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In the Balance |

Why I Voted “No” to Truvada PrEP FREE

Lauren V. Wood, MD
[+] Article and Author Information

From the National Cancer Institute, Bethesda, Maryland.

Disclaimer: The commentary and opinions expressed herein are solely those of the author and do not reflect the official position of the National Cancer Institute or the National Institutes of Health.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1788.

Requests for Single Reprints: Lauren V. Wood, MD, National Cancer Institute, Building 10, Room 6B04, 10 Center Drive MSC 1578, Bethesda, MD 20892-1578; e-mail, woodl@mail.nih.gov.

Author contributions are available at www.annals.org.

Author Contributions: Conception and design: L.V. Wood.

Analysis and interpretation of the data: L.V. Wood.

Drafting of the article: L.V. Wood.

Final approval of the article: L.V. Wood.


Ann Intern Med. 2012;157(7):519-520. doi:10.7326/0003-4819-157-7-201210020-00511
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There is an urgent need for new prevention approaches to HIV infection (1). The principal interventions used to date have included condoms, risk-reduction counseling, and voluntary HIV testing. However, these interventions have been inadequate and there has been a cry for “new tools in the HIV prevention toolbox.” One such new tool is HIV preexposure prophylaxis (PrEP), the treatment for persons who are HIV-negative and at high risk for infection with antiretroviral drugs, which has now been studied in several randomized clinical trials, using Truvada (Gilead Sciences, Foster City, California), a licensed combination pill consisting of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). On the basis of these and other studies, the manufacturer of Truvada, Gilead Sciences, submitted a new drug application to the U.S. Food and Drug Administration (FDA) for approval of a PrEP indication. On 10 May 2012, the FDA Antiviral Drugs Advisory Committee, of which I was a member, met to advise the agency on this application.

The committee considered data from 3 clinical trials in its individual and population PrEP risk–benefit assessment: iPrEx (Preexposure Prophylaxis Initiative), Partners PrEP, and CDC (Centers for Disease Control and Prevention) 4323 (2). The iPrEx study examined daily oral FTC–TDF in 2499 high-risk adult men who have sex with men (MSM) conducted in Brazil, Ecuador, Peru, South Africa, Thailand, and the United States (3). Partners PrEP was conducted in Kenya and Uganda, comparing daily oral TDF or FTC–TDF in 4758 heterosexual couples who are serodiscordant (4). The small CDC 4323 was conducted in the United States, in which 373 adult MSM were randomly assigned to receive immediate versus delayed treatment with daily oral TDF. The committee considered the results from the iPrEx and Partners PrEP studies for the efficacy indication of reducing HIV transmission, whereas data from all 3 trials were considered for safety evaluation. The FDA briefing document (5) provides an excellent and comprehensive summary of the results of oral TDF, oral FTC–TDF, and vaginal TDF clinical trials published or presented to date. Several critical issues resulted in my voting against all 3 approval indications considered by the committee.

In a modified intention-to-treat analysis done by the FDA, the iPrEx trial documented a relative risk reduction of 42% (95% CI, 22% to 63%) (3, 5). Although it was a statistically significant finding, it did not exclude the possibility that the true risk reduction was 30% or less, a threshold previously discussed at scientific meetings (5). In contrast to iPrEx, the Partners PrEP study unequivocally ruled out an efficacy lower than 30%. Compared with placebo, TDF reduced the risk for HIV acquisition by 67% (CI, 44% to 81%), whereas FTC–TDF reduced the risk by 75% (CI, 55% to 87%), with no statistically significant difference seen in treatment effect between TDF and FTC–TDF (4). In both studies, by plasma and intracellular drug concentration analysis, overall adherence seemed to be low and age younger than 25 years seemed to correlate with worse adherence and reduced PrEP efficacy (5).

Of importance, data were presented that documented a statistically significant increase in condom use, a decreased number of sexual partners or acts of unprotected receptive anal intercourse, and reduced rates of syphilis for both studies. In this context, I found it difficult to get a sense of the additional benefit contributed by Truvada PrEP in reducing HIV transmission and would have liked to have had the effects of PrEP confirmed in a multiple logistic regression analysis of the data.

