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FDA Offers Generally Favorable Review of Truvada for PrEP
  Mark Mascolini
May 10, 2012, 1:30 PM US Eastern Time

FDA analysts presented a largely favorable review of Truvada (tenofovir/emtricitabine) efficacy and safety for pre-exposure prophylaxis (PrEP) at a meeting of the agency's Antiviral Drugs Advisory Committee meeting, which is ongoing today, May 10, 2012.

Although a favorable FDA analysis does not guarantee that the Advisory Committee will recommend licensing Truvada for PrEP, it carries some weight. Nothing in the FDA summary, presented by Peter Miele, suggested serious reservations about Gilead Sciences' application for a Truvada PrEP indication.

The licensing change formally requested by Gilead is that "Truvada is indicated for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults."

Four factors probably determine the risk/benefit equation of Truvada for PrEP: efficacy, safety, resistance risk, and sexual disinhibition--the possibility that people using PrEP will ignore other measures that protect them from HIV, such as consistent condom use.

Gilead proposed that Truvada PrEP efficacy rests on results of two large, placebo-controlled trials, iPrEx in men who have sex with men [1] and Partners PrEP in HIV-discordant heterosexual African couples [2]. Both trials randomized HIV-negative participants to Truvada (coformulated tenofovir/emtricitabine) or placebo; Partners PrEP also tested tenofovir alone to prevent HIV acquisition by HIV-negative partners with an HIV-positive partner.

In their primary analyses, iPrEx documented a 42% lower HIV acquisition risk with Truvada, while Partners PrEP found a 75% lower risk with Truvada and a 67% lower risk with tenofovir alone. An FDA analysis presented today indicated that iPrEx men with measurable intracellular drug concentrations had an 87.5% lower risk of HIV infection (95% confidence interval 66% to 95%) than men taking placebo.

As detailed below, Partners PrEP and iPrEx participants randomized to Truvada had higher rates of certain renal and bone toxicity markers than did people taking placebo, but overall Truvada did not appear to pose a short-term risk of kidney damage or fractures (follow-up in both studies extended up to 3 years).

On the basis of these findings, the FDA concluded that "safety and efficacy of [Truvada] for the prevention of HIV-1 infection in high-risk individuals is supported by two large clinical trials."

Data presented by the iPrEx and Partners PrEP principal investigators showed that resistance did not emerge in anyone randomized to Truvada who became infected during the course of the trial. Resistance developed in a few people who took Truvada or tenofovir during early HIV infection that had gone undetected. Neither trial found evidence of risk compensation. In fact, study participants generally practiced safer sex after enrolling in the trials.

The FDA advised that "regular HIV testing, adherence and behavioral counseling on safer sex practices, including condom use, are essential components of healthcare delivery around PrEP."

FDA officials did raise some safety concerns in their analysis of iPrEx and Partners PrEP. Noting that renal failure or Fanconi syndrome did not occur among Truvada takers in iPrEx, the FDA cautioned that cases of concurrent proteinuria, glycosuria, and hypophosphatemia primarily in the Truvada arm "may be potentially concerning for subclinical proximal renal tubulopathy, although the limited numbers and poor adherence observed in this trial, as assessed by drug level monitoring, preclude reliable interpretation" [3].

In Partners PrEP only 7 people permanently withdrew because of adverse events, and 6 withdrawals were attributed to grade 2 renal toxicity, 3 in people taking tenofovir alone, 2 in people taking Truvada, and 1 in the placebo group [3]. All renal toxicity (creatinine clearance below 50 mL/min) resolved in 5 women when they stopped study drugs. Results are pending on the 1 man who endured renal toxicity.

Analyzing renal toxicity in other ways, the FDA found no evidence linking toxicity to tenofovir or Truvada in Partners PrEP [3]. Treatment-emergent creatinine increases affected 5% taking tenofovir, 7% taking Truvada, and 5% taking placebo. "Drug-related" creatinine toxicity affected only 8 people overall (0.2%), and 5 of those 8 were taking placebo.

The FDA noted that men enrolled in iPrEx had lower bone mineral density (BMD) when they entered the trial than does the general population. Men randomized to Truvada had small but statistically significant drops in BMD compared with the placebo group throughout the trial. BMD declines of more than 5% from baseline affected 14% of iPrEx participants taking Truvada versus 6% taking placebo. The FDA pointed to similar BMD declines among MSM in a CDC study of tenofovir safety [4].

The FDA mentioned renal toxicity in its overall premeeting briefing conclusion of Truvada PrEP efficacy and safety: "The decision to prescribe [Truvada] for the prevention of sexual acquisition of HIV infection should carefully weigh the individual risks for acquiring HIV, their understanding of the importance of adherence to medication, and their potential for development of renal toxicity" [3].

Before clinicians start Truvada PrEP, the FDA said in its premeeting document, they should (1) test the person for HIV, (2) measure renal function and serum phosphorous, and (3) assess risk factors for renal and bone toxicity [3]. Clinicians might also consider supplementing vitamin D and calcium in someone taking Truvada PrEP, the FDA advised. Everyone using Truvada for PrEP should get tested regularly for HIV and monitored for renal problems. Some Truvada takers may benefit from DEXA bone scans before and during PrEP, the FDA suggested.

The FDA offered this final conclusion in its briefing document: "If physicians prescribe and individuals utilize [Truvada] in the manner described for PrEP, in combination with other strategies to prevent HIV infection, the individual at risk may be spared infection with a serious and life-threatening illness that requires lifelong treatment with a three-drug antiretroviral regimen. That regimen, in line with current treatment guidelines for HIV-infected treatment-naive patients, will almost certainly contain [Truvada]" [3].


1. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587-2599. http://www.nejm.org/doi/full/10.1056/NEJMoa1011205.

2. Baeten J, Donnell D, Ndase P, et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 29. http://www.natap.org/2012/CROI/croi_57.htm.

3. FDA Review Team for NDA 21-752/S-30. Background Package for NDA 21-752/Supplement 30. April 16, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM303213.pdf.

4. Grohskopf L, Gvetadze R, Pathak S, et al. Preliminary analysis of biomedical data from the phase II clinical safety trial of tenofovir disoproxil fumarate (TDF) for HIV-1 pre-exposure prophylaxis (PrEP) among U.S. men who have sex with men (MSM) 18th International AIDS Conference. July 18-23, 2010. Vienna. Abstract FRLBC102. http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200741348.