Pre-exposure prophylaxis for HIV: panacea or Pandora's box?

For the video version of this post, click here. Pre-exposure prophylaxis for HIV - PrEP - basically entails taking a medication, typically a combination pill of tenofovir and emtricitabine to reduce the risk of acquiring HIV. PrEP is highly efficacious, with several randomized trials demonstrating a sharp reduction in transmission rates when PrEP is used in high-risk populations. In fact, among men who have sex with men, you need to provide PrEP to about 12 people to prevent one HIV infection.  That’s a very low number needed to treat for such a costly disease.

But efficacy isn’t the same as effectiveness. Efficacy is an ideal. Clinical trials follow their patients extremely closely, ensure they are taking their medication, and select their participants very carefully.  Effectiveness is the real-world performance of a drug, and, until now, we haven’t had great data to see how PrEP would work in practice.

And there have been concerns. PrEP should be used with a condom, it doesn’t replace a condom. It can’t be taken immediately prior to risky sexual behavior - it’s a daily medication. There is a low, but real, risk of kidney dysfunction with the drug. But the real controversy surrounds a small but vocal group of physicians and AIDS activists who suggest that PrEP will ruin so-called “condom culture”, opening the door to less safe sex, increased sexually transmitted infections, and even an increase in HIV transmission rates.

That’s why this article, appearing in JAMA Internal Medicine is so important.  The study followed 557 men who have sex with men and transgender women in three clinics across the US for about a year. All were HIV negative, but at increased risk of HIV infection, and all were provided PrEP free-of-charge.

Adherence was high - over 80% of individuals had therapeutic tenofovir levels when checked. Encouragingly, adherence was highest among those who engaged in the highest risk sexual behaviors. That’s right - our patients at risk understand they are at risk.

Over the course of the study, there were 2 new HIV infections, both in men with subtherapeutic levels of the drug. Based on baseline rates we would have expected around 11.  But that impressive result is not what really matters in this study.

Rates of receptive anal sex without a condom didn’t change at all over the course of the study.  Sexually transmitted infection rates didn’t change. In other words, the availability of a drug that can really prevent HIV transmission didn’t open some time portal to 1983. PrEP did not destroy condom culture, not that condom culture is all that pervasive. This is one of those situations where we have to respect the intelligence of our patients.  Educate them clearly on how this medication is to be used, and trust that they, as consenting adults, will use the drug the right way.

Have we been giving kids juvenile idiopathic arthritis inadvertently?

For the video version of this post, click here. If you’ve ever taken care of a kid with juvenile idiopathic arthritis, it sticks with you.  This disease, which is occasionally referred to as juvenile rheumatoid arthritis, isn’t fatal, but it can rob children of the ability to be active, play, and grow - the real essence of childhood. And to date, we still don’t know what causes it.  It’s clearly auto-immune, but there isn’t even a serologic test for the disease.

An article appearing in Pediatrics, from Daniel Horton, and - full disclosure - several of my former Penn colleagues - links antibiotic exposure in childhood to the subsequent development of JIA.

The researchers used the huge Health Improvement Network dataset, which captures much of the primary care activities that go on in the United Kingdom.  Examining over 140,000 children, they found 152 cases of JIA, and matched them based on age and gender to 10 controls each.  The bottom line?  88% of cases had been exposed to antibiotics.  75% of controls had been exposed.

Of course, you get antibiotics for infections. And cases were more likely to have infections as well: 93% versus 85%.  A question and an observation, then.  Question: is it the infection that causes the JIA and the antibiotics are just a bystander? Observation: man, we give a lot of antibiotics to kids.

The authors did a tremendous job putting the blame on antibiotics here.  With multivariable adjustment, infection fell away as a risk factor - antibiotics persisted. There was a dose-response finding as well - more antibiotic courses were associated with higher risk.  There was also a temporal component - there was a higher risk of JIA if antibiotics were given within a year of the index date compared to earlier time points. Finally, they tried to rule out reverse causation by considering the diagnosis of JIA whenever the first symptom (like limp or joint pain) appeared.

Bottom line? I believe that this finding is real.  Whether the offered explanation - that antibiotics affect the intestinal microflora and alter immunity - is true remains to be seen, of course.

But I want to use this study to illustrate one issue that plagues almost every study of risk factors - and that is a failure to give us a sense of the attributable risk.  In other words - how many of the cases of JIA can be explained by antibiotic use, compared to other possible risk factors (like the things that went into the multivariable adjustment)? Can every case of JIA be traced back to some antibiotic exposure? Of course not - but how much of the variation is explained by this variable.  That’s the information we need to actually counsel our patients.

One thing this study does is open the door to future research.  Given the microflora argument, that research will likely involve a lot of stool collections.  And that, my friends, is why I’m occasionally glad that I’m a nephrologist.