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PrEP: A Possible Approval Like No Other

| 14 Comments
Truvada.jpg
In early March, AIDS Healthcare Foundation began a paid advertisement campaign urging Gilead Sciences to refrain from seeking approval from the U.S. Food and Drug Administration for Truvada for use of the combination tablet as HIV prevention, in an approach known as pre-exposure prophylaxis, or PrEP. 

The ads were met by an outcry from the community. One prominent organization, the HIV Prevention Justice Alliance, issued a sign-on letter, dated March 16, urging the FDA "to examine the study results of PrEP rather than playing to speculation and fear." 

While I agree that PrEP should be considered as an option in the HIV prevention toolkit and would ultimately support an effort by Gilead to expand Truvada's labeling to include PrEP--should the company petition the FDA for approval--I am also of the mind that a green light from the FDA should not be met with the rush-to-treatment that typically follows approval of a drug.  
Given how little we know about the safe application of PrEP in a real-world setting--read: outside of a clinical trial--not to mention the expense of a comprehensive prevention program that includes PrEP, I think more feasibility studies need to take place before we consider a widespread HIV prevention program involving PrEP.

Here's what we do know: 

PrEP is effective in one population of at-risk individuals: men who have sex with men (MSM).  The iPrEx clinical trial, sponsored by the National Institute of Allergy and Infection Diseases (NIAID) of the U.S. National Institutes of Health (NIH) and co-funded by the Bill & Melinda Gates Foundation, involved a large sample size (approximately 2,500) of MSMs. The study, which had sound design and statistical analysis, proved Truvada use resulted in significantly fewer infections compared with those using a placebo. 

What is less clear, however, is how effective PrEP--and all that is required for it to be safe and have maximum efficacy, including frequent HIV testing, blood tests before PrEP is prescribed as well as during treatment (to monitor for side effects), and strong adherence support--will be in the real world. A breakthrough in HIV prevention science it may be, but a simple pill to ward off the scourge of our times it is not. On this point, I agree with AHF.

The iPrEx study demonstrated that there were 44 percent fewer HIV infections among those who were assigned to take Truvada for an average of 1.2 years according to the original results published November 23, 2010, in the New England Journal of Medicine (NEJM).  And according to follow-up data reported by Robert Grant, MD, of the Gladstone Institute of Virology and Immunology in San Francsico at the 18th Conference on Retroviruses and Opportunistic Infections, this efficacy rate was basically sustained out for almost two years of PrEP (42 percent fewer HIV infections were documented among those assigned to the PrEP arm for up to 144 weeks). 

AIDS Healthcare Foundation argues that the 44 percent efficacy rate--and likely the longer-term 42 percent efficacy rate--"is much too low to merit approval." Even advocates who already support Truvada PrEP admit that the overall efficacy rate isn't exactly outstanding. 

What has been a major talking point by PrEP proponents, however, is the fact that iPrEx volunteers who actually took their Truvada as prescribed likely did much better than average. According to the NEJM report, there were 73 percent fewer HIV infections among those who took their Truvada 90 percent or more of the time as measured by pill counting and self-reports, compared with those who received placebo. Even more telling are data involving Truvada levels in blood and cell samples provided by patients--proof positive of adherence. In those with detectable levels of Truvada, there was a 92-95 percent reduction in the risk of contracting HIV. 

Additional data from iPrEx, reported at CROI, optimistically pointed out that the drug detection rate was high among those participating in the study at sites in San Francisco and Boston, the two United States cities selected to participate in the clinical trial. In these two cities, Truvada was detected in 97 percent of patients randomized to Truvada. 

What is important to understand when considering the data, however, are the small numbers of people involved in these "subgroup analyses." Consider the fact that drug levels were tested in less than 5 percent of those who received Truvada, out of 1,251 who initially randomized to receive the drug. 

Additionally, if we're only looking at adherence rates among those in the United States--and there's no doubting that excellent adherence was associated with near-perfect efficacy--consider the fact that less than 10 percent of the overall iPrEx study population were from either Boston or San Francisco.
 
To my knowledge, we've never approved a drug, or developed new public health strategies, based on cherry-picked numbers. While the iPrEx study's rosy subset analysis will undoubtedly pique the interest of FDA reviewers, the agency has a long history of being primarily concerned with overall study results, as it is tasked with safeguarding the public against the worst possible outcomes. This means seriously weighing the worst outcomes--the risk of new HIV infections and the possible development of drug resistance as a result of poor adherence in the real world--against the best possible outcomes associated with excellent adherence.

Virtually everyone working in HIV/AIDS treatment advocacy has, at one time or another, been dazzled by a drug that showed early promise, but there's generally agreement that approval isn't merited until additional studies have been conducted to help us learn as much as we possibly can. There is a big difference between what happens in drug trials, and what happens outside of them. When considering the use of Truvada as PrEP, even if the FDA only approves the drug for MSM in the United States, we still have much more to learn.  

For example, we still don't know if the high efficacy rates among predominantly white gay and bisexual men in affluent cities like Boston and San Francisco will be seen in poorer cities, such as Oakland and Baltimore, homes to a large number of disenfranchised black and Latino MSM.  

We also have no idea if Truvada can be used intermittently, for example, taken only before potentially risky sexual activity. And, if so, what is the time span for which the drug must be taken prior (and potentially after) sexual activity. 

While iPrEx successfully answered some important fundamental questions regarding the safety and efficacy of PrEP in MSM, it did not answer a number of questions critical to other groups for whom PrEP could potentially prove effective.

For example, will PrEP's safety and efficacy prove comparable in women and injection drug users? We won't know this until a clinical trial exploring Viread as PrEP for injection drug users are reported in 2012 and a study exploring Truvada as PrEP in heterosexual men and women are reported a year later. 

The iPrEx study had many safeguards in place--rapid HIV testing and adherence counseling every four weeks and frequently laboratory testing to look for adverse effects--to maximize efficacy and to ensure that those who tested positive while on treatment or experienced serious side effects (fortunately, there weren't any) stopped PrEP as quickly as possible. Is such an intensive approach necessary outside of the clinical trial setting to maximize benefits and minimize risks? If yes, are health care systems in the U.S. (not to mention the rest of the world) financed and staffed adequately to offer up such comprehensive preventive medicine? And at what cost? Truvada alone is $36 a day--add in regular HIV testing, lab tests and adherence counseling and the price tag, per person, becomes a hefty one indeed.   

Consider the following from George Carter of the Foundation of Integrative AIDS Research, which is based on iPrEx data and economic considerations: 

It will require treating at least 45 people over a year to prevent one infection: economies of scale notwithstanding, from some source or another a minimum of $146/pt/year * 44 patients or US$6,570 to prevent one infection per year or in the places where Gilead happily charges whatever they want, we'll give a mid-range $12,000/pt/year * 45 = US$540,000/pt/year to prevent a single infection. And that is just the (arbitrary and vicious) cost of the DRUG! A [quality-adjusted life year] analysis of physician, nurse and outreach time and costs will add substantially to that per patient cost.

All of this said, resisting FDA approval of Truvada as PrEP is futile. Truvada is widely available and extensively used for the treatment of HIV and, if anecdotal reports are to be believed, already being prescribed and used "off label" as PrEP. What's more, the U.S. Centers for Disease Control and Prevention (CDC) has already issued interim guidelines on the use of Truvada as PrEP, recognizing that, unlike experimental drugs only available through clinical trials, there's little standing in the way of Truvada PrEP prescriptions. 

My hope is that a potential approval will allow Gilead--which stands to make a good chunk of change, given its considerable potential market expansion with PrEP along with the fact that iPrEx (and other efficacy studies) aren't being funded by the company--and health agencies to address the numerous outstanding questions regarding the safety and efficacy of PrEP in diverse at-risk populations and to develop sound educational and support programming to at-risk individuals and health care providers hoping to use Truvada for the prevention of HIV. 

Ideally, we'd have much of this settled before a drug becomes commercially available, like we do with experimental agents for the treatment of HIV. But in this case, there's no returning the genie from whence she came--Truvada can be gotten with a prescription, by anybody, and the results of iPrEx, while limited, are compelling in their suggestion that Truvada can be an effective agent when used as part of a comprehensive prevention strategy. 

This is where I disagree with AHF. The real fight isn't in holding up the FDA's approval of Truvada as PrEP, but in holding Gilead's (and the government's) feet to the fire to ensure that Truvada is not only safe and effective in the real world, but actually accessible and affordable to communities that will need it most.

14 Comments

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Comments on Tim Horn's blog entry "PrEP: A Possible Approval Like No Other"

This article proves that we have come a long way. Or have we? I hate to complain, i really do, with so much progress that has been made. But...shouldn't we be focusing on the cure? We have already proved that the vaccine will not work. Now, this prep business doesn't seem to be the answer either. I'm afraid that we will spend the next 10 years avoiding the focus on the cure, in exhange for "pre exposure" medicines that won't amount to anything. If we foucs on the cure, our attention and our money...we could be helping so many on so many levels. Does anyone agree with me on this??? But thanks again, Tim, for your insight and information.

