Is the World Ready for Long-Acting HIV Treatment?

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How can science improve on its own miracle?

This is the conundrum at the heart of an ongoing conversation in HIV medicine over the future of long-acting antiretroviral therapy, or LA-ART. The promise of LA-ART lies in the freedom it can potentially offer people living with HIV from the traditional burdens of treatment: LA-ART drugs can theoretically be administered as infrequently as once every several months, as opposed to the daily oral dosing that is generally required today.

The invention, production, and increasing global distribution of daily oral antiretroviral therapy for HIV is, in itself, "one of the great success stories of medicine of the last century," said Carl Dieffenbach, Ph.D., at the Controlling the HIV Epidemic Summit in Geneva, Switzerland, on May 3. "Antiretroviral therapy is a modern miracle -- provided people adhere to therapy."

Dieffenbach, the director of the Division of AIDS within the National Institute of Allergy and Infectious Diseases, spoke before the international gathering of leading HIV care providers and policy experts to offer an update on how ready the world is to utilize LA-ART and improve on the modern miracle. The title of Dieffenbach's talk included a provocative question: "Are we ready?"

It would be easy to assume the answer is yes, given that a pair of long-acting HIV drugs are already making their way into the world: ibalizumab (Trogarzo) was approved by the U.S. Food and Drug Administration (FDA) in March while albuvirtide got a green light from the Chinese Food and Drug Administration in June.

But two drug approvals in two countries do not equal a complete, successful rollout. "I'm maybe a little hesitant to say we're ready," Dieffenbach said.

Myles Helfand is the executive editor and general manager of and Follow Myles on Twitter: @MylesatTheBody.

Carl W. Dieffenbach, Ph.D., courtesy of NIAID

What Problems Does LA-ART Solve?

"As we look at this question [of] where do long-acting antiretrovirals fit into the armamentarium," Dieffenbach said, "we have to ask ourselves the question: What problems are long-acting or sustained-release formulations solving, and what problems or concerns are the introduction of these type of formulations actually creating?"

For Dieffenbach, the answer appears to boil down to one word: adherence. Adherence encapsulates both the promise and the peril of LA-ART, even as a range of new drug candidates move through the development pipeline.

The promise, of course, is that by dramatically reducing the frequency at which a person is required to take HIV medications, we reduce the person's risk of missed doses that can potentially lead to treatment failure. Poor adherence to therapy not only leads to a risk for declining health in an individual living with HIV; it also facilitates low-level viral replication that can lead to HIV drug resistance. The worldwide prevalence of HIV drug resistance is on the rise, Dieffenbach said -- and a relative lack of widespread drug-resistance testing only exacerbates the problem, even as we witness increasing global distribution of a new generation of integrase inhibitors that sport a high barrier to resistance, alongside excellent potency and minimal toxicity.

Dieffenbach pointed to an abundance of literature on female contraceptive patches, implants, and injections as evidence that less-frequent dosing can improve adherence. What is less certain at this point is what dosing frequency -- via what method of administration -- is going to be optimal for HIV.

And therein lies the peril of LA-ART. While Dieffenbach noted the potential for non-daily medication dosing to improve adherence, he acknowledged that it could potentially worsen the very problem it's trying to solve: "Long-acting, sustained-release formulations can not eliminate adherence challenges; they simply increase the urgency of getting patients back for redosing," he said. "It changes the risk profile."

A truly effective LA-ART regimen, therefore, would have a "reasonably long" elimination phase, Dieffenbach said. Each dose would have to walk a tightrope between toxicity and efficacy, giving people with HIV a reliably long window of time during which they could receive a new dose before the prior dose lost its ability to suppress the virus. And an infrastructure would need to exist around the therapy that helped to ensure a person with HIV got his or her next LA-ART dose before the virus had a chance to rebound.

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A Robust LA-ART Pipeline

More than a dozen drugs are currently being explored for use as LA-ART or as a long-acting preventive intervention (both for pre-exposure prophylaxis [PrEP] and post-exposure prophylaxis [PEP]), Dieffenbach noted. The majority are broadly neutralizing antibodies, each of which have identifiers like 3BNC117, 10E8, or VRC01 -- a soup of letters and numbers that look as if the people responsible for naming them accidentally typed out their email passwords. But a few antiretrovirals, most of which have actual names, are also in the mix:

  • albuvirtide, a fusion inhibitor that was approved by China's Food and Drug Administration on June 6.
  • cabotegravir, an integrase inhibitor in Phase 3 study.
  • ibalizumab, a post-attachment inhibitor that was approved by the FDA on March 6 for heavily treatment-experienced individuals.
  • MK-8591, a first-in-class nucleoside reverse transcriptase translocation inhibitor, currently in Phase 2 study.
  • rilpivirine, an FDA-approved NNRTI currently available as a daily oral dose (brand name: Edurant), but in Phase 3 study as a long-acting injection.

One of the challenges facing LA-ART is that these medications not only must individually make it through clinical trials successfully to see the light of day, but also ultimately need to be prescribed in combination with one another in a regimen that's as effective as the fixed daily-dose, orally administered, single-pill combination drugs available today.

Each LA-ART candidate has its own development pipeline with potential variations in dosing schedule and administration method, making a viable treatment regimen more complicated than a viable prevention intervention. Dieffenbach noted that a long-acting prevention method may need only a single active agent to be successful.

