Pipeline of PrEP Alternatives Grows, but There Are No Easy Answers

This spring, when the United States Preventative Services Task Force announced its “Grade A” recommendation for pre-exposure prophylaxis (PrEP), advocates for people at risk of acquiring HIV cheered, hoping the move would lead to increased access for patients who currently have difficulty finding or paying for the daily pill.

However, a new study published in the journal Current HIV/AIDS Reports, notes that cost isn’t the only significant barrier. Matthew R. Beymer, PhD, MPH, and colleagues, say PrEP medication adherence is also a serious problem—1 that must be solved for the promise of PrEP to be realized.

“Among individuals who decide to initiate PrEP, demonstration projects and clinical databases suggest that medication adherence is insufficient to provide high levels of HIV protection among select population,” wrote Beymer, of the Department of Health and Mental Health Services at the Los Angeles LGBT Center.

The research team notes that although 1.2 million Americans are believed to be at sufficient risk of HIV to warrant daily PrEP use, only about 70,000 Americans had an active prescription for the drug as of the last quarter of 2017. In addition to the burden of taking a daily pill, some patients report side effects from the drug tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).

In short, Beymer and colleagues say, additional options are needed. And indeed, many new options for PrEP are in development.

“These options range from alternative dosing of oral products (both existing and novel); injectable preparations; topical products delivered as gels, rings, films, and long-acting/extended release (LA/ER) systems such as microneedles and implants,” they write.

One strategy that’s most readily available is alternative dosing, such as the strategy of taking a double-dose before potential exposure to HIV, and then a single dose 24 and 48 hours later, with additional doses if exposure continues. Such “on-demand” strategies have shown promise in clinical trials, and would drive down the cost of treatment since patients would ultimately take fewer pills. However, some studies suggest daily dosing is still the most reliable way to protect against HIV infection.

A number of other pharmaceutical approaches are in various stages of investigation. A combined formulation of tenofovir alafenamide with emtricitabine is currently the subject of a phase 3 study, though it, too, would require daily dosing.

Two injectable drugs, rilpivirine and cabotegravir, have been investigated at potential prophylactic solutions. Each would require a dose by injection every 8 weeks. Phase 3 efficacy studies are ongoing for cabotegravir, but rilpivirine has not yet progressed to phase 3 for PrEP.

A number of other options, such as gels, vaginal films, vaginal rings, and subdermal implants, are also being studied, though all are in the early stages of development. Beymer and colleagues also mention that many drug companies are currently working on broadly neutralizing HIV-1 monoclonal antibodies. The strategy might provide longer-lasting protection, although studies of bNAbs are still in phase 2.

Although considerable research is taking place in order to advance alternatives to TDF/FTC, Beymer and colleagues say regulators have been slow to appreciate the particular difficulties faced by investigators designing trials that test HIV prevention.

“For example, it is more difficult to discern the true efficacy of a new PrEP modality when the control arm allows for daily PrEP or on-demand PrEP,” Beymer and colleagues write. “Novel trial design strategies, including counterfactual analyses that try to estimate hypothetical untreated/placebo incidence in the same or a similar population, will be paramount to the feasibility of studying new interventions.”

Unfortunately, they say, statistically sound but creatively designed trials have faced skepticism from regulators.

Even if new modalities and HIV-prevention strategies are approved, Beymer and colleagues say the solution to HIV transmission will still require population-specific strategies.

“[D]ecision-making about whether to use these new PrEP modalities will depend on individual-level, interpersonal-level, community-level, and structural-level factors that must be considered in future research,” the investigators concluded.