Since my last post on this subject I have heard a variety of different views as well as discussed the issue with several interested individuals.
As a result I have come to see the issue somewhat differently; I suppose I could just amend my last post, but it’s better to leave it as it is and describe the differences in how I now view PrEP efficacy trials after having heard several different descriptions of ways in which these are seen.
I listened to presentations at two conferences during the last few weeks. A teleconference organized by CHAMP, a community group, and one organized by the Centers for Disease Control (CDC). These conferences attempted to engage and inform individuals about PrEP. As a consequence I realize that I was mistaken in stating so categorically that efficacy trials of PrEP, unlike safety trials, could not be undertaken in human research subjects. However I do not think that if all the ethical requirements are met, that is to provide condoms, consistent counseling and sterile injecting equipment, a generalizable result will be obtained indicating that it is an effective prevention strategy. Of course I don’t know this, and was wrong in my view that trials of PrEP efficacy should not proceed.
The most important concern with the way the promotion of PrEP, at least as a concept, is being pursued is the neglect of encouraging prevention education.
Prevention education remains the most important tool we actually have, as opposed to theoretical and unproven approaches. The latter include PrEP, and the test and treat every infected person proposal. We absolutely know that in principle prevention education, including the use of condoms can work. It worked in curbing the increase in the epidemic among gay men in the late 1980s .
The principle is thus established, admittedly without application to those who have no control over the use of condoms by the male partner. This group is therefore in need of prevention strategies they can control themselves, and PrEP may be the only realistic possibility.
For everyone else, the sexual transmission of HIV can be controlled by the use of condoms, even if not with 100% efficacy. We have a powerful tool in our hands, and if there are new infections, this is certainly not an indication that it does not work well enough. It indicates that it is an activity that receives insufficient support, or it may well be that some of those doing it are just not very good at it. Maybe there is little societal support for HIV prevention education, even little support from individuals at risk who could use condoms but would like not to.
Unfortunately, from what I have experienced, the several groups supporting and promoting PrEP seemed to have given little thought to prevention education in presenting this intervention to stakeholders. . They may be diligent in the context of efficacy trials, in ensuring the availability of condoms and counselling to participants.
But what seems to be missed is this: Unless the promotion of PrEP is accompanied by very clear advocacy of prevention education with condom use, PrEP can be seen as an alternative to safer sex practices as now recommended.
This cannot be the intention, but from comments I have heard after the CHAMP and CDC conferences this seems to be a dangerous conclusion that some have drawn.
The explanation of the utility of PrEP must be accompanied by a strengthening of prevention education to avoid this unfortunate misinterpretation. The very promotion of the concept of PrEP in the way it has so far been done can actually be seen as an undermining of condom use. A possible alternative to condoms is presented. One can only hope that in the absence of accompanying prevention education there will not be instances sex with available antiretroviral drugs rather than with condoms.
Prevention education is in a dismal state as it is, and we should be aware of any activity that can undermine it further, unless care is taken in how it is presented.
I have commented in other posts that in HIV medicine a one-size-fits-all approach seems to be the norm. Admittedly it’s cheaper to deal with populations rather than individuals. A single size that fits everybody is even cheaper than providing small, medium or large varieties, let alone customizing the size to fit individual needs.
So in HIV medicine, treatment recommendations have been made for all infected individuals, without considering the rate of disease progression, and many other characteristics applicable to any given person.
So it is with PrEP. Its relevance is different to different constituencies.
At one extreme, for those who have no power to control the use of a condom by their male partner, PrEP may be the only realistic possibility of avoiding infection with HIV. PrEP to these individuals is obviously of vital importance.
In fact it is so important that it would be useful even if its efficacy, if this can be demonstrated, proves to be inferior to the consistent use of condoms. Such individuals have no alternative.
The situation of people who are perfectly capable of consistent condom use is different.
The power of the receptive partner in this case is the power to say no. No condom, no sex. Both partners have an effective means of preventing the sexual transmission of HIV. There is no need for PrEP to prevent infection, except that some may welcome an additional layer of protection.
There are others whose hopes for PrEP are different. The desire to conceive is one.
Yet others hope that PrEP will make sex without condoms safe with respect to HIV transmission. In this case the efficacy of PrEP would have to be known to be at least equal to the consistent use of condoms (and free from toxicity and affordable). Of course individuals decide to take risks that involve danger to themselves only, but full information should be available, and certainly we should take care not to disseminate material that can mislead, even if only by implication. We do not have full information on the efficacy of PrEP, and I can see no way of testing its efficacy without the use of condoms. But it is here that we need to take great care not to mislead, even by implication, that PrEP is as safe as using condoms unless in the unlikely event, it is actually proven to be so.
