Use of long-acting cabotegravir-rilpivirine in people with HIV

INTRODUCTION — Some patients with HIV who are virologically suppressed may benefit from a switch of their antiretroviral therapy (ART) regimen. Reasons for the switch may include side effects, pill burden, new or worsening medical comorbidities (eg, chronic kidney disease), drug-drug interactions, and/or use of an older regimen with a higher risk of long-term toxicity. When switching regimens, both oral and injectable options are available.

This topic will review the use of the long-acting injectable regimen, cabotegravir-rilpivirine, for the treatment of HIV in patients with virologic suppression. A detailed discussion of how to select a regimen for those switching to new oral therapy is presented separately. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

SWITCHING TO INJECTABLE CABOTEGRAVIR-RILPIVIRINE

Reasons for switching ART — Some patients who are virologically suppressed may need to change their regimen due to side effects or concerns about long-term toxicity. Two-drug regimens may be suitable for patients who have developed or are at risk for developing toxicity from nucleoside reverse transcriptase inhibitors (NRTIs) like tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and abacavir [1-3]. There are several oral options, such as dolutegravir-lamivudine and dolutegravir-rilpivirine, as well as the long-acting injectable regimen, cabotegravir-rilpivirine.

Long-acting, injectable, two-drug therapy may be a good option to replace oral antiretroviral therapy (ART) in select patients who have difficulty swallowing pills, difficulty storing their medications at home due to concerns around confidentiality or stigma, or a preference for nondaily dosing or injectable therapy.

Reports from two large, phase 3 randomized studies found that individuals who met specific enrollment criteria and who received intramuscular (IM) rilpivirine and cabotegravir every four weeks were able to maintain virologic suppression similar to those who received a standard oral antiretroviral regimen [4,5]. In these studies, which together included 1178 participants, approximately 93 percent of those who received the injectable regimen achieved an HIV-1 RNA <50 copies/mL at week 48 compared with 93 to 96 percent of those receiving daily oral therapy. Although many experienced mild or moderate injection site reactions, this rarely led to treatment discontinuation.

The efficacy of cabotegravir-rilpivirine administered at a higher dose every eight weeks was supported by data from a trial of 1045 virologically suppressed patients who received long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) every eight weeks or a loading dose of cabotegravir-rilpivirine followed by cabotegravir (400 mg) plus rilpivirine (600 mg) every four weeks [6,7]. After 96 weeks of treatment, the percent of patients who had an HIV-1 RNA ≥50 copies/mL in the eight- and four-week groups was similar (2 versus 1 percent, respectively; adjusted treatment difference of 0.8, 95% CI -0.6 to 2.2) [7]. Confirmed virologic failure (two consecutive HIV RNA measurements >200 copies/mL) was low in both arms but several-fold higher in the every eight-week group (2 percent versus <1 percent, respectively) [7]. (See 'Risk of virologic failure' below.)

A detailed discussion of regimen selection in patients switching ART, including the decision to use oral versus injectable therapy, is presented in a separate topic review. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Determining eligibility — Cabotegravir-rilpivirine is a suitable regimen for certain nonpregnant adults. There are insufficient data to recommend this agent during conception, pregnancy, or breastfeeding. (See "Antiretroviral selection and management in pregnant individuals with HIV in resource-rich settings".)

General criteria — To be eligible for cabotegravir-rilpivirine, patients must:

●Be virologically suppressed and adherent to a stable oral regimen for at least 6 to 12 months.

●Have no documented or suspected resistance mutations that affect activity of cabotegravir or rilpivirine; reasons to suspect such resistance include imperfect adherence or virologic failure while taking a non-nucleoside reverse transcriptase inhibitor (NNRTI) or an integrase strand transfer inhibitor (INSTI) in the past. In some studies, baseline rilpivirine proviral resistance mutations were a significant predictor of virologic failure with cabotegravir-rilpivirine [6,7].

Ideally, patients should have no history of virologic failure (even with NNRTI/INSTI regimens). However, certain acquired resistance mutations may be acceptable if there are no other good treatment options. Trials generally excluded individuals with any history of virologic failure; the only resistance mutation typically permitted for enrollment in the trials was a K103N mutation (the NNRTI mutation associated with resistance to efavirenz, which may be acquired at time of HIV acquisition).

●Be able and willing to adhere to clinic visits for IM injections [8]. The injections must be administered by a health care professional; they are not approved for at-home use or self-administration.

