HIV-1 infection remains a major public health problem, with an estimated 38.4 million people living with HIV and 1.5 million new HIV infections reported worldwide in 2021. The risk of HIV infection varies both geographically and demographically and is highest among certain populations, with 70% of global infections occurring among key populations such as men who have sex with men (MSM), sex workers and their clients, people who inject drugs (PWID), and transgender people (Figure 1).1

The Joint United Nations Programme on HIV/AIDS (UNAIDS) aims to eliminate the public health threat posed by HIV/AIDS by 2030 by focusing on reducing inequalities in HIV testing, treatment, and prevention efforts. A critical HIV prevention strategy is pre-exposure prophylaxis (PrEP) with antiretroviral treatments for individuals at high risk of acquiring HIV.2

Oral PrEP

The first PrEP regimen, daily oral coformulated tenofovir disoproxil fumarate plus emtricitabine (TDF-FTC), was approved by the US Food and Drug Administration (FDA) in 2012 and was recommended by the World Health Organization in 2015 for individuals at high risk for HIV infection.3,4 Numerous studies have demonstrated that oral PrEP is highly effective at preventing new HIV infections, but there have been issues with uptake, adherence, and persistence with daily oral TDF-FTC.5

There have been 2 multinational, randomized, placebo-controlled trials that showed oral daily TDF-FTC can provide 75% to 92% risk reduction against HIV infection when taken as directed. These studies indicated that TDF-FTC is safe, with no serious toxicities and high tolerability.6,7 Another oral PrEP agent, tenofovir alafenamide fumarate combined with emtricitabine (F/TAF), was similar in effectiveness to TDF-FTC as daily PrEP among MSM and was approved by the FDA for that population in October 2019.8

Clinical trials showed that reductions in HIV infection risk with oral daily PrEP are strongly correlated with adherence and persistence with treatment.9 However, serious issues with PrEP adherence have been observed; a meta-analysis found that 37.7% of users had suboptimal adherence in the first 6 months of oral PrEP treatment and that 41% discontinued PrEP within 6 months.10 Another study estimated that only 41% of users continued to use oral PrEP after 2 years.11 Low persistence with oral PrEP poses a serious issue, as many individuals who stop PrEP are still at high risk for HIV infection.12 Causes of low adherence and persistence with oral PrEP are varied and include cost, being of younger age, and not perceiving high levels of HIV risk.5

UNAIDS aims to make PrEP available to 10 million people who are at high risk for HIV infection by 2025.13 However, at the end of 2022, only about 3.8 million individuals had initiated some form of PrEP.14 The introduction of new PrEP regimens that address some of the challenges posed by daily oral PrEP may help to increase the uptake and effectiveness of PrEP, and long-acting PrEP is a promising alternative to address these issues.

Long-Acting PrEP Options

Several long-acting PrEP options are in development or have been approved for use in recent years, including injectables, vaginal rings, implants, and broadly neutralizing antibodies. Long-acting options do not require daily dosing to be effective and provide protection for up to several months; additionally, long-acting PrEP options could help address concerns regarding privacy and potential stigmatization due to difficulties with discreetly storing daily oral PrEP.15 Thus, long-acting PrEP regimens could prove more simple to use than daily PrEP, helping to address adherence issues and increasing persistence among key populations at high risk for HIV infection. Long-acting PrEP options approved for use in the US or currently under investigation in clinical trials ( identifier: NCT04994509 and identifier: NCT04925752) are listed in Table 1.5,16,17

The First Approved Long-Acting Injectable PrEP Option: CAB-LA

Cabotegravir (CAB) is an integrase strand transfer inhibitor (INSTI) that has been shown to have strong antiviral activity. CAB can be formulated as a long-acting suspension, which allowed for the development of injectable CAB-LA.5,18

There have been 2 key clinical studies that examined the safety and efficacy of CAB-LA for the prevention of HIV infection: HIV Prevention Trial Network (HPTN) 083 ( identifier: NCT02720094) and HPTN 084 ( identifier: NCT03164564). HPTN 083 and HPTN 084 were both randomized, double-blind double-dummy, active-controlled trials comparing the efficacy of CAB-LA and daily oral TDF-FTC in individuals with high risk for HIV infection. HPTN 083 enrolled cisgender MSM and transgender women who have sex with men (N=4566), and HPTN 084 included individuals assigned female at birth from 7 countries in sub-Saharan Africa with high HIV prevalence (N=3224). In both studies, participants in the CAB-LA group received intramuscular gluteal injections of 600 mg CAB-LA every 8 weeks, after 2 initial injections given 4 weeks apart.19,20

In HPTN 083, CAB-LA was significantly more effective for preventing HIV infection than daily oral TDF-FTC in MSM and transgender women with a high risk of acquiring HIV during 153 weeks of follow-up. A total of 52 trial participants acquired HIV infections after enrollment, with 13 new infections in the CAB-LA group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years). The hazard ratio for HIV infections acquired after enrollment in the CAB-LA group compared with the TDF-FTC group was 0.34 (95% CI, 0.18-0.62; P <.001).19 In the first year after unblinding, similar efficacy was observed in both groups, with 11 new infections in the CAB-LA group (incidence, 0.76 per 100 person-years) and 31 in the TDF-FTC group (incidence, 2.20 per 100 person-years).5

Similarly, in HPTN 084, significantly fewer new HIV infections were observed after enrollment among women in the CAB-LA group (4 infections; incidence, 0.2 per 100 person-years) than the TDF-FTC group (36 infections; incidence, 1.85 per 100 person-years). The hazard ratio for acquiring HIV infection in the CAB-LA group compared with the TDF-FTC group was 0.12 (95% CI, 0.05-0.31; P <.0001).20

CAB-LA was generally safe and well tolerated in both HPTN 083 and HPTN 084, with no increased risk of serious grade ≥2 adverse events (AEs) compared with TDF-FTC. The most common AE in both studies was injection site reactions, which were reported in 81.4% of participants in the CAB-LA group in HPTN 083 and 38% of participants in the CAB-LA group in HPTN 084. In HPTN 083, injection site reactions led to discontinuation of CAB-LA in 2.4% of participants, whereas no participants discontinued CAB-LA due to injection site reactions in HPTN 084. CAB-LA was associated with small weight gains in both studies. Among women who became pregnant during the trial, no congenital abnormalities or pregnancy-related AEs related to the study drug were observed.19,20

Based on the data from HPTN 083 and HPTN 084, CAB-LA received FDA approval for HIV PrEP in at-risk adults and adolescents in December 2021.21 Eligible individuals must weigh at least 35 kg and must test negative for HIV-1 infection before administration of the initial dose of CAB-LA. CAB-LA is approved for gluteal intramuscular injection, with a recommended dosing schedule of 600 mg (3-mL) given 1 month apart for 2 consecutive months followed by injections every 2 months. Before starting CAB-LA injections, an oral lead-in dose of CAB may be administered for 1 month to determine whether a patient can tolerate CAB.22 In 2022, the World Health Organization also provided a conditional recommendation based on moderate certainty of evidence that CAB-LA be offered as a PrEP option for individuals with high risk for HIV infection.23 More recently, the US Department of Health and Human Services commissioned an extensive review of the evidence on the benefits and risks of available PrEP options, including CAB-LA, which noted that CAB-LA treatment reduced the risk for HIV more than oral TDF-FTC in MSM, transgender women, and women at substantial risk for HIV infection.24

What is the most common AE experienced when using CAB-LA?
Injection site reactions, while usually minor, are the most common AE experienced by patients being treated with CAB-LA.

Interest in Long-Acting Injectable PrEP Among Key Populations

Numerous studies have examined interest in long-acting PrEP options among key populations at high risk for HIV infection and found that there is considerable interest in injectable long-acting PrEP.25 In 3 studies in MSM on their preferences for PrEP regimens, long-acting injectables were ranked the highest among different PrEP delivery methods and were the preferred PrEP option; in 1 of these studies, 74% of MSM surveyed said that they were likely to use long-acting injectable PrEP.26-28

In the US, HIV incidence is particularly high among Black and Hispanic individuals, but despite this, oral PrEP use remains lower among Black and Hispanic MSM than among their White counterparts.29 However, this may speak to a lack of awareness, not of interest: in a survey of MSM in Washington, DC, 59% (95% CI, 48%-69%) of non-Hispanic Black men and 69% (95% CI, 48%-86%) of Hispanic men reported interest in long-acting injectable PrEP over daily oral PrEP, while only 48% (95% CI, 34%-63%) of non-Hispanic white men reported a similar interest.30

PWID have an increased risk for HIV infection but have particularly low rates of uptake and adherence to daily oral PrEP.31 Low uptake and adherence among this population reflects the barriers to PrEP that they face, including challenges with adhering to a daily pill-based regimen, low perceived HIV risk, and complex and competing health needs due to drug use and dependence.32 Clinicians have also reported concerns about prescribing daily oral PrEP to PWID, at least in part due to concerns over low adherence.15 Both qualitative and quantitative studies surveying PWID have reported a high degree of willingness among study participants to use long-acting injectable PrEP. However, studies have shown that the awareness of PrEP options remains very low among PWID, suggesting that further PrEP education efforts are needed.15,33

CAB-LA Tail and Potential for INSTI Resistance

The long half-life of CAB-LA is a major strength, allowing for it to be administered at much longer intervals than oral PrEP. However, it also results in an extended period after discontinuing CAB-LA during which the drug concentrations are too low to provide protection but are high enough to pose a risk for developing drug resistance to INSTIs. As INSTIs are a first-line HIV treatment worldwide, if INSTI mutations were to spread due to the implementation of CAB-LA, it would greatly limit effective HIV treatment options.34

To address the risk posed by the CAB-LA tail phase, patients who miss a CAB-LA injection or discontinue treatment are recommended to receive oral PrEP while they remain at risk for HIV infection.22 This strategy was implemented in HPTN 083 and HPTN 084, and while no mutations related to INSTI resistance were detected in participants in HPTN 084, mutations were detected in 5 participants receiving cabotegravir in HPTN 083.20