Even a modest degree of efficacy is better than nothing for those who are unable to avoid sex with a partner who cannot be relied on to use a condom. There actually is nothing else to protect them.
A modest degree of efficacy is insufficient for those who are well able to refuse to have sex if a condom is not used. That’s my opinion, and I would believe that of many others, but as always risking harm to oneself only, is an individual choice; our obligation is not to mislead, and ensure that full and accurate information is available.
So, PrEP is of undoubted importance to individuals who have no control over the use of a condom by their male partner. Apart from the female condom, it is the insertive partner who has to use a condom. All the receptive partner has as protection now, is the ability to just say no. We recognize that there are situations when this is not possible, and no practical remedy is available to change this.
Of course there are other situations when it is possible to attempt a change. If an individual just cannot say no to a partner who cannot be relied on to use a condom because he or she is ignorant of safer sex practices this is something we must try to remedy with intensive prevention education. This will include imparting the knowledge of the lapses in judgement that can accompany the use of drugs or alcohol.
Getting away from the one-size-fits-all approach, there probably will be some individual situations in which PrEP, even if less effective than consistent condom use may be considered. An example noted by one commentator is when condom use may be associated with sexual dysfunction.
Prevention education with consistent condom use is the best available means we have to prevent the transmission of HIV. Prevention education should be strengthened and care taken not to undermine it.
Where individuals have no control over the use of a condom by their male partners we should do what we can to provide them with the means to protect themselves, and PrEP may be all we have to work on at present.
Others may look to PrEP as a means to avoid the use of condoms. The price of failure seems to be an extraordinary high one, considering that condom use is known to be highly effective in preventing HIV transmission.
There are people who need PrEP. There are also people perfectly able to use condoms but who want PrEP.
In promoting PrEP studies we must take great care not to undermine efforts at prevention education, even by implication. Promotion of PrEP must go hand in hand with promotion of HIV prevention education.
Pre exposure prophylaxis in relation to HIV infection refers to the administration of anti HIV medications to uninfected people as a means of protecting them from becoming infected with HIV. It is not known if this intervention will succeed in achieving its goal. Several trials have been underway to test it for safety and efficacy, and many more are planned worldwide.
I have paid little attention to these initiatives but was prompted to do so by notices of a meeting to discuss pre exposure prophylaxis – now known as PrEP – in the coming weeks. The wording of this notice is quite vague, but the notice suggests that it is urgent to start planning for the implementation of PrEP as the analysis of initial safety and efficacy trials are expected within the next year.
This is quite startling in its implication that PrEP actually works and presumably is safe. The actual words of the notice are:
“Results and analyses of initial safety and efficacy trials are expected within the next year, which highlights the urgency to beginning to plan now for how PrEP might be used to maximize its public health impact”.
This is a convoluted statement, to the point of being quite unintelligible. It can be misleading in the implication that can easily be drawn from it that PrEP works. Why else begin to plan for how to use it?
I had not been aware of just how extensive the PrEP initiative has been. To get some idea of the many trials that are underway or planned, take a look at this website:
Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).
FHI has produced a set of slides listing PrEP trials.
Among the “research consortia” listed as involved in PrEP research are the Bill and Melinda Gates Foundation, Gilead Sciences, the Centers for Disease Control (CDC), The National Institutes of Health (NIH), and UCSF. These trials are conducted in many countries, including Peru, Botswana, Thailand, the US and Malawi.
Organizations listed under “community consortia” are GMHC, AVAC, Global Campaign for Microbicides, CHAMP, and the IAS.
The websites of these organizations contain information about PrEP.
AVAC : http://www.avac.org/
Global Campaign for Microbicides: http://www.global-campaign.org/
The International AIDS Society: www.iasociety.org
All the trials use a once daily drug, tenofovir, with or without emtricitabine (FTC). Tenofovir is manufactured by Gilead in the US although I believe a generic version is produced in India.
The trials vary in design. Some require daily tenofovir, some are used intermittently or specifically before sexual intercourse. Some use a gel formulation.
Previous trials had run into difficulties; several were stopped for different reasons. For example a trial in Cameroon was stopped amid allegations that those who seroconverted did not receive adequate treatment. A trial in Nigeria was stopped because of inadequate standards in laboratory testing.
A trial of PrEP among Cambodian sex workers was stopped in 2004 by the Cambodian government. This was perhaps the most publicized of the several PrEP trials that were stopped, because several activist groups brought attention to it at the XV International AIDS Conference in Bakgkok. Among the many reasons stated for pressure by activist groups to stop the trial were poor HIV prevention counselling, and a lack of medical services to those who seroconverted. Act Up-Paris was active in stopping PrEP trials both in Cambodia and Cameroon, although it is reported that this organization is supportive of tenofovir trials in general.