Two-drug regimens, including long-acting injectable therapy, should generally be avoided in patients with chronic hepatitis B virus (HBV) infection, as such patients should receive a tenofovir-containing ART regimen whenever possible. (See "Treatment of chronic hepatitis B in patients with HIV".)

Additional considerations — When determining if cabotegravir-rilpivirine is a suitable regimen for a patient, we also assess the following factors:

●Drug-drug interactions – There are a few drug-drug interactions that are contraindications to parenteral cabotegravir-rilpivirine. These include rifamycins (rifampin, rifabutin, rifapentine), certain anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), St. John's wort, and dexamethasone (if more than a single dose).

IM cabotegravir-rilpivirine should also be used with caution with drugs known to cause prolonged QT or Torsade de Pointes or in patients with a history of these conditions.

Cabotegravir may lead to decreased levels of methadone. Although use of methadone is not a contraindication to IM cabotegravir-rilpivirine, clinical monitoring is recommended and patients may need adjustment of their methadone dose if withdrawal symptoms occur [9].

In persons with mpox, initiation of long-acting cabotegravir-rilpivirine should be avoided during tecovirimat therapy and for two weeks after the conclusion of tecovirimat [10].

Additional information on drug interactions can be found in the drug interactions program within UpToDate.

●Buttock implants/fillers – For patients with buttock implants or fillers, the injections may not be an option. The medications are approved only for administration in the gluteal region. Data for injections in the vastus lateralis are anticipated in the future.

●HIV subtype – In some studies, there was a higher likelihood of virologic failure in patients with HIV subtype A1 or A6 virus (which most often occurs in Eastern Europe and Central Asia [11] and which has been associated with certain integrase gene polymorphisms) [12,13]. In general, this finding doesn't impact our decision to initiate cabotegravir-rilpivirine since virologic failures were rare in the trials (13 out of 1039 participants) and viral subtypes are usually not known [13]. However, we would discuss the possible increased risk of virologic failure if it is known that a patient has subtype A virus or comes from a region with predominance of subtype A virus (see "Global epidemiology of HIV infection"). Viral subtype may not be known though sometimes is reported as part of a genotype resistance assay so a clinician may be able to confirm this information by reviewing past resistance assay results.

●Body mass index – In one study, body mass index (BMI) above 30 kg/m² was associated with an increased risk of virologic failure [12]. However, the association of high BMI and virologic failure has not been reproduced [13]. With elevated BMI, we do generally opt for a longer needle for injections and pay extra attention to site of administration. (See 'Dosing and administration' below.)

●Lack of feasible alternatives – On rare occasion, it may be reasonable to prescribe long acting cabotegravir-rilpivirine to select patients who do not fulfill the eligibility criteria described above (see 'General criteria' above). However, given the limited data with this approach, we only consider this option for those with progressive or advanced HIV who have no other feasible alternatives (eg, they have significant psychological or physical barriers to oral ART adherence or have unfavorable drug interactions with oral regimens). For such individuals, substantial adherence support is needed, and the patient should be counseled that if missed doses and virologic failure occur, other salvage antiretroviral agents that have more side effects may be necessary.

The experience prescribing long-acting injectable cabotegravir-rilpivirine for individuals with detectable viral loads, past history of virologic failure, or significant barriers to adherence (eg, certain mental health conditions, ongoing substance use, housing instability) has only been described in small case series [14,15]. In one report of 51 patients, 39 received at least two follow-up injections, and of those, 36 were able to achieve or maintain viral suppression [14]. In this study, significant resources were employed to support ART adherence and offer reminders and outreach, and follow-up time was limited to less than one year. In another report that described compassionate use of long-acting injectable cabotegravir-rilpivirine in 35 people with HIV, 22 achieved or maintained virologic suppression through 10 months [15]. However, new NNRTI and/or INSTI resistance mutations developed in half of the patients who did not achieve virologic suppression and had detectable viral loads at study entry; these patients required a new regimen with a boosted protease inhibitor to suppress their viral load.

Patient counseling

Optional oral lead-in therapy — For those who are concerned about adverse reactions to the long-acting regimen, we discuss the potential role of an oral lead-in (which is typically prescribed as 28 days or more of daily, oral cabotegravir and oral rilpivirine). The oral lead-in can allow the patient to assess for adverse reactions prior to receiving the long-acting formulation. (See 'Adverse reactions' below and 'Oral lead-in' below.)