Another potential source of INSTI resistance is CAB-LA administration to individuals with HIV infections. A recent study found that HIV RNA screening could allow for earlier detection of breakthrough HIV infections in individuals who receive CAB-LA, reducing the risk for INSTI resistance.35

Implementation of CAB-LA in Clinical Practice

Several challenges to the implementation of CAB-LA must be addressed in order for it to be widely adopted as a PrEP option, including making CAB-LA more cost-effective and developing protocols to ease the administration process. Future research studies on implementation and efforts to manufacture and supply generic versions of CAB-LA could help usher CAB-LA into wider clinical use.5


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2. The Joint United Nations Programme on HIV/AIDS (UNAIDS). Global AIDS strategy 2021-2026. Accessed January 30, 2023.

3. Fenton, K. CDC statement on FDA approval of drug for HIV prevention. CDC National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention. Published July 16, 2012. Accessed February 22, 2023.

4. World Health Organization. WHO expands recommendation on oral pre-exposure prophylaxis of HIV infection (PrEP). Published November 2015. Accessed February 1, 2023.

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8. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. News release. US Food and Drug Administration. October 3, 2019. Accessed February 14, 2023.  

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19. Landovitz RJ, Donnell D, Clement ME, et al; HPTN 083 Study Team. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016

20. Delany-Moretlwe S, Hughes JP, Bock P, et al; HPTN 084 Study Group. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022;399(10337):1779-1789. doi:10.1016/S0140-6736(22)00538-4

21. FDA approves first injectable treatment for HIV pre-exposure prevention. News release. US Food and Drug Administration. December 20, 2021. Accessed January 31, 2023.

22. ApretudeTM. Prescribing information. ViiV Healthcare. Accessed January 30, 2023.

23. World Health Organization. Guidelines on long-acting injectable cabotegravir for HIV prevention. Published July 28, 2022. Accessed January 24, 2023.

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25. Sued O, Nardi N, Spadaccini L. Key population perceptions and opinions about long-acting antiretrovirals for prevention and treatment: a scoping review. Curr Opin HIV AIDS. 2022;17(3):145-161. doi:10.1097/COH.0000000000000734

26. Mansergh G, Kota KK, Stephenson R, Hirshfield S, Sullivan P. Preference for using a variety of future HIV pre-exposure prophylaxis products among men who have sex with men in three US cities. J Int AIDS Soc. 2021;24(1):e25664. doi:10.1002/jia2.25664

27. Chan C, Vaccher S, Fraser D, et al. Preferences for current and future PrEP modalities among PrEP‑experienced gay and bisexual men in Australia. AIDS Behav. 2022;26(1):88-95. doi:10.1007/s10461-021-03344-3

28. Dean LT, Predmore Z, Skinner A, Napoleon S, Chan PA, Raifman J. Optimizing uptake of long‑acting injectable pre‑exposure prophylaxis for HIV prevention for men who have sex with men. AIDS Behav. 2023;1-11. doi:10.1007/s10461-023-03986-5

29. Kanny D, Jeffries WL, Chapin-Bardales J, et al. Racial/ethnic disparities in HIV preexposure prophylaxis among men who have sex with men — 23 urban areas, 2017. MMWR Morb Mortal Wkly Rep. 2019;68(37):801-806. doi:10.15585/mmwr.mm6837a2

30. Levy ME, Agopian A, Magnus M, et al. Is long-acting injectable cabotegravir likely to expand prep coverage among MSM in the District of Columbia? J Acquir Immune Defic Syndr. 2021;86(3):e80-e82. doi:10.1097/QAI.0000000000002557

31. Brokus C, Kattakuzhy S, Gayle B, et al. Suboptimal uptake, retention, and adherence of daily oral prexposure prophylaxis among people with opioid use disorder receiving hepatitis C virus treatment. Open Forum Infect Dis. 2021;9(3):ofab658. doi:10.1093/ofid/ofab658

32. Biello KB, Bazzi AR, Mimiaga MJ, et al. Perspectives on HIV pre-exposure prophylaxis (PrEP) utilization and related intervention needs among people who inject drugs. Harm Reduct J. 2018;15(1):55. doi:10.1186/s12954-018-0263-5

33. Allen ST, O’Rourke A, White RH, et al. Barriers and facilitators to PrEP use among people who inject drugs in rural Appalachia: a qualitative study. AIDS Behav. 2020;24(6):1942-1950. doi:10.1007/s10461-019-02767-3

34. Meyers K, Nguyen N, Zucker JE, et al. The long-acting cabotegravir tail as an implementation challenge: planning for safe discontinuation. AIDS Behav. 2023;27(1):4-9. doi:10.1007/s10461-022-03816-0

35. Eshleman SH, Fogel JM, Halvas EK, et al. HIV RNA screening reduces integrase strand transfer inhibitor resistance risk in persons receiving long-acting cabotegravir for HIV prevention. J Infect Dis. 2022;226(12):2170-2180. doi:10.1093/infdis/jiac415

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Reviewed March 2023