bulawayo warning one not to swim in them because of the danger of bilharzia.

Peter Hotez and colleagues article is a welcome addition to the already substantial literature that strongly suggests that many endemic infections, not only with helminths, but also with bacteria, protozoa and viruses can increase the transmission of HIV and most probably  have a detrimental effect on the course of HIV infection.

This paper concentrates on the local effects of S.haematobium on the female genital tract , where lesions caused by  schistosome egg deposition result in mucosal patches, that can bleed during sexual intercourse. The authors state “Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry” and go on to compare this to the process by which herpes simplex ulcers increase susceptibility to HIV.

This does seem obvious – there is a mucosal break, so HIV has a way in.

In fact in the case of herpes simplex, this seemingly obvious connection is probably not correct.   The large Partners in Prevention study, recently completed, found that acyclovir, a drug effective in treating herpes does not reduce the risk of HIV transmission.  The drug however was associated with a reduction in the number of recurrences of herpetic ulcerations, and significantly slowed HIV disease progression.  I have written about this in another post.

As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant, or at least as significant, as local effects in enhancing the transmission of HIV.    Of course, both local and systemic effects may play a role in enhancing HIV transmission.  The systemic effects include an impairment of virus specific immune responses; immune activation may also increase susceptibility to HIV and promote its replication.

The influence of associated infections on the infectivity of HIV extends far beyond that of schistosomiasis.  Peter Hotez  (the lead author of the above article) has done a great service by bringing attention to a number of devastating neglected tropical diseases.  This important article can be seen in the Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575).

The title of the article is:

“Rescuing the bottom billion through control of neglected tropical diseases”

By Peter J Hotez, Alan Fenwick, Lorenzo Savioli and David Molyneux

I have copied this table from the above article:

tropical

These are incredibly huge numbers.

Many of these infections occur in children and young adults and not only  have an impact on life expectancy, but significantly are the cause of chronic debility particularly in young people.

Some also have an activating effect on HIV replication by several mechanisms, some of which  have been understood for well over ten years.  The resulting acceleration of HIV infection,  by  increasing  HIV viral loads,  as well as by other mechanisms increases the transmission of this virus.

The health of hundreds of millions of individuals could be improved by efforts to prevent and treat these infections.  These infections are also appropriate therapeutic targets in the fight against HIV/AIDS.

Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections and HIV,  this association has been inexplicably neglected in providing  additional approaches to controlling the epidemic..

I had what might be described as a  misfortune to have been a member of President Mbeki’s panel on AIDS, an almost surreal experience I should write about.  The following is an excerpt from something I wrote for this panel almost 10 years ago:

“The crucial difference in Africa, as opposed to the US, is the high prevalence of associated infections. These include STDs, TB, malaria and other protozoal infections, helminthic and bacterial  infections. Such infections would supply sustained signals, such as IL-1  IL-6 and TNF, known to activate HIV.  Some can also upregulate the expression of chemokine co receptors required for HIV entry.  Some of these infections are  somewhat immunosuppressive themselves, an effect contributed to by the secretion of IL-10.37 Sexual transmission of HIV is also known to be facilitated by a high viral burden.38 This would also be the consequence of the HIV activating effect of frequent associated infections in Africa.”

This was almost 10 years ago, and since then literature has continued to accumulate documenting the detrimental interactions between HIV and multiple infectious agents.

About two years ago I made a presentation at the Prevention Research Center at Berkeley, trying to understand why endemic diseases had been so neglected in our attempts to control AIDS, particularly in Africa.  I thought that part of the problem was poor interdisciplinary communication and understanding.   Specifically, there might be difficulties in   communications between public health experts and microbiologists.   Possible public health implications of the findings of microbiologists might not be perceived without additional explanation.  I illustrated this with a specific article.

I used an excellent article to illustrate this problem.

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

This is part of what I said in California  in trying to illustrate the difficulty in communication:

“Of great interest – because of its implications for disease control was the discovery that other infections, viral, bacterial, protozoal and helminthic, could influence the course of HIV disease.  Generally the effect was to enhance HIV replication, but a few seemed to ameliorate – at least temporarily, the course of infection.  Scrub typhus, measles and perhaps a form of viral hepatitis, may have a  transient beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.

We now come to an example of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS in Africa.   This example is a review (cited above)  explaining in great technical detail how the replication of HIV can be enormously enhanced by concurrent endemic infections, and how this not only accelerates the progression of HIV disease, but also facilitates its transmission. The authors show in molecular detail how many viral, bacterial, protozoan and helminthic infections can affect HIV replication.  Included among these are common intestinal worms and water borne bacterial infections, causing severe diarrhea particularly in infants.  The discussion is largely concerned with the possible beneficial effect of drugs that might counteract this enhancement of HIV replication. There is one short sentence on public health interventions that might eliminate this problem altogether. It is of particular interest because of its brevity in a rather long article.   There is also a curious statement that where antiretroviral drugs are unavailable, measures to control endemic infections may be a useful approach.  This comment is reproduced below, and somehow ignores the significance of the implication that control of these endemic infections requires no other justification than as a measure to control AIDS.