Previously, one month of oral therapy was considered necessary prior to receiving the injectable agents; however, this is now considered optional since serious adverse reactions to the medications are rare. In addition, in clinical trials, the use of cabotegravir-rilpivirine with or without an oral lead-in demonstrated similar safety, tolerability, and efficacy [16].

Importance of adherence — Prior to initiating cabotegravir-rilpivirine, we review the importance of adherence to injections, which requires visits to the clinic since cabotegravir-rilpivirine is not designed for self-administration. If doses are missed, patients may experience prolonged periods of subtherapeutic ART levels, which puts them at risk for developing virologic resistance [8].

We also counsel the patient about the importance of alerting their provider early if they need to miss a dose by more than seven days or wish to discontinue injectable ART. This allows sufficient time to formulate a plan for bridging the missed dose with oral ART or for transitioning to oral ART after discontinuation of the injectables. (See 'Missed doses' below and 'Discontinuing treatment' below.)

Risk of virologic failure — The majority of patients will maintain virologic suppression with every four-week or every eight-week dosing if they meet the strict selection criteria necessary before the switch to long-acting cabotegravir-rilpivirine [4-7]. In clinical trials evaluating cabotegravir-rilpivirine, participants had an HIV RNA below 50 copies/mL within the 6 to 12 months prior to starting cabotegravir-rilpivirine, were receiving a stable oral ART regimen with no recent interruptions or regimen switches, were without evidence of chronic HBV infection, had no history of virologic failure, and had no documented or suspected resistance to cabotegravir or rilpivirine (eg, a prior acquired K103N mutation was generally the only resistance mutation allowed) [4]. (See 'Determining eligibility' above.)

Among those who do not achieve virologic suppression, a small number will experience virologic failure (HIV RNA ≥200 copies /mL on two occasions). In clinical trials, most of these patients developed integrase and/or NNRTI resistance-associated mutations, even though none had missed an injection dose by more than seven days (ie, they received on-time injections). This may necessitate a switch to an oral salvage antiretroviral therapy regimen, such as with a boosted protease inhibitor plus other agents. (See "Evaluation of the treatment-experienced patient failing HIV therapy".)

There may be an increased risk of virologic failure in those receiving cabotegravir-rilpivirine every eight versus every four weeks. In the trial comparing these two regimens, nine participants in the every eight-week group versus two in the every four-week group developed virologic failure [7]. The reason for this difference is unclear. One possible explanation is that more individuals with confirmed virologic failure in the eight-week group were found to have baseline proviral rilpivirine resistance mutations compared with those in the four-week group (most participants who experienced virologic failure in the every eight-week arm had baseline rilpivirine resistance-associated mutations) [7]. However, this has not been confirmed to be the explanation. Of the eleven participants in the trial who met criteria for confirmed virologic failure, six had two or more factors that may predict virologic failure with this regimen (pre-existing proviral rilpivirine resistance-associated mutations, HIV-1 subtype A1 or A6, or BMI greater than 30 kg/m²) and ten achieved resuppression of the viral load on oral ART (mostly protease inhibitor-based regimens). (See 'Determining eligibility' above and 'Additional considerations' above and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Selecting the dosing interval (four versus eight weeks) — The combination of cabotegravir-rilpivirine can be administered every four or eight weeks (table 1). However, the dose of cabotegravir and rilpivirine varies depending upon which interval is used. (See 'Continuation regimens' below.)

In some cases, the dosing interval may be dictated by clinic resources and insurance company reimbursement since the majority of patients will maintain virologic suppression with either dosing schedule, as described above. (See 'Reasons for switching ART' above.)

When there is a choice, we counsel patients on the trade-offs. Every eight-week dosing offers more convenience with fewer visit than every four-week dosing. However, the risk of virologic failure appears to be higher than with every four-week dosing, although the risk of virologic failure with every eight-week dosing is still low. (See 'Risk of virologic failure' above.)

DOSING AND ADMINISTRATION

General principles — All patients receiving cabotegravir-rilpivirine require an initial induction dose. After that, there are two dosing interval options for the continuation (maintenance) injections. One option is administered every four weeks and the other is administered every eight weeks (table 1). Several clinical trials have evaluated the efficacy of these regimens, as described above, although data outside of the clinical trial setting remain limited. (See 'Reasons for switching ART' above and 'Selecting the dosing interval (four versus eight weeks)' above.)