These events are described in an article entitled “The Abandoned Trials of Pre-Exposure Prophylaxis for HIV: What Went Wrong?” The authors are Jerome Singh and Edward Mills. It can be seen here.
For reasons I will describe I do believe that there is no way to design a trial of the efficacy of PrEP that can meet acceptable ethical standards. On the other hand, it is perfectly possible to conduct trials to determine the safety of tenofovir for pre exposure prophylaxis.
So maybe an answer to Drs Singh and Mills as to what went wrong with the abandoned trials of pre exposure prophylaxis is that the question of efficacy, unlike that of safety, cannot and should not be tested on human research subjects.
Here are the reasons why this cannot be done, at least regarding the use of tenofovir to prevent sexual transmission of HIV.
No ethically designed and conducted trial can definitely prove that PrEP works. Definite proof of course may be an unattainable goal, but even credible evidence regarding efficacy would not be found if the trial were to be conducted in an ethical manner, simply because with the availability of condoms, and the imperative to provide counselling that they be consistently used, such a trial could not answer the question asked of it. This is essentially because the consistent use of condoms will ensure that insufficient seroconversions occur in participants receiving placebo.
In any trial that studies the ability of a new intervention to prevent sexual transmission of HIV, participants must receive persistent counselling about the need to use condoms. These must be provided, with ongoing support for their continued use. This is the ethical requirement.
Quite clearly if great care is taken to meet this requirement there will be few infections in people receiving placebo. The investigators are presented with a conflict of interest that no amount of verbal assurance can resolve. The conflict is that on the one hand the investigator must always be cognisant of the importance of doing all that’s possible to encourage condom use to prevent the sexual transmission of HIV infection, and on the other hand the investigator has an interest in demonstrating an effect of PrEP in preventing it.
It is only when condom use falls below a certain level that the effect of another preventative measure can be assessed. We are obliged to do all we can to ensure that this does not happen.
The Centers for Disease Control (CDC) are sponsoring several trials of PrEP[i]. They are very sensitive to the need to provide risk reduction counselling to participants.
Here is an excerpt from material published by CDC:
“One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that individuals at risk will reduce their use of existing HIV prevention strategies. It will therefore be crucial to reinforce proven behavioral prevention strategies, both within and beyond these trials. All three trials are taking multiple steps to address this issue during the education and enrolment of trial participants and through ongoing participant counselling.
First, it is critical to ensure that participants understand that trial participation may not protect them from HIV infection—either because they may receive a placebo or because they may receive a study drug, the efficacy of which remains unproven. This and other key aspects of the trial, including the potential risks and benefits of participation, are explained to potential volunteers in the language of their choice, prior to their enrolment. To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent. Study participants are also free to withdraw from the trial at any time and for any reason”.
So there is clear recognition that there may be a falling off in the use of proven prevention approaches, importantly, the use of condoms.
Here is another excerpt:
“To assist participants in eliminating or reducing HIV risk behaviours, extensive counselling is provided at each study visit, and more often if needed. This interactive counselling has proven effective in reducing the risk of HIV and other STDs in multiple populations, including past participants of similar HIV prevention trials. Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection”.
If such counselling is effective, the prevention of sexual transmission of HIV particularly through the consistent use of condoms will make it impossible to detect an effect of PrEP. As mentioned the investigators are presented with a conflict that it is not possible to resolve.
PrEP is an experimental approach to prevention, while consistent condom use is an established method to substantially reduce the sexual transmission of HIV.
The argument that may be presented by those who are proponents of PrEP is that condom use is not consistent, and that we need an alternative
The implication of such an argument supporting PrEP is that prevention education, essentially the use of condoms, has not been sufficiently effective. This cannot be known to be true of prevention education in principle.
What is definitely true is that those responsible for prevention education have not been sufficiently effective.
Our efforts should be focussed on improving prevention education and support for the consistent use of condoms,
There is so much more that can be done with persistent, culturally sensitive, highly targeted prevention education. In order to improve our efforts at prevention education we have to first confront the fact that we may have not been too successful in this endeavour, understand why, and absolutely not take the position that the undertaking is an impossible one.
