May 11, 2012
Truvada Receives PrEP Approval Recommendation
by Tim Horn
In a series of votes by the U.S. Food and Drug Administration’s Antiviral Drugs Advisory Committee, Truvada (tenofovir plus emtricitabine) has been recommended for approval as the first prescription drug—to be used daily and in conjunction with condoms and other safer-sex measures—to prevent HIV among those at risk for the infection.
At a May 10 meeting on the FDA’s White Oak Campus in Silver Spring, MD, which lasted more than 12 hours, the strongest vote—19 in favor and three against—was to recommend approval for men who have sex with men (MSM) at risk for HIV. A similar vote—19-2, with one abstention—resulted in Truvada being recommended as as pre-exposure prophylaxis (PrEP) for HIV-negative partners in serodiscordant relationships. The closest vote—12 in favor and eight against, with two abstentions—was for other individuals at risk for acquiring HIV through sexual activity.
Though the FDA is not required to follow the approval recommendations of its independent advisory committees, it usually does so. The agency is expected to announce its decision on or before June 15, which will likely reflect other key discussion points at the May 10 meeting, including the frequency of HIV testing and safety assessments for individuals using Truvada as PrEP, Gilead’s proposed strategies to minimize risks associated with Truvada as PrEP and any post-approval study requirements.
During a contentious public comment period, in which roughly 50 activists and health care professionals testified, the majority argued against the approval of Truvada as PrEP, based on efficacy and safety concerns.
Michael Weintstein, who founded and currently heads the Los Angeles-based AIDS Healthcare Foundation, an organization that has waged a long-standing campaign against GIlead's PrEP approval request, likened the situation to the U.S. government’s Tuskegee syphilis experiment—designed to study the progression of untreated syphilis in poor, rural black men—and said that FDA approval “would be a reckless act.”
Several people did testify in favor of approval, based on safety and efficacy data reported previously and fully summarized at the May 10 meeting. "We need additional tools in our prevention toolbox,” explained Richard Elion, MD, of the Whitman Walker Clinic in Washington, DC. "We are not winning the battle. We’re asking for a modality that's still being developed to be added to our toolbox."
“The only way we are going to end the epidemic is through a combination approach,” said Susan Buchbinder, MD, of the San Francisco Department of Health, in a scheduled overview of existing HIV prevention strategies at the start of the meeting. Noting that condoms are not 100 percent effective—in part because of improper use and breakage—and that behavioral intervention strategies aren’t universally successful, she explained that what’s needed “are new treatments and prevention strategies to have a major impact on the US epidemic.”
Specific concerns raised by those offering public testimony, by those for and against approval, and the advisory committee panel—which included HIV-treating clinicians, researchers and three consumer representatives—included the need for daily adherence, which was a problem in many of the clinical trials conducted to date. Other worries included the risk of drug resistance emerging in those who become infected while using the drug and the known side effects of Truvada, notably kidney damage and bone loss.
Whether Truvada as PrEP is associated with significant safety issues has not been fully determined. Though several placebo-controlled clinical trials have been conducted, HIV infections and serious side effects while receiving Truvada have been rare. Additional research, including well-designed feasibility studies, are needed to allow for a more complete assessment of Truvada’s risks and benefits as an HIV prevention strategy.
Numerous data sets from the clinical trials were reviewed by the advisory committee, including results from the National Institutes of Health (NIH)-funded international iPrEx study; the University of Washington’s Partners PrEP study conducted in Kenya and Uganda; the U.S. Centers for Disease Control’s TDF2 safety study conducted in Botswana; Family Health International’s FEM-PrEP study conducted in Kenya, South Africa and Tanzania; and the NIH VOICE study conducted in Uganda, South Africa and Zimbabwe.
Results from iPrEx were used to support the approval recommendation for MSM. In that study, involving roughly 2,500 MSM at risk of HIV, Truvada PrEP was associated with an average 44 percent reduction in the risk of HIV infection, compared with those who took placebo. Among the 10 percent of study participants who used the drug at least 90 percent of the time, the risk reduction was 73 percent.
Data supporting the approval of Truvada PrEP for HIV-negative individuals partnered with people living with HIV comes from the Partners PrEP trial. In that study, involving more than 4,500 individuals, daily Truvada was associated with a 75 percent reduction in the HIV transmission risk.
The advisory committee’s more divided vote ultimately in favor of Truvada’s approval for other individuals at risk for acquiring HIV through sexual activity is based on the mixed results of TDF 2, FEM-PreP and VOICE. FEM-PrEP, for example, originally planned to enroll 4,000 adult at-risk women before it was discontinued prematurely due to the lack of an efficacy difference between those receiving daily Truvada and those receiving placebo. Conversely, while TDF2 demonstrated a 62 percent risk reduction among adult heterosexual men and women at risk for HIV, the study was not specifically designed to determine the efficacy of Truvada as PrEP.