This paper, because of its immunological and molecular detail is not too likely to find its way to an epidemiologist or public health expert,  but for one trained in these technicalities, I would suppose the public health implications would be immediately evident.

This particular paper also is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.

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

lawn1

However if one turned a few pages the following diagram may just be of some interest. But again this is unlikely.

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

lawn21

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

“Prevention and Treatment of Coinfections

The widespread use of HAART in the treatment of HIV-

infected persons in westernized countries has resulted in a

phenomenal decrease in the incidence of opportunistic infec-

tions and has greatly increased survival. For these individuals,

the antiretroviral drugs are the major determinant of prognosis

and the potential cofactor effect of opportunistic infections is

now a more minor consideration. However, the vast majority

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

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

developing countries, where the quality and access to health

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

endemic infectious diseases such as malaria, TB, and infections

by helminths and waterborne pathogens which may adversely

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

ment of these diseases may therefore represent an important

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

tries”. –

In the above quotation, the authors are overoptimistic in their assertion that the cofactor effect of opportunistic infections is now a more minor consideration in developed countries.  Valacyclovir, a drug that inhibits the replication of  many members of the herpes virus group, but has no direct effect on HIV was reported to reduce HIV viral loads in the absence of antiretroviral therapy. In the developed world, active herpes virus infections are common in the setting of HIV infection, although most will be asymptomatic. For example, Cytomegalovirus, Epstein Barr Virus and Human herpes virus type 6 are not infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these viruses, and may well find a place in the treatment of HIV infection in developed countries.  Indeed it may not be uncommon for experienced physicians here (in the US) to prescribe related anti herpes medications to their HIV infected patients. I certainly do.

There is another aspect, a little more difficult to establish and perhaps altogether conjectural.  This is that we are presented with the question of why we need AIDS to justify interventions that have long been established to themselves improve the health of populations.  These include the provision of sanitation and clean water, the control of malaria and TB, and something as simple as getting rid of worms.  In the public’s assessment of the health needs of developing countries the information that is used is largely to be found in popular media, newspapers, magazines and TV.  Those who report in turn receive information from professional sources, and maybe it is here that the interdisciplinary barriers to communication I have been talking about have their effect. Thus the AIDS epidemic is perceived to be the greatest threat to the future of Africa, even though malaria kills more people, and common endemic infections contribute to an abysmal life expectancy.   (This was written 2-3 years ago and was probably incorrect even at that time;  estimates are that today there are  1.5-2 million deaths from AIDS in Africa, with close to 1 million deaths from malaria.  Malaria though  is responsible for a greater  number of deaths in children under 5 years of age).

It continues to be remarkable that although evidence has existed for years that many of these infections can interact with HIV infection to increase its infectivity and accelerate disease progression, those who advocate for, and allocate funds to fight HIV/AIDS seem oblivious to the relevance and implications of these interactions.

This effort of course needs absolutely no justification, but its funding is small compared to the resources that have been made available to combat HIV/AIDS –  but from all that has been described funding for these endemic infections is in fact also funding to fight HIV/AIDS “.

Those were comments made 2-3 years ago.

While malaria and tuberculosis are now receiving attention and are included with AIDS in some programs,   many other endemic infections  continue to be neglected.

Going back much further in time,  interest in the activating effects of associated infections on HIV replication began within the first 10 years of the epidemic.  This started with the demonstration that proinflammatory cytokines, TNF alpha or IL 6, for example could greatly accelerate HIV replication.

Of course these cytokines appear in the course of many different infections.  When viral load tests became available this effect was well understood by patients and physicians in N America and Europe. It became common wisdom that an HIV infected person who had a febrile illness, or had even received a flu vaccine  should delay viral load testing because the infection or vaccination was frequently associated with temporary rises in HIV viral loads.

The implications for geographic areas where the infections were far from temporary seemed to escape notice.

Thus endemic infections in Africa do have everything to do with HIV/AIDS.  There are numerous preventative and therapeutic measures available to control many of these infections,  and some are inexpensive.  Even something as simple as deworming may be useful.  Ascaris lumbricoides, the common intestinal round worm also is associated with immune activation and is easily got rid of.  There is a report that doing this with a drug called albendazole actually raised CD4 counts. (Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609, 2008).

