“We help with translating people’s thoughts into numbers,” Donnell said.
Non-inferiority trials — as this type of trial is called — tend to be larger and longer than other trials because the drugs being compared are each likely to prevent infections, lowering overall infection rates and thus requiring a larger sample to show they work similarly. The cabotegravir clinical trial will enroll 4,500 HIV-negative men and transgender women who have sex with men in the United States and South America and follow them for up to four and a half years.
It will be a randomized, double-blinded study, which is considered the gold standard design. This means that half of the study participants, all of whom will be HIV-negative, will be assigned to an “arm,” or group, that receives cabotegravir and the other half to an arm that receives Truvada. But neither the volunteer participants nor the scientists and clinicians overseeing the study will know which treatment which arm is receiving. This helps keep the trial’s outcome from being influenced by participant or observer bias.
Since the two drugs are delivered by such different methods that it's obvious who is getting which drug, the “blindness” of the trial is maintained by both groups of participants receiving injections and pills. However, the injection will be a placebo in one group and the pill a placebo in the other.
“And then we march on and see what the infection rates are in each of the arms,” Donnell said. “Essentially, there are two outcomes we can hope for. One is that cabotegravir is slightly better than Truvada, and we can prove that it’s not worse. The other is that cabotegravir is way better.”
Beyond a pill a day
In either case, the hope is that by giving people an alternative to taking a daily pill, cabotegravir will encourage more people to try PrEP and then use it regularly enough to be effective.
Previous studies have shown that daily Truvada can reduce by more than 90 percent the risk of HIV acquisition in men who have sex with men. But the level of protection provided depends on the level of medication in the bloodstream — that is, on taking the pills consistently, as directed.
And that can be hard to do.
“In every branch of medicine, taking daily pills is a challenge,” Donnell said. “A really good parallel is contraceptive use. Oral pills’ adherence is not as good as an IUD, which stays in for five years, or an injection, which lasts three months. You just get more success when you can take out the human tendency to not be very good at taking something every day.”
Studies on Truvada in women have been mixed. In small clinical trials and in trials in which HIV-negative women were enrolled with their HIV-positive partners, Truvada showed protection. In larger trials of women at risk, not so much. The difference may be in adherence, which was lower in the larger trials. Because of the mixed results, the evidence is not yet considered convincing enough to say that Truvada protects women as it does men.
Researchers have been looking for preventive methods that women could use discretely, particularly for cultures in which men dominate decisions about using condoms or taking pills. Donnell and fellow biostatisticians Dr. Brett Hanscom of Fred Hutch and Dr. James Hughes of the Hutch and University of Washington are planning a second cabotegravir clinical trial in the HPTN that will enroll women in South Africa, where women bear the brunt of new HIV infections. The study will again compare it to Truvada, but the design for that study is not yet finalized.
The changing prevention landscape
The three early pillars of HIV prevention — education, testing and condoms — initially did bring about a decline in infection rates. But rates plateaued in the early 1990s and have remained dismayingly constant since.
Then came a remarkable breakthrough in treating HIV. Up until the mid-'90s, being infected with HIV — which decimates the immune system — was essentially a death sentence. But intensive research paid off with the development of antiretroviral drugs, approved in 1996, which hold the virus in check. By 2006, combination treatment contained in one or two pills largely replaced numerous medications taken throughout the day and night.
Antiretroviral drugs began to transform the prevention landscape as well. Early advances included putting pregnant women with HIV on treatment to prevent transmitting the virus during childbirth and protecting healthcare workers after accidental needle pricks by immediately treating them with antiretroviral drugs.
In 2010, studies showed that antiretroviral drugs also could be used by people without HIV to protect against infection, giving rise to PrEP. Truvada, a combination of two antiretroviral medications in one pill, was approved for use in 2012. (Cabotegravir is a next-generation, long-acting antiretroviral developed by ViiV Healthcare.)
Around the same time, clinical trials showed that people infected with HIV who adhered to their medication and kept the virus suppressed were less likely to transmit it to noninfected partners. This has become known as "treatment as prevention."
Other studies showed moderate protection from gel microbicides used before sex. In July, researchers announced that a lightweight, flexible plastic vaginal ring laced with an antiviral drug called dapivirine effectively protected women against HIV infection for up to four weeks if used consistently. The ring could be licensed for use by 2018. A longer-acting ring that could be used for three months will be tested in new studies.
Having more options may increase both access to prevention and adherence, researchers say, much as has been the case, again, with birth control. For now, the uptake of Truvada has not been as widespread as public health officials had hoped, and it is not yet available in all countries. And while keeping the virus suppressed may help prevent its spread, only about 17 million of the approximately 35 million people living with HIV are on medication, and far fewer still are suppressing the virus consistently enough to prevent transmission.