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

June 6, 2009 1 comment

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

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

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

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

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

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

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

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

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

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

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

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

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

The title of the article is:

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

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

I have copied this table from the above article:

tropical

These are incredibly huge numbers.

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

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

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

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

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

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

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

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

I used an excellent article to illustrate this problem.

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

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

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

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

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

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

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

lawn1

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

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

lawn21

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

“Prevention and Treatment of Coinfections

The widespread use of HAART in the treatment of HIV-

infected persons in westernized countries has resulted in a

phenomenal decrease in the incidence of opportunistic infec-

tions and has greatly increased survival. For these individuals,

the antiretroviral drugs are the major determinant of prognosis

and the potential cofactor effect of opportunistic infections is

now a more minor consideration. However, the vast majority

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

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

developing countries, where the quality and access to health

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

endemic infectious diseases such as malaria, TB, and infections

by helminths and waterborne pathogens which may adversely

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

ment of these diseases may therefore represent an important

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

tries”. –

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

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

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

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

Those were comments made 2-3 years ago.

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

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

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

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

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

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

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

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

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

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

Treatment as Prevention: Protecting individual autonomy. May 2010

May 18, 2009 2 comments

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

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

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

This document can be seen here:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Instead we should:

Offer treatment to all who need it.

Facilitate testing, identifying and removing barriers that impede it.

Intensify and improve our efforts at targeted prevention education.

Promote condom use and make them available.

There is a final issue.

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

The Not So SMART Study

April 27, 2009 2 comments

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

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

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

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

There were a total of 85 deaths in the study.

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

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

.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

8 people died from substance abuse, 7 from violence.

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

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

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

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

There are two distinct  questions to be asked.

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

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

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

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

I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals”. This current entry on the SMART study, which I’m leaving unchanged,  should be looked at in conjunction with my subsequent post. LINK TO LATER POST ]

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

I doubt if information on compliance is available.

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

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

There could be a connection with general patient care.

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

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

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

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

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

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

To put the questions in another way:

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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




When is it best to start antiretroviral treatment: an update

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

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

But is this confidence justified?

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

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

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

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

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

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

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

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

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

prespecified thresholds significantly improved survival, as compared with deferred

therapy

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

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

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

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

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

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

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

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

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

Here is another serious problem with this study.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A previous post discusses the  issue of individualization of treatment.


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

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

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

April 13, 2009 2 comments

“Starting HIV Therapy Earlier Saves Lives”

“Study: Treatment for HIV Should Start Earlier”

“Starting Therapy Earlier Found to Improve Survival”

“Earlier HIV Treatment Boosts Survival”

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

But is this confidence justified?

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

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

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

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

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

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

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

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

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

prespecified thresholds significantly improved survival, as compared with deferred

therapy

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

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

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

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

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

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

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

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

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

Here is another serious problem with this study.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A previous post discusses the  issue of individualization of treatment.


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

Often forgotten, the second pillar is individual clinical judgement.

HIV Infection in HIV Antibody Negative Individuals

April 1, 2009 2 comments
  • HIV infection in HIV antibody negative individuals

The possibility that there are individuals who are infected with HIV but who are negative on the test for HIV antibodies has always been theoretically possible. Considerable evidence has accumulated for many years that there are indeed such individuals. Despite the importance of this phenomenon, it receives relatively little comment.

It sometimes seemed to me ever since I first tried to discuss this possibility in the mid 1980s that there was a wilful discouragement of any discussion of this topic.

In 1989 David Imagawa reported that that 31 of 133 HIV antibody negative men showed the presence of HIV.

In 27 of them this persisted for 36 months despite remaining seronegative  [1]. This resulted in a vigorous response culminating in what almost looked like a retraction by the authors. At that time many unsuccessful attempts to replicate these results were reported, and the findings of David Imagawa were generally presented as due to technical errors, such as incorrect specimen labelling. In view of many subsequent findings, the likelihood is that David Imagawa and his colleagues were correct. The furious response to Imagawa’s paper is an indication of how non rational considerations can influence the progress of science. This is of course nothing new.

Curiously in a recent book, Imagawa’s findings are included in a list of what are stated to be errors and controversies in the HIV/AIDS epidemic that impeded scientific progress [2]

What in fact impeded progress was a rigid adherence to what was only a hypothetical, not an empirical model of the course of HIV infection.

David Imagawa died shortly after this controversy, and sadly did not live to see that his initial conclusions were absolutely consistent with what has been learned of the complexity and diversity of individual responses to HIV infection.