In contrast, the FEM-PrEP (Preexposure Prophylaxis Trial for HIV Prevention among African Women) and VOICE (Vaginal and Oral Interventions to Control the Epidemic) trials in African women, evaluating daily dosing with oral FTC–TDF (FEM-PrEP) or daily oral TDF or 1% TDF vaginal gel (VOICE), were halted because of lack of a protective effect of FTC–TDF or TDF PrEP (56). The comparison between the oral FTC–TDF and placebo groups of the VOICE trial is ongoing. The reasons for the vastly different outcomes in women in the oral PrEP trials are the focus of intense investigation.

In summary, the objective evidence for the benefit of PrEP is not consistent across all PrEP studies, and the benefit is even more questionable for women among studies conducted to date.

A second key issue is inadequate adherence based on a subset analysis of measured plasma TDF concentrations done in many studies. For iPrEx, adherence was less than 10% because 44 of 48 participants (92%) had levels that were below the limit of quantitation (5). Adherence for Partners PrEP was only slightly better at 15% because 11 of 13 participants (85%) had TDF levels that were sometimes or never measurable (5). Despite substantial counseling efforts, drug adherence was also documented to be low in the FEM-PrEP study (6).

A representative of Gilead Sciences publicly stated that greater than 90% adherence would be necessary to ensure success of Truvada PrEP. However, based on TDF drug levels, adherence was far less than 90% in both efficacy trials reviewed for the pivotal indication.

Although it was assumed that lack of measured drug equated to nonadherence, I also believe that lower or undetectable plasma drug concentrations could reflect increased TDF clearance based on body weight–serum creatinine ratios, as documented in population pharmacokinetic studies conducted in persons with HIV (78). In the safety data presented, low body weight was associated with an increased risk for TDF nephrotoxicity, which seems to confirm the potential influence of body weight on TDF clearance. Of importance, neither iPrEx nor Partners PrEP examined the pharmacokinetics of FTC–TDF in genital tract secretions, an important parameter that may have further influenced the observed HIV transmission outcomes.

Across studies, no acute safety issues were identified and rates of serious adverse events were similar between treatment and placebo groups. However, there was still extensive discussion by the committee related to concerns of long-term renal and bone toxicity associated with long-term drug exposure and how best to monitor for them. Although not part of the formal safety analysis, statistically significant declines in bone mineral density were seen in participants treated with FTC–TDF in the TDF2 study (9) and an increased risk for irreversible renal events documented in patients who have HIV with long-term TDF exposure (10) raises additional safety concerns about its long-term use for PrEP.

Concerns remain that inadvertent PrEP use in persons already infected with HIV or those who become infected will lead to resistance that could compromise first-line treatment regimens for HIV that universally recommend Truvada. Preexisting HIV infection was documented in every PrEP study; fortunately, treatment-related resistance developed in a small amount of HIV seroconverters. Although the numbers were small, the documented transmission of HIV in persons despite measurable TDF levels warrants further scientific investigation.

An effective tool used incorrectly or inconsistently is reduced to an ineffective tool. The data presented by Gilead Sciences objectively document that most persons enrolled in the 2 pivotal efficacy trials on which the PrEP approval indication is based did not use the Truvada “tool” consistently or correctly, thereby substantially limiting its potential efficacy and overall utility in preventing HIV infection.

Centers for Disease Control and Prevention.  HIV in the United States: at a glance. March 2012. Accessed at www.cdc.gov/hiv/resources/factsheets/us.htm on July 7, 2012.
 
U.S. Food and Drug Administration.  Slides for the May 10, 2012 Antiviral Drugs Advisory Committee (AVDAC) Meeting [Slide 10]. Accessed at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm305776.htm on July 7, 2012.
 
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al, iPrEx Study Team.  Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010; 363:2587-99.
PubMed
CrossRef
 
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al, the Partners PrEP Study Team.  Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012..
PubMed
 
U.S. Food and Drug Administration . Briefing information for the May 10, 2012 meeting of the Antiviral Drugs Advisory Committee. Accessed at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm303212.htm on July 7, 2012.
 
Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al, the FEM-PrEP Study Group.  Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012; 367:411-22.
PubMed
 
Jullien V, Tréluyer JM, Rey E, Jaffray P, Krivine A, Moachon L, et al.  Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy. Antimicrob Agents Chemother. 2005; 49:3361-6.
PubMed
 
Gagnieu MC, Barkil ME, Livrozet JM, Cotte L, Miailhes P, Boibieux A, et al.  Population pharmacokinetics of tenofovir in AIDS patients. J Clin Pharmacol. 2008; 48:1282-8.
PubMed
 
Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al, the TDF2 Study Group.  Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012..
PubMed
 
Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, et al.  Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012; 26:867-75.
PubMed
 

This article was published on www.annals.org on 22 July 2012.

