Impact of the First Long-Acting Injectable Antiretroviral Therapy in HIV Treatment

Ken Ho, MD, MPH
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Key Takeaways

  • Clinical trials demonstrated the efficacy and safety of the long-acting injectable combined regimen of the integrase strand transfer inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine (CAB/RPV) when dosed every 4 or 8 weeks in individuals with HIV who have undetectable viral loads.
  • The success of this long-acting injectable antiretroviral therapy (ART) depends on the patient’s ability to attend regular in-person appointments, as well as the treatment facility’s protocols to ensure follow-up and re-engage patients when needed.
  • While increased convenience and privacy are among the potential benefits of CAB/RPV, the need for periodic clinic visits may represent a burden or a privacy risk for some patients, and these factors must be weighed among other risks and benefits when helping a patient determine their preferred approach.
  • Injection site reactions (ISRs) of mild or moderate severity, including pain, redness, and bruising, affected roughly 85% of patients receiving injectable CAB/RPV in clinical trials. Most of these symptoms resolved after 7 days, and the frequency of ISRs diminished with repeated treatments.
  • Prior to initiating CAB/RPV, providers may give patients a “lead in” consisting of oral CAB/RPV taken 2 times daily for approximately 1 month. This allows providers to monitor side effects before starting patients on the long-acting regimen.

Ongoing advances in ART have led to significant reductions in HIV-related morbidity and mortality.1 However, standard oral ART regimens present potential barriers to long-term adherence, including frequent dosing requirements and privacy concerns. The relatively new long-acting injectable ART regimen CAB/RPV, approved for dosing schedules of every 4 and 8 weeks,2,3 may help to address some of these barriers.
Ken Ho, MD, MPH, is an assistant professor of medicine in the division of infectious diseases at the University of Pittsburgh School of Medicine and medical director of the Pitt Men’s Study, a branch of the Multicenter AIDS Cohort Study. In this article, Dr Ho discusses the impact of long-acting injectable ARTs in HIV treatment, relevant risk-benefit considerations, and topics in this therapeutic area that warrant further investigation.

Since the US Food and Drug Administration (FDA) approved the long-acting injectable CAB/RPV for HIV treatment in 2021,4 how has it affected the landscape of HIV treatment? What are you personally observing in practice?

Long-acting injectable CAB/RPV has diversified HIV treatment options, especially for people living with HIV who struggle with adherence to taking pills by mouth. Most first-line treatment regimens for HIV involve a once-daily pill; CAB/RPV is the first long-acting injectable regimen to be approved for treatment of HIV.
CAB/RPV was first approved for monthly dosing in 20214; the FDA subsequently approved dosing of CAB/RPV every 2 months and also for people with undetectable viral loads.5 Adherence to HIV treatment is critical because HIV can become resistant to a medication regimen if adherence is suboptimal. Because CAB/RPV is a long-acting agent, it removes the burden of having to remember to take a daily pill. The ability to visit the medical office only every 2 months and not have to invest the energy into a daily pill yet still have effective levels of drug in the body is a game changer for a significant group of patients.
The success of this regimen does hinge on the patient’s ability to show up for regular in-person appointments, which may present a different kind of struggle for certain patients in terms of scheduling appointments, parking, taking time off work, and other factors.
There has certainly been community interest in CAB/RPV; in our clinic, we put interested patients on CAB/RPV through a program that is largely managed by our clinic pharmacist. For many, the experience of being on CAB/RPV has been positive overall — and in some cases, life-changing — allowing patients who were previously nonadherent on pills to become stably suppressed on injectables.
The success of CAB/RPV as an effective HIV treatment option also hinges on establishing a system that ensures appropriate follow-up every 2 months and protocols to quickly re-engage those who are lost to follow-up.

For many, the experience of being on CAB/RPV has been positive overall — and in some cases, life-changing — allowing patients who were previously nonadherent on pills to become stably suppressed on injectables.

In a recent review, Durham and Chahine noted the range of benefits associated with long-acting injectable CAB/RPV, including convenience and increased privacy implications.1 Can you comment on these findings?

