Taking a pill that combines two antiretrovirals before and after sex lowered the risk of HIV infection by 86% in gay or bisexual men in France and Canada.1 Taking this tablet before and after sex -- rather than every day as in other studies of this strategy -- could simplify this approach to protecting oneself from HIV infection and could lower the rate of side effects from the antiretrovirals used.
Several research groups around the world have tested PrEP -- which stands for pre-exposure prophylaxis -- with a pill called Truvada that combines two antiretrovirals, tenofovir and emtricitabine (abbreviated TDF/FTC). Only people who have a recent negative HIV test should take PrEP. These studies found that PrEP with TDF/FTC can lower the risk of HIV infection in gay men and other men who have sex with men,2 in heterosexual HIV-negative people with a steady HIV-positive sex partner,3,4 and in people who inject drugs.5 In two studies of heterosexual African women, PrEP did not prevent HIV infection, probably because many women did not take their PrEP pills often enough.6,7 Trials of successful PrEP also found the highest rates of protection from HIV in people who took their PrEP pills as scheduled.
In all of these previous PrEP trials,2-7 people tried to take their PrEP pill every day. Researchers working with the French national HIV trials group suggested HIV-negative people would have an easier time taking PrEP pills just before and after having sex with a partner who might have HIV. They decided to test this as-needed PrEP strategy in sexually active gays and other men who have sex with men.
How the Study Worked
Researchers invited gay men or transgender women who have sex with men to join the study. All participants had to be 18 or older, and all had anal sex without a condom with at least two male partners in the past 6 months. The study did not include anyone with hepatitis B virus or hepatitis C virus infection or anyone with laboratory signals of poor kidney function. Tenofovir (TDF), one of the antiretrovirals in the PrEP pill, can hurt kidney function.
Researchers randomly assigned participants to use the TDF/FTC PrEP pill or a look-alike dummy pill called a placebo. Participants were told to take (1) two PrEP pills (or placebo) 2 to 24 hours before having sex, (2) one PrEP pill (or placebo) 24 hours after the first two pills, and (3) another PrEP pill (or placebo) 24 hours after that (Figure 1). Participants completed an at-home computer interview about basic personal information (like age and race) and about sexual behavior and use of drugs and alcohol.
Participants made study visits 4 weeks after entering the study, 4 weeks after that, then every 8 weeks. At each visit they received enough PrEP pills (or placebo) for daily use, counseling about taking these pills according to the study plan, free condoms and gel, and a test for HIV-1 and HIV-2 (the two types of HIV). Participants returned study-drug bottles at each visit so researchers could count the pills they had left as a measure of PrEP pill taking. Researchers also measured levels of TDF and FTC in blood of some participants to see whether they had taken PrEP pills. Before every study visit, participants completed a computer interview to report whether they had taken their PrEP pills according to the study plan.
The primary goal of the study was to determine how many participants in the PrEP group and the placebo group became infected with HIV-1 or HIV-2. The study also aimed to compare the safety of taking PrEP pills versus placebo.
What the Study Found
Researchers randomly assigned 199 participants to receive PrEP with TDF/FTC (Truvada) and 201 to receive placebo (the dummy pill). No transgender women enrolled in the study. Median age was similar in the two groups -- 35 in the PrEP group and 34 in the placebo group. About 90% of participants were white, and about three quarters were not members of a gay couple. One quarter of participants had more than 5 alcoholic drinks daily for the past month, and about 45% reported using party drugs. Participants averaged about 8 sex partners in the past 2 months. While 89% of participants lived in France, 11% lived in Montreal.
During the 24-month study period, 94% or more of men in the PrEP group and the placebo group attended each scheduled study visit. Men in the PrEP group took a median of 15 pills monthly, as did men in the placebo group. TDF and FTC levels measured in blood reflected reported PrEP use in the preceding week. The PrEP group did not differ from the placebo group in total number of sex acts in the 4 weeks before each study visit or in the proportion of sex acts involving receptive anal sex without a condom. Similar proportions of men in the PrEP group (41%) and the placebo group (33%) picked up a sexually transmitted infection during the study period.