The person who has been studying immune activation and the association of parasitic infestations and AIDS for the longest time is  Zvi Bentwich.   I can’t remember when his first  publication on this issue appeared but by the mid 1990s he was publishing on this association in Ethiopian immigrants to Israel.   Zvi Bentwich deserves the greatest credit for his early recognition of the importance of this association, its significance regarding immune activation and for his continuing contributions.   He pointed out the relevance of schistosomiasis to AIDS  (and TB) at least 10 years ago.

The connection of so many endemic infections with AIDS  in Africa is also a connection of poverty with AIDS.  I saw an absurd and instantly forgettable paper entitled something like “Poverty does not cause AIDS” a few years ago.    Of course poverty is not the direct  cause of ascariasis,  schistosomiasis, tuberculosis, or any number of devastating infections.  Poverty is a very significant factor in  the acquisition of these infections, and as such can certainly be regarded as having a causative role.

The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.  For example the debility associated with schistosomiasis has an impact on an individual’s productivity, with economic consequences not only for the individual but for the larger community.

Controlling the AIDS epidemic in Africa must also include measures to prevent and treat the multiple endemic infections that affect hundreds of millions of individuals.

To conclude this post I want to recommend a book published about four years ago by Eileen Stillwaggon, a professor of economics.  It is called “AIDS and the ecology of poverty” and is published by the Oxford University Press.

Treatment as Prevention: Protecting individual autonomy. May 2010

May 18, 2009 2 comments

I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.

This document discusses treatment as prevention at the individual and the population level together.

It  places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf.   I have come to see the issues in a somewhat  different way after reading the French document.

This document can be seen here:

http://www.cns.sante.fr/spip.php?article296&lang=en

It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.

At an individual level  it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.

The term is also applied at a population level, where the goal of treatment as prevention is  the control of the epidemic, even as suggested by some,  a means to end it.

The principle underlying the proposals to use treatment as prevention in both of these situations is the same.  It is the reduction in infectivity that results from the effect of antiretroviral therapy.

Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.

Treatment as prevention is not the same when applied to individuals as opposed to populations.  For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.

To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.

For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.

For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.

Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%.   Transmission would be slowed but not reversed with treatment rates below 50%.

Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.

At an extreme, if the stated objective is to end the epidemic, as has been proposed by some,  the proportion of infected people who would need to be  treated would be so large that it would have to include those who do not need treatment for their own benefit.

I have written about the multitude of problems arising from this situation in previous posts on this topic.  Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.

However if, as I believe,  an additional  goal of treating  infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.

Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment.  Therefore we must  also intensify and improve  our efforts at targeted prevention education with the promotion of condom use.

But we will avoid the insuperable problems and threats to personal autonomy associated with  treating individuals who do not need to be treated for their own benefit.

The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.

It might be preferable to simply state that the goal is to provide treatment to every individual who needs it.  This goal must therefore be coupled with enhanced efforts to facilitate regular testing.

If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.

There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .

When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.

One reason why the French document is so significant is that it stresses the importance of individual autonomy.

It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ  coercive measures in the name of the public good.  Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.

Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.

” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,

Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.

Instead we should:

Offer treatment to all who need it.

Facilitate testing, identifying and removing barriers that impede it.

Intensify and improve our efforts at targeted prevention education.

Promote condom use and make them available.

There is a final issue.

Who needs to be treated?  Certainly everyone with a CD4 count below 200.  Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.

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

May 17, 2009 1 comment

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

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

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

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

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

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

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

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

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

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

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

(NEJM 2007  356:790)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Nothing much can be made of these contradictory early results.

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

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

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

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

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

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

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

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

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

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

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

The appropriate  title  was  coined by Richard.

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

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

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

Safer sex recommendations.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

HIV ACTIVATION

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

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

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

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

antigen mediated immune activation occurs in HIV-1-infected

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

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

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

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

Transactivation  of HIV by herpes viruses.

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

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

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

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

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

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

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

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

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

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

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


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

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

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

Interferon: Another Historical Digression

This is about something I wrote in 1964, which was recently reproduced and is now available on line.

It can be seen by clicking on this link:

1964 interferon article.

Seeing this 45 year old document prompted me to write this post.

It is about interferon and has nothing to do with AIDS, at least not in any immediately obvious fashion.

It is an interesting story, about at least one of the ways in which science progresses.  It is a story of how an apparently insignificant change in an experiment can sometimes lead to very significant advances.  In this instance, about how cytokines exert their effects.

Cytokines are protein or peptide molecules released by cells which then attach to the surfaces of other cells.  As a consequence, the behaviour of the cells to which they attach is altered.  In this respect cytokines are similar to hormones.

Generally, each cytokine will only attach to a specific receptor on the surface of the cell.