I certainly experienced considerable resistance and disbelief when I raised the possibility of silent HIV infections. In the late 1980s I took part in a NPR program, and was quite abruptly dismissed by another scientist (I have forgotten who) when I raised the absolutely reasonable theoretical possibility of persistent latent infections in antibody negative individuals.

Apart from very few exceptions there was an almost complete lack of interest in HIV seronegative, but infected individuals, by science writers; there was no shortage of community commentators who also seemed to be oblivious or uncaring of this phenomenon.

To be sure there were occasional reports of seronegative but infected individuals. Gus Cairns, a UK journalist wrote about this in the UK magazine, Positive nation. I wrote something about this as a result of an interview with him in 2000, which he published. I have scanned the article. I was unable to make a perfect copy, but a legible version can be seen by clicking HERE.

In the US reports confirming the existence of seronegative infected people continued to receive very little comment; what little there was was generally quite hostile..

Today this issue was again brought to my attention by an article I saw reporting the presence of HIV proteins and HIV RNA in cervical biopsies from women who were persistently HIV seronegative , at least for the duration of the study which was one year [3]. They did not have antibodies to HIV despite being infected; of course it is possible that they are in an unusually long “window period” and will eventually seroconvert.  If we use “window period” in this sense then we  can speak of a distribution of window periods of different lengths, including an indefinite one.

I expect that, as is usual this report will provoke little or absolutely no interest.

But it is enormously interesting; (just one of many questions: can these women infect their male partners?)

Seeing this article is the reason why I decided to make this issue the subject of this post.

It was no great surprise when evidence appeared that there were some individuals who were HIV infected but remained negative on the HIV antibody test. It must be said that there were probably more papers in the early years in which silent HIV infections in HIV antibody negative individuals was not observed.

In another approach, reports started to appear that HIV antibody negative individuals had T lymphocyte responses to HIV which means that they were exposed to the virus, not necessarily that they were infected – although that is quite a real possibility. Some early papers, before 2000, including those showing T cell responses can be seen by clicking HERE . There was quite an extensive literature at that time, but most, as mentioned reported that there was no such thing as a silent antibody negative infection, apart from the short window period following infection.

Why has the possibility of prolonged latency always been theoretically possible?

As part of its life cycle HIV is turned into DNA and is then incorporated into the host genome. In infected cells it effectively becomes part of our genetic material. Once inserted into human DNA, it must be activated to start the process of making new virus particles. Cellular signals that start the process of activating HIV DNA include cytokines, which are messenger molecules produced and released by cells, which can then act on other cells to evoke a variety of responses. Amongst these HIV activating cytokines are those that are called proinflammatory cytokines.  These appear during the course of many different infections.  Once HIV DNA is activated, and at least some of its proteins made, these then mediate further activation.

There are some other factors that can activate HIV DNA.

Alloantigens are antigens expressed on foreign cells. When these antigens are in contact with a cell containing integrated HIV DNA, activation occurs; HIV DNA is transcribed and new viral particles made. In earlier days HIV was isolated from infected lymphocytes in this way. Latently infected lymphocytes were induced to produce HIV by culturing them together with lymphocytes from an uninfected donor.

It is the nature of HIV infection that it is frequently acquired in situations which involve exposure to foreign cells (to alloantigens). This may be exposure to semen in sexual transmission, or blood cells in the case of infection by shared needles, or by blood transfusion.

Herpes viruses have the ability to activate HIV if a cell is infected with both viruses. I suppose this must happen but I imagine doubly infected cells may not be found  too frequently. Of course active herpetic infections in non HIV infected cells may be associated with the production of pro inflammatory cytokines, which circulate and can activate HIV DNA in a cell at a distance.

There is absolutely no reason not to expect that in some circumstances incorporation of HIV DNA into human DNA will result in a state of stable integration. This means that HIV DNA remains in the genome, it is not activated, and no virus is produced. Since antibodies are made as a response to viral proteins, and as none are made, the HIV antibody test will be negative.

So it was no surprise when such individuals were again reported in 1999 [4]. These individuals remained in good health and were reported to be antibody negative as long as they were observed [5].

We cannot know if these individuals may seroconvert (or maybe already have), but what is established is that stable integration of HIV DNA without seroconversion can occur. In such individuals limited expression of HIV can occur, at least sufficient to induce, if not antibodies, a cellular immune response.

The presence of such cellular immune responses in HIV antibody negative individuals is further evidence consistent with HIV DNA persistence, but in itself does not indicate this.

