Posted on August 5th, 2011 No comments
Prevention of HIV infection by pre-exposure prophylaxis (PrEP) is not sufficiently effective
PrEP is a prophylactic intervention where uninfected people take anti HIV medications before sexual intercourse to prevent becoming infected with HIV. The use of a vaginal gel containing anti HIV drugs has also been tested.
The results of several trials of PrEP have been reported in the past year, all but one hailed as huge successes, with reported efficacies of up to 90% among those adhering to the treatment regimen.
The efficacy of PrEP in preventing HIV infection was reported to be so great that this intervention has been trumpeted as signalling a revolution in HIV prevention. A new era has opened up we are told; PrEP is a “game changer”.
With such enthusiastic coverage it may come as a surprise that none of the reports explicitly told us what the actual efficacies of the interventions were in preventing HIV infection. Perhaps because they were so low, as I’ll explain. Maybe what’s even more startling is that this omission seems to have gone completely unnoticed, at least in the universally jubilant press reports and equally enthusiastic press releases from AIDS advocacy organizations.
How has this been possible?
The reason is that the results have been reported as reductions in relative risk only. This tells you nothing about actual risk reduction. What is reported is a percentage reduction in risk from a number that was never clearly stated. For example in the iPrEx trial of PrEP among men who have sex with men, the drug, Truvada, was reported to reduce the risk of infection by 44%. But 44% of what? We were not explicitly told, although it’s possible to calculate what it is.
In fact we can calculate that the absolute risk reduction conferred by Truvada is a measly 2.3%, a number nowhere to found in the trial report. The relative risk reduction may have been 44%, but this translates into only an actual 2.3% reduction in risk, as is shown below.
Reporting relative risk reduction only is the oldest trick in the book to exaggerate the effects of an intervention, used by salesmen, but apparently also by clinical researchers.
What makes the unquestioning acceptance of these reports of relative risk reductions achieved by PrEP even more remarkable is that there is a tremendous amount of material explaining the difference between relative and absolute risk reduction. Just type the words “relative risk absolute risk” into the Google search box.
Relative risk reduction tells you the percentage reduction in risk in the treated group compared to that in the group receiving placebo, or how much lower the risk with the intervention is relative to the risk to begin with.
If you are not clearly told what the risk is to begin with, then you can’t tell what the actual reduction in risk is when taking the intervention; all you know is how much lower it is than a number that’s not clearly presented to you.
Although not included in the iPrEx trial report there is information that allows one to calculate the absolute risk reduction conferred by Truvada. To do this we need to know what the risk of infection is to begin with.
This is the number of infections occurring in the placebo group over the time period of the study.
64 out of 1248 people in the placebo group were infected, which is 5.1%, or 0.051 in 1. (since then there have been additional infections reported at the Rome AIDS conference, reflecting an increase in the number of infections over a longer time period).
In the group receiving Truvada 2.8% of 1251 people were infected.
The absolute risk reduction conferred by Truvada is simply 5.1 minus 2.8 which is 2.3.
A 2.3% reduction in absolute risk conferred by Truvada is the more accurate measure of its efficacy. Hardly something to celebrate.
A 44% reduction in relative risk sounds much better, although far from spectacular, but unfortunately it’s a number that tells you nothing about actual risk reduction.
Relative risk reduction is calculated as follows:
It is the number of events in the treatment group subtracted from the number of events in the placebo group divided by the number of events in the placebo group.
On its own, relative risk reduction is not a helpful number.
Of much greater help to a person considering Truvada PrEP is knowledge of the actual risk while taking Truvada (over the period of the study, a median of 1.2 years).
That number is 2.8%.
Knowing the absolute risk reduction allows one to calculate another important measure. This is the number of people who need to be treated to prevent one infection (NNT). From information contained in the trial report 45 people need to be treated to prevent one infection. I did not notice this number in the trial report nor was the absolute risk reduction of 2.3% reported. NNT is a useful number as it allows one to estimate what it would cost to prevent a single infection with Truvada.
