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PrEP: Welcome Back to the 1980s

| 13 Comments

I read Regan Hofmann's blog-post last week titled "Not Drinking the PrEP Kool-AIDS" with a mixture of dread (would I be accused of being an irresponsible PrEP cheerleader?) and a growing sense of déjà vu. By the end of the piece I had been carried back to the days when pitched battles on the floors of ACT UP meetings took place over where scarce government funding ought to be focused--prevention versus care--and when a heinously powerful North Carolina Senator, Jesse Helms, ensured that dollars devoted to "hedonistic faggots" and "irresponsible druggies" was a no go before a bill ever made it to the floor of the Senate. While I'm certain Regan intended only to spark productive dialogue, I fear that her words could actually hinder it. Let me explain.


I actually agree heartily with one of Regan's key contentions--that offering treatment to all HIV-positive people who need it will probably do more on a population-based level to reduce new HIV infections than offering the same drugs to most HIV-negative people to keep them free of the virus. It's a twofer made in heaven--preserve the health and lives of people with HIV while simultaneously making them far less likely to pass on HIV to those with whom they have sexual relationships--though I disagree with Regan's suggestion toward the end of her post that our only option is to choose between ARV scale up in people with HIV and PrEP for HIV-negative folks.


I also share Regan's concern for the fact that we have barely made a dent in rolling out antiretroviral (ARV) therapy everywhere it is needed, even by old-fashioned treatment guidelines. Indeed, as she states:


"Currently, there are 33.3 million people estimated to be living with HIV worldwide. To date, only 6 million of those people have access to ARVs. This means the bulk of the remaining 27.3 million people are headed toward near-certain death. Some of them quite rapidly."


This fact, combined with the knowledge that the U.S. government and other nations are failing to make good on the promise of global ARV scale-up, means we are indeed at a difficult crossroads. These next several years will be a time of great debate and difficult choices. Where should a paucity of resources be devoted and how can we deploy them in the smartest most cost effective manner? Where should activists focus their might and energy?


Those conversations must be had, and they won't be easy. Talking about money never is. They won't, however, be facilitated by mischaracterizing people who've been working to better understand PrEP's potential, by overstating the prevention possibility of "treatment as prevention," or by playing to the divisions and resentments between wealthy nations and resource-poor countries or between mainstream communities and those who are most disenfranchised.


I suppose Regan would consider me one of the Kool-Aid drinkers. I do believe that the three successful PrEP studies, iPrEx, PARTNERS and TDF2, are a watershed moment in the epidemic and a reason for celebration. I never, however believed that PrEP should be in the prevention "toolbox" for everyone. For one thing, it is quite expensive compared to behavioral interventions and condoms. It is also, like condoms, vulnerable to less than perfect adherence and the average human being has a notoriously difficult time taking a pill everyday, especially when their immediate survival doesn't depend on it.


Activists have not had the last word, however, in regards to the price of Truvada in the settings where PrEP will be needed most. We have already achieved price reductions in ARVs for HIV treatment around the globe and concessions from the pharmaceutical industry that most once believed impossible. We have only begun to discuss pricing and access for PrEP in the United States, but are already making headway. Activists are powerful and wily individuals and we should not assume that we've done all we can on a global scale.


Regan also seems to assume that those taking PrEP are taking it for life. That's not my understanding for how many people will be using it. Rather, many of us hope that PrEP could provide us with the breathing room to guide people safely through periods where individual and structural factors make it difficult or impossible to use condoms consistently.  What's more, it is possible, though not yet proved, that some form of intermittent PrEP might ultimately be an alternative, which would further reduce the cost.


PrEP also has tremendous promise for people at exceptionally high risk of infection. What excites me is that PrEP is something we can offer to such individuals when the current alternatives are largely unacceptable, ineffective or inappropriate. In this case something (PrEP) is a hell of a lot better than nothing--which is the alternative that many are currently left with.


But PrEP has the potential not only to prevent an individual from becoming infected, it could also help slow down the spread of HIV through an entire sexual network in at least some settings in a way that testing and linkage to care alone might not. Experts have demonstrated that a significant proportion of new HIV transmissions occur between individuals in the days and weeks after infection, often well before even the most strenuous test and treat programs could reach such people.


