It sounds too good to be real: You take one pill every day, and your risk of contracting HIV is reduced upwards of 90 percent. But the Pre-Exposure Prophylaxis (PrEP) program is an actual thing, which the CDC and the WHO have been recommending since last spring. Is daily Truvada as effective as it sounds, and how does it work?

Top image: Truvada clinical trials poster, 2012, photo by Torbakhopper

The PrEP regimen has been the subject of massive debate in the gay community over the past year, as it's become more widely used and accepted among sexually active men who have sex with men (MSM). Star Trek star Zachary Quinto set off a firestorm recently when he warned that this medication should not be used "to increase our ability to have recreational sex." Back in July, Gawker's Rich Juzwiak wrote about the controversy, and his own experiences with the pill.

The first federal guidelines for PrEP only came out in May, but it's already being recommended for anybody who's sexually active with a HIV-positive partner, or one or more partners of unknown status.

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But is PrEP really up to 92 percent effective in reducing HIV risks, and how did we discover that a therapy to treat people who already have HIV could prevent new cases?

PEP vs PrEP

For years now, we've been giving HIV drugs to anyone who had a suspected exposure to HIV. For example, if a health care worker was accidentally stuck with a needle that might have infected blood, or if a condom broke during one particular sex act, people could be prescribed Post-Exposure Prophylaxis, or PEP. (This only works within 72 hours after exposure, and generally, the sooner the better.)

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We've known since the late 1980s that HIV drugs could help protect uninfected people from getting infected after exposure, and this was formalized in the mid-2000s as a prevention protocol.

The study that proved that you could prevent HIV infections with an ongoing regimen of just one pill, Truvada (which is actually a combination of two drugs) happened in 2010. You can read the entire research paper here. In a nutshell, the researchers studied 2,500 men and transgender women, giving half of them a placebo and the other half daily Truvada.

Unfortunately, the study had a huge problem with patient compliance — only about 18 percent of the Truvada group seems to have been taking it daily. Some 48 patients in the Truvada group contracted HIV during the study, but only four of those had any detectable amount of the drug in their system. None of the patients whose blood tests indicated actual daily use of Truvada were infected HIV.

Plus you have to account for other factors in the study, like the fact that all the people enrolled in it were receiving education and counseling, and many of them apparently changed their behavior to become less risky once they were enrolled.

Still, the researchers were able to build a statistical model, based on the amount of the drug in the systems of the participants and the rates of infection, that the daily Truvada regimen could be up to 92 percent effective. (Gilead, the maker of Truvada, provided the drugs for free to this study and provided some "travel-related support," but did not fund the study.)

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The researchers admit in the discussions section of their paper that the protective effects of Truvada were "significant but not as high as originally hypothesized during the design of the study," due to the aforementioned compliance issues. But they also concluded that PrEP "is effective for slowing the spread of HIV." And the study suggests that once you adjust for certain factors, the effectiveness could be closer to 95 percent, not 92 percent, among people who actually take the pill daily.

How it works

Truvada is what's known as a nucleoside reverse transcriptase inhibitor (NRTI), a class of drugs which target retroviruses like HIV. Retroviruses consist of single strands of RNA that are converted into DNA by an enzyme called reverse transcriptase. This process goes against the central dogma of molecuar biology, which says DNA gets converted into RNA, which then gets converted into protein.

When HIV first gets into a cell, it consists of a single strand of viral RNA, surrounded by various proteins that are necessary for infection. One enzyme, reverse transcriptase, builds a complementary strand to the single-stranded HIV RNA, creating double-stranded viral DNA. The virus then moves into the nucleus of the cell, which contains the cell's own genetic material (genome). Another viral enzyme, called integrase, then inserts the HIV now-DNA into the host cell's genome. Once HIV's DNA has been integrated into the host genome, the infection becomes permanent, and copies of HIV's RNA can be produced from that DNA to eventually infect other cells.

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NRTIs like Truvada work by disrupting reverse transcriptase, preventing HIV's RNA from becoming DNA. They accomplish this by mimicking the DNA building blocks that reverse transcriptase uses to build up a complementary strand to the initial, single-stranded HIV RNA.

In essence, NRTIs look very similar to regular nucleotides, but they possess a chemical modification that prevents the chain from lengthening. When reverse transcriptase tries to incorporate an NRTI, the enzyme stalls, and the HIV virus remains stuck as RNA.

When Truvada and other similar drugs were developed, they aimed to stop HIV from spreading in people who were already infected. For patients who already have HIV, the infected cells are constantly producing new HIV RNA, but these drugs can prevent additional cells from being infected.

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But in HIV-negative people, NRTIs will keep any newly introduced HIV from converting into DNA and permanently infecting any cells. However, the therapy only works if NRTI molecules are regularly floating around, ready to stall out the HIV reverse transcriptase. Which is why the patients who were taking Truvada irregularly, rather than once per day, were still at risk.

What are the side effects?

Most sources, including AIDS.gov, say that the main side effects of daily Truvada are pretty mild: stomach aches, minor headaches, and loss of appetite. And they tend to go away after the first month. Some have warned that Truvada can cause decrease in renal function, but that apparently isn't permanent. More information may be needed about the long-term effects of Truvada on bone mineral density.

Why did this drug take so long to take off?

We had a study in 2010 suggesting that Truvada could reduce HIV risk by 92 percent, and it was approved by the FDA for preventive use in 2012. So why has it only taken off as a preventive treatment in the past year?

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This New Yorker article from late 2013 pretty much breaks it down: Gilead has not been very active in promoting Truvada as a preventive therapy. Doctors were hesitant to be first out of the gate in promoting the treatment. Some AIDS organizations have insisted that PrEP is a drug-company scam or that it could lead to a rise in infections of other STDs due to riskier behavior (something not borne out by the admittedly small number of studies on the issue.)

So while doctors who have studied Truvada are confident that it works, its position as a prophylactic for HIV, in a time where HIV/AIDS can be better managed in general, has not caught on outside of certain subgroups.

But meanwhile, HIV has also been spreading less quickly lately — because HIV-positive people who take retrovirals, like Truvada, become much less contagious.