The cost of the drug is the least of it. A person taking Truvada PrEP needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to avoid the inevitable emergence of resistant viruses as a result of sub optimal treatment.
If Prep is implemented on a large scale which some AIDS advocates seem to be calling for, but is unlikely to happen, then there may well be increases in new infections with viruses resistant to the drugs in Truvada in men who have sex with men, in IV drug users and in Africans.
PrEP is not a success, at least not with Truvada. However such a failure was transformed into a triumph, part of the explanation is the use of relative risk reduction numbers with care taken to remain silent on absolute risk reduction. Despite all the literature available to help people tell the difference between absolute and relative risk reduction, this evidently was a resource not used by those cheering along this ineffective intervention.
Posted on February 23rd, 2011 No comments
Pre-exposure prophylaxis – called PrEP, is an HIV prevention intervention where antiviral drugs are taken by HIV uninfected individuals in the hope that sexual transmission of HIV will be prevented. A recent trial of daily Truvada, a combination of two anti-HIV drugs demonstrated only a 44% reduction in the risk of becoming HIV infected by sexual transmission among men who have sex with men (MSM). I have written about this trial a few months ago.
Unbelievably, the use of this intervention has in effect been endorsed by the US Centers for Disease Control (CDC). True, the CDC call their recommendations on the use of daily Truvada as PrEP an “interim guidance”. But anything short of “don’t risk your life by taking an intervention that cannot even halve the chance of becoming HIV infected” is in effect an endorsement. Simon Collery has also written about this calling the CDCs recommendations a “mixed message”.
The CDC is not alone in regarding an intervention that is only 44% effective in preventing a potentially lethal infection to be good enough to be implemented. Quite surprisingly some groups claiming to represent the interests of those at risk share this bizarre view. One implication is that these groups, supposedly representing people at risk for sexually transmitted HIV, as well as the CDC have given up on persuading MSM to use a condom, as described by Michael Weinstein in a recent article .
In reality groups calling for an implementation of an insufficiently effective intervention to prevent a life threatening infection may be a small minority whose real influence is probably insignificant in relation to their noisy irrational advocacy.
People on the ground, dealing with risk are often wiser than those who claim to advocate on their behalf, but do not have the means to influence the way issues are reported in the media. They know that a 44% efficacy in reducing the chance of acquiring a life threatening infection is just not good enough. They know that condoms are the most effective way to prevent sexual transmission of HIV.
But when this insufficiently effective measure was first announced in November of 2010, it was hailed as a triumph. Time magazine even called this ineffective intervention the most significant medical breakthrough of 2010! I suspect these accolades may have resulted from the skill of publicists rather than of independent investigative reporting.
But of course I may be part of a minority in considering that a trial demonstrating that an intervention that is only 44% effective in preventing a potentially lethal infection is far from a triumph and rather is an emphatic failure because a much more effective protective measure is readily available that’s cheaper and safer.
Concerns that condoms may not be used regularly in appropriate situations to prevent the sexual transmission of HIV are better expressed by a support for extended properly targeted prevention education.
PrEP trials began in the early 2000s and have had a troubled history. Trials were planned and even several started in African countries and in Thailand and Cambodia. Some never got off the ground, and several were stopped for a variety of reasons. There were vigorous activist demonstrations in connection with some. The varied concerns of activists included provision of care to trial participants who became infected, or the provision of sterile injection equipment to IV drug users in Thailand.
I posted a blog on the POZ magazine website in August 2009 describing an ethical problem with PrEP trials, essentially that PrEP would have to be tested with an imperative to provide and encourage the use of effective means already available to prevent HIV transmission, namely condoms and sterile needles. If these measures are conscientiously provided and their use encouraged it’s unlikely that any effect solely attributable to PrEP could be measured. iPrEx told us that self-reported adherence to medication is unreliable, so there is no reason to believe that self-reported frequency of unprotected sexual intercourse is any less so.