Figures

Tables

References

Centers for Disease Control and Prevention.  HIV in the United States: at a glance. March 2012. Accessed at www.cdc.gov/hiv/resources/factsheets/us.htm on July 7, 2012.
 
U.S. Food and Drug Administration.  Slides for the May 10, 2012 Antiviral Drugs Advisory Committee (AVDAC) Meeting [Slide 10]. Accessed at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm305776.htm on July 7, 2012.
 
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al, iPrEx Study Team.  Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010; 363:2587-99.
PubMed
CrossRef
 
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al, the Partners PrEP Study Team.  Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012..
PubMed
 
U.S. Food and Drug Administration . Briefing information for the May 10, 2012 meeting of the Antiviral Drugs Advisory Committee. Accessed at www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/ucm303212.htm on July 7, 2012.
 
Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al, the FEM-PrEP Study Group.  Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012; 367:411-22.
PubMed
 
Jullien V, Tréluyer JM, Rey E, Jaffray P, Krivine A, Moachon L, et al.  Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy. Antimicrob Agents Chemother. 2005; 49:3361-6.
PubMed
 
Gagnieu MC, Barkil ME, Livrozet JM, Cotte L, Miailhes P, Boibieux A, et al.  Population pharmacokinetics of tenofovir in AIDS patients. J Clin Pharmacol. 2008; 48:1282-8.
PubMed
 
Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al, the TDF2 Study Group.  Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012..
PubMed
 
Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, et al.  Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012; 26:867-75.
PubMed
 

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Regarding wrong doctors and FDA interventions
Posted on October 22, 2012
Fernando L. Cuadra, MD.
Internal Medicine, private practice Humble, Texas.
Conflict of Interest: None Declared

As doctors caring for mostly the sick, but also in the prevention of diseases, we must be compassionate. We unfortunately tend to forget this compassion, and everything becomes about the “business” of medicine. Examples are so abundant, so part of every hourly practice of our profession.And now we have misguided compassion. FDA just approved Truvada, antiretroviral medication, for pre-exposure prophylaxis to avoid sexually transmission of the HIV virus. This just reflects a lenient attitude, an unacceptable tolerance to an abominable human behavior. The only intervention to avoid acquire the HIV virus sexually, seen from the absolute commandment of God which is above any human law or humanistic approach, is to abstain of such sexual practices, being this heterosexual in which there is a knowledge of the infectivity of one of the couple, or completely avoid homosexual intercourse, which is indeed an abomination.This misguided compassion will keep leading into more mistakes, as one sin carries into another and multiple sins. Doctors emphasize frank discussion with the affected sexual partners. What more honest than to tell them the truth, that man was not created to have sex with man, a purposeless, abominable action? Three-fifths of the new HIV infections come from this population.When I studied medicine homosexuality was classified as a psychiatric disorder, disorder of sexual identity. As with most of human diseases, except many infections and some cancers, no cure is known, but diseases can be controlled. A misguided tolerance (compassion?) or giving up to a pressure from homosexual people led to a wrong acceptance of this abomination. No condemnation of homosexual people is promoted as this is a human weakness, a disease as just classified before, and these people are subject to our compassion and help (but not a dishonest help, not blinded, or misguided, opinions like that use of Truvada for prophylaxis does not disinhibits this aberrant sexual behavior-it is already aberrant), but condemnation of the homosexual practices which is pure abomination without any reproductive purpose, which is the commandment of God, to multiply through the marriage.As doctors we must direct the people to which is the best for their body and mind health. Otherwise we are just another business, like the tobacco industry, that knows about the damage of smoking, but keeps doing it and disguises his uncaring for persons health promoting different low nicotine cigarettes. Let the tobacco lords face our God at their time as this is what they freely choose to do, we will pray for them, as let the pharmaceutical lords face Him, we will also pray for them, but we doctors have received the gift to help people, our judgment will be more severe, so let’s do it correctly.

Fernando L. Cuadra, MD.

Internal Medicine, private practice

Humble, Texas.

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