Carl W. Dieffenbach, Ph.D. 2018 Controlling the HIV Epidemic Summit; Long-Acting Antivirals -- Where Are We Headed? Are We Ready? Reprinted with permission.

LA-ART Trials of the Past

Long-acting, non-oral antiretrovirals have been explored as possibilities for maintenance therapy for years, Dieffenbach said. In July 2015, prominent clinician-researchers Martin Markowitz, M.D., and Kathrine Meyers, DrPH, edited an issue of Current Opinion in HIV and AIDS that featured more than a dozen studies and analyses on LA-ART. In 2016, the Conference on Retroviruses and Opportunistic Infections -- arguably the most reputable HIV-focused scientific conference -- shined a spotlight on the LATTE-2 trial, which showed promise for a maintenance regimen consisting of cabotegravir and rilpivirine that was injected no more than once every four weeks. LATTE-2 has continued to yield encouraging results through 96 weeks of study.

However, when we think about the prospects of a massive rollout of monthly injectable HIV treatment, one snag with trials like LATTE-2 is that they are therapy maintenance studies. The FDA requires the studies to feature a "lead-in" period in which a person must achieve viral suppression with orally administered antiretrovirals. This greatly complicates the course of a person's treatment, Dieffenbach explained. "It makes it almost impossible for a group like PEPFAR [the U.S. President's Emergency Plan for AIDS Relief], or somebody globally, to roll out this for prevention and/or for treatment," he said. "You can't have the multiple clinic visits that are required." The only way to eliminate the lead-in period, he said, was through the construction of drug safety databases that can increase FDA confidence in LA-ART's low risk for adverse events through the accumulation of Phase 3 and Phase 4 study data. At the moment, few LA-ART candidates have reached that advanced level of study.

Adapted from Carl W. Dieffenbach, Ph.D. 2018 Controlling the HIV Epidemic Summit; Long-Acting Antivirals -- Where Are We Headed? Are We Ready?

Present and Future LA-ART Trials

Although advanced study data on LA-ART candidates are hard to come by at the moment, that is likely to change significantly over the coming months and years.

A pair of high-profile Phase 2B/3 studies, HPTN 083 and HPTN 084, are exploring LA-ART for PrEP. Each study will pit injectable cabotegravir (dosed every four weeks initially, then every eight weeks) against daily oral emtricitabine/tenofovir disoproxil fumarate (Truvada), which remains the only FDA-approved PrEP intervention nearly six years after its July 2012 approval for that purpose. HPTN 083 is a non-inferiority study enrolling HIV-negative transgender women and men who have sex with men; HPTN 084 is a superiority study enrolling HIV-negative cisgender women.

Meanwhile, a proof-of-concept study known as ACTG 5357 will explore a long-acting regimen consisting of two experimental agents, cabotegravir and the broadly neutralizing antibody VRC01LS. It's being investigated as a maintenance regimen in people whose HIV is already suppressed on existing antiretroviral therapy. The study is expected to begin enrollment in a couple months, Dieffenbach said.

Among the other broadly neutralizing antibodies in development, a candidate currently known as CODV-Fab seemed to excite Dieffenbach most. According to Dieffenbach, it sports three distinct potential binding sites and has shown potency against 98% of viral strains. The drug's manufacturer, Sanofi, has the capacity to scale up its production significantly, Dieffenbach said. In the wake of promising findings in macaques, initial human studies will begin later this year. "This may be our future; it may not be our future: We'll see what happens when we put this kind of molecule in people this fall," Dieffenbach said.

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The Bottom Line on LA-ART's Potential

Dieffenbach ultimately ended his talk in Geneva with a note of cautious optimism on the future value and potential of LA-ART.

The most promising immediate avenue for LA-ART development lies more on the prevention side than the treatment side, given that an effective biomedical prevention intervention doesn't require the same level of antiretroviral activity -- or the regimen complexity -- of an effective HIV treatment combination. "We will see a steady improvement and refinement in products" for HIV prevention, Dieffenbach said. This refinement will likely involve the development of a range of delivery methods and coverage duration, which will provide people with a set of options they can use to maximize adherence (and thus efficacy).

On the treatment front, we'll need to reach a point where enough effective options have advanced through clinical trials that researchers can begin to assess combinations of three long-acting drugs evaluated together as a single regimen, Dieffenbach suggested.

Any way you slice it -- whether it's for PEP, PrEP, or treatment -- for LA-ART to truly revolutionize the antiretroviral landscape, it's going to have to prove that it can move the needle on adherence rates and reduce the emergence of HIV drug resistance. "For long-acting prevention -- and maintaining and enhancing [treatment] -- adherence is going to be essential," Dieffenbach said.

"This is the problem we have with PrEP; this is one of the major problems we had with the microbicide rings," he warned, referring to study results earlier this decade that initially suggested low efficacy for HIV prevention interventions in women -- both for oral PrEP and vaginal microbicide rings -- but turned out to be tied to low adherence rates among study participants. A key takeaway from these explorations was that simply providing an effective biomedical intervention isn't enough to guarantee its use.

"Helping people to adhere is ultimately a goal," Dieffenbach said. "Whether ... long-acting can be used as a tool to achieve that, I think, is in large part a social and behavioral question that we need to partner with to answer as we move forward with these studies."