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An unwise recommendation by the WHO.

July 20, 2014 Leave a comment

 

PrEP is an HIV prevention intervention in which antiviral medications are taken to interrupt sexual transmission of the virus. It is now being recommended by the WHO for, it seems all   sexually active gay men.  Actually it’s not quite that stark – they continue to recommend condom use as well.   Despite this, many will probably see this as a recommendation to rely on PrEP as an alternative to condoms.

 

The WHO recommendation is a population based proposal, a public health recommendation as opposed to recommendations for specific individuals.   Recommendations for individuals are different because they take into account individual circumstances, such as the extent to which a specific person is at risk.  Population based recommendations are recommendations made across the board, in the case of the WHO, addressed to all men who have sex with men.

 

While assuring us that the recommendations are evidence based and providing the customary explanation of how the strength of evidence is graded, we learn that the WHO has made a sweeping worldwide population based recommendation on evidence provided by just one randomized study!    This was the iPrEx study, which was beset with interpretative difficulties, not least because few took the medication as directed, if at all.

 

We simply do not know enough about PrEP to make a sweeping population based recommendation. .  We have little idea of what adherence to the medication might look like in various populations, we know little about the degree of protection in specific sexual acts.  Different sex acts carry different risks, for example, to the receptive or insertive partner in anal sex.   Also, how effective is PrEP  in situations of exposure to high and low viral loads.  In addition we have little idea of the extent to which condom use will be abandoned.

 

It’s clear that there is a widespread view that PrEP is an alternative to condoms, despite official recommendations stating that PrEP  should be part of a comprehensive prevention approach that includes condom use.

 

 

A more balanced response would have been a call for more research, and importantly, for a fuller description of those individual situations where PrEP use is a rational preventative intervention at the present time.

 

 

The use of PrEP by an individual is very different.     The degree of risk to individuals will vary considerably and on an individual basis PrEP use can be a completely appropriate intervention in situations of very high risk, even if we do not have precise information of its efficacy without condom use.   The use of  PrEP could also be considered when there is an inability to maintain an erection with a condom.  It might be an option to enable a fuller sexual expression among what is probably   a large number of men whose difficulty with condoms, for whatever reason,  stands in the way of satisfactory   sex.      Medical supervision is also more likely in individual situations. It is important to check for HIV infection and to monitor for sexually transmitted infections and drug toxicities.

 

 

Monitoring for sexually transmitted infections is important.  Since PrEP alone offers no protection from the transmission of infections that might be interrupted by condoms we might expect an increase in such infections with a wide roll out of PrEP.  The current increase in sexually transmitted infections among gay men in some cities is most likely attributable to an increase in unprotected sex.    Many sexually transmitted infections facilitate the transmission of HIV which may be another factor that could drive an increase in new HIV infections.

 

 

 

The way PrEP has been promoted during the past few years has surely contributed to the poor support received for prevention education.   One way in which this has happened is the shifting of budgets for prevention to those entities, private or government insurers that pay for drugs used in biomedical prevention.

 

There seems to be a widespread view that prevention education does not work.  But we know that it can work. The adoption of safe sex practices including condom use in the early 1980s curbed the spread of the epidemic, although admittedly conditions are not the same today.  There is little support for continued condom use, and rather than take the view that condoms don’t work, we might try to understand the obstacles that stand in the way of effective prevention education.

 

 

 

If prevention education has been ineffective it’s  be because there has been so little of it, and what little there is has not been properly targeted.  The move of the epidemic into African American communities during the 1990s  was occurring in plain view yet the federal government was churning out expensive vacuous untargeted prevention messages in the form of “America responds to AIDS,” a futile exercise that helped to discredit prevention education.

I get the sense that some younger gay men feel they have missed out in not experiencing the abandon of the 1970s and see PrEP as a way to make up for this.  The real lesson of the 1970s is that sex with multiple different partners on such a vast scale, as occurred in NYC in the 1970s, permits any pathogen that can be transmitted sexually to disseminate widely. That’s what started to happen with amebas and other intestinal parasites and HIV, and is happening with syphilis, gonorrhoea, herpes, hepatitis and many other infections.  There surely will be others beyond HIV.

