An Interview With Robert M. Grant, M.D., M.P.H.
Mascolini: What are you telling providers about the potential risk of side effects with Truvada PrEP and what they should be watching for if they decide to prescribe it?
Grant: The side effects that we see most frequently are short-term side effects, and it's important to be aware of them. Trials indicate that somewhat less than 1 in 10 uninfected people who start Truvada PrEP will have some sort of symptom -- nausea, abdominal cramping, dizziness, or headache. Typically these problems occur in the first week or 2 of PrEP use, and they resolve if people continue taking their medications. Some reassurance through that first period can help people decide whether they want to continue trying to take PrEP. It's useful to have a check-in visit after 2 or 4 weeks of PrEP use just to see how it's going. At that visit, clinicians can see whether people decided to actually take the pill and whether those who did are having that start-up syndrome, which is reminiscent of the startup syndrome that may occur when people start taking antiretroviral drugs for treatment of HIV. Making PrEP users aware that this syndrome can occur and that it usually resolves spontaneously is important for early adherence.
There were no excess moderate to severe side effects in people taking PrEP versus those taking placebo in the phase 3 trials.1,3-5 We did see that a small number of individuals taking Truvada PrEP had elevations in their serum creatinine, which is an indicator of renal function. We agree with the CDC's recommendation that serum creatinine should be monitored in people taking PrEP.7,8
If serum creatinine increases more than 50% above baseline or if serum creatinine is abnormally high, the first thing to do is to recheck the blood test, because most serum creatinine elevations will resolve without stopping the drugs. If there's a confirmed increase in serum creatinine, we do recommend that PrEP be stopped and that serum creatinine be allowed to return to normal. If it does return to normal, PrEP can be restarted with careful monitoring.
We saw elevated serum creatinine in about 1 in 200 PrEP users in iPrEx.1 It's rare, but if a clinician is writing prescriptions for 200 PrEP users, they may see 1 or 2 people who have confirmed elevations in serum creatinine.
Finally we saw an average 1% loss in bone mineral density in people taking Truvada PrEP.1 This average change in bone mineral density occurred in the first 6 months of PrEP and did not progress with ongoing exposure to PrEP, and it was not associated with an excess in bone fractures. The FDA package insert indicates that the preventive use of these drugs can cause a small decrease in bone mineral density, and people who have risk factors for osteoporosis might consider DEXA scanning during PrEP use.
We did not see any change in fat distribution in HIVnegative people taking Truvada PrEP in iPrEx.1 There had been concerns that lipodystrophies might occur with Truvada PrEP -- that we might see the kinds of fat redistribution observed in people taking antiretrovirals for HIV treatment. But we did not see anything like that in people taking PrEP. Risk of intermittent PrEP, and research priorities
Mascolini: Is there a danger that people will use Truvada PrEP as a presex or morning-after pill?
Grant: We think Truvada PrEP is most useful when it's taken daily, so we recommend that people who want to protect themselves by using PrEP should take it daily. There is interest in intermittent dosing, but we emphasize that one pill is not enough for protection: Protective concentrations of the drugs continue to increase over the first 21 days of use, so if people want the maximum level of protection they should take it daily.
Will people try to take this in a more casual way? I think it's too early to know. We do know and have published in Science Translational Medicine that people in iPrEx were protected by PrEP even though adherence was less than perfect.9 The drug concentrations that we observed in iPrEx were commensurate with 3 to 7 doses per week, yet we did see high levels of protection in all people who had detectable levels of drug in their blood, even if drug levels were relatively low. Although people should try to take Truvada PrEP daily, there is some forgiveness for missing some doses, especially if people are taking it daily. If they try to take it just before and after sex, that may provide some protection, but there's no forgiveness if they miss the preexposure dose or the postexposure dose or if they take it a little late -- the regimen becomes fragile if people try to take it just pre- and postexposure.
Mascolini: What are the priorities for ongoing PrEP research?
Grant: The main priority is how to make PrEP easier to use. We do have studies in the field looking at nondaily Truvada regimens: Can people take it pre- and postintercourse?10 Can they take it twice a week with a postintercourse boost?11 [See "Prospects for Intermittent PrEP Dosing" in the article preceding this interview.] PrEP formulations that can be used in different ways are important to develop, perhaps an injection once a month.
