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Director, STD/HIV Clinical Research Laboratory
Instituto Nacional de Infectologia Evandro Chagas
Oswaldo Cruz Foundation
Rio de Janeiro, Brazil
Beatriz Grinsztejn, MD, PhD, has disclosed that she has received consulting fees from Janssen and Merck and funds for research support from Gilead Sciences and GSK/ViiV.
Clinical trial data show that daily oral tenofovir disoproxil fumarate (TDF)–based pre-exposure prophylaxis (PrEP) safely protects against HIV infection across diverse exposures, sexes, and gender identities. However, maintaining adherence is one of the greatest challenges to effective PrEP implementation—a challenge that may be overcome through use of long-acting (LA) PrEP. Here, I share my thoughts on important new data on 2 promising LA PrEP agents, islatravir and cabotegravir, presented at the 4th HIV Research for Prevention Conference (HIVR4P // Virtual).
Phase IIa Trial of Islatravir vs Placebo in Adults at Low Risk for HIV Infection
Islatravir (MK-8951), a first-in-class nucleoside reverse transcriptase translocation inhibitor with multiple mechanisms of action, is under development for both HIV treatment and prevention. Preclinical and clinical data indicate that islatravir has high potency, a long intracellular half-life, and high tissue penetration, along with affording complete protection against intrarectal SIV challenge. Islatravir is being evaluated as a monthly oral tablet and as a yearly LA subdermal implant for PrEP.
At HIVR4P // Virtual, Hillier and colleagues presented exciting interim results of a randomized, double-blinded, multicenter phase IIa trial comparing monthly oral islatravir at 60 mg vs 120 mg vs placebo as PrEP in adults aged 18-65 years at low risk for HIV infection. Most participants were women (67.2%), relatively young (median age: 32 years), and White (64.1%). The interim analysis focused on safety and pharmacokinetics.
Islatravir was well tolerated at both doses, with most adverse events (AEs) being mild or moderate and none leading to discontinuation. The most common AEs were headache (7.3%), diarrhea (5.7%), and nausea (4.7%). No serious AEs or deaths occurred. Regarding pharmacokinetics, islatravir-triphosphate trough concentrations following both doses were sustained above a prespecified threshold of 0.05 pmol/106 cells. A preliminary analysis observed rapid, adequate, and sustained distribution of islatravir in rectal, cervical, and/or vaginal tissues.
Thanks to these supportive results, 2 phase III trials are planned. IMPOWER-022 will compare monthly islatravir 60 mg vs daily emtricitabine (FTC)/TDF in cisgender women at high risk of HIV infection in several countries in Africa, and IMPOWER-024 will compare monthly islatravir 60 mg vs daily FTC/TDF or FTC/tenofovir alafenamide in men and transgender women who have sex with men at high risk of HIV infection.
HPTN 084: LA Injectable Cabotegravir vs FTC/TDF in Cisgender Women at Risk for HIV Infection
Women face numerous barriers to regular daily oral PrEP use, particularly in sub-Saharan Africa. Thus, LA injectable PrEP may be more effective in this population.
At HIVR4P // Virtual, Delany-Moretlwe and colleagues reported results from the landmark double-blind, placebo-controlled phase III HPTN 084 trial, which compared LA injectable cabotegravir vs daily oral FTC/TDF in preventing HIV sexual acquisition in cisgender women at increased risk of HIV infection. Earlier, the sibling HPTN 083 trial showed that a PrEP regimen containing LA cabotegravir injected once every 8 weeks was superior to daily oral FTC/TDF for HIV prevention among cisgender men and transgender women who have sex with men.
In HPTN 084, cabotegravir was administered daily by mouth for 5 weeks and then via intramuscular injection at 8-week intervals for up to 185 weeks, with the option for both arms to then use open-label daily oral FTC/TDF for 48 weeks. Those who became pregnant were offered open-label FTC/TDF during pregnancy and breastfeeding. Most participants were young, with 57% being 25 years of age or younger; 82% did not live with a partner; 54% reported ≥ 2 partners in the past month; and 34% had a primary partner either living with HIV or with unknown HIV status. Sexually transmitted infection prevalence was high, with 17% positive for Chlamydia trachomatis and 7% having gonorrhea. Slightly more than one half had a body mass index ≥ 25.
In total, 40 infections occurred during 3892 person-years of follow-up, yielding a pooled HIV incidence of 1.03 (95% CI: 0.73-1.4) per 100 person-years, indicating that both cabotegravir and FTC/TDF are highly effective as PrEP in this population. There were 4 incident infections in the cabotegravir arm (0.20%) vs 36 incident infections in the FTC/TDF arm (1.86%). Thus, cabotegravir reduced the risk of HIV infection by 89% vs FTC/TDF.
In a planned adherence subset analysis, plasma tenofovir (TFV) concentrations and TFV-diphosphate were measured in 375 participants receiving FTC/TDF. Overall, 62% had detectable TFV levels (46% > 40 ng/mL), consistent with daily use. Detectable TFV concentrations were initially high (77%) but declined to 53% after 1 year, reflecting the challenges of taking a daily pill over the long term.
By comparison, injection coverage remained high at approximately 90% throughout follow-up. Of the 4 incident infections in the cabotegravir arm, 2 occurred in the absence of recent cabotegravir exposure whereas the other 2 infections occurred despite receiving cabotegravir injections. Testing is ongoing to evaluate the timing of infection, drug concentrations at seroconversion, and viral resistance profile.
Both cabotegravir and FTC/TDF were safe and well tolerated. Most AEs were mild or moderate and balanced between arms, although nausea was slightly more common with FTC/TDF. Injection-site reactions were reported by 9% of participants in the FTC/TDF arm (who received an injectable placebo) vs 32% of participants in the cabotegravir arm. Injection-site reactions typically consisted of mild to moderate pain and/or tenderness at the first injection. No participants discontinued due to injection-related AEs. Sexually transmitted infection incidence was high in both arms, and there was no difference in overall weight gain. In total, there were 50 pregnancies (1.3%), with no difference between arms.
In summary, both agents were highly effective in preventing HIV, and LA injectable cabotegravir was superior to daily oral FTC/TDF in preventing HIV infection among cisgender women. Testing is underway to fully understand reasons for breakthrough infections. These results complement data from HPTN 083 and confirm cabotegravir as a safe and effective injectable PrEP for cisgender women.
Real-World Considerations for LA PrEP
Historically, the introduction of evidence-based technologies into public health programs has been fraught with delays and missed opportunities, at least partly due to a lack of preparatory evidence critical for introduction into programs at scale. Product registration timelines in low- to middle-income countries are usually long and sometimes never occur.
Planning for implementation of LA PrEP should build on knowledge gained from recent implementation and scale-up of relevant biomedical interventions (eg, ART, voluntary medical male circumcision, family planning, oral PrEP programs), as well as from data generated within ongoing trials of these technologies. Study agents are administered in a clinic-based setting, but the best site for real-world delivery will need to be determined. A major priority is promoting effective, equitable access, and engagement with emerging LA PrEP.
Although LA PrEP can be quite beneficial, especially for highly vulnerable populations, we still need studies to address key questions and implementation issues. System capacity assessments should be performed because as LA PrEP is implemented, particularly with an intramuscular injectable option, the number of clinical visits and appointment duration will likely increase. We should also explore alternative locations of service delivery, such as community-based services, pharmacies, mobile health vans, and in-home services. A discreet product can have a large impact in places and populations where HIV stigma is rampant.
How do you anticipate incorporating LA PrEP options into your HIV prevention practice when they become available? Answer the polling question and join the discussion by posting a comment.