When a cytokine attaches to its matching receptor, a cascade of events is set in motion resulting in the activation of specific sequences in nuclear DNA.

Messenger RNA molecules are then transcribed from specific DNA sequences and these direct the synthesis of specific proteins that ultimately are the molecules that cause the particular effects produced by the cytokine.

Therefore, as the picture below demonstrates, cytokines are not themselves the molecules that directly mediate the effects they cause.  Through a complex series of signalling events in the cell, set in motion by the binding of the cytokine to its receptor, specific proteins are made by the cell.  These proteins are the actual mediators of the cytokine’s effects. [1]

In the illustration, the right angled arrow in the nucleus represents the messenger RNAs which will direct the synthesis of these proteins.

HIV DNA is integrated into host DNA.   Should certain cytokines,  IL-6 or TNF alpha for example,  attach to their receptors on the cell membrane,  a series of events follow, ultimately resulting in sequences in nuclear DNA being activated which in turn causes HIV DNA to make RNA which directs the synthesis of HIV proteins and ultimately of new HIV particles.

cytokine

Since many of those cytokines that can activate HIV in this way are produced during the course of many different infections, this then is but one of the several ways in which HIV replication can be enhanced by many different concurrent infections.  TB and malaria are among them, as are the bacterial diarrheal infections associated with a lack of sanitation and clean water.   Controlling these many  HIV enhancing infections,  is  with the exception of TB,  a neglected target in the fight against the epidemic.

Interestingly,   discoveries about the ways in which cytokines exert their actions have largely been made since AIDS was first recognized in 1981.

Thus HIV research has progressed in tandem with research on molecular cell biology.  There have been reciprocal benefits.  HIV research has both contributed to our understanding of molecular cell biology, as well as itself being advanced by discoveries in this field.

Interferon was the very first cytokine to be discovered.  It was discovered by Alick Isaacs and Jean Lindenmann .   Actually it was not really discovered as a specific molecule; the term interferon was coined by Alick  Isaacs in 1957, to describe an activity – an antiviral activity released by virus infected cells. It was perhaps a bit premature to assume that this activity resided in a single molecule. But that was what we all thought at the time; it was nonetheless a concept that facilitated research as probably did the coining of the word “interferon” to describe this antiviral substance.

We now know that there are many types of interferon, and we therefore should properly speak of the interferons.  Also, as is the case with cytokines generally, the interferons have multiple effects, but the antiviral effect is how it was first recognized and also measured.

Alick Isaacs  was my mentor in the laboratory study of viruses; I shared a lab with him and  worked on the mechanism of the antiviral action of interferon.

In 1963, we had no idea about how interferon exerted its antiviral effect. We at least knew that it did not directly inactivate viruses.  Molecular biology – at least as far as eukaryotic cells were concerned, had hardly developed.

The 1964 article that can be seen by following the link at the beginning of this post resulted from the work of Joyce Taylor.1964 interferon article.

Joyce Taylor is a biochemist.  She also worked in Alick’s lab in 1963.  It was rather unusual,  in those days for a biochemist to be working in a lab concerned with animal viruses. Animal virology was just beginning to employ biochemical methods.

Joyce was attempting to show that interferon blocked the synthesis of viral RNA.   This of course required the use of biochemical techniques to identify and measure viral RNA.

She was able to demonstrate that viral RNA was not made in cells treated with interferon. This was accomplished by using a compound that blocked DNA directed cell RNA synthesis, actinomycin D.  It was necessary to use actinimycin D because there is so much background  cellular  DNA directed  RNA synthesis that unless this can be stopped it would be impossible to observer viral RNA synthesis. She used an RNA virus (SFV) that was unaffected by actinomycin D.

Joyce very clearly showed that the synthesis of SFV RNA was blocked in cells treated with interferon.  as with the availability of actinomycin D,  she was able to detect and measure viral RNA.

We are now coming to the happy, but at the time seemingly  insignificant change in the sequence of steps in an experiment,  that had such far reaching consequences.

This is how Joyce did her experiments.  Cells were exposed to interferon for some hours, and then the SFV virus added with actinomycin D, to allow the measurement of viral RNA synthesis by removing the background of cellular RNA synthesis.  As mentioned,  in this way, Joyce was able to show very clearly that pre-treatment of the cells with interferon blocked the synthesis of SFV RNA.

One day, because Joyce had to leave early and she did not want her technician to handle actinomycin D, she added this drug with the interferon, at the beginning of the period of interferon treatment  .  Nobody at that time would have thought that this would make the slightest difference.   It is this change in the time when the actinomycin was added that was critical, but it was not at all expected to have any effect.