Demonstration of cell mediated immunity to HIV:

Apart from the identification of antibodies, specific immunity to HIV can also be detected by a much more elaborate test that measures cellular immunity rather than immunity determined by detecting specific anti HIV antibodies. In this case what is measured is the ability of lymphocytes to recognize HIV. They will do so only if they have been exposed to the virus, which would obviously be the case if they were taken from an infected individual.

The detection of such lymphocyte responses in the mid 1990s was one of the first indications that there may be infected people who don’t make antibodies. Other interpretations are that the infection was overcome, or that that the individual was infected with defective virus.

Gene Shearer was I believe the first to report this phenomenon. HIV antibody negative sexual partners of HIV positive people, as well as individuals who had occupational contact with HIV were among those showing these responses.

It is unknown how widespread this phenomenon of silent HIV infection is. It may be exceedingly rare. It is also unknown if this condition of stable integration is really just a prolonged “window” period that always follows all HIV infections.

But it is entirely possible that there are individuals in whom the ability to control HIV is such that they will remain healthy and HIV negative.

A number of different  outcomes of HIV infection are possible:

Some of the factors that influence this:


Host genetic factors.

Size of the inoculum – the amount of infecting virus.

Route of infection

The particular virus strain.

The presence of associated systemic infections.

these provide signals activating HIV proviral DNA. In the case of some tropical infections there may be cytokines (IL 10) that blunt immune responses.

Sexually transmitted infections with genital ulcers.

Double infection of a cell with HIV and herpes viruses – probably an unusual occurrence.

Exposure to alloantigens; a theoretical possibility.

These are some of the known influences.

Maybe the most common outcome is a productive infection where viral DNA is activated within a few weeks.

But this scenario is also possible:

Infection is followed by insertion of HIV DNA into cellular nuclear DNA. Possibly with small inoculums, and in the absence of strong or sustained activation signals, the proviral DNA remains silent. This has been observed.

Or this one:

There is a limited burst of viral production, not sufficient to elicit an antibody response but enough to induce a cell mediated response with the generation of lymphocytes that recognize HIV antigens and can kill HIV infected cells. HIV seronegative individuals with such specific lymphocyte responses have certainly been observed. In this case if there is an incipient burst of HIV production, the producing cells are promptly killed. Each time this happens the cellular immune response is primed and strengthened. Such a mechanism has been well studied in EBV infections. This common virus is totally unlike HIV, but it does similar things. It remains present in B lymphocytes rather than T lymphocytes for life. The mechanism of persistence is quite different – EBV is not a retrovirus. But the majority of individuals carry this virus – which in rare situations can have lethal effects, in their B lymphocytes for life. We have evolved many mechanisms to keep this virus in check. The ability of some types of lymphocytes to kill EBV infected cells which start to make virus is well understood. Similar mechanisms must exist for HIV – but obviously for most, are insufficiently effective. But in those with very limited HIV production these killer lymphocytes may actually be what allows such rare fortunate individuals to remain HIV seronegative.

With this outcome, one can view the infection as actually having an immunizing effect.

If there were not yet enough reason to study the phenomenon of persistently seronegative HIV infection, this is an important one. What are the circumstances that produce this outcome?

So, for many reasons individuals who are seronegative but have lymphocyte responses to HIV are of great interest.

Yet another scenario is one of stable integration, but where some HIV proteins, but not complete virus, are produced. Maybe the women referred to whose cervical biopsies contained HIV antigens might be in this category. This is a strange situation as antigens were detected but these women apparently did not develop antibodies.

Another very early observation that can be explained by the prior presence of integrated HIV  DNA that is only activated by a subsequent non HIV  infection is the finding that  episodes  of EBV reactivation may precede HIV seroconversion. [6].  This raises the possibility that at least some illnesses associated with primary HIV infection are nothing of the sort. They instead may represent rather non specific viral infections that activate already present integrated HIV DNA, and thus  followed by HIV seroconversion. This is a completely plausible scenario. Of course self reported sexual histories may sometimes  not be too reliable, but nontheless, I well recall an older gay male patient of mine who told me that he had had no sexual contact for years, he had several negative HIV tests over a period of a few years, and then tested positive.  I wondered  then if he may possibly have been infected years before, that he carried latent HIV DNA and this was subsequently activated by some febrile illness. I know this is only an anecdote, and that individuals can be guarded about their sexual histories.  I wonder if others have had similar experiences?

