19/05/11

HIV treatment really IS prevention, but…

For some time now, I’ve been waltzing around casting doubt on the “treatment is prevention” mantra, the idea that putting people infected with HIV on meds sooner will reduce new infections, despite pretty good observational evidence that people on treatment are less likely to infect their partners. If I had been praying at the altar of the randomised controlled trial for more reliable evidence, my prayers would now be answered: a trial involving 1,763 couples in 13 countries has found that putting heterosexuals on meds earlier cuts the chances that they’ll pass on HIV by 96%.

That’s huge. So huge that the study was stopped early. We still don’t have many details about things that I would find interesting — how good were people at taking their pills, did they people on meds have more or less unprotected sex than people who weren’t on pills, etc. — but it seems incontrovertible that if you’re infected with HIV, one way to protect your sex partners is to start taking antiretrovirals when you’re immune system is still in relatively good shape.

I’m still left with two major questions. First: it is clear you’ll protect your partners, but will you protect yourself? What do we really know about the long-term effects of taking antiretorvirals early for your partners’ benefit? We’ll get more information about that from another trial by the same group, but they’re not scheduled to report for another five years. People who got treated earlier in the the treatment-as-prevention trial were just as likely to die during the course of the study as those who didn’t, though encouragingly, they were signigicantly less likely to get sick with TB. It may well be that starting meds earlier is good for the infected person as well as for those they shag.

Second major question: this study (known as HPTN 052) has made it clear that an HIV infected person whose CD4 count is between 350 and 550 when they start treatment is less infectious than a person who doesn’t start until their cell count falls below 250. For those individuals, treatment is prevention. But does that necessarily mean that expanding treatment will reduce new infections at a population level? For an interim period, at least, it may well not. Before I’m accused of raining on the parade yet again, I want to point out that the same question was raised by Myron Cohen, the principle investigator of HPTN 052 in an e-mail exactly a year ago. Speaking of a stampede towards using earlier treatment as a means of prevention, in part as a result of a lot of “utopian” modelling, Myron said:

“I am not convinced that this will all come out the way it now appears, and we do not yet know how to measure population level benefit of ART, if it is to occur.”

Logically, if you reduce the infectiousness of every infected person by 96%, new infections will fall very dramatically. But we know that can’t happen. It certainly can’t happen overnight. It’s worth noting that genetic analysis of the virus shows at least 18% of the new infections in the study (and possibly up to 28% — not all the analysis is finished) came from someone who was not the “regular partner” recruited into the study. Until everyone gets treated sooner, those infections will continue. Indeed some will continue even with universal earlier treatment, because some will probably have come from people who are newly-infected, very infectious and unlikely to be treated. That’s a continuing worry in places where the all-too-visible face of AIDS-related emaciation, disfigurement and death prompted a change in behaviour; less sex, fewer partners, more condoms. As expanded treatment removes that visible death-mask, communities revert towards pre-AIDS behaviours. Where condom use rose rapidly, for example among gay men in rich countries, it has fallen back since relatively early HIV treatment has been universally available. The effect may be less pronounced in the hyperendemic countries where behaviour has not changed all that much, but it’s something to watch out for. More unprotected sex with a variety of partners also pushes up STIs, and an active STI can in turn unleash spikes of HIV in the genital fluids and undermine the protective effect of antiretrovirals. Note that I’m not talking here about the behaviours of discordant couples who have been to counselling and are on HIV treatment, I’m talking about people who believe (or assume, or just hope) that both they and their partners are negative.

It’s perhaps worth clocking that researchers shifted their original “deferred treatment” threshold to a CD4 count of 250 (from 200) when the WHO treatment guidelines (and the national guidelines of many countries they were working in) shifted. They did not, however, change it again when WHO guidelines were revised upwards again to 350, because “the second revision was not readily adopted by all of the countries participating in the study, primarily due to a lack of drug supply.”

The fact that 1.8 million people died of AIDS in 2010 confirms that many countries have trouble getting drugs even to those people who depend on them for survival. Getting them to the larger number who might benefit from them as a transmission risk and TB reduction measure will be harder still. That will eat into the potential prevention gains in two ways — obviously people who don’t have drugs don’t have lower viral loads. But relatively healthy people who sometimes have drugs may present more of a transmission risk than those who never do, because HIV tends to spike upwards into a brief, highly infectious phase when treatment is interrupted. Frequent interruptions can undermine the effectiveness of the drugs; resistance is another source of nasty, infectious spikes in viral load. Though we don’t yet have any information about adherence, we can assume that people in the HPTN 052 trial had uninterrupted access to meds, and we know from the study protocols that they were actively encouraged to keep taking them. We also know that they deliberately excluded drunks, people with drug problems, people with mental problems or “Any condition that, in the opinion of the study staff, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives”. In the real world, we can expect a more erratic drug supply, sloppier adherance and bouncier viral loads. That may will turn in to protection of far less than 96%.

Overall, more people on treatment means, we hope, more people living longer, healthier, more sexually active lives. That also means more opportunities for sex with someone when viral load is spiky, and thus for onward transmission over HIV. Add together more unprotected sex with people who may be in not-yet-treated primary infection, and more sex during times after the start of treatment when HIV is bouncing around because of STIs, treatment interruption, treatment failure or whatever. If the sum of those two adds up to more than the sex a person has between the time their CD4 count hits 550 and the time it would otherwise have hit 250, new infections are likely to rise, even if earlier treatment reduces transmission during that notional window to zero.

That is absolutely no reason at all not to push to use antiretrovirals to reduce infectiousness in people who are infected. I am persuaded that we should be doing that, and I think HPTN 052, with its relatively sober threshold for starting even the “early” treatment points us in the right direction. But I think it will be a long time before we have the cash and the systems in place to make this an effective prevention tool at the population level. And since none of the other prevention tools we have are working very well at the population level either (at least in unpaid sex of any persuasion), we certainly can’t declare victory quite yet.

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This post was published on 19/05/11 in Science.

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  1. Comment by Roger, 19/05/11, 03:53:

    To partially answer your first question: there were 65 critical events in the delayed arm versus 40 in the immediate arm. Critical means infection or death (unclear what kind of infection). The trial used a composite value to determined individual benefit of starting ART early and the DSMB said teh benefit were obvious.

    I have no answer to the second question, but I have a view which is that it could indeed be a zero sum game but not a negative one!

  2. Comment by nb, 24/05/11, 04:28:

    interesting post as usual. nice to hear a voice of someone capable of pondering the evidence as it is without adding spin. this is great news for sure but the distance between the population level dynamics of hiv transmission and medicating individuals is a long way indeed. my question has to do with medication adherence. as you scale up treatment it seems to me that the issue of medication adherence becomes quite profound. how good are populations at taking their meds and what level of adherence would need to be achieved and maintained for years to avoid the adherence variability from contributing to viral load variability which in turn could feed new infections…seems to me that with a low efficiency virus like hiv that is sustained by big diffuse networks that any any HIV prevention intervention must battle against merely adding noise to the network, which risks creating chaotic change exploited by the virus…

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