But it did have an extraordinary effect.  When cells were treated with interferon in the presence of actinomycin D it had no antiviral effect.  At first it was thought that an inactive preparation of interferon was used, but the same result was obtained when the experiment was repeated.

The significance of the change in the order in which actinomycin was added was that now, while the cells were exposed to interferon, DNA directed RNA synthesis was also blocked.

The implications of this were quite extraordinary.  At that time, 1963 and 1964, the foundations of our understanding of basic molecular cell biology were being worked out mostly in bacterial systems.  The structure of DNA had been worked out, messenger RNA discovered (although there is some dispute as to who discovered it) and there was some understanding of derepression – that is the ability of certain molecules to cause the synthesis of specific proteins by bacteria.

The result of the changed order of Joyce’s experiment suggested that something similar might be happening in animal cells- that interferon was inducing the synthesis of a specific messenger RNA which in turn directed the synthesis of a  protein  responsible for its antiviral effect.  This is what prompted me to write the short article that can be seen by clicking the link at the beginning of this post.

What was described in 1964 was  in fact the first demonstration that cytokines exert their effect by attaching to a receptor on the cell surface,  and  as a result of this,    specific regions on cellular  DNA are activated,and  RNA synthesized.  Work showing that this RNA is responsible for the synthesis of proteins followed immediately.

Robert Friedman, was visiting the laboratory from the National Cancer Institute, and we worked together to show that not only RNA synthesis, but also protein synthesis was required for interferon action – and as was to be found, for the action of all cytokines.

Joyce Taylor remembers this story somewhat differently, but I trust that my version is correct.  I have repeated it so frequently since the events in question, as an illustration of how science sometimes progresses.

Joyce changed the order of adding reagents. As a result we knew that interferon action needed cell the participation of cell DNA and the synthesis of RNA.  Bob Friedman and I then showed that interferon action also required cell protein synthesis. Ian Kerr who was also in the lab around that time, and others then showed a part of what changes interferon induced in cells.

Interferon was the tool by which a signalling pathway was demonstrated that could account for the effects exerted on nuclear DNA by a molecule interacting with its receptor at the cell surface.   Ian Kerr was a key contributor to this work.

This post was not directly connected with HIV/AIDS.  But cytokines are most certainly  connected with HIV/AIDS.  This will be the subject of future posts.

[1]  The genetic code is defined by the sequence of the four bases that make up genomic DNA. A particular sequence of three nucleotides can be regarded as a code component  which ultimately defines a particular  amino acid; amino acids are the building blocks of proteins.  The DNA code is conveyed from the nucleus to the protein synthesizing apparatus in the cell cytoplasm in the form of messenger RNA. This RNA molecule is made from a DNA template and exactly reflects the nucleotide sequence of the section of DNA from which it is transcribed.

genetic-code

Treatment as Prevention. A last short postscript

I have written several posts dealing with “Treatment as Prevention”  referring to proposals that the epidemic could be controlled by testing and treating all infected people.   However, as this phrase is also used in a different, although related context, I am adding this last postscript.

Thus,  “treatment as prevention” has a context that concerns populations and considers a strategy to  control and even end the epidemic.    The same phrase  also has a context that deals with prevention of infection at an individual level, and focuses on transmission risks  between two people.

The latter context was brought to attention in 2008 by the Swiss Federal Commission on HIV/AIDS.  Their publication essentially states that, under certain conditions,  with effective antiviral treatment achieving an undetectable viral load, the risk of sexual transmission without condom use is not greater than that with the use of condoms.

Among the conditions stipulated is that there is no sexually transmitted infection, and that the viral load has been undetectable for at least six months.

http://www.aids.ch/e/fragen/pdf/swissguidelinesART.pdf

Now a German voluntary organization, Deutsche AIDS-Hilfe, has added support – with some modifications to the Swiss statement.

http://www.aidshilfe.de/media/de/0904_DAH-Papier_HIV-Therapie_und_Praevention_Englisch.pdf

There was a huge controversy when the Swiss recommendations were first made public in 2008.  Their conclusions were rejected  by groups  in the US,  even by those who promoted the application of the same principle – the reduction in infectivity conferred by treatment – as a means of controlling the epidemic.

I was – and am – absolutely supportive of the Swiss recommendations as applied to individuals.  Here is an excerpt from a letter I wrote when the Swiss document was published:

“The report is absolutely reasonable. There are caveats and cautions in it, and since I can see no reasonable objection to them, we have to look elsewhere to try and understand why the report has provoked such a furious response. I know it is a bit pedantic and pretentious but I’m going to add a quotation that is over 100 years old that recognizes that scientists can be as irrational as anyone else (especially about sex), here it is:

In Man Adapting, Rene Dubos notes that:

“The presuppositions on which medicine operates are thus conditioned by the general philosophy of the social group as a whole” and adds the words of Oliver Wendell Holmes in 1860:

“The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes in atmospheric density”10
I would bet that some who have commented have not even read the cautious Swiss text, and have allowed their prejudices and squeamishness about sex in general to surface at the very mention of sex without condoms.