I think around 1996  a description of the course of infection was produced. Everyone interested in this disease will have seen this picture: Here it is again:

hivaids_9_fig-53

This may represent a typical course of infection.  But HIV disease is probably so variable in the course it can take that there may well not be such a thing as a typical infection.

This depiction does however give the impression that there is,  and discourages an appreciation of the probably  immense variations in the course of  HIV disease.  The notion of a “standard” course of HIV disease has  had implications for treatment.  Recommendations are made that take no account of  individual  rates of disease progression;  a one size fits all approach has been adopted.

The  rapid acceptance that there is a typical – or an  average  course of HIV infection is particularly odd as not only is the disease new – we have no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease are themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea then of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced as the epidemic is proceeding.

A model was constructed before sufficient evidence was available to justify it.  It really had no empirical basis; moreover it seemed to utterly ignore what we knew of other chronic viral diseases.  For example, hepatitis B and Hepatitis C can both have very variable courses.  These can range from clearing the infection, running a fulminant course ending fatally  to the establishment of a chronic active state which may progress at varying rates.  If we were to construct a model of the course of HIV disease only about  12 to 15 years after the disease was first seen, why on earth did we not consider the precedents of other chronic viral diseases?   Thus we might have  included the real possibility that some exposures may result in infections that may be cleared , as well as the now demonstrated situation where silent antibody negative infections occur.    The picture shown above – and presented in every text on HIV disease may indeed represent the most common course of HIV infection. But even this is not  known.

HIV infection, like other chronic viral infections  can progress in different ways. If we were more open to this there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. This has obvious therapeutic implications  –  for example as proinflammatory cytokines promote HIV replication, the control of endemic infections in some areas where they are highly prevalent is absolutely relevant to the control of HIV infection.  Steps as simple as the provision of sanitation and clean water may well have an impact on the control of HIV infection in some geographical areas.  Had we not been so tied to the notion of  a fixed course of HIV infection, we might have placed importance on the individualization of therapy, not only considering a fixed CD4 count as a signal to start therapy, but also considering each individuals rate of disease progression.

HIV disease is in this sense like  every other infectious disease, the course of which  to a greater or lesser extent can be influenced by many different factors , including host factors, factors related to the pathogen, the particular variant , the size of the infecting dose, the route of infection amongst many others.

I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease  does not necessarily  take the course  shown above.

In conclusion, the study of prolonged HIV seronegativity in infected people is important. Some reasons are:

1. There are obvious implications for vaccine development.

2. Seroprevalence may significantly underestimate the prevalence of HIV infection.

3. Understanding the phenomenon will advance our understanding of the pathogenesis of this disease, which in turn will open new therapeutic approaches.

4. There are instances of infected people remaining seronegative and in good health.

[1]

Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al..

Human immunod­eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods.

New England Journal of Medicine 1989 320:1458-1462.

[2]

Scientific Errors and Controversies in the U.S. HIV/AIDS Epidemic: How They Slowed Advances and Were Resolved

By Scott D. Holmberg

Published by Greenwood Publishing Group, 2008

[3]

Human Immunodeficiency Virus (HIV) Antigens and RNA in HIV-Seronegative Women with Cervical Intraepithelial Neoplasia
Jayasri Basu, Seymour L. Romney, Ruth H. Angeletti, Sten H. Vermund, Edward Nieves, Anna S. Kadish, Magdy S. Mikhail, and George A. Orr

The publisher of this journal kindly sends me the contents of each issue as I started this journal around 1983 and was its first editor, seeing it through its first two volumes. It was then simply called AIDS Research.

[4]

Zhu T, Corey L, Akridge R, Change Y, Feng F, Kim J, Alef C, Mcelroy J, Mullins J, Mcelrath J.

Evidence for HIV-1 latent infection in exposed seronegative individuals.

Abstract No.8, 6th Conference on Retroviruses and Opportunistic Infections. Chicago. 1999.

[5]

Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

Journal of virology, {J-Virol}, Jun 2003, vol. 77, no. 11, p. 6108-16,

Zhu-Tuofu, Corey-Lawrence, Hwangbo-Yon, Lee-Jean-M, Learn-Gerald-H, Mullins-James-I, McElrath-M-Juliana.

Abstract

Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specific cytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence for HIV-1 infection in ES individuals below the detection limit of standard assays, suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1 strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection.

[6]
Schattner, A, Hanuka N, Sarov B, Sarov I, Handzel Z, Bentwich Z.

Sequential serological studies of homosexual men with and without HIV infection. Epstein-Barr virus activation preceding and following HIV seroconversion.

