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PrEP Trial Reports: iPrEx

| 5 Comments
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Data on risk reduction derived from trials can be expressed in different ways.  Too often the results of prevention trials are presented in ways that exaggerate the benefits of an intervention, and information is withheld that would allow us to more realistically understand the degree to which risk is reduced.

The most common way in which results are presented in order to throw a more favourable light than is warranted is to only present the reductions in relative risk, and to withhold information on  absolute risk reduction.

 In iPrEx for example we were told that the relative risk reduction in people taking Truvada was 44%.

But what does a 44% reduction in relative risk mean?   Certainly not a 56% risk of infection without PrEP, as several people have said when asked this question.   It's because of these answers that I'm writing this.

Relative risk reduction tells you the percent reduction in risk in the treated group compared to that in the control group, or how much lower the risk with an intervention is relative to the starting risk.

 

If you are not clearly told what the risk is to begin with, then you can't tell what the actual reduction of risk is when taking the intervention; all you know is how much lower it is than a number that is not clearly presented to you. 

 

 

Although it is not clearly stated in the published trial report, we can work out what the starting chance of infection is. 

It's the number of infections occurring in the placebo group during the time period of the study. We were told that   64 out of 1248 people in the placebo group were infected, which is 5.1 in 100, or 0.051 in 1.     (Since then there have been additional infections, reported at the recent conference in Rome, reflecting an increase in the number of infections over a longer time period).

The absolute risk reduction, as opposed to the relative risk reduction conferred by Truvada tells you how much lower the risk is than in the placebo group in absolute terms.

2.8% of the 1251 people in the Truvada arm became infected compared to 5.1% in the placebo group.

The reduction of risk in the Truvada group is therefore 5.1 minus 2.8, which is 2.3.

Truvada PrEP reduces the absolute risk of infection by 2.3%.

A 2.3 % reduction in absolute risk is nowhere nearly as impressive as a 44% reduction in relative risk.

Yet this lower number is a more accurate measure of the efficacy of Truvada PrEP. (1)

 

The actual risk of infection in the Truvada arm was 2.8%, which surely is a figure that is more useful to an individual considering PrEP.  (2)

Not clearly stating the absolute risk reduction conferred by Truvada was unfortunate.  I haven't checked, but will look to be sure that  absolute risk reductions were clearly stated in the other recent PrEP trial reports.

Maybe in Rome, the absolute risk reduction conferred by Truvada was in fact clearly stated.

 

Knowing the absolute risk reduction allows one to calculate another important measure, which again I did not notice in the trial report.

This is the number of people who need to be treated (NNT) in order to prevent one infection. From the information presented it appears that about 45 people need to be treated in order to prevent a single infection.  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 needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to prevent the inevitable emergence of resistant viruses as a result of sub optimal treatment.

It should be possible to make a ball park estimate of what it will cost to prevent one infection. Whatever it is, it's the cost of treating and monitoring 44 people who will derive no benefit and be subjected to the adverse effects of tenofovir on their kidneys as well as other adverse effects. There will be additional costs if they generate resistant virus.

 

 

 

 

There is a great deal of information written to inform people about the differences between relative and absolute risk and how risk data can be manipulated to make the results appear to be better or worse than they really are.

 

I would recommend "Know Your Chances" by Steven Woloshin  and others .  The book opens with this statement.

Numbers can make people sick.

But they don't have to.

Learn how to make them help you.

 

Or just put "absolute and relative risk" into the google search box.

(1)

I have copied this from a website in the UK addressed to patients:

 

Helping to decide about taking a treatment

The decision on whether to take a treatment needs to balance various things such as:

  • What is the absolute risk of getting the disease to start with.
  • How serious is the disease anyway.
  • How much is the absolute risk reduced with treatment.
  • The risks or side-effects in taking the treatment.
  • How much does the treatment cost - is it worth it to an individual if the individual is paying, or is it worth it to the country if the government is paying?

 

To which must be added:

  • More effective, cheaper and safer interventions are readily available (at least in developed countriers)

(2)

 Unfortunately even knowing absolute risk and absolute risk reduction is still of limited help.

