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HIV TREATMENT AS PREVENTION

March 27, 2009 4 comments

The proposal that testing and treating everyone who is HIV infected would end the epidemic is back in the news.

It is not a new idea. It has been discussed at HIV/AIDS conferences. At the beginning of the year an exercise in mathematical modelling was presented in the Lancet providing some support for this notion of universal testing and treatment. Now some experts in molecular biology and virology have added their personal opinions in favour of this approach; I notice that at least on one web site addressed to HIV and Hepatitis virus infected individuals, the views of these pioneer researchers are reported with, as seems to be usual, no analysis or criticism. http://www.hivandhepatitis.com/recent/2009/032409_a.html

It begins to look almost like an advertising campaign, with the touch of a skilled publicist; an idea is gradually brought to public attention, it is widely endorsed and the hope is that public support will ensure that funders and politicians will move the project forwards.

The merits of the proposal, and the way it is being promoted are two different issues.

Regarding the proposal, in principle it is certainly a worthwhile idea that deserves consideration.
But there are several problems, not mentioned in public reports of this proposal, and barely dealt with in the professional literature, which may constitute insuperable barriers to its implementation.

Leaving aside for the moment the question of whether such a project is even feasible, perhaps the most important problem is that infected people who do not need treatment will be asked to receive it to achieve a social benefit.

This proposal then involves the general concept of a public health intervention on individuals who will not themselves derive any benefit from the intervention, but will only be exposed to its risks.

We have thankfully not yet reached the point where enforced testing and treatment can be seriously proposed. (We may be getting close in the removal of written informed consent for HIV testing).

Certainly the spectre of mandatory testing and treatment is lurking behind this proposal to test and treated everyone infected. This would do wonders for drug and testing equipment sales.

So we would have the situation where some individuals will voluntarily take treatments that despite what we may be told can most certainly not be regarded as absolutely free of possible adverse effects, Many infected people will of course benefit from this. Others however will agree to take risks, with no benefit to themselves but for the benefit of others. Quite apart from many other issues, we can only ask these individuals to participate in the project if there is an overwhelming chance of success. At the moment we do not have this assurance.

It is not a digression to compare this situation with that in which an individual is asked to join a clinical trial and who may be randomly assigned to receive a new treatment of as yet only conjectural benefit. We are absolutely obliged to ensure that the trial design is such that reliable information will be obtained from the study.

Since the testing and treatment of all infected individuals to end the epidemic can in no way be regarded as an undertaking with an assured successful outcome, it really is a trial, based on an hypothesis somewhat supported perhaps by mathematical modelling. As such it will require written informed consent from the participants.

I wonder what such a consent form would look like. It is possible, actually likely, that a consent form outlining possible risks and benefits would dissuade many from participating.
The disincentive would be felt by those infected individuals who do not themselves require antiretroviral treatment.

This inconvenient obstacle can be easily eliminated.

All that is needed is for treatment guidelines to include a recommendation that antiviral treatment should be offered to all infected individuals, even those with greater than 500CD4 lymphocytes. A precedent has now been set where treatment recommendations can be made on the flimsiest of evidence. The inappropriate use of retrospective observations to justify an earlier start to antiretroviral treatment is a good example.

So all one needs to do is to move the goal posts a little further and declare that antiretroviral treatments should be given to all HIV infected individuals, irrespective of CD4 count. There should be no difficulty in selecting retrospective observations that will support this recommendation. In the field of HIV/AIDS you can probably find retrospective data to fit whatever idea you are interested in promoting.

There is another tool available to promote the contention that every HIV infected individual, irrespective of CD4 count will benefit from antiviral therapy. This useful tool is called “expert opinion”. (Actually, people billed as “experts” have already expressed this opinion).

The problem with this is: what does it take to be regarded as an expert?

We may well be in an era where we have “experts” for hire.

Defining what was meant by “expert” was once much easier. Years of experience and significant contributions to the field might have been required attributes. But no longer.

Experts can seemingly be created overnight, at least by commercial entities interested in marketing a product. Their credentials are easily supplied. These instant experts will give talks at conferences, they will appear on educational programs, and even put their names to ghost written articles.

[http://healthcare-economist.com/2008/05/03/ghostwriting-by-pharmaceutical-companies/

Revealed: how drug firms ‘hoodwink’ medical journals Pharmaceutical giants hire ghostwriters to produce articles – then put doctors’ names on them.
http://www.guardian.co.uk/society/2003/dec/07/health.businessofresearch
]

As for the practice of ghost writing , there is a great deal of evidence for this, a little shown above. I’m ashamed to admit that I once (only once many years ago) allowed an employee of a drug company to write an article which carried my name. But I had done the work without their support, and in my defense, I checked every word, changing some, – an experience the writer was evidently not used to. This was my first (and only) personal encounter with this practice

I will hazard a prediction; before the year is out we will have arrived at the point that experts will state that every HIV infected person benefits from treatment, irrespective of CD4 count. If required we will see retrospective observational studies which show that in people who started treatment above a CD4 count of 500, mortality from all causes was reduced as compared to those starting below 500 CD4 cells. It should be just as easy to find retrospective data that shows that starting treatment immediately on diagnosis confers a benefit not seen when treatment is delayed to CD4 count of 350.

