I may as well jump in immediately: The iPrEx trial of pre-exposure prophylaxis is a failure. Maybe a shocking statement in view of the universally jubilant press reports:
"a breakthrough that will accelerate the prevention revolution."
"This discovery alters the HIV prevention landscape forever"
"Daily Pill Greatly Lowers AIDS Risk, Study Finds"
"The results are in--pre-exposure prophylaxis (PrEP) works"
But do the results of iPrEx warrant such over the top praise? Let's take a look at them.
Firstly does daily Truvada work as PrEP
Yes, but nowhere near well enough to be of any use at a population level (an intervention that may work for a particular individual has to be thought of in a different way to one that can be effective for populations - I'll come back to this).
Daily Truvada reduced new HIV infections by only 44%. This is useless so how on earth can this be construed as a triumph?
We are told that this poor performance was seen because few people took their pills as prescribed. Unfortunately this is not a reassurance. Confining the analysis to a sub group of trial participants can lead to misleading interpretations of clinical trial results. I know this sounds counterintuitive, but subgroup analysis is less politely called data dredging.
Intention to treat analysis is widely accepted as the most reliable way to analyze clinical trials. Essentially, participants should be analysed in the group to which they were randomized, irrespective of whether they dropped out, or didn't adhere to the treatment or strayed from the protocol in other ways. Again, this may sound counterintuitive, but intention to treat is now recognized as the most reliable way to analyze trial data. It also provides a better picture of real world conditions. Take a look at this: Making sense of intention to treat
So the most reliable estimate of Truvada's efficacy, when administered in conjunction with an intensive HIV prevention education effort, condom distribution, counselling, rapid HIV tests and risk analysis every single month, in reducing new infections is 44%.
This is unacceptable for an HIV prevention intervention. Even 73% is not good enough.
What about the danger of the development of resistant virus?
"a breakthrough that will accelerate the prevention revolution."
"This discovery alters the HIV prevention landscape forever"
"Daily Pill Greatly Lowers AIDS Risk, Study Finds"
"The results are in--pre-exposure prophylaxis (PrEP) works"
But do the results of iPrEx warrant such over the top praise? Let's take a look at them.
Firstly does daily Truvada work as PrEP
Yes, but nowhere near well enough to be of any use at a population level (an intervention that may work for a particular individual has to be thought of in a different way to one that can be effective for populations - I'll come back to this).
Daily Truvada reduced new HIV infections by only 44%. This is useless so how on earth can this be construed as a triumph?
We are told that this poor performance was seen because few people took their pills as prescribed. Unfortunately this is not a reassurance. Confining the analysis to a sub group of trial participants can lead to misleading interpretations of clinical trial results. I know this sounds counterintuitive, but subgroup analysis is less politely called data dredging.
Intention to treat analysis is widely accepted as the most reliable way to analyze clinical trials. Essentially, participants should be analysed in the group to which they were randomized, irrespective of whether they dropped out, or didn't adhere to the treatment or strayed from the protocol in other ways. Again, this may sound counterintuitive, but intention to treat is now recognized as the most reliable way to analyze trial data. It also provides a better picture of real world conditions. Take a look at this: Making sense of intention to treat
So the most reliable estimate of Truvada's efficacy, when administered in conjunction with an intensive HIV prevention education effort, condom distribution, counselling, rapid HIV tests and risk analysis every single month, in reducing new infections is 44%.
This is unacceptable for an HIV prevention intervention. Even 73% is not good enough.
What about the danger of the development of resistant virus?
Many of the reports claimed this was not a problem. When it was
acknowledged that resistant HIV was detected in two individuals, some
reports, including one in POZ, dismissed this because the infections
were acquired before randomization. This is a completely inappropriate
argument. If this happened in the trial it will of course happen in real
life.
The New England Journal of Medicine Editorial accompanying the iPrEx study report explains the issue:
" ...and most worrisome, viral resistance to FTC was documented in both of the subjects who were found to have had acute HIV infection at enrollment. Secondary FTC resistance after exposure to the drug clearly developed in one of these subjects, and the second subject had indeterminate resistance on baseline testing but showed FTC resistance 4 weeks after enrollment. This raises very serious concern about the deployment of oral FTC-TDF in populations of men who have sex with men...."