In anal intercourse the risks of infection to receptive and insertive partners are not equal.  The receptive partner is at greatest risk, and may well be  responsible for the bulk of the overall 2.8% risk of infection in the published report.     It's probably impossible to reliably break down the risks in the trial according to self-reported sexual act. 

 The investigators were easily able to discern the unreliability of self-reports on drug adherence.   I don't know why they were so willing to trust the reliability of self-reports about specific sexual acts..     Unlike verifying adherence reports by measuring drug levels, there is no way to verify self-reports of unprotected receptive anal intercourse.      Self-reported sexual practices in epidemiological investigations have been repeatedly proven to be unreliable in several studies.

Given that the receptive partner is at greater risk, their best protection is of course to refuse sex with a partner who will not use a condom.  Among men who have sex with men there surely can only be very limited situations when the receptive partner would choose the more dangerous course. For example, in a relationship where the insertive partner cannot maintain an erection with a condom, or where a couple feels that intimacy is diminished with a condom. We should be supportive of PrEP  in these circumstances  We should also make clear what we know about risk, and provide more information than simply relative risk reduction numbers. 

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Comments on Joseph Sonnabend, MD's blog entry "PrEP Trial Reports: iPrEx"

These kind of "number games" go on all the time in science. The state of science in this country is just depressing. Our medical scientists and doctors are willing slaves to the pharmaceutical companies. The biggest problem is education though and the dumbing down of the public.

People don't understand math anymore, not even on an elementary level. A simple semester or two of statistics would clear a lot of the confusion up. It's a sad sad state.

AIDS activists are usually so knee jerk about everything; they embrace everything, instantly, that seems even slightly like it may be beneficial. AIDS activists, in my experience, although their hearts are in the right place are the biggest bunch of morons I have ever met.

So if 44 people are required to be treated for 18 months to prevent one infection, that translates into nearly five years (592 months) of treatment to prevent one infection.

In a hypothetical situation where treatment--including the very necessary doctor's visits and lab work--costs $10,000/year, would that mean it costs $59,200 to prevent an infection (in that 18 month window) via PrEP.

I realize treatment costs are highly variable, but otherwise is my math correct?

I looked at the NEJM report again and note that the median time on the study was 1.2 years. So that's the period to consider rather than 18 months. The costs would be less than $59,200 but not by much.
Also it's unlikely that all would comply with regular monitoring that anyway may not be available everywhere. Any savings would probably be offset by additional costs down the line from the consequences of inadequate monitoring.

Even with appropriate monitoring, there are certainly some additional costs down the road for those who do not seroconvert but do develop osteoporosis, heart, kidney or other problems from taking the treatment. We continue to learn more about the side effects of the treatments in people who have HIV; there is no reason to think those taking treatments who do not HIV won't have any side effects.

None of those costs are included in my hypothetical $10,000 per year cost of treatment.

Too bad Sonnabend and Strub are stll using numbers they know are inaccurate to begin with. It doesn't matter how you parse and manipulate the data. If you know the data you start with are incorrect, you're still lying.

To his credit, however, Sonnabend hedges: "where the insertive partner cannot maintain an erection with a condom, or where a couple feels that intimacy is diminished with a condom. We should be supportive of PrEP." In other words, the doctor will allow that chemoprophyllaxis may be worthwhile for anyone who thinks condoms suck (and not in a good way). It would be interesting to see some believable data on how many men fall outside this gaping exception.

But ultimately what it comes down to is this: freedom of choice and individual responsibility. If I get pregnant and don't want to be, should I have the option of terminating the pregnancy or not. From the logic of their recent arguments, it is clear that Sonnabend, Strub and Hoffman think not. Birth control, especially abortion, is just a pricey sex toy to them. Likewise for fertility medicine. If I'm having trouble conceiving in a world of seven billion, should I really be allowed to spend the huge sums of money needed to make the miracle happen for me? Or more to the point, if I have HIV and find myself pregnant or wanting to be, should I really have any options?

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This page contains a single entry by Joseph Sonnabend published on August 3, 2011 11:41 AM.

Treatment as Prevention: Protecting patient autonomy was the previous entry in this blog.

HIV and Herpes Viruses is the next entry in this blog.

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