Of course these expert views will be very widely disseminated in press reports and on numerous web sites – some will even provide the opportunity for doctors to earn CME credit. In this way conjectures are transformed into established facts.

I don’t know how we might obtain real evidence that testing and treating all infected people is not only feasible, but would achieve its goals. The two are related.

For example, how does one ensure that all people are tested? Or that they will agree to be treated? Or that they will adhere to their treatments?
As imperfect as this is maybe one approach is to test these issues in a limited setting where mobility in and out of the selected areas can be controlled for.

This could more usefully be a trial where two different strategies were compared – the present practice of starting treatment at 350 CD4 cells, and treating everyone infected, while promoting HIV tests in both groups. Despite complications introduced by the movement of people, we might get an idea if this is a feasible and effective approach.

Sadly those bodies that instruct physicians on how to treat HIV infected people, and who tell HIV infected people what is best for them, seem to be averse to calling for prospective studies, designed to shed some light on what may in fact be best for infected people. Those who manufacture the treatments appear to prefer trials that are designed to provide them with the answer most congenial to them. Here is an account of the practice of designing trials to provide the answer most desired.
[http://www.washingtonpost.com/wp-dyn/content/article/2008/07/14/AR2008071402145.html]

They can also rummage in retrospective data collections selecting observations best suited to the outcome they have already decided on. Of course there is always an expert to be created to promote this outcome.

When the mathematical modeling referred to above supporting the idea of a “test and treat everyone infected” approach appeared, I wrote a reply to the Lancet which published the article. Not my letter, which was politely rejected.
I am adding a slightly edited copy of that letter here.

A recent Lancet article suggests that we could end the HIV epidemic by testing and treating all who are infected, irrespective of whether or not the individual would benefit from such treatment (R. Granich et al. 2009 Lancet 373:48).

This represents an intervention on individuals, primarily for a public health benefit. At the present time, ethical considerations make this proposal a completely indefensible approach.
The available drugs are far from benign; for a particular individual, their use is desirable and justified when their benefits clearly outweigh their risks. Treating individuals to achieve a population benefit requires a similar risk benefit assessment. F M Hodges and colleagues have addressed this issue. (EM Hodges, JS Svoboda, RS van Howe
Prophylactic interventions in children: balancing human rights with public health. J Med Ethics 2002; 28: 10-26)

To protect individual liberties they propose six conditions that should be met before for such interventions are taken. All of these are reasonable. I quote a passage from their article that outlines them.

“PROPHYLACTIC INTERVENTIONS FOR PUBLIC HEALTH BENEFIT”
Prophylactic medical interventions are frequently performed on healthy individuals who have given informed consent. …..
The most common example arises when the patient is at significant risk of contracting a life- and public health-threatening illness for which the proposed prophylaxis is a proven preventive. In order to safeguard individual liberties, the situations in which such procedures may be undertaken for public health benefit must meet the following requirements:
1. The danger to public health must be substantial.
2. The condition must have serious consequences if transmitted.
3. The effectiveness of the intervention in safeguarding the majority of the public against the particular malady must be well established.
4. The intervention must be the most appropriate, least invasive, and most conservative means of achieving the desired public health objective.
5. The individual must be provided with appreciable benefit not dependent on speculation about hypothetical future behaviours of the patient.
6. The burden to the individual’s human rights and health must be balanced against and found to be substantially outweighed by the benefit to society in helping prevent a highly contagious disease or other potentially calamitous condition from affecting the public health”.
Clearly the proposal to treat all infected people will include some in whom the fifth consideration will not be met, but the concerns are covered in the sixth one. But here the benefit to society must be assured, or more practically, be considered to be highly probable, with credible evidence produced to support the contention (as stated in the third consideration).

While the first two criteria are very clearly met, the present proposal to treat all who test positive fails utterly on the third point. It is far from well established that antiviral treatment of all who are infected will protect the “majority of individuals” in diverse settings. Among problems acknowledged by the authors are those related to toxicity, adherence and the development of resistance to the antiviral drugs. To this must be added the possible negative effects on behaviour deriving from a perception of being non infectious. The fourth condition is also not met. We cannot state that we have exhausted the utility of prevention education and promotion of condom use.

Let alone the questionable wisdom of mounting an extensive and expensive public health intervention that is based only on mathematical modeling, we are very far from possessing information that would supply the slightest confidence that such a measure would effectively meet its objective.
Regarding adherence, the optimism presented by the authors based on studies in Malawi is hardly justified. Adherence by individuals who may be ill, and certainly know they are receiving medications for their own benefit tells us nothing about adherence by people who feel healthy and know they are not taking the medications to benefit themselves.