Every new infection today represents a failure, not of prevention education as an undertaking, but a failure to provide it effectively. The introduction of condom use among gay men in the US in the 1980s originated in this community, it was promoted and effectively advocated for by this community and proved to be effective.. In those early years there was certainly no help from the Government which was to spend enormous sums on a vacuous and ineffective untargeted campaign “ America responds to AIDS” which did absolutely nothing to stop the advance of this disease into African American communities , although this was happening in plain sight.
What we can learn from this is that different affected communities are best able to understand the issues specific to their communities that must be emphasized and promote prevention education that is most effective for each of them. Their input is therefore absolutely vital.
The design and implementation of well funded and highly targeted prevention education has been neglected. These initiatives need to be specifically targeted to different groups, the needs of which must be assessed, barriers identified, continuing support provided, as well as some instrument developed to evaluate the success of the programs. . It is an enormous challenge.
We know that gay men were able to make it work for them before the concept of risk reduction had even been articulated. It can work and this is where our efforts must be concentrated. Not on trials of the efficacy of PrEP that are impossible to conduct in an ethical fashion.
However It is entirely possible that PrEP may add an additional layer of safety to condom use during sexual intercourse. This may be of particular importance in certain circumstances such as among sex workers. This is also the case among some women who are unable to rely on the use of a condom by their male partners. Trials of the safety of once daily tenofovir are absolutely possible and even desirable. Such trials would be unburdened with the ethical problems that make efficacy trials impossible to conduct. It will be clear that the trials are to determine the safety of tenofovir when used with condoms to provide an additional level of safety. It is true that we may never be able to firmly establish its efficacy, but if it proves to be safe, there is sufficient – if far from conclusive evidence to justify its use.
It is clear that all that has been written about concerns the sexual transmission of HIV. For those in whom the risk of infection is through intravenous drug use there is an entirely different set of considerations. The only known prophylactic measure, the reliable provision of sterile injecting equipment is probably just unavailable for most, and efficacy trials are therefore not burdened with the same ethical constraints.
One cannot help but note that at least in two initiatives, pharmacological rather than behavioural approaches to prevention are now being emphasized. Of course PrEP to prevent transmission of HIV is one. The other is the attempt to end the HIV epidemic by testing and treating all HIV infected people, whether or not a particular infected individual needs treatment for his or her benefit. Both are beset with ethical problems.
The use of condoms can significantly reduce the sexual transmission of HIV. We know this. Therefore our greatest efforts should be placed in improving prevention education. It is a tremendous challenge given the cultural diversity of the populations involved, and the special difficulties experienced by some. This is particularly true where women are disempowered.
We know that untargeted efforts such as “America Responds to AIDS” do not work. We need to understand the barriers to effective prevention education.
A denial of the importance of sexual expression to the human experience, stigmatization of those infected, homophobia, racism, bigotry in general and the fact that unlike the use of drugs, prevention education provides no financial return, are surely amongst them.
[i] [i] http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm
I believe the SMART study team have submitted a response to Justin Stebbing and Angus Dalgleish’s comments in the Lancet Infectious Diseases, that was referred to in a previous post:
The explanation that the huge discrepancy in the number of deaths in the US and non US sites was due to the fact that non US sites started to enrol participants 2-3 years later than US sites, was addressed in the comments in the Lancet Infectious Diseases.
Here is the relevant part:
“Whereas most non-US sites commenced patient recruitment 2—3 years after the US sites, it is unlikely that longer protocol exposure could account for this difference. We are told that there were 38 deaths in the first year and 47 deaths thereafter. Hence, assuming that all six non-US deaths occurred in the first year, there remain 32 deaths (38 minus six) in the USA from the first year of the study—about five-fold more than expected based on the non-US mortality rate”.
Whatever explanation is to be offered by the SMART team, even if turns out to be consistent with their conclusions, the following questions remain.
Why was information on the distribution of deaths withheld for so many years?
Why was this information, when it did appear in the article by Kuller et al in PLoS last year, ignored by community commentators to whom HIV infected people and their advocates look to for help.?
Did they not notice it? (I did not).
Did they think it was of no significance?
Hopefully the SMART team’s response will put an end to this mystery of why, with more or less the same number of participants in US and non US sites, 79 people died at US sites while there were only 6 deaths at sites outside the US.
Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.
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:
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:
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.
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.
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-
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.
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:
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 relationship between herpes viruses and HIV disease is also discussed in a subsequent post:
The relationship between herpes simplex virus type 2 and HIV is in the news again. This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.
This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died. A reduction in HIV viral load was also observed in those treated with acyclovir.
The concept on which this study was based is absolutely solid.
Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.
The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.
There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.
Herpes viruses – and not just herpes simplex virus, have an impact on the course of HIV infection. This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.
Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.
“Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .
(NEJM 2007 356:790)
It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed. The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.