After men started taking their PrEP pills or placebo, 16 men became infected with HIV: 14 men assigned to take placebo (the dummy pill) and 2 assigned to take TDF/FTC PrEP became infected (Figure 2). Based on those numbers, the researchers calculated new-infection rates of 6.60 per 100 person-years in the placebo group and 0.91 per 100 person-years in the PrEP group. A rate of 0.91 per 100 person-years means about 1 of every 100 people in the PrEP group got infected every year. The new-infection rate in the placebo group was more than 6 times higher. The researchers calculated that men assigned to TDF/FTC PrEP had an 86% lower HIV infection rate than men in the placebo group.
When the researchers looked more closely at the 2 men in the PrEP group who became infected with HIV during the study, they found that one man returned 60 of 60 PrEP pills at study visit pill counts, meaning he never took one of the pills. The other man returned 58 of 60 PrEP pills at study visits, meaning he took only two pills. Neither of these two men had TDF or FTC levels detectable in blood.
None of the men in the PrEP group or the placebo group had any serious medical problems that might be caused by antiretrovirals like TDF or FTC. A higher proportion of men in the PrEP group than the placebo group (14% versus 5%) had minor stomach or bowel problems like nausea, vomiting, or diarrhea.
What the Results Mean for You
This study of 400 men without HIV infection showed that taking two PrEP pills in the 24 hours before sex and two PrEP pills after sex (Figure 1) lowered the risk of HIV infection 86%. Previous studies of PrEP with a pill containing the same two antiretrovirals (TDF/FTC or Truvada) helped protect gay men, heterosexual men and women, and people who inject drugs from getting HIV infection.2-5 But all of those previous studies required participants to take a PrEP pill every day. The new study required men to take their PrEP pills only before and after sex. Taking PrEP pills only before and after sex could make it easier for PrEP users to take as many pills as they need to protect themselves from HIV infection.
It is important to note that the U.S. Centers for Disease Control and Prevention (CDC) PrEP guidelines specifically state that timing PrEP to sex is not recommended.8 Whether the CDC will change that advice after reviewing findings from the French study is unknown. The latest CDC guidelines limit PrEP to daily TDF/FTC (Truvada) -- or to daily TDF alone (Viread) for people who inject drugs and heterosexual men and women, but not for gay men and other men who have sex with men.
The CDC recommends that people considering PrEP to prevent HIV infection should get tested for HIV immediately before starting PrEP and every 3 months after starting PrEP. Taking TDF/FTC (Truvada) or TDF (Viread) without other antiretrovirals would be bad for people with HIV infection because those drugs would not control HIV. As a result, HIV resistant to TDF, FTC, and possibly other antiretrovirals could develop. The CDC suggests certain groups of people who might consider PrEP (see "Who Should Consider PrEP?").
Another potential advantage of as-needed PrEP versus every-day PrEP is a lower risk of drug side effects. TDF, one of the two antiretrovirals in the most-tested PrEP pill, can cause kidney or bone problems. CDC PrEP guidelines call for kidney function testing before starting PrEP with TDF/FTC and every 6 months while on PrEP.8 Tenofovir alafenamide (TAF), an antiretroviral similar to TDF but with a lower side-effect potential, will probably become available in a single pill with FTC. Early studies of TAF-based PrEP have begun.
|Who Should Consider PrEP?|
- You should consider PrEP if you are a man or woman who sometimes has sex without using a condom, especially if you have a sex partner who you know has HIV infection.
- You should also consider PrEP if you don't know whether your partner has HIV infection but you know that your partner is at risk (for example, your partner injects drugs or is having sex with other people in addition to you) or if you have recently been told by a health care provider that you had a sexually transmitted infection.
- If your partner has HIV infection, PrEP may be an option to help protect you from getting HIV infection while you try to get pregnant, during pregnancy, or while breastfeeding.
Source: U.S. Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States -- 2014. Clinical providers' supplement.
- Molina JM, Capitant C, Spire B, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373:2237-2246.
- 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.
- 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.
- Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083-2090.
- 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.
- Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372:509-518.
- U.S. Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States -- 2014. A clinical practice guideline. 2014.