The general relationship between viral load and infectivity is well established. The success of the proposed strategy according to the model presented depends on achieving a significant reduction in viral load from the pre-treatment value. The solid evidence of the potent ability of antiviral drugs to very substantially reduce viral loads in a sustained fashion derives predominantly from observations in settings where untreated endemic or concurrent infections are uncommon. The ability to achieve a sustained significant drop in viral load may be more difficult where there is a high prevalence of untreated endemic or associated infections. This is the case in parts of Sub Saharan Africa. Many of these infections are able to activate and enhance HIV replication, through the action of pro inflammatory cytokines. Should these infections be associated with genital ulceration there are additional uncertainties.
HIV disease is characterized by an enormous variability in the rates of disease progression. There is no such thing as a standard course of disease progression that is one of the assumptions used in the modeling. We know very little about the distribution of different rates of disease progression among infected individuals, or about the influence on this of associated untreated infections.
Risking individual harm for a public benefit is a slippery slope. Will we see a proposal to administer (with consent, of course) antiretroviral medication to the whole sexually active population, HIV infected or not?

AIDS is a preventable disease. We have far from exhausted less conjectural, as well as less speculative approaches to its prevention.

Addendum
Apart from this proposed strategy to treat all infected people, there definitely are situations where treatment as prevention is absolutely appropriate and desirable. One is post exposure prophylaxis (PEP), where individuals who have been exposed to HIV attempt to prevent infection by rapidly taking antiretroviral drugs – that is within 72 hours of exposure. This applies to both occupational and sexual exposure. Regarding sexual exposure – where feasible, which is certainly the case in N America Europe and in many other regions, a 3 day supply of drugs should be available 24 hours of the day, given the limited time frame for action. Measures to immediately start PEP immediately should of course be available where occupational exposure is a risk. Emergency departments should be equipped and ready to start the protocols for PEP. People at risk should even be encouraged to keep a 3 day supply of drugs at home to cover times when medical care is not available – at night or weekends. .Very importantly people at risk must be informed of the availability of PEP.

The second is pre exposure prophylaxis. This is taking antiretroviral drugs on specific occasions when there might be a risk of exposure. This absolutely cannot replace the use of condoms, but some individuals may wish to take an additional even if unproven preventative measure. This really is a matter for individual choice. Our obligation is to make it very clear that this is not a substitute for condoms.

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HIV disease and alpha interferon

March 21, 2009 Leave a comment

I had intended to continue writing about individualization of treatment for HIV infection with an emphasis on the variability of the natural history of HIV disease. Instead, I will make an historical digression. I’ll do this from time to time. An account of the diverse AIDS related issues with which I have been involved since 1981 (and even before the epidemic was first recognized) is on my web site aidsperspective.net. I’m slowly adding content. This should speed up; a lucky circumstance has provided me with access to professional web advice. I have until now had to rely on “how to” articles to get the site going. Surprised that at 76 I have got this far. At the outset I had said that one purpose of this blog was to bring attention to the web site, and that is one reason for this short introduction.

This post is concerned with the connection between alpha interferon and AIDS. I should say connections; there are many.

Today, most people will probably only be aware of interferon in connection with the treatment of hepatitis C in HIV infected and uninfected individuals. The benefit conferred by interferon treatment to many people with Hepatitis C, even those co infected with HIV is tremendous. The FDA first approved interferon alpha for the treatment of hepatitis C in 1991.

There are many connections between interferon and AIDS; the first of these became evident in 1981, the year the epidemic was recognized.

People with AIDS produce large amounts of interferon themselves. The sustained production of large amounts of interferon by untreated HIV infected people with more advanced disease is not only a part of the disease, but the most compelling evidence suggests that its various actions contribute to producing some of the abnormalities associated with it. But, paradoxically, in the early years of the epidemic more was injected into patients in attempts to treat the underlying disease. (There is an important difference between this and treating Kaposi’s sarcoma or Hepatitis C in coinfected people with interferon).

That interferon can be seen as both contributing to the disease and also as a means of treating it makes for a confusing but interesting story [1]

It will be helpful to start with a very brief description of the interferon system.

The interferons – there are several types, are a family of proteins produced by vertebrates. They are cytokines, the name given to polypeptide or protein molecules produced by cells which act as signals that can influence their behavior, and that of other cells distant from the producing cell. In acting at sites distant from where they are produced, cytokines are akin to hormones.

All the interferons share some common properties, and it is easier to write about interferon in the singular. Interferon is best known for its broad antiviral effect. It is produced by cells in response to viral infections, and circulates to render other cells resistant to infection, thereby playing a central role in recovery.