In that post there are links to two significant articles published in 2005. The first represents the view sympathetic to those who demonstrated against PrEP trials. It can be seen by following this link:
The second is the view of PrEP researchers.
One of the ways suggested to forestall the problems that have beset so many PrEP trials in the past was to solicit a greater degree of community involvement early in the process with a view to obtaining their commitment.
An effort was made to obtain community support for PrEP trials with the help of UNAIDS. There have been many teleconferences and many publications about PrEP best seen by looking at this website. http://www.avac.org/
It’s evident that much effort and expense has been placed into engaging communities in the design and conduct of PrEP trials. Apparently with some success as I believe the earlier upheavals associated with PrEP trials have not been repeated.
As for as expenditure on PrEP trials and PrEP promotion, the following figure indicate funding amounts and sources.
Despite this expenditure, it’s most unlikely that PrEP with Truvada will be used by more than a very small minority of individuals.
Apart from the cost of the medication, it will be necessary to pay for regular tests for HIV infection and for monitoring for drug toxicity. It’s likely that some of those who choose to use Truvada as PrEP will forgo these regularly needed tests, because of cost and other reasons. Not only are these individuals risking infection with an insufficiently effective preventative measure, they also risk the development of virus resistant to the antiviral drugs in Truvada because of receiving a suboptimal dose during an unidentified infection.
With only a 44% reduction in the risk of becoming HIV infected, unidentified infections are a very real possibility among individuals who choose to use daily Truvada as PrEP. It’s realistic to be concerned that some of these individuals will not be tested regularly to detect infection. Individuals with an undetected infection could then pose a risk to their uninfected sexual partners. Who knows how suboptimal treatment will influence the course of initial HIV infection?. Even the illness of primary infection that could be an alert, may be less likely to occur. Failure to be tested regularly would also mean that drug toxicity, specially to the kidneys is less likely to be detected.
With all these hazards, not only to the individual using PrEP, and with the likelihood that Truvada, and indeed other antiviral medications can be obtained without a prescription, the CDC’s interim guidance is unwise. It’s also unfortunate that there may be some who will see additional significance in that the guidance is specifically directed at “high risk” MSM.
Properly targeted prevention education with the promotion of, and support for condom use needs all the support it can receive.
Daily Truvada as PrEP is a really bad idea.
Posted on December 12th, 2010 No comments
Pre-Exposure prophylaxis - PrEP - iPrEx trial results.
Pre-exposure prophylaxis, or PrEP, is an HIV prevention intervention in which anti-HIV drugs are taken to prevent infection. A safe, effective and affordable drug that could achieve this would be a powerful prevention intervention even possibly capable of halting the spread of the epidemic.
Last week we were told the results of the iPrEx trial that tested the efficacy of PrEP with Truvada, a combination of two anti-HIV drugs, in reducing new HIV infections among a group of men who have sex with men considered to be at high risk for HIV infection.
The announcement of the results was greeted with almost universal jubilation.
“That’s huge,” said a prominent AIDS researcher, “That says it all for me.”
“Today marks a major step forward in our quest to combat HIV among MSM
“This discovery alters the HIV prevention landscape forever,”
“….. the new data “represents the most promising development in HIV/AIDS since the introduction of triple combination drug therapy in 1996.”
“This is a game-changing trial result,”
Science magazine reported that..
“The researchers applauded and some even cried when they heard the bottom line”; “I have not cried this hard in years” – said one researcher.
These exultant cheers are usually reserved for the most momentous of breakthroughs.
Demonstrating that a drug could be safe and effective in preventing infection would indeed be a momentous breakthrough as already noted.
But the iPrEx results, far from representing such a breakthrough, indicated that PrEP, at least with Truvada, together with counselling and provision of condoms, reduced new HIV infections among men who have sex with men only modestly. It’s unlikely that the 44% reduction in new infections that was seen is of sufficient magnitude to make PrEP with Truvada viable as a public health prevention intervention. Moreover, as will be described there are significant safety concerns, a demonstrated danger of the emergence of drug resistant HIV, and the drug is far from affordable.
