Can this new injectable deliver on its promise to reduce HIV transmission?

SAN FRANCISCO — New clinical evidence shows that cabotegravir, an investigative injectable drug under development for HIV prevention and treatment, is 66% more effective than oral preexposure prophylaxis.

On Tuesday, the AIDS division at the U.S. National Institutes of Health, the primary sponsor of a recent study on cabotegravir, announced the superior efficacy of the drug, which is injected into the buttocks every two months, over daily oral tenofovir/emtricitabine combination pills widely used for PrEP.

This is based on new data analysis of HPTN 083, a study from the HIV Prevention Trials Network that enrolled over 4,500 cisgender men who have sex with men, and transgender women who have sex with men in the United States, Brazil, Peru, Argentina, South Africa, Thailand, and Vietnam to compare ViiV Healthcare’s injectable cabotegravir with Gilead Sciences’ pill Truvada.

In May, the study came to an end, following a review from the independent data safety and monitoring board. Cabotegravir was so highly effective at preventing HIV in this population that the board recommended the blinded phase of the study to end early, rather than continue for three years.

When taken daily, PrEP provides between a 92% and 99% reduction in HIV risk. But because people don’t always take their pills as prescribed, there is a demand for long-acting HIV prevention tools.

While there is sure to be excitement around cabotegravir’s effectiveness at AIDS 2020, the conference where the final data analysis from the study was revealed, a number of barriers stand in the way for this drug to deliver on its promise to reduce HIV transmission.

Finding the balance between push and pull

Even where there is demand for daily oral PrEP, there are problems with usage.

“The challenge that we’ve observed is the same populations who are disproportionately affected by HIV also have had challenges accessing, uptaking, adhering to, persisting with something that requires a daily oral pill,” said Raphael Landovitz, a professor at the University of California, Los Angeles who served as protocol chair of HPTN 083.

There is a range of barriers that can stand in the way of people taking their daily PrEP, including forgetting to take it, facing the stigma that comes along with a pill associated with HIV, a lack of access to medical care, or distrust of the medical system.

“We were very excited to be able to test a product that could take away some of the barriers to getting these really incredible preventive benefits that we’ve seen TDF/FTC offer if taken as subscribed,” Landovitz said.

As impressive as the results of the HPTN 083 study may be, and as promising as it sounds to reduce dosing from daily to six times a year, it remains to be seen how providers in fragile health systems further strained by COVID-19 can deliver an injection every two months to people most at risk of HIV.

“I’d love to be optimistic,” Shannon Hader, deputy director at UNAIDS, said about cabotegravir at the opening press conference of AIDS 2020. For many people, injectable cabotegravir may be an easier intervention than a daily pill, but demand generation is still key, she said.

The partners working on getting cabotegravir from the lab to the field can learn from the problems that arose with daily oral PrEP, several experts told Devex.

In 2012, Truvada became the first drug approved to reduce the risk of sexually acquired HIV infection. The results came out earlier than expected, and plans for delivery lagged behind the advance in research and development, leading to a slow rollout. While the global UNAIDS target is 3 million active PrEP users by the end of 2020, as of June, only 575,000 people have enrolled.

To avoid history repeating itself with cabotegravir, in 2018 a range of partners came together to form the Biomedical Prevention Implementation Collaborative, or BioPIC, which is focused on developing a product integration agenda and access strategy in order to translate clinical trial results into public health impact.

“This gap between clinical trials and impact is huge and we’re all trying to shorten it,” said Mitchell Warren, executive director at AVAC, a nonprofit that focuses on HIV prevention.

Through BioPIC, AVAC, together with partners including the Bill & Melinda Gates Foundation, ViiV, and multilaterals including PEPFAR, is doing product acceptability work, community engagement, and health systems strengthening. In the two months since the HPTN 083 study came to an early end, there have been urgent consultations to accelerate this work.

“There’s got to be demand as well as supply. There needs to be that pull as well as a push. We’ve got to get that balance right,” said Helen McDowell, head of government affairs and global public health at ViiV, which is involved in BioPIC.

Ensuring the drug works for men and women

The partners behind the HPTN 083 study are calling attention not only to the high effectiveness of the drug, but also the breadth of the population that was surveyed.

“Often in the past clinical studies for prevention were focused on white gay men,” ViiV’s McDowell said, explaining that for the HPTN 083 study, two-thirds of people enrolled were under 30, half identified as Black or African American, and 12% were transgender women.

While HPTN 083 ended early, a study is still underway on the safety and efficacy of cabotegravir for sexually active women in sub-Saharan Africa, where infections among adolescent girls are on the rise.

Approximately 3,200 women who are at risk for acquiring HIV are enrolled in HPTN 084, which is co-funded by the NIH, ViiV Healthcare, and the Gates Foundation.

As that study continues, the BioPIC partners are already discussing what the cabotegravir rollout would look like. McDowell said they are discussing what lessons they might learn from long-acting injectable contraceptives that have been delivered at scale in low- and middle- income countries. BioPIC partners are also exploring whether sexual and reproductive health services, such as family planning, would be more effective pathways to get HIV prevention drugs to girls and women.

Because it is focused on women, the HPTN 084 study faces complexities that the HPTN 083 study did not, including pregnancy and breastfeeding.

“We certainly want prevention drugs that can be used in both men and women at different age ranges, and ideally during pregnancy as well, because we know many of our new infections are happening during pregnancy,” Meg Doherty, treatment and care coordinator at the World Health Organization Department of HIV/AIDS, said in the opening press conference.

She mentioned the long tail of cabotegravir, referencing the period of time when people who stop receiving injections could develop drug resistance if they catch HIV, which is more problematic for women than men.

Potential users of PrEP are often concerned about stereotypes, for example sexual promiscuity, and many women who take PrEP feel the need to hide it from partners and family members.

In accessing PrEP, women face the additional challenges of political will, poverty, and gender- based violence, said Yvette Raphael, executive director of the new South Africa-based organization Advocacy for Prevention of HIV and AIDS.

She said the long-acting injectable would “remove the pill burden” for women, and because it would be easier to stick with the regimen, it “would be a revolutionary and empowering tool.”

Warren of AVAC said many of the big questions about cabotegravir have to do with innovation — not just in research and development, but also in delivery.

“Cabotegravir works for this one population,” Warren said. “But will it work for women? Will regulators approve it? And can we deliver it at scale?”