Seven years after the Food and Drug Administration (FDA) approved Truvada (FTC/tenofovir disoproxil fumarate) as pre-exposure prophylaxis (PrEP), it's become clearer that not everyone who uses it as a primary HIV intervention takes the pill daily. Some people have sex intermittently, which has led to the growing acceptability of a 2-1-1 dosing regimen, also known as "on-demand" or "event-driven" PrEP. The 2-1-1 dosing, which consists of taking two tablets of Truvada at least two hours before having sex, and then two more pills -- one pill 24 hours and another 48 hours after the double dose -- is an increasingly popular HIV prevention method for people who don't feel like a daily pill is right for their lifestyle, experts say. But with many primary care physicians lacking the knowledge of daily PrEP or the desire to prescribe it -- let alone 2-1-1 dosing -- understanding of the benefits and challenges of this regimen is coming from the bottom up.
That is, from patients learning about 2-1-1 on their own.
"When PrEP was first approved, often it was the patients educating the providers, and that's what is happening (with 2-1-1)," says Hyman Scott, M.D., M.P.H., clinical research medical director at Bridge HIV, a program of the San Francisco Department of Public Health. Scott admits that his city is ahead of the curve in educating at-risk populations and their health care providers about the benefits of PrEP, both the daily and the 2-1-1 regimens. This year, the health department sent letters to doctors in the city informing them of the importance of 2-1-1 as an effective method of dosing, with guidance for instructing patients on how to use it.
San Francisco is one of only three municipalities (New York and Los Angeles are the other two) in the U.S. that have endorsed 2-1-1 as a safe alternative to daily PrEP. However, in its advisory, the department emphasized that PrEP 2-1-1 is effective for men who have sex with men (MSM) and it is not recommended for cisgender women, cisgender men who have sex with women, transgender men and women, or people who inject drugs, mainly because of lack of study in these populations. "Current research suggests that non-daily Truvada should be effective for insertive and receptive anal sex but is not likely to reach or remain at high enough levels in the cervix or vagina to provide effective protection against HIV infection caused by exposure to HIV at these anatomical sites," the advisory stated.
The Los Angeles Department of Health is the other California city agency endorsing 2-1-1 PrEP dosing, also only for cisgender MSM. Last month, the department's associate medical director for HIV and STD programs, Leo Moore, M.D., M.S.H.P.M, endorsed 2-1-1, saying, "We recognize that curbing the HIV epidemic will require the use of multiple dosing strategies for PrEP that are tailored to a person's sexual practices and way of life."
The San Francisco City Clinic promotes 2-1-1 as a dosing option for MSM, as does the Strut clinic, a health and wellness clinic that primarily serves the gay, bisexual, and transgender community in San Francisco.Kaiser Permanente in San Francisco has also included 2-1-1 or on-demand dosing in its PrEP guidance to doctors.
2-1-1 PrEP Is Approved by Public Health Agencies, Yet the U.S. Faces Challenges in Rollout
The 2017 guidelines from the U.S. Centers for Disease Control and Prevention (CDC) recommend daily PrEP use for preventing HIV, not intermittent dosing. Hyman and other experts familiar with guideline updates say the CDC is likely to endorse 2-1-1 with its next guideline revisions, though it's unclear when that would be. International Antiviral Society-USA has also endorsed the 2-1-1 PrEP regimen as an option for MSM. The U.S. Preventive Services Task Force last year gave an "A" rating to PrEP as primary HIV prevention intervention, but is calling for more research into 2-1-1 dosing before it can recommend it.
The FDA, however, still has only approved PrEP for daily usage, although it has stated that it's legal and often routine for health care providers to recommend or prescribe medicines for "off-label," that is, alternate dosing to what is actually approved.
Elsewhere in the world, 2-1-1 dosing is uncontroversial. Clinical guidance in Australia, Canada, and Europe includes the 2-1-1 PrEP sequence alongside the option of a daily PrEP regimen for MSM. And earlier this year, the World Health Organization endorsed 2-1-1 for MSM. But there is still much work to do in informing health care providers, PrEP programs, and other HIV programs throughout the U.S. about the efficacy of 2-1-1. Proponents of 2-1-1 say that spreading awareness of this dosing regimen could expand the use of PrEP widely and bring in many new patients who balk at the thought of taking a daily dose of Truvada when they're only having risky sex one or two times a month.
For men practicing anal sex, the verdict is in regarding the safety and efficacy of 2-1-1 as an HIV preventative tool. So, why aren't more U.S. doctors recommending it? According to Shannon Weber, M.S.W., founder and director of PleasePrEPMe, although PrEP champions can be found all over the nation, there are many "PrEP deserts."
"Early adopter physicians know about 2-1-1 in bigger cities -- maybe they're on PrEP themselves," Weber says. "Mainstream and later adopters, it will sometimes be uncomfortable for them to recommend."
"There are gaps even in California, outside San Francisco and Los Angeles," Weber continues. "If you are in Fresno or Riverside, you will find it harder to get a doctor to prescribe it for daily use or intermittent. In San Francisco, when PrEP was rolled out, men were asking their providers to adopt it. It's important to give credit to the community." But she adds, "The burden shouldn't be on all primary care doctors to inform their patients [about 2-1-1]."
Which means, as with the rollout of PrEP, it's up to customers to inform themselves, with the help of HIV/AIDS professionals and social service organizations. But how that information is disseminated is hard to predict, and data on how best to inform and educate patients and providers is scarce.
Researchers Are Investigating Why Some Men Choose 2-1-1 PrEP
One team of researchers is attempting to determine how patients learn about 2-1-1 as a dosing regimen and what might be some barriers to using it. In March, the San Francisco AIDS Foundation launched a pilot study of the patient experience in using PrEP 2-1-1. Data from the study, which will be available next March, will be sent to the FDA, according to the study's author, Chris Hall, M.D., vice president of medical affairs at the foundation.
"We are collecting data on why people chose 2-1-1," Hall says. "Some come in asking for it, but most say they want PrEP -- and then they learn about 2-1-1 as an option." Hall offers everyone who seeks PrEP the opportunity to be in the study. "Right now, there are 3,300 people being followed actively. Since March, there are 712 new PrEP enrolments."
Hall speculates that the population at the clinic is more educated about PrEP and HIV prevention generally, which would suggest patients elsewhere in the U.S., let alone U.S. physicians, have some learning to do about on-demand dosing. That education is especially important, Hall adds, due to the added complexity of 2-1-1 and the possibility of getting the dosage wrong.
"On-demand PrEP is more challenging than once-daily PrEP," Hall says. Because 2-1-1 dosing may be less forgiving about missing or mis-timing a dose, patient follow-up is important, he adds. "Patients may need more support and hand-holding, like a call or phone app reminder," Hall adds. That hand-holding is something primary care physicians -- even if they do prescribe 2-1-1, or prescribe PrEP at all -- are not likely to provide, he says.