The FDA recently approved the use of an extended-release injectable formulation of the integrase inhibitor cabotegravir (CAB) for preexposure prophylaxis (PrEP) for adults and adolescents at risk for HIV infection. After two initial intramuscular (IM) injections given 1 month apart, it is administered every 2 months; it is the first non-oral PrEP therapy to become available.
Just before the FDA approval of IM CAB, the CDC published PrEP Guidelines, with recommendations for use of CAB plus important updates on oral PrEP (see Updated CDC PrEP Guidelines).
Approval of CAB for PrEP was based on two large randomized double-blind double-dummy studies in which injectable CAB was shown to have superior efficacy to daily oral TDF/FTC in MSM and transgender women, and in cisgender women:
- HPTN 083 studied >4500 MSM and transgender women (12.5% were transgender women) at risk for HIV in multiple countries including the United States. It found a 66% reduction in risk of HIV infection compared with TDF/FTC (69% according to a reanalysis that eliminated one subject who was found to be infected at baseline); the incidence rate was 0.37% vs 1.22%, respectively. CAB appeared to be more effective than TDF/FTC in all subgroups including transgender women, Black individuals, and those age <30 years.
- HPTN 084 studied >3200 cisgender women at risk for HIV in sub-Saharan Africa. It found an 88% reduction in HIV infections (90% after elimination of 1 infection found to be present at baseline) compared with TDF/FTC; the incidence rate was 0.15% vs 1.85%. Both studies were stopped early based on the superiority of CAB.
Important information about PrEP CAB, from the clinical trials, the new PrEP Guidelines, and the product Prescribing Information includes:
- Starting CAB PrEP: In the HPTN 083 and 084 trials, subjects were initially given oral cabotegravir for up to 5 weeks to check tolerability before starting injections. None had adverse reactions that precluded them from continuing to the injection phase of the study. Thus, the FDA states that an oral lead-in period is optional.
- Dosing (with or without oral lead-in): CAB 600 mg IM monthly x 2 doses (eg, day 0 and day 28), then 600 mg IM every 2 months. Injections should be in the gluteal muscles (the package insert says that ventrogluteal injection is “recommended;” dorsogluteal site is “acceptable”).
- Monitoring: Both HIV Ag/Ab and HIV RNA test should be done every 2 months, because CAB (as well as oral PrEP medications) can significantly slow seroconversion and thus delay detection of HIV by Ag/Ab tests.
- Infection on CAB; INSTI resistance: In clinical trials, some subjects who became infected with HIV while on CAB (or who had unrecognized HIV at the time CAB was started) were diagnosed late, because PrEP can delay seroconversion. Additionally, in HPTN 083, INSTI resistance mutations developed in a number of CAB recipients who were infected with HIV -- 1 in 4 of those with unrecognized HIV at baseline, 4 of 9 of those with incident HIV during the study); for HPTN 084, no resistance data are yet available. Thus, PrEP guidelines emphasize that it is crucial to rule out HIV infection before starting CAB (including use of an HIV RNA test for persons with possible recent exposures) and to check for new HIV infection every 2 months (before subsequent injections) using both Ag/Ab and HIV RNA tests.
- Stopping CAB: CAB has a long pharmacokinetic “tail;” thus it is important to switch to oral PrEP medications for persons who stop CAB but have ongoing risks for HIV infection, both to prevent HIV infection and to avoid the development of INSTI resistance mutations (if HIV infection were to occur during the period of declining CAB levels).
- Late or missed doses: The Prescribing Information for the injectable CAB PrEP product (see References, below) has specific instructions for management of anticipated or unanticipated late or missed CAB injections, including use of oral CAB to cover anticipated delays and dosing/timing of injections upon resumption of IM CAB for either anticipated or unanticipated late doses.
- Adverse effects: in the clinical trials, adverse effects predominantly consisted of injection site reactions (ISR) (81% in HPTN 083, 38% in HPTN 084) these were mostly mild/moderate and decreased in frequency with time. 2.4% of participants in HPTN 083 discontinued CAB because of ISR, and none in HPTN 084. Rare adverse effects included depression, hypersensitivity reactions, and liver toxicity.
- Drug-drug interactions: UGT1A1 inducers decrease CAB plasma concentrations; certain medications including rifampin, rifapentine, and some anticonvulsants should not be given with CAB, and concurrent use of with certain drugs (eg, rifabutin) requires adjustment of CAB frequency.
- Restrictions: CAB is approved for persons age 18 or older and weighing at least 35 kg. There are no restrictions for use in people with kidney disease, osteoporosis, or hepatitis B. IM CAB has not been studied in pregnancy, and the FDA recommends a risk-benefit discussion before use in persons who are pregnant or may become pregnant while using IM CAB. IM CAB has not been approved for persons under age 18: studies in adolescents are underway.
- Clinic infrastructure: Clinics that provide CAB PrEP will need to have facilities and protocols for storage and administration of injectable CAB, mechanisms for tracking patients and supporting adherence to every-2-month injections, and for plans for identifying and managing those who are late to injections.
Clinical bottom line:
IM CAB has the potential to contribute very substantially to HIV prevention – in the studies mentioned above, it was highly effective in both men and women (cis and trans) and was well tolerated. It is likely to be appealing to a wide swath of people who do not want to take or who cannot take oral PrEP medications, either because of adherence challenges, concerns about inadvertent disclosure of HIV risk practices, or other reasons. And it may make HIV prevention easier and more effective for vulnerable populations that are at high risk for HIV infection.
In implementing CAB PrEP, clinics will need to develop workflows and systems that ensure that persons with HIV risks have low-barrier access to CAB, that adherence support is available and that persons who are late for injections are identified quickly and encouraged to present for injections (or are offered alternative PrEP options). Meanwhile, other long-acting PrEP approaches are under investigation, including implants, injections, vaginal ring, and long-acting oral formulations, and may soon offer multiple PrEP options.
Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention
in Cisgender Men and Transgender Women. NEJM. August 12, 2021.385;7, 595-608.
Delany-Moretlwe S, Hughes J, Bock P, et al. Long-acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: interim results from HPTN 084. R4P Conference, January 2021. Abstract 1479.
U.S. Centers for Disease Control and Prevention: U.S. Public Health Service: Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2021 Update: A Clinical Practice Guideline. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf. Published December 2021.
U.S. Centers for Disease Control and Prevention: U.S. Public Health Service: Preexposure Prophylaxis for the Prevention of HIV Infection in the United States—2021 Update: Clinical Providers’ Supplement. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-provider-supplement-2021.pdf. Published December 2021.
ViiV Healthcare, Apretude Prescribing Information, December 2021. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/