While I don't think that PrEP is *the* answer to the HIV pandemic, I think it will add something important to our HIV prevention arsenal. For high-risk individuals who are MOTIVATED to keep themselves HIV negative (e.g., willing to adhere to daily treatment, be tested frequently for HIV and side effects while using the drugs, etc.), but are either unwilling to use condoms or have a difficult time negotiating condom use, PrEP could be highly effective. PrEP definitely won't be for everybody, but it will be useful for some people.

All of that said, I do think cure research is coming back into vogue, given that technology and our understanding of the virus has evolved to the point where we're not simply firing shots into the dark. AIDSmeds and POZ have been reporting on cure research and we're starting to see a number of foundations pump money into the science that will ultimately make this possible. To learn more, search on "cure" via AIDSmeds or check out the AIDS Policy Project's website to get involved (http://www.aidspolicyproject.org/).

I think urging FDA to not approve at this time is not harmful to anyone, esp as people can get the drugs off-label if they want it. Arguing against approval I think is merited because this sets an even more rotten precedent for an FDA already too much in bed with pharma--we're going to start approving drugs on a single study? (I'm thinking of the recent approval of a drug for pregnant women that allowed the price to shoot from $15 to $1500 as but one example.)

I wrote a paper available at http://www.fiar.us that explains my criticisms of iprex more thoroughly and you add some important caveats about the really rather bizarre touting of the subgroup analyses. I have NEVER heard that before and if you did that with, say, a botanical, people would justifiably roll their eyes and dismiss it as merely "on-treatment" analysis.

A question: have you ever heard WHERE the infections occurred? What was the distribution? Grant pointedly refused to answer that question. Tho he did admit that it would take treating 45 people to prevent one infection--and with the longer-term data suggesting a deterioration in relative risk reduction, let alone the marginal absolute risk reduction...it just seems insane to me. (For those curious, see the end of this comment for a discussion of the relative and absolute risk numbers.)

I really do NOT like to be the nattering nabob and I really really REALLY would like to be enthusiastic about this--but we have 7000+ on ADAP waiting lists who might better benefit from getting Truvada...and another 10 million men, women and children who are HIV+ and CLINICALLY ELIGIBLE (i.e., probably 1 MILLION will die this year if they don't get ARV)...and yet somehow the most at-risk, vulnerable populations are going to get TDF/FTC? Not even at $0.10 a day is that going to happen. Hell, people have enough trouble staying on the meds, let alone accessing them, who HAVE HIV.

The data are also NOT clear on long term toxicities. This stuff rots bones--and may damage the kidneys. At least people should be given Vitamin D3 with it if they choose to and can access the drugs! Nor is the longer term issue of resistance in the community....I agree. We need a CURE. (Oh--and condom and needle access programs and harm reduction...that's where we need to spend prevention money--and on treating people....)

Here's the portion from my paper:

Most of these studies that toss around huge numbers assess relative risk as opposed to absolute risk. It’s not so complicated. They looked at a total of 2499 participants 1251 in the FTC-TDF arm and 1248 in the placebo arm. There were a total of 110 infections in the study, but 10 appeared to have been seroconversions at the start of the trial, so they used a modified intent-to-treat that ignored those 10.

So there were 100 infections over a median of 1.2 years on the drugs: 36 in the drug arm and 64 in the placebo arm. The 44% we hear about is the difference of 100-36/64 or 44%. But another way to look at it is the ABSOLUTE RISK. That is, 36 out of 1251 people in the drug arm became HIV+ over a median of 1.2 years. The calculation of 36/1251 yields about 2.87% risk of becoming infected on the drugs, but that’s a rough estimate. According to lead author, Robert Grant: "The annual incidence was 3.86 in the placebo group and 2.16 in the FTC/TDF group." (This was during an email exchange with Dr. Grant prior to a conference call with Dr. Grant and others on 12/3/10.)

I do not understand why they care about HIV negative people. How about HIV status people? Why can't they focus on people who already have infected to find a cure? I was always told that it's too expensive to find a HIV cure sooner. They spend too much money on research other than focus on HIV cure. Why can't they use a condom to save their money and spend money on HIV cure? I can't stand they don't care about HIV positive people. They let HIV people so happy that they can take new drug to prevent getting HIV virus. Is that right?

The AHF is wrong targetting the FDA but a critical question remains access in developing countries, particularly those that generously contribute to the development of these new prevention approaches through their participation in clinical trials.

Thanks for this thoughtful story, Tim.