Most viruses are sensitive to interferon and it was once hoped that interferon might prove to be a broad spectrum antiviral agent, similar to broad spectrum antibiotics that act against bacteria. There was great difficulty in purifying interferon for human use but in 1980 recombinant DNA technology permitted the manufacture of large amounts of pure interferon by inserting the gene for interferon into bacteria or yeast. Apart from its antiviral effect, interferon has numerous other effects, particularly on the function of the immune system. It can inhibit the growth of certain cancers, and has an inhibitory effect on new blood vessel formation. It therefore has been effective in the treatment of AIDS related Kaposi’s sarcoma. Unfortunately its clinical utility is more limited than originally hoped. Its greatest success is in the treatment of hepatitis C. Here are some brief reviews:

http://pathmicro.med.sc.edu/mhunt/interferon.htm

http://www.isicr.org/pdf/IFNprimer_ISICRApril_2006.pdf

To return to interferon and its connections with HIV:

This paradoxical situation – in which interferon is seen at the same time to be harmful and helpful, has given rise to some peculiar interpretations. Research directions have been influenced; on balance the desire to treat HIV disease itself with interferon (as opposed to treating Kaposi’s sarcoma and Hepatitis C in coinfected individuals) has probably inhibited research into its role in pathogenesis. It is notable that the overproduction of alpha interferon, a striking abnormality in people with AIDS, known since 1981, was barely studied, let alone discussed, in the first years of the epidemic.

This strange story of a substance seen by some to be harmful, and by others to be beneficial in the same circumstances, is best told in the light of my own experiences in both fields; in AIDS and in interferon.

The two areas that have occupied my professional life have been the laboratory study of the mechanism of interferon’s antiviral action, and clinical work in HIV disease, providing direct medical care to a very large number of HIV infected people as well as conducting clinical and laboratory research on this disease.

In the strangest of circumstances these two fields came together as early as 1981. In that year, AIDS was first recognized, although I and others had already noted early manifestations of what was to be called AIDS among our patients.

The first information I received concerning the occurrence of Kaposi’s sarcoma in several gay men in New York City came from Dr Joyce Wallace. She had received a biopsy report of a diagnosis of Kaposi’s sarcoma in one of our patients. Joyce had called the National Cancer Institute to ask if there was a physician in New York who was familiar with what was then a very rare condition. She had been told that there were – I think at that time, about 20 men with this condition in New York who were under the care of Dr Alvin Friedman-Kien.

This was quite astounding. Unsurprisingly, I did not immediately connect this with what I had been seeing in my own practice, – enlarged lymph nodes, enlarged spleens, low white blood cell counts, low blood platelets among other abnormalities.

Jan Vilcek, who was head of the virology lab at NYU is an old friend and interferon colleague, and I knew Alvin, because he also worked in Jan’s laboratory. So I immediately called to obtain more information about this remarkable news.

Given my training and experience as a microbiologist and the nature of my practice, there was no question that I needed to contribute to the response.

So, in 1981, I also started to work in the virology laboratory at NYU.

I divided my time. Mornings were spent in the lab, and patients seen in the afternoons.

My work in the lab was initially focussed on cytomegalovirus (CMV) as there was evidence that many gay men at risk for this new disease were actively infected with this ubiquitous virus and excreting it at rates higher than noted in others. There also was literature at that time suggesting that CMV was involved in the development of non AIDS related Kaposi’s sarcoma (an idea that was not to hold up).

Once in the lab a strange circumstance brought interferon back into my life in connection with this new disease.

I read a preprint of a paper of Jan Vilcek’s where he described the ability of an antibody to lymphocytes – specifically anti CD3, to induce the synthesis of gamma interferon. Because of other observations that were made on our first patients, I had the idea that we would find gamma interferon in the circulation of patients with AIDS. This incident has been recorded and published by Jan Vilcek and an extract of the article can be seen by clicking here.

This is just the relevant part from a longer article, appearing in the annual “Interferon” series published by Academic Press and edited by Ion Gresser.

It explains how we came to look for interferon in the blood of people with AIDS. Alvin Friedman-Kien provided sera from his patients, and Jan Vilcek provided just about everything else. Gene De Stefano, who is the lead author on the paper we finally published,[2] was a student working in Jan’s lab. The author’s names are in alphabetical order, as this seemed the best way to deal with the matter of precedence, as so many collaborators had become involved. I had sent sera to Robert Friedman in Bethesda, another old friend and interferon colleague, and we joined forces in pursuing this work.

As Jan Vilcek’s account describes, my idea proved to be wrong, the interferon we found was not gamma interferon, but alpha interferon.

Many years later gamma interferon was detected in the circulation of people with AIDS.

This was the first of many connections between interferon and AIDS, a connection made in the first year of the epidemic.

It immediately suggested that the sustained presence of large amounts of interferon in the circulation might be contributing to pathogenesis, and that there was an autoimmune component to AIDS. Apart from AIDS, at that time the only other situation in which there was the sustained presence of large amounts of interferon was in auto immune diseases such as lupus. Also, as individuals with various diseases, including Hepatitis C were treated with interferon, auto immune complications were noted among them.

Since I will be critical of some aspects of AIDS research in relationship to interferon it is very important that, before I get into this, I make the following point very clearly.

Interferon has been of inestimable value to people infected with Hepatitis C, including those coinfected with HIV. Interferon in combination with ribavirin has been able to cure many individuals of Hepatitis C infection. It has thus been life saving, as the consequences of Hepatitis C infections can include liver cirrhosis and liver cancer. It is probably the case that interferon’s greatest clinical triumph has been in the treatment of hepatitis C. At one time it was also the only available treatment for Hepatitis B.