Thus, if we can successfully reach enough people within high prevalence and high incidence communities with both PrEP and treatment to those who test positive--it could, for the first time in the course of the epidemic actually come close to shutting down an entire generation of new infections. That is something to celebrate, in my book. What's more, the additional time spent in supporting a person to successfully stay on their PrEP regimen would offer multiple opportunities to deal with the other behavioral and structural issues that have placed them at greatest risk of becoming infected in the first place. The days when a yearly HIV test or a plastic bin of condoms in the bathroom of a bar may be deemed sufficient are long gone.


While Regan states in the middle of her post that she supports PrEP in limited situations, she later offers this apparently contradictory conclusion:


"Given the efficacy of treatment as prevention for people with HIV...I have to again ask: In a time of limited resources, how can we afford to invest in PrEP? Do we need to spend millions of dollars on drug trials and feasibility studies for PrEP? Wouldn't the world be better protected and more lives saved if that money instead was dedicated to increasing access to care for people with HIV?"


The problem is that all we currently know is that PrEP can work--for men who have sex with men (MSM) and for heterosexual men and women--within the confines of a study. What we don't know are the most cost-effective and safest ways to use it in the real world, and such feasibility studies are the only way we'll ever find out. Besides, I think the question shouldn't be whether we do testing and linkage to care and treatment for people found to be positive (TLC+) or PrEP, but how to do both together, and demonstration projects are our best way to answer that question.


In my role as the director of research advocacy for Project Inform, an HIV advocacy organization based in San Francisco, I will be working with my colleagues in the coming weeks to pose tough questions that PrEP demonstration projects must answer. To argue against funding such projects seems to me penny-wise and pound-foolish. It is also a shameful neglect of the most disadvantaged communities who may need PrEP most and who we have been shoved to the back of the bus (and sometimes under the bus) for the last thirty years: black and Latino MSMs, transgenders, sex workers, people who have problems with substance use and mental illness, and people in relationships where the other partner has all the power.


Again, no one can argue that getting ARVs to the HIV-positive people who need them should be our highest priority, but we should be equally wary of overstating the potential of treatment as prevention as Regan says we are of overstating PrEP's promise. At the end of the day, the most potent ARVs are worthless if people don't take them, and keep on taking them regularly, and we know from several studies that up to 50 percent of people either fail to make it into care or to stay in care in the year following their HIV diagnosis. For those who do remain in care, daily adherence is no joke. This is as true in the dusty villages and shantytowns of sub-Saharan Africa as it is in the graffiti-covered neighborhoods of the South Bronx, and it portends sickness and death for those not taking treatment and zero protection for their sexual partners.


It should also be noted that universal access to HIV treatment for people with HIV would not be the same as universal use of ARVs. In rich Western nations a substantial number of people with HIV will probably choose not to start taking the meds until they are certain that they need it for their own health. In resource poor countries, it's going to take herculean efforts to ensure that we can begin offering drugs to all people based on the newest World Health Organization (WHO) guidelines--starting at a CD4 count of 350--let alone offering it to people at higher CD4s or to people as soon as they test positive.


If I felt that Regan had simply mischaracterized PrEP supporters or underplayed the relative merits of PrEP compared with treatment as prevention, I might have devoted this inaugural blog post to highlighting the most promising cure-related research being presented at the International AIDS Society Conference taking place this week in Rome. I would have simply worked on Project Inform's position paper on PrEP demonstration projects and let the facts speak for themselves over time.


What caused me to gasp as I read Regan's post, and left me feeling I had to devote this blog entry to a rebuttal of sorts was her parting shot:


"Make no mistake: PrEP is a profit-driven sex toy for rich Westerners, disguised as a harm-reduction and prevention tool for disenfranchised people at risk for HIV."


Reading that drew me back to the darkest days of the epidemic, when there were "innocent victims" and everyone else. Whether intended or not, this statement implies that some people in whom PrEP might actually be appropriate (can she possibly mean gay white party boys?) are somehow less deserving of this tool than others.


If there's one thing that this epidemic has taught me like no other it's that we really will fail if we are divided, rather than united. Pitting gay against straight, rich against poor, HIV-positive against HIV-negative, even inadvertently, is terribly counterproductive. Our enemies are doing an excellent job of making the case that we are doing too much, and not too little, to fight HIV on a global scale. Conceding to that "new normal" of funding and politics and giving up on a robust prevention toolkit may be realistic, but when have activists ever been satisfied with the possible, and where would we be today if they had?