Truvada PrEP was generally safe and well tolerated. As noted by the FDA, both in its pre-advisory committee briefing document and in oral comments to the panel, “[Truvada] appeared to be well tolerated overall amongst HIV-uninfected individuals in these clinical trials. No new safety issues were identified. In general, adverse events appeared to be balanced between active and control arms. In iPrEx, unintended weight loss, nausea, vomiting, flatulence, and abdominal pain were reported more often in subjects receiving [Truvada]. In Partners PrEP, moderate to severe neutropenia was observed more frequently in subjects receiving [Truvada] or tenofovir as compared with placebo.”
The FDA noted some kidney-related laboratory abnormalities that could potentially be linked to Truvada use in iPrEx, but not in FEM-PrEP. As for bone mineral density (BMD) changes, mild but statistically significant decreases were more likely to occur among men using Truvada in iPrEx, compared with placebo.
As for the risk of drug resistance among those who become infected with HIV while receiving Truvada, the FDA noted that uncertainties remain. “Analysis of HIV isolates from individuals [in clinical trials] who became infected while taking PrEP have failed to identify resistance mutations that developed following seroconversion, consistent with the finding that study subjects who seroconverted were generally not adherent to medication. Selection of resistance among trial participants may have been minimized due to monthly monitoring for seroconversion.
“The impact of PrEP on resistance beyond a clinical trial setting is difficult to predict,” the FDA briefing document adds, “but resistance is expected among infected individuals using PrEP. The frequency of resistance might be minimized by limiting the duration of drug exposure after infection occurs with frequent monitoring for HIV seroconversion.”
To mitigate risks of Truvada PrEP, Andrew Cheng, MD, of Gilead described the company's risk evaluation and mitigation strategies (REMS), which were reviewed and discussed by the advisory committee members.
Gilead’s plans are primarily educational in nature and are intended “to inform and education prescribers, health care professional and individuals at high risk for acquiring HIV infection.”
First, the company has proposed dispensing a Truvada medication guide with each Truvada PrEP prescription. Second, Gilead will implement voluntary training and education through a Truvada for PrEP educational program for health care providers. Both initiatives will address two identified risks associated with Truvada as PrEP—HIV acquisition and the development of drug resistance—and a potential, but very serious, risk: the need for careful prescribing, adherence and follow-up practices for individuals with chronic hepatitis B virus (HBV) infection, who can experience acute liver disease exacerbations if tenofovir and emtricitabine (both are effective against HBV) are not taken correctly or are stopped abruptly.
Gilead said it is also committed to providing vouchers for free HIV testing, HBV testing and condoms. The company will also provide assistance for drug-resistance testing for individuals who become infected with HIV while using Truvada, an opt-in testing reminder service and has established a PrEP registry project to assess adherence over time.
Search: truvada, pre-exposure prophylaxis, prep, tenofovir, emtricitabine, hiv, prevention, transmission, iprex, partners prep, fda, advisory committee, aids healthcare foundation
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comments 1 - 14 (of 14 total)
Jeton Ademaj, Harlem, NYC, 2012-06-14 11:05:47
Vauban shows us just how low PrEP opponents can go. all agree that Truvada is a powerful medication with the potential for serious side effects...that's helped save MILLIONS of lives from a nearly 100% deadly virus. to simply call it a "poison" is to sink beneath all contempt...especially here of all places! i suppose Vauban and his pals are outraged that HIV+ with less than 200 t-cells r put on Bactrim...that is, if he and his pals have any moral consistency! hey, they're not sick YET!
Vauban, Salt Lake City, 2012-06-09 13:32:15
The most sacred responsibility of a licensed physician is to, “Do no harm.” By prescribing Truvada to healthy HIV negative individuals the doctor breaks that oath. Nucleotide and nucleoside reverse transcriptase inhibitors are toxic in the short and long term to the patient. We do not prescribe poisonous anti cancer drugs prophylactically nor should we prescribe potent antiretrovirals to healthy patients.
Frederick Wright, Coachella Vally, 2012-05-24 12:40:05
It seems like a little democracy is happening in the debate over the mornings before HIV pill. I am for the studies to go forward and for the concept behind Prep, however I do not think doctors will buy in to writing scripts for this drug until Gilead release all The Trufull data in all studies concerning Truvada Prep. I believe that studying Rx with people should have a 100 percent transparency on all test subjects and results that are good and bad, then transcribe in plan language.