So, to emphasize the point, interferon for the treatment of hepatitis C in HIV infected individuals can be life saving. It may be useful in some instances of Kaposi’s sarcoma unresponsive to antiretroviral drugs.

But I believe it has absolutely no place in the treatment of HIV disease itself. There are early reports of benefits conferred by interferon treatment [3] but there is also a great deal of persuasive evidence that long term treatment is hazardous[4]. (This article contains numerous references supporting a role in pathogenesis for interferon).

So this is an illustration of the Jekyll and Hyde view of interferon. Does it mediate some of the pathological features of HIV disease, or should we use it to ameliorate these features?

On balance, I believe the evidence supports the view that overproduction of alpha interferon contributes to the manifestations of HIV disease. In specific instances, particularly in Hepatitis C in coinfected individuals and in some cases of AIDS related Kaposi’s sarcoma, the benefits of interferon most definitely outweigh the risks. This is particularly true in people with higher CD4 counts.

Nonetheless overproduction of interferon is a feature of AIDS. But It took many years for work to be done to identify the interferon producing cell. This was achieved by Frederick Siegal in 1999.

Quite early in the epidemic, AIDS was described as a disease characterized by a dysregulation of cytokine production. Interferon is a cytokine, in fact the very first to have been described, but it rarely appeared in the list of cytokine abnormalities associated with AIDS.

Here are some of the biological effects of interferon that resemble features characteristic of HIV disease:

Interferon inhibits the development of white blood cells and platelet and red blood cell precursors. It causes fevers. It stimulates the production of a molecule called beta2microglobulin, which was used as an adverse prognostic marker in AIDS. It affects lipid metabolism and can cause an increase in serum triglycerides, observed in AIDS patients before the era of HAART. It modulates the activity of B cells, which make antibodies, and B cells are overactive in AIDS.

But perhaps of greatest interest is the ability of Interferon α to selectively inhibit the proliferation of the CD4 lymphocyte subset, a finding that was published as early as 1983.[5]It also has a slight stimulatory effect on CD8 lymphocytes.

This is the “dark and sinister” side to interferon.

Given these effects of interferon it is hard to understand what the researchers hoped to achieve by injecting yet more of into people who were already full of it.

Two reasons were given for administering interferon. Firstly interferon has antiviral properties. This rationale was resistant to the obvious problem that despite large amounts of interferon in the circulation, HIV continued to replicate. Indeed, as the disease progressed and viral production increased, so did the levels of interferon.

The second reason given was that cells taken from people with AIDS could not be stimulated to produce interferon in the test tube. This was an early finding of Dr Siegal.

The inability of cells from people with advanced HIV disease to make interferon in the test tube is actually exactly what is to be expected. It has been known for many years that when cells are exposed to large amounts of interferon for long periods, they cannot be stimulated to make interferon. They are in what is called a refractory state. The authors describing the inability of patient’s cells to make interferon seemed to not consider this, and so the strange idea that the inability to make interferon was an intrinsic abnormality in AIDS was advanced as a reason to administer interferon.

The inability to induce interferon production in cells derived from people with AIDS is indeed strange as the circulation from which they are removed is full of it. The interferon must come from somewhere. It is possible that it comes from cells in solid tissue. The reason for suggesting this is that membrane fragments from HIV infected cells are excellent inducers of interferon. This suggests that in the body, interferon may be made by cells that are in apposition to HIV infected cells in solid tissue.

This may be more difficult to study now. AZT promptly removes interferon from the circulation, and this is probably true for all effective antiretroviral drugs.

The prompt removal of interferon by antiretroviral treatment must make one wonder if this is at least part of the reason for the benefits of treatment. Inhibition of HIV replication, associated with the loss of circulating interferon definitely suggests that HIV is responsible for the high levels of interferon.

In this connection here are some results that we observed:

aidsinf-12

The solid line represents HIV levels, and the dotted line interferon levels. These two individuals, A and B were treated with AZT for one week at weekly intervals. Both interferon and HIV levels promptly decline when on AZT and just as quickly go up when AZT is removed.


aids-inf-2

These three people started AZT at time 0. Both HIV (p24) and interferon rapidly decline.


aids-inf-3

These are individuals on continuous AZT therapy. Interferon rapidly declines in all, but returns at varying times despite continued treatment with AZT. Is it possible that the transient and variable duration of benefit experienced, coincides with the period when interferon is absent?


aids-inf4


This is one person on continuous AZT treatment. Interferon starts to return and rise before 18 weeks. P24 only returns after 33 weeks. However this does not necessarily mean that interferon returns to the circulation before HIV. P24 measurements are not that sensitive and if PCR had been used HIV may have been detectable much earlier.

This is turning out to be a long post, and I will just make a few more points and end it.