13 Comments

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Comments on David Evans's blog entry "PrEP: Welcome Back to the 1980s"

Well written and very well reasoned rebuttal. The original piece was provocative in the extreme using exactly the kind of divisive language that thwarts not expands dialogue on tough policy issues. Regan's heart may be in the right place but she blew it in her blog post and denigrated the work and the promise that many of us who are not living with HIV continue to fight for. We must turn the HIV incidence faucet off and the combination of treatment as prevention, and PrEP are steps that must be taken, in tandem, to achieve that goal. It's long past time for a cure but in the meantime let's do our due diligence, and after the facts are in, embrace new prevention opportunities to reduce new HIV infections and improve the health and well being of people with HIV.

David I want to thank you for this piece. It helps to highlight what I think folks need to always keep in mind; we've never found a silver bullet that has worked for this pandemic.And probably won't ever find one not as long as human behavior in one of the major factors. But I think at the end of the day Ernest is correct we have to do something about new incidents and the best way is going to be a united community that has worked so hard to get as where we are. We are stronger for this struggle when we fight united and together by pooling our joint strengths and resources, passions and intellects we will turn the tides of the epidemic and save the lives of so many in need. Finally I think what should be exciting to people is that for the first time in a long time we are even able to have a discussion around new preventions and what different strategies we might want to deploy in different areas. In the spirit of David piece it is a time for us to stand together and figure out how we get more to change more to move to that universal goal of ending the epidemic for everyone.

To be fair: Regan says "Make no mistake: PrEP is a profit-driven sex toy for rich Westerners, disguised as a harm-reduction and prevention tool for disenfranchised people at risk for HIV." And long before I got to that line in this rebuttal (I had not read the original piece at that time) I thought that myself: If you're Gideon, why provide Atripla, say, to HIV+ people in sub-Saharan Africa at $1.65 a pill when you can provide the same drug to "gay white party-boys" in the US for $60 a pill?

Well put.

PrEP will never be used by everyone, or even a majority. But it's super important for those at very high risk of getting HIV themselves, who will then be at very high risk for infecting others. It could help overcome the biggest weakness of treatment as prevention -- the extreme difficulty of getting people with early infection diagnosed and treated in time, when they are highly infectious to others. It could do this by keeping these people from getting HIV at all.

And do look behind the "44% effective" headline that went out with the iPrEx study results of PrEP in gay men; that unfortunate headline makes PrEP seem inadequate and unattractive. But of those who did become infected despite being assigned to take PrEP, more than 90% had no detectable drug in their bodies when tested. That is why the headline result was so poor. It is likely that they were not taking PrEP at all, but giving or selling the pills to others who needed them to stay alive.

And the other 10% assigned to take PrEP had very inadequate drug levels. NO ONE who took the PrEP as directed (or even close to that) got HIV in this study -- vs. 64 who got HIV in the placebo group, who had not used PrEP at all.

I provided more details in "HIV PrEP Explained: Critical Prevention Opportunity," at www.aidsnews.org.

The 90% efficacy of Truvada in people who were adherent referred to by John James was derived by a post-hoc analysis; the subgroups, those who were and who were not adherent were defined after randomization. This type of analysis is unreliable. While it's pretty obvious that something will only work if it's taken, its efficacy when taken may indeed be more than 44%, but may also be far less than 90%. For example, it's entirely possible that people who adhere to pills are also the kind of people who adhere to condom use. If self reports about adherence to drugs proved to be completelyb unreliable, why be so trusting about the accuracy of self reports regarding unprotected anal intercourse?

Anyway a 44% relative efficacy is a real world estimate - a real world where people are not 100% adherent. Actually adherence in a trial may even overestimate adherence when not in a trial setting.

PrEP is a harm reduction strategy as Regan states, for those who do not make a safer choice for whatever reason, from sexual dysfunction with condoms or for those who feel that condoms are an impediment to intimacy. We can and should support those few individuals who make a more dangerous choice while at the same time doing all we can to promote and support the most effective prevention strategy we have, which is consistent condom use.

This is a good article, and John, you clarify the essential feature of THIS form (tenofovir/emtricitabine) of PrEP: it only works with extremely high adherence.