Not everyone was able to tolerate Truvada in PrEP trials. The vast majority of people who took Truvada PrEP could tolerate it, but some people didn't. So alternative antiretrovirals, possibly maraviroc or raltegravir, should also be explored. Some antiretrovirals, such as the nonnucleoside dapivirine, have very long half-lives. Discovering whether they can be used as PrEP is also very important.
|Key Findings From the iPrEx Study of TDF/FTC PrEP1|
- 2499 men and transgender women who have sex with men enrolled in Peru, Ecuador, South Africa, Brazil, Thailand, and the United States
- Participants randomized to once-daily TDF/FTC or placebo
- Half of participants (47% TDF/FTC, 53% placebo) 18 to 24 years old
- Almost three quarters of participants (72% TDF/FTC, 73% placebo) Hispanic
- About 10% of participants (9% TDF/FTC, 10% placebo) from US (San Francisco or Boston)
- Average number of sex partners in last 12 weeks: 18
- Unprotected receptive anal intercourse in past 12 weeks: 59% TDF/FTC, 60% placebo
- Any grade 3 or 4 adverse event: 12% TDF/FTC, 13% placebo
- Elevated creatinine: 2% TDF/FTC, 1% placebo
- Overall decrease in HIV acquisition risk with TDF/FTC: 44%
- Decrease in HIV acquisition risk with TDF/FTC with at least 50% pill use*: 50%
- Decrease in HIV acquisition risk with TDF/FTC with at least 90% pill use*: 73%
- Decrease in HIV acquisition risk with detectable TDF/FTC in plasma: 92%†
- No significant between-group difference in protection on the basis of region, race or ethnic group, male circumcision, education level, alcohol use, or age
* Determined by study-drug dispensation and returns.
† Decrease 95% after adjustment for reported unprotected receptive anal intercourse.
Mascolini: What are you looking for in iPrEx OLE -- the open-label extension of the iPrEx trial?
Grant: iPrEx OLE is fully enrolled with 1770 individuals. We offer PrEP to everyone, and we follow them whether or not they choose to protect themselves with PrEP. We are looking at who chooses to take PrEP and who chooses not to, and we will measure HIV infection rates in both groups. Over the 1.5 years that we will follow this cohort, we are hoping that all 1770 participants remain free of HIV, regardless of how they chose to protect themselves from HIV.
Among people who start PrEP in this open-label format, we want to learn how well they adhere to the regimen and how their sexual practices might change: Do they stop using condoms? Do they have more sexual partners? Or rather do they focus more on intimacy with one or a few partners? We see that people do change their sexual practices and their sexual goals when they start PrEP, but interestingly the change is often in the direction of seeking more intimacy with fewer partners rather than the opposite. Our overall goal is to discover what people will do when PrEP becomes a real opportunity accompanied with real information about what the pill is, how effective it can be, and how safe it is.
Mascolini: Is there anything we didn't discuss that you think prescribers or PrEP candidates should know?
Grant: PrEP is a new approach. We're still discovering a lot about it, so having an attitude of discovery with potential PrEP users is appropriate. Let's explore for whom this is a good intervention, how long they want to take it, and how well they can achieve their goals by PrEP or alternative means. I think an attitude of exploration is appropriate, and I think it's equally important to move away from stigmatizing language. We need to stop thinking in terms of "risk groups" and "risk behavior" and start appreciating people for who they are and for their desires to remain healthy and socially engaged.
- 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.
- Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505.
- Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399-410.
- Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367:423-434.
- Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367:411-422.
- Grant R, McMahan V, Liu A, et al. Completed observation of the randomized placebo-controlled phase of iPrEx: daily oral FTC/TDF pre-exposure HIV prophylaxis among men and trans women who have sex with men. 6th IAS Conference on HIV Pathogenesis and Treatment. July 17-20, 2011. Rome. Abstract WELBC04.
- Centers for Disease Control and Prevention. Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR. 2011;60:65-68.
- Centers for Disease Control and Prevention. Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR. 2012;61:586-589.
- Anderson PL, Glidden DV, Liu AI, et al. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med. 2012;4:151ra125.
- ClinicalTrials.gov. On demand antiretroviral pre-exposure prophylaxis for HIV infection in men who have sex with men (IPERGAY).
- ClinicalTrials.gov. The ADAPT study: use of emtricitabine and tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP).