Trend towards long-acting HIV medications continues

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Just two shots every other month

The ATLAS-2M study found that taking long-acting HIV therapy every other month was as good as taking it once a month. The trial used long-acting cabotegravir (CAB-LA) plus long-acting rilpivirine (RPV-LA). The two-drug regimen is set to be approved this year by the U.S. Food and Drug Administration (FDA). The injectable therapy is given as two intramuscular shots.

There were 522 individuals switched from monthly shots to shots given every eight weeks instead. Another group of 523 individuals continued being given their two shots every four weeks.

At 48 weeks, the 8-week therapy was found to be non-inferior to the 4-week therapy. Undetectable viral load (less than 50) was achieved by 94.3% of the 8-week group and 93.5% of the 4-week group. The safety and tolerability were reported to be similar.

Of the 8-week group, 90% said they preferred their new dosing of every other month.

ATLAS-2M results were presented by Edgar T. Overton, MD, of the University of Alabama at Birmingham. See Abstract 34 at and webcast at

Stopping those injections

So, taking HIV medication once a month or every other month sounds good. But what happens if therapy stops?

Individuals who stopped the long-acting injectable regimen of CAB-LA plus RPV-LA were put on long-term follow-up (LTFU) oral therapy. No drug interaction problems were found in switching to oral therapy.

Good thing, since “CAB and RPV remain measurable in plasma for a year or longer.” But the half-life—the time it takes for half the drug to leave the body—is 5.6 to 11.5 weeks for CAB-LA and 28 weeks for RPV-LA. Or, as the report puts it, “CAB and RPV have low drug interaction potential as perpetrators and pose no PK-related limitations to alternative ART [antiretroviral therapy] selection after discontinuation of injections.” No safety or efficacy concerns were observed.

The findings were reported by Susan Ford, PharmD, of GlaxoSmithKline. The research tracked 38 individuals who had withdrawn from the LATTE-2 and ATLAS studies.  

HIV therapy every six months

That’s the potential of long-acting GS-6207. The HIV capsid inhibitor drug is a first-in-class medication, meaning that it has a new take on treatment that hasn’t been used before.

GS-6207 was reported as generally safe and well tolerated in the 39 individuals who received dosing in an early Phase 1b study. The most common adverse event was mild to moderate injection site reaction.

With the favorable findings, GS-6207 will be observed in two new studies. NCT04143594 will enroll people taking HIV medication for the first time (treatment-naïve). NCT04150068 will study the drug in people who are heavily treatment-experienced.

Hang on to your hats, because the results are still early. GS-6207 has a lot more research to undergo.

Findings of the drug’s dose-response relationship were presented by Eric Daar, MD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. View the poster presentation at and the poster video at Watch the webcast at


Another new HIV drug in development is islatravir (ISL, also called MK-8591). Islatravir is in a new class of HIV medications, called nucleoside reverse transcriptase translocation inhibitors (NRTTIs). It is being studied for both HIV treatment and HIV prevention.

Islatravir is potent. A single half-milligram was found to suppress HIV for longer than seven days. Islatravir has the potential for once-a-week dosing in addition to daily dosing. It also has a high barrier to drug resistance.

At Virtual CROI 2020, there was a report that in early research using a primate model, a weekly oral dose provided efficacy for HIV prevention as post-exposure prophylaxis (PEP). This raises the hope for pre-exposure prophylaxis (PrEP). There is a PrEP study with islatravir using a once-monthly 60 mg dose compared to 120 mg in people at low risk of HIV.

Last year, Merck & Co. reported that an MK-8591 implant was tolerable in early research with primates. Drug levels showed adequate concentrations for protection against HIV. The implant showed potential for protection lasting a year.

A low dose of 0.75 mg of islatravir is also being studied as a two-drug regimen with doravirine (Pilfeltro) in three scenarios: first-time treatment; highly treatment experienced people (with at least three drug class resistance); and switch studies (for people changing

over from Biktarvy).

Another study, DRIVE2Simplify, is looking at treatment simplification. Participants are started out with the triple drug regimen ISL/DOR/3TC and then the 3TC is dropped at 24 weeks (six months).