When cells are exposed to interferon for prolonged periods several changes are noted in addition to their diminished capacity to make interferon when stimulated to do so. The antiviral action of interferon depends on the attachment of interferon to a specific cell receptor. The number of interferon receptors is reduced in cells taken from patients with AIDS, most probably as a result of exposure to endogenous interferon, and this may partly explain the diminished antiviral effect of interferon in advanced disease. This finding also has implications about possibly diminished effects of added interferon

From the point of view of interferon’s antiviral action only, it might seem advantageous for interferon to always be present. But there are active mechanisms to turn off its production, usually after a matter of days, which supports the view that prolonged exposure to interferon can be detrimental. Its many actions – other than its antiviral action are in fact deleterious. Apart from untreated HIV disease, lupus, an autoimmune disease is also associated with the sustained production of interferon α. There are studies in this disease on the mechanisms that sustain interferon production that may also have relevance to HIV disease. In HIV disease, it may of course be the persistence of HIV, but the opportunity to do study this has probably been lost as antiretroviral treatments remove interferon from the circulation.

When the question was asked, why add more interferon to people who already had lots of it, the answer was that the interferon already in the patient, (the endogenous interferon), was different to that to be injected. The basis for this claim of difference was that endogenous alpha interferon was unstable in acid, unlike conventional interferon.

But endogenous alpha interferon did everything that conventional interferon did – most importantly it had the same antiviral properties. Further, there was evidence that the acid instability was not an intrinsic property of the interferon molecule[6].

The neglect in pursuing a possible role in pathogenesis of high levels of circulating interferon was connected with a desire to use it to treat people with AIDS. This was a strange initiative. Apart from Kaposi’s sarcoma and hepatitis C it helped nobody in the long term and subjected people to extremely unpleasant side effects. Considering what interferon can do, one must wonder what effect it might have had on disease progression in the longer term.

Here is an extract from a transcript of a meeting in New York City that Dr Fauci attended to answer questions. This is the response to a question about administering interferon to people who already had more than enough of it in their circulation:

Fauci:

No. I think that acid-labile alpha interferon is an abnormal form of alpha interferon that really doesn’t have the same effects as the kind of interferon we’ve been infusing. It’s almost as though it’s two different drugs. It’s very confusing, because that’s been in the literature and in the paper a lot. It really is different. It’s different. It isn’t the same. There are some similarities, obviously, because it’s the same type of species of an agent, but there are some differences. Whether or not it’s doing harm or good, we don’t know, because there’s so many other things going on ………………………

Fouratt:…….

You said there are differences, and then you went on. But I didn’t hear what the differences were between the two.

Fauci:

Yeah. In vitro effects. Joe, you look like you had a question about that.

Sonnabend:

I’m not aware that there are any biological differences between acid-labile interferon and conventional interferon. Acid-labile interferon is neutralized by antibodies to conventional interferon. There’s been a recent report that, as you know, in lupus, a similar interferon appears, and there’s quite some conjecture that indeed it may play a role in pathogenesis. More recently, from Jan Vilcek’s lab, there’s been a demonstration that the acid lability may be due to another protein that sticks to it. If that’s so in lupus, my guess is that there’s no reason to think it’s different in AIDS. As far as I know the biological properties of acid- labile interferon are identical to those of –

Fauci:

Yeah, well –

The other argument for using treatment with interferon was that cells from AIDS patients could not make interferon. As noted, the problem with this justification is that the people from whom these cells were taken were full of interferon, which had to come from somewhere. So if the cells taken from the patients were unable to be stimulated to make interferon, other cells are actually overproducing it.

There are still some attempts to treat HIV infection (as opposed to hepatitis C and Kaposi’s sarcoma) with interferon. It is possible that a place may eventually be found for its use, but this would almost surely be on temporary basis and in those who do not already have interferon in their circulation.

The presentation made in 1991 from which the figures in this post were taken can be seen by clicking HERE; there are a few contemporary annotations.


[1] “For, like the character of Dr Jekyll and Mr Hyde, interferon , while possessing great virtues, has a dark and sinister side” Susan Krown, in “Interferon 7” 1986 Academic press p 185-211

[2] DeStefano-E, Friedman-R-M, Friedman-Kien-A-E, Goedert-J-J, Henriksen-D, Preble-O-T, Sonnabend-J-A, Vilcek-J

Acid-labile human leukocyte interferon in homosexual men with Kaposi’s sarcoma and lymphadenopathy. The Journal of infectious diseases, {J-Infect-Dis}, Oct 1982, vol. 146, no. 4, p. 451-9, ISSN: 0022-1899.

Abstract

Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-alpha) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of Hu IFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

[3] Marroni M., Gresele P., Landonio A. et al. Interferon-alpha is effective in the treatment of HIV-1-related, severe, zidovudine resistant thrombocytopenia. A prospective, placebo-controlled, double-blind trial. Ann Intern Med 1994; 121(6): 423–429.