A 44% reduction in new infections is not huge; even those extolling the trial results would agree (at least I think they would, but who knows considering the over-the-top responses).
But what is most troubling is that the researchers have squeezed an efficacy of Truvada of over 90% by a questionable statistical sleight of hand, an improper use of sub-group analysis, a technique of data dredging has been soundly discredited. I’ll return to this.
This has resulted in headlines such as “PrEP works – if you take your pills”, I don’t know if this will persuade some people to abandon condoms and religiously take their pills. Unfortunately the type of analysis that provides confidence to do so is not reliable. Maybe consistent use of Truvada will reduce new infections by over 90%. Maybe not.
For the moment staying with the ability to reduce new infections by 44%, as a public health intervention to be used on a wide scale, this degree of efficacy is just not good enough to justify using Truvada to prevent a life threatening infection. Even if the risk of infection is low this must be balanced against the gravity of the infection. About 3% of participants in the Truvada arm of the trial became infected as opposed to about 5% among those receiving placebo.
Perhaps it’s on this issue that I’m at odds with the huge acclaim given to the trial results. Maybe the prevailing view is that a 44% reduction in new infections is indeed good enough; some commentators are even discussing implementation.
PreP proponents like to compare it to malaria prophylaxis. If the efficacy of malaria prophylaxis were of the same order as that of Truvada in relation to HIV, I suspect many people might think twice before visiting an area where there was a risk of malaria.
Let’s take a closer look at the trial results, particularly the claimed greater degree of efficacy in compliant participants reported in the New England Journal of medicine.
I have commented briefly on this in my blog on the POZ magazine website.
The medication used in the trial, Truvada, is a combination of two HIV anti-HIV drugs, FTC and tenofovir. It was compared with placebo in over 2000 men who have sex with men, considered to be at high risk for HIV infection.
The 44% reduction in new infections was achieved in conjunction with counselling, provision of condoms and monthly tests to monitor for infection.
This is not a good enough performance to justify widespread use of Truvada to protect against infection. The investigators then looked at blood and tissue levels of the drugs in people who became infected and those who did not. They found that those who remained uninfected had detectable drug levels while those who became infected did not.
They incautiously trumpeted this result as proving that Truvada works well if the pills are taken consistently – stating that in those who took their pills more consistently the relative risk reduction was well over 90%.
On the surface this sounds good. Almost all the commentators thought so.
However looking at the results in a sub-group of participants can be misleading. Most particularly in a sub-group that is defined after randomization; who would or would not comply with treatment could not have been known. The problems with subgroup analyses will be clearer after a short account of intention to treat analysis.
Intention to treat analysis is the most reliable way to analyse clinical trial data. In such an analysis participants are 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. This seems counter-intuitive, but there are sound reasons why intention to treat is regarded as the best way to analyse trial data, among them that it more reliably reflects what happens in real life, rather than in a clinical trial. For example, one reason why pills may not work is because they are not taken. If they are not taken in a trial we have to be concerned that they may not be taken in real life. Take a look at this excellent explanation of intention to treat: Making sense of intention to treat.
As noted, the trial investigators made a lot of the sub-group analysis showing greater efficacy in those who took Truvada pills as measured by finding the drugs in blood and tissue samples.
This is surprising as the pitfalls inherent in such post-hoc sub-group analyses have been recognized for years. Commentators, some of whom are clinical researchers, in their over-the-top exultation at the results of the analysis in those compliant with Truvada may have forgotten about the treachery inherent in sub group analysis. A few commentators give the problem only passing acknowledgement.
This is a classic paper on sub group analysis:
Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials.
Journal of the American Medical Association 1991 , 266:93-98
This is from that paper:
“Analysis of improper subgroups, though seductive, can be extremely misleading, because a particular treatment effect may influence classification to the subgroup. Thus, an apparent subgroup effect may not be a true effect of treatment but rather the result of inherent characteristics of patients that led to a particular response or to the development of side effects”.