Just one correction - the study was not just in MSM. It also included transgender women who have sex with men - TSM... For example, 25% of the participants in the Thai site were transgender women. So, while there were not enough transwomen to do a statistically-significant sub-group analysis, it is important to note that they were active participants in the study.

Great job, Tim. I completely agree with you that the primary challenge is holding Gilead and our health care infrastructures responsible for doing the right thing re: pricing, education, monitoring (esp. population level resistance monitoring) etc.

And is anyone other than me concerned about creating street market (AKA black market) demand for these drugs? If I am dirt poor and getting Truvada for treatment, how am I not going to sell it on the street when a jumped up demand for it exists among affluent people who want it for prevention but don't want to go to an MD and get the condom lecture?

Seems to me that there are some pretty serious ethics questions to be addressed there, also. Just one woman's opinion.

I agree!!! I really do. Of course we don't want people to become infected...but then, what about those who are infected? I guess i'm concerned too about those infected who can't get medicine, who are sick. I mean, Elizabeth Taylor is gone and we didn't find the cure in time for her to see....can we find it for those who are sick? Please!

Writing for GNPUSA healthcare open letter publication, GNPUSA is for opening up Pre-exposure prophylaxis or PreP for over the counter sale from the FDA, to create fair and free trade for the American Healthcare consumer, if it is safe and effected, Also just like we are for rapid HIV home screening kits over the counter and safe microbicides over the counter and over the counter clean needle access too. Let’s get the facts straight for a moment concerning PrEP, for it is now available and assessable to some, like Doctors, first responders and the informed, along with free access to HIV positive mothers to stop the transfer of HIV to a new borne infant in most USA counties and Truveda is just a new generation of PreP and can be prescribed off label to the informed, educated and for those who have money to purchase it. If this HIV prevention tool works well like the first generation of PreP treatment for pregnant mothers and infants, which successfully stopped all most 99 percent of Mother to Child transmissions of HIV infection in the USA. Then open assess of PrEP could reduce new HIV cases safely for many, until marriage or once a loving monogamous partnership is obtain for many, if marketed right and safely in unity with our communities and within AIDS inc. Then logic tell us that new HIV infections might be reduced by 25 percent globally to knock out 100s of thousands of new HIV infections from accruing globally. Yes, the HIV morning after pill or morning before pill that is safe called PrEP needs to be accessible to all people, not just for First Responders, Doctors, Nurses, Police, Government Employees and Pregnant Mothers, but for all people, including prisoners should have access to these medical treatments. If Pre Exposure Prophylactics (Pre-Exposure Pill) (PrEP) could stopped new HIV infection and what a blessing it would be to start turning the tide on New HIV infection while savings lives and huge savings in Medicare and State Medicaid expenditures or the people's monies. If PreP and related social marking education reduction new HIV cases by 25 percent a year then the proof would be for all to see and if it did not as in all fair and free market places then PreP would go away.. The new knocking it out message for preventing new HIV cases needs to have a demonstration projects, in major cities to expand HIV prevention and HIV Education and the this new toolbox could look like this, beginning with Healthier Relationships, Condoms use, "Don'T do it, don't do it" message, and 3 new concepts , Over the Counter (OTC) fair access to rapid HIV home screening Kits for private home uses, OTC Safe Microcopies, OTC Safe affordable PrEP , and Over the Counter Clean Needle access, making fair knowledge and creating life saving enterprises in knocking out new HIV infections and Hep C too. Again, these combine tools old and new would cause HIV to be discussed more openly and could reduce new infections just in the social media discussions for many and bring new conversation around Healthcare Treatment and Equal Access in Fair and assessable healthcare knowledge, treatment options, prevention, and improve patient safety for the consumer to know their options to stop New HIV infections within the USA and beyond. FDA must approve and allow the free market place to move forth in hopes Gilead will create a fair price and help create a free market place for Global Assess to many which GNPUSA believes is a win, win for our communities to strive for eradicating new HIV infections.

The issues surrounding PrPE have yet to be fully identified! This is going to be a very wild ride through unchartered terrain. Every PrPE meeting I attend I feel sucked back into time when we were demanding AZT be made available at any cost. Is history repeating itself?

