Posted on August 17th, 2011 No comments
In my last post I wrote about the very small reduction in the absolute risk of HIV infection in the iPrEx trial among those taking Truvada as pre-exposure prophylaxis.
The 44% reduction in relative risk conferred by Truvada was the only efficacy measurement explicitly presented by the investigators. That the absolute risk reduction was only 2.3% was not mentioned in the various presentations.
I suspect that many reading press reports of this so called breakthrough were unaware that in fact, the actual risk to people taking Truvada was 2.8%. (36 infections in 1251 participants). True, this is less than the 5.1% risk to those on placebo, but by very little. Certainly not enough to justify the bewildering acclaim given to the iPrEx trial results.
Failing to clearly state the absolute risk reduction of an intervention is something we have come to expect from salesmen to inflate the efficacy of a product, but not from clinical researchers. Large reductions in relative risk can be associated with minute reductions in absolute risk when the events prevented are low to begin with.
Another important reason why absolute risk reduction should be stated in a report is that this allows one to calculate the number of people who need to be treated to prevent one event, in this case, one HIV infection.
Although the iPrEx investigators did not explicitly provide these numbers, they can be worked out from data presented, as I did in my last post and was also done in a letter published in the New England Journal of Medicine of April 7, 2011 in response to the iPrEx trial report, where the authors report that 44 people need to be treated to prevent one infection (I got 45).
They then went on to calculate that it would cost $400,000 a year to prevent a single infection.
This figure does not even include the cost of the necessary monitoring for infection. In another letter, it was suggested that such monitoring be done monthly to prevent the emergence of resistant virus by detecting infection early.
From Sean Strub’s calculations (in his comment to my post on the POZ magazine website) which included doctor’s visits and tests, the annual cost would be about $500.000.
These figures are based on drug costs in the US.
Truvada PreP not only does not work well enough it will cost a half million dollars a year to prevent a single infection.
Maybe this is indeed a “game changer” but not in the sense intended by the triumphalist reports coming from the recent Rome AIDS conference.
There definitely seems to be a perception that PrEP is a viable prevention option for everybody; there even have been calls for its general implementation. These cost estimates alone would make it unfeasible as a public health measure but there are additional reasons, importantly its relatively low efficacy.
PrEP is a reasonable option for only a very small number of individuals at high risk for infection who are able to be regularly checked for infection. I believe there is no disagreement about this; the controversy is only about its general use.
Implementation of PrEP on a wide scale will almost certainly result in an increase in new infections. It’s not only adherence to the drug regimen that will not be maintained by all. Adherence to a schedule of regular testing for infection cannot be relied on.
The way PrEP has been promoted has probably already damaged targeted prevention education programs with support for continued condom use, an activity already in great need of support.
Drugs for prevention are paid for from a different budget than prevention education programs, and health departments already under budgetary constraints may feel that prevention needs can now be paid for by those entities that pay for drugs, private insurers or Medicaid/Medicare.
The amount of almost uniformly uncritical publicity given to PrEP is completely out of proportion to its utility. It’s a hugely expensive and very poorly effective prevention intervention, of use to only a very small number of individuals, and its misleading promotion has probably already damaged prevention education programs.
Considerable resources must have been devoted to publicize and promote PrEP over many years, in a way that has not taken care to reinforce prevention education with support for continued condom use. One can only wonder why.
Drs Dong Heun Lee, M.D. and Ole Vielemeyer, M.D of Drexel University College of Medicine in Philadelphia are the authors cited.
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.