Clin Exp Immunol 1991; 85: 209-13.

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.

AIDS and MINORITIES

February 25, 2009 2 comments

February 24th 2009

AIDS and Minorities

In the US, African Americans constitute 12% of the population, yet almost half of the total number of AIDS cases in the country occurs among them. This disaster is only now being generally recognized, with the leadership of the Federal AIDS response finally turning their attention to this tragedy, at least publicly.

This is a tragedy that has been developing in full view for more than twenty years. One only has to look at statistics provided by the Centers for Disease Control (CDC) since the epidemic started to know, as early as 1987 that without intervention a preventable disease was inexorably moving into African American communities.

Firstly, take a look at the situation in 2006 (data from the Kaiser family Foundation).

2006c3

Now take a look at this picture that clearly tells a horrible story that words cannot match.

usepidemic3

In the light of this devastating evidence how is one to understand the comments of Dr Fauci, who can be regarded as the head of the Federal scientific and medical response to AIDS?

He noted that these “shocking statistics would be tragic anywhere but are particularly inexcusable in a wealthy country such as the United States.”

His complete statement can be seen here: http://www3.niaid.nih.gov/about/directors/news/BAAID_09.htm

Look at the above picture again. Cases in African Americans started to exceed those in white Americans in 1994, but the trends were quite evident long before this. We knew in 1988-1989 what was coming. So, one must wonder why it took all of twenty years to announce only in 2009, that these statistics are shocking.

A preventable tragedy was taking shape in full view of the Federal AIDS leadership, who rather than fund a vigorous prevention education campaign directed towards those most in danger, instead chose to support a wasteful, vacuous untargeted prevention education program in the form of “America Responds to AIDS”.

It is not only the federal AIDS leadership that failed to respond to warning signals flashing brightly right in front of them. In the early days of the epidemic there was a vigorous and exemplary community activist response. This was a terrific example of people dealing with a deadly disease taking action on their own behalf, fighting for the best medical and scientific response and against the all too frequent shameful stigmatization of HIV infected individuals.

The flowering of AIDS activism in the late 1980s and early 1990s achieved a great deal. All people dealing with serious illness have benefitted from the precedent that was set. Yet, in recognizing this achievement, we must also wonder why many of these experienced advocates, who no doubt were aware of the demographic trends shown above, seemed generally less willing to at least try to avert the disaster threatening their fellow citizens? Of course some tried, and maybe were overwhelmed by massive indifference.

Whatever the reasons, the advocacy of US activists abroad, particularly in Southern Africa, proved to be more effective than anything they were able to achieve in their own country for their fellow African American citizens. There are also other groups where AIDS has been, and continues to be a growing problem, but have been relatively neglected.

Not for profit organizations, that raise funds to help and advocate for people with AIDS were also aware of what was developing, but if there were any efforts devoted to preventing a calamity visibly descending on the largest community at greatest risk, these clearly were of little benefit.

What is almost, but not quite, as shocking as the neglect of a disaster developing in front of our eyes, is the complete absence of any sense of contrition, let alone a simple acknowledgment of failure, on the part of those who might have helped to prevent it.

If justice includes the notion of equity then prevention resources should be distributed in proportion to the needs of different communities. This clearly has not happened and it might be helpful to give some thought as to why this has been the case.

We need to know and admit what it is that we did unsuccessfully, or failed to do, to stop a preventable disaster, so that we can get it right in the future.

Instead we have a wringing of hands by those who could have done something, but did nothing, to stop this.

A similar article was posted on a health related web site in December of last year. There was no response to the issue I raised.

This post can be seen here.

http://Aidsperspective.net/articles/AIDS_AND_MINORITIES.pdf

Take yet another look at the picture showing the changes in the proportion of AIDS cases according to racial/ethnic group over the past 20 years. It tells the whole story; no comment is really needed.

AIDSPERSPECTIVE

February 4, 2009 1 comment

February 19th 2009

Why another AIDS blog?

In order to just get started on this blog, the various reasons for creating it will be described on my web site: aidsperspective.net One of these reasons, which I suppose is self evident, is to bring some attention to the web site, where I am attempting to create a record of various AIDS related activities I have been involved with since the epidemic was first recognized in 1981. I have more or less learned how to construct a web site – at least to the extent that I am able to post legible material, and I am gradually adding to its content.

Another reason for creating this blog is to provide an opportunity for comment on contemporary HIV/AIDS related events.

With that I can start with the first post on this blog.