And therein lies the rub. A "responder analysis" can be informative but it can also be misleading (which is why "intent-to-treat" is a more rigorous and accurate approach). The 42% figure from iprex may more accurately reflect real world outcomes--IF the approach is considered "generalizable" to at-risk populations. And indeed, it may well be that it fares worse among the at-risk population as they do not have the kind of intensive relationship with a clinic to make it practical as was available to trial participants.

This and the limited funds available for prevention and treatment programs as they exist now deeply concerns me. As a marginally useful tool in the prevention toolkit, this form of PrEP runs the risk of trying to "medicalize" (i.e., here's your pill, good-bye we're busy) prevention, reducing funds for paying the people we need to do counseling, and the funds needed for testing, syringe access, for free condoms and safe lube and public programs to help reduce stigma and discrimination.

Finally and foremost, I find it astonishing and despicable that all these trials in developing nations are being done given the severely unlikely eventuality that this form of prep will be available to those people, especially in light of the fact that least 10 million (more if you raise the CD4 count cutoff) HIV+ are CLINICALLY eligible for ARV and they are not receiving treatment. Regan's comment rings all the more true: this is just a cynical ploy by Gilead to corner the western market at $12,000/pt/year and heck, whatever they can suck up from Africa, in typical "Confessions of an Economic Hit Man" style.

To the extent this form of PrEP is available to the small population of HIV-negative at-risk people who are also willing and able to sustain the high level of adherence (and the high cost), it is a tool for prevention....that may well take treating 45 people to prevent one infection. Thus, a minor tool hardly worth all the hoopla it is being accorded.

A question: what is the incidence rate in Kenya and Uganda? How does that compare to the incidence seen in this study? Are they equivalent?

If the incidence rate in the study in both arms is less than the background incidence of the general population, it means the overall intervention of frequent clinic visits, reminders, "selection bias" of being a trials participant and other factors all figure in to the outcome.

Here - http://www.avert.org/africa-hiv-aids-statistics.htm
Kenya - 6.3% incidence.

According to http://www.aidsmeds.com/articles/hiv_prep_truvada_2636_20846.shtml
In the Partners Prep study, 4,758 patients
78 total infections or an incidence OVERALL of what? 1.6%?

This means the program ITSELF helped bring down the incidence dramatically. The ABSOLUTE risk produced by either tenofovir alone or the combination is really rather marginal for a very costly, toxic drug.

Again--I say THIS form of PrEP is more hype than hope.

I hate to argue against some good points by Dr. Sonnabend and by George Carter -- we agree on so much more. But PrEP is important enough to explore all the angles, to be as sure as we can about getting it right.

"Intent to treat" reporting of clinical trials -- meaning that you count results from everyone randomized to take the treatment, whether they actually took it or not -- is the most conservative (meaning that it usually makes a new treatment look least good). That doesn't mean it's always the best headline to report to the public.

Yes, separately analyzing the volunteers who do well in a trial, who "respond" to a treatment (volunteers selected after you see the results) is unreliable. But that rule doesn't exclude "as treated" analysis (tabulating results only from those who actually took the treatment), which is common and totally accepted in clinical trials. Here, the data used for selection after randomization was the blood test to show who was taking the drug as directed and who was not. And EVERYONE in the Truvada arm who got HIV was not taking the pills as directed.

In this case, "intent to treat" gives us the 44%-effective headline, and "as treated" says over 90% effective (well over 90%, I would argue). Both are correct. When they are so very different, we need to investigate what actually happened.

In this case (the iPrEx trial), the adherence at the two U.S. sites, in Boston and San Francisco, was close to 100% by drug-level testing -- very different from adherence at non-U.S. sites (closer to 50%, depending greatly on how you measure it -- usually the drug levels from those who did not get HIV were not tested, at least not yet). My personal guess: the key difference is that there is no underground market or other distribution channel for approved AIDS drugs in Boston and San Francisco, while there is in much of the world. Regardless of whether or not this guess is correct, or other causes were more important, the U.S. experience does show that adherence (almost everyone in the group taking one Truvada pill once a day) is possible.

Much of the reason for "intent to treat" is that if a drug works when taken, but is so hard to take that few patients will use it, than that drug should not be counted as highly effective. But that's not the situation here, in the U.S. sites at least. What counts for prevention planning is that very high group adherence and therefore very good protection IS POSSIBLE when conditions are right. When doing prevention, we will have to work on consistently getting them right.


