Science - USA (2020-05-22)

SCIENCE sciencemag.org 22 MAY 2020 • VOL 368 ISSUE 6493 807

PHOTO: ISTOCK.COM/SARITWUTTISAN

I

t’s not an AIDS vaccine, but it may be the

closest thing to one so far. A long-acting

antiretroviral drug given as an injection

every 2 months powerfully protected un-

infected people from HIV in a large-scale

clinical trial. Although it was cut short

by the COVID-19 pandemic and has not

been published in a peer-reviewed journal or

presented at a meeting, the study holds out

hope of preventing HIV infections in high-

risk groups without the need to take pills

every day, which many people find difficult.

The trial compared the experimental drug

cabotegravir with Truvada, a daily pill com-

bining two antiretroviral compounds that is

the standard regimen for pre-exposure pro-

phylaxis (PrEP), as the strategy of preventing

infection with drugs is known. Sponsored

by the U.S. National Institute of Allergy and

Infectious Diseases (NIAID), the trial began

in December 2016 and enrolled more than

4500 men who have sex with men and trans-

gender women. Participants were randomly

assigned to Truvada, intramuscular injec-

tions of cabotegravir, placebo pills, or dummy

injections. As of late April, 12 infections oc-

curred in the cabotegravir group versus

38 in the equally sized group that received

Truvada: a 0.38% incidence in the cabotegra-

vir arm versus 1.21% in the Truvada one. This

overall result, reported by press releases on

18 May, indicates cabotegravir works just as

well as Truvada, and perhaps better, though

the trial saw too few infections for that con-

clusion to reach statistical significance.

“It’s really exciting,” says Jared Baeten, an

epidemiologist at the University of Wash-

ington, Seattle, who conducted a landmark

PrEP study of anti-HIV pills—including

Truvada—in Kenya and Uganda. “It gives

another option for people who can’t or don’t

want to take daily pills.” That may get more

people to try PrEP, Baeten adds, noting that

more women began to use contraception as

options increased. Epidemiologist Kevin De

Cock, who heads the Kenya program for the

U.S. Centers for Disease Control and Preven-

tion, says, “A new vista of HIV prevention has

been opened.”

Several PrEP studies with Truvada have

shown that, by and large, people who became

infected with HIV did not take the daily pills.

(Blood measurements can reveal levels of

the drugs.) To address that problem, “Peo-

ple are looking aggressively for long-acting

agents,” says Myron Cohen, a microbiologist

at the University of North Carolina School of

Medicine, who is co–principal investigator

of the NIAID HIV Prevention Trials Net-

work. Cabotegravir, which has worked well

as a treatment in clinical trials, is further

along in development than other long-act-

ing drugs. Made by ViiV Healthcare, a joint

venture of GlaxoSmithKline, Pfizer, and

Shionogi that focuses on AIDS drugs, the

compound targets integrase, an HIV pro-

tein that is essential to its replication.

COVID-19 shut down 11 of the trial’s

43 sites in seven countries, and participants

at others increasingly had trouble attend-

ing appointments, says Raphael Landovitz

of the University of California, Los Angeles,

the study’s protocol chair. The investigators

told the study’s independent data and safety

monitoring board (DSMB) about this prob-

lem in early April and asked that the end-

point of the trial be changed to make sure

the study had an “undisrupted data set.”

Instead of evaluating whether the injections

were superior to the Truvada pills—the origi-

nal goal—they decided to assess a lower stan-

dard of “noninferiority.”

On 14 May, the DSMB members took a

scheduled interim peek at the data. They

found that the cabotegravir arm met that

threshold and that the injections appeared

safe and mostly well-tolerated. Study orga-

nizers now plan to offer the injections to all

participants. “With cabotegravir lasting at

least a couple of months we’re moving in

the direction of providing people with some

of the benefits of a vaccine,” Cohen says.

Landovitz says ongoing analyses should

reveal why people who received shots of the

drug became infected. Earlier studies found

that men and transgender women who are

underweight more rapidly eliminate the

drug from their blood. Another possibility

is that participants who got infected may

have missed some doses of the cabotegravir

pills they had to take for 5 weeks—for safety

reasons—before starting the injections. Or

someone could have been infected with an

HIV variant that is resistant to cabotegravir.

Injected cabotegravir is also being tested

in a large study of heterosexual women,

which could have clear data as early as No-

vember. ViiV said in a statement it is “ac-

tively working with global health partners”

to make sure that people in resource-limited

countries have access to cabotegravir injec-

tions, but it did not reveal any information

about pricing. Cohen says the addition of

long-acting cabotegravir as PrEP provides

a powerful new HIV prevention weapon.

“This agent really could contribute to the

goal of ending AIDS by 2030.” j

IN DEPTH

Cabotegravir provided long-term protection

from HIV when injected intramuscularly.

Long-acting drug acts like

a short-term AIDS vaccine

Simpler than daily pills, injections to prevent HIV infections

protect people for 2 months

BIOMEDICINE

By Jon Cohen

Published by AAAS