A little note about AZT, we know that it was harmful in the full doses prescribed in the 80's and I watched my first partner have hope and then go from hope to death, from his bone marrow being drain out by overdosing of the prescribed AZT and I thank God and him for having the courage to lead the way in new HIV treatment options, for with out him and many others that die for us HIV people, than many may not be on safer treatment now, however AZT became one of the most prescribed safer drugs in HIV cocktails in small doses for decades and worked for many and many are still taking small doses, plus a flood of new drugs in competition came to light because of one drug. It is kind of like sugar in moderation it is not harmful, but in super doses it can be harmful. Like an aspirin, if taken in moderation, it is safe and effective, but take a whole bottle then it is unsafe. I am not tiring to be rude, but for some reason D.C think tanks that help mold new public policy believe that the public doesn’t have a brain and are to stupid to take control of their healthcare, and I find that offensive to say the reason some have assess is that the other are not educated enough to follow directions on the label to do their own research or will sell the drugs for food or even worst a small number my sell their drugs for illegal drugs , in that case, we might want to take bleach off the market for some may drink it by mistake. Even better, let us go back to only allowing the educated to vote for in the past some believed the uneducated are not smart enough to vote for a representative. This proposed policy is not just about HIV people or non-HIV people or MSM or TSM, it is about assess to affordable safe treatment and knowledge that is available now, for many progressive counties have Over the Counter treatment options that reduce healthcare cost allowing people to go buy preventive treatment with out going through thousands of dollars in doctor visits, lab cost, over and over again and then to buy an over price drug that may work. (How can a market place drive prices down in healthcare, if four powerful unions like doctors, labs, pharmacists and insurance companies have their hands and control in the treatment options with out regards to the consumer?) We must change our old ways of thinking about healthcare education, prevention and treatment to empower the consumer to take action in research, informed decisions and obtainable open assess to treatment options with patient safety being the focus and the patient being in control of the directions and out comes with professional advice in the process, with out having to bribe doctors, big labs i.e (Abbot), pharmacists (i.e CVS, Walgreens) and insurance companies to allow open assessable treatment options and transparent knowledge for all Americans.

for all the hostility directed at the FDA, Gilead and "Big Pharma" in general, i have yet to see a single comment anywhere addressing the issue of poor adherence to PrEP...it seems to be accepted as a given in the "real world".

HIV medications only work for the adherent, and i see very little attempts at offering POZ and at-risk people even a basic education in Evolutionary Microbiology...specifically, that microbes exposed to toxins (such as HIV meds) will quickly produce mutated/resistant versions of themselves if HIV drugs are not taken faithfully. I find many HIV+ people fairly oblivious to this truth, despite all the pamphlets available that warn of resistance. I expect similar levels of scientific ignorance amongst the HIV- at-risk populations...we need to educate our peers better in this regard.

there is no good reason to fight FDA approval of PrEP, doing so will not provide leverage for lowering ARV pricing, nor will it help the ADAP waiting lists. These are separate issues requiring and deserving of separate focus. All that fighting PrEP approval by the FDA will achieve is making some doctors scared to provide PrEP to patients that need it. some of those patients will go on to seroconvert as a result.

i see many parallels with the contraception/abortion debate here: many prevention activists seem to fear PrEP the same way they fear "Test And Treat", as some sort of back-door rejection of the "use a condom every time" message they have pushed for decades. that message is no panacea and never will be, no matter how much or for how long it is pushed...yet many seem to feel that "if you don't want to use condoms then you deserve HIV".

many abortion opponents feel that pregnancy is the proper consequence of sex, and if it amounts to a punishment, so be it. many activists ostensibly dedicated to HIV prevention very definitely seem to feel that HIV-infection is the proper and deserved consequence of bareback sex...and if it amounts to a punishment, so be it.

this attitude is addled, but it appears quite widespread.

THANK YOU TIM! I am "sick" from all the emails I receive from AHCF asking me to write our government and stop further research into this VERY important advancement in the treatment of HIV/HIV prevention.

Information is vital for our community to correctly respond to the epidemic. As we have seen over the last 20 years, ignorance = death.

Why not provide a means to stop transmission of the HIV virus? No (or reduced levels of) transmission would be a welcomed addition to the current risk reduction model most informed medical professionals subscribe to.

This form of treatment might help to decrease those persons at risk of infection who do not have the luxury of requiring their partners use a condom. Women in many countries are denied the right to protect themselves by using condoms (male or female versions). This form of prevention could be of great use.

Enough with the drama.. Information saves lives.

News flash.. there are "street" versions of every FDA approved drug where there is a demand.

I have even heard of pain management clinics which prescribe addictive drugs to persons who do not actually need them except to get high. Imagine that.

Educate our communities on the best use of this drug for the prevention (risk reduction of) transmission of HIV. Anything less is not acceptable.

Police people, not medications/treatments.

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This page contains a single entry by Tim Horn published on March 29, 2011 12:50 PM.

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