PS: Gilead

Far from salivating at potential PrEP profits, Gilead has been surprisingly reluctant on its drugs being used for PrEP -- ever since tenofovir looked good for prevention, in animal studies well over 10 years ago. Take a closer look, and you will see why. I suspect that widespread PrEP use of its products (in the U.S. at least) could be an almost existential threat to Gilead -- and even to other pharmaceutical companies as well.

Gilead's price for Truvada is about $13,000 per year retail. That's what the treatment market will bear (and basically all AIDS drugs in the U.S. are priced at what the market will bear -- which maximizes corporate profits, while not counting at all the social costs of many thousands of people left untreated solely because of the price). But for PrEP, it's hard to see the market bearing a tenth of that price -- same drug, same dose, different people (who are not facing death, often don't think AIDS is their problem, and usually don't like to think about it period). So it's hard to see how PrEP could happen on any scale in the U.S., if the high treatment price is maintained. The two may be simply incompatible.

And the U.S. financial crises, driven in large part by medical profiteering, are getting bad enough that even Congress might someday consider some drug price restraints, like other industrialized countries. Just possibly the social costs of millions untreated for AIDS, cancer, and many more serious illnesses might come to balance or even outweigh the personal costs of lost campaign contributions, career opportunities, and other big favors delivered to powerful legislators by rich corporations.

This is why industry fears PrEP and won't push it; their sky-high treatment pricing, already at some risk, could butt heads again with public health, at a critical time. If activists also don't support PrEP, then how many people will? We could lose important opportunities to end the epidemic.

That's why we need to get this right.

Welcome, David...bravo to you for your well-reasoned rebuttal, and for sparking this especially revelatory back and forth on the real issues raised by PrEP. I am particularly intrigued by the possibility that PrEP could greatly mitigate the bloom of new infections spread by newly infected (and thus most highly infectious) persons participating in very active sexual networks.

i remain surprised at all the sexual anxiety endemic throughout the HIV-activist community, continually manifesting under various guises. David might have gone that final, controversial step in describing the divisions in the POZ community: the slutty versus the non-slutty, and the formerly-slutty.

i do recall Regan Hoffman posting a blog asking/demanding that all HIV+ people should not be seen as/presumed to be "one of those people". you know, "those" less-than-virtuous people that Jesse Helms helped us all to see, and wag our fingers at.

I do indeed agree with John James on many other issues.
George Carter brings up an issue that seems to have been missing in every report and comment on PrEP trial results. The absolute risk reduction achieved by PrEP is never mentioned. I took another look at the iPrEx paper in the NEJM and I couldn't find the absolute risk reduction reported, nor the number needed to treat in order to prevent one infection. Only relative risk reduction is reported.

It's the oldest trick used by advertisers and sadly even in some clinical trial reports to make results seem more impressive than they really are. That is to only report relative risk reduction and remain silent about absolute risk reduction.
From the numbers in the iPrEx trial report it's possible to work out the absolute risk reduction.
5.1% of the placebo group were infected vs 2.8% in the PrEP arm. The absolute risk reduction is not nearly as impressive as the relative risk reduction - which isn't itself that impressive.
The number needed to treat to prevent one infection is 1/absolute risk reduction.
In order to prevent one infection about 43 people would need to be treated.
I don’t think I made a mistake, but anyone can check.

It's not only the cost of Truvada that's involved. People will need to be monitored for toxicity, and importantly, to detect infection because continuing suboptimal treatment will surely result in resistant virus.

You can probably estimate what it will cost to prevent one infection with PrEP.

Truvada is currently available to be prescribed for "off label" use by a doctor who feels their HIV negative - patient would benefit.

Let me express my gratitude to David Evans, Ernest Hopkins, John S. James and Jeton Ademaj for their honest, balanced, well-reasoned and important contributions to this discussion. Wild-eyed statistical manipulations driven by anger at drug companies and homophobic, sexphobic rants from our "leaders" and "allies" only threaten to perpetuate and widen this epidemic. Perhaps they just want to keep their jobs.

I highly doubt Hoffman is trying to "keep her job" by questioning the drug companies who write checks to POZ.

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This page contains a single entry by David Evans published on July 20, 2011 12:58 PM.

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