Both dosing intervals are endorsed by the US Food and Drug Administration and either regimen can be used. However, it is important to note that the dosage of intramuscular (IM) cabotegravir and IM rilpivirine differs depending on the interval selected (ie, a person cannot switch between every four-week and every eight-week dosing without changing the dosage administered). For either dosing interval option, an oral lead-in phase prior to the injections is considered optional.

When administering the injectable formulations of cabotegravir and rilpivirine, the injections should be administered at separate gluteal sites, either on opposite sides or at least 2 cm apart on the same side. The order of administering the medications (cabotegravir first versus rilpivirine first) does not matter, but they should be given at the same visit.

Injections should be given using a Z-track technique and should be administered at the ventrogluteal (gluteus medius) site if possible (figure 1). The gluteus medius is preferred instead of the gluteus maximus, due to greater distance from neurovascular structures. For individuals with elevated body mass index (BMI), such as above 30 kg/m², a longer needle may be necessary to ensure injections are IM (as opposed to subcutaneous) [9]. Longer needles are not included in the dosing kit. More detailed information on storage and administration can be found in the Lexicomp drug information monograph for cabotegravir-rilpivirine included within UpToDate.

Oral lead-in — A patient can receive oral cabotegravir (30 mg) plus oral rilpivirine (25 mg) once daily with food for one month prior to transitioning to the long-acting injectable formulations. If a patient opts for the oral lead-in, it is usually taken for at least 28 days. The pills should be taken with a meal (because of the rilpivirine).

There are also certain drug-drug interactions with oral cabotegravir and rilpivirine that are not present with the injectable formulation. As an example, proton pump inhibitor (PPI) use is a contraindication to oral rilpivirine but is not a contraindication to injectable rilpivirine. Similarly, cation-containing vitamins or antacids interact with oral but not injectable cabotegravir. (See "Overview of antiretroviral agents used to treat HIV".)

If a person opts for the oral lead-in, we emphasize the importance of adherence to the daily dosing, as missed doses during this period could lead to virologic failure with resistance.

Induction dosing — All patients initiating cabotegravir-rilpivirine should receive one 600 mg (3mL) dose of IM cabotegravir and one 900 mg dose (3 mL) of IM rilpivirine at the same visit (table 1). These dosages are the same regardless of whether the patient will receive every four-week or every eight-week injections for continuation therapy. (See 'Continuation regimens' below.)

If the patient opted to take the oral lead-in, this initial injection should be given on the last day of oral therapy.

Continuation regimens — After the initial induction dose, the regimen can be administered every four or every eight weeks; however, the dose of cabotegravir and rilpivirine will differ depending on the dosing interval (table 1).

●Every four-week dosing – Patients who transition to monthly dosing after the initial injection should receive 400 mg (2 mL) of IM cabotegravir and 600 mg (2 mL) of IM rilpivirine every month. This dose is lower than the initial dose of cabotegravir-rilpivirine. (See 'Induction dosing' above.)

●Every eight-week dosing – Patients who transition to every eight-week dosing should receive the same dose for all injections (600 mg [3 mL] of cabotegravir and 900 mg [3 mL] of rilpivirine). This regimen should be administered once four weeks after completing the initial dose and then every eight-weeks thereafter.

Some patients may choose to transition from every four- to every eight-week therapy or vise-versa. When this occurs, it is important to adjust the dose of cabotegravir-rilpivirine accordingly.

For both the four- and eight-week regimens, it is acceptable to administer the injections within seven days before or after a scheduled dosage, if needed. However, we emphasize to patients the importance of adherence to the visit schedules and try to administer the injections as close to the target date as possible. (See 'Patient counseling' above and 'Missed doses' below.)

Patient monitoring

Safety monitoring — Patients receiving long-acting cabotegravir-rilpivirine should undergo routine safety monitoring similar to those receiving other antiretroviral therapy (ART) regimens. (See "Patient monitoring during HIV antiretroviral therapy".)

However, for those with chronic liver disease or elevated hepatic transaminases at baseline, more frequent monitoring of the transaminase levels is generally warranted since cabotegravir-rilpivirine can be associated with hepatotoxicity. As an example, we typically measure the alanine and aspartate aminotransferases and total bilirubin two to four weeks after switching to cabotegravir-rilpivirine and then every three months thereafter. If the aminotransferase levels remain stable, the interval can be extended to every six months.

Additional information on the adverse reactions associated with cabotegravir-rilpivirine is found below. (See 'Adverse reactions' below.)

