A clinical trial set to begin later this year will test whether an experimental drug injected every two months protects against HIV infection as effectively as a once-a-day pill called Truvada. If it does, the long-acting PrEP drug — for “pre-exposure prophylaxis” — would add another major tool to an HIV prevention toolbox that for the global pandemic's first 30 years was limited to education, testing and condoms.
The study comes as the HIV field enters what researchers are calling a new era of prevention, with additional clinical trials launching that will test infusions of anti-HIV antibodies and a promising vaccine candidate. That’s extraordinarily good news for a pandemic in which 35 million people worldwide have died from AIDS-related illnesses since the first cases were reported in 1981 and 2.1 million are newly infected each year.
But prevention advances, as welcome as they are, come with a twist: They complicate the task of designing the very clinical trials needed to test additional tools.
A prime example involves the experimental, injectable drug called cabotegravir. Because it is a new version of a PrEP rather than an entirely new method of prevention, it will be tested against the PrEP pill, Truvada, which was approved for use in 2012, rather than against a placebo.
These types of trials are more complex to design, run and interpret than trials that simply show whether something works.
“Once you have something that actually works to prevent HIV, you move from trials where you’re trying to prove something works to trials where you’re trying to prove that something works as well as the existing thing,” said Dr. Deborah Donnell, who helped design the trial. “It is a hard trial to do, scientifically. It’s just easier to prove that things are different than to prove that things are the same.”
Donnell, a biostatistician at Fred Hutchinson Cancer Research Center and the University of Washington, will describe the challenges of doing so Monday at a satellite meeting on the eve of the second, biennial HIVR4P conference in Chicago. (“R4P” stands for “research for prevention.”) She is also the head biostatistician for the HIV Prevention Trials Network, or HPTN, which is conducting the cabotegravir trial.
The HPTN is headquartered in North Carolina and made up of a global network of scientists and others working to develop and test HIV prevention methods. It is a sister network to the HIV Vaccine Trials Network, headquartered at Fred Hutch and focused on preventive HIV vaccines. Fred Hutch also is home to the Statistical Center for HIV/AIDS Research and Prevention, or SCHARP, which provides statistical support to both networks as well as a third HIV prevention collaborative, the Microbicide Trials Network, which is based in Pittsburgh.
What biostatisticians do is run the numbers: If this is what researchers want to discover, how many trial participants will the study need? They take into account the researchers’ hypothesis, based on earlier studies, of how well the product they are testing will work. They also weigh how consistently participants will take the drug being tested, which is called “adherence.”
“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.”
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 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.
And as much as antiretrovirals have contributed to prevention efforts, researchers continue to pursue the tool that has proven the most effective and affordable at controlling and ending epidemics throughout history: A vaccine.
That was clear at AIDS 2016, the biennial international global health conference held in July in Durban, South Africa, where just-launched and soon-to-launch vaccine clinical trials took center stage.
“We all agree that an HIV vaccine remains the most important tool for HIV prevention,” said Dr. Olive Shisana, the head of South Africa’s Human Sciences Research Council, at that conference’s closing ceremony. “This is not the time for complacency. So much more needs to be done to end AIDS.”
The HIV vaccine field itself is entering a new phase, with researchers optimistic about the two large clinical trials now getting underway. The HVTN is on the brink of rolling out a large-scale trial in South Africa involving 5,400 HIV-negative men and women that could, after decades of disappointment, lead to the first licensed vaccine regimen against HIV. The HVTN and HPTN also have joined forces to test an experimental, broadly neutralizing antibody that could potentially protect people from infection against almost all strains of the rapidly mutating virus that causes AIDS. It is enrolling 1,500 women at 15 sites in South Africa and 2,700 men and transgender people who have sex with men at 24 sites in the U.S. and South America.
Although the two vaccine-related trials won’t be tested against another vaccine or broadly neutralizing antibody because none have yet been shown to work, they, too, are affected by the changing prevention landscape. In every HIV prevention clinical trial undertaken, the participants who volunteer are given information and counseling on minimizing the risk of HIV infection, including advice on limiting risky behaviors, using condoms and — since its 2012 approval — taking Truvada.
Biostatisticians designed the trials to be large enough to show results if Truvada uptake increases, and they will continue to monitor data on adherence and infection rates throughout the trial.
Falling infection rates are, after all, the kind of challenge that HIV prevention researchers welcome.
“That’s the point, right?” Donnell said. “You want HIV to go away, you want to have no research left to do. But I don’t think we’re there yet.”
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
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