In iPrEx the subgroups were categorized by events that happened after randomization, so the adherent group is an “improper” subgroup. “Subgroups of clinical trial subjects identified by baseline characteristics … is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup”.
In actuality the attention given to the subgroup that had blood and tissue drug levels is an example of the treachery of such sub-group analyses.
As an illustration, the reduction in new infections seen in this group may well have resulted from the following possibility.
People who take their pills consistently are more likely to use condoms consistently and in general are more attentive to risk. So if it were possible to do a subgroup analysis of people who adhered to placebo we might conclude that the placebo also works – (and it’s cheaper).
This is not so fanciful.
“In one study , those who adhered to the trial drug (clofibrate) had reduced
mortality; but those who adhered to the placebo pill had the same reduction in mortality”.
This is from:
Coronary Drug Project Research Group. Influence of adherence to treatment
and response of cholesterol on mortality in the coronary drug
project. Engl J Med 1980;303:1038-1041
A classic example of the pitfalls of subgroup analysis is what it demonstrated in the ISIS-2, a trial examining the effects of aspirin after myocardial infarction. A subgroup analysis showed it was of benefit to all except in people who were either Libras or Geminis.
Maybe Truvada taken consistently can reduce new infections by over 90%; maybe not. There was no basis for the investigators and commentators to present the first possibility with such overwhelming confidence.
We must accept that a 44% reduction in new infections is at this time the most reliable estimate of Truvada’s efficacy as PrEP. Although, the confidence interval , a measure of reliability, was wide.
We have an intervention that can reduce new infections by 44%, if taken in conjunction with a program of counselling, condom use, and monthly tests for HIV infection. That is the benefit. What about the down side?
The two most important are the development of resistance of HIV to the component drugs of Truvada and the toxicity of the drugs.
The utility in treating HIV infection of FTC and tenofovir – Truvada’s component drugs is lost if the virus becomes resistant to the drugs. Moreover, some mutations conferring resistance to these drugs can also affect sensitivity to some other drugs. The danger of resistance, and even cross resistance to other drugs developing when Truvada is used as PrEP is not a trivial concern. Truvada used as PrEP provides a suboptimal dose in treating established HIV infections. This is precisely the situation in which resistance is likely to develop. There were in fact two instances of developed resistance in the iPrEx trial in individuals who became infected, but undetected before the trial began.
Resistant viruses in the community are a danger to all, so the risk of generating resistance is not confined to the individual taking Truvada as PrEP.
What about safety?
The claim in many reports that Truvada is without significant toxicity is also misleading.
Maybe poor adherence has some bearing on the lack of significant toxicity.
A median of 1.2 years exposure to Truvada 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. Renal toxicity, sometimes severe occurs not uncommonly. It’s mostly but not always reversible on stopping the drug. Thinning of bones, osteopenia and osteoporosis is also seen. There are additional adverse effects associated with the drugs.
There were small abnormalities in some paramaters measuring kidney function among those treated with Truvada. Although these changes were reversible on stopping the drug, the fact that they were seen at all is a reason for great concern about the effects of longer term treatment.
With the experience we have gained from longer term treatment with Truvada, it is disingenuous to stress its overall safety from just 1.2 years of very inconsistent use.
It’s important to point out that for HIV infected individuals, the benefits of treatment with Truvada far outweigh the risks. For uninfected individuals, an entirely different risk benefit analysis must be made.
Despite the disappointing results of iPrEx, PrEP is important.
Why is PrEP important?
There are at least two important reasons.
PrEP could protect receptive partners in sexual intercourse, both men and women, who are unable to ensure that a condom is used by their partner and for a variety of reasons are unable to refuse sex . The best and most respectful way of addressing this would be to find ways to empower these individuals; in some way providing them with the means to protect themselves could be seen to also have the effect of perpetuating their subjugation and abuse.
