Issue: February 2021
Disclosures: Ross reports no relevant financial disclosures.
February 23, 2021
5 min read

Long-acting injectable PrEP: An exciting alternative

Issue: February 2021
Disclosures: Ross reports no relevant financial disclosures.
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The target to end the 40-year HIV/AIDS epidemic in the United States is 2030. However, the persistent threat of HIV/AIDS amid ongoing stigma has cast doubt that 2030 is a realistic goal.

As of the end of 2019, 32.7 million people had died from AIDS-related illnesses globally, with around 700,000 deaths occurring annually. In the U.S., an estimated 1.2 million Americans have HIV, including 37,968 new diagnoses in 2018. Reduced spread among individuals and across communities is attributable to advancements in pharmacological therapies when integrated with nonpharmacological prevention practices. PrEP and postexposure prophylaxis have proven to be effective strategies, but gaps in prevention still exist. Long-acting injectable formulations, namely cabotegravir, have shown superiority when compared with traditional PrEP regimens. An HIV/AIDS vaccine is the ultimate silver bullet. Cabotegravir is a formidable alternative strategy in the interim.

Jennifer Ross
Jennifer Ross

Current state

The FDA has approved two, once-daily antiretroviral combinations for HIV-1 PrEP. Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is widely regarded as first-line therapy, followed by tenofovir alafenamide/emtricitabine (TAF/FTC). The preventive efficacy of daily TDF/FTC is proportional to adherence and lowers the risk for HIV infection by upward of 99%. TDF/FTC PrEP has demonstrated efficacy in men who have sex with men (MSM), transgender women, people who inject drugs and heterosexuals with HIV-positive partners, prompting the United States Preventive Task Force to issue a grade A recommendation for this regimen in 2019. TAF/FTC has been investigated less for PrEP. A single study showed TAF/FTC was noninferior to TDF/FTC in gay and bisexual men and a small number of transgender women.

TAF/FTC has largely replaced TDF/FTC in HIV-1 treatment. TAF/FTC PrEP uptake has been slower, possibly reflective of how cost remains a major barrier to PrEP in the U.S. Despite TAF achieving higher drug levels more rapidly in peripheral blood cells than TDF, TAF yields lower concentrations in the genital and rectal mucosa. The infection transmission implications of this are unknown. From an adverse effect profile, TDF/FTC was associated with decreases in renal glomerular function biomarkers and bone mineral density, whereas TAF/FTC was linked to weight and hyperlipidemia. In the direct TDF/FTC vs. TAF/FTC PrEP trial, no patients stopped therapy because of adverse effects. Both options have similar challenges in those with very low HIV exposure frequency. The large pill burden and disproportionate expense may outweigh the established high efficacy when adherent.

Looking ahead

Cabotegravir is a novel integrase strand transfer inhibitor under investigation for HIV-1 treatment (in combination with long-acting rilpivirine) and as a single agent for PrEP. The FDA designated cabotegravir as a breakthrough therapy for PrEP last November. Cabotegravir has been studied as both an oral formulation (30 mg tablet) and a long-acting, injectable nanosuspension (600 mg). The half-lives of the oral and injectable preparation are 40 hours and 21 to 50 days, respectively, posing potential therapeutic implications. Patients will likely be required to start on oral cabotegravir for some time before transitioning to the long-acting injectable to ensure tolerance. Another therapy implication is that the long-acting injection remains present in the plasma at detectable but subtherapeutic levels months after an intramuscular injection. This may increase the risk of inducing cabotegravir resistance. Although a structural analogue of dolutegravir, cabotegravir does not have as high a barrier to resistance. Preliminary data from two trials show promise for an alternative PrEP option to the daily regimens.

The HIV Prevention Trials Network (HPTN), a worldwide research collaborative, has two ongoing cabotegravir PrEP trials. Preliminary data from HPTN 083, a phase 2b/3 study, were presented at the 2020 International AIDS Society virtual conference. The interim analysis showed an 8-week, injectable cabotegravir regimen yielded threefold fewer HIV infections than those who were administered a standard daily oral PrEP regimen consisting of TDF/FTC. In this randomized, double-blind trial, 4,566 MSM (approximately 88%) and transgender women (12%) were assigned either 5 weeks of oral cabotegravir (30 mg tablet daily), followed by intramuscular cabotegravir (600 mg once every 4 weeks for two doses, then every 8 weeks received in a clinic) or the standard TDF/FTC regimen at 43 different sites in seven countries. Patients were required to take the placebo formulation of the regimen they were not assigned. The median age was 25 years, with nearly half of the patients in the U.S. being African American. Thirteen patients in the cabotegravir cohort acquired HIV by the end of the study compared with 39 patients in the TDF/FTC arm. Three of the HIV infections in the cabotegravir cohort occurred during the oral therapy phase, five after a prolonged break from intramuscular cabotegravir and five while optimally adherent to intramuscular cabotegravir. Notably, about 75% of patients in the TDF/FTC arm had drug levels that correlated to high-level protection. This trial was stopped early because cabotegravir showed superiority in the interim results.

More recently, researchers announced initial data from HPTN 084, a phase 3, double-blind, randomized trial evaluating the efficacy of long-acting intramuscular cabotegravir vs. daily TDF/FTC for HIV PrEP in cisgender women in sub-Saharan Africa. The same oral-to-intramuscular cabotegravir regimen was followed. The trial enrolled 3,223 participants with an average age of 26 years. In all, 82% of the women were not living with a partner, 55% reported two or more partners in the past month and 34% to having a primary partner either living with HIV or having an unknown HIV status. A total of 38 HIV infections occurred during the follow-up phase, with four infections in the cabotegravir cohort and 34 infections in the TDF/FTC group. The most commonly associated adverse reactions in the cabotegravir group were headache, as well as discomfort, tenderness, swelling and possibly small lumps at the injection site. Similar to HPTN 083, this trial was stopped early because of superior results. [Editor’s note: For reaction to the results of HPTN 084, click here.]

The early results examining long-acting cabotegravir are exciting. It has strong potential to be another pharmacological PrEP therapy as a more efficacious long-term option compared with an already superb oral regimen. Both are still dependent on adherence. Only a vaccine will eliminate patients having to take a daily tablet, going to a clinic or pharmacy on a monthly or 2-month basis or even using a pill-in-the-pocket approach. There are many complexities with vaccine trial design in the era of PrEP, but progress is being made to end the HIV epidemic. The question remains if this progress is enough to reach the bold 2030 goal. As Benjamin Franklin once said, “An ounce of prevention is worth a pound of cure.”