 

Since we really have very little information about PrEP, and almost none about its use on a population level  such a broad recommendation by the WHO is absolutely inappropriate, so maybe  faced with increasing HIV  infections among gay men,  the WHO is simply giving up  and proposing an unproved intervention out of desperation.  When I say unproven, I mean it is unproven as a viable population based intervention.    Looked at this way, it’s a put down –  a response that may be no more than gestural to people who continue to harm themselves by refusing to use condoms in sex with partners of unknown sero status.

 

This unwise WHO recommendation may also have the effect of increasing new HIV infections if it results in an increase in unprotected sex where adherence is inadequate.

 

I hope there will be a critical look at the WHO panel and funders responsible for producing such unhelpful recommendations.

 

 

 

 

HIV Treatment as Prevention. March 2010

March 4, 2010 Leave a comment

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

August 30, 2009 Leave a comment

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

August 11, 2009 Leave a comment

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

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

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

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

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

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

http://www.prepwatch.org/

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

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

FHI has produced a set of slides listing PrEP trials.

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

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

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

The websites of these organizations contain information about PrEP.

AVAC :   http://www.avac.org/

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

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

The International AIDS Society:  www.iasociety.org

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Here is an excerpt from material published by CDC:

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

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

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

Here is another excerpt:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The finding regarding cardiovascular disease is particularly relevant.

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

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

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

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

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

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

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

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

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

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

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

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

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

Here it is:

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

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

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

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

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

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

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

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

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

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

stop treatment. The LOTTI study does not justify a

recommendation in that regard, but it does give clinicians

useful information that it is probably safe to stop

treatment within the limits of CD4 cell counts of

LOTTI. Continued vigilance is needed so that excellent

adherence is maintained when patients are on HAART

to prevent the emergence of resistance.

The LOTTI study adds important information to the

continued question of whether there is a role for

interrupted therapy. Further study is justified, particularly

with newer combination therapies, which may well

have less toxicity and therefore shift the balance towards

continuous treatment. Clinicians will welcome the

information from LOTTI because it can allay some of

the concerns regarding the safety of treatment interruptions

at high CD4 cell counts”.

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

So, further study is absolutely warranted.

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

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

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

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

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

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

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

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

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

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

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

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

Kuller 2

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

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

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

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

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

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

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

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

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

This lack of interest is really puzzling.

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

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

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

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

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

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

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

Refs

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

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

3:    Staccato                           Lancet 2006   368: 459-465

4:    LOTTI                                AIDS     2009   23:799-807

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

6:      AIDS  2003    17:2257-2258

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The finding regarding cardiovascular disease is particularly relevant.

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

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

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

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

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

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

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

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

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

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

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

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

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

Here it is:

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

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

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

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

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

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

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

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

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

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

stop treatment. The LOTTI study does not justify a

recommendation in that regard, but it does give clinicians

useful information that it is probably safe to stop

treatment within the limits of CD4 cell counts of

LOTTI. Continued vigilance is needed so that excellent

adherence is maintained when patients are on HAART

to prevent the emergence of resistance.

The LOTTI study adds important information to the

continued question of whether there is a role for

interrupted therapy. Further study is justified, particularly

with newer combination therapies, which may well

have less toxicity and therefore shift the balance towards

continuous treatment. Clinicians will welcome the

information from LOTTI because it can allay some of

the concerns regarding the safety of treatment interruptions

at high CD4 cell counts”.

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

So, further study is absolutely warranted.

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

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

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

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

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

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

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

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

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

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

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

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

Kuller 2

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

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

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

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

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

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

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

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

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

This lack of interest is really puzzling.

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

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

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

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

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

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

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

Refs

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

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

3:    Staccato                           Lancet 2006   368: 459-465

4:    LOTTI                                AIDS     2009   23:799-807

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

6:      AIDS  2003    17:2257-2258

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

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

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.

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