These assumptions about the reasons for increased HIV transmission may all be mistaken.
We do know with some confidence that transmission of HIV is related to viral load in the infecting partner. It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.
An individual with higher HIV viral loads will more easily transmit the infection, and also experience more frequent recurrences herpetic ulcers. This of course only applies to HIV infected individuals.
As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.
Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.
Sometimes individuals know what provokes a recurrence. Recurrences can be associated with febrile illnesses. It is completely reasonable to suggest that the effects of some intercurrent infections may cause both herpetic recurrences and increase susceptibility to HIV.
Whatever infection causes the fever may also increase susceptibility to HIV, possibly by an association of the infection with perturbed immunological function. Transient immunological perturbations can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.
For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2. At least regarding what is reported to the public.
However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.
Cytomegalovirus (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important. These viruses are also sensitive to the anti herpes drugs used in these two trials.
Since infections with CMV and EBV are so widespread how can effects of acyclovir and Valtrex on reducing HIV viral loads be attributed to an effect of these drugs on herpes simplex type2?
I cannot recall that these two other members of the herpes virus family – or even a third, HHV6 were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.
It is entirely possible that suppression of two viruses, CMV and EBV, contributed, perhaps to the greatest extent, to the anti HIV effects seen.
One can only hope that sera from these studies were frozen and stored. Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.
As an historical comment, acyclovir was tried as a treatment for AIDS in 1987 around the time AZT was introduced.
There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.
AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.
One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.
Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir. Another retrospective observational study found no benefit.
Nothing much can be made of these contradictory early results.
But now, with newer techniques for measuring HIV activity by viral load assays, we have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.
With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease, Unfortunately most of the emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe, of even greater importance.
Actually there had been interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.
I have been involved in AIDS research and treating patients with this disease from the time it started and so can provide some historical perspective on the interest in herpes viruses, that dates to the late 1970s, even before AIDS was described and long before HIV was discovered. At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.
As another historical interlude, interest in herpes viruses also provided the basis for safer sex, as it is understood today. As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV. Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.
From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.
I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men. By 1983 over 40% of a cohort of gay men in New York City carried CMV in their semen. Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections. (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al. AIDS Research 1983 1: 59)
At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods, and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.
But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease. It was thus possible to propose a way to at least prevent the sexual transmission of CMV.
This formed the basis for the first published recommendations for condom use.
With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.
The appropriate title was coined by Richard.
The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007. Although it is in fact a landmark event in the history of the epidemic.
Richard is only now receiving some acknowledgement for this life saving proposal because a documentary film called Sex Positive has brought attention to his achievement.
An account of our collaboration in producing the safer sex guidelines can be seen by following this link.
Michael Callen is remembered by many for his activism. There is even a clinic in New York City named for him and Audre Lorde .
I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.
I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.
Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.
As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS. This is quite apart from their multiple clinical manifestations as opportunistic pathogens. Both of these viruses almost definitely contribute to pathogenesis.
Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated for many years.
In fact some evidence for this was already apparent when AIDS was first described.
This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.
As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.
I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.
Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.
The role of CMV in immune system activation, a major force in driving HIV infection.
The systemic effects of CMV and EBV infections are most probably of great importance in this respect.
Systemic effects resulting in immune system activation and activation of HIV replication may also accompany reactivated herpes simplex virus infecteions.
Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines. These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles. So, this is but one way in which an active herpes virus infections can promote the replication of HIV. The general mechanisms are described in a previous post..
An important and interesting paper that also deals with EBV and CMV in relation to HIV replication was published by V Appay and colleagues. It can be seen by clicking the following link.
I am reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references. The references can be seen in the complete text seen by following the above link.
“HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”
“In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in
the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained
antigen mediated immune activation occurs in HIV-1-infected
patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.
“CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears
to monopolize a significant fraction of the whole T cell repertoire , so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects “.
Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface. These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.
Transactivation of HIV by herpes viruses.
In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.
In the early 1980s when we had no effective measures against this disease I treated my patients with high dose acyclovir.
There then was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.
In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.
But interestingly, at that time, none of these theoretical considerations placed much importance on HSV 2.
The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.
Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.
But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending interventions.
What I have written of this experience with bactrim in the early years can be seen by following this LINK
In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.
[i] Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc. But this drug has a truly remarkable quality. The cellular enzyme that adds phosphate to make drugs of this type active, does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues. But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears in herpes virus infected cells has the ability to add the phosphate group and turn acyclovir into an active drug. This is the reason why acyclovir is such a safe drug. It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.
However, if the same cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to terminate HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.
This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.