Skillman D. R., Malone J. L., Decker C. F. et al. Phase I trial of interferon alfa-n3 in early-stage human immunodeficiency virus type 1 disease: evidence for drug safety, tolerance, and antiviral activity. J Infect Dis 1996; 173(5): 1107–1114.

Rivero J., Fraga M., Cancio I., Cuervo J., Lopez-Saura P. Long term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy 1997; 10(2): 107–113.

Mauss S., Klinker H., Ulmer A., et al. Response to treatment of chronic hepatitis C with interferon alpha in patients with HIV-1 is associated with higher CD4+ cell count. Infection 1998; 26(1):16–19.

Yabrov,A. It is hazardous to treat HIV patients with interferon-a

Medical Hypotheses (2000) 54(1), 131–136

[5] Selective effects of alpha interferon on human T-lymphocyte subsets during mixed lymphocyte cultures.

Scandinavian journal of immunology, {Scand-J-Immunol}, Jun 1983, vol. 17, no. 6, p. 559-67, ISSN: 0300-9475.

Hokland-M, Hokland-P, Heron-I, Schlossman-S-F.

Abstract

Mixed lymphocyte reaction (MLR) cultures of human lymphocyte subsets with or without the addition of physiological doses of human alpha interferon (IFN-alpha) were compared with respect to surface marker phenotypes and proliferative capacities of the responder cells. A selective depression on the T4 (inducer) T-cell subset could be demonstrated as a sequence of events: decreased fluorescence intensity of the T4 inducer cells (day 2 of culture), decreased percentages of T4 cells as demonstrated by cell cytofluorometry (days 3-6 of culture) , and decreased 3H-thymidine incorporation of purified T4 cells and decreased numbers of T4 cells harvested from IFN MLRs (days 5-6 of culture). In contrast, it was shown that the T8 (cytotoxic/suppressor) subset in MLRs was either not affected or slightly stimulated by the addition of IFN. The depression of the T4 cells by IFN was accompanied by a decrease in the number of activated T cells expressing Ia antigens. On the other hand, IFN MLRs contained greater numbers of cells expressing the T10 differentiation antigen. In experiments with purified T-cell subsets the IFN effect was exerted directly on the T4 cells and not mediated by either T8 suppressor cells or monocytes. These findings are discussed in relation to other immunoregulatory effects of IFN-alpha.

[6] Endogenous “acid labile” interferon is neutralized by monoclonal antibodies against conventional “acid stable” interferon. The amount of interferon in a preparation was measured by observing how much the interferon containing sample could be diluted before it lost antiviral activity. Samples from patients contained antiviral molecules other than alpha interferon, and those that synergized with alpha interferon to increase its effects. Gamma interferon and TNF would be examples. These are destroyed by acid – not the interferon.

Individualization of HIV therapy

March 8, 2009 1 comment

Why treatment of HIV infection must be individualized.

HIV disease is usually a progressive disease. That is, it has a starting point; the time of infection. The disease then progresses, and without treatment will generally end fatally. There are some very fortunate HIV infected individuals who are able to control viral replication and remain disease free. But for most, HIV disease does progress. But, for each individual, the rate at which it progresses varies widely. Disease progression is reflected in the fall in the numbers of CD4 lymphocytes.

So any single CD4 count measurement is really a point on a descending curve, one that does not necessarily proceed in a straight line, and falls at widely differing rates in different individuals.

Recommendations for the treatment of HIV infected individuals are issued periodically by DHHS and bodies such as the International AIDS Society. These recommendations, particularly those concerning when to start antiviral treatment, have always included a particular CD4 count as a signal to start or to consider starting antiviral treatment.

All individuals with a CD4 count of less than 200 should be on therapy. They are in great danger of acquiring a possibly fatal opportunistic infection and evidence derived from clinical studies makes it absolutely clear that antiretroviral treatment is life saving.

But what about people with higher CD4 counts? Here there is uncertainty about when in the course of HIV infection it is best to start treatment. Of course, if the drugs were completely harmless (including cost) it might be less important to have an answer to this question. However the drugs can have significant adverse effects, some of which only become evident after years of use. For people with fewer than 200 CD4 lymphocytes, the benefit of antiviral treatment overwhelmingly outweighs the risks.

For others, a very mixed group, with CD4 cells anywhere from 200 to over 1000, and each with a different rate of disease progression, we cannot, with any security, make a “one size fits all” recommendation as to when it is best to start treatment.

The best way to resolve clinical uncertainty remains randomized prospective clinical trials. By now we might already have obtained reliable evidence as to whether, on average, it is best for infected individuals with more than 200 CD4 lymphocytes, and who have no symptoms, to start antiviral treatment immediately, or to defer it. (A suggestion made in 1997 when the first guidelines were issued: http://aidsperspective.net/articles/guidelines1.pdf )

The current recommendations, regarding people with greater than 200 CD4 lymphocytes, and who are without symptoms, propose a CD4 count of 350 as a point to start treatment ( many believe this number should be 500). This recommendation is made for all individuals – it is a one size fits all approach[1]. This kind of approach is appropriate for some aspects of treatment; for others it is very wrong[2].