The danger of resistance developing is unfortunately quite realistic.
What about safety?
The claim in many reports that Truvada is without toxicity is also misleading.
Maybe poor adherence has some bearing on the lack of significant toxicity. A median of 1.2 years exposure can tell us little about cumulative and long term effects. Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic.
All of the above does not mean that PrEP has no place as a prevention strategy. It does seem on the showing of this trial, that it is not viable at a population level. However, as mentioned, there is a difference between an intervention at a population level and one involving particular individuals.
For certain individuals,in very limited settings, PrEP with daily Truvada may prove to be significant in protecting them from HIV infection, including some receptive partners in sexual intercourse who are unable to ensure condom use by their partners.
Also this trial does give some hope that intermittent PrEP might be effective.
It has been puzzling why this trial report provoked such hype about efficacy data and downplayed the problems, rather than present a more realistic picture of what this trial tells us.
Hopefully these glowing accounts of the trial will not prompt people to abandon the use of condoms or begin to use PrEP with unrealistic expectations.
The trial has also been trumpeted as "a proof of concept", the concept presumably being that daily Truvada can reduce new infections. This is pretty meaningless if the reduction achieved is too low to be useful.
Not working at all and not working well enough to be useful is the same thing.
The concept that was proved is that daily Truvada has no place as a prevention strategy on a widespread population level.
Gilead, who manufacture Truvada have made a public statement about iPrEx that includes the following.
Truvada is not indicated for the prevention of HIV. Based on the results of this study, known as the iPrEx or Pre-Exposure Prophylaxis Initiative trial, Gilead will be working with the appropriate regulatory agencies to determine if data from this study warrant inclusion in the prescribing information for Truvada.
Regardless of any action taken by the FDA or other public health agencies, Gilead believes that condoms, clean needles and behavioral interventions should remain the first line of defence for preventing HIV transmission.
The New England Journal of Medicine Editorial accompanying the iPrEx study report explains the issue:
" ...and most worrisome, viral resistance to FTC was documented in both of the subjects who were found to have had acute HIV infection at enrollment. Secondary FTC resistance after exposure to the drug clearly developed in one of these subjects, and the second subject had indeterminate resistance on baseline testing but showed FTC resistance 4 weeks after enrollment. This raises very serious concern about the deployment of oral FTC-TDF in populations of men who have sex with men...."
The danger of resistance developing is unfortunately quite realistic.
What about safety?
The claim in many reports that Truvada is without toxicity is also misleading.
Maybe poor adherence has some bearing on the lack of significant toxicity. A median of 1.2 years exposure can tell us little about cumulative and long term effects. Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic.
All of the above does not mean that PrEP has no place as a prevention strategy. It does seem on the showing of this trial, that it is not viable at a population level. However, as mentioned, there is a difference between an intervention at a population level and one involving particular individuals.
For certain individuals,in very limited settings, PrEP with daily Truvada may prove to be significant in protecting them from HIV infection, including some receptive partners in sexual intercourse who are unable to ensure condom use by their partners.
Also this trial does give some hope that intermittent PrEP might be effective.
It has been puzzling why this trial report provoked such hype about efficacy data and downplayed the problems, rather than present a more realistic picture of what this trial tells us.
Hopefully these glowing accounts of the trial will not prompt people to abandon the use of condoms or begin to use PrEP with unrealistic expectations.
The trial has also been trumpeted as "a proof of concept", the concept presumably being that daily Truvada can reduce new infections. This is pretty meaningless if the reduction achieved is too low to be useful.
Not working at all and not working well enough to be useful is the same thing.
The concept that was proved is that daily Truvada has no place as a prevention strategy on a widespread population level.
Gilead, who manufacture Truvada have made a public statement about iPrEx that includes the following.
Truvada is not indicated for the prevention of HIV. Based on the results of this study, known as the iPrEx or Pre-Exposure Prophylaxis Initiative trial, Gilead will be working with the appropriate regulatory agencies to determine if data from this study warrant inclusion in the prescribing information for Truvada.
Regardless of any action taken by the FDA or other public health agencies, Gilead believes that condoms, clean needles and behavioral interventions should remain the first line of defence for preventing HIV transmission.