Previous clinical trials have shown that CAB/RPV dosed either monthly or every other month for the treatment of HIV in individuals who have undetectable viral loads is safe and efficacious. In addition to being an especially attractive option for people who struggle with adherence to oral pills, CAB/RPV may help people overcome many barriers, such as pill fatigue, fear of disclosure of HIV diagnosis, and pill taking as a daily reminder of living with HIV.
CAB/RPV is indicated for use in people who already have suppressed viral loads. Less is known about its use in people who do not have suppressed viral loads before starting the medication. CAB/RPV is often presented as an option for those who struggle with adherence; ironically, these patients have the most difficulty maintaining an undetectable viral load and therefore may not meet the eligibility criteria for the drug. There are some emerging data to suggest that CAB/RPV can be used to treat people who have lower viral loads, but more studies are needed.6
CAB/RPV is largely thought to be favorable from a convenience and privacy perspective, but it may also present a mixed picture. While a long-acting injectable agent offers the convenience of not having to remember to take pills once or sometimes twice a day, this may be counterbalanced by the inconvenience of having clinic visits either monthly or every other month. CAB/RPV is a more discreet option for those wanting to conceal having to take medications for HIV, as administration occurs within the clinic visit, but frequent visits to the clinic may also increase the risk for exposure to other members of a community.

What are the most common side effects associated with long-acting injectable CAB/RPV, and how are these managed? Can you comment on therapeutic monitoring and dosing adjustments?

CAB/RPV is well tolerated, with the most common reported side effects being ISRs, which were seen in a significant majority of participants — about 85% — in the ATLAS ( identifier: NCT02951052) and FLAIR ( identifier: NCT02938520) trials. Symptoms included pain, redness, and bruising or nodule formation. Almost all of these ISRs were considered mild or moderate in severity and resolved within 3 days on average, with the majority of cases resolving after 7 days, and the frequency of these ISRs diminished over time. Other common side effects reported on the package insert include nausea, dizziness, headache, and fever.3,7

Given the long-acting pharmacology of CAB/RPV, some providers give patients an optional oral “lead in” consisting of 2 pills taken daily — oral cabotegravir and rilpivirine. In clinical trials of CAB/RPV, the oral lead in was about 1 month. During this time, the provider can assess the patient for concerning side effects prior to initiating the long-acting form of the medication.3,7
Currently, there are no clinically available assays for therapeutic drug monitoring available for CAB/RPV. Prior research has suggested variability in drug pharmacokinetics based on sex and weight. Ultimately, further follow-up studies have determined that the drug dosed as recommended is still sufficient to treat HIV despite these variables and does not require dose adjustment.8

Side effects associated with CAB/RPV
In addition to ISRs that include redness, pain, bruising, and nodule formation, other common side effects associated with CAB/RPV include dizziness, headache, fever, and nausea.

Can you review the risk-benefit conversations you would have with patients regarding daily oral ART regimens vs a long-acting injectable regimen? Which patient populations would benefit from each type of therapy?

Risk-benefit discussions allow individual patients to make an informed decision with regards to which type of therapy would be best for them. Long-acting injectables offer many benefits, including convenience and increased privacy. They have been described as “liberating” for some, allowing people with HIV to live without being reminded of their diagnosis on a daily basis.
Conversely, taking a daily pill may not represent a challenging hurdle to everyone, whereas coming into the office every 2 months could be significantly burdensome for some patients. This speaks to the importance of having a discussion to determine whether or not CAB/RPV makes sense in the context of the individual patient.
It is also important to carefully review medication lists with attention to drug-drug interactions, as some medications are contraindicated with CAB/RPV. Many of these reduce antiretroviral levels, increasing the chance of treatment failure. The ISRs described earlier typically resolve after a few days and are less likely to occur with repeated doses of medication.
Regular monthly or bimonthly injections maintain the drug levels needed to stably suppress HIV. Because CAB/RPV persists in the body for several months — almost a year — there is a greater concern about resistance in those who go off CAB/RPV or miss doses. This is oftentimes called the “pharmacokinetic (PK) tail.” During this tail phase, it is important for the patient to be on coverage with an alternative, oral agent to prevent the emergence of resistance.9

In a 2022 study, Chounta et al established the noninferiority of long-acting CAB/RPV every 8 weeks compared with daily oral ART.10 In addition to the longer gap between treatment administration, what do you see as the comparative benefits or drawbacks of a 4-week vs 8-week treatment interval?