Perhaps the most important  example of a  recommendation, where its application across the board  is problematic,  is that which deals  with the time when antiretroviral treatment should be started in individuals with greater than 200 CD4 lymphocytes.  This recommendation specifies a specific CD4 count at which to start. As noted, for individuals with a CD4 count below 200, there is no doubt that they will benefit from therapy. For others who have no symptoms, specifying a CD4 count for all is mistaken. It is here that individualization is necessary.

The reason is that no two HIV infected people are the same with respect to the rate of disease progression. During the early years of the epidemic, before antiretroviral treatment was introduced, we soon noted that the CD4 count declined at different rates in different people, and not necessarily in a straight line. As noted, at one extreme, there were the few fortunate individuals in whom there seemed to be no disease progression, at the other there were the few people whose CD4 cells fell very rapidly after infection, and who did not survive for more than 2-3 years, but most fitted somewhere between these extremes .

To illustrate this I have considered four possible situations. This is a picture of the possible rates of CD4 decline in four different individuals. . It is true that these pictures are constructs, but they do accurately reflect the observed variability in disease progression; real examples showing this variability would be easily found in my medical records, and of course in those of other physicians during the period between 1981 and about 1993.

The dip in CD4 cells following infection is usually seen when there is an opportunity to observe this. CD4 cells then rebound to a level called the set point, which will be different in relation to the pre infection level in different people. From then on it declines, but at a very variable rate, and can remain steady for varying periods before declining, again at varying rates.

img049

Look at where three of them (A ,B and C) reach a count of 450 CD4 lymphocytes; A (an unusual rapid progressor) gets there in about one year, B in about 3 years, C in 7 years, and D, who is a fortunate non progressor is nowhere close after 18 years.

The arguments for starting early are not only to forestall reaching the dangerous level of 200 CD4 lymphocytes. The continuous deterioration of the immune system and diminished chances of recovery at lower counts are also arguments for an earlier start. There is also the possibility that there is a greater incidence of cancer, – other than lymphoma and Kaposi’s sarcoma, at higher CD4 counts in HIV infected people. If this is so then it remains to be shown how frequently these events occur and whether antiviral therapy can avert them.

Treatment itself, particularly if extended over many years, is not without risks, some of which cannot even be completely known yet, particularly with the newer antiviral agents. We have to do the best we can in making a risk benefit assessment. In order to do this we should attempt to obtain information on the rate of disease progress in any one individual. This may not be entirely possible, as the rate of disease progression in any one individual may not be steady; it may accelerate or slow down. But it is possible to obtain a good, if not perfect, picture of the course of HIV disease in any one person.

How might we obtain some information about a given individual’s rate of disease progression? Apart from obvious exceptions, and in people below 200 CD4 cells, there are no emergencies in HIV medicine. For each person we generally will have time to observe the CD4 count and viral load over a period of 6 to 12 months and obtain some idea of the rate of progress. A rapid fall in CD4 count might result in a decision to start in less than six months of observation. Or a consistent fall in CD4 count might lead to a decision to start treatment at CD4 numbers higher than even 500. This is far from perfect, as changes in CD4 cell numbers do not necessarily follow a straight line. But it is far better than basing a decision on a snapshot – which is what the experts are telling us to do.

Individualization involves more than considering the rate of disease progression. There are other factors, such as associated diseases, domestic and social circumstances such as a lack of housing, as well as mental health issues, and many other considerations that are involved in individualization. Observing people also provides the time to establish a doctor patient relationship and for the physician to become familiar with the patients particular circumstances.

The natural history of untreated HIV disease is relevant to the “when to start treatment” issue and will be the topic of the next post.


[1] Evidence supporting the recommendation is derived in part from retrospective observations. The reasons why these are unreliable guides are outlined in the previous post. It is critical to as far as possible, eliminate bias in study designs because this increases the probability that a particular outcome can be interpreted as indeed resulting from a particular intervention. In this case it would be that improved survival is due to an earlier start of antiviral therapy and that the medications mediate the effect – and not for example, from simply being under the supervision of a physician. Retrospective observations, that is, looking back at information already gathered cannot be free of confounding factors as described in the previous post. In a prospective study people would be randomly assigned to receive immediate treatment or to defer it. This will give us the most reliable answer to the question of which approach is better on average.

[2]Examples of measures that should be taken in the treatment of every HIV infected person, irrespective of the rate of disease progression are the types of tests that are performed on the initial assessment of an infected person. For example, the initial assessment of an HIV infected person should always include not only CD4 counts and HIV viral load measurements, but also tests for hepatitis, toxoplasmosis, and many other investigations. Another example of an intervention that is appropriate for categories of infected people is treatment to prevent Pneumocystis pneumonia in people with less than 200 CD4 cells. And of course, people in this category must always be offered antiretroviral therapy.

aidsperspective.net

March 6, 2009 1 comment

Today, March 6th 2009, I have moved this blog to aidsperspective.net/blog.  All new posts will be to that site.

Categories: Uncategorized