The Swiss authors do deserve some recognition for their courage. There are circumstances in which it is not irresponsible to have sex without condoms. And even for those for whom these circumstances do not apply, the knowledge of the possibility of sex without condoms will be an encouragement, in at least two ways.

Firstly, to continue using condoms when this is necessary, and then as a support with treatment adherence and monitoring.

I say these things as someone who had something to do with the original introduction of condom use for AIDS prevention in 1983, – briefly described here:

http://aidsperspective.net/articles/Callen-Berk_collaboration4.pdf

and until now thought – as probably most did, that condom use  would be forever.

Knowing that this is not necessarily so is a tremendous encouragement and I believe this thought alone will help our prevention efforts”.

I have continued to encourage the use of condoms, but I do welcome the Swiss document for pointing out, with appropriate documentation and caution, that there are circumstances when it is not irresponsible to dispense with them.

This also means that there are circumstances when conception is possible. There are also implications in situations where there are laws that criminalize sexual contact with HIV infected people under certain circumstances.

A large part of the irrational responses to the proposal are I believe based on a disparaging attitude towards sex.

For many, the use of condoms is a barrier to intimacy.  The knowledge that if certain circumstances can be met, an infected person is not endangering their sexual partner by dispensing with condoms is in fact a life affirming celebration of sex, one of life’s joys.

Admittedly, dispensing with condoms will not be possible for most individuals.  It is probably most relevant to serodiscordant couples in a stable relationship – that is where only one of the partners is HIV infected.

But knowing that this might be achieved could be a great support to most HIV infected people  who must continue to use condoms   It will also be a greater incentive to remain adherent to one’s treatment regimen.

Of course the diminished infectivity of effectively treated individuals is the basis for the proposals to use treatment of all infected people as a means of controlling the epidemic.

This is a very different situation, most importantly because it will involve treating people who do not need to be treated for their own personal benefit. These healthier people will derive no benefit from the medications and only be exposed to their side effects.  I have written about this in previous posts on treatment as prevention.

Except for the relatively uncommon situations outlined in the Swiss document, and more cautiously and explicitly, in the German document, the consistent use of condoms remains one of the most important measures we have to prevent infection.

The Not So SMART Study

April 27, 2009 2 comments

I have borrowed this title from a comment in the journal, Lancet Infectious Diseases, entitled “Not so Smart?” by Justin Stebbing and Angus Dalgleish.

The SMART study as many will recall was a randomized comparison of two antiretroviral treatment strategies.

HIV infected individuals were randomized to receive either  continuous antiviral treatment or to receive it intermittently while the CD4 count had fallen below 250. This trial received a tremendous amount of publicity.  Deaths from all causes – including those that were not obviously related to HIV infection, were significantly increased in the group that were treated intermittently.  This seemed to dampen enthusiasm for treatment interruptions and brought attention to a possible relationship between HIV infection and deaths from causes previously not associated with it.

5,472 patients participated in this study at 318 sites in 33 countries.

There were a total of 85 deaths in the study.

79 of these 85 deaths occurred in the US where 55% of the patients were randomized.

There were only 6 deaths among the 45% of patients randomized in countries outside the US.

.

It would seem that treatment interruptions are quite safe, as long as they occur in countries outside the US.

Did I miss this information in the original report of the study published in 2006?

There were numerous discussions of the SMART study on websites and newsletters addressed to HIV infected people and their health care providers.  Did I miss those that reported on the fact that only 6 of the 85 deaths occurred in countries outside the US?

Of course I looked at the original report again but could not find this information – perhaps it was buried in a supplementary appendix?

For some reason, it seems that the authors of the report on the SMART study did not feel it necessary to draw attention to this information – at least not with the prominence that it deserved, if it was mentioned at all.

Most of the deaths on the study were not from AIDS associated opportunistic infections or malignancies.

With a presumption (maybe this  suggestion is too harsh) that despite this, the deaths were indeed related to HIV,  a possible relationship with this virus was sought. One obvious possibility of connecting these deaths with HIV was by linking them with the inflammation that is associated with HIV disease.

Thus, as a follow up to the SMART study, various markers of inflammation were looked at in both groups, and not surprisingly these were increased in the group with the most deaths, those receiving intermittent treatment rather than continuous treatment. As mentioned almost all of these deaths were confined to the US.