Jeton Ademaj, Harlem, NYC, 2012-05-22 17:19:40
ah, here comes Mitch with the AHF propaganda. in previous attacks, he HAD at least conceded that the big issue with Truvada-PrEP is adherence...since then he has stooped to online stalking and now willfully distorts the efficacy data beyond all credibility AND accuses the FDA of taking bribes. it's THAT caliber of argument that sank the AHF like a stone tossed in a deep well at the FDA hearings...PrEP works, FDA approval means that it may soon be covered for poorer folks who need it. BRAVO!
Mitch, Brooklyn, 2012-05-22 16:27:21
LOL, you mean lies and willful distortions like "taken as directed, Truvada works better than condoms", when the actual number is less than half, right? Or implying that nonmongamous barebacking is already normal amongst negative gay men? Don't worry, im sure the FDA has already accepted its bribe and you'll get more bareback sex Jeton. I hope we all like a heaping plate of hepatitis C, syphilis, reinfection or celibacy, this is gonna be a fun couple years.
Jeton Ademaj, Harlem, NYC, 2012-05-22 12:28:53
taken as directed, PrEP works better than condoms. taken 6 days out of 7, it works about as well...it's horrifying to watch so-called prevention activists attack a new mode of HIV-prevention with lies and willful distortions. it's a joke to warn that PrEP discourages condom use when 2/3 of all MSM anal sex in the USA is already condom-free according to poz.com. no one deserves HIV, condoms or not...i hope the FDA looks past this shameful "poz-crabs in a bucket" display and approves PrEP in June.
Tony, , 2012-05-21 13:03:18
The question could be why "poz folks" are advocating a drug that will increase infections, maim users, complicate treatment for all and make the cost situation of this drug worse for those of us who NEED it. Nothing about this makes sense. If it reduces infections, it is corporate suicide for Gilead, and that would be out of character for a profit seeking company. BTW, ads for this drug's efficacy are already deceptive. How dare you mischaracterize this as opposing "healthly" options
frederick wright, plam desert, 2012-05-19 13:22:31
I do not think Gilead a is pushing this for it is risky at best for any business opprotunity. This is coming from your belt way folks and the Catholic lobbyist for the could take the Pope off the hot seat. Plus I think many really want to reduce new HIV case yearly,we must try something different if the old is not working. Why are Poz folks afraid of new concepts,such as Prep and In home HIV screening to help negative people stay safe and healthly. What's up?
earlyriser, austin, 2012-05-17 15:25:10
1) Gilead's lobbyists must have been pushing hard for this. My pharmacist says the cost of making the drug is only $37 for a 30 day prescription. 2) There are many reports that HIV treatment drugs also impede the libido, even among patients who are asymptomatic and have undetectable viral loads.
frederick wright, plam desert, 2012-05-16 16:55:54
GIleada is putting out the red carpet with many claims of if one become HIV,for they seem very sincere and confident of the protection provided by Tuvada. I also think the appeal to have natural sex is overwhelming for some. Can a woman conceive while taking Truvade and protect the unborn from HIV, for this could help millions in developing communties and most of them being women and children like the theory behind microbosices. Gilead is know for it progressive charity and inside market gain
Peteskier, Deltona FL, 2012-05-16 11:14:08
Why was it approved?
1. Its not 100% effective against the spread of HIV
2. It has Kidney and Bone side effects.
3. It cost 900 a month.
4. This will add many more people to the pool of developing drug resistance.
5. People will have a false sense of security and have unprotected sex.
6. This is a drug company scam to make more money by getting more people to take and pay for their overpriced medication.
I will tell my HIV- partner of 16 years that it is not worth the risk.
Andy, , 2012-05-16 09:44:19
As the + half of a sero discordant, I'm curious whether or not there are really enough transmissions from treated + to - partners to make this worthwhile. As far as im aware, we almost never transmit the virus and i resent the implication that we do without some proof. I'm also curious how effective dosing the - with truvada is going to be when the + has already been receiving it. I resent my partner being used as a poster boy for this drug whose benefit to him just isnt clear.
JamesInCA, , 2012-05-15 18:54:35
keith -- Firstly, as half of a sero-discordant couple, I'd like to at least have the option. Without the FDA approval, there's little chance my insurance company would cover the drug for prevention. Secondly, there's really no discussion here of the U.S. government *providing* the drug to anyone for prevention. That would only be at issue in the particular instances where the government provides health care or coverage directly, which is a minority of the population.
keith, Dublin, 2012-05-11 20:52:45
comments 1 - 14 (of 14 total)
I dont quit get this.
Who is this been giving to, other than serco couples who counts as “high risk”.
People who have unprotected sex, are they going to go to the doctor and say “I dont use condoms but would like to take pills everyday so I dont get HIV”
Sex workers, is the US government going to provide drugs worth $9,000 a month to what are under US law criminals.
While any progress in provention is welcomed I dont see how this will have any serious effect on infection rates.
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