Islatravir metabolics

A report found that the metabolic profile of a drug regimen containing islatravir was similar to a comparative regimen.

The two-drug combination of islatravir with doravirine (DOR) was compared to Delstrigo (DOR/3TC/TDF).

The research team noted that, “As HIV has become a chronic, manageable disease through effective antiretroviral therapy (ART), increased emphasis is being placed on long-term safety and toxicity, including weight gain, fractures, and metabolic disorders. Certain components of approved ART have been associated with long-term adverse events (AEs), including weight gain, loss of bone mineral density (BMD), and metabolic abnormalities. The combined attributes of islatravir (ISL; MK-8591) and doravirine (DOR) create the potential for a potent, simple, 2-drug regimen with efficacy comparable with approved regimens that may address some of the long-term safety and toxicity concerns of traditional regimens.”

There were 121 participants out to one year on either ISL plus DOR or Delstrigo. The research team concluded, “The ISL regimens, regardless of dose, demonstrated minimal impact on BMD and similar changes in fat distribution, weight, and BMI compared to the DOR/3TC/TDF group, through 48 weeks of treatment.”

The highly detailed report was presented by Grace A. McComsey, MD, of the University Hospitals Cleveland Medical Center. Read the abstract report at

Adios to perfect adherence?

Finally, one doctor dared to say out loud what other doctors have feared to say: The need for perfect adherence with HIV therapy may be a thing of the past.

José R. Castillo-Mancilla, MD, of the University of Colorado Denver, laid it out with a simple graphic.

Old Dogma

Viral Suppression = Perfect ART Adherence

New Dogma

Viral Suppression = Good ART Adherence

It’s not that HIV medical providers and researchers haven’t discussed this topic for years. Promoting perfect adherence with medication is a difficult job, especially when treatment is lifelong. Nor are providers happy with the burdens this can place on their patients. Changing the need for perfect adherence is one of the forces behind the development of new HIV medications.

Dr. Castillo-Mancilla detailed findings of clinical research and discussed technologies that can be used for improving adherence. Watch the webcast, “Getting It Right: Practical Approaches to Adherence with Modern ARVs,” at

In his presentation abstract report, Dr. Castillo-Mancilla writes that, “Along with the remarkable advancements in antiretroviral therapy (ART), new paradigms have emerged on the importance of adherence. Early studies with older antiretrovirals (ARVs) proposed that [more than] 95% adherence was required to achieve and maintain virologic suppression, which led to the concept that an undetectable HIV viral load (VL) was equivalent to full adherence. However, the potency and favorable pharmacology of the new ARVs have allowed for more forgiveness to missed doses, with recent studies demonstrating that the minimal level of ART adherence required to sustain viral suppression may range between 80-85% (and as low as 75%). While advantageous, achieving viral suppression despite variable ART adherence has de-emphasized the focus on adherence in clinical practice, limiting our understanding of its consequences at the individual (i.e., biological, virological) and population (i.e., transmission) levels. This is essential to maximizing the benefit of ART and controlling the HIV epidemic, since maintaining an undetectable HIV VL (mainly driven by adherence) is indispensable for the U=U (Undetectable = Untransmittable) strategy to be effective, and because adherence remains a lifelong challenge. However, despite its critical importance, we currently lack a gold-standard measure to quantify ART adherence. In response to this gap, several innovative methods and strategies to objectively measure ART adherence have emerged in recent years. These include: a) pharmacologic methods that inform about cumulative adherence and recent dosing by quantifying drug concentrations in plasma, urine, hair and dried blood spots; b) advances in electronic medication dispensers that monitor pill-taking behavior, and; c) digital pills that confirm medication ingestion. These novel methods have proven more accurate than self-report, can predict adverse clinical outcomes (i.e., viremia), and provide real-time adherence information that can lead to actionable interventions during a routine clinical visit. Moreover, pharmacologic methods can assess inter-individual pharmacokinetic differences not captured by HIV VL monitoring or other adherence measures.”

With all the advances and all the potential, at the conclusion of his presentation slides, Dr. Castillo-Mancilla wrote, “Work in adherence is not done!”

Open discussions should help lead the way.