Viral load monitoring — Following a switch to cabotegravir-rilpivirine, with or without an oral lead-in, we typically monitor the viral load every four weeks for the first three months until it is clear that the viral load remains suppressed and the patient is able to adhere to the regular clinic visits for injections. Thereafter, we reduce the frequency of monitoring to every three to six months.

For patients who achieved virologic suppression, but have a subsequent increase in the viral load, our approach is as follows:

●If the viral load is >200 copies/ml, we repeat the viral load and check genotype resistance assays (including integrase). We also ensure that there are no contraindicated drug-drug interactions and that the cabotegravir-rilpivirine injections were administered correctly, on time, and at the recommended dosages (table 1). The decision to continue IM cabotegravir-rilpivirine or change to a new salvage ART regimen depends upon the results of this investigation. These patients should be managed in conjunction with an expert in HIV care.

●If the viral load is ≤200 copies/mL, we repeat it in two to four weeks. If the viral load is then suppressed, it was likely a viral blip, and we resume previous monitoring. If low-level viremia persists despite on-time injections and correct administration, we would have a low threshold to switch back to a three-drug oral ART regimen with a high barrier to resistance. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Missed doses — Our approach to missed injections (ie, more than seven days have passed since the scheduled date of injection) depends on whether or not the missed dose is planned.

●If a missed dose is planned – If a patient plans to miss a scheduled injection by more than seven days, that person should take oral cabotegravir and rilpivirine; the oral regimen can be administered for up to two consecutive months prior to resuming injectable therapy (table 1).

Prior to prescribing oral therapy as a bridge, the person should be counseled about the meal requirement with oral rilpivirine and drug-drug interactions that exist with the oral, but not the injectable, formulations of cabotegravir-rilpivirine. (See 'Oral lead-in' above.)

●Unplanned missed dose(s) – If the missed dose (or doses) was not planned, and the person did not take oral therapy, the approach to treatment depends upon the specific regimen and the duration of time since the last dose, as described in the table (table 1).

Prior to reinitiating treatment, providers should reassess the appropriateness of injectable therapy by evaluating the barriers to adhering to regular injections.

In addition, we typically check a viral load test if a person has missed one or more doses to assess for the possibility of virologic failure.

•If the viral load remains undetectable and the patient and clinician decide that continuing injectable ART is preferred, injections can be resumed, but if more than two months have passed since the last injection, the injections should be restarted with the higher initial loading dosage (3 mL of each drug), even if resuming with monthly dosing (if resuming with monthly dosing, following the higher initial loading dosage, injections can then be continued with the lower dosage every month).

•For those with viral rebound, oral ART with a fully active regimen should be initiated, with the goal of achieving viral suppression again. In such patients we typically do not reinitiate injectable therapy since the injectable two-drug regimen has only been studied and approved for individuals adhering to oral ART with a routinely suppressed viral load. If the viral load is ≥200 to 500 copies/mL we obtain a genotype resistance assay (including integrase resistance) to help guide regimen selection. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Additional information on missed doses of cabotegravir-rilpivirine can be found in the Lexicomp drug information topic within UpToDate.

Discontinuing treatment — If injectable therapy is discontinued, patients should initiate a different fully suppressive ART regimen within one month of the final injection. Levels of cabotegravir and rilpivirine remain detectable for 6 to 12 months (or sometimes longer) after IM injections; thus, if the person does not take a fully suppressive regimen after discontinuing injectable therapy, low residual drug levels increase the risk of developing resistance mutations if viral rebound occurs. (See "Interpretation of HIV drug resistance testing".)

A discussion of regimen selection for patients switching therapy is presented elsewhere. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

ADVERSE REACTIONS — Cabotegravir-rilpivirine is generally well tolerated; however, mild to moderate injection site reactions are common. The most common local reactions at the injection site are pain, redness, and swelling. Induration, nodules, bruising, and itching may also occur. For most individuals, these are mild and do not lead to discontinuation of the treatment, but patients can be counseled to apply an ice pack or warm compress, massage the area, or take as needed over-the-counter analgesics to help with the reactions (assuming there are no medical contraindications to these). The majority of reactions resolve spontaneously within a few days (median duration three days) [5].

Other adverse reactions can also occur but are generally mild and nonspecific (eg, pyrexia, fatigue, headache, muscle aches, nausea, sleep disorders, dizziness, and rash). In <1 percent of patients, serious postinjection reactions due to rilpivirine have been reported (dyspnea, flushing, sweating), but these typically resolve within minutes and may be related to accidental intravenous administration (instead of intramuscular [IM]) [9].

Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. As such, more frequent monitoring of liver function is generally indicated. (See 'Safety monitoring' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)

SUMMARY AND RECOMMENDATIONS

●Reasons for switching to cabotegravir-rilpivirine – Some patients who are virologically suppressed may need to change their regimen due to side effects or concerns about long term-toxicity. There are several oral options as well as the long-acting injectable regimen, cabotegravir-rilpivirine. (See 'Reasons for switching ART' above.)

Long-acting injectable therapy may be a good option to replace oral antiretroviral therapy (ART) in patients who have difficulty swallowing pills, difficulty storing their medications at home due to concerns around confidentiality or stigma, or a preference for nondaily dosing or injectable therapy. Clinical trials have found that individuals who received intramuscular (IM) rilpivirine and cabotegravir can maintain virologic suppression similar to those who received a standard oral antiretroviral regimen as long as they meet certain eligibility criteria.

●Eligibility – To be eligible for cabotegravir-rilpivirine, patients must meet the following criteria (see 'Determining eligibility' above):

•Be virologically suppressed and adherent to a stable oral regimen for at least 6 to 12 months.

•Have no documented or suspected resistance mutations that affect activity of cabotegravir or rilpivirine. Ideally, patients should have no history of virologic failure, even with non-nucleoside reverse transcriptase inhibitor (NNRTI)/integrase strand transfer inhibitor (INSTI) regimens; however, certain acquired resistance mutations (eg, K103N) are acceptable.

•Be able and willing to adhere to clinic visits for IM injections [8]. The injections must be administered by a healthcare professional; they are not approved for at-home use or self-administration.

In general, two-drug regimens, including the long-acting injectable option, should be avoided in patients with chronic hepatitis B virus (HBV) infection as such patients should receive a tenofovir-containing ART regimen whenever possible.

●Importance of adherence – Prior to initiating cabotegravir-rilpivirine, we review the importance of adherence to injections, which requires visits to the clinic. Cabotegravir-rilpivirine is not designed for self-administration. If doses are missed, patients may experience prolonged periods of subtherapeutic ART levels, which puts them at risk for developing virologic resistance. (See 'Importance of adherence' above.)

●Selecting a dosing interval – The combination of cabotegravir-rilpivirine can be administered every four or eight weeks (table 1). In some cases, the dosing interval may be dictated by clinic resources and insurance company reimbursement since most patients will maintain virologic suppression with either dosing schedule. (See 'Selecting the dosing interval (four versus eight weeks)' above.)

When there is a choice, we counsel patients on the trade-offs. Every eight-week dosing offers more convenience with fewer visits than every four-week dosing; however, there appear to be more virologic failures (HIV viral load >200 copies/mL on two occasions) with every eight-week dosing, although the risk of virologic failure even with every eight-week dosing is low. (See 'Selecting the dosing interval (four versus eight weeks)' above and 'Risk of virologic failure' above.)

●Dosing and administration

•Induction dose – All patients receiving cabotegravir-rilpivirine require an initial induction dose (table 1). If there is concern about the tolerability of the long-acting injectable regimen, a patient can receive oral cabotegravir plus oral rilpivirine once daily for one month prior to transitioning to injectable therapy. (See 'Induction dosing' above and 'Oral lead-in' above.)

•Continuation regimens – After the initial injection, the continuation (maintenance) injections can be administered every four or eight weeks. The dosage of IM cabotegravir and IM rilpivirine differs depending on the interval selected (table 1). (See 'Continuation regimens' above.)

With either dosing option, we monitor the viral load closely (monthly) after the transition to cabotegravir-rilpivirine until it is clear that viral suppression has been maintained. (See 'Viral load monitoring' above.)

•Missed doses – It is acceptable to administer the injections within seven days before or after a scheduled dose, if needed. However, if more than seven days will pass before the next scheduled dose, the patient should take oral cabotegravir and rilpivirine to bridge the gap. (See 'Missed doses' above.)

●Discontinuing treatment – If injectable therapy is discontinued, patients should initiate a different fully suppressive ART regimen within one month of the final injection. Levels of cabotegravir and rilpivirine remain detectable for 6 to 12 months or longer after IM injections; thus, if the person does not take a fully suppressive regimen after discontinuing injectable therapy, low residual drug levels increase the risk of developing resistance mutations if viral rebound occurs. (See 'Discontinuing treatment' above.)