CAB/RPV is approved for 4- or 8-week dosing intervals. If using the 4-week dosing strategy, patients receive an initial loading dose administered in the gluteal muscle. The loading dose consists of 2 injections, an injection of cabotegravir 600 mg and an injection of rilpivirine 900 mg. Following this, the patient receives monthly injections at a lower dose — cabotegravir 400 mg/2 mL and long-acting rilpivirine 600 mg/2 mL. For the 8-week dosing strategy, each dose involves 2 injections of the higher-loading dose — cabotegravir 600 mg plus long-acting rilpivirine 900 mg. The initial 2 doses are given 1 month apart, and the following doses are given 2 months apart.10
In the trial referenced above, efficacy was comparable, and the majority of participants preferred the 8-week dosing interval to the 4-week dosing interval.10 An advantage of the 4-week dosing involves a lower volume, which may be potentially less painful if ISRs are of particular concern. It is also important to consider that more frequent dosing could be more burdensome for clinic sites from the standpoint of scheduling and staffing.
Certain populations may benefit from more frequent visits with health care providers. Data from pre-exposure prophylaxis (PrEP) trials in adolescents suggested that adherence to taking oral PrEP for prevention of HIV was better when participants were followed monthly, and adherence declined when participants switched to visits every 3 months.11 While this may or may not apply to long-acting injectable medications, it speaks to the fact that adherence varies between different groups of people. This underscores the importance of having a tailored discussion in order to determine whether CAB/RPV is right for the individual patient.

What future developments do you anticipate or hope for in the area of long-acting ART regimens for HIV?

CAB/RPV is the first long-acting injectable HIV treatment, and its approval may open the door for a variety of opportunities and innovations in the future. First of all, the field would benefit from additional long-acting agents in other antiretroviral classes to allow more options for individuals who have resistance to integrase inhibitors or non-nucleoside reverse transcriptase inhibitors. Longer dosing intervals may also reduce the burden of frequent clinic visits. The long-acting injectable lenacapavir was recently approved by the FDA as a 6-month injection.12 However, it would need to be paired with another agent that could be dosed every 6 months to exist as a complete treatment regimen.
Measures that could allow for safe home-based or self-dosing of CAB/RPV could reduce the burden for both patients and the clinics administering medication. CAB/RPV requires refrigeration, and once it is brought to room temperature, it must be used within 6 hours,5 which creates logistical issues regarding home dosing and speaks to the need for medications that have greater stability and do not require refrigeration.
Further research is needed to understand the PK tail and the extent to which integrase resistance may emerge in individuals who are lost to follow-up. Novel methods that allow long-acting medications to be safely removed may also help to mitigate concerns about resistance.
Finally, implementation science is needed to help us understand how communities can optimally access and benefit from long-acting injectable medications. In particular, how can these medications be used to treat groups that have been traditionally hard to reach or engage? We need more data on how to engage these populations and to learn from these experiences in order to achieve the promise and fully unlock the potential of long-acting injectables.
This Q&A was edited for clarity and length.


1. Durham SH, Chahine EB. Cabotegravir-rilpivirine: the first complete long-acting injectable regimen for the treatment of HIV-1 infection. Ann Pharmacother. 2021;55(11):1397-1409. doi:10.1177/1060028021995586
2. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. doi:10.1016/S0140-6736(20)32666-0
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4. FDA approves first extended-release, injectable drug regimen for adults living with HIV. News release. US Food and Drug Administration. January 21, 2021. Accessed February 7, 2023.
5. McGowan JP, Fine SM, Vail RM, et al. Use of injectable CAB/RPV LA as replacement ART in virally suppressed adults. Baltimore, MD: Johns Hopkins University Press; 2022.
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8. Elliot E, Polli JW, Patel P, et al. Efficacy and safety outcomes by BMI category over 48 weeks in phase 3/3b cabotegravir and rilpivirine long-acting trials. Poster presented at: 18th European AIDS Conference; October 27-30, 2021; London, UK.
9. D’Amico R, Margolis DA. Long-acting injectable therapy: an emerging paradigm for the treatment of HIV infection. Curr Opin HIV AIDS. 2020;15(1):13-18. doi:10.1097/COH.0000000000000606
10. Chounta V, Snedecor SJ, Wu S, Van de Velde N. Indirect comparison of 48-week efficacy and safety of long-acting cabotegravir and rilpivirine maintenance every 8 weeks with daily oral standard of care antiretroviral therapy in participants with virologically suppressed HIV-1-infection. BMC Infect Dis. 2022;22(1):428. doi:10.1186/s12879-022-07243-3
11. Hosek SG, Rudy B, Landovitz R, et al. An HIV preexposure prophylaxis demonstration project and safety study for young MSM. J Acquir Immune Defic Syndr. 2017;74(1):21-29. doi:10.1097/QAI.0000000000001179
12. FDA approves new HIV drug for adults with limited treatment options. News release. US Food and Drug Administration. December 22, 2022. Accessed February 7, 2023.

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Reviewed March 2023