So, what we have is the observation that people who were to die within a relatively short period had increases in markers of inflammation. Of these, D-dimer, CRP and IL 6 had already been associated with all cause mortality, even in people not infected with HIV.

With respect to the cardiovascular deaths in the study, here is a quotation from PM Ridker:  “In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis”.

IL-6 is a pro inflammatory cytokine and levels were increased in those receiving intermittent therapy.  IL-6 promotes HIV replication,  and can be produced by HIV infected cells but also by many other stimuli.

So IL 6, which is associated with atherogenesis,  also directly increases the replication of HIV.  IL 6 secretion is increased by numerous and diverse factors. For example bacterial toxins induce IL 1 which in turn stimulates IL 6 release and  hepatitis C virus core proteins induce IL 6.  HIV infected cells can also release IL 6.

But with so many different agents able to do this it is difficult to attribute IL 6 production to HIV.  This is of course muddied by the fact that whatever stimulates IL 6 secretion, IL 6 itself will accelerate the replication of HIV.

But possibly the most intriguing feature of the report of this follow up study  is the first sentence of the Results section:

“Most of the deaths (79 of 85) occurred in the US”.

Having made this rather startling statement, the authors never return to it.  It remains undiscussed,  as if it is of no consequence!

Are we to believe that intermittent therapy with antiviral agents  promotes inflammation with its lethal consequences only in the US?

The outcome measurement of the SMART study included death from all causes. Only 8% were the result of opportunistic disease.

There were 16 deaths from cancer ( 11 in the intermittent therapy(IT) group and 5 in the continuous therapy group(CT)), 11 deaths from cardiovascular   disease  (7, IT, 4,  CT);

8 people died from substance abuse, 7 from violence.

18 deaths were from causes that could not be determined. Of these 18, 15 occurred in those on intermittent treatment and only 3 in those receiving continuous treatment.  This last rather large difference leads one to ask if it is possible that the two groups were treated differently. At least, in the US, where almost all the deaths occurred.

This may seem like an outrageous question. But unintentional bias in unblinded studies cannot be ignored and I will return to this.

Many of the deaths reported –  certainly far from all, were caused by  conditions that might have been ameliorated by appropriate medical care ( this does not only mean from the point of view of the physician. The patient is also involved – for example, were medical visits made? Did the patient pay attention to symptoms? Was there compliance with prescribed treatment?)

With almost all of the mortality confined to the US,  it looks like something else must be at play here, something other than the antiretroviral treatment strategies, and the first place to look is the overall quality of medical care – which,as mentioned, includes issues that may entirely be related to the patient – such as poor compliance with recommendations, despite adequate support.

There are two distinct  questions to be asked.

Firstly,  why was there such  a difference  in  the trial outcomes between US and non US sites?

Secondly, in the US can we reliably attribute the differences in outcomes in the two treatment arms to the differences in the antiviral treatment strategies?

The first two questions one would ask in trying to explain the difference between 6 deaths and 79 deaths is related to the quality of general medical care in the US as compared to the non US countries, and then to possible differences in the patient populations.   The patient populations may have differed for example in the extent of co- morbidities,  and in the degree of compliance with recommended treatments.

But  I don’t know that one can come up with an answer about the quality of medical care.   We must assume that there were probably no great differences.  However there was some information on co- morbidities such as Hepatitis b and C,  but not enough to attribute the differences in the number of deaths to this factor.  [Note`added on April 4 2010. The difference in co-morbidities is in fact probably  the reason for the striking difference in mortality between US and non US sites. Here is a link to a later post where a table is reproduced  from the paper describing the mortality difference referenced below. The population enrolled in US sites, where most of  the deaths occurred,  were much more likely to suffer from non HIV related health problems than those enrolled in non US sites.  Here are two sentences from the later post:  ”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:

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”. This current entry on the SMART study, which I’m leaving unchanged,  should be looked at in conjunction with my subsequent post. LINK TO LATER POST ]

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.

I doubt if information on compliance is available.

Even if one could show differences between the US and non US sites ,  how would  this  affect the study outcome?  More people died in the intermittent treatment arm compared to those receiving continuous treatment. So this is the second question.

Could there be an explanation for the differences noted between the study arms (albeit only in the US) other than the antiviral treatment strategies?

There could be a connection with general patient care.

In order to minimize bias in a study, where possible when treatments are compared, participants and those conducting the trial do not know what treatment is being received by particular participants.

The study is blinded, so that as far as it is possible, we can attribute any effects observed to the treatment, not to any anything else.  For example, if patients knew what they were or were not receiving in a treatment trial, they may behave differently, and  in ways that may affect the outcome, which then could not be attributed to the particular treatment being studied.