But there are women and men who need protection now and providing them with a means to prevent infection that they can control is vital. This can go hand in hand with working to empower them and helping them to try to ameliorate or leave abusive relationships.
Sex is one of life’s joys. It is vitally important to the human experience.
Condoms can be a barrier to intimacy which for many is the most essential aspect of sexual intercourse, for both receptive and insertive partners. So recommending the use of condoms without acknowledging the significant obstacle they may present to a fulfilling sexual experience is a real problem. Pleasure is part of that fulfilment and for some insertive partners condoms are a significant impediment to experiencing it.
A fully effective and safe means of pre-exposure prophylaxis may also allow the removal of a barrier to conception.
But people are different; for example some individuals have found that condoms can increase intimacy in the reassurance they provide concerning their and their partners safety.
We should never minimize or trivialize the difficulties condoms can present. We should also keep in mind that their use is the most effective means of preventing sexual transmission of HIV.
Their use will remain necessary in order to remain uninfected until we are free from HIV or a safe an effective PrEP method can be found.
These considerations, a prevention method that the receptive partner can control,allow conception and remove an impediment to full sexual expression are reasons to work towards finding a safe and effective form of PrEP. If this can be achieved safely and affordably it could even help to bring the epidemic to an end.
Truvada unfortunately has not proved to be sufficiently effective or safe to be of utility as a general recommendation. The use of condoms still remains the most efficient way to prevent the sexual transmission of HIV.
A few words about prevention education and condoms:
The consistent use of condoms is the most effective means to prevent sexual transmission of HIV.
PrEP proponents agree but many go on to say that people just don’t use condoms consistently. This is an attitude that has apparently concluded that prevention education does not and cannot work.
But how can one conclude that it does not work when there has been so little of it? This has some analogy with the claims made for the efficacy of Truvada. It works, if you take the pills
If prevention education has been a failure, it’s not because it doesn’t work, but because we have not provided it well enough. There has been too little and most has not been properly targeted.
Proper targeting to those most at risk is critical. I have written about this. We need more and better prevention education.
The CDC now tells us that the group at greatest risk by far in the US is men who have sex with men. Nothing has changed except the ethnic distribution, so why are they only telling this to us now? For over twenty years we were told that AIDS was an equal opportunity infection making prevention education targeted to those at greatest risk even more difficult.
It’s only now, 25 years too late, that the CDC appears to recognize the urgency of providing prevention education to gay men.
Neglect of properly targeted prevention education, with encouragement for condom use and continuing support to sustain their use helped to allow the spread of HIV into African American communities in plain view while millions were spent on “America Responds to AIDS” a vacuous prevention message.
Similarly we have known for years that in the US younger men who have sex with men are at particular risk. We know where to target prevention messages, but we don’t do it well enough.
We know that highly targeted prevention education, when crafted by the communities at greatest risk can work. This was demonstrated in the earliest years of the epidemic in San Francisco and New York City.
In 1982 when Michael Callen, Richard Berkowitz and I first recommended condom use to gay men in New York City, we stressed that in doing so it was important to celebrate sex, recognizing that for some individuals condom use, or perhaps more precisely, HIV, could present a barrier to its full expression. We have come far in freeing ourselves from long standing societal constraints that for too many have stood in the way of a fulfilling sexual experience burdening it instead with guilt. It’s important to take care in providing continuing support for condom use and recognize that for many they do get in the way. But it’s really HIV that’s getting in the way, and consistent condom use can help to bring it to an end.
Finding conditions where sex without condoms is safe is important. On the showing of iPrEx – despite its ecstatic reception, PrEP unfortunately is not yet ready.
At the moment consistent condom use is the best protection there is.
The often uncritical response to iPrEx should not persuade anyone that Truvada is a safe and effective alternative.
iPrEx is a large and complicated study. The investigators deserve the highest praise for completing this difficult phase and for havine provided a result. It may not be the result that many had hoped for. But providing clear information is a great achievement and a major advance . iPrEx results clearly show that continued condom use is still necessary to prevent the sexual transmission of HIV.