Sean on:
Comments on Joseph Sonnabend, MD's blog entry "PrEP iPrEx Trial Reports"
I am confused Dr. Joe, in a thread at Seth Kalichmans' Denying Aids, the resident experts have stated that you are just downright wrong about the ineffectiveness of Truvada in preventing new infections. With this sort of conflicting information, how am I meant to make an informed decision?
Regards
http://denyingaids.blogspot.com/2010/11/snake-oil-for-sale-gary-null-and-void.html#comments
James, there's no conflict about the information. Truvada was able to reduce new infections by 44%. There may be conflicting interpretations of the significance this information. I wrote that the ability of a prevention intervention to reduce new infections by only 44% makes it useless as a recommendation for widespread use. I have not been able to see the thread you mentioned but I would be surprised if the experts you cite would regard a 44% reduction as acceptable.
I also wrote that there is a difference in looking at a prevention intervention as a general recommendation for widespread use and looking at how it might be applied to particular individuals. The trial told us that Truvada does not work well enough.in a population of 1251 people. in part because people don't take their pills regularly.
It may work well enough for a limited number of particular individuals who take their pills regularly, can afford the monthly tests and satisfy some other conditions, but this has yet to be proven prospectively.
If only we would devote as much energy and funds to developing and disseminating targeted HIV prevention education, promotion of and continuing support for condom use, making PEP easily available and providing clean needles.
''Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic.''
Truvada is a widely prescribed drug, bundled into Atripla, now the foremost anti-HIV front line medication, as well as being prescribed along with protease inhibitors.
So what are the longer term issues with Truvada toxicity and can we expect to see a generation of HIV medicated individuals blighted by its side effects, in the same way we did with lipodistrophy not long after combination therapy first went on stream?
Zohar, yes, the drugs, including Truvada can be associated with adverse effects, sometimes severe, but in people who are already HIV positive their benefits vastly outweigh their risks when properly used. For many, the drugs are life-saving. With careful and responsive medical care adverse effects can often be managed, and many individuals are able to take the drugs without difficulty. But nobody should minimize the difficulties associated with taking anti-HIV medications.
For uninfected individuals the use of Truvada for pre-exposure prophylaxis requires a different balancing of risks and benefits.
The most important toxicity concern with Truvada is the effect of tenofovir, one of its components, on the kidneys and bones. The effects on the kidneys are related to drug levels in the body. Blood levels can tell you something and this can vary between people. Tenofovir only becomes active once in the cell, and the intracellular concentrations of active drug are what’s most important. Kidney damage is mostly, but not always reversible on stopping the drug.
Osteopenia and osteoporosis, thinning of the bones may become a more significant problem with longer term use in an aging population.
Aidsmeds.com has information on Truvada.
I'm so glad you posted this! As I keep hearing from people who've rented SEX POSITIVE on DVD, in more and more of the emails I'm receiving, people are expressing grave concerns that the coverage and almost lockstep cheer-leading about PrEP is overshadowing the continued need for safe sex education and practices at a time when education efforts are dwindling drastically. More has to be done but there are lots of ordinary, invisible people around the country who share your skepticism and concerns....R
Dr. Sonnabend,
I don't know if you still review these comments but I had no other way of contacting you.
I am in a Master's programme attempting to earn Master's degree in Nursing. I am writing my thesis paper on the pathophysiology, cofactors, and treatment of AIDS. I know you are big on the idea of Co-factors.
Anyway, I saw an abstract from back in 1994-1995 in which high doses of aspirin were being used to treat HIV but the study was stopped because of side effects. Do you happen to remember the dose that they were using? I would be most grateful if you could give me that information.
Thank you,
Ms. Torres
Dear Ms Torres,
We did indeed try to study the effects of aspirin on HIV replication. Dr Kotler at St Luke's-Roosevelt in New York had observed an effect of salicylates on reducing HIV as detected by in situ hybridization in colon biopsies. Based on this I, with Elena Klein looked at the effect of acetylsalicylic acid on in vitro HIV replication. It was able to inhibit HIV replication in lymphocytes from HIV infected patients in mixed lymphocyte cultures, as well as inhibit TNF induced HIV replication in ACH-2 cells, in a dose dependent fashion in both cases. Aspirin was able to inhibit HIV replication by about 70% at a dose that represented tissue levels achieved in the treatment of rheumatic fever. This was about 150-300 mcg/ml. a high dose of aspirin that would not have been practical as a treatment.
