By Rebecca Bowers

EXECUTIVE SUMMARY

Researchers with the University of North Carolina at Chapel Hill and the Centers for Disease Control and Prevention are examining a new drug delivery system that uses dolutegravir, an established HIV drug, in a potential long-acting treatment and prevention system. The system has been tested in animal models.

  • The injectable formulation includes the anti-HIV drug, a polymer, and a solvent. Once injected under the skin, the three-component liquid solidifies into an implant. Drug release occurs as the polymer in the implant slowly degrades.
  • Other implant options in development include a drug delivery device to help prevent both HIV and pregnancy, as well as a match­stick-sized silicone device that houses the antiretroviral drug tenofovir alafenamide.

When it comes to HIV/AIDS, getting patients to adhere to antiretroviral therapy remains a challenge for clinicians. Studies indicate adherence varies between 27% and 80% across different populations, compared with the required level of 95%.1

Researchers with the University of North Carolina at Chapel Hill (UNC-CH) and the Centers for Disease Control and Prevention are examining a new drug delivery system that uses dolutegravir, an established HIV drug, in a potential long-acting treatment and prevention system.2 The system has been tested in animal models.

Once the formulation of an anti-HIV drug, a polymer, and a solvent is injected under the skin, the three-component liquid solidifies into an implant. Drug release occurs as the polymer in the implant slowly degrades.

“Our study found that the formulation delivered the drug effectively, and the implants were well tolerated with little or no sign of toxicity, for five months,” said Martina Kovarova, PhD, co-principal investigator of the study, assistant professor of infectious diseases at UNC-Chapel Hill, and a member of the UNC Center for AIDS Research, in a press statement. “It seems to us to be the ideal drug formulation for the prevention and treatment of HIV and AIDS.”

The implant can be removed in a quick, safe manner by making a small skin incision at the implant site, researchers note. This offers a safety advantage if a patient develops an adverse reaction or becomes pregnant while the implant is in place, noted study co-author Rahima Benhabbour, PhD, co-principal investigator in the study and an assistant professor in the UNC-NCSU Joint Department of Biomedical Engineering.

“Adherence to medications is essential for treatment success,” said J. Victor Garcia, PhD, co-investigator of the study and Oliver Smithies Investigator at UNC-Chapel Hill School of Medicine. “This is clearly important for HIV/AIDS treatment and prevention, but also for the treatment of many other chronic conditions like mental illnesses, hypertension and diabetes, where this technology might have applications.”

The UNC researchers recently received the award of a five-year, $3.8 million grant from the National Institute of Allergy and Infectious Diseases to build upon their current research. The National Institutes of Health funded the initial investigation.

“Our long-term goal for this collaborative is to develop a delivery system for long-acting therapy and PrEP [pre-exposure prophylaxis] that can offer durable and sustained viral suppression and protection from HIV transmission while providing flexibility in the choice of active ingredient, high efficacy of HIV inhibition, and increased user compliance,” said Angela Wahl, PhD, assistant professor of infectious diseases at the UNC School of Medicine.

Additional Implant Options in Development

What other implant options are in development? The U.S. Agency for International Development has awarded RTI International, a Research Triangle Park, NC-based nonprofit organization, a $4.8 million cooperative agreement to develop a drug delivery device to help prevent both HIV and pregnancy. The grant, issued in 2017, was made through the U.S. President’s Emergency Plan for AIDS Relief. In a three-year program, the RTI-lead team is scheduled to develop an implant that provides long-acting prevention of pregnancy and HIV. Known as the Subcutaneous Contraceptive and HIV Implant Engineered for Long-Acting Delivery (SCHIELD), the device will include dual protection while offering the advantages of being discreet, simple to administer, and biodegradable.

RTI scientists also are collaborating with academic partners to develop a similar long-acting implant for delivery of antiretroviral therapy. Made of poly­caprolactone material, the implant is biodegradable but otherwise remains retrievable during the drug delivery phase. The implant currently is in preclinical studies, and research indicates sustained drug release up to three months in the rabbit animal model.3

A match­stick-sized silicone device that houses tenofovir alafenamide is under development by the Oak Crest Institute of Science in Monrovia, CA. Research in beagle dogs indicates successful delivery of the study drug.4

Northwestern University scientists are investigating implantable PrEP systems. Through the Sustained Long-Acting Protection from HIV (SLAP HIV) program, researchers are working toward developing and testing a long-acting drug delivery system of either cabotegravir or tenofovir alafenamide fumarate.

Scientists will examine reservoir implants, degradable implants, and controlled-release injectables as vehicles for drug delivery.

Scientists at Houston Methodist Research Institute are investigating a refillable silicon-based nanochannel device to deliver HIV/AIDS drugs. Preclinical studies of the refillable implant indicate positive results.5

REFERENCES

  1. Iacob SA, Iacob DG, Jugulete G. Improving the adherence to antiretroviral therapy, a difficult but essential task for a successful HIV treatment-clinical points of view and practical considerations. Front Pharmacol 2017;8:831.
  2. Kovarova M, Benhabbour SR, Massud I, et al. Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nat Commun 2018;9:4156.
  3. Gatto G, Girouard N, Brand RM, et al. Pharmacokinetics of tenofovir alafenamide by subcutaneous implant for HIV PrEP. Paper presented at: Conference on Retroviruses and Opportunistic Infections. Boston; March 2018.
  4. Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother 2015;59:3913-3919.
  5. Chua CX, Jain, P, Hu M, et al Transcutaneous refillable nanofluidic implant for constant delivery of HIV PrEP. Paper presented at: Conference on Retroviruses and Opportunistic Infections 2017. Seattle; February 2017.