For example if a patient knew they were receiving a placebo, they may then take other medications that might affect the outcome of the trial, or if doctors knew patients were taking a medicine they believed worked they might treat their patients with greater care or with less care.  We do recognize that some behaviors that may alter the outcome of a study are  certainly not intentional.

It was impossible to blind the SMART study.  So, both participants and physicians knew which arm of the study patients were randomized to.

If the study doctor was also the person who provided  general  care than the specter of bias unfortunately is lurking and may confound interpretations.

This is not to say that differences in general care between both study arms, if indeed there were differences, were intentional.

To put the questions in another way:

1: Can general patient management strategies ( not the strategy of antiviral treatment being studied) have an impact on all cause mortality?  In other words, can the way health care providers manage the general  health of their patients make a difference to survival?

2: Can bias influence the ways physicians take care of their patients?

The answer is of course yes., although we may not like to admit this.    So bias might be a factor in an unblinded study and affect the outcome.

So we are still in the dark regarding regarding the value or danger  of treatment interruptions.

As a postscript, a similar problem hangs over the original AZT study – the study that led to the approval of this drug by the FDA.  Of course the dramatic life saving effect of zidovudine seen in this trial  has never been observed again.

This placebo controlled study was also in effect unblinded. Patients and doctors knew who was receiving placebo or active drug.

Deaths were mostly due to opportunistic infections. Patient management strategies can make the difference between life and death with regard to these infections. Rapid diagnosis, effective treatments obviously make a difference. Can bias influence patient management strategies?

I wrote about this in – I think 1989, and the article can be seen by clicking here.

I suppose that one must conclude that the fact that almost all the deaths in the SMART study occurred in the US was not known to journalists and those who specialize in informing us about issues related to AIDS.  I also missed it when it was  published in 2008 [iii].

The report of Dr Kuller may be the first public mention of this odd result. But it is just mentioned and not discussed at all.

Here is what Justin Stebbing and Angus Dalgleish wrote in the Lancet Infectious diseases about this report:

” The follow-on case-control study by Kuller and colleagues showed that it is apparently safer to be off  HAART outside the USA rather than on HAART within the USA”

As a clinician I don’t know what to make of the SMART results. In the lamentable absence of firm evidence one has to use one’s best judgment in caring for patients.  Numbers of my patients have – at their request and at my recommendation, temporarily interrupted their treatments, using a variety of strategies, with no harm, and with a better quality of life.

I imagine that some will have been persuaded to stop this practice  by their new physicians. But I am still in touch with one, who had a CD4 count of 0 when first seen, who still regularly interrupts his treatment.  He is extremely well, leading an active and productive life.


The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 268 – 269, May 2009

The New England Journal of Medicine [NEJM 355(22): 2283-96 (2006)

PLoS Medicine 5 (10); e203.doi:10.1371/journal.pmed.0050203

Kuller LH, et al. (2008) Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV infection.

HarrisTB et al 1999  Association of elevated IL6 and CRP levels with mortality in the elderly, Am J Med 106: 506

Ridker PM et al 2000 Plasma concentrations of IL 6 and the risk of future myocardial infarction among apparently healthy men.  Circulation  101 1767

Shorr AF et al 2002 D-dimer corerelates with proinflammatory cytokine levels and oycomes in critically ill patients, CHEST 121: 1262

HIV disease is in fact characterized by multiple examples of positive feedback systems – a subject for another post.




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

April 23, 2009 1 comment

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A few introductory words are needed.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

img0822

img083

img084

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Surely the payors, will want to know.


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

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

When is it best to start antiretroviral treatment: an update April 2009

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

But is this confidence justified?

Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

“The early initiation of antiretroviral therapy before the CD4+ count fell below two

prespecified thresholds significantly improved survival, as compared with deferred

therapy

One of these prespecified thresholds was a count 500 CD4 lymphocytes.

This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified.

I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

Here is another serious problem with this study.

Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

This information was not given – at least I was unable to find it.

Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions.

All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

It is the “on average” limitation that needs fine tuning for each individual patient.

Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

A previous post discusses the  issue of individualization of treatment.


If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

Often forgotten, the second pillar is individual clinical judgement.

When is it best to start antiretroviral treatment: an update

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

But is this confidence justified?

Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

“The early initiation of antiretroviral therapy before the CD4+ count fell below two

prespecified thresholds significantly improved survival, as compared with deferred

therapy

One of these prespecified thresholds was a count 500 CD4 lymphocytes.

This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified[i].

I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

Here is another serious problem with this study.

Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

This information was not given – at least I was unable to find it.

Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions[ii].

All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

It is the “on average” limitation that needs fine tuning for each individual patient.

Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

A previous post discusses the  issue of individualization of treatment.


[i] If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

[ii] Often forgotten, the second pillar is individual clinical judgement.