Once-Monthly HIV Drugs on the Horizon?

Scientists Edging Closer to Long-Lasting Solutions for HIV Therapy, PrEP

The insertion of a novel, subdermal implant could provide sustained delivery of antiretroviral therapy.. Photo courtesy Oak Crest Institute of Science

One of the main barriers to HIV drug success is the high level of adherence needed to attain the clinical goals of therapy. For some, the daily task of taking antiretroviral drugs can be overwhelming, particularly when accompanied by emotional or functional issues that can adversely impact the lives—and adherence—of people with living HIV. 

So profound are these issues that, in the U.S. today, more than 20% of people on antiretroviral therapy are able to maintain an undetectable viral load, the measure for treatment success.

In response, scientists have now begun to explore long-acting drugs, as well as drug delivery systems, that may eventually allow for once-monthly—or even once-quarterly—dosing, either to treat HIV infection or to prevent it.

Long-Lasting Investigational Drugs

In 2013, two long-acting antiretroviral agents were introduced at the 7th annual International AIDS Society (IAS) Conference in Kuala Lumpur. The investigational drugs were both developed as injectable nanosuspensions, wherein tiny crystals of active drug are suspended in liquid, allowing for the slow and steady release of the medication into the system.

The first, cabotegravir (also known as GSK1265744) belongs to a class of drugs called integrase inhibitors, which blocks an enzyme called integrase that HIV needs to multiply. The second, TMC278-LA, is a long-acting formulation of the drug Edurant (ripilvirine) currently used in HIV therapy.


A number of Phase II clinical trials have shown the cabotegravir delivered intramuscularly is generally well tolerated with a mean half-life of between 21 to 50 days (compared to 40 hours following a single, oral dose). Similar studies demonstrated that the drug also ensured sustained drug concentration in rectal and vaginal tissues, suggesting that it could be administered as an effective, long-acting means of pre-exposure prophylaxis (PrEP).

By comparison, a Phase I study showed that TMC278-LA was able to maintain target plasma drug concentrations from 12-26 weeks. The drug also demonstrated promise as PrEP, with stronger concentrations seen in rectal tissues when compared to vaginal tissues.

On-going investigations are planned with the goal of expanding research to Phase II and III clinical trials.

Subdermal Antiretroviral Implants

Scientists at the Oak Crest Institute of Science in Pasadena, California reported developing a matchstick-sized implant that could deliver steady concentrations of antiretroviral medications when implanted beneath the skin.

Similar in design to long-acting contraceptive implants, the device was shown in early research to be able to deliver controlled, sustained release of the drug tenofovir alafenamide (TAF) for up to 40 days.

[Unlike tenofovir disoproxil fumarate (TDF), popularly marketed at Viread and contained in the drugs Truvada and Atripla, TAF is considered a precursor molecule able to reach ideal drug concentration at far smaller doses than TDF.]

While research is currently focusing on the device for PrEP, it is suggested that other long-acting agents could eventually be used to provide combination antiretroviral therapy (cART) to people living with HIV.

Future research hopes to open the door to the development of implants that can last for up to a year or more.

Intravaginal Microbicidal Rings

Scientists have long endeavored to provide at-risk women the means for self-protection from HIV, particularly in regions where female sexual empowerment is high. Many of the strategies, either in the way of oral PrEP or vaginal microbicides, have largely failed in research due to the lack of adherence as well as low levels of drug bioavailability in vagina tissues, even in women with high levels of adherence.

To address these conundrums, a number of research teams are exploring the use of intravaginal rings which could ideally release antiretroviral drugs for up to a month at a time. The ring, an impermeable elastomer scaffold impregnated with active drug, would allow the woman to wear the device invisibly for the duration of use.

Early results have demonstrated tolerability of an intravaginal ring containing the experimental drug dapivirine (TMC120) with successful distribution of the drug to the lower genital tract for a period of 33 days.

Two concurrent Phase III trials, the Ring Study and ASPIRE, are underway to evaluate the ring's safety as well as its long-acting protective efficacy among a cohort of 4,500 HIV-negative women.


U.S. Centers for Disease Control and Prevention (CDC). "CDC Fact Sheet | HIV in the United States: The Stages of Care." Atlanta, Georgia; published July 2012.

Spreen, W; Margolis, D.; and Pottage, J.;"Long-acting injectable antiretrovirals for HIV treatment and prevention." Current Opinions on HIV and AIDS. November 2013; 8(6):565-571.

Margolis, D.; Brinson, C; Eron, J.; et al. "744 and rilpivirine as two-drug oral maintenance therapy: LAI116482 (LATTE) week 48 results." 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014); Boston, Massachusetts; March 3-6, 2014; abstract 91LB.

Gunawardana, M.; Remedios-Chan, M.; Miller, C.; et al. "Pharmokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis." Antimicrobial Agents and Chemotherarpy. April 20, 2015; doi: 10.1128/AAC.00656-15.

Nel, A; Smythe, S.; Young, K.; et al. "Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women." Journal of Acquire Immune Deficiency Syndrome. 2009; 51(4):416–423.

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