Based on these results I then wrote a protocol for a placebo controlled clinical trial. I can't remember the actual dose used but it would have been around 4G a day.
I was then medical director of CRIA and that's where the trial was conducted. With IRB approval and informed consent, we enrolled about 5-6 individuals. All took sucralfate as well and great care as taken to monitor for GI bleeding. It was understood that this was a proof of concept trial.
As was to be expected there was a small drop in haematocrit in some individuals, so I asked three investigators to unblind the results and advise me regarding continuation. Of course it was the treated individuals who showed a small haematocrit drop and I was advised to stop, although I disagreed with their decision I stopped the trial.
I felt that we had a great opportunity to open a door to a new approach to treat HIV infection. With very close supervision, with full on-going consent, we might have been able to show that drugs of this sort - obviously not aspirin itself, might be developed as not only a directly acting anti-HIV agent, but also as an anti-inflammatory agent. This was a proof of concept trial, a collaboration of community researchers with their patients.
I don't know what abstract you saw, I did send my in vitro aspirin results to the Yokohama AIDS conference as a poster and asked Dr Kotler to present them. So this is probably what you saw.
I must have copies somewhere, maybe among my papers at the NY Public Library.
Unfortunately there was some personal discord that resulted in a letter written by one of us and submitted to the Lancet being withdrawn. I was quite busy at the CRIA, in the lab, and seeing patients so in this case - as with some others, I never did write up the results, feeling that my poster at the AIDS conference should be enough. It certainly must have been seen by scientists, journalists and patient advocates.
Coincidentally, during the conference there was a report in Science of the effect of aspirin in blocking the NFkappaB pathway - providing a basis for its anti HIV effect. I did not know this when I did the TNF/ACH-2 experiment!
It's quite a sad story. Who knows what might have been developed in the almost 20 years since these observations were made.
Thanks for your interest,
With good wishes,
Joseph Sonnabend
Well, as we all know, HAART therapy is hardly without its own side effects. Gastrointestinal bleeding can easily be countered with coating the aspirin and using a GI protective agent. It would seem to me that there really was no interest in developing it due to how cheap it is. I can get a 1 year supply of aspirin for $4 at my local Costco. If I were HIV+, I would surely take some GI bleeding over lipoatrophy/dystrophy, liver toxicity, CNS toxicities, etc.
Aspirin, in many longitudinal studies, has been shown the reduce the risk of different types of dementia, certain cancers, heart attack and stroke, and many other things. Things that people with HIV that tend have to deal with that HAART generally can not help with or even makes worse. So even if aspirin did not help to reduce the HIV viral load, it would still be of an advantage to people with HIV who are at increased risk of developing dementia, cancer, and heart disease than their HIV- counterparts.
I sometimes wonder whether or not looking at the viral load and CD4 cells are the best measurements of health in persons with HIV. People with undetectable viral loads still are unable to develop dementia. I think blood markers of inflammation should also be measured at the same time.
I was diagnosed with Type II Diabetes about a decade ago. I have since worked to reverse the disease. But about 5 years ago I read an abstract where people with diabetes were given 7 grams of aspirin for a week or two to see if it lowered their blood glucose and other markers and it did. There were no GI effects during this short study, but I would imagine with longer studies there would have been. But it actually worked for me. It brought my fasting blood glucose down by about 35%.
It's true that drugs that generate no profits are unlikely to be developed - there are few (if any) organizations in our society that have the resources to do this. This was something I had hoped the CRIA would be able to raise funds to do and the aspirin trial actually is an appropriate example.
Unfortunately our trial was stopped before we could obtain any meaningful information on HIV levels.
The in vitro results with aspirin were a great encouragement. However I don't think high dose aspirin would be tolerated over a longer period, but there just may be safer alternatives.
The benefits of aspirin in so many conditions you mention were I believe achieved with a lower dose, and it's quite likely that lower dose aspirin, if studied would prove to be beneficial in HIV infection as an anti-